Kalsi P S Organic Reactions and Their Mechanisms New Age Science

3rd Edition
Organic Br
H
Reactions
and their Br
H
Mechanisms
P S KALSI
Organic
Reactions
and their
Mechanisms
This page
intentionally left
blank
Organic
Reactions
and their
Mechanisms
Third Edition
P S KALSI
Formerly
Dean of Colleges, Punjab Technical University
Jalandhar, India
and
Professor & Head, Department of Chemistry
College of Basic Sciences and Humanities
Punjab Agricultural University, Ludhiana, India
The Control Centre, 11 A Little Mount Sion

Tunbridge Wells, Kent TN1 1YS, UK
www.newagescience.co.uk • e-mail: [email protected]
Copyright © 2010 by New Academic Science Limited
27 Old Gloucester Street, London, WC1N 3AX, UK
www.newacademicscience.co.uk • e-mail: [email protected]
ISBN : 978 1 78183 175 5
All rights reserved. No part of this book may be reproduced in any form, by photostat, microfilm,
xerography, or any other means, or incorporated into any information retrieval system, electronic
or mechanical, without the written permission of the copyright owner.
British Library Cataloguing in Publication Data
A Catalogue record for this book is available from the British Library
Every effort has been made to make the book error free. However, the author and publisher
have no warranty of any kind, expressed or implied, with regard to the documentation contained
in this book.
Foreword
The organic chemistry that serves the needs of society is becoming increasingly spohisticated.
The students of organic chemistry want not only to creativity enrich the existing scientific
knowledge for the betterment of mankind but also apply it for the sustainable development of
the subject. However, they are hard pressed to find a general text to support their learning
during the first year at University. The general organic chemistry texts have been written to
accompany traditional curricular courses and with rather precisely defined requirements. Thus,
the students are left with a limited scope to learn chemistry which encourages creativity.
One of the greatest challenges of organic chemistry is to make complex organic molecules.
Effective synthetic strategy requires the development of novel selective reactions and reagents.
The area has been playing an increasingly important role in serving as a source of understanding
organic reactions and their mechanisms. The present book reveals author’s belief that students
benefit most of all from a book which leads from familiar concepts to unfamiliar ones, not just
encouraging them to know but to understand and to understand why. A practitioner of organic
chemistry must be aware of the fundamental reactions along with their mechanisms to have a
thorough knowledge and understanding of this area. It is this understanding of organic reactions
which provides an impetus into developing new tools for organic synthesis. For the same reason,
an indispensable mechanistic insight is provided which is crucial to those who wish to apply
these existing tools rationally and to contribute to the further developement of novel reagents
and methodologies.
Compared with the earlier edition of the book, the present edition offers much more
material to be learnt. Thus, this book on organic reactions is far from just a remake or update of
a successful earlier version but, as the Publisher notes, is essentially a new book. Previous
chapters have been extensively reworked and updated.
vi Foreword
The “Organic Reactions and their Mechanisms” is a timely account of the current depth
of this area of chemistry. The systematic presentation of the organic reactions will introduce
students to the taste of ever growing organic chemistry. In the present work, Prof. Kalsi has set
himself the goal of organizing the splendid array of organic reactions with their mechanisms.
This provides a concise summary that should be of enormous assistance to those searching for
a selective reaction to achieve a desired transformation. Coming from one of the leading authors,
“Organic Reactions and their Mechanisms” is an authoritative source for a rapidly expanding
field. One must admire Prof. Kalsi’s courage in undertaking this monumental task.
Ganesh Pandey
Head, Division of Organic Chemistry
Preface to the Third Edition
In this edition of the book “Organic Reactions and their Mechanisms” each chapter has been
thoroughly revised, updated and largely rewritten. The new edition has been provided with
new exercises along with their solutions all through the text in separate boxes in order to clarify
the important aspects in a more intellectually stimulating manner. Keeping in view the impor-
tance of problem solving, more new end-of-chapter problems have been added.
The new edition has been modified and is aimed to develop ideas on organic reaction
mechanism along with sequential presentation of facts. The text has been rewritten to fit into
the needs of today’s students and modern university courses. This revised edition presents
different organic reactions and their mechanisms as a teaching text, and avoids to simply present
the material in an encyclopaedic manner. I have thus deliberately omitted detailed discussion
of several obscure reactions of little value.
I sincerely hope that this revised new edition singles itself out from the long-standing
textbook traditions on this subject. The material is selected and presented keeping in mind the
needs of today’s students and modern university courses.
P. S. Kalsi
This page
intentionally left
blank
Preface to the First Edition
Organic chemistry is a rapidly changing field and each year, new exciting advances are made.
It may seem to the student that he needs ever more to learn year by year. However, fortunately,
this is not so. A deep understanding of the reaction mechanisms helps a student to appreciate
as to how and why reactants go to products. The mechanistic principles are relatively few, and
yet these account for the wide range of reactions of organic compounds. A conceptual
understanding of the mechanisms of organic reactions, therefore, helps a student to interrelate
and remember the various reactions.
The purpose of the present book is to incorporate advances in the area of reaction
mechanisms even as basic rules and concepts are emphasized in teaching organic reaction
mechanisms.
I have been fortunate to have had the opportunity to teach a great variety of students at
both the graduate and undergraduate level not only at Punjab Agricultural University, but at
other universities in the country as well. I came in close contact both with the postgraduate
students and my fellow teachers during my teaching programmes, particularly at refresher
courses in different universities in the country. Out of this teaching and my ongoing desire to
teach the subject-matter in a lively and understandable manner, this, yet new book, on organic
reactions and their mechanisms was born.
A fairly comprehensive review of organic structures and material which provides
background to the study of mechanisms is presented in the first few chapters. The further
presentation follows so that the student appreciates that despite a large number of organic
reactions, a relatively few principles suffice to explain all of them.
The study of organic chemistry is much like learning a language where the reactons are
the vocabulatary and their mechanisms the grammar. The design of the present textbook is,
therefore, to ensure that the student has an intellectual grasp of the subject to prepare him not
only for his qualifying examination but for various competitive examinations as well. In line
with this objective, the references have been kept to a minimum. However, a student may like
to pursue individual topics further, thus relevant reviews and books are noted, but the references
to the original literature are limited to points of outstanding interest and some recent work.
The objective has been to convey a deep understanding of reactions and their mechanisms
rather than to bring out a reference text.
An attempt has been made to incorporate several important and recent developments in
the subject. Every chapter has been brought up to date to include these. Some of these topics
are the use of organo-transition-metal reagents, newer reagents and role of organosilicon
compounds.
The text is extensively cross-referenced in order to call the students attention to the
related material already presented in earlier chapters or to the material that is to come.
The best way to learn organic chemistry is by solving problems. In each chapter problems
are presented not only to create thinking in students mind, but also also for the introduction of
new material. Answers to these problems can be found at the end.
P. S. Kalsi
This page
intentionally left
blank
Important Reactions and
Rearrangements
Acyloin condensation, 592 Gattermann-Koch reaction, 357
Aldol condensation, 220 Gomberg reaction, 590
Alkene metathesis, 272 Heck reaction, 267
Allylic shift, 51 Hoffmann rearrangement, 555
Arbuzov reaction, 282 Hunsdiecker reaction, 590
Arndt-Eistert synthesis, 553 Jones oxidation, 462
Aza-Cope rearrangement, 659 Knoevenagel reaction, 232
Baeyer-Villiger oxidation, 493, 559 Kolbe electrolytic reaction, 591
Barton reaction, 594 Lossen rearrangements, 556
Beckmann rearrangement, 558 Mannich reaction, 247
Benzilic acid rearrangement, 552 Meerwein-Ponndorf-Verley reduction, 534
Benzoin condensation, 238 Michael addition, 234
Birch reduction, 514 Mitsunobu reaction, 288
Chichibabin reaction, 376 Mozingo reaction, 522
Claisen ester condensation, 236 Neber rearrangement, 563
Claisen reaction, 229 Norrish type I and II cleavage, 393, 396
Claisen rearrangement, 661 Oppenauer oxidation, 467
Claisen-Schmidt reaction, 226 Oxo reaction, 269
Clemmensen method, 519 Oxy-Cope rearrangement, 659
Cope rearrangement, 655 Paterno-Büchi reaction, 400
Curtius rearrangement, 556 Pauson-Khand reaction, 270
Dakin reaction, 492 Perkin reaction, 230
Darzens condensation, 231 Peterson reaction, 298
Degenerate rearrangements, 653 Photo-Fries rearrangement, 355, 413
Dieckmann condensation, 237 Prevost reaction, 485
Diels-Alder reaction, 630 Pinacol rearrangement, 550
Enamine reactions, 239 Prins reaction, 246
Ene reaction, 663 Pschorr ring closure, 590
Epoxides, 477 Reformatsky reaction, 230
Favorskii rearrangement, 560 Reimer-Tiemann reaction, 355
Friedel-Crafts alkylation, 334, 336 Retro-aldol reaction, 229
Friedel-Craft acylation reaction, 336 Robinson annulation, 235
Fries rearrangement, 355 Rosenmund reduction, 508
Gattermann-Aldehyde synthesis, 357 Schmidt rearrangement, 556
Semipinacol rearrangement, 551
xi
xii Important Reactions and Rearrangements
Shapiro reaction, 521 Tiffeneau-Demjanov reaction, 293

Simmons-Smith synthesis, 434 Ullmann reaction, 591
Sommelet reaction, 469 Wacker reaction, 269
Stobbe condensation, 231 Wadsworth-Emmons reactions, 285
Sommelet-Hauser rearrangement, 564 Wadsworth-Emmons variant, 281
Stevens rearrangement, 563 Wagner-Meerwein rearrangement, 545
Stork enamine reactions, 239 Wittig reaction, 280
Swern oxidation, 465 Wittig rearrangement, 563
Thorpe reaction, 238 Wolff rearrangement, 553
Wolff-Kishner reduction, 520
Some More Important
Reagents
Acyl-iron complexes, 275 Lithium dialkylcuparates, 323

AIBN, 571, 573 Manganese dioxide, 468
Allylsilanes, 301 Nickel and its complexes, 278
Alkyl mercury halides, 573 N-Bromosuccinimide, 52, 575
9-BBN, 306 Organolithium reagent, 322
Bakers yeast, 538 Palladium chloride, 488
Boron containing reagents, 304 PCC, 463
Butyl lithium, 113 PDC, 463
Catecholborane, 306 Peroxyacids, 474
Carbenoid, 434 Periodic acid, 486
Chloranil, 473 Phosphorous ylides, 280
Collins reagent, 463 Selenium dioxide, 469, 470
Chromium arene complexes, 277 Selectride, 531
Chromium trioxide, 462 Silicon reagents, 297
Dimethylformamide, 358 Silyl ether protecting groups, 302
Dioxiranes, 476 Sodium cyanoborohydride, 539
Disiamylborane, 306 Sterically congested boranes, 306
DCC, 464 Sulphur ylides, 290
DDQ, 473 Tebbe reagent, 273
DMP, 467 TEMPO, 467
DMSO, 464, 466, 467, 471 Thexylborane, 306
Epoxides, 537 Trimethylsilyl iodide, 303
Gilman reagents, 323, 339 Triphenylphosphine, 481
Grignard reagents, 316, 574 Tributyltin hydride, 573
Ipc.BBN, 534 Vinylsilanes, 300
Ipc2 BH, 308 Wilkinson’s catalyst, 266, 505
LDA, 112, 114, 199 Ziegler-Natta catalyst, 271
Lead tetraacetate, 486, 600
xiii
This page
intentionally left
blank
Contents
Chapter 1 Fundamental Principles and Special Topics 1–38
1.1 Structure and Bonding in Organic Compounds 1

1.2 Electronegativity—Dipole Moment 12
1.3 Inductive and Field Effects 14
1.4 Hydrogen Bond 18
1.5 Other Weaker Bonds 21
1.6 Bond Dissociation Energy 28
1.7 The Hammett Equation—Linear Free Energy Relationship 30
1.8 Taft Equation 33
1.9 Steric Effects, Strain and Bredt Rule 34
Problems 37
Answers to the Problems 38
Chapter 2 Delocalized Chemical Bonding 39–86
2.1 1, 3-butadiene a Typical Conjugated System 39

2.2 Resonance 41
2.3 Aromaticity 53
2.4 The Terms Aromatic, Antiaromatic and Nonaromatic 57
2.5 Annulenes 59
2.6 The Frost Circle—Molecular Orbital Description of Aromaticity and
Antiaromaticity 62
2.7 Aromatic and Antiaromatic Ions 63
2.8 Other Non-Benzenoid Aromatic Compounds 68
2.9 Heterocyclic Aromatic Compounds 70
2.10 Metallocenes and Related Compounds 71
2.11 Fused Benzenoids and Fullerenes 72
2.12 Homoaromatic Compounds 77
2.13 Hyperconjugation 78
2.14 Hexahelicene 79
xv
xvi CONTENTS
2.15 Tautomerism 79
Problems 83
Chapter 3 Organic Acids and Bases 87–121

3.1 The Bronsted-Lowry Concepts of Acids and Bases 87
3.2 The Lewis Definition of Acids and Bases 90
3.3 The Relation Between Structure and Acidity 91
3.4 Bases 106
3.5 Relation Between Structure and Basicity 106
3.6 Synthetic Applications of Lithium Diisopropylamide (LDA) 114
3.7 Acid-Base Reactions 116
3.8 The Effects of the Solvent on Acid and Base Strength 117
3.9 Leveling Effect 118
3.10 Hard and Soft Acids and Bases 118
Problems 119
Chapter 4 Organic Reactions and the Determination of 122–175

their Mechanisms
4.1 Mechanistic Classification 122
4.2 Nucleophiles and Electrophiles 130
4.3 Electron Movement 131
4.4 Equilibria and Free Energy 131
4.5 Free Energy Change in Relation to Bond Strengths and
Degree of Order in a System 132
4.6 Reaction Rates 134
4.7 The Transition State—Activation Energy 135
4.8 Transition State Theory—Measurement of Activation Energy 135
4.9 Reaction Profile Diagrams 137
4.10 The Rate Determining Step 138
4.11 Thermodynamic and Kinetic Control 139
4.12 Applications of Kinetic Principles 141
4.13 The Curtin-Hammett Principle—Importance of Transition State 144
4.14 Microscopic Reversibility 145
4.15 Methods of Determining Mechanisms 146
4.16 Reactive Intermediates 154
Problems 174
CONTENTS xvii
Chapter 5 Aliphatic Nucleophilic Substitution and 176–215

its Synthetic Applications
5.1 Introduction 176

5.2 Synchronous Substitution—SN2 Process 182
5.3 Substitution by Ionization—SN1 Mechanism 196
5.4 SN1 Versus SN2 Reactions 198
5.5 Other Aliphatic Substitution Pathways 200
5.6 The Role of Ion Pairs 202
5.7 Neighbouring Group Participation and Nonclassical Carbocations 204
5.8 Nucleophilic Substitution at Silicon 212
Problems 212
Chapter 6 Common Organic Reactions and their 216–262

Mechanisms
6.1 Base Catalysed Reactions (Formation of Carbon-Carbon Bonds) 216

6.2 Stork Enamine Reactions (Formation of Carbon-Carbon Bonds)— 239
Reaction of an Enamine with Reactive Electrophiles
6.3 Acid Catalysed Reactions (Formation of Carbon-Carbon Bonds) 246
6.4 Reactions of Carboxylic Acids and their Derivatives 250
6.5 Hydrolysis of Amides 257
Problems 258
Chapter 7 Reagents in Organic Synthesis and Relevant 263–328

Name Reactions
7.1 Organotransition Metal Reagents 263

7.2 Some Transition Metal Organometallic Reactions 266
7.3 Phosphorus Containing Reagents 280
7.4 Organosulphur Compounds: Sulphur Ylides 289
7.5 Silicon Reagents 297
7.6 Boron Containing Reagents 304
7.7 Organometallic Reagents 316
Problems 326
xviii CONTENTS
Chapter 8 Electrophilic Aromatic Substitution 329–365
8.1 General View—The Arenium Ion—The Arenium Ion

Mechanism—SE2 Reaction 329
8.2 Electrophilic Substitution on Monosubstituted Benzenes—Orientation 340
and Reactivity
8.3 Electrophilic Substitution in Naphthalene and Larger Polycyclic 352
Aromatic Hydrocarbons
8.4 Attack of the Electrophile at a Carbon already Bearing a Substituent 353
(Ipso Position)—Ipso Substitution
8.5 Aromatic Rearrangements 355
8.6 Some Name Reactions 357
8.7 Electrophilic Substitution on Heteroaromatic Compounds 358
8.8 Diazonium Coupling 361
Problems 362
Chapter 9 Aromatic Nucleophilic Substitution 366–379
9.1 The SNAr Mechanism—The Addition—Elimination Mechanism— 366

The General Nucleophilic Aromatic Ipso Substitution
9.2 The SN1 Mechanism in Nucleophilic Aromatic Substitution— 369
The Aryl Cation Mechanism—Diazonium Salts
9.3 Nucleophilic Aromatic Substitution by Elimination—Addition— 370
The Benzyne Mechanism
9.4 Benzyne—A Strained Cycloalkyne 373
9.5 Nucleophilic Substitution of Pyridine—The Chichibabin Reaction 376
9.6 Nucleophilic Substitution to Arenechromium Carbonyl Complexes 376
Problems 378
Chapter 10 Photochemistry 380–420
10.1 Absorption of Electromagnetic Radiation—Quantum Yield 380

10.2 Excited States 381
10.3 The Fate of the Molecule in S1 and T1 States (Jablonski Diagram) 381
10.4 Energy Transfer 383
10.5 Energy Transfer and Photosensitization 383
10.6 Forbidden Transitions—Intersystem Crossing 384
10.7 Photochemical Reactions 385
Problems 415
CONTENTS xix
Chapter 11 Addition to Carbon-Carbon and Carbon-Hetero 421–437

Multiple Bonds
11.1 Addition of Electrophiles to a Multiple Bond 421

11.2 Nucleophilic Additions to Alkenes and Alkynes 432
11.3 Addition of Carbenes 433
11.4 Nucleophilic Additions to Carbonyl Compounds 434
(Aldehydes and Ketones)
11.5 Nucleophilic Additions to the Carbonyl Carbon of a Carboxylic 435
Acid Derivative
11.6 Radical Additions to Alkenes 436
11.7 Nucleophilic Attack on Carbon-Nitrogen Triple Bond 436
Problems 437
Chapter 12 Elimination Reactions 438–461
12.1 The Bimolecular Mechanism for Elimination—E2 Process 439

12.2 The Unimolecular Mechanism for Elimination—E1 Process 451
12.3 Pyrolytic syn Elimination—Ei—Elimination Internal 454
Problems 458
Chapter 13 Oxidation Methods 462–499
13.1 Oxidation of Alcohols to Aldehydes, Ketones or Carboxylic Acids 462

13.2 Allylic Oxidation of Alkenes 469
13.3 Oxidation of Saturated C—H Groups 470
13.4 Addition of Oxygen at Carbon-Carbon Double Bonds 474
13.5 Ozonolysis 485
13.6 Cleavage of Glycols and Related Compounds 486
13.7 Oxidation of Alkenes to Aldehydes and Ketones Catalysed with 488
Palladium and Oxidation of Alkylboranes
13.8 Oxidation of Ketones 490
13.9 Oxidation of α-Ketols 493
13.10 Oxidative Decarboxylation of Acids 493
13.11 Aromatic Rings of Phenols—Coupling 494
13.12 Oxidation of Amines 495
13.13 Photooxidation of Alkenes 495
Problems 496
xx CONTENTS
Chapter 14 Reduction Methods 500–542
14.1 Catalytic Reduction-Reduction with Diimide and Hydroboration 501

14.2 Reduction by Dissolving Metals—Metal and Ammonia 510
14.3 Addition of Hydrogen and Reductive Coupling of Carbonyl 515
Compounds—Dissolving Metal Reductions
14.4 Reductive Removal of Functional Groups and Reductive 516
Fission—Hydrogenolysis
14.5 Reductive Deoxygenation of Carbonyl Groups 519
14.6 Reduction by Hydride Transfer Reagents 522
14.7 Stereoselectivity of Reduction with Small Hydride Donors 529
14.8 Stereoselectivity of Reduction with Hindered Hydride 531
Donors-Selectride
14.9 Chiral Boranes—Enantioselective Reduction of Carbonyl 533
Compounds
14.10 Meerwein-Ponndorf Reduction—The Hydride Transfer 534
Reaction
14.11 Cannizzaro Reaction 535
14.12 Reduction of Aldehydes and Ketones with an Adjacent 535
Stereocenter (Asymmetric Induction)
14.13 Reduction of Epoxides 537
14.14 Reductions with Enzymes—Bakers Yeast 538
14.15 Less Reactive Modified Borohydrides—Sodium Cyanoborohydride 539
and Sodium Triacetoxyborohydride
Problems 541
Chapter 15 Molecular Rearrangements 543–568
15.1 Rearrangements to Electron Deficient Carbon 545

15.2 Rearrangements to Electron Deficient Nitrogen 554
15.3 Rearrangements to Electron Deficient Oxygen 559
15.4 Rearrangement to Electron Rich Carbon 560
15.5 Aromatic Rearrangements 565
15.6 Free Radical Rearrangements 566
Problems 566
Chapter 16 Free Radical Reactions 569–604
16.1 Structure, Stability and Geometry 569

16.2 Preparation 569
16.3 Properties of Free Radicals 574
CONTENTS xxi
16.4 Aromatic Nucleophilic Substitution—SRN1 Substitution 588

16.5 Homolytic Aromatic Substitution 589
16.6 Some Name Reactions 590
16.7 The Coupling of Alkynes 595
16.8 Reactions Involving Electron Transfer Steps 596
16.9 Molecular Rearrangements 597
16.10 Some Further Substitution and Other Reactions 599
Problems 602
Chapter 17 Pericyclic Reactions 605–682
17.1 Conservation of Molecular Orbital Symmetry 608

17.2 Methods to Explain Pericyclic Reactions 608
17.3 Electrocyclic Reactions (FMO-Approach) 609
17.4 Cycloadditions (FMO-Approach) 630
17.5 1, 3-Dipolar Cycloadditions 644
17.6 Cheletropic Reactions 645
17.7 Sigmatropic Rearrangements 647
17.8 The ENE Reaction 663
17.9 Aromatic Transition States 664
17.10 Möbius-Hückel Analysis (PMO) Approach 665
17.11 Correlation Diagram Method 671
Problems 676
References and Further Reading 683-684

Index 685-693
This page
intentionally left
blank
CHAPTER 1
Fundamental Principles
and Special Topics
One begins a study of reaction mechanisms by examining some of the basic principles. A basic
understanding of these concepts helps largely in understanding of reactions and their
mechanisms. Thiols undergo an oxidative coupling when treated with mild oxidizing agents to
give disulphides: 2RS—H + H2O2 → RS—RS + 2H2O. The understanding of this reaction
requires a knowledge of bond dissociation energy. The bond dissociation energy of the S—H
bond of thiols (~ 80 kcal/mol) is much lower than the O—H bond of alcohols (~ 100 kcal/mol). It
is this weakness of the S—H bond which allows thiols to undergo an oxidative coupling, and
the alcohols do not display this reaction. On treatment with oxidizing agents, oxidation at the
weaker C—H bond (~ 85 kcal/mol) takes place rather than at the strong O—H bond. Thus a
knowledge of the nature and strength of bonds is essential for the chemical investigation of
organic molecules. Similarly the properties of molecules are influenced by their structure.
1.1 STRUCTURE AND BONDING IN ORGANIC COMPOUNDS

A. Atomic Orbitals
The motion of the electrons around the nucleus can be described by wave equations. The solutions
to these equations are atomic orbitals, which roughly delineate regions in space where there is
a high probability of finding the electron. An s orbital is spherical; a p orbital looks like two
touching spheres, or a “spherical figure eight” (Scheme 1.1). The sign of the orbital can be
positive, negative, or zero (node). These signs do not represent positive or negative charges,
since both lobes of an electron cloud must be negatively charged. They refer to the signs of
y nodal plane
y
z
x x x
z z
y
1s orbital 2px orbital
2px, 2py, and 2pz
orbitals superimposed
SCHEME 1.1
1
2 Organic Reactions and their Mechanisms
the wave function ψ. When two parts of an orbital are separated by a node, ψ always has
opposite signs on the two sides of the node. With increasing energy, there is an increasing
number of nodes. Each orbital can be occupied by a maximum of two electrons of opposite spin
(Pauli exclusion principle, Hund’s rule).
B. Molecular Orbitals and Bonding

In the molecular orbital method, a bond is formed when two atomic orbitals overlap. Atomic
orbitals of the same sign overlap to give a bonding molecular orbital of lower energy. Atomic
orbitals of opposite sign give rise to an antibonding molecular orbital of higher energy and
containing a node. The number of molecular orbitals is equal to the number of atomic orbitals
from which they derive. The overlap of atomic orbitals leads to the formation of sigma and pi
bonds. Bonds made by overlap along the internuclear axis are called σ bonds (as in H2, I; HF,
II; F2, III, Scheme 1.2) and those made by overlap of p orbitals perpendicular to the internuclear
axis are called π bonds. (Scheme 1.2).
+ + + + – – + + – + +
1s 1s 1s 2px
2p 2p
s bond s bond
s bond – –
+ + F2 2p 2p
p bond
H2 d+H—F d –
(I) (II) (III)
SCHEME 1.2
The hydrogen molecule is cylindrically symmetrical about a straight line drawn through
the two nuclei and a cross-section of the molecular orbital when cut perpendicular to the bond
axis is circular. This type of molecular orbital is termed σ orbital or σ bond. Similarly in the
molecule of H—F, the σ bond is again cylindrically symmetrical about a line passing through
the two nuclei. The electrons in the σ bond of H—F are however, not shared equally between
the two dissimilar atoms of different electronegativities and unlike in H2 or F2 in H—F, the
electron distribution is highly polarized (Scheme 1.2).
C. Hybrid Orbitals: Bonding in Complex Molecules

Hybridization of atomic orbitals accounts for observed bond angles and molecular geometries
of the molecules.
(i) sp Hybrids give Linear Structures
In e.g., beryllium hydride BeH2, formation, consider the following points. In its ground state
the beryllium atom has 1s2 2s2 electronic configuration. Only a small amount of energy is
needed to promote one electron from the 2s orbital to one of the 2p levels. In the 1s2 2s1 2p1
configuration (I, Scheme 1.3) beryllium could enter into bonding, as now two singly filled atomic
orbitals are available for overlap. Energy lost in possible promotion of an electron from the 2s
orbital to one of the 2p levels could be regained by bond formation. A bond formation could
occur by overlap of the 2s orbital of Be with the 1s orbital of one H, on the one hand and the 2p
Fundamental Principles and Special Topics 3
orbital of Be with second H, on the other (Scheme 1.3). This possible arrangement would give
two different bonds of unequal length and at an angle. Theory of electron repulsion, however
predicts that compounds like BeH2 to have linear structure with the bonds to Be of equal
length (Scheme 1.3).
2 H
1s
Be H
2s
2p H
Be Not correct
(I) Hybridization Back lobe
180°
2 H
+ – Be – + H—Be—H
Correct
Front lobe
180°
sp sp
Hybridization in beryllium to create two sp hybrids
SCHEME 1.3
A way to explain the geometry of BeH2 and other molecules is the approach called orbital
hybridization. Like mixing of atomic orbitals on different atoms to give molecular orbitals, the
mixing of atomic orbitals on the same atom gives new hybrid orbital. In beryllium, mixing the
2s and one of the 2p wave functions gives two new hybrids, called sp orbitals, made up of 50% s
and 50% p character. This process rearranges the orbital lobes in space (Scheme 1.3). The
major parts of the orbitals (front lobes) point away from each other at an angle of 180°. There
are two additional minor back lobes (one for each sp hybrid) with opposite sign. The remaining
two p orbitals are unchanged and overlap with the two hydrogen 1s orbitals gives linear BeH2.
Thus a 2s and a 2p orbital mix in a sp hybridization to give two linear sp hybrids and the
remaining two p orbitals remain unchanged. This bonding is found both in alkynes and nitriles.
The nitrogen and carbon atom of a nitrile group (C N) are both sp hybridized.
(ii) sp2 Hybrids give rise to Trigonal Structures
Structure of Borane (BH3) has a triangular (trigonal planar) shape with the equivalent boron-
hydrogen bonds. In its ground state boron has the electronic configuration 1s2 2s2 2p1. Promotion
of a 2s electron to one of the 2p levels gives three singly filled atomic orbitals (one 2s two 2p)
necessary for the formation of three bonds (Scheme 1.4). Mixing these three orbitals gives
three equivalent hybrid orbitals which are sp2. These have one part the character of an s
orbital and two parts the character of p orbital. These orbitals are pointed toward the corners
of an equilateral triangle with angles of 120° between their axes. The formation of borane is
via the overlap of each of these three sp2 orbitals with s orbitals of three hydrogen atoms. The
sp2 hybridization also offers a satisfactory model for carbon atoms which form double bonds.
2py
H
:
2s
120° .
3 H
B Hybridization B : H
2px 2
Three sp
:
hybrid orbitals
H
Triangular structure of BH3
5B
2 2 1
1s 2 s 2 p x
SCHEME 1.4
Trigonal boranes BH3 and BF3 have an empty 2p orbital. There is no positive charge on
these compounds, but both are Lewis acids and react like cations (Scheme 1.4a).
Empty 2p
orbital –
:F :
: :
: F:
:
–
H: F:
: :: :
–
:F
: :
H B B
F:
: :
F: :F
: :
+
H
H C C : F:
H H H :
H Empty 2p
orbital
‡ The p bond is electron rich and borane electron poor. In

H
+ BH3 ¾® hydroboration the p bond of alkene acts as nucleophile
BH2 and reacts with the strong Lewis acid BH3.
SCHEME 1.4a
(iii) sp3 Hybridization gives Tetrahedral Shape

In the case of carbon the promotion of one electron from 2s to 2p leads to four singly filled
orbitals for bonding (Scheme 1.4b). The shape of the four C—H bonds of methane in space with
minimum electron repulsion is tetrahedral. For this geometry the 2s orbital on carbon is
hybridized with all three 2p orbitals to give four equivalent sp3 orbitals with a tetrahedral
arrangement (symmetrical arrangement) and each occupied by one electron. The overlap with
e.g., four hydrogen 1s orbitals gives methane.
2py
H
4 109.5°
Hybridization
C
H
4(H) H
2px H
2pz
6C
2 2 1 1 2 3 3 3 3
1 s 2 s 2 px 2 py Carbon atom with an electron promoted 1s 2(sp )2(sp )2(sp )2(sp )
from the 2s orbital to the 2pz orbital
2 1 1 1 1
(1s )2s , 2px, 2py, 2pz
1s Four sp 3 hybrid
atomic orbitals
1s 2s 2p
3
Structure of methane, CH4 showing four equivalent s bonds (s—sp molecular
bond orbitals) and tetrahedral structure
SCHEME 1.4b
A Double Bond
Consider the sp2
(trigonal) hybridized carbon in e.g., a carbon-carbon double bond in
ethene which is a flat molecule with bond angles close to 120°. Hybridization of the
2s orbital and two of the 2p orbitals leads to three equivalent sp2 hybrid orbitals and
one unhybridized 2p orbital (Scheme 1.4c) on each carbon. In ethene the C—C bond
is an sp2–sp2 molecular σ bond while the C—H bonds are s–sp2 molecular σ bonds.
The π bond results from the parallel overlap through space of the p orbitals.
p
2
1 1 1 1 hybridize 2s sp
2
1s 2s2px2py2pz or C sp2
and 2p orbitals
1s 2s 2p sp2
Carbon atom with an electron promoted from
the 2s orbital to the 2pz orbital 2
An sp hybridized carbon
2 2 2 2
1s 2(sp )2(sp )2(sp )2p or
2
1s Three sp 2p
. hybrid orbitals
p-bond p 2H
1s (orbital)
H
sp 2 C
p
H
H H H
s bond
C C C sp2
H H H
Ethene
SCHEME 1.4c
D. Bond Angles, Shapes of Molecules (VSEPR model) and Reactivity

(i) Structure of Methane
Using the valence-shell—electron-pair repulsion (VSEPR) model, an atom is surrounded by an
outer shell of valence electrons. These valence electrons may be involved in the formation of
single, double, or triple bonds, or they may be unshared. Each of these combinations leads to a
negatively charged region of space, and since like charges repel each other, the various regions
of electrons density around an atom is spread out so that each is as far away from the others as
possible. The Lewis structure for CH4 shows a carbon atom surrounded by four separate regions
of electron density, each of which consists of a pair of electrons forming a bond to a hydrogen
atom. Using a VSEPR model, the four regions radiate from carbon in a way so that they are as
far away from each other as possible. This is possible when the angle between any two pairs of
electrons is 109.5°. Therefore, all H—C—H bond angles are predicted to be 109.5°, and the
shape of the molecule is predicted to be tetrahedral. The H—C—H bond angles in methane as
measured experimentally are 109.5°. Thus, the bond angles and shape of methane predicted
by the VSEPR model are identical to those observed (Scheme 1.4b).
(ii) Structure of Ammonia and Water
In the molecule of NH3 the N—H bonds are formed via the overlap of an sp3 orbital of nitrogen
with the s orbital of a hydrogen. The lone pair of electrons is on an sp3 orbital. In nitrogen all
the three 2p orbitals are available for bonding (Scheme 1.4d), however, direct overlap with 1s
orbital of hydrogen would give, three N—H bonds perpendicular to each other with bond angles
of 90°, the geometry of p orbitals. The bond angles in NH3 are 107.3°, to show that nitrogen
uses hybrid orbitals to form covalent bonds.
..
Hybridization
¯ N H
3 3 3 3
sp sp sp sp H
H
Hybrid orbitals
NH3
7N
2 2 1 1 1 (Ammonia)
1s 2s 2p x 2p y 2p z
..
Hybridization
¯ ¯ O H
3 3 3 3
..
sp sp sp sp
H
Hybrid orbitals
H2O
8O
2 2 2 1 1 Water
1 s 2 s 2p x 2p y 2p z
SCHEME 1.4d
Oxygen has two p orbitals which can be used for bonding. Again as seen in NH3 an
attempt to overlap 1s orbitals of two hydrogen atoms would lead to H—O—H angle of 90°.
However, the bond angle in water is 104° close to that in NH3. One can account for the bond
angle of 104° in water provided oxygen uses the hybrid orbitals to form covalent bonds
(Scheme 1.4d).
The Lewis structure of NH3 shows nitrogen surrounded by four regions of electron density.
Three regions contain single pairs of electrons forming covalent bonds with hydrogen atoms.
The fourth region contains an unshared pair of electrons. These four regions of electron density
are arranged in a tetrahedral fashion around the central nitrogen atom (Scheme 1.4d). The
four regions of electron density (VSEPR model) around nitrogen are arranged in a tetrahedral
manner with H—N—H bond angles 109.5°. The observed bond angles are however, 107.3°,
this small difference between the predicted and observed angles can be explained due to
repulsion between the unshared pair of electrons on nitrogen and the bonding pairs. This
repulsion is greater than the electron repulsion between the two bonding pairs.
In water molecule, oxygen is surrounded by four separate regions of electron density.
Two of these regions contain pair of electrons used to form covalent bonds with hydrogen; the
remaining two contain unshared electron pairs. The four regions of electron density around
oxygen (VSEPR model) are arranged in a tetrahedral manner, and the predicted H—O—H
bond angle is 109.5°. The actual measured bond angle is 104.5°, a value smaller than predicted
and even smaller than in NH3. The explanation is the same as used to explain bond angles in
NH3, in the case of water the still smaller angle is due to the influence of now two lone pairs on
oxygen instead of one on nitrogen.
(iii) Structure of a Double Bond
A double bond according to the VSEPR model, is treated as a single region of electron density.
In formaldehyde (methanal), carbon is surrounded by three regions of electron density, two of
which contain single pair of electrons forming single bonds to hydrogen atoms, while the third
region of electron density has two pairs of electrons forming a double bond to oxygen.
(Scheme 1.4e). In ethene (ethylene) each carbon atom is again surrounded by three regions of
H H
:
C O 116.5° C O
:
H H
121.8°
Top view Side view
Methanal trigonal planar
H H H H
C C 117.2° C C
H H H H
121.4°
Top view Side view
Ethene trigonal planar

::
::
O C O H—C C—H
180° 180° 180° 109.5°
60°
Linear carbon dioxide (Ethyne) Linear acetylene
The orbitals forming the

C—C bonds of cyclopropane
SCHEME 1.4e
electron density: two contain single pairs of electrons, and the other contains two pairs of
electrons. Three regions of electron density about an atom are farthest apart provided these
are in the same plane and make angles of 120° with each other. Thus, the predicted H—C—H
and H—C—O bond angles in methanal are 120°; the predicted H—C—H and H—C—C bond
angles in ethene are also 120°. Such an arrangement of an atom is called trigonal planar.
(iv) Structure of Linear Molecules
In other types of molecules, a central atom is surrounded by only two regions of electron density.
In carbon dioxide e.g., carbon is surrounded by two regions of electron density: each contains
two pairs of electrons and forms a double bond to an oxygen atom. Same is the case with
ethyne where each carbon is surrounded by two regions of electron density: one contains a
single pair of electrons and forms a single bond to a hydrogen atom, and the other contains
three pairs of electrons and forms a triple bond to a carbon atom. In each case, the two regions
of electron density are farthest apart if they form a straight line through the central atom and
generate an angle of 180°. Carbon dioxide and ethyne are therefore, linear molecules (Scheme
1.4e). The bond angle is thus, dependent on the orbital used by carbon in bond formation. The
greater the amount of s character in the orbital the larger the bond angle. For example, sp3
hybridized carbons have bond angles of 109.5°, sp2 hybridized carbons have bond angles of
120°, and sp hybridized carbons have bond angles of 180°. The bond angles of sp3 carbon are
tetrahedral only when the four groups are identical as in CH4 or CCl4. In most of the cases the
angles deviate a little from the tetrahedral value. For example, the C—C—Br angle in
2-bromopropane is 114.2°. Similarly, slight variations are generally found from the ideal values
of 120° and 180° for sp2 and sp carbon, respectively. These deviations are due to slightly different
hybridizations, i.e., a carbon bonded to four other atoms hybridizes one s and three p orbitals,
but the four hybrid orbitals thus formed are generally not exactly equivalent, nor does each
contain exactly 25% s and 75% p character. With the four atoms with different
electronegativities, each makes its own demand for electrons from the carbon atom. In strained
molecules the bond angles are largely distorted from the normal values.
VSEPR MODEL/SHAPE OF MOLECULES

One can predict bond angles of molecules and polyatomic ions using Lewis
structures and the valence-shell electron-pair repulsion (VSEPR) model. The
atoms surrounded by four regions of electron density, predict bond angles of 109.5°;
by three regions of electron density, predict bond angles of 120° while for two regions
of electron density, predict bond angles of 180°. Thus benzene must be a flat hexagon
since each carbon in benzene has three areas of electron density around it, thus the
carbon atoms are trigonal planar, C—C—C bond angles 120° as well as H—C—C
bond angles also 120° and all the carbon atoms in the ring are sp2 hybridized.
Similarly according to VSEPR theory a carbocation e.g., t-butyl cation is predicted
to have a trigonal planar geometry (there are three areas of electron density around
the central carbon atom).
(v) Strained Molecules

In cyclopropane (Scheme 1.4e), for geometric reasons, the internuclear C—C—C angle is 60°.
The carbon-carbon bonds in cyclopropane have more p character than normal sp3. The orbitals
thus, from bent bonds, which are weaker than those in normal alkanes. To compensate for the
extra p character for C—C bonds extra s character is used for the C—H bonds, therefore, these
bonds are shorter and stronger than alkyl C—H bonds (C—H bonds in ethane 1.10 Å).
(vi) Role of Bond Angles in Reaction Mechanism

Halocycloalkanes undergo SN2 reactions, however, with significant rate differences depending
on the size of the ring (Table 1.1). The strained cyclopropyl bromide does not undergo
substitution, due to prohibitive strain in the transition state. In a SN2 reaction the reacting
carbon adopts an sp2 configuration as the nucleophile replaces the leaving group (see,
Scheme 5.7). The normal bond angle of sp2 hybridization is 120° and the cyclopropane cannot
be squeezed much from 60° (in cyclopropane which has a shape of regular triangle, the internal
angle must be 60°).
Table 1.1 Relative reactivities of cycloalkyl

bromides in the SN2 reaction
–
H Alkyl Group Relative Rate
Nu C X Isopropyl 1.0
Cyclopropyl negligible
additional bond
angle strain H2C Cyclobutyl 0.008
CH2 Cyclopentyl 1.6
Cyclohexyl 0.01
Transition state for SN2 reaction
on cyclopropyl halide Cycloheptyl 1.0
SCHEME 1.4f
The ring provides a rigid framework which should be capable to tolerate this additional
strain. Thus the low reactivity of cyclobutyl bromide is also due to these reasons. Cyclopentyl
and cyclohexyl bromides display SN2 reactivity which is close to their a cyclic counterparts,
since these rings are more capable to attain sp2 hybridization at the reacting carbon (see also
Scheme 5.9).
E. Hybridization and Length and Strength of a Bond

Both the length and strength of a carbon-hydrogen bond is dependent on the hybridization of
the carbon atom to which the hydrogen is attached. When there is more s character in the
orbital used by carbon to form the bond, the shorter and stronger bond results. An s orbital is
closer to the nucleus than a p orbital and thus the carbon-hydrogen bond formed by an sp
(50% s) hybridized carbon is shorter and stronger than carbon-hydrogen bond formed by an
sp2 (33.3% s) hybridized carbon and this in turn in shorter and stronger than a carbon-hydrogen
bond formed by an sp3 (25% s) hybridized carbon.
The following points may be noted:
• In general shorter bonds are stronger bonds. Increasing s character shortens bonds,
thus bonds strength increase with increasing s character.
• More the bonds holding two carbon atoms together, the shorter and stronger is the
carbon-carbon bond. Triple bonds are shorter (C C, 1.20 Å) and stronger
(C C, 200 kcal/mol) than double bonds (C C, 1.33 Å, 152 kcal/mol), which are shorter
and stronger than single bonds (C—C, 1.54 Å, 88 kcal/mol).
Thus double bonds are both shorter and stronger than corresponding single bonds,
however, not twice as strong, since π overlap is less than σ overlap. This means that
a σ bond is stronger than a π bond. The difference in energy between a single bond,
say C—C, and the corresponding double bond is the amount of energy necessary to
cause rotation around the double bond.
F. Shapes of Some Reactive Intermediates

A carbocation contains a positively charged carbon atom bearing three substituents to suggest
a trigonal planar arrangement as e.g., in tert-butyl cation. In a carbocation the carbon is sp2
hybridized and the unhybridized 2p orbital lies perpendicular to the sigma bond framework
and has no electrons (is vacant). In BF3 as well, one has the same situation, the boron atom is
sp2 hybridized and has a vacant p orbital perpendicular to BF3 plane, and same is the case
with BH3.
2
sp hybridized empty 2p orbital
:
1.10 Å
CH3 CH3
–
H 3C C+ H3C C+ C
H H 21.4°
120° CH3 CH3 H
tert-Butyl cation 107.5°

–
Vacent 2p orbital lies perpendicular Structure of the methyl anion, :CH3
to plane of carbon atoms
empty 2p orbital
H
H B
H
Borane
SCHEME 1.4g
A methyl anion has two more electrons than the cation. The orbitals have density at the
positively charged nucleus, thus a negatively charged electron would be more stable (lower in
energy) in an orbital with more s character. A pyramidal structure seems reasonable for the
methyl anion however, the molecule is not a perfect tetrahedron. Hybridization and bond angles
are closely related. With more s character in the orbital containing the nonbonding electrons,
the pyramidal shape is likely to increase.
As per the calculations the structure of methyl anion is as shown (Scheme 1.4g). With
the three sigma bonds and a lone pair, a carbanion is electronically similar to an amine. Consider
the hybridization change on formation of methyl radical from methane (Scheme 1.4h). At present
it is however not possible to choose between a planar or a pyramidal structure for a free radical
e.g., for neutral methyl radical which can be obtained by the removal of hydrogen atom from
methane. Spectral measurement have however, shown that methyl radical has nearly planar
configuration described by sp2 hybridization with unpaired electron in the remaining p orbital
perpendicular to the molecular plane (Scheme 1.4h). In the pyramidal arrangement, the carbon
would be sp3 hybridized and odd electron would occupy an sp3 hybridized orbital in one corner
of the tetrahedron.
Csp3 —H1s H . .
:
. H
–H
H C
Csp3 —H1s H C H
C H H
H
H H Pyramidal structure
Nearly planar resembles methane
Methane methyl free radical (less likely)
(favoured)
Hybridization change on forming methyl radical from methane
SCHEME 1.4h
G. Hyperconjugation
The planar structure of methyl and other alkyl radicals helps Hyperconjugation
to explain their relative stabilities by hyperconjugation
H
(Scheme 1.4i). Thus there is a conformer in e.g., ethyl radical
:
in which C—H bond of the CH3 group is aligned and overlaps
with one of the lobes of singly occupied p orbital on the radical H
centre. Thus the bonding pair of electrons in the σ orbital H
C C
H
spread into the partly empty p lobe a phenomenon known
H
as hyperconjugation. Like resonance, hyperconjugation is
also a form of electron delocalization which are distinguished Hyperconjugation in ethyl radical
by the type of orbital. Resonance generally refers to π type .
overlap of p orbitals, while hyperconjugation involves (CH2—CH3)
overlap with the orbital of σ bonds. With the increase in

number of alkyl groups, the number of hyperconjugation SCHEME 1.4i
interactions increases as in isopropyl group (more details are in sec. 2.14).
H. Sigma and FE Bonds

A C—C sigma bond is formed by the overlap of hybrid orbitals. In ethane e.g., this bond
consists of two sp3 hybrids, when these roughly sp3 hybridized carbons approach for the
overlap of singly occupied orbitals (Scheme 1.4 j).
s-bond
H H H H
H H
C . + . C C—C
H H
H H
H H
H3C. + .CH3 H3C—CH3
Two methyl radicals Ethane
SCHEME 1.4j
Bonds made by overlap along the internuclear axis are called σ bonds, while those made
by overlap of p orbitals perpendicular to the internuclear axis are called pi bonds (Scheme 1.4k).
In contrast to the sigma orbital, the pi molecular orbital has zero electron density along
the molecular axis, but has the maximum electron density above and below the internuclear
line. All the sigma bonds around the pi bonds are coplanar, the bond angles being 120°. The
plane of the molecule is the nodal plane of the pi bond.
A nodal plane
s bond
p bond
SCHEME 1.4k
1.2 ELECTRONEGATIVITYDIPOLE MOMENT

Carbon is unique among the elements, since it is able to form a huge number of compounds by
bonding to itself and to the atoms of other elements e.g., hydrogen, oxygen, nitrogen, sulphur
and the halogens. This bonding is almost always covalent.
The sharing of electrons in a covalent bond is not exactly equal when the linked elements
are different. The relative attractive power exerted by an element on the electrons in a covalent
bond can be expressed by its electronegativity. According to one quantitative definition of
electronegativity, there is an increase in electronegativity along the series towards fluorine as
shown (Scheme 1.5).
Hydrogen with electronegativity 2.0 is close in this respect with carbon (for further
details on electronegativity see, Scheme 3.9). When two atoms with different electronegativities
form a covalent bond, the atom with greater electronegativity draws the electron pair to it and
a polar covalent bond results as in hydrogen chloride and can be represented by the usual
symbol (I, Scheme 1.5) when necessary. In fact the hydrogen chloride molecule is a resonance
hybrid of two resonating structures.
C N O F + – d+ d–
H—Cl H Cl H—Cl + –
2.5 3.0 3.5 4.0
Relative electronegativities a dipole
(I)
SCHEME 1.5
As a consequence of a partially positive end (δ+) and a partially negative end (δ–) in HCl
molecule represents a dipole (II, Scheme 1.5) and therefore, has a dipole moment (a physical
property). Thus the dipole moment is a property of the molecule which is due to charge
separations. It is defined as the product of the magnitude of the charge (e) in electrostatic units
(esu) and the distance (d) which separates them in centimeters (cm):
µ=e×d
Dipole moments are typically of the order of

positive end negative end
10–18 esu cm, since charges are typically of the order
of 10 –10 esu and the distance is of the order of
10–8 cm. For convenience this unit (1 × 10–18 esu cm) A vector quantity
is defined as one Debye (abbreviated D). The direction
Scheme 1.6
of polarity of a polar bond is usually symbolized by a
vector quantity (Scheme 1.6).
The arrow head points to be the negative part of the molecule, while the crossed end is
the positive end. A molecule with polar bonds, may, however, not possess a dipole moment i.e.,
the molecule itself may be non-polar. This is so when a particular molecule has a shape
(or symmetry) so that the dipoles of the individual bonds cancel each other. Thus one is concerned
with the total moment of the molecule which is the vectorial sum of the individual bond moments
as e.g., in the case of 1, 2-dichloroethene isomers (Scheme 1.7).
Cl Cl Cl H ..
C C C C O C O S
H H H Cl Carbon dioxide O O
Sulphur dioxide Net moment
vector sum = vector sum = 0
m = 2.95 D m=0
b.p. = 60°C b.p. = 48°C
cis-1, 2-dichloroethene trans-1, 2-dichloroethene
SCHEME 1.7
Similarly carbon in CO2 is sp hybridized and the molecule is linear. The C—O bond
moments oppose each other and cancel, in SO2 however, S is sp2 hybridized with two σ bonds
to O and one with unshared electron pair. The O—S—O bond angle is around 120° and S—O
moments do not cancel. Thus unlike CO2, SO2 has µ = 1.6 D.
The carbonyl group is polar. The carbon atom is bonded to the more electronegative
oxygen atom. The resulting imbalance in the electron density leads to a permanent dipole of
2–3 Debyes (D) in the case of simple carbonyl compounds (Scheme 1.8).
+ – H3C
+ – d d
O:
: :
: :
C O C or C O C O
Hybrid
H3C
Resonance structures for the carbonyl group
Acetone
m = 2.88 D
SCHEME 1.8
2-chloroethanol is much more acidic than ethanol. This can be

explained due to electrostatic interaction of the C—Cl dipole with the Cl
negative charge of the alkoxide ion (Scheme 1.9). The negative charge CH2—CH2
on oxygen is nearer to the positive end of the dipole than it is to the
O
negative end. Consequently, electrostatic attraction exceeds repulsion,
2-chloroethanol
leading to the stabilization of the anion. This stabilization of the anion
increases its ease of formation and the conjugate acid, 2-chloroethanol,
SCHEME 1.9
is more acidic than ethanol itself.
In the equilibrium for 2-halocyclohexanones (Scheme 1.10) there is an increase in the

per cent of axial conformer on going from 1, 4-dioxane to heptane as solvent. The C—Cl and
C O dipoles reinforce each other in the equatorial form, however, these cancel to some extent
in the axial form. Thus the equatorial form is more polar and should be favoured by the more
polar solvents.
X
X O
The equatorial form is more polar
Halogen % Axial (heptane) % Axial (1, 4-dioxane)

Br 85 62
Cl 76 37
2-halocyclohexanones
SCHEME 1.10
To cite one example of the involvement of carbon-halogen dipole is the electrophilic

aromatic substitution in a halobenzene. A halogen is o, p — directing substituent. Substitution
at the meta position of a halobenzene can lead to three resonance structures (Scheme 1.11). All
the three structures are strongly destabilized by electrostatic interaction of the positive charge
in the ring with the carbon-halogen dipole. As a consequence the meta position in a halobenzene
is strongly deactivated. Though similar situation is also obtained during o and p attack, however,
in these cases additional stable halonium ion structures make the o, p attack for more facile
(Scheme 8.42).
X X X
+ +
H H H
+ E E E
Reaction at the meta position
C—X
SCHEME 1.11
1.3 INDUCTIVE AND FIELD EFFECTS

One may observe a change in the rate constant or equilibrium constant of a reaction by replacing
a hydrogen atom by another atom or group of atoms. These substituent effects may be the
result of the size of the substituent (steric effect) and/or its influence on the availability of
electrons (electronic effect) on the site of the reaction. The electronic effect which a substituent
can exert may be either electron releasing or electron withdrawing. These electronic effects
are further subdivided into an inductive and a resonance (mesomeric effect). The inductive
effect (I) is a result of a substituents’ intrinsic ability to supply electrons (electron donation, + I
effect) or withdraw electrons (electron withdrawing) – I effect, i.e., the inductive effect depends
on the electronegativity of the substituent. The inductive effect is transmitted through σ bonds
and weakens as the distance between the substituent and the reactive center increases. Thus
the effect is greatest for the adjacent bond and may be felt weakly farther away (see,
Scheme 3.18). The effect may be represented for ethyl chloride (Scheme 1.12). In this case
chlorine atom has –I effect and thus C-1 atom looses some of its electron density and as a
result C-1, Cl bond is polarized and a slight positive charge is generated on C-2. In this way the
replacement of hydrogen atom by a more electronegative atom results in electron displacements
throughout the molecule.
A slightly positive charge on the C-2 atom dd+ d+ d– A – I group will draw electrons
CH3 CH2 Cl
A polarization of this bond
SCHEME 1.12
The other effect operates through space (and not through σ bonds) or through solvent
molecules and is called the field effect. Normally the field effect depends on the geometry of
the molecule whereas the inductive effect depends only on the nature of the bonds. As an
example of the field effect (long range polar interactions) the two acids (I and II, Scheme 1.13)
have different pKa values. The inductive effect of the chlorine atoms on the position of the
electrons in the COOH group must be same since the same bonds intervene. Consequently, the
acidity must have been equal. However, this difference in pKa value shows the operation of
field effect, since the two chlorine atoms are placed closer in space to the COOH group in I
than in II.
H Cl Cl H
H Cl Cl H
CO2H CO2H
(I) (II)
SCHEME 1.13
The inductive effect (+I) of alkyl group has been invoked to explain the carbocation
stability. This effect also helps in explaining the orientation and reactivity during electrophilic
substitution on benzene derivatives (Sec. 8.8).
The resonance effect (see, Schemes 2.14 and 2.15) involves delocalization of electrons
through resonance via the π system. Atoms and functional groups may be arranged according
to their ability to donate or withdraw electrons. The inductive and resonance effects of many
groups are in the same direction. Other groups display opposite effects in the two cases. Normally
atoms which are more electronegative than carbon and which also have non-bonding electrons
possess opposing characteristics. The halogens illustrate these opposing effects (Scheme 1.14).
A good example is found during electrophilic substitution when the inductive effect of a halogen
on the benzene ring slows the rate of further substitution (Scheme 1.14).
+ –
:
: :
: :
: Cl—C— : Cl—C C— : Cl C—C—
:
the inductive effect resonance
Cl Cl +
The C—Cl bond is strongly polarized. The d on the
+ carbon slows a substitution reaction which places
E more positive charge on the ring. A halogen, however
+ denotes electrons in the ring via resonance. Thus a
halogen in o, p director.
H E
SCHEME 1.14
EXERCISE 1.1
How one can explain that acetic acid (pKa = 4.7) is stronger acid than
2, 2, 2-trifluoroethanol (pKa = 12.8) and ethanol is the least acidic (pKa = 15.9)
from among these three compounds?
ANSWER. Consider the species after the loss of a proton from each of these
compounds. In the case of ethanol the negative charge resides on its single oxygen
i.e., the charge is localized (Scheme 1.14a). In the carboxylate ion both inductive
withdrawal of electrons and the ability of two atoms to share the negative charge
via resonance renders the conjugate base of the carboxylic acid more stable than
the conjugate base from ethanol. 2, 2, 2-Trifluoroethanol is much stronger acid
than ethanol, since in the former the highly electronegative fluorines help in the
stabilization of its alkoxide ion.
O
– –
: :
CH3—CH2—O : CH3—C O
Charge is localized –I effect of carbonyl group in
on the alkoxide ion acetate anion also stabilizes it
–
:
O :O: d
–
F
CH3—C CH3—C d
+
–
: :
:O: –
O F C—CH2—O:
:
F
Charge is shared by oxygen Strong–I effect of fluorines
atoms via resonance stabilizes the alkoxide ion
SCHEME 1.14a
EXERCISE 1.2
Acidity order of alcohols in aqueous solution is :
CH3OH > CH3CH2OH > (CH3)2CHOH > (CH3)3COH. Can inductive effect explain
this order?
ANSWER. Electron donating inductive effect (+ I) of
alkyl groups will retard the formation of an alkoxide to d+ d– –
reduce the acidity of an alcohol. Thus t-Butanol is the H3C C—O
weakest acid (Scheme 1.14b).
The electron donating inductive
However, in the gas phase it is found that the acidity effect destabilizes the
order of alcohols is opposite to that found in solution. alkoxide ion
Thus it is probably not the + I effect of alkyl groups
SCHEME 1.14b
that is important but stabilizing effect of the solvent. A
smaller alkoxide ion is approached more easily by the solvent to solvate it (see
Scheme 3.18).
EXERCISE 1.3
Which of the alkenes (Scheme 1.14c) is expected to react ClCH2—CH CH2
faster with HX?
(I)
ANSWER. Consider the protonation of the double bond CH3—CH CH2

in (I, Scheme 1.14c) which is according to Markovnikov (II)
rule.
SCHEME 1.14c
– + – +
d d H—X d d +
Cl CH2—CH CH2 Cl—CH2—CH—CH2—H
–I effect of
chlorine Unfavourable interaction
between like positive charges
SCHEME 1.14d
Due to the –I effect of chlorine a positive charge on the methylene group would be
in opposition to the expected carbocation formed during the addition of HX. No
such effect is operative in (II).
EXERCISE 1.4
Discuss in terms of resonance and inductive effect the addition of HX to methyl
vinyl ether.
ANSWER. The –I effect of oxygen generates a partial positive charge on the adjacent
carbon, which will get enhanced on protonation (Markovnikov rule) during the
first step of addition of HX i.e., during the formation of intermediate carbocation

which is an unfavourable situation. However, resonance stabilization dominates
the inductive effect and the addition occurs smoothly (Scheme 1.14e).
d– d+ d– d+ –
H—X + X
: :
CH3O CH CH2 CH3O—CH CH2 CH3O—CH—CH3 CH3O—CH—CH3
(I)
X
+
CH3O CH—CH3
:
SCHEME 1.14e
1.4 HYDROGEN BOND

The hydrogen atom which is bonded to an electronegative atom can form a hydrogen bond to a
second electronegative atom. The hydrogen bond, is thus a force of attraction between opposite
partial charges, e.g., δ+ charge on H in the OH group and δ– charge on the O of another group
(Scheme 1.15).
No such partial charges exist in the molecules of alkanes since C and H have nearly
same electronegativities. Only three elements, F, O and N, have atoms that are electronegative
enough to participate significantly in hydrogen bonds. A hydrogen bond requires a hydrogen
bond donor and a hydrogen bond acceptor as in the alcohol molecule (Scheme 1.15).
H-bond acceptor
H H
d– d+ H
O—R water H—O
CH3—O HF H—N H—O
H d+ O d– H
CH3 H
R¢ R
R—O
Ether
H-bond donor
Hydrogen bonding between
alcohol molecules
SCHEME 1.15
An ether has no O—H proton, therefore, the ether group cannot donate hydrogen bonds
and thus cannot form a hydrogen bond with another ether molecule. Since, ether molecules
are not held together by hydrogen bonds, they are more volatile than alcohols of the same
molecular weight. The oxygen of the ether group can however, form hydrogen bonds with an
alcohol or a other hydrogen bond donor e.g., water (Scheme 1.15). So ethers are more soluble in
water than in alkanes. The hydrogen bond is conventionally represented by a dotted line.
The hydrogen bond (bond dissociation energy about 1–9 kcal/mol) is weaker than an
ordinary covalent bond. When there are many such bonds as in carbohydrates, the total strength
is very great. The bond may be formed both between molecules of the same type as in alcohols
(Scheme 1.15) and carboxylic acids
CH3—C—CH3
(Scheme 1.16) and molecules of different d– d+
type as in an ether and alcohol (Scheme 1.15) O H—O O
or as in the interaction between the proton R—C C—R
of an alcohol and the oxygen of a carbonyl O—H O
H
group. Two types of hydrogen bonding have d+ d–
O—CH3
been recognized: intramolecular (within the
same molecule) and intermolecular (between SCHEME 1.16
two or more molecules).
Due to hydrogen bonding, there is an increase in intermolecular ‘aggregation’ forces
which is reflected in the boiling point and solubility of the organic compound. There is an
increase in the boiling point since energy is required to separate the hydrogen bonded molecules
in their translation to the gaseous state. Hydrogen bonds exist in the liquid and solid phases
and in solution. Compounds which form strong hydrogen bonds may be associated even in the
gas phase. Thus acetic acid exists as a dimer in the gas phase.
Intramolecular hydrogen bonds may also be formed and these have particular
significance. When the resulting ring is five or six membered then the phenomenon is termed
chelation. An example of chelation is for the enolic form of acetylacetone (Scheme 2.50). Since
on chelation, intermolecular aggregation forces are not operative, chelated compounds have
normal boiling points (Scheme 1.17). Thus, o-nitrophenol is much more volatile than its p-isomer,
since only the latter can form intermolecular hydrogen bonds.
–
O O
+
N H O
+ –
O HO N O
+
O HO N
–
O
o-nitrophenol
(more volatile because of p-nitrophenol
intramolecular hydrogen bonding) (less volatile because of intermolecular hydrogen bonding)
SCHEME 1.17
An important way to detect hydrogen bonding is via IR and NMR spectroscopy. A free
OH group of an alcohol or a phenol shows a sharp infrared absorption around 3600 cm–1
(O—H stretching vibrations). On hydrogen bonding the band becomes broad and is shifted to
lower frequencies (around 3400 cm–1). In several cases in dilute solutions, there may be partial
hydrogen bonding, i.e., some hydroxyl groups are free and others bonded. In these cases one
therefore, observes two bands, one sharp band at high frequency (around 3600 cm–1) and another
broad band at lower frequency (around 3400 cm–1). A distinction can also be made between
inter- and intramolecular hydrogen bonding on the basis of infrared spectroscopy. In very
dilute solution, formation of intermolecular hydrogen bonds does not take place as the molecules
are widely separated. Increasing the concentration of the alcohol or phenol causes the sharp
band around 3600 cm–1 to be replaced by a broad and lower frequency band which is assigned
to OH groups that are associated through intermolecular hydrogen bonding. Intramolecular
hydrogen bonds remain unaffected and as a result the absorption band also remains unaffected.
In the case of o-nitrophenol the OH band (intramolecular hydrogen bonding) is at 3200 cm–1 in
KBr pellet as well as in CHCl3 solution, whereas in the p-isomer, the values are different in
the two media KBr (pellet 3330 cm–1; CHCl3 solution 3520 cm–1). In the 1H NMR spectrum a
hydrogen bonded hydroxyl group shows a downfield shift of its proton.
EXERCISE 1.5
(a) Why the O—H stretching frequency for t-butyl alcohol is a more sharper band
compared with methanol?
(b) Which of the following norbornane systems can be detected by IR spectroscopy:
HO CH3 H 3C OH HO CH3
(I) (II) (III)
SCHEME 1.18
ANSWER. (a) Due to steric effects it is far more difficult for
O R
t-butyl alcohol to involve in intermolecular hydrogen bond H
formation.
(b) In (I, Scheme 1.18a), intramolecular hydrogen bonding
would be detected.
SCHEME 1.18a
Hydrogen bonding effects structure (chemical properties) and molecular shape of

molecules. Thus e.g., the role of intramolecular hydrogen bonding is reflected in the large
amount of enol present in some tautomeric equilibria (see, Scheme 2.48). It also influences
conformation of molecules. The six membered heterocycles of oxygen closely resemble the chair
conformation of cyclohexane. In heteroxyclic rings the steric repulsions for axial substituents
are reduced due to the replacement of a methylene groups of cyclohexane by oxygen or nitrogen.
Since the divalent oxygen has no substituents, therefore, the 1, 3-diaxial interactions which
are the main unfavourable interactions for axial substituents in cyclohexanes are absent
(Scheme 1.18). With the presence of a polar substituent, interactions between the substituent
and the ring heteroatom can become important. Thus, the preferred conformation of 5-hydroxy-
1, 3-dioxane (Scheme 1.18b) has the hydroxyl group in the axial position. This conformation is
favoured due to hydrogen bonding of the hydroxyl group with the ring oxygen which is possible
only with the axial hydroxyl group to serve as a stabilizing force for this conformation.
H
O
O —N—H O C
O Peptide group
SCHEME 1.18b
The three dimensional structures of proteins and nucleic acid molecules is due to hydrogen
bonding. In α-helices, hydrogen bonds extend from the H atoms of polar NH units in peptide
groups to oxygen atoms of polar carbonyl units (Scheme 1.18b).
The nucleophiles may be solvated by hydrogen bonding to become less reactive in a
nucleophilic substitution.
1.5 OTHER WEAKER BONDS

A. Charge Transfer and π Complexes
In several cases the molecules of the starting materials remain more or less intact and weak
bonds hold the molecules together. Electron donor-acceptor (EDA) complexes provide an
excellent example, where weaker bonds operate. In the case of EDA complexes, one always
has a donor molecule and an acceptor. The donor may donate an unshared pair (an n donor) or
a pair of electrons in a π orbital of a double bond or aromatic system (a π donor). Formation of
an EDA complex is confirmed from the electronic spectrum. These complexes normally display
a spectrum (a charge transfer spectrum) that is not the same as the sum of the spectra of the
two individual molecules. This is due to the fact that the first excited state of the complex is
relatively close in energy to the ground state, there is usually a peak in the visible or near
uv-region and EDA complexes are often coloured. Generally in EDA complexes the donor and
acceptor molecules are present in an integral ratio, most often 1 : 1. Several metal ions (acceptor)
notably Ag+ form stable complexes (which are often solids) with olefins, dienes or aromatic
rings (donors) as shown (Scheme 1.19).
CH3
O2N NO2
+
Me2C CMe2 + Ag Me2C CMe2
Ag+ H 3C CH3
(I) Humulene NO2
SCHEME 1.19
In the case of an olefin-silver ion complex of the type (I, Scheme 1.20) there are two
bonds between the metal ion and the olefin. One of these is a σ bond which is formed by overlap
of the filled π orbital of the olefin with the empty 5s orbital of the silver ion, while the other is
a π bond formed by overlap of a filled 4d orbital of the silver ion and an empty antibonding π*
orbital of the olefin. The bond is not from the silver ion to one atom but to the whole π center.
Consequently, some electron density is transferred from the olefin to the metal ion. In several
cases olefins are isolated and purified through their metal complexes. Thus the sesquiterpene
humulene (Scheme 1.19) is purified through its solid adduct with AgNO3, from which humulene
is regenerated by steam distillation.
Silica gel, impregnated with AgNO3 displays a highly selective adsorption properties
regarding the geometry, degree of substitution and the number of double bonds in a compound.
The impregnated adsorbent is highly useful for the sharp separation of such compounds.
1, 3, 5-Trinitrobenzene and other poly-nitro compounds form complexes with a variety
of organic compounds including aromatic hydrocarbons, aromatic amines, olefins etc.
(Scheme 1.19). The complex with picric acid e.g., a complex between picric acid (acceptor) and
1, 3, 5-trimethylbenzene (donor) is called a picrate. Picrates are solids with definite melting
points and are used as derivatives of the compounds.
The bonding in these compounds is more difficult to explain. The difficulty is that although
the donor has a pair of electrons to contribute (both n donors and π donors) the acceptor does
not have a vacant orbital. One may explain the bonding in these complexes results from
attractive forces between electron-rich and electron-poor substance (attraction of the dipole
induced dipole type). The designation, charge transfer complex, orginates from a resonance
description where the structure of the complex receives contribution from resonance forms
involving transfer of an electron from the donor to the acceptor molecule. The name π complex
is often used since normally atleast one component of the complex has a π electron system.
Metallocenes, e.g., ferrocene (see, Scheme 2.41) and benzenechromium tricarbonyl
(see Scheme 9.21) provide further examples of this class.
In complexes where the acceptor is iodine or bromine, the acceptor molecule accepts
electrons from both n and π donors, probably by expansion of the outer shell to hold ten electrons.
It is because of this complex formation that iodine does not have its normal purple colour in
solvents like acetone or benzene. As an evidence for charge transfer complex formation, the
iodine-benzene complex has a dipole moment, while iodine and benzene are individually
non-polar.
B. Crown Ether Complexes and Cryptates

Crown ethers are large ring polyethers. The compounds are cyclic polymers of ethylene glycol,
(OCH2CH2)n, and are named in the form x-crown-y, where x is the total number of atoms in the
ring and y is the number of oxygens. An example is [18]-crown-6, the cyclic hexamer of ethylene
glycol (Scheme 1.20), Crown ethers are used as cheleting agents (from Greek Chele, ‘‘Crab’s
claw’’) and are important for their property of forming complexes with positive ions. Normally
the cations are held tightly in the center of the cavity and each crown ether binds different ions
depending on the size of the cavity. In each case the ‘‘cavity size’’ is a good match for the ionic
diameter of the cation.
: :
O O
:
O O
:
:
:
O O O O
:
+
+ – Na
K MnO4 : O: : O:
–
I
:
: :
O O O O O
:
:
: :
O O
[18]-crown-6 [18]-crown-6 [15]-crown-5

chelates K + chelates Na+
SCHEME 1.20
Thus 18-crown-6 binds K+ (ionic diameter, 2.66 Å) but not Li+ (ionic diameter 1.20 Å),
similarly 12-crown-4, binds Li+ but not K+. Crown ethers have use in separating mixtures of
cations and much use in organic synthesis. Potassium permanganate with deep violet colour is
completely insoluble solid in benzene, it however, readily dissolves in benzene if 18-crown-6 is
added to give a violet coloured solution. This solution is useful because it allows oxidations
with KMnO4 to be carried out in organic solvents. The solubility of KMnO4 in benzene in the
presence of [18]-crown-6 to give pink benzene is due to the fact that the six oxygens in 18-crown-6
are ideally situated to solvate a potassium cation. In the resulting complex the cation is solvated
by the polar oxygens, but the exterior has hydrocarbon properties. As a result, the complexed
ion is soluble in non-polar solvents (for their role in nucleophilic substitutions see Scheme, 5.17).
Crown ethers not only bind simple metal ions, but they can also bind ammonium and
alkyl ammonium cations. This binding involves three N+—H----O hydrogen bonds as well as
electrostatic interactions (Scheme 1.20a). Thus crown ethers can act as receptor molecules for
ammonium and alkyl ammonium cations as well. [18] Crown-6 forms a strong complex however,
no such opportunity is made available by a smaller crown ether and therefore, in (II) there is
a mismatch for the formation of three N+—H----O hydrogen bonds.
H H
Me
O N+ O
H Me O O
O O O O Me
Me Me H H
+ H H
(guest) +
Me Me
O O O O O Me Me O
H
H
O O
O
[18]-crown-6 (I) (II)
(host) Stronger complex
Weaker complex
with [15]-crown-5
SCHEME 1.20a
The bonding of ammonium and alkyl ammonium cations by crown ethers gives a perching
complex. Azacrowns are even better at binding ammonium ions because the nitrogen atoms
are more basic than oxygen atoms. Another example shows a crown ether with a pyridine ring
in the core structure (Scheme 1.20b). The complex (I, Scheme 1.20a) has to be viewed on the
same lines as the perching complex (Scheme 1.20b). One calls this as ‘‘perching’’ on the crown
ether, whereas K+ can ‘‘nest’’ in it.
Me
Me Me
C
Me
O O + N+
Me——NH3 CIO4– H
H
Me N H
N O O O
O ClO4–
O O O
O
SCHEME 1.20b
The chiral crown ether (Scheme 1.20c) is capable of enantioselective recognition of chiral
ammonium salts. This represents an excellent application of the separation (resolution) of
chiral pharmaceuticals. A pharmaceutical industry has to often resolve two enantiomers of a
chiral drug which display completely different activities.
CH3
Ph
O Ph H CO2H
O O H H
C2 = N
+
O O +
H CO2H H H
O
H H
CH3
R R
A chiral (R, R)-binaphthyl crown ether D-enantiomer of phenylglycine cation
SCHEME 1.20c
The R, R receptor preferentially binds salts of D-α amino

acids and esters and the complexes can be extracted by CDCl3 O
H3C Ph
from an aqueous (D2O) solution. The D-amino acid salts fit OH H O
better in the chiral circular cavity than their enantiomers. In
+
every case it was found that D-enantiomer was selectively CO2H
O H O
complexed. The chiral recognition between the enantiomers of H3C H
e.g., PhCH(COOH) NH3+ is a consequence of steric interactions O
between the bulky substrate substituents with the methyl R, R-binaphthyl crown
groups of the chiral crown ether (guest). Thus the selective ether Scheme 1.20c with
binding is due to the fact that in the L-enantiomer of the D-phenylglycinate cation.
phenylglycine cation the COOH group will come into close
proximity to maximize steric interactions with CH3 substituent SCHEME 1.20d
of the host (Scheme 1.20d).
Cryptands are cage like bicyclic molecules which are like crown ethers except that these
contain an additional ‘‘strap’’. Crown ethers are essentially two-dimensional molecules while
cryptands are their three dimensional versions which like crown ethers can incorporate positive
ions into the roughly spherical cavity within the cage. The crown ethers as well as cryptands
O O [18]-crown-6 is a floppy molecule which becomes

+
rigid on binding a K ion, thus some entropy is lost
N O O N
on binding. The three dimensional cryptand is
O O more rigid than the crown ether leading to less
entropy loss on binding.
O O
O O O O O O
N N N N N N
O O O O
O O O O K
+ O O
a [2.2.2] cryptand a cryptate
SCHEME 1.20e
reflect on new techniques to mimic metalloprotein core chemistry. These are named depending
on the number of oxygen atoms in each nitrogen-nitrogen linker (Scheme 1.20e) and [2.2.2]
cryptand is the most important. The binding of K+ by [2.2.2] cryptand in methanol e.g., is some
104 times stronger than its crown analogue [18] crown-6. The [2.2.2] cryptand is based on a
similar sized ring to [18]-crown-6 and thus this cryptand shows selectivity for K+ over the
other/alkali metal ions. This is largely due to the more flexible crown ether (entropy) than the
rigid cryptand as well as the three dimensional nature of the cavity in the later.
A cyclodextrin consists of six, seven, eight, or more D-glucose units joined through
1,4-alpha linkages in a way so as to form a ring—a chain bracelet each link of which is a
pyranose hexagon. These rings are doughnut-shaped, somewhat like crown ethers but with a
number of important differences. The smallest of them, α-cyclodextrin, has a diameter about
twice that of 18-crown-6, and its hole (4.5 Å across) is also about twice as broad. The molecule
may be viewed as a pail without a bottom (Scheme 1.20f). The faces of a cyclodextrin are
termed as primary and secondary faces, the primary face is the narrow end of the ‘‘pail like’’
structure and comprises the CH2OH groups. The interior of the cavity of this arrangement is
non-polar and can bind different guests. Hydrogen bonds or charge stabilization from a large
number of OH groups are likely factors which contribute to the binding strength of the guest
and may alter the selectivity. The following points may be noted:
HOH2C O
O O
OH OH
OH OH OH OH OH
HO OH
HOH2C O
HO OH OH
HO CH2OH HO OH HO
O HO
O O O
OH
HO O
O
HOCH2 CH2OH
OH O
HOH2C OH
O CH2OH
HO OH
HO
O O
O CH2OH
a-cyclodextrin (top view)
SCHEME 1.20f
• Just like a crown ether a cyclodextrin behaves as a host to a variety of guest molecules
and it was with cyclodextrins, the host-guest relationship was initially recognized.
• A cyclodextrin has a polar hydrophobic outside and a relatively non-polar
lipophilic inside.
• The lipophilic interior of a cyclodextrin holds a guest but not an ion and the guest can
be a non-polar organic molecule or the non-polar part of an organic molecule.
• The hydrophilic exterior confers water solubility on the resulting complex. How well
a guest molecule is accommodated depends upon its size and polarity, and the size of
the particular cyclodextrin.
• A cyclodextrin is thus capable of hiding a part of the guest molecule in the cavity and
expose other parts for reactivity.
• For all practical purposes a cyclodextrin can be drawn as in (Scheme 1.20g).
13.70 Å 15.30 Å 16.90 Å

5.70 Å 7.80 Å 9.50 Å
7.80 Å
a-cyclodextrin (a-CD) b-cyclodextrin (b-CD) g-cyclodextrin (g-CD)

six-glucose units seven-glucose units eight-glucose units
SCHEME 1.20g
p-Nitrophenol esters undergo hydrolysis at strikingly increased rates in the presence of

β-CD.
CH3
H3C O
O NO2— O CH3
– –
OH O O O O
NO2
NO2
(I) (II) (III)
–
H 3C H 3C O
– O –
O O O
O O
– NO2
OH
NO2
+ (A)
CH3
–
O
O
SCHEME 1.20h
When one of the OH groups of cyclodextrin is deprotonated it yields a nucleophilic

functional group (II, Scheme 1.20h). This nucleophile is in close proximity to the hydrophobic
cavity which binds a substrate. Thus the situation is similar to a substrate in the active site of
the enzyme undergoing catalytic activity by the suitably placed amino acid residues. The
mechanism of hydrolysis of p-nitrophenyl acetate is given (Scheme 1.20h) which follows the
usual mechanistic pathways and involves the formation of a tetrahedral intermediate
(A, Scheme 1.20h).
Selective aromatic substitution has been brought about by using CH3
–4
α-cyclodextrin. When e.g., anisole (10 M) in water is treated with O
HOCl (10–2 M) and an excess of α-cyclodextrin at room temperature,
96% chlorination was observed at the p-position of anisole ring. The
hydroxyl group of α-cyclodextrin converted into hypochlorite brings
about the chlorination of the exposed para position, while the other
positions are protected by the cavity of cyclodextrin where the anisole
molecule fits (Scheme 1.20i). This is an example of noncovalent
O
catalyst, when the host provides the cavity for the reaction to take Cl
place without the involvement of a covalent intermediate.
SCHEME 1.20i
C. Inclusion Compounds
Inclusion complexes are formed when the host compound is capable to form a crystal lattice in
which there are spaces (of the shape of long tunnels or channels) which are of suitable size for
the second compound (the guest) to fit. There is no bonding between the compounds acting as
the host and guest but for the van der Waals forces. For the successful formation of an inclusion
compound, the guest molecule must fit into the space properly. In case the guest molecule is
either too large or too small, will not go into the lattice and the addition compound will not form.
Urea is an important host molecule for inclusion compound formation. Although ordinary
crystalline urea is tetragonal, however when a suitable guest molecule is present it crystallizes
in a hexagonal lattice with the guest trapped in long channels. The diameter of the channel is
about 5 Å, and the shape and size of the molecule determines if or not it can be a guest (no
chemical or any electronic effects are involved), e.g., octane and 1-bromooctane form complexes
with urea while 2-bromooctane, 2-methylheptane and 2-methyloctane are not suitable guests.
The size and shape of the guest thus determines its entrance in the channels where it has to
remain firmly in position.
Oleic acid (Scheme 1.21) gives erythro 9, 10-dihydroxy steric acid (m.p. 132°) on syn
hydroxylation. The threo isomer has (m.p. 95°). The configurational assignment to these diols
was made on the basis of formation of a urea inclusion complex. The low melting threo isomer
forms a urea complex, while the erythro isomer does not. When one writes the staggered
conformation of the two isomers it is the erythro diol in which the hydroxyl groups are on
opposite side of the chain. The presence of these protruding groups prevents entrance of the
erythro diol into the urea channel.
CH3(CH2)7CH CH(CH2)7COOH
Oleic acid
(cis isomer)
OH
CO2H
OH
SCHEME 1.21
D. Clathrate Compounds
Inclusion compounds have spaces in the form of long tunnels or channels,
whereas in clathrates (cage compounds) the spaces are completely OH
enclosed. In sharp contrast to the inclusion compounds, the crystal lattices
in clathrates can exist partially empty. Three molecules of hydroquinone
(Scheme 1.22) e.g., when held together by hydrogen bonding result in a
cage structure where the guest molecule has to fit in. The guests in this OH
case are methanol (not ethanol), SO2, CO2 and argon (not neon). Water is
another host. Normally six molecules of water form a cage where guests SCHEME 1.22
e.g., chlorine and methyl iodide can fit. These clathrates are solids at low
temperatures, and decompose at room temperature.
E. Catenanes and Rotaxanes

A catenane (I, Scheme 1.23, n ≥ 18) is a compound consisting of two interlocking rings, arranged
like two links of a chain. Its unusual feature being the absence of any covalent bonds holding
the two rings together.
(CH2)n (CH2)n
(I) (II)
SCHEME 1.23
In a rotaxane (II, Scheme 1.23) a linear portion is threaded through a ring, and cannot
get out due to bulky end groups.
1.6 BOND DISSOCIATION ENERGY

When atoms combine to form molecules, energy is released as covalent bonds are formed e.g.,
hydrogen atoms combine to form hydrogen molecules, this reaction is exothermic and evolves
104 kcal of heat for every mole of hydrogen formed. For covalent bond cleavage energy must be
supplied. Reactions in which only bond breaking occurs are always endothermic. The energy
required to break the covalent bonds of hydrogen homolytically exactly equals, the energy
evolved when the separate atoms combine to form molecules. The energies required to break
covalent bonds homolytically are called homolytic bond dissociation energies which are generally
designated by the symbol DH°. These energies (Table 1.2) vary widely, from weak (I—I
36 kcal/mol) to very strong bonds (H—F 136 kcal/mol).
Bonds made by overlapping orbitals which are closely matched both in energy and size
are stronger than those not meeting these criteria. Consider the strength of bonds between
hydrogen and halogens which decrease in the order F > Cl > Br > I, since the p orbital of the
halogen which contributes to bonding becomes more larger and more diffuse with each element,
the degree of overlap with the relatively smaller 1s orbital on hydrogen diminishes along the
series (Table 1.2).
Table 1.2: Single-bond homolytic dissociation energies DH° kcal/mol at 25°C
A : B → A· + B· DH° = Homolytic bond dissociation energy or D(A B)
HH 104 CH3H 104

DD 106 C2H5H 98
FF 38 CH3CH2CH2H 98
ClCl 58 (CH3)2CHCH2H 98
BrBr 46 (CH3)2CHH 95
II 36 (CH3)3CH 93
HF 136 CH3CH3 90
HCl 103 C2H5CH3 86
HBr 87.5
HI 71
The C—H bond in an alkane has a strength

of about 98 kcal/mol, while a C—C bond is
relatively weaker as seen for the central bond in
ethane, DH° = 90 kcal/mol (Table 1.1). In H2C . . CH
2
Cyclopropane
cyclopropane e.g., the strain introduced by the bond dissociation energy of
reduction of the ideal tetrahedral angle of 109.5° a carbon-carbon bond
in cyclopropane is
to 60° is shown by unusual reactivity of the C—C only 65 kcal/mol
bonds (hydrogenation to propane, bromination to
give 1, 3 dibromopropane) and bond dissociation SCHEME 1.24
energy (Scheme 1.24) which is only 65 kcal/mol
as compared to 90 kcal/mol for ethane.
In alkanes e.g., the DH° depends on the CH3 DH°
–1
character of the radical products. The DH° for . kcal mol
CH3CHCH2 + H .
dissociation of a terminal C—H of an alkane is 98
CH3
always around 98 kcal/mol. The product of such
cleavage being a primary alkyl radical. On the CH3CHCH3
other hand a C—H bond at a branch point is CH3
the weakest type of C—H bond (DH° 93 kcal/ . 93
mol). This fission gives a tertiary free radical. CH3CCH
. 3 + H
The relative stability of alkyl radical is:

SCHEME 1.25
tertiary > secondary > primary > methyl.
Bond dissociation energies reflect on the stability of alkyl free radicals. If one studies
the fission of two types of C—H bonds in 2-methylpropane (Scheme 1.25), one of the products
•
(H ) is the same in each case. The difference in ∆H° (∆H° is the enthalpy of a bond dissociation
reaction) of these reations provides a direct measure of the difference in stability of two alkyl
radicals. Thus, t-butyl radical is more stable than the isobutyl radical by 5 kcal/mol.
The bond dissociation energy of an allylic and a benzylic C—H bond is indeed low (around
85 kcal/mol) and this information is helpful in the study of the mechanism of free radical
allylic substitution (problem 2.3, Scheme 2.19).
Heterolytic bond dissociation energies (AB → A+ + B:–) are also known (H—H, 401
kcal/mol; H—F, 370 kcal/mol). On heterolysis of a neutral molecule a positive and a negative
ions are formed. Separation of oppositely charged particles needs energy (~ 100 kcal/mol). In
gas phase therefore, bond dissociation normally occurs via an easier route i.e., homolysis. In
an ionizing solvent, heterolysis is the preferred pathway for fission.
1.7 THE HAMMETT EQUATIONLINEAR FREE ENERGY RELATIONSHIP

For the study of reaction mechanism, one has to collect several evidences which point to the
mechanism of a reaction. An important concept is that a given structural feature will effect
related reactions in generally the same way. Thus if replacement of a hydrogen by chlorine
makes acetic acid to become a stronger acid, then introduction of a chlorine at the α-position of
propanoic acid will also result in an increase in its acidity. A linear free energy relationship is
simply a quantitation of this concept. The first and most important linear free energy
relationship is the Hammett σρ equation which is based on the acidities of aromatic carboxylic
acids.
Acidities of benzoic and phenylacetic acids were measured by changing the substituent
group on the aromatic ring. In these experiments the positions of acid-base equilibria were
measured as functions of the substituent groups. In case the different acidity values for each
series of compounds are only due to the influence of the substituents, then a relation between
the sets of data should exist. When the pKa values obtained from the two series of compounds
were plotted against each other, a linear relation (expressed by the mathematical equation,
I, Scheme 1.26) was obtained.
the s values
1.0 0.5 0 –0.5
the pKa values for phenylacetic
and benzoic acids 4.5
YC6H4CH2COOH
p-Me
H
pKPA r(pKB) + C (I) p-OMe
p-Br
p-F
m-I
m-Cl p-I
r (rho) = a proportionality constant— p-Cl
is the slope of the line 4.0
m-NO2 slope (r) = 0.46
or
pKa
log KPA = r log KB + C¢ p-NO2
C or C¢ = the intercept of
2 3 4 5
the straight line
pKa YC6H4COOH
SCHEME 1.26
The acidity values of unsubstituted carboxylic acids (pK0—substituent = H) are taken

as standards with which the effect of a substituent is compared and the equation
(II, Scheme 1.27) is for this standard. An expression (III, Scheme 1.27) is obtained on subtracting
one equation from the other, and this expression relates the substituent effects on the two
series of compounds (the K and K0 represent the equilibrium constants for substituted and
unsubstituted compounds.
log K0PA = r log K0B + C¢ (II)
KPA K
log = r log B (III)
K0PA K0B
SCHEME 1.27
sigma the substituent constant KB

s = log (IV)
K0B
SCHEME 1.28
KPA
log = sr (V)
K0PA
Hammett equation
SCHEME 1.29
The acidities of different benzoic acids in aqueous media (25°C) are the standard measure
of the effect of each substituent group and the substituent constant sigma (σ) for every
substituent group is defined in the expression (IV, Scheme 1.28). The Hammett equation—the
linear relation is thus expressed as in equation (V, Scheme 1.29). Sigma (σ), the substituent
constant is a measure of the effect of a substituent on the acidity of benzoic acid. Those
substituents which enhance the acidity relative to unsubstituted benzoic acid will show positive
values (σ > 0), the hydrogen atom having a sigma value of zero. The Hammett equation can
thus be used:
1. To account for the influence of substituents on molecular reactivity.
2. It explains the influence of polar meta- or para-substituents on the side chain reactions
of benzene derivatives. Table 1.3 summarizes σ values for different meta and para
substituents. The σ constant is generally independent of the nature of the reaction
and is a quantitative measure of the polar effects in a given reaction by a m- or
p-substituent relative to hydrogen. A negative σ value signifies an electron donating
group whereas a positive value of σ signifies an electron attracting group. The larger
the magnitude of σ, the greater is the effect of the substituent. The ρ constant (ρ is
the reaction constant) is dependent on the nature of the reaction and on conditions.
It is a measure of the sensitivity of a given reaction series to the polar effect of ring
substituents i.e., to the changes in the σ values of the substituent.
Table 1.3: Hammett substituent constant values of common groups
Substituent σm σr
NH2 0.16 0.66

CH3 0.07 0.17
OH 0.12 0.37
C6 H5 0.06 0.01
OCH3 0.12 0.27
SCH3 0.15 0.0
F 0.34 0.06
I 0.35 0.18
Cl 0.37 0.23
Br 0.39 0.23
CF3 0.43 0.54
CN 0.56 0.66
NO2 0.71 0.78
Scheme 1.26 is a Hammett plot with ρ = 0.46. The value of ρ indicates the
sensitivity of a reaction or an equilibrium to a particular substituents. A positive ρ-
value shows that the reaction or equilibrium is aided by electron attracting
substituents (withdrawal of electrons from the reaction site). In the case of phenyl
acetic acids, for ionization, the ρ of + 0.46 points that a given electron attracting
substituent facilitates ionization but has only 0.46 of the effect that the same
substituent has in facilitating ionization of benzoic acid.
3. Reactions that are assisted by high electron density at the reaction site have negative
ρ values.
4. The Hammett equation is however, not applicable to the influence of ortho
substituents, since these exert steric effects.
When one considers the rates of hydrolysis of substituted benzoates with hydroxide ion
(in aqueous acetone), one observes a straight line on plotting against the Hammett σ-constants
with a slope (ρ) of 2.23. These data show that the substituent groups which facilitate ionization
of benzoic acid, facilitate the hydrolysis of benzoate as well. For ester hydrolysis the transition
state (Scheme 1.30, the reaction involves nucleophilic attack by the hydroxide ion on the carbon
atom of the carbonyl group), has considerable negative charge, since positive ρ indicates
stabilisation by electron attracting group. Indeed, in keeping with this observation the
mechanism of ester hydrolysis which proceeds through an anionic tetrahedral intermediate
gets support. Moreover, this hydrolysis will be further facilitated when electron withdrawing
group (σ is positive, Table 1.3) is attached to the aromatic ring. With an electron releasing
group (σ is negative) the reaction will be retarted.
–
O O
– –
Ar—COCH3 + OH Ar—C—OH ArCO2 + CH3OH
OCH3
SCHEME 1.30
Hydration of styrenes (HClO4, 25°C) shows a –ρ value, to show that the transition state
of the reaction is like a carbocation intermediate.
1.8 TAFT EQUATION

Taft equation is yet another linear free energy relationship which represents a structure-
reactivity equation and correlates only field effects (inductive effects). The Hammett equation
fails with aliphatic compounds (and o-substituted benzene derivatives) due to the different
conformations the chains can adopt and because substituents may interact sterically with the
reaction center.
A large number of aliphatic reaction rates can be correlated by this equation. Taft assumed
that the hydrolysis of the esters (RCOOR′) will be subject to the same steric and resonance
effects whether the hydrolysis is catalysed by acids or bases. Rate difference would thus be
caused only by the field effects of R and R′ in RCOOR′. The transition state for acid-catalyzed
hydrolysis (I, Scheme 1.31) has a greater positive charge (destabilized by –I and stabilized by
+I substituents) than the starting ester, while the transition state for base-catalyzed hydrolysis
(II, Scheme 1.31) has a greater negative charge than the starting ester. Field effects (inductive
effects) of substituents X can thus be determined by measuring the rates of acid- and base-
catalyzed hydrolysis from a series XCH2COOR′ where R′ is kept same. From these rate constants
a new parameter σ* (the polar substituent constant) which is believed to represent the I effect
only, is introduced. This can be evaluated from the equation:
1
σ* = [log (k/k0)B – log (k/k0)A]
2.48
where k = rate constant for the hydrolysis of XCH2COOR
k0 = rate constant for the hydrolysis of the reference ester CH3COOR′. The subscripts B
and A denote the base and acid catalysed hydrolysis at the same temperature. The factor 2.48
is an arbitrary constant, which is introduced to bring σ* values on the same approximate scale
as the Hammett σ values.
d+ d–
OH2 OH
R—C—OR¢ R—C—OR¢
HO O
d+ d–
(I) (II)
SCHEME 1.31
The data of the reaction can be correlated by the Taft equation:

k
log = ρ* σ*
k0
when ρ* is the reaction constant.

1.9 STERIC EFFECTS, STRAIN AND BREDT RULE

Strain causes a permanent deformation in the structure of a molecule and this raises its energy
when compared to a structure which is not deformed. Steric strain is brought about in a molecule
when two or more non-bonded atoms approach close to a position where their electron clouds
start to repel each other. Example is of boat deformation of cyclohexane.
Steric effects in a molecule arise due to the presence of bulky groups near the reaction
site. A decrease in the reaction rate due to this steric hindrance is a result of entirely a physical
blockage to the attack of the reagent. However, in some cases the reaction may be much faster
than expected on the basis of electrical effects alone. Lastly a reaction may take a different
course due to steric effects.
When one considers nitration of toluene (HNO3 + Ac2O) at 0°C, o-, m- and p-nitrotoluene
is formed in the ratios (expressed as percentages 61.5 : 1.5 : 37 (Scheme 1.32). The total reactivity
of toluene in comparison with benzene is 27, and combination of this result with the isomer
distribution of the nitrotoluenes gives the following data for the relative reactivities of each
nuclear position in toluene compared with one position in benzene: o, 50; m, 1.3; p, 60. (This
measure of the reactivity of a particular nuclear carbon in a given reaction is referred to as the
partial rate factor). These data show the directive and activating effect of a substituent, CH3,
of +I type. Other alkyl-benzenes also give predominantly the ortho and para derivatives, as
shown by the partial rate factors for the nitration in acetic anhydride (Scheme 1.33). A significant
point is a sharp fall in the ortho; para ratio as the size of the alkyl group is increased and is a
consequence of steric hindrance to ortho-substitution.
Substitution at carbonyl groups is very sensitive to steric hindrance. Thus tertiary acids
such as (CH3)3 C—CO2H, unlike primary and secondary acids, cannot be esterified by an alcohol
in the presence of acid, nor can their esters be hydrolyzed by treatment with hydroxide ion or
aqueous acid.
CH3 CH2Me CHMe2 CMe3
50 31 15 4.5
1.3 2.3 2.4 3.0

60 70 72 75
the ortho:para ratio falls off sharply
SCHEME 1.32
Alcohols are synthesized by reacting aldehydes and ketones with Grignards reagents.
In the case of sterically congested cases when either the ketone or the Grignard reagent have
bulky groups then enolization or reduction may be dominating reactions and the normal addition
reaction is retarded the following points may be noted:
• Methyl magnesium bromide reacts with diisopropyl ketone to afford the corresponding
tertiary alcohol in high yield (Scheme 1.33), however, with the bulkier reagents e.g.,
isopropyl and t-butyl Grignards reagents the same ketone fails to react.
MeMgBr
HO Me
A Grignard reagent e.g., CH3Mgl
does not react with ketones with
very bulky groups, however, an
O Me2CHMgBr organolithium undergoes a
Diisopropyl ketone successful reaction.
(with less bulky groups)
Me2CHLi
HO
SCHEME 1.33
• Organolithium compounds, however, undergo a successful reaction and enolization

and reduction are not observed.
• During enolization in a reaction between methylmagnesium bromide and a sterically
hindered ketone which has an α-hydrogen (activated proton) the Grignard reagent
acts as a base and not as a nucleophile. The Grignard reagent abstracts an α-proton
from the ketone to yield an enolate which on reaction with acid gives the starting
ketone (Scheme 1.33a).
R² R¢ R²
R¢ H CH3 –CH4 R¢ R² H
+ R¢ R² tautomerization
a H
MgBr
R O R OMgBr R OH R O
a hindered ketone
SCHEME 1.33a
• When the Grignards reagent is hindered and has a β-hydrogen, the carbonyl compound
is reduced by hydride ion transfer. The reduction occurs with the Grignard reagent
coordinated with the carbonyl compound and involves a six-membered cyclic transition
state (Scheme 1.34).
A hindered Gringard reagent
R¢
R H R¢ H
R² R² R
C MgX R OH
R O
SCHEME 1.34
• Normally predominant 1, 2-addition of a Grignard reagent to a relatively unhindered

aldehyde carbon is observed. With increased steric hindrance at the carbonyl carbon
an α, β-unsaturated ketone gives both products of 1, 2- as well as 1, 4-addition (see,
Scheme 2.14b).
When an intermediate carbocation is formed in a reaction, elimination of a proton
competes with the addition of a nucleophile. Elimination is favoured when the addition is
sterically hindered (Scheme 1.35).
Ph3C Ph3C + Ph3C Ph3C

Br2 + –H
C CH2 C—CH2Br C—CH2Br + C CHBr
CH3 CH3 CH2 CH3
SCHEME 1.35
In the case of a tertiary alkyl halide (I, Scheme 1.36), when one or more alkyl groups are
bulky (e.g., R = t-butyl) these will be pushed together to generate steric hindrance among
themselves and therefore, strain (B strain, for back strain). This is due to the fact that the
central carbon being sp3-hybridized, has angles of 109.5°. The rate of ionization in such molecules
with B strain and consequently the solvolysis rate (SN1 mechanism) is often accelerated. Thus
in such compounds on solvolysis the central carbon is converted into a carbocation, the
hybridization becomes sp2 (angle 120°) and therefore, the strain is relieved.
R
R
R—C—Cl R—C +
R
B strain, three alkyl R
groups are bulky (I)
Eclipsing strain (I) strain
CH3 CH3
Cl Cl
t-BuCl
1-chloro-1-methylcyclopentane
Relative solvolysis rates 1.0 43.7 0.35
SCHEME 1.36
Several cyclic compounds may suffer from internal strain (I strain), a strain which arises
from changes in ring strain which results from conversion of a tetrahedral to a trigonal carbon
or vice versa. The SN1 solvolysis of 1-chloro-1-methylcyclopentane (25°C, 80% EtOH) occurs
about 44 times faster compared to the reference compound t-butyl chloride (Scheme 1.36). On
solvolysis of 1-chloro-1-methyl-cyclopentane the eclipsing strain in the molecule is relieved.
This enhancement in the rate of solvolysis is not observed in the corresponding cyclohexyl
derivative, since it is not subject to eclipsing strain.
Small rings e.g., three and four membered have internal bond angles which are smaller
than the preferred tetrahedral angle of 109.5°. Cyclopropane (Scheme 1.36 a) e.g., reflects this
strain by high reactivity of its C—C bonds.
C—C—C bond 60° 90°

angles
SCHEME 1.36a
The boat conformation of cyclohexane suffers from torsional strain from eclipsed bonds
on the side of the molecule and van der Waals strain involving the flagpole hydrogens. This
makes boat form less stable than the chair conformation (Scheme 1.36b). In a chair conformer
a substituent in the axial position makes it less stable than when it is in equatorial position.
The methyl group is in

an axial position
H The methyl group is

H H in an equatorial
Flagpole hydrogens
position
H C
H 1 H 6
H H 5 4 5
6 H ring flip H
H
3 H 2 C H
H H 4 2 3 1
H H
H H H
van der Waals strain Smaller van der Waals
H H
between hydrogen of axial strain between hydrogen
CH3 and axial hydrogens at C-1 and axial hydrogens
Torsional strain at C-3 and C-5 at C-3 and C-5
boat conformer of less stable more stable
cyclohexane chair conformer chair conformer
SCHEME 1.36b
Unlike (I, Scheme 1.37), II does not exist, this being a carbon-carbon bridgehead alkene
(Bredt rule). Similarly, C—N bridgehead alkenes cannot exist. The system in II cannot exist
due to excessive steric strain. This bridgehead carbon cannot flatten out since the rigid cage
prevents this. As the bridge gets longer as in (III, Scheme 1.37), flexibility return to the system
and such bridgehead alkenes (Anti Bredt alkenes) are capable to exist.
bridgehead C
(I) (II) (III)

Bicyclo[2.2.1]hept-2-ene Bicyclo[2.2.1]hept-1-ene Bicyclo[5.2.1]dec-1-ene
SCHEME 1.37
β-Keto acids undergo decarboxylation very easily, via the enol form of the ketone (see,
Scheme 6.52). The bridgehead β-Keto acids are, however, resistant to decarboxylation, since
the product would be a highly strained bridgehead olefin (see, Scheme 6.53).
PROBLEMS
1.1 Why alkanes have very small dipole moments?
1.2 Why cyclic 1, 2-diketones exist mainly in the enolic form?
1.3 What is the usual upper limit of dipole moment of organic molecules?
1.4 The reaction of substituted dimethylanilines with methyl iodide (in aqueous acetone)
gives the trimethylanilinium iodide with ρ = – 3.30. Explain the result.
1.5 What is the sign of ρ expected for the following reaction?
– d– d–
– OH –
ArO + EtI [ArO Et I] ArOEt + I
EtOH
(SN2) reaction
1.6 Predict the sign of ρ expected for the following reactions:

(i) ionization of benzoic acids (water), 25°C.
(ii) ionization of benzoic acids (40% aq. EtOH) 25°C.
(iii) ionization of phenols (water) 25°C.
ANSWERS TO THE PROBLEMS

1.1 Due to the small difference in electronegativities of carbon and hydrogen.
1.2 The main driving force for enolization is relief of the electrostatic repulsion that occurs
when the two electrophilic carbonyl groups are adjacent to each other.
O O
d–
O O OH O
:
:
H
d–
::
O O
Dipole-dipole Minor Major Repulsions relieved;
repulsions stabilized by hydrogen
bonding
1.3 7D
1.4 The reaction proceeds through the usual SN2 transition state. The electron donating
substituents help in stabilizing the developing positive charge close to the ring and lead
to a negative ρ value.
CH3
+ – +
Ar—N(CH3)2 + CH3I Ar—N CH3 I Ar—N(CH3)3
–
I
CH3
SN2 Transition state
1.5 A negative ρ value. (actual value, ρ – 0.99). Thus electron-releasing groups will increase
the rate and electron withdrawing group will decrease the rate. In this reaction ArO– is
the nucleophile, the more the charge on the oxygen atom, the faster will be the reaction.
Thus electron release will increase the charge on the oxygen atom, whereas electron
withdrawing group will decrease the charge on oxygen atom.
1.6 All are expected to show positive ρ.
CHAPTER 2 H
Delocalized Chemical Bonding H
The bonding in some compounds can be adequately described by a single Lewis structure
(a problem with Lewis structure is that these impose an artificial location on the electrons).
However, in several other compounds a Lewis structure does not represent a correct
representation for a molecule or an ion. These compounds contain one or more bonding orbitals
which are not restricted to two atoms, but which are spread out over three or more. This type
of bonding is said to be delocalized. Consider a conjugated molecule 1, 3-butadiene, e.g.,
2.1 1, 3-BUTADIENE A TYPICAL CONJUGATED SYSTEM

The heat of hydrogenation of a terminal alkene is about –30 kcal/mol as in the case of 1-butene.
A compound with two non-interacting (i.e., separated by one or more saturated carbon atoms)
terminal double bonds should be about twice this value (– 60 kcal/mol). This is found to be so in
the case of 1, 4-pentadiene CH2 CH—CH2—CH CH2 (∆H° = –60.5 kcal/mol). However, on
hydrogenation a conjugated diene e.g., 1, 3-butadiene generates less energy. The difference,
about 3.6 kcal/mol, is a result of stabilizing interaction between the two double bonds and is
called resonance energy of 1, 3-butadiene, (Scheme 2.1).
H2, Pt
H 2C CH—CH CH2 CH3—CH2—CH2—CH3 DH° = – 56.6 kcal
1, 3-butadiene
H2, Pt
H2C CH—CH2 CH3 CH3—CH2—CH2—CH3 DH° = – 30.1 kcal
1-butene × 2 = – 60.2 kcal
Resonance energy of 1, 3-butadiene = 60.2 kcal – 56.6 kcal = 3.6 kcal
SCHEME 2.1
The stability of a conjugated diene depends on two factors. Firstly it is the hybridization
of the orbitals forming the single bonds. The single bond in 1, 3-butadiene is formed due to
overlap of an sp2 orbital with another sp2 orbital, while the single bonds in 1, 4-pentadiene
result from the overlap of an sp3 orbital with an sp2 orbital (Scheme 2.1a). As on average a 2s
electron is closer to the nucleus than a 2p electron, the electrons in an sp2 orbital (with 33.3%
s character) are closer to the nucleus than the electrons in an sp3 orbital (with 25% s character).
The length of a bond depends on the closeness of the electrons in the bonding orbital to the
nucleus. Thus, the more the s character in the orbitals forming the σ bond, the shorter is the
39
bond. This means that a σ bond formed by an sp2-sp2 overlap is shorter than a σ bond formed
by an sp3-sp2 overlap. Shorter bonds are more stable, therefore, the molecule is more stable.
A change in hybridization also affects the length of a carbon-hydrogen bond but not as much it
affects the length of a carbon-carbon bond.
Single bond formed by Single bond formed by

2 2 3 2
sp -sp overlap sp -sp overlap
CH2 CH—CH CH2 CH2 CH—CH2—CH CH2

1, 3-butadiene 1, 4-pentadiene
SCHEME 2.1a
Secondly a conjugated diene is more stable than an isolated diene due to resonance
which means that the compound had delocalized electrons. The π electrons in a conjugated
double bond are not localized between two carbons, but instead over four carbons. As a
consequence of resonance the single bond in 1, 3-butadiene is not a pure single bond and has a
partial double bond character. This feature contributes to the fact that an sp2-sp2 bond is
shorter and more stable than an sp2-sp3 bond (Scheme 2.1b).
+ –
:
+
:
–
Best resonance form (II) (III)
(I)
The resonance forms of 1, 3-butadiene
SCHEME 2.1b
The planar conformation of butadiene with the aligned p orbitals of the two double
bonds allows overlap between the pi bonds. Precisely the electrons in the two double bonds are
delocalized over the entire molecule to create some pi overlap and pi bonding in the C2—C3
bond. The length of this bond is intermediate between the normal length of a single bond and
that of a double bond. (Scheme 2.1c) Lewis structures are not adequate to depict delocalized
molecules like 1, 3-butadiene. To represent the bonding in conjugated systems such as
1, 3-butadiene accurately, one must consider molecular orbitals that represent the
entire conjugated pi system and not just one bond at a time. Apart from adding stability to
Double bond character

2
3 3
sp2-sp s bond 1.47 Å
sp -sp s bond 1.53 Å H
H H CH C
H H
C CH
H C2 C4 H
C1 C3 H
1.32 Å
H H An orbital view of 1, 3-butadiene, showing
Central carbon-carbon bond length in the favourable pi bonding interaction
1, 3-butadiene is in between that between C2 and C3
for an alkane and an alkene
SCHEME 2.1c
Delocalized Chemical Bonding 41
1, 3-butadiene this π interactions raises the barrier to rotation about the single bond. Thus, of
the two extreme coplanar conformations (Scheme 2.2), the s-cis form is about 3 kcal/mol less
stable than the s-trans conformation.
H Mild interference
H
rotation rotation H
H H
H
H H
H H
(‘‘single’’-trans) (‘‘single’’-cis)
s-trans s-cis H H
s-trans (‘‘single’’-trans) and s-cis (‘‘single’’-cis)
Interconversion of s-trans and s-cis conformations of 1, 3-butadiene
SCHEME 2.2
2.2 RESONANCE
(A) What is Resonance?
Two or more structures of the same molecule or an ion with same geometry, with the same
number of paired electrons, but differing in the pairing arrangement of these electrons are
termed resonance structures. These structures are conventionally shown as related to each
other by a single double-headed arrow (↔) to emphasize that these structures have no physical
reality or independent existence and do not represent different substances in equilibrium.
Consider e.g., the carbonate ion (CO32–, Scheme 2.3), it has no unique Lewis structure, but one
can draw three different but equivalent structures (I–III, Scheme 2.3). These three structures
are resonance structures which have the characteristic property of being interconvertible by
electron pair movement only and the nuclear positions in the molecule (or an ion) remain
unchanged.
d–
: –: : –: : O
:
O O O
C Carbonate ion
C C C d– d–
– – – – O O
:
::
O
::
O O O O O
:
:
:
:
Resonance hybrid
(I) (II) (III)
SCHEME 2.3
X-ray studies indicate that carbon-oxygen double bonds are shorter than single bonds
and the carbonate ion shows that all of its carbon-oxygen bonds are of equal length. One is not
shorter than the others as expected from either of the representations (I–III). Carbonate is
perfectly symmetrical with a trigonal central carbon atom with all C—O bonds of equal length
(between that of a double and a single bond). The negative charge is evenly distributed over all
three oxygens i.e., it is delocalized. Thus none of the Lewis structures written for this molecule
is structurally correct. One arrives at a correct description if one creates conceptually an average
structure out of all three (a resonance hybrid). Carbonate is thus a resonance hybrid of the
three resonance structure I, II and III. Since all three structures are equivalent, they contribute
equally to the true structure of the molecule, but none of them accurately represents it.
Resonance structures are thus not structures for an actual molecule or ion; these exist only in
theory and thus can never be isolated. No single contributor adequately represents the molecule
or ion. In resonance theory one views the carbonate ion, a real entity, as having a structure
(Scheme 2.3) that is a hybrid of these three hypothetical resonance structures.
One may, therefore, mentally fashion a hybrid of all the resonance structures or may
depict it on the paper (Scheme 2.3) as a non-Lewis structure which attempts to depict the
hybrid. Thus e.g., for carbonate ion the bonds are shown by a combination of a solid-dashed
lines. This is to show that the bonds are something in between a single bond and a double
bond. One also places a δ– (partial minus) beside each oxygen to show that something less than
a full negative charge is present on each oxygen atom.
(B) Resonance Structures of BenzeneDewar Structures

Several possible resonance structures can be drawn for the molecule of benzene (Scheme 2.4).
In fact the real structure is the resonance hybrid. Of these resonance structure. (I and II,
Scheme 2.4) are called Kekulè structures i.e., the structures of cyclic conjugated systems
represented by conventional alternating single and double bonds. The rest of the resonance
structures (III–V) of benzene (or other aromatics) with a single ‘‘long’’ bond between opposite
atoms are called Dewar structures. The following points come to light when the wave equation
is solved:
1. The energy value obtained by considering that (I and II) participate equally is lower
than that for I or II individually.
2. On considering the Dewar structures, the value gets still lower.
3. Each of the Kekulé structures (I and II) contributes 39% to the actual molecule,
while others contribute 7.3% each.
(I) (II) (III) (IV) (V)
Kekulé structures Dewar structures

(F. A. Kekulé, 1829–1896) (J. Dewar, 1842–1923)
SCHEME 2.4
(C) Canonical FormsClaus Benzene

In the valence bond method, various possible Lewis structures called canonical forms are drawn
and the molecule is taken to be a weighted average of them i.e., the resonance hybrid. Canonical
form is the term which is almost, but not quite synonymous with resonance structures. The
mathematical requirements (e.g., orthogonality) for a canonical set of structures of a cyclic
compound preclude structures with bonds that intersect. The rules for drawing proper resonance
forms when applied to the π system of benzene permit not only the three Dewar structures, but
also the unfamiliar crossed structure known as Claus benzene (Scheme 2.5). However, such a
structure is not part of a canonical set.
Various investigators proposed many incorrect structures for benzene such as Dewar
benzene, Claus benzene, Ledenburg prismane, and benzvalene (Scheme 2.5), Dewar benzene,
prismane, and benzvalene (but not Claus benzene) have been synthesized. These compounds
are unstable and isomerize to benzene via exothermic transformations.
Dewar benzene Claus benzene Ladenburg prismane Benzvalene
SCHEME 2.5
(D) Writing One Best StructureRepresentation of Resonance Hybrid Structure

Benzene is the classic example used to illustrate resonance structures. Benzene is best described
by two equivalent cyclohexatrienic resonance structures (I and II, Scheme 2.4). Similarly the
three structures of carbonate are equivalent, i.e., indistinguishable. The importance of resonance
structures becomes apparent in explaining that each C—C bond in benzene is intermediate
–
between a single and double bond, as is each C—O bond in CO 23 .
The problem of writing one best structure to position the pπ electrons in compounds or
ions or radicals which may be represented by two or more equivalent structures is frequently
solved by using broken lines connecting the atoms over which the pπ electrons are delocalized.
–
Thus for benzene the single structure, (Scheme 2.6) and for CO 23 the single structure, (Scheme
2.3) are representations showing π electron distribution. In the case of a cyclic sextet of
delocalized π electrons a solid circle inside the ring, as shown for benzene (Scheme 2.6) is used.
Originally the circle notation referred to a sextet of electrons but now it has been extended to
indicate any monocyclic aromatic system with (4n + 2) π electrons as well as to show the
electrons in the rings of polycyclic aromatic compounds.
or
Resonance structures for benzene Representation of hybrid
SCHEME 2.6
(E) Nonequivalent Resonance Structures

The resonance structures for the carbonate and the Kekulé structures of benzene are equivalent.
However, many molecules can be described by a set of Lewis structures that are not equivalent;
three of the resonance structures of butadiene (Scheme 2.1b) indicate this. The first structure
(I) is a lower energy structure than the other two (II and III) which are charge-separated
equivalent species. The structure (I) is said to make a larger contribution to the ground state
structure than either of the charged structures. Thus the uncharged structure is the single
best representation of butadiene. The fact that, experimentally, butadiene shows some double
bond character between atoms 2 and 3 indicates that the charged structures (II and III) also
make a contribution to the ground state.
For the enolate ion (Scheme 2.7, this is an oxygen analog of the allyl ion), the two
resonance structures differ in the location of double bond and the charge. As in the case of
butadiene, here as well, one of the structure is closer to the real one than the other and neither
structure represents the actual molecule. One can use several guidelines to deal with such
situations. In the two examples discussed above, two of the many guidelines help to pick up a
preferred structure. According to the first, the more covalent bonds a structure has, the more
stable it is (forming a covalent bond lowers the energy of atoms). Thus structure (I, Scheme 2.1b)
for 1, 3-butadiene is by far the most stable and makes the largest contribution since it contains
one more bond. Moreover, since separating opposite charges requires energy, thus structures
in which opposite charges are separated have greater energy. For this reason as well, the
structure (I) of butadiene is the most stable.
Secondly, charges should be preferentially H H H
–
H
located on atoms with compatible
:
C C C C Enolate
electronegativity. For the enolate ion, structure – ion
::
:
H O H O
(I, Scheme 2.7) is preferred where the negative
:
(I)
charge is present on the more electronegative
oxygen atom. SCHEME 2.7
Resonance contributors can be obtained by moving π electrons towards a π bond, moving
π electrons towards a positive charge or moving a lone pair towards a π bond.
(F) Rules for Resonance-Contribution of a Resonance Structure to the Overall Hybrid

1. Resonance structures (canonical forms) exist only in one’s imagination
One useful way to depict the actual structure of a molecule, a radical or an ion containing
delocalized bonds is to draw several possible canonical forms. These structures are connected
by double-headed arrows, and one assumes that the real molecule, radical or ion is like a
hybrid of all of them. The resonance structures i.e., canonical forms have no existence except
on paper or in our imagination.
2. Only electron movement is allowed CH3 H CH3 H
The nuclei in each of the canonical structures C C C C
must be in the same relative positions. Thus, CH3 H H CH3
structure (II, Scheme 2.8) does not contribute 2-methylpropene trans-2-butene
to the structure of isobutylene (I) which is Isobutylene
(I) (II)
instead the isomeric compound, trans-2-butene.
SCHEME 2.8
3. All resonance
. structures .must have the same number of unpaired electrons
Thus, e.g., CH 2 —CH CH— CH 2 is not a valid canonical form for butadiene, but is one
representation of an electronically excited state of this molecule in which the complete pairing
of the ground state is lost due to spin inversion.
4. All the atoms taking part in resonance i.e., the atoms that are a part of delocalized
systems must lie in a plane or be nearly planar
Consequently resonance may be prevented or reduced in systems in which the involved atoms
are sterically forced out of planarity (steric inhibition of resonance). In picryl iodide the bond
lengths (1 and 2, Scheme 2.9) for the ortho and para-nitro groups are different. This shows
that the oxygens of the para-nitro group are in resonance with the benzene ring, these being in
the same plane. However, the oxygens of the ortho-nitro group are not, these being pushed out
of the plane by the bulky iodine atom. Steric inhibition of resonance, explains the effect of
ortho-substituents on the basic character of anilines (See, Scheme 3.35b).
I I
NO2 NO2 NO2 + NO2
1.45 Å
1.35 Å NO2 N
:
:
–O O–
:
:
Steric inhibition of resonance
SCHEME 2.9
In several molecules benzene ring is forced out of planarity (I and II, Scheme 2.10). In I,
a short bridge forces the benzene ring to become boat shaped. Although the compounds are
still aromatic (NMR) but the properties are different from those of ordinary compounds with
benzene rings.
CH2
CH2
CH2
CH2
CH2
(I) (II)
[5] Paracyclophane Corannulene
SCHEME 2.10
5. The energy of the actual molecule (resonance hybrid) is lower than the energy that
might be estimated from any contributing structure
Allylic radicals, and cations are unusually stable and in Lewis terms, this stabilization is
explained by electron delocalization (resonance stabilization, Scheme 2.11). This stability also
reflects on the effect of a neighbouring double bond on the reactivity of a carbon center. Thus,
even though the allyl cation is a primary carbocation it is more stable than a primary carbocation.
In contrast with saturated primary haloalkanes (CH 3—CH 2—CH 2Cl), 3-chloropropene
(CH 2 CH—CH 2Cl) dissociates fast under S N1 (solvolysis) conditions to undergo rapid
unimolecular substitution through a carbocation intermediate e.g., heating with CH3OH it
gives 3-methoxypropene (CH2 CH—CH2—OCH3, SN1 product) through the stable allyl cation
intermediate.
The primary C—H bond in propene is relatively weak (weaker than CH bond of ethane)
and it is even weaker than a tertiary C—H bond (see, Scheme 1.25) to show the special stability
associated with the allyl radical due to resonance.
The pKa of propene is about 40 and it is more acidic than propane (pKa = 50) to show that
allyl anion formed by deprotonation is a facile process.
In terms of molecular orbitals each of three carbons in allyl system is sp2 hybridized and
bears a p orbital perpendicular to the molecular plane. The three p orbitals overlap to give a
symmetric structure with delocalized electrons.
6. All resonance structures do not contribute equally to the hybrid
Resonance has significance when the canonical forms are of comparable energy. Thus the two
Kekulé structures for benzene (Scheme 2.4) which are equivalent canonical forms contribute
equally consequently stabilization energy is considerable. The Dewar structures (Scheme 2.4)
which are more energetic are less important, however, their inclusion as the canonical forms
results in still greater reduction in the total energy. The total stabilization energy being 150
kJ mol–1. Thus each resonance structure contributes in proportion to its stability.
H H H
The positive charge shared
H C H H C H C by C1 and C3
+
+C C C C+ or H2C CH2
H H H H
The allyl cation
H H H
2 2 CH2 CHCH2 H
H C H H C H C. –1
3 3 DH° = 87 kcal mol
.C
1
C
1
C C. or H2C CH2 CH3CH2 H
–1
DH° = 98 kcal mol
H H H H
The allyl radical
H H H
pKa of propene is about 40
H C H H C H C
– propane (pKa ~ 50)
– :C C C C: – or H2C CH2
H H H H
The allyl anion
Delocalization in the 2-propenyl (allyl) system
SCHEME 2.11
(G) The Stabilities of Resonance Structures

All canonical forms do not contribute equally to the resonance hybrid, while the others may
− +
not contribute at all. For ethylene the high energy form, CH2 — CH2 may be neglected when
compared to CH2 CH2. Some of the following rules tend to help in deciding the relative
stabilities of resonance (imaginary) structures. To find the most important resonance contributor
to a given molecule, consider the octet rule, make sure that there is a minimum of charge
separation, and place on the relatively more electronegative atoms as much negative and as
little positive charge as possible.
1. Structures with a maximum of octets are preferred
This is so in the case of e.g., nitrosyl cation NO+ (Scheme 2.12). Additionally, the major resonance
contributing structure has more covalent bonds than the minor contributor, cf. rule 2.
+ +
: :
Major resonance :N O: :N O Minor resonance Nitrosyl cation

contributor contributor
Structures with a maximum of octets are most important
SCHEME 2.12
2. The more covalent bonds a structure has, the more stable it is

From among the resonance structures of 1, 3-butadiene (Scheme 2.1b), the uncharged structure
is the single best representation of butadiene.
3. Charge separation decreases stability
Separating opposite charges requires energy, thus resonance structure in which opposite charges
are separated have lower stability. Of the three structures for 1, 3-butadiene, the two charge
separated structures (II and III, Scheme 2.1b) make a smaller contribution to the hybrid.
4. Charge separation may be enforced by the octet rule
In some situations, however, charge separation is acceptable to ensure octet Lewis structures
as in carbon monoxide (Scheme 2.13). When several charge-separated resonance structures
can be drawn the most favorable is the one in which the charge distribution is compatible with
the relative electronegativities of the component atoms. In diazomethane, nitrogen is more
electronegative than carbon (Scheme 2.13).
H H
+ – – +
– +:
:
:C :C C N N: C N N:
::
O O :
H H
Minor Major
Major Minor
Carbon monoxide Diazomethane
SCHEME 2.13
Thus in summary, the greater the predicted stability of a resonance structure, the more
it will contribute to the resonance hybrid.
(H) The Resonance EffectMesomeric Effect

The resonance effect (mesomeric effect) involves delocalization of electrons through resonance
via the π system. This effect involves decrease in electron density at one position with
corresponding increase elsewhere. The resonance effect depends upon the overlap of certain
orbitals. One may consider the operation of this effect in conjugated compounds with, π-bond-
π-bond conjugation and π-bond-p-orbital conjugation. In the compounds of the first type,
butadiene is the simplest example and has been described (Scheme 2.1b). It is a symmetrical
molecule and therefore, conjugation does not lead to the appearance of a dipole. Thus
+ − − +
contributions from the ionic structures CH 2 —CH CH— CH 2 and CH 2 —CH CH— CH 2 are
necessarily equal and consequently their dipoles nullify each other. This however, is not so
when π bonds of different types are in conjugation. Consider the α, β-unsaturated compound
3-buten-2-one (Scheme 2.14) in which structure (I) contributes the most to the resonance hybrid.
This is due to the octet rule satisfied at every atom and there are no formal charges on this
structure. However, structures (II and III, Scheme 2.14) are important contributors to the
resonance hybrid, though their contribution is minor. In these structures C-2 and C-4 are
electron deficient and this feature reflects on the chemical behaviour of these compounds. One
thus finds that a β-carbon of an α, β-unsaturated compound is electrophilic like the carbonyl
carbon itself and a nucleophile can bond with either of these two electrophilic carbons to give
1, 2- or a 1, 4-addition (Scheme 2.14, see also Scheme 7.83).
: O :– : O :–
:
: O:
2
C C+ C
4 3 1 +
H 2C C CH3 H 2C C CH3 H2C C CH3
H H H
(I) (II) (III)
3-buten-2-one
(an a, b-unsaturated ketone)
–
O O OH
Normal H—A
CH2 CH—C—CH3 CH2 CH—C—CH3 CH2 CH—C—CH3
1, 2-addition
Nu :– Nu Nu
O O
Conjugate –
CH2 CH—C—CH3 Nu—CH2—CH—C—CH3 :
addition
–
Nu :
–
O OH
H—A
Nu—CH2—CH C—CH3 Nu—CH2—CH C—CH3
Tautomerization
O
Nu—CH2—CH2—C—CH3
A 1, 4-conjugate addition is characteristic of many a, b-unsaturated compounds
SCHEME 2.14
Excellent yields of 1, 4-addition products can be obtained by reacting an α, β-unsaturated

compound with a lithium diorganocuparate reagent, a reagent which is called Gilman reagent
with an organic group attached to a copper atom (Scheme 2.14a, also see Scheme 7.91).
2CH3Li + CuI (CH3)2CuLi + Li

Lithium dimethylcuparate
O O
(1) (CH3)2CuLi
R—CH CH—C—OR¢ + R—CH CH—C—OR¢
(2) H3O
CH3 H
SCHEME 2.14a
When a Grignard reagent adds to an α, β-unsaturated aldehyde, 1, 2-addition generally

predominates by the addition of the nucleophile to the unhindered aldehyde carbon
(Scheme 2.14b), while with increased steric hindrance as shown in the reaction of a Grignard
reaction with a ketone leads to both 1, 2- as well as 1, 4-addition.
H
R=H
CH3—CH CH—C—OH
R R¢
(1) R¢MgX Predominant 1, 2-addition 80%
CH3—CH CH—C O +
(2) H3O
CH3
CH3—CH CH—C—OH
R=CH3
R¢
1, 2-addition 40%
+
CH3
CH3—CH—CH2—C O
R¢
1, 4-addition 40%
SCHEME 2.14b
Vinyl chloride (Scheme 2.15) provides a good example of π bond-p orbital conjugation. In
this compound, the p orbital on the carbon which is linked to chlorine can overlap both with
the p orbital on the second carbon atom and also with one of the p orbitals on chlorine (Scheme
2.15). As the p orbital of chlorine is initially filled, therefore, its participation in a delocalized
π system requires a partial removal of electrons from chlorine leading to a dipole moment
directed from chlorine towards carbon, which is in opposition to the dipole generated in the
C—Cl σ bond because of the –I effect of chlorine. The net result is that the dipole moment of
vinyl chlorine (1.44 D) is much smaller than that of ethyl chloride (2.0 D) where only the – I
effect is operative. This donation of electrons by chlorine into a molecular π system is described
as a +M effect. Using valence bond method, vinyl chloride may be represented as a hybrid of
the structures (I and II). Both representations indicate that the C—Cl bond should be shorter
than that in a saturated alkyl halide, and this is found to be so. The sp2 carbon orbital involved
is likely to produce a shorter and stronger bond than the ethyl sp3 orbital. Moreover, an
additional factor which leads to a still shorter and stronger bond is π overlap between the π
orbital of the double bond and the lone-pair orbital of the halogen (Scheme 2.15).
:
+ –
:
: :
: :
Cl :Cl—CH CH2 :Cl CH—CH2 :Cl C—

:
H
C C (I) +M effect of chlorine (II)
H –I effect of chlorine
H
Vinyl chloride
SCHEME 2.15
Resonance effects (i.e., mesomeric effects +M or –M) of substituents help in explaining

directive and rate controlling factors in electrophilic aromatic substitution.
(I) Resonance Energy

The difference in energy between the actual molecule and the Lewis structure (resonance
structure) of lowest energy is called resonance energy (stabilization energy). The resonance
stabilization arises as a result of the delocalization of the electrons over a conjugated system.
Benzene e.g., is found to be more stable than a system in which each of its three double bonds
were individually similar to the one present in cyclohexene. This difference has been shown
experimentally, e.g., by measuring the heat of hydrogenation of benzene to cyclohexane
(208.4 kJ mol–1 or 49.8 kcal mol–1) and comparing it with the heat liberated by the hydrogenation
of three moles of cyclohexane 361 kJ (3 mol)–1 or 86.4 kcal (3 mol)–1. The difference in these
heats (36.6 kcal) is equivalent to the resonance energy of 1 mole of benzene. Usually the greater
number of equivalent structures which can be written for a compound, the greater is its
resonance energy.
(J) Resonance and Some Aspects of Chemical Behaviour and Other Properties
Theory of resonance helps greatly in explaining molecular structure and unusual chemical
reactivity. Thus declocalization in the allyl system gives rise to the unusual reactivity of allylic
bonds. Allylic halides undergo relatively rapid SN1 and SN2 reactions, as well as a new type of
biomolecular substitution SN2′ (See Scheme 2.20).
Conjugation is reflected in the molecular structure of 1, 3-butadiene, revealing a relatively
short central carbon-carbon bond with a small barrier to rotation of about 4 kcal/mole. Moreover,
conjugated dienes are electron rich and are attacked by electrophiles to yield intermediate
allylic cations on the way to 1, 2- or 1, 4-addition products (Scheme 4.18a). Acyclic extended
conjugated systems display increasing reactivity since in these, many sites are open to attack
by reagents and the ease of formation of delocalized intermediates. The conjugated system of
benzene, is however, unusually unreactive because of its cyclic form.
Delocalization of electrons from F to B (Scheme 2.15a) helps in reducing the electron
deficiency of electrons on B in BF3 (increased stability) which is known to exist. On the other
hand, BH3 does not exist, since in this case no delocalization can occur. Thus, there is some
double bond character in BF3 and as expected it has a shorter B—F bond than in BF4− .
d+
:
:F + : F:
:
: F: F The delocalization of
– – – + – d+ electrons from F to B
: :
: :
B—F: B—F: B F: or B F reduces the deficiency

:
+ F: of electrons on B
: F: : F: F d+
:
SCHEME 2.15a
The following selected examples are only presented to show the strength of the method
of delocalization in explaining structure and reactivity:
1. Resonance and acid strength
The major reason that a carboxylic acid e.g., acetic acid is acidic is due to the resonance
stabilization of the carboxylate ion. The two resonance structures of this ion (Scheme 2.16) are
equivalent and moreover the negative charge is shared between the two oxygens equally. The
resonance stabilization of anion is greater compared to acetic acid. This resonance stabilization
is not available to an alkoxide ion (Scheme 2.17). Phenols are also acidic (pKa = 8–10), due to
resonance, the negative charge in the conjugate base called the phenoxide ion is stabilized by
delocalization into the ring (see, Scheme 3.20).
– 1–
O
:
:
O O O 2
:
+
H3C—C H + H3C—C H3C—C H3C—C
– 1–
O—H O O O
:
:
2
:
:
:
More resonance stabilization due to
equivalent resonance structure
: :–
:
:
:O O
H3C—C H3C—C
+
O—H O—H
:
:
:
Less resonance stabilization, structures are not equivalent
one structure requires charge separation
SCHEME 2.16
–
: :
: :
R—O—H + H2O : R—O : + H3O+
Alcohol Alkoxide ion
has no special stability
SCHEME 2.17
2. Allylic rearrangement (allylic shift)

Allylic reactants e.g., allylic halides undergo nucleophilic substitution reactions readily and
are usually accompanied by a rearrangement known as an allylic rearrangement (allylic shift).
When allylic reactants are treated with nucleophiles under SN1 conditions two products are
usually obtained one of which is normal and the other is rearranged. This is seen in the case of
either 1-chloro-2-butene or 3-chloro-1-butene (Scheme 2.18). Two products are formed since
the intermediate carbocation is a resonance hybrid (C-1 and C-3 each carry a partial positive
charge and both are attacked by the nucleophile). An allylic rearrangement cannot, however,
4 3 2 1
+
CH3CH CHCH2 Cl
CH3CH CHCH2Cl – –
CH3CHCH CH2
–Cl –Cl
1-chloro-2-butene + 3-chloro-1-butene
CH3CHCH CH2
4 3 2 1
Allylic cation
(resonance structures)
+
H2O/–H
OH
CH3CH CHCH2OH +
CH3CHCH CH2
2-buten-1-ol
80% 3-buten-2-ol
20%
SCHEME 2.18
be detected in the case of symmetrical allylic cations. Moreover, different allylic halides may
give identical products upon solvolysis provided they dissociate to the same allylic cation
(Scheme 2.18). This mechanism has been called SN1′ mechanism (i.e., substitution unimolecular
with rearrangement). The regioselectivity when nucleophile attacks depends on steric hindrance,
the attack at the less hindered end of the allylic system being faster.
An allylic shift is also observed during free-radical allylic bromination reactions on
unsymmetrical alkenes e.g., in 1-butene (Scheme 2.19). The reaction proceeds through a free
radical mechanism involving abstraction of a hydrogen from comparatively weaker allylic
C—H bond than those in saturated systems (see, Schemes 1.26, 2.11 and 16.26, cyclohexene
being a symmetrical substrate, reaction at either position gives 3-bromocyclohexene). Free
radical allylic bromination requires a very low concentration of bromine in the reaction mixture
to enhance allylic substitution over ionic addition. Adding bromine would make the
concentration too high, and ionic addition of bromine to the double bond would occur. A
convenient bromine source for allylic bromination is N-bromosuccinimide (NBS, see,
Scheme 16.8).
. –HBr . .
CH3—CH2—CH CH2 + Br [CH3—CH—CH CH2 CH3—CH CH—CH2]
Resonance-stabilized allylic radical
Br2
.
CH3—CH—CH CH2 + CH3—CH CH—CH2 + Br
Br Br
SCHEME 2.19
Allylic halides and tosylates also display enhanced reactivity toward nucleophilic
displacement reactions by the SN2 mechanism which occur without allylic shifts or other
rearrangements. Thus allyl bromide reacts with nucleophiles by the SN2 mechanism about 40
times faster than n-propyl bromide (see, Scheme 5.18). Nucleophilic substitution at an allylic
carbon can take place by an SN2 mechanism when no allylic rearrangement takes place.
However, under SN2 conditions an allylic rearrangement can take place when the nucleophile
attacks the γ carbon (C-3) rather than the usual carbon (Scheme 2.20) and is then termed SN2′.
The SN2′ reactions may occur on substrates of the types C C—CH2Cl, while compounds of the
type C C—CR2Cl retard SN2 reaction because of steric hindrance at α position and then these
give SN2′ rearrangement exclusively (Scheme 2.21, also see Scheme 5.20).
– –
: :
N C: CH3—CH CH—CH2—Cl CH3—CH—CH CH2 + :Cl :
An SN2-prime (SN2¢) mechanism CN
SCHEME 2.20
3. Resonance helps to provide a clear picture of species

In case e.g., the structure of allyl radical was the fixed Lewis structure (classical structure),
the ESR spectroscopy would be expected to display four signals for the non-equivalent hydrogens
on it (Scheme 2.22). ESR spectrum of a free radical provides information about different ‘‘kinds’’
of hydrogen on it (see, Sec. 16.8, VIII). In the classical structure of the allyl radical, the two
vinylic hydrogens (Ha and Hb) on the terminal carbon would be non-equivalent, since one is cis
R R² R R²
–
:
R—C C—C—X R—C—C C + X
–
Nu : R¢ R² Nu R¢ R²
An SN2-prime (SN2¢) mechanism
SCHEME 2.21
and the other trans to —CH2. The two hydrogens (Hc) of —CH2 would be equivalent because of
rotation around the carbon carbon single bond. The vinylic hydrogen Hd on the middle carbon
is different from all the others. The theory of resonance predicts a highly symmetrical structure
for the allyl radical (Scheme 2.21a) and as expected displays only three ESR signals.
Hd Hc
C C
. c
H—C
a CH2 H—C
a C—Ha
Hb
1
2
. H Hb .
1
2
b
Allyl radical Allyl radical
Classical structure Actual structure
expect 4 ESR signals gives 3 ESR signals
SCHEME 2.22
2.3 AROMATICITY
Aromatic compounds are those that resemble benzene. The aromatic properties of the benzene
ring (it has physical and chemical properties entirely different than those expected of a
conjugated triene) are related to the presence of a closed loop of electrons (the aromatic sextet).
The special properties are reflected in equivalent C—C bond distances (1.39 Å, rather closer to
a normal double bond 1.34 Å than to a normal single bond 1.54 Å), large resonance energy i.e.,
delocalization energy (Sec. 2.1, I), the ultraviolet spectrum and in its relative chemical inertness.
These properties arise because the π-electrons are delocalized over all carbon atoms of ring.
Thus for a compound to be aromatic like benzene it must obey the following conditions:
• It must be cyclic and planar
• It must have uninterrupted cloud of π electrons
• The π cloud must contain an odd number of pairs of π electrons
The molecular-orbital describes benzene to have six sp2-hybridized carbon atoms, each
of which forms σ-bonds with two carbon atoms and one hydrogen atom. The six remaining
electrons are in p orbitals each of which overlaps with two neighbours. The planarity of the
ring (strainless C—C—C angles 120°), allows maximum overlap of these p obitals. Six delocalized
π-orbitals are thus established of which the three of lowest energy (i.e., bonding orbitals) are
occupied. Their relative energies are shown (Scheme 2.22a).
Antibonding
Energy
p MOs
The bonding
p MOs
Overlapping p orbitals
Relative energies of the p-orbitals in benzene

SCHEME 2.22a
Interestingly, unlike the situation in butadiene, where the freedom of movement of the
π electrons in the delocalized MOs is opposed by electron repulsion, the π electrons in benzene
can circulate round the ring in a synchronized manner without increasing their mutually
repulsive forces. Consequently the delocalization energy in benzene is much more than in
butadiene.
In addition to accounting for the stability of benzene, both the resonance theory and
orbital theory explain the equivalence of the bonds and account for the inertness of benzene to
addition.
(A) What are Aromatic Compounds?

An aromatic compound must meet the following criteria:
• The molecule must be cyclic, (aromaticity is the property of ring compounds) having
conjugated pi bonds.
• Each atom in the ring must have an unhybridized p orbital. (The ring atoms are
usually sp2 hybridized, or occasionally sp hybridized).
• The unhybridized p orbitals must overlap to form a continuous ring of parallel orbitals.
The structure must be planar (or nearly planar) for effective overlap.
• For a compound to be aromatic, it will be cyclic, fully conjugated, planar and contain
(4n + 2)π electrons where n is an integer, 0, 1, 2, 3. Common aromatic systems, thus
have 2, 6 and 10π electrons for n = 0, 1 and 2. Benzene is cyclic with a continuous
ring of overlapping p orbitals. It obeys Hiickel’s rule (6π electrons), is planar and is
therefore, aromatic. 1, 3, 5-Cycloheptatriene is not aromatic. It has the correct
number of π-electrons to be aromatic, however, the p orbitals at the end of the cycle
do not overlap and the orbital connectivity is thus broken by the CH2 group
(Scheme 2.22b, see also Scheme 2.34), the molecule behaves as a normal triene.
CH2 p-orbital connectivity at C(7)

is broken here by the
CH2 CH2 group (no p orbital)
Cycloheptatriene
SCHEME 2.22b
Cyclooctatetraene is a conjugated eight carbon ring system (Scheme 2.23), the molecule
is not planar but is tub-shaped. A regular octagon has angles of 135° while sp2 angles are close
to 120°. To avoid this angle strain the molecule adopts a non-planar conformation that avoids
most of the overlap between adjacent π bonds i.e., non-planarity uncouples the p orbitals and
interrupts orbital connectivity.
Poor 2p connectivity here
Cyclooctatetraene
SCHEME 2.23
The bond lengths in cyclooctatetraene are characteristic of localized single (1.46 Å) and
double bond (1.33 Å). Cyclooctatetraene undergoes addition reactions that are typical of
alkenes and is therefore, not an aromatic compound.
On the other hand cyclobutadiene (Scheme 2.24) is cyclic, planar and fully conjugated,
however, Hückel’s rule predicts no aromatic character since cyclobutadiene is a 4n
molecule and not a 4n + 2 molecule. Cyclobutadiene is very unstable (unlike an aromatic
compound) and dimerizes by a Diels Alder reaction. It is however, stable in complexes
with metals when electron density is withdrawn from the ring by the metal. These
cyclobutadiene metal complexes are to be looked as systems with an aromatic duet, the
ring is square planar and these undergo aromatic substitution.
H H
H H
Fe(CO)3
Cyclobutadiene H Organometallic
H compound stable
or [4]annulene H
(not aromatic) H
Cyclobutadiene
SCHEME 2.24
(B) NMR Spectroscopy and Aromaticity

The ring hydrogens of an aromatic system resonate at a very low field δ 7–8, significantly
downfield from the already rather deshielded alkenyl hydrogens δ 4.5–5.5 (Scheme 2.24a).
This downfield shift is due to a ‘‘ring current’’ that results from circulation of the pi electrons
when the molecule is placed in the external applied magnetic field B0 of the NMR instrument.
The circulating electrons generate a magnetic field which is opposed to the external magnetic
field in the center of the ring (shielding) but is parallel to the external magnetic field outside
the ring in the region where the hydrogens are placed (deshielding). Since the induced field is
parallel to the external field where the hydrogens of the benzene rings are located, less external
field is needed to reach the total field required for the absorption of the electromagnetic radiation
and the hydrogens appear at a downfield position. However, if a hydrogen is positioned near
the center of the ring, then an upfield shift is observed. Thus one of the CH2 groups in
(A, Scheme 2.24a) is placed directly over the center of the aromatic ring. These protons appear
upfield from TMS at the extremely high field position of δ –0.01. These unusual chemical
shifts are associated with diamagnetic anisotropy.
5.3 ppm
CH3CH2CH CH2 H
4.7 ppm 7.37 ppm
Here the induced magnetic field Bi is in

opposition to the applied field B0; a hydro-
gen held here ‘‘feels’’ a net magnetic field,
Bnet = B0 – Bi. A relatively high B0 will
have to be applied to bring this The induced magnetic field, Bi
shielded hydrogen into resonance
H H
At this ring hydrogen the induced
magnetic field, Bi augments the applied
field B0; the hydrogen will ‘‘feel’’ a net
Circulating pi electrons magnetic field, Bnet = B0 + Bi, and requires
of benzene ring reduced applied field to come into
resonance. This (as well as other) ring
B0
hydrogens are thus deshielded
An applied magnetic field (B0)
The CH2 protons are held

CH2 above the benzene ring and
are thus shielded d –0.01
(A)
SCHEME 2.24a
All the six hydrogens of benzene therefore, show an expected unusual deshielding and
appear around δ = 7.37. Cyclooctatetraene is tub shaped. 1H NMR spectrum of cyclooctatetraene
shows a sharp singlet at δ = 5.69 typical of an alkene. Its chemical reactivity is typical of a
polyene, it can be catalytically hydrogenated to cyclooctane, and undergoes electrophilic
additions and cycloaddition reactions.
H H
7.37 d 5.69 d
This simple resonance picture is incorrect Benzene: 6p electrons Cyclooctatetraene: 8p electrons

cyclooctatetraene is not planar Aromatic Nonaromatic
SCHEME 2.25
Diamagnetic Anisotropy
Diamagnetic anisotropy describes an environment in which different magnetic
fields are found at different points in space. Anisotropy in Greek stands for ‘‘different
in different directions’’. Thus the protons in the vicinity of an aromatic ring are
deshielded while those which are placed above or within the ring would be highly
shielded. Examples are benzene, paracyclophane (A, Scheme 2.24a) and [18]
annulene (see, Scheme 2.25a).
Conditions for Aromaticity

In fact a unified theory has been developed that relates ring currents, resonance
energies and aromatic character. For a compound to be aromatic one looks for,
diamagnetic ring current, equal or approximately equal bond distances, planarity,
chemical stability and the ability to undergo aromatic substitution.
2.4 THE TERMS AROMATIC, ANTIAROMATIC AND NONAROMATIC

(A) Aromatic Compounds
A planar cyclic system of unsaturated atoms containing (4n + 2) π-electrons will be aromatic,
where n is a positive integer or zero. An aromatic compound will have extra stabilization.
Some slight deviation from planarity is allowed. Thus benzene a cyclic compound with a
continuous ring of overlapping p orbitals obeying the Hückel’s rule (4n + 2π electron system) is
aromatic.
The presence of diamagnetic ring current i.e., deshielding of the hydrogens outside the
ring while shielding of protons held over or within the ring further provides a powerful
experimental criterion for the presence of aromaticity in a compound. Thus like benzene, [18]
annulene with (4n + 2) π electrons can achieve a planar conformation and has aromatic
behaviour. It shows two signals in its 1H NMR spectrum one at δ –9 and other at very high
field (beyond TMS signal) at δ –3 (Scheme 2.25a).
H H
H H
H H H
d –3
H H d –9
H H
H H H (Aromatic) 1, 3, 5-hexatriene
More stable Less stable
H H
H H
[18] Annulene
(aromatic)
SCHEME 2.25a
Aromatic structures are more stable than their open chain counterparts, thus benzene
is more stable than 1, 3, 5-hexatriene.
(B) Antiaromatic Compounds

(i) Cyclobutadiene
These are planar cyclic compounds with an uninterrupted ring of p orbital bearing atoms and
the π cloud must contain an even number of pairs of π electrons i.e., these are 4n π systems.
Antiaromatic compounds display a different ring current called paramagnetic, which
induces a magnetic field that is parallel to the external magnetic field in the center of the ring
while opposed to it outside the ring. Thus the hydrogens on the outside of the ring appear
upfield from the position of a normal alkene hydrogen, a result exactly the opposite to the
effect found for aromatic compounds (diamagnetic ring current).
Cyclobutadiene is an example of an antiaromatic compound (see Scheme 2.24), it is
planar, cyclic and fully conjugated. It fails only the criterion, that it does not have a Hückel
number of (4n + 2) π electrons, it being a 4n π system. Cyclobutadiene is less stable than its
open-chain counterpart (1, 3-butadiene) and it is antiaromatic and expected to be very unstable.
In fact its structure is rectangular and not square (Scheme 2.25b) with alternating short and
long bonds. Thus the two diene forms (I and II, Scheme 2.25b) are isomers which equilibrate
through a symmetrical transition state (III), rather than resonance forms.
Antiaromatic 1, 3-butadiene
(Less stable) (More stable) (I) (II) (III)
SCHEME 2.25b
Its highly reactive nature is evident from the fact that it is very difficult to isolate, it
reacts with itself to give a dimer (Scheme 2.25c). One thus calls the molecule of cyclobutadiene
as antiaromatic. It adopts the structure which minimizes the delocalization of its electrons,
i.e., in a rectangular cyclobutadiene, p orbital connectivity is minimized.
SCHEME 2.25c
(ii) Stable cyclobutadienes, push-pull effect (captodative effect)

Consider the case of tri-tert-butylcyclobutadiene, it is stable at room temperature for a short-
time because the bulky tert-butyl groups hinder the dimerization reaction that destroys less
hindered cyclobutadienes. The ring hydrogen of this compound displays its 1H NMR signal at
5.38 δ, a position upfield from that of the hydrogens of a nonaromatic model compound such as
cyclobutene (5.95 δ). This upfield shift is due to paramagnetic ring current (Scheme 2.25d).
–
O
t-Bu t-Bu Et2N COOEt Et2N C—OEt
etc.
d5.38
t-Bu H EtOOC NEt2 EtOOC NEt2
+
Tri-tert-butylcyclobutadiene
shows paramagnetic (I)
ring current
(antiaromatic) A stable cyclobutadiene stabilized
via resonance by a push-pull effect
H d5.95
For comparison of
chemical shift
SCHEME 2.25d
The cyclobutadiene (I, Scheme 2.25d) is stable due to two electron-donating and
two-electron withdrawing groups and due to resulting resonance (a push-pull or captodative
effect). Indeed the ring is a distorted square with bond lengths of 1.46 Å and angles of 87° and
93° and represents another case of antiaromaticity.
(C) Nonaromatic Compounds

Recall that Hückel’s rule is commonly used to depict a compound which is aromatic (4n + 2) π
electrons or antiaromatic 4n π electrons provided it has a continuous planar ring of overlapping
p orbitals. If this is not the case then the compound is called nonaromatic. Cyclooctatetraene is
a 4n cycle, it is however, non-planar and thus is not antiaromatic. Cyclooctatetraene by not
being planar avoids being antiaromatic. Similarly 1, 3-cyclohexadiene does not have a continuous
overlapping ring of p orbitals and is thus nonaromatic compound and is almost as stable as
cis, cis-2, 4-hexadiene (Scheme 2.25e).
CH3 Both have similar

CH3 stabilities
Nonaromatic
SCHEME 2.25e
2.5 ANNULENES
Annulene is a general name for completely conjugated monocyclic hydrocarbons. The ring size
of an annulene is indicated by a number in brackets. Since the carbon atoms occur as doubly
bonded pairs, an annulene must have an even number of carbon atoms. The aromaticity of
cyclobutadiene a [4] annulene, Benzene a [6] annulene and cyclooctatetraene a [8] annulene
has already been discussed. Large-ring annulenes display aromaticity or antiaromaticity
depending on whether, these belong to (4n + 2) or 4n systems respectively and whether the
molecule can adopt the necessary planar conformation.
(A) [10] AnnulenesSystems of Ten Electrons

[10] Annulene can have three geometrical isomers, all cis, mono trans and di trans. In the all
cis [10] annulene (I, Scheme 2.26), the planar conformation would have excessive amount of
angle strain. For a regular decagon the angles would be 144°, much larger than 120° required
of sp2 angles. The [10] annulene isomer (III) with two trans-double bonds with all the angles
120° cannot adopt a planar conformation due to interaction (strain) between the two interior
hydrogens. The 1H NMR spectrum of the all cis form shows its protons in the olefinic region.
When conflicting hydrogens of cyclodecapentaene (III) are replaced by a bridging methylene
group, the resulting molecule is a bridged 10π electron system. This hydrocarbon which is a
bridged cyclodecapentaene (IV) is not a completely coplanar π-system, even then cyclic overlap
is substantial to give the compound significant aromatic character i.e., it undergoes aromatic
substitution, and displays diamagnetic ring current (Scheme 2.26).
H H H
(I) (II) (III)

cis, cis, cis, cis, cis- trans, cis, cis, cis, cis- trans, cis, trans, cis, cis-
Cyclodecapentaene Cyclodecapentaene Cyclodecapentaene
(nonaromatic) (nonaromatic)
[10] Annulenes-none is aromatic because none is planar
d – 0.5
CH2 CH2 CH2
d 7.1
H
(IV)
Bridged cyclodecapentaene (aromatic)
SCHEME 2.26
Compounds (I and II, Scheme 2.26) have been isolated as crystalline solids at – 80°C.
The mono trans form (II) suffers from the same problems as faced by the all cis form (I) though
–
. :–
:
2K +
+ 2K N—H
–
:
Cyclooctatetraene Cyclooctatetraenyl
Cyclononatetraenyl Azonine
dianion
anion
10p electron systems (aromatic)
SCHEME 2.26a
there is only one hydrogen inside the ring, there is severe angle strain and its planar form for
aromaticity is again destabilized. Its 1H NMR spectrum again shows that all its hydrogens lie
in the olefinic region.
That aromaticity can compensate for strain effects is shown by the synthesis of a stable
aromatic dianion (Scheme 2.26a) derived from cyclooctatetraene with ten π electrons
(see, Scheme 2.36). Its planar structure is also favoured since the repulsive destabilization of
two negative charges is avoided. Other 10π electron systems which are aromatic are in
(Scheme 2.26a). Interesting case is of azonine which is planar and aromatic. The oxygen analog
of azonine (oxonin) is non-planar and thus nonaromatic.
(B) Higher Annulenes

Both [12], and [16] annulenes, are not aromatic these being 4n compounds (Scheme 2.27) (n = 3
and 4 respectively) and not 4n + 2 compounds. Both [12] annulene and [16] annulene do not
display antiaromaticity either since these have the flexibility to adopt non-planar conformations
e.g., [16] annulene is non-planar and shows a pattern of alternating short and long bonds. As
expected these show reactivity of conjugated polyenes.
These 4n systems adopt non-

planar conformations and are thus
not antiaromatic. These behave as
partially conjugated dienes
[12] Annulene [16] Annulene
Not aromatic and not even antiaromatic

SCHEME 2.27
On the other hand some of the larger annulenes e.g., [14] and [18] annulenes (4n + 2
compounds) are aromatic compounds (Scheme 2.28) since these can achieve planar
conformations (also see problems 2.7 and 2.8). Comparison of [14] annulene with [18] annulene
is interesting. Both are aromatic since both can achieve planar conformations and as expected
both display diamagnetic ring current. [14] annulene is somewhat destabilized by steric strain
caused by hydrogens inside the ring while in [18] annulene repulsions among six interior
hydrogens are almost removed since the ring is large enough. These differences are displayed
by somewhat stronger diamagnetic ring current effects in [18] annulene compared to [14]
annulene. Significantly comparable diamagnetic ring current is displayed in the bridged [14]
annulene (I, scheme 2.28) which is now free from steric interactions among inside hydrogens,
and is a stable aromatic compound with all bond distances close to 1.4 Å and it displays
substitution rather than addition.
d9
7.6 d H d 8–8.7
H H
H d –3 CH3
H H d –4.2
0.0 d
HH
H H
HH H
CH3
[14] annulene [18] annulene A bridged [14] annulene
SCHEME 2.28
2.6 THE FROST CIRCLEMOLECULAR ORBITAL DESCRIPTION OF

AROMATICITY AND ANTIAROMATICITY
Without the use of mathematics, the relative energies of the molecular orbitals of planar, fully
conjugated molecules can be determined. One simply inscribes a polygon corresponding to the
ring of the compound being considered as a circle so that one corner of the polygon is at the
bottom. The points where the corners of the polygon touch the circle correspond to the energy
levels of the π molecular orbitals of the system. The nonbonding line divides the hexagon
exactly in the half, and also divides the bonding orbitals from antibonding orbitals. When an
orbital falls on this line it is nonbonding orbital.
If one considers benzene, to locate molecular orbitals, one inscribes a hexagon in a circle
and following the procedure described above one finds that there are no nonbonding molecular
orbitals and a picture (Scheme 2.28a) exactly seen before (see, Scheme 2.22a) emerges. This
means that an aromatic system like benzene has completely filled bonding orbitals with no
electrons in either nonbonding or antibonding orbitals (stability of aromatic compounds).
For cyclobutadiene, a set of four molecular orbitals emerges of which one is bonding, one
is antibonding while the other two are equienergetic (degenerate) nonbonding molecular orbitals
(Scheme 2.28a). Thus cyclobutadiene has a pair of π electrons left after the bonding orbitals
are filled.
The unfilled bonding orbitals or the unpaired electrons in nonbonding or antibonding
orbitals lead to destabilization of antiaromatic molecules.
Antibonding
molecular
orbitals
Nonbonding
Bonding
molecular
orbitals
Benzene Cyclobutadiene
(delocalized)
SCHEME 2.28a
EXERCISE 2.1
Using Frost circle method show why cyclooctatetraene
is not aromatic ?
ANSWER. Cyclooctatetraene has eight electrons (4n
system). If the molecule was planar like cyclobutadiene
it must have two electrons in nonbonding orbitals
(Scheme 2.28b). Since stability is not attained by being
planar, cyclooctatetraene, prefers to adopt instead a
Cyclooctatetraene
non-planar tub shape (In non-planar form most of the (Frost circle model)
angle strain is relieved).
SCHEME 2.28b
2.7 AROMATIC AND ANTIAROMATIC IONS

π Electron Systems
(A) 2π
Cyclopropene (I, Scheme 2.28c) is not aromatic since it does not have an uninterrupted ring of
p orbital bearing atoms, one of its ring atoms is sp3 hybridized (Compare with cycloheptatriene
Scheme 2.22b). A theorectical loss of a hydride ion from cyclopropene gives the cyclopropenyl
cation (II). This cation (sp2 hybridized) with a trigonal planar geometry has an empty p orbital
and the ion has a cycle of three p orbitals. Thus cyclopropenyl carbocation has two π electrons
distributed over three carbon atoms and fits Hückels rule and is aromatic.
H H H sp2
H
sp3
– + A circle with a charge
–H inside it, when inscribed in
+ a ring indicates a 4n + 2
electron system
(I) (II)
Cyclopropene (non-planar) Cyclopropenyl carbocation (planar)
(Not aromatic) 2p electron system
(Aromatic)
The cyclopropenyl cation is aromatic since it has an uninterrupted ring of p orbital-bearing
atoms and the p cloud has one (odd number) pair of delocalized p electrons
SCHEME 2.28c
Significantly these cyclopropenyl carbocations are far more stable than other carbocations
despite the strain associated with the internal bond angles of only 60°. As an example generally
carbocations react rapidly with water which is a weak nucleophile. On the other hand tri-tert
-butylcyclopropenyl perchlorate (I, Scheme 2.28d) which is a carbocation salt is sufficiently
t-Bu CH3
H3C H3C CH3 H3C CH3
+ Cl – +
– SbF5 –
ClO4 2+ 2SbF5Cl
SO2
Cl +
t-Bu t-Bu
H3C CH3 H3C CH3 H3C CH3
(I) (II)
SCHEME 2.28d
stable (Scheme 2.28d) and is crystallized from water. One has already seen that cyclobutadiene
is unstable antiaromatic 4n system. Loss of two chloride ions when (II, Scheme 2.28d) is dissolved
in SbF6/SO2 generates a 2π electron aromatic system which is a square stable cyclobutenyl
dication. As expected 13C NMR shows that all methyl groups of the ring are magnetically
equivalent as are the four ring carbons. The ring carbons are far down (δ 209). These are
deshielded even more due to the low electron density on the ring.
Cyclopropenyl Cation and Anion

Cyclopropenyl cation (cyclopropenium ion) can be generated readily since it is an
aromatic system. The Frost circle depicts the molecular orbital system. In the
cyclopropenyl cation, there are only two π electrons. Therefore the bonding molecular
orbital is full and there are no electrons in the antibonding orbitals. (Scheme 2.28e).
Cyclopropenyl anion (Scheme 2.28e) is antiaromatic with antibonding molecular
orbitals occupied. It is an unstable system.
.
R R R
R + – .
C (C6H5)3C BF4 C +
C C R +
C –(C6H5)3CH C R R
H
R R
The cyclopropenium ion planar, cyclic,
fully conjugated (aromatic system)
with 4n + 2 (n = 0) p electrons Frost circle
–
R . Two electrons in
R antibonding orbitals
– . ..
:
R Nonbonding
R R
R
Cyclopropenyl anion
(antiaromatic)
4n (n = 1) p electrons
SCHEME 2.28e
(B) The Cyclopentadienyl Ions

Cyclopentadiene is not aromatic, but is unusually acidic for a hydrocarbon. It is found to have
a pKa of 16. Recall that a hydrogen bonded to an sp hybridized carbon is more acidic than a
hydrogen bonded to an sp3 hybridized carbon. Thus acetylene has a pKa of 25 while that of
ethane is 50. The pKa of cyclopentadiene is 16 which is surprisingly acidic for a hydrogen
bonded to an sp3 hybridized carbon. The reason for this low pKa of cyclopentadiene is that it
can be converted to its anion, by deprotonation with moderately strong bases (Scheme 2.29).
On deprotonation (loss of a proton), the resulting carbanion (cyclopentadienyl anion) is greatly
stabilized by resonance, its resonance energy being 24–27 kcal/mol. 1H NMR spectroscopy has
shown that all five hydrogen atoms in the anion are equivalent. The Hückel’s rule predicts
that the cyclopentadienyl anion (4n + 2 system) is aromatic. Cyclopentadiene itself is not
aromatic. Firstly it does not have the proper number of π electrons and secondly the π-electrons
cannot be delocalized about the entire ring because of the intervening sp3 hybridized —CH2—
group with no available p orbital. One may recall the definition of an aromatic and antiaromatic
compounds. To be aromatic or antiaromatic, a cyclic structure should have some number of
conjugated p bonds, each atom in the ring must have an unhybridized p orbital. The unhybridized
p orbitals must be able to overlap to give a continuous ring of parallel orbitals.
–
Me3CO
–
:
– :– etc. –
H H :
H
:
– A
Cyclopentadiene Aromatic (Aromatic)
anion Cyclopentadienyl anion
pKa = 16
(6p electrons)
(not aromatic)
SCHEME 2.29
When the —CH2— carbon of cyclopentadiene becomes sp2 hybridized after the proton
loss, the two electrons left behind can occupy the new p orbital which is formed. Now, this new
p orbital can overlap with the p orbitals on either side of it to give a ring with six delocalized
π electrons to make cyclopentadienyl anion aromatic. The six electrons of the anion can be put
into molecular orbitals and like benzene these occupy, the set of three molecular orbitals
(Scheme 2.30) without requiring antibonding or nonbonding molecular orbitals to be occupied.
As a carbanion, cyclopentadienyl anion however, is quite reactive and it reacts readily with
electrophiles. Thus, when one says that this ion is aromatic it does not mean that its stability
is like benzene. Here the comparison is with the corresponding open chain ion (Scheme 2.30).
:–
:–
Open chain ion
Cyclopentadienyl anion
(Aromatic)
SCHEME 2.30
Hückel’s rule predicts that cyclopentadienyl cation with four π electrons is antiaromatic
and as a consequence, the cyclopentadienyl cation is not easily formed (Scheme 2.31). The fact
that one can draw equivalent contributing structures for cyclopentadienyl cation like that for
the anion does not reflect aromaticity. An aromatic system should meet the Hückel’s criteria of
aromaticity, (4n + 2π electrons). Here one has a situation which is similar to planar
cyclobutadiene which has two pairs of π electrons and is highly unstable antiaromatic compound
(see, Scheme 2.24). The cyclopentadienyl cation has also two pairs of π electrons, thus this
cation is antiaromatic and unstable.
Recall aromaticity reflects stability while antiaromaticity is characterized by instability
and the relative stabilities are: aromatic compound > cyclic compound with localized electrons
> antiaromatic compound.
H I H
SN 1 +
–
–I
Cyclopentadienyl cation
(Antiaromatic) Cyclopentadienyl cation
(Antiaromatic)
+
+
etc.
+
SCHEME 2.31
EXERCISE 2.2
On reaction with AgBF4, 3-chlorocyclopropene precipitates AgCl. The crystalline
organic material is soluble in polar solvents like nitromethane but has no solubility
in hexane (non-polar solvent). The organic material dissolved in nitromethane
containing KCl gives back the original reactant (3-chlorocyclopropene). Explain
why 5-chloro-1, 3-cyclopentadiene does not react under these conditions?
ANSWER. Due to the ready formation of an aromatic carbocation as a salt
(Scheme 2.32). 5-chloro-1, 3-cyclopentadiene does not react under similar conditions
since the corresponding salt if formed would be antiaromatic.
H –AgCl H
+ – + –
+ AgBF4 H BF4 + AgBF4 H BF4 + AgCl
Cl Cl
3-chlorocyclopropene Cyclopropenyl 5-chloro-1, 3- Cyclopentadienyl
tetrafluoroborate cyclopentadiene tetrafluoroborate
would be antiaromatic
Stable aromatic carbocation salt if formed
SCHEME 2.32
(C) The Cycloheptatrienyl Ions

Cycloheptatriene has six π electrons however, these cannot be fully delocalized due to the
presence of the –CH2– group which does not have an available p-orbital (see the example of
cyclopentadiene). The loss of a hydride ion from cycloheptatriene is facile and the resulting ion
i.e., cycloheptatrienyl cation (tropylium ion) is found to be highly stable. Tropylium bromide
(Scheme 2.33) is actually an ionic compound (unlike aliphatic bromides) to show that this ion is
aromatic and therefore, strongly resonance stabilized. On removal of a hydride ion from
—CH2— group of cycloheptatriene, a vacant p orbital is generated, and the carbon becomes sp2
hybridized. The resulting tropylium ion, i.e., the cycloheptatrienyl cation has seven overlapping p
orbitals with six delocalized π electrons. This situation therefore, makes tropylium cation, an aromatic
species (Scheme 2.33). Its 1H NMR spectrum shows that all the seven hydrogen atoms are equivalent.
The tropylium ion is an aromatic ion and as expected it is much less reactive than many
carbocations and several tropylium salts can be isolated and stored and do not undergo
decomposition. The Frost circle device shows that the three bonding molecular orbitals are
fully occupied (Scheme 2.34) while the antibonding molecular orbitals are unoccupied. This
molecular orbital picture of tropylium ion is in close resemblance to that of benzene
(see, Scheme 2.28a). However, the tropylium ion is not as stable as benzene. The aromaticity
of tropylium ion implies that the cyclic ion is more stable than the corresponding open chain
ion.
+
H H –
+ Br
–HBr – –
+ Br2 Br + Br
CH2
1, 3, 5-cycloheptatriene is The cycloheptatrienylium

not fully conjugated (tropylium) ion is fully conjugated
Cycloheptatrienyl bromide is an ionic compound,

since its cation is aromatic
SCHEME 2.33
In sharp contrast to cyclopentadiene, one finds that cycloheptatriene has no unusual

acidity. Thus unlike in cyclopentadiene, here the corresponding anion (Scheme 2.35) is difficult
to make, since it is antiaromatic on the basis of Hückel’s rule and as expected very reactive.
+ +
Aromatic Open chain ion

(Stable) (Less stable)
Tropylium ion
SCHEME 2.34
H H H
:
– –
B:
+ B—H
Cycloheptatriene Cycloheptatrienyl anion

eight pi electrons
(Antiaromatic)
SCHEME 2.35
(D) The Cyclooctatetraene Dianion

Unlike cyclooctatetraene (Scheme 2.23), which is a tub shaped molecule, its dianion (Scheme
2.36, a 4n + 2 species) is planar and is an aromatic dianion. Its successful preparation shows
that the angle strain (135°) is not insurmountable. The dianion has a planar regular octagonal
structure with all bond lengths equal. This example is another case where the cost in strain
energy to achieve planarity is lower than the extra stability which would be gained from the
aromatic ring.
. :– +
+ 2K 2– + 2K
–
:
Ten pi electrons
Cyclooctatetraene Cyclooctatetraene an aromatic dianion
(Tub-shaped) (Not planar) (Planar)
SCHEME 2.36
2.8 OTHER NON-BENZENOID AROMATIC COMPOUNDS

[6] Annulene (i.e., benzene), naphthalene, phenanthrene and anthracene are examples of
benzenoid aromatic compounds. On the other hand, the cyclopentadienyl anion, the
cycloheptatrienyl cation and some aromatic annulenes (other than [6] annulene) are the
examples of nonbenzenoid aromatic compounds.
The aromatic system of electrons (4n + 2) can be spread over two rings only provided 10
electrons (and not 8 or 12) are available for aromaticity. Attempts to prepare pentalene and
heptalene (Scheme 2.37) have failed since these do not contain (4n + 2) electrons. Azulene is
found to be a stable compound while the other two are not and this has been confirmed
experimentally. Azulene has a resonance energy of 49 kcal/mol. It has considerable dipole
moment (1.0D) while the dipole moment of the isomeric compound naphthalene is 0. The dipole
moment of azulene suggests that charge separation exists in the molecule and that each ring
approximates to a six π-electron system. Azulene (I, Scheme 2.37) may be regarded as a
combination of aromatic cyclopentadienyl anion and aromatic cycloheptatrienyl cation. Thus
in valence bond terms, the ionic structure of azulene (a non-benzenoid aromatic compound) is
an important contributor to the resonance hybrid.
+ – +
:
–
Pentalene Heptalene Azulene (I)
(Aromatic)
(Antiaromatic if planar)
SCHEME 2.37
EXERCISE 2.3
Explain the following observations (Scheme 2.38)
(a) Why the triene (I) is readily deprotonated with butyllithium twice?
(b) The compound (II) has a high dipole moment.
(c) Why 2, 4, 6-cycloheptatrienone is very stable and can be isolated while
2, 4-cyclopentadienone is unstable and cannot be isolated?
O
O
(I) (II) (III) (IV)

2, 4, 6-cycloheptatrienone 2, 4-cyclopentadienone
(Stable) (Unstable)
SCHEME 2.38
ANSWER. (a) Due to the formation of an stable aromatic dianion with 10 π

electrons (V, Scheme 2.39); (b) since its resonance structure (VI) has both of its
rings aromatic; (c) the resonance structure of (III) shown in (VII, Scheme 2.39) is
aromatic while from (IV) shown in (VIII) is antiaromatic.
O– –
O
+
+
– : :– +
:
–
(V) (VI) (VII) (VIII)
(Aromatic) (Antiaromatic)
SCHEME 2.39
EXERCISE 2.4
Diphenylcyclopropenone (Scheme 2.39a) is a stable compound which displays
aromatic character. Its reaction with hydrogen bromide gives a stable ionic salt.
Explain.
ANSWER. Diphenylcyclopropenone is a stable aromatic compound due to the
resonance structure with two π electrons which is aromatic (compare Scheme 2.39).
Of the different sites where protonation could occur, the Lewis basic carbonyl oxygen
is the most unusual. Recall that only on this addition stable aromatic cyclopropenyl
cation would be generated.
H H
+
O O O OH
+
HBr –
+ Br
C 6H 5 C6H5 C6H5 C6H5 C 6H 5 C 6H 5 C6H5 C 6H 5

Stable aromatic
cyclopropenyl cation
SCHEME 2.39a
Chemical behaviour of cyclic conjugated compounds can be largely understood by

considering aromaticity or antiaromaticity of a reactant, intermediate or the final
product by looking for a planar cycle of p orbitals.
2.9 HETEROCYCLIC AROMATIC COMPOUNDS

Heterocyclic compounds can also be aromatic since for the application of Hückel’s rule what
one needs is a ring of atoms, all with unhybridized p orbitals, in a planar arrangement in order
that the p orbitals overlap in a continuous ring. Thus, the heterocyclic compounds (Scheme
2.39b) are all aromatic. Pyrrole, furan and thiophene infact represent 1-hetero 2,
4-cyclopentadienes and contain a butadiene unit bridged by a heteroatom bearing lone electron
pairs. In electronic structure, these three compounds are similar to cyclopentadienyl anion
(see, Scheme 2.29).
Both benzene and pyridine have a similar Kekulé structure. Pyridine with a resonance
energy of 27 kcal (113 kJ) per mole shows typical characters of an aromatic compound. The
nitrogen atom in pyridine is sp2 hybridized. The sp2 hybridized nitrogen donates one electron
to the π system and this along with one each from the five carbon atoms provides pyridine a
sextet of electrons similar to that in benzene. The nonbonding electrons of the nitrogen (in an
sp2 orbital which lies in the plane of the ring) do not interact with the π system of the ring. The
unshared pair of nonbonding electrons confers on pyridine the properties of a weak base. Thus
pyridine protonates to yield the pyridinium ion which retains its aromatic character since the
process does not disturb the electrons of the aromatic sextet.
In pyrrole only four π electrons are contributed by the carbon atoms of the ring. To make
an aromatic sextet the sp2 hybridized nitrogen further contributes two electrons (Scheme 2.39b).
Lone pair in
sp2-hybridized p orbital
. . . .
. H H . H H
. . .. . ..
H N
.
:
N N H N—H
:
H H
Lone pair in H H
sp2 orbital
Six p electrons sp2-hybridized
Six p electrons
(Pyrrole is a five membered
(Pyridine is an aromatic heterocycle)
aromatic heterocycle)
SCHEME 2.39b
Pyrrole is far less basic than pyridine (pKb = 8.8). Because these apparently unshared electrons
are in the aromatic π cloud and are not available for bonding with a proton.
Furan (Scheme 2.39c) is similar to pyrrole. In furan which is an aromatic five-membered
heterocycle; the oxygen atom has two lone pairs of electrons. One of these pairs is made available
to provide two electrons needed to satisfy the 4n + 2 rule. The oxygen atom is sp2 hybridized.
One lone pair is placed in the unhybridized p orbital which combines with the four electrons in
the double bonds to provide an aromatic sextet. The second electron lone pair occupies one of
the sp2 hybrid orbitals in the plane and thus with no opportunity to achieve overlap.
sp2 hybrid orbital
:
The hetero atom in both furan
: and thiophena is sp 2 hybridized
X and provides one delocalized
: :
: :
O S p orbital electron pair.

Furan Thiophene
Furan X = O
Thiophene X = S
SCHEME 2.39c
In thiophene, (which is similar to furan) as well one of the lone electron pair occupies
one of the sp2 hybrid orbitals which is again in the plane and has no opportunity to achieve
overlap. In thiophene however, the sulphur atom instead uses an unhybridized 3p orbital to
contribute a pair of electrons to the π cloud to achieve aromaticity.
All the three heterocyclopentadienes (pyrrole, furan and thiophene) display unusual
stability and undergo electrophilic aromatic substitution. All display ring currents and the
consequent deshielding of the protons in their 1H NMR spectra.
2.10 METALLOCENES AND RELATED COMPOUNDS

Ferrocene is prepared by reacting cyclopentadienyl anions with ferrous ion Fe2+ in the ratio of
2 : 1 respectively (Scheme 2.40). Thus the Grignard reagent of cyclopentadiene on reaction
with ferrous chloride gives ferrocene as an orange solid. Ferrocene like other compounds with
similar structure has two cyclopentadienide rings forming a sandwich around an iron atom.
These compounds as a class are called metallocenes. Ferrocene is an aromatic compound
(nonbenzenoid) which is highly stable and displays electrophillic aromatic substitutions. Thus
ferrocene on heating with acetic anhydride and phosphoric acid gives acetyl ferrocene
(Scheme 2.40, one may note that all C—H bonds on ferrocene are equivalent).
CH3CO O
O
CH3CO
CCH3
Fe Fe
H3PO3/heat
Ferrocene Acetylferrocene
SCHEME 2.40
The carbon-iron bonding in ferrocene arises from overlap between the inner lobes of the
p orbitals of the cyclopentadienyl anions and 3d orbitals of the iron atom. Moreover, this
arrangement is such to allow the rings of ferrocene to rotate freely around the axis that passes
through the iron atom and is perpendicular to the rings. A noteworthy feature of many organic
derivatives of transition metals is that the organic group is bonded to the metal through the π
system rather than by a σ bond as in (benzene tricarbonylchromium, which interestingly
undergoes nucleophilic attack (see, chapter 9).
H 2+ –
+ C6H5MgBr – MgBr + C 6H 6
Et2O
H
Cyclopentadiene Phenylmagnesium Cyclopenta- Benzene
bromide dienylmagnesium
bromide
2+
2+ – Fe
2 – MgBr + FeCl2 (C5H5)2Fe Fe + 2 MgBrCl
Ferrocene
Ferrocene
SCHEME 2.41
The iron of ferrocene with 18 valence electrons is coordinately saturated and one
calculates this number like this.
Iron has 8 valence electrons in the elemental state. The oxidation state of iron in ferrocene
is + 2, thus dn = 6 (dn = 8 – 2 = 6).
Each cyclopentadienyl (Cp) ligand of ferrocene donates 6 electrons to the iron and the
valence electron count for iron is thus 18.
[ total number of valence electrons = d n + 2(Cp) = 6 + 2(6) = 18]
2.11 FUSED BENZENOIDS AND FULLERENES
(A) Naphthalene, Phenanthrene and AnthraceneConcept of Partial Bond Fixation

Naphthalene is a fused benzenoid hydrocarbon and is aromatic, 1H NMR spectrum explains
its aromaticity as it shows two symmetric multiplets at δ = 7.40 and 7.77, characteristic of
aromatic hydrogens deshielded by the ring current effect of the π-electron loop.
The UV spectrum displays peaks (as long as 320 nm) typical of an extended conjugated
system.Thus it shows that the added four π electrons enter into efficient overlap with those of
the attached benzene ring. Consequently, several resonance forms can be drawn (Scheme 2.41a).
When an aromatic compound is ingested or inhaled, it gets converted into an arene oxide
(enzymatically). Naphthalene gives only one arene oxide which also reflects on its aromatic
character (Scheme 2.41a).
1.37Å
8 1
7 2
6 3
5 4 1.40Å
O
The double bond shared by two rings is not
epoxidized. Only 1,2 bond reacts, since it
leaves one of the benzene rings intact
Naphthalene oxide
SCHEME 2.41a
If one assumes that the three resonance forms of naphthalene (not considering Dewar forms
and the forms with charge separation) contribute equally, the 1, 2 bond has more double bond
character than the 2, 3 bond and this is shown by the bond distances. Clearly these bond
distances are different from pure single (1.54 Å) and double bonds (1.33 Å) and the 1, 2- and
1, 3-bond distances in naphthalene deviate in length from those in benzene (1.39 Å). Ozone
attacks preferentially the 1, 2-bond in naphthalene. This nonequivalency of bonds is termed
partial bond fixation which is displayed by almost all fused aromatic systems. When one
considers phenanthrene (Scheme 2.41b) only in structure (V) 9, 10-bond is single bond, partial
6
5 7
4
8
3
2 9
1 10
(I) (II) (III)
(V) (IV)
SCHEME 2.41b
bond fixation is thus at its maximum and as a consequence 9, 10-bond of phenanthrene is

attacked easily by many reagents. Moreover, in four of the five resonance structures, the 9, 10
bond is double and its length is almost the same as of an alkenic C C bond.
Phenanthrene is a hybrid of the five canonical forms and is more stable than anthracene
which is best regarded as the resonance hybrid of four structures (Scheme 2.41c).
8 9 1
7 2
6 3
5 10 4
H Br
8 9 1
7 2 Br2
6 3
5 10 4
Anthracene H Br
SCHEME 2.41c
An inspection of canonical forms shows that in anthracene all the three rings cannot be
benzenoid at the same time. Moreover, the central ring contains a four-carbon fragment with
a relatively high degree of double bond character.
Resonance Energies and the Number of Principal Canonical Forms

Recall that the resonance energies of fused systems increase as the number of
principal resonance structures increases. Thus, for benzene, naphthalene,
anthracene, and phenanthrene, for which one can draw, respectively, two, three,
four, and five main canonical forms, the resonance energies are: 36, 61, 84, and
92 kcal/mol respectively. Phenanthrene, which has a total resonance energy of
92 kcal/mol after reaction at 9, 10 bond e.g., by bromine two complete benzene
rings remain, each with 36 kcal/mol that would be lost if other position is attacked.
For the same reasons, in anthracene as well a reagent e.g., bromine adds via 1, 4-addition
in the central ring.
The Numbering System in Anthracene

The numbering system shown in anthracene is somewhat unusual and was
introduced during early chemical studies to indicate special behaviour associated
with the 9, 10 bond.
EXERCISE 2.5
Anthracene and phenanthrene represent aromatic hydrocarbons containing three
fused benzene rings. If one continues this building process one can draw a fused
system (I, Scheme 2.41d). Comment on its aromaticity?
ANSWER. The system as drawn with circles is misleading. When one draws this
system in Kekulé form then there is no way for each carbon to be sp2 hybridized if
each carbon has four valences i.e., double bonds cannot be distributed so that each
carbon has one double and one single bond. Thus the molecule is not stable, being
not fully aromatic. This molecule (phenalene) as expected is acidic and on treatment
with base gives the aromatic anion (II, Scheme 2.41d).
In these two rings each

carbon is sp 2 hybridized.
Examine this ring,

and this carbon :–
(I) (Kekulé form) (II)
SCHEME 2.41d
(B) Fused Ring Systems and Annelation

When one draws all the fused polynuclear aromatic systems from four benzene rings, one faces
several problems with some arrangements and only two of these are discussed (Scheme 2.41e).
The situation in (I) is similar to the one discussed in Scheme 2.41d. A consideration of
(II, Scheme 2.41e) shows that in a fused system each ring cannot get six electrons. One has
â
â
â
This molecule cannot

be fully conjugated
(I) (II) (III)
SCHEME 2.41e
already seen that in naphthalene only one of the rings has six electrons while the other has
only four. Naphthalene is more reactive than benzene due to the fact that it contains one
benzene ring and the other ring has only a butadiene system. This type of situation is extreme
in the case of triphenylene (II, Scheme 2.41e) where one can draw eight canonical forms like
(II) and (III). In all the canonical forms of the type II, the three bonds marked by arrows are
only single bonds and none of these represents a double bond. In the resonance structure (III)
only the middle ring is like benzene while the outer rings have butadiene type system. Thus
considering (II, Scheme 2.41e) along with maximum number of canonical forms similar to it,
the molecule represents a system in which 18 electrons are arranged so as to give only the
outer rings a sextet each and the middle ring is ‘‘empty’’. The middle ring thus behaves as if it
has given up a part of its aromaticity to adjacent rings and is called annelation, an effect which
can be observed by UV spectroscopy (also see problem 2.7).
(C) Fullerene C60

The two well known crystalline modifications of carbon are graphite and diamond. Graphite is
a completely fused polycyclic benzenoid π system consisting of layers. These sheets are fully
delocalized with all carbons sp2 hybridized and thus graphite is conducting. In diamond all the
carbons are sp3 hybridized and form an insulating network of cross-linked cyclohexane chair
conformers (Scheme 2.41f).
There is yet another spherical allotrope of carbon, the molecule C60 with a shape of a
soccer ball and is called ‘‘footballene’’ or ‘‘soccerballene’’. Due to the similarity of the structure
with a geodesic dome designed by the architect, Buckminster Fuller, the compound C60 has
been named ‘‘buckminster fullerene’’. It is made by evaporating graphite electrodes into an
atmosphere of helium followed by extraction of the soot like product with benzene and purified
by chromatography. C60 is a closed shell polygon with 60 vertices and 32 faces of which 20 are
hexagonal (aromatic) and 12 are pentagonal.
extend
Diamond
Adamantane, building
block of diamond
Diamantane
Graphite, an infinitely extended planar
array of fused benzene rings.
Buckminsterfullerene C60 Structural fragment in C60
SCHEME 2.41f
C60 is a member of an interesting new group of aromatic compounds called fullerenes.

Each carbon of fullerene is sp2 hybridized and each six membered ring has three π-bonds
through which delocalization occurs over the entire molecule (Scheme 2.41f). However C60 is
not aromatic as benzene.
C60 does not react by electrophilic aromatic substitution as no hydrogen atoms are
available to substitute, however, addition does take place. Interestingly OsO4 adds to C60 in
the presence of 4-tert-butylpyridine (4-tert-butylpyridine enhances the rate or osmylation).
This reaction (Scheme 2.41g) is typical of alkenes. It may be noted that due to curvature, the
constituent benzene rings in C60 are strained and consequently interesting addition reactions
CH3
CH3CCH3 C(CH3)3
O
O N
C60 + OsO4 + C60 Os
N O N
O
1 equivalent 2 equivalents
C(CH3)3
SCHEME 2.41g
are expected. For example, the 13C-NMR spectrum of C60 shows a single peak to show that all
of the carbon atoms in C60 are equivalent. The position of this peak at 142.6 ppm is more
typical of a strained aromatic structure, than it is of a structure like naphthalene which gives
a peak at 133.7 ppm.
As another example of enhanced reactivity, C60 undergoes a facile Birch reduction (with
Li in liquid NH3–t-BuOH) to give a hydrocarbon C60H36 as a major product. This reaction is a
reduction of each cyclohexatriene fragment into a cyclohexene moiety, the latter being stable
to Birch conditions. Treatment of (II, Scheme 2.41h) with 2, 3-dichloro-5, 6-dicyanobenzoquinone
(DDQ) gives back the starting C60.
Li/NH3 (+36H)
C60 C60H36
DDQ (–36H)
(I) (II)
SCHEME 2.41h
Electrophiles e.g., bromine add to the double bonds in C60, addition of chlorine however,
occurs at higher temperatures (Scheme 2.41i). The chlorinated compound on treatment with
potassium hydroxide in methanol gives a product which shows a broad peak at δ 3.7 in the
1H NMR spectrum. This shows that nucleophilic substitution of chloride ion by methoxide ion.
The molecular weight of 1526 amu of the compound points to the formula C60(OCH3)26.
C60 + Br2 C60Br2 + C60Br4

25°C
C60 + Cl2 C60Cln

> 300°C
n = ~ 24 – 36
CH3OH + –
C60Cln + CH3OH + KOH C60(OCH3)n + K Cl
SCHEME 2.41i
Metal ions can be captured inside the cage, e.g., when graphite is soaked in a solution of
the metal salt and dried and vaporized, some of the C60 cages that are generated have metal
ions in them.
2.12 HOMOAROMATIC COMPOUNDS

In a homoaromatic compound there are one or more sp3-hybridized carbon atoms in an otherwise
conjugated cycle. An example is provided by tub shaped cyclooctatetraene which adds a proton
to one of the double bonds to give a homotropylium ion (Scheme 2.41j) in which the aromatic
sextet is spread over only seven carbon atoms as in tropylium ion. The eighth sp3 carbon is
thus forced to get placed vertically above the plane of aromatic system of seven carbons. One of
these two protons is placed directly above the aromatic sextet and as expected is highly shielded
(diamagnetic anisotropy).
d –0.3
d 5.1
H H
3 2
+
+ H 4 H1 H2—H6 protons d 8.5
5 H7
6
SCHEME 2.41j
2.13 HYPERCONJUGATION
The tertiary carbocations are more stable than secondary carbocations which in turn are more
stable than primary carbocations (see, Scheme, 4.28). If one assumes that a methyl group can
stabilize a carbocation by hyperconjugation (Scheme 2.42) then three methyl groups
H CH3 H + CH3 H CH3 H CH3

+
H—C—C+ H—C C H C C H—C C+ etc.
+
H CH3 H CH3 H CH3 H CH3
Isovalent hyperconjugation
SCHEME 2.42
will be the most effective (no change i.e., ‘‘Sacrifice’’ of a bond, thus the name isovalent
hyperconjugation). Hyperconjugation i.e., the overlap between a p orbital and a sigma bond
reflects on the carbocation stability. Alkyl groups have filled sp3 orbitals which can overlap
with the empty p-orbital on the positively charged carbon atom leading to stability of the
carbocation (Scheme 2.43). Though the attached alkyl group rotates, one of its sigma bonds is
always aligned with the p-orbital on the carbocation (II, Scheme 2.43). The electron pair of the
H
+
+
H H
H C H C C
H H
H
(I) (II)
SCHEME 2.43
sigma bond slightly spreads out into the empty p-orbital to provide stabilization. In the methyl
cation CH 3+ (I, Scheme 2.43), however, the C—H bonds lie in the nodal plane of the vacant
2pz-orbital and prevent an overlap with it. The relative stabilities of tertiary, secondary and
primary alkyl radicals are also explained similarly. In case of alkyl radicals there is overlap
between the p orbital occupied by the odd electron and a σ orbital of the alkyl group
(hyperconjugation). In terms of resonance theory, the ethyl radical for e.g., is a hybrid of the four
structures (Scheme 2.44, also see Scheme 1.4i).
H H H H .H H H H
. .
H—C—C H C C H—C C H—C C
H H H H H H H. H
The ethyl radical (hyperconjugation in an alkyl free radical)
SCHEME 2.44
2.14 HEXAHELICENE
Two benzenes when fused together give naphthalene and this process when continued in a
linear fashion gives anthracene and so on. All these molecules are achiral due to plane of
symmetry. When the new benzene rings are added to naphthalene generating a curve one gets
phenanthrene and ultimately hexahelicene which has three naphthalene units (Scheme 2.45)
and is a chiral molecule without a stereocenter.
The terminal benzene rings in hexahelicene, are not able to occupy the same plane
without coming in serious conflict with one another. The molecule of hexahelicene in thus
forced to adopt a non-planar shape in which one side of the molecule must lie above the other
because of crowding.
Hexahelicene is chiral due to its helical shape which could be either left-or-right-handed
in orientation. The entire molecule is infact less than one full turn of the helix, but this is
enough to generate chirality in hexahelicene. It has been resolved into remarkably stable
enantiomers (Scheme 2.45) which display very high optical activity and correspond to ‘right’
and ‘left-handed’ spirals.
In hexahelicene the middle rings (3 and 4) lie in a plane, while the terminal rings (1 and 6)
fall above and below this plane.
Mirror plane
Hexahelicene
Hexahelicene
SCHEME 2.45
2.15 TAUTOMERISM
(A) Keto-enol Tautomerism
An example of this phenomenon is found in the hydration of acetylene (Scheme 2.46 H2O,
H2SO4, Hg SO4). The initially formed vinyl alcohol spontaneously rearranges to the isomeric
carbonyl compounds. However, the equilibrium greatly favours the keto structure. Another
case is of acetone in aqueous solution.
H H O OH
hydration CH3—C—CH3 CH2 C—CH3
H—C C—H H—C C—H H—C—C
99.9% 0.1%
Acetylene
H O—H H O An aqueous solution of acetone
Vinyl alcohol Acetaldehyde
Keto-enol tautomerism
SCHEME 2.46
The greater stability of keto forms in the case of a monocarbonyl compound e.g., acetone
is assigned to the greater strength of the carbon-oxygen π bond (~ 364 kJ/mol) than the
carbon-carbon π bond (~ 250 kJ/mol).
The interconversion of keto and enol forms is catalyzed both by acids and bases. In a
basic solution, the base e.g., hydroxide ion removes a proton from the α-carbon and the electrons
are delocalized onto oxygen, to give an enolate. Its protonation by water gives the enol. In an
acidic solution, the carbonyl oxygen is protonated and water removes a proton from the α-carbon,
forming the enol (Scheme 2.47).
H—O
O: : O :– : OH
:
H :
–
RCH—CR RCH CR RCH C—R + HO
H
Keto tautomer An enolate Enol tautomer
–
HO :
: :
+
O: : OH
:
OH
+
+H
RCH2—CR RCH—C—R RCH CR + H3O+
+
–H
H
Keto tautomer Enol tautomer
H2O:
:
Keto-enol interconversion
SCHEME 2.47
The steps are reversed in the base- and acid-catalyzed mechanisms. In the base-catalyzed
mechanism, the first step is removal of an α hydrogen and the second step is protonation of the
oxygen. In the acid-catalyzed mechanism, the first step is protonation of the oxygen and the
second step is removal of an α-hydrogen.
Phenol is an unusual compound since its enol tautomer is more stable than its keto
tautomer. That is because the enol tautomer is aromatic but the keto tautomer is not
(Scheme 2.48).
In the case of compounds having a second carbonyl group on the β-carbon i.e., in 1,3-
dicarbonyl compounds for e.g., a β-diketone, the amount of enol present at equilibrium is far
more. Thus acetylacetone exists in the enol form to the extent of about 76%. This stability of
the enol form is explained by resonance stabilization of the conjugated double bonds and also
via hydrogen bonding present in the cyclic form (Scheme 2.48).
O OH
H O O OH O
H C C C C
H 3C CH2 CH3 H3C CH CH3
24% 76%
2, 4-cyclohexadienone Phenol
Keto tautomer Acetylacetone Enol form
keto form enol form
a b-diketone
Hydrogen bond
H H
–
:
:O O +O: O
C C C C
H 3C C CH3 H3C C CH3
H H
Enol form stabilized via hydrogen bonding and resonance
SCHEME 2.48
(B) Other Proton Shift Tautomerism

For simple phenols, equilibrium favours the enolic over keto form (Scheme 2.49). Phenol does
not show any of the properties of a ketone. Compared with the situation for acetone, the enolic
form of phenol has the stabilization energy of the aromatic ring with which oxygen is conjugated
(ca. 150 kJ mol–1). The ketonic form is conjugated but not aromatic, and thus has a very much
smaller stabilization energy (ca. 20 kJ mol–1). The enthalpy change on enolization is thus
approximately 80 + 20 – 150 = – 50 kJ mol–1, which favours the enol form. However, the keto
form may predominate in some situations, e.g., when a second OH group is present as in
resorcinol (Scheme 2.49). In resorcinol two strongly bonded carbonyl groups are present in the
keto form to overweigh the aromatic stabilization energy of the enol. Resorcinol has properties
typical of both a phenol and a ketone. Therefore, this undergoes electrophilic substitutions and
is reduced by sodium amalgam to 1, 3-cyclohexanedione a characteristic reaction of α,
β-unsaturated carbonyl compounds. In contrast to phenol, β-naphthol displays certain ketonic
OH O H H
H
OH O
H
OH O
H H 2-naphthol
1, 3-benzenediol
(b-naphthol)
(resorcinol)
SCHEME 2.49
properties. In this case however, both the tautomers have aromatic stabilization energy (Scheme
2.49). The loss of this energy of ketonization is approximately the difference in stabilization
energies of naphthalene and benzene (105 kJ mol–1). Thus when compared with the ketonization
of phenol for which the corresponding loss is 150 kJ mol–1, the ketonization of β-naphthol is
more favourable by about 45 kJ mol–1.
In several heterocyclic compounds in the liquid phase or in solution the keto structure
displays more stability as in the case of 4-pyridone (Scheme 2.50). In the ethanolic solution,
only the keto form is detectable while the enolic form is the predominant product in the vapour
phase.
O OH
R2CH—N O R2C N—OH

Nitroso Oxime
N N
H
Nitroso-oxime tautomerism
4-pyridone 4-hydroxypyridine
SCHEME 2.50
Nitroso compounds are stable only when these do not have α-hydrogen, otherwise the
oxime form predominates (Scheme 2.50).
The aliphatic nitro compounds exist in equilibrium with aci form (Scheme 2.51). The aci
form is much less stable than the nitro form. Unlike nitroso-oxime situation, in this case the
enol structure of the aci form is less stable. This is due to resonance stabilization of the nitro
form as against in nitroso case where such resonance is not possible.
–
O O OH
+ + +
R2CH—N R2CH—N R 2C N
O– O O–
Nitro form Aci form
SCHEME 2.51
Primary amines react with aldehydes and ketones to give compounds with a carbon
nitrogen double bond known as imines or Schiff bases (Scheme 2.52). Enamines are usually
stable only when there is no hydrogen on the nitrogen.
R2CH—CR NR R 2C CR—NHR
Imine Enamine
Imine-enamine tautomerism
SCHEME 2.52
Proton shift tautomerism is found in sugars where it is named ring chain tautomerism.
In these cases equilibrium generally lies far to the right (Scheme 2.53). The compound that is
formed as a result of an addition of an alcohol to the carbonyl group of an aldehyde is called a
hemiacetal where the same carbon carries an ether and an alcohol group [R—CH(OH)(OR)].
H
1
C O H H H H
HO OH HO OH
2
: :
H—C—OH H 3 2
H OH
: :
4 1 C O
3 H
H—C—OH or H :O : H
:
4 :O H
H—C—OH
H
H
Aldose sugar Chain form Ring form
An aldose e.g., can form a five or a six

membered ring which exists predominantly
O as a cyclic hemiacetal in solution.
O
Pyran Furan
SCHEME 2.53
PROBLEMS
2.1 After 1,3-butadiene accepts a proton, an allylic cation is formed. Which out of the
structures I–III does not represent a resonance structure any why?
+ + +
CH3—CH—CH CH2 CH3—CH CH—CH2 CH2—CH2—CH CH2
(I) (II) (III)
2.2 Structures (I–III) represents the resonance forms of a single compound. Can structures
(IV and V) be considered as resonance structures of (I–III).
– – – . O:
:
H O: H : O: H : O: H : O: H :
–
C: C.
:
:
:
N—C N—C + +N C N N
H H H H H H H H H H
(I) (II) (III) (IV) (V)
2.3 Under certain defined conditions, reaction with NBS under the influence of heat or light
the following bromination of cyclohexene can be accomplished. Explain.
O Br O
CCl4
+ N—Br + N—H
D
O O
N-bromosuccinimide Succinimide
(NBS)
2.4 Comment on the resonance structures (I–III of nitric acid) and (IV–V of cyanate ion).
–
:
:
O: :O: O:
– –
: :
: :
: :
: :
HO—N+ HO—N+ HO—N :N C—O : :N C O:
:
: O :– O: O: (IV) (V)
:
:
(I) (II) (III) Cyanate ion
Nitric acid
2.5 Comment on the aromaticity of the compounds (I and II), and tropone.
O
H
H
(I) (II) Cycloheptatrienone

tropone
2.6 Why indene and fluorene are acidic (pKa around 20 and 23 respectively) but less than
cyclopentadiene (pKa = 16). Why the acidity of (I) is more than of nitric acid?
CF3 CF3
CF3 CF3
H CF3
Indene Fluorene (I)
2.7 Why compared to [14] annulene (Scheme 2.28), [18] annulene is more stable?
2.8 Comment on the reactions (I and II).
I + (I) I + (II)
1 2
2.9 Why cyclopropenone is a stable compound while cyclopentadienone has not been
prepared? Why dehydro [14] annulene is more stable aromatic compound compared to
[14] annulene itself?
H H
O O
Cyclopropenone Cyclopentadienone Dehydro[14]annulene
2.10 Why the optically active ketone racemizes on treatment with a trace of acid or a base?
O
H
A CH3

2.1 Structure (III) is not the proper structure since a hydrogen atom has been moved. In
writing resonance structures, the positions of the nuclei of the atoms remain the same
in all the resonance structures.
2.2 All structures (I–III) have 18 valence electrons and a net charge of 0, even though they
differ in respect to formal charges on individual atoms. Structure IV has 20 valence
electrons and a net charge of – 2. Thus it cannot be a resonance structure of (I–III).
Arrangement in (V) though has the same number of electrons and the same atomic
positions, but this structure has two unpaired electrons whereas all electrons in (I–III)
are paired. Thus (V) also is not a resonance structure of (I–III).
2.3 The reaction is successful due to the low bond dissociation energy of allylic carbon
hydrogen bonds in free radical halogenation. The reaction is initiated with a small amount
•
of B r formed by the dissociation of the N–Br bond of NBS. The reaction steps are similar
are shown for propene.
. .
CH2 CH—CH2—H + Br CH2 CH—CH2 + HBr
Propene
. .
CH2 CH—CH2 + Br—Br CH2 CH—CH2Br + Br
2.4 In structure (III) there are ten electrons around nitrogen thus it is not allowed resonance
structure. Structures (I–II) are major contributors since the negative charge is on oxygen.
2.5 The [10] annulene (I 4n + 2 compound) cannot adopt a planar conformation because two
hydrogen atoms interfere with each other. The aromatic compound (II, naphthalene) is
formed when these hydrogens are replaced by a bond.
Tropone would have an aromatic sextet if two of the C O electrons keep away from the
ring and are located near the electronegative oxygen. Thus the dipolar structures which
provide a aromatic tropylium system provide a better picture of tropone. Such dipolar
structures also explain the lack of ketonic properties in tropone.
+
– –
O + O O
2.6 Annelation effects the electrons to be less

CF3
available to the five membered ring both in CF3
indene and fluorene. For example, in
fluorene as shown in the structure drawn
CF3 CF3
under problem both the terminal rings are
:
–
:
two benzene rings while the five membered –

CF3
ring looks like empty (annelation effect). On H
the removal of acidic H from the CH2 group
of the five membered ring gives an aromatic anion (now each of the outer six membered
ring contains only a butadiene system). The strong acidity of (I) is due to the formation
of the aromatic conjugate base which is also stabilized by the – I effect of four
trifluoromethyl groups.
2.7 [18] Annulene is a larger annulene, therefore, the inner hydrogens do not interfere with
each other. This makes [18] annulene almost planar and with its 4n + 2 system of electrons
is a stable aromatic compound.
2.8 The reaction (I) is a solvolysis reaction where the carbocation is the intermediate. The
related reaction (II) does not occur under the conditions of solvolysis used for reaction
(I, treatment with silver perchlorate in propionic acid), since unlike 1, species 2 are
antiaromatic.
2.9 Electronegative oxygen atom pulls electrons towards it and in the process leaves only
four electrons in cyclopentadienone which is thus unstable. Cyclopropenone for similar
reasons should represent a potential aromatic system of two electrons. In 4n + 2 systems
there is decrease in aromaticity with decreasing planarity. [14] Annulene is not completely
planar due to conflicting inner hydrogens. In dehydro [14] annulene the presence of the
linear triple bond eliminates the hydrogen interferences present in the parent [14]
annulene molecule. The two extra electrons of the triple bond donot play any role in the
aromatic system and should not be counted.
2.10 Enolizable hydrogens are available on the ketone (I). Since the stereogenic carbon has
also an enolizable hydrogen, its configuration will be inverted via the enol.
H
O O O
H + – CH3
H H or OH CH3
A CH3 H
H
(R)-configuration Achiral (S)-configuration

3 H ELECTR
ONEGATIVITIES
CHAPTER
2.3 C N O F
2.5 3.1 3.6 4.2
Si P S Cl
Organic Acids and Bases

1.9 2.3 2.6 2.9
Br
2.7
I
2.4
Most of the reactions in organic chemistry are either acid-base reactions outright, or they
involve acid-base reaction at some stage. A knowledge of acid-base chemistry allows us to
understand the relationship between structure of molecules and their reactivity, mechanisms
of reactions, and throws light on several other aspects of organic chemistry.
3.1 THE BRONSTED-LOWRY CONCEPTS OF ACIDS AND BASES

According to this concept an acid is any species that can donate a proton and a base is any
species that can accept a proton. Acids and bases are necessarily conjugate entities (Scheme
3.1). After accepting a proton a base becomes capable of returning that proton i.e., it becomes
an acid. When an acid donates its proton, it can accept that proton back to become a base. The
molecule or ion which is formed when an acid loses its proton is called the conjugate base of
that acid. The chloride ion is thus the conjugate base of HCl. The molecule or ion which is
formed when a base accepts a proton is termed the conjugate acid of that base. The hydronium
ion is thus called the conjugate acid of water.
H
H—Cl : + H—O : + : Cl :–
: :
: :
: :
HOH +
H
Acid Base
(proton (proton Hydronium Conjugate
donor) acceptor) ion conjugate base of HCl
acid of H2O
SCHEME 3.1
Like HCl, H2SO4 is also a strong acid and it completely transfers a proton when dissolved
in water. Since H2SO4 has two protons which it can transfer to a base (Scheme 3.2), it is called
a diprotic or dibasic acid.
+ – +
H2SO4 + H2O H3O + HSO4 HSO4– + H2O H3O + SO 4
2–
SCHEME 3.2
87

• The stability of the conjugate base formed on the loss of a proton determines the
strength of an acid. The more stable the base, the stronger will be its conjugate
acid.
• A stabler base is the one which can readily accomodate the electrons which it
had shared with the proton.
• Weak bases are stable bases, as these cannot share their electrons well. Thus
when the base is weaker, its conjugate acid will be strong.
The proton transfer occurs in a stepwise fashion; the first proton transfer occurs
completely, while the second transfer is only to the extent of ~ 10%. The strength of an acid is
expressed by the extent of its ionization in water. The general reaction of a hypothetical acid
(HA) with water is given (Scheme 3.3). The equilibrium constant for this reaction (Scheme 3.3)
is written as the concentrations of the products divided by the concentrations of the reactants.
The concentration of water is not considered as water is used as the solvent and its concentration
is almost constant.
Ka + –
HA + H2O H 3O + A
Acid Base
+ –
[H3O ] [A ]
Ka =
[HA]
pKa = – log Ka
+
pH = – log [H3O ]
SCHEME 3.3
Ka is called the acidity constant and its size reflects on the relative strength of the acid.
The stronger the acid the more it dissociates, giving a large value of Ka. Strong acids are
almost completely ionized in water and their dissociation constants are larger than 1. Most
organic acids are weak acids with values of Ka that are less than 10–4. Many organic compounds
are very weak acids; e.g., methane and ethane are essentially nonacidic with Ka values less
than 10–40. Chemists usually express the acidity constant Ka as its negative logarithm pKa.
This is analogous to the hydronium ion concentration as pH. Strong acids generally have values
of pKa around 0, and weak acids, such as most organic acids, have values of pKa that are
greater than 4. Notice that the values of pKa decrease as the values of Ka increase. The larger
the value of pKa, the weaker is the acid (Scheme 3.4).
The pH value indicates the concentration of hydrogen ions in a solution. The pH scale
ranges from 0 to 14. The lower the pH, the more acidic the solution. The pH of a solution can be
changed on adding acid or base to the solution (adding of base increases the pH by removing
protons from the solution as a result of reacting with them to form water). The pKa is
characteristic of a particular compound, like its melting point or a boiling point, it tells how
easily the compound gives up a proton. The pH scale is used to describe the acidity of a solution;
pKa describes a compound.
Organic Acids and Bases 89
CH3CO2H < CF3CO2H < HCl
Weak acid Very strong acid
pKa = 4.76 pKa = 0 pKa = – 7
Increasing acid strength
SCHEME 3.4
The acidity or basicity of a species depends on the structure of the species and on the
nature of the solvent. Aniline is a weak base in water (which is a weak proton-donor) but a
strong base in sulphuric acid; amide ion is a far stronger base in water than in liquid ammonia
(since water is a stronger proton-donor than ammonia). There is a relationship between the
strength of an acid and that of its conjugate base. For a given hypothetical acid (HA) to be
strong, its conjugate base (A–) must be stable in its anionic form; otherwise, HA would be
reluctant to lose its proton. Thus, the stronger the acid, the weaker will be its conjugate base.
One can therefore, relate the strength of a base to the pKa of its conjugated acid. The larger the
pKa of the conjugated acid, the stronger is the base (Scheme 3.5).
–
HCl + H2O H3O+ + Cl
Strong acid Weak base
+ –
+ CH3O:
: :
: :
CH3—OH + H2O H3O

Weak acid Strong base
–
O –
Cl – OH
: :
CH3—C—O :
Weak base Strong base
pKa of conjugate pKa of conjugate pKa of conjugate
acid (HCl) = – 7 acid (CH3CO2H) = 4.75 acid (H2O) = 15.7
The strength of a base
SCHEME 3.5
Thus acetic acid has greater acidity in water than in methanol, which is due to the
solvents’ abilities to solvate the product ions. The more polar water is better solvator of ions
than is MeOH, thereby shifting the equilibrium in water more to the right. (Scheme 3.5a).
+
HOAc + H2O OAc– + H3O HOAc + MeOH
– +
OAc + MeOH 2
Equilibrium lies more to the right
SCHEME 3.5a
One finds that HSbF6 is a very strong acid (pKa > – 12). It is so strong that it is called a
‘‘super acid’’, its conjugated base SbF6− is the weakest base; CH3—CH3 is the weakest acid
(pKa 50), while its conjugated base CH3 CH 2− is the strongest base.
3.2 THE LEWIS DEFINITION OF ACIDS AND BASES

Lewis acids are defined as electron-pair acceptors while Lewis bases are electron-pair donors
(Scheme 3.6). The neutralization of HCl by NaOH in aqueous solution, involves the transfer of
a proton from H3O+ to OH–. The transfer of a proton can be written in an oversimplified way
(Scheme 3.6). BF3 has an empty orbital (2p) in the valence shell of boron and is a Lewis acid.
NH3 has an unshared pair of electrons on nitrogen and is the Lewis base. In this example, each
atom takes on a formal charge; the resulting structure, however, has no net charge.
An empty
2p orbital
F H F H
– + F d– + d
F—B + :N—H F—B— N—H F—B :O: F3B O:
F
F H F H
Lewis acid Lewis base
Boron trifluoride Diethyl ether Diethyloxonium
(a Lewis acid) (a Lewis base) fluoroborate
SCHEME 3.6
EXERCISE 3.1
Reduction of an imine with NaBH4 in CH3OH is not very effective. On adding BF3
to the mixture, the reduction proceeds efficiently. Explain.
ANSWER. Many reactions of amines and nitriles are analogous to those of
aldehydes and ketones. Reductive aminations involve hydride addition (reduction)
to carbon-nitrogen double bond of imine (Scheme 3.6a). BF3 complexes with the
lone pair in imine to make it more electron deficient and the complexed form behaves
as a much better electrophile.
R1 R3 R1 R3
– – NaBH4
:
: :
Nu: C N— Nu—C—N— N H N
R2 CH3OH
R2 H
BF3
SCHEME 3.6a
Several compounds with Group IIIA elements e.g., boron and aluminum are Lewis acids
since Groups IIIA atoms have only a sextet of electrons in their outer shell. Several other
compounds with atoms which have vacant orbitals also act as Lewis acids. Zinc and iron (III)
halides (ferric halides) are often used as Lewis acids in organic reactions (Scheme 3.7). Bromine
as such is not sufficiently electrophilic to attack benzene. Bromine in the presence of FeBr
donates a pair of electrons to the Lewis acid FeBr3 to give a reactive intermediate, which now
has a weakened Br—Br bond with a partial positive charge on one of the bromine atoms
(Scheme 3.7).
+
–
: :
:
R—O—H + ZnCl2 R—O—ZnCl2
Lewis base Lewis acid H

electron-pair electron-pair
donor acceptor
d+ d–
: :
: :
: :
: :
: Br—Br : + FeBr3 : Br—Br—FeBr3
Lewis base Lewis acid Br2 FeBr3 intermediate

electron-pair electron-pair (a stronger electrophile)
donor acceptor
SCHEME 3.7
When the acid base reaction involves formation of a bond to some other element (especially
carbon), one refers to the electron donor as a nucleophile (Lewis base) and the electron acceptor
as an electrophile (Lewis acid). The nucleophile is said to ‘‘attack’’ the electrophile, and a curved
arrow is used to indicate the flow of an electron pair from the electron donor to the electron
acceptor. The movement of each pair of electrons involved in making or breaking bonds is
indicated by its own separate arrow (Scheme 3.8).
H H
– –
: :
: :
: :
: :
CH3—O: + H—C—Cl : CH3—O—C—H + : Cl :
H H
Nucleophile Electrophile Bond formed
SCHEME 3.8
3.3 THE RELATION BETWEEN STRUCTURE AND ACIDITY

(A) The Strength of the Acid in Relation to Size of Atom to which Proton is Attached/Strength of the
Bond to a Proton
When atoms of different sizes are involved, the stronger acid has its proton attached to the
largest atom. Going down a column, the elements get larger with a decrease in their
electronegativity. As a consequence the acidity of the hydrogen attached to it increases. For
example, with an increase in the size of the halide ion its charge is spread over a larger volume
of space and its stability increases (electron density decreases). One may also recall that the
acid strength of a compound depends on the extent to which a proton can be released from it
and transferred to a base. This involves the removal of a proton leading to cleavage of a bond
to it to make the conjugate base more electrically negative. The strength of a bond to a proton
gains significance in compounds in a vertical column of the periodic table as in the case of
hydrogen halides (Scheme 3.9).
Thus among the halogen acids HF is the weakest and HI is the strongest acid; H—F
bond being the strongest and H—I bond the weakest. As HI, HBr, and HCl are strong acids
their conjugate bases (I–, Br–, Cl–) are all weak bases (Scheme 3.9). One will notice a similar
H—F H—Cl H—Br H—I
pKa 3.2 –7 –9 – 10
SCHEME 3.9
trend in acidities and basicities in other vertical columns of the periodic table. Thus considering
the column headed by oxygen, the acidity increases in the order H2O < H2S < H2Se. As O—H is
the strongest bond, H2O is the weakest acid, Se—H bond is the weakest, therefore H2Se is the
strongest acid, and the basicity increases in the order SeH– < SH– < OH–.
Thiols are the sulphur analogues of alcohols. A thiol is less basic and more acidic (and
more nucleophilic) than the corresponding alcohol. Unlike alcohols, thiols do not undergo
substitution reactions since it is difficult to make SH group a good leaving group. Sulphur
compounds being less basic are difficult to protonate and this is due to larger size of sulphur.
Further S—H bonds are weaker than O—H bonds, thus thiols are stronger acids. Most alcohols
have pKa’s of 16–18 while the corresponding value for a thiol is around 11. Consequently a
thiol can be quantitatively converted into its conjugate base (RS– a thiolate ion) by hydroxide
(Scheme 3.9a).
– –
: :
: :
: :
: :
RS—H + : OH RS : + H—OH
Alkanethiol Hydroxide ion Alkanethiolate ion Water
(stronger acid) (stronger base) (weaker base) (weaker acid)
(pKa = 11) (pKa = 15.7)
SCHEME 3.9a
EXERCISE 3.2
How do you explain the outcome of the substitution reactions (Scheme 3.9b)?
CH3CH2CH2SH
(I) + HCl
Cl CH3OH SCH2CH2CH3
H 3C CH3
NaOCH2CH3
(II) CH3CHCH3 CH3CH CH2 + CH3CHCH3
CH3CH2OH, 55°C
(major)
Br OCH2CH3
Isopropyl bromide (minor)
H Cl C 6H5 S H H
Cl
C6H5SNa –
(III)
: :
via C6H5—S:
THF
3-chlorocyclopentene 2-cyclopentenyl
phenyl sulphide (75%)
SCHEME 3.9b
ANSWER. (I) Because thiols are weaker bases, these act as nucleophiles in SN1
reactions and an alcohol (CH3OH) is used as a protic solvent without competition.
(II) The major pathway for reaction of alkoxide ions with secondary alkyl halides
is E2 elimination and not SN2 reaction.
(III) Alkane thiolate ions RS– are weaker bases than alkoxide ions RO– and bring
about SN2 reactions even with secondary alkyl halides.
(B) Electronegativity of the Atom Bonded to the Hydrogen

When the atoms are almost similar in size, the more acidic compound will be that in which the
hydrogen is attached to the more electronegative atom. Recall that elements in the second row
of the periodic table have almost the same size, but these differ in electronegativities
(C < N < O < F). The acidities of the hydrides increase in the order CH4 < NH3 < H2O < HF
and therefore, the bases formed from these compounds have the relative stabilities
– – – –
(CH3 < NH2 < OH < F), the more electronegative atom can bear the negative charge better.
These data help to explain as to why an alcohol is more acidic compared to an amine since
oxygen is more electronegative than amine. In the same way the protonated form of an alcohol
is more acidic than a protonated amine (Scheme 3.9c).
+ +
CH3OH CH3NH2 CH3OH2 CH3NH3
pKa 15.5 40 – 2.5 10.7
SCHEME 3.9c
(C) The Effect of Hybridization

The hybridization of the carbon atom attached to a hydrogen greatly effects the acidity of that
hydrogen. With more p character the acidity of a C—H bond decreases and thus acidity increases
appreciably from alkanes through alkenes to alkynes. The pKa of ethane (with an sp3 hybridized
C—H bond) is about 50, that of ethene (with an sp2 hybridized C—H bond) is about 44, and
that of ethyne (with an sp hybridized C—H bond) is about 25.
The sp hybridized atoms are more electronegative than sp2 or sp3 hybridized atoms.
A lone pair in an sp3 hybrid orbital (25% s character) is held farther from the nucleus than in
an sp2 hybrid orbital (33% s character) which is farther from the nucleus than the one in an sp
hybrid orbital (50% s character). Since it is more favourable for the negative charge of an anion
to be in an orbital closer to the positively charged nucleus, an sp hybridized anion is more
stable than an sp2 hybridized anion, which is more stable than an sp 3 hybridized anion
(Scheme 3.10).
Compound pKa Conjugate base Hybridization s character %
H H H H
–
H—C—C—H 50 H—C—C : 3
(sp ) 25
H H H H
H H H :– 2
C C 44 C C (sp ) 33
H H H H
–
H—C C—H 25 H—C C : (sp) 50
SCHEME 3.10
Generally, acid-base reactions always favour the formation of the weaker acid
and the weaker base.
As a result of the acidity of C—H bond in an alkyne, it is ionized on treatment with a

strong base e.g., amide ion in liquid ammonia to form its anion. This is a acid-base reaction
which as expected favours the formation of the weaker acid and the weaker base. The position
of the equilibrium for this reaction lies largely towards the right (Scheme 3.11).
+
–
Na –: H [(CH3)2CH]2 N :– Li+
:
–
:
HC CH + :NH2 HC C: + :NH3
pKa 25 pKa 38 Sodium hydride Lithium diisopropylamide
(LDA)
Stronger Stronger Weaker Weaker
acid base base acid
SCHEME 3.11
Other strong bases used to form acetylide anions are sodium hydride and lithium
diisopropylamide (LDA). Water is a stronger acid than acetylene thus the hydroxide ion is not
sufficiently strong base to convert acetylene to acetylide anion (Scheme 3.11a). Other examples
of acid-base reactions to determine whether reactants or products are favoured at equilibrium
are given (Scheme 3.11a).
–
: :
:OH C :– H2O :
:
HC CH + HC +
pKa 25 pKa 15.7
Weaker Weaker Stronger Stronger
acid base base acid
O O
+
C + NH3 C + NH4
–
CH3 OH CH3 O
Stronger acid Stronger base Weaker base Weaker acid
pKa = 4.8 pKa = 9.4
– +
CH3CH2OH + CH3NH2 CH3CH2O + CH3NH3
Weaker acid Weaker base Stronger base Stronger acid
pKa = 15.9 pKa = 10.7
SCHEME 3.11a
Synthesis Using Acetylide Ions

A useful reaction to form carbon-carbon bond is the reaction of an acetylide ion in
an SN2 pathway. Because acetylide anions are strong bases as well as good
nucleophiles, alkylation of acetylide anions is successful only with methyl and
primary halides (Scheme 3.11b). With secondary and tertiary halides, E2
elimination is the major reaction. By choosing an appropriate alkyl halide, terminal
alkynes can be converted into alkynes of any desired chain length. This therefore,
provides an example of alkylation reaction i.e., any reaction in which a new carbon-
carbon bond to an alkyl group is formed.
d+ d– SN 2
C–
:
CH3CH2C + CH3CH2CH2—Br CH3CH2C CCH2CH2CH3 + Br –
A useful synthetic reaction
H
H
Br E2
HC :–
C Na + +
HC CH +
H – NaBr
H
H
Sodium Bromocyclohexane Acetylene Cyclohexene
acetylide
Scheme 3.11b
(D) Inductive and Mesomeric Effects

The most important elements in organic systems which can donate protons are oxygen, sulphur,
nitrogen and carbon. The acidities of the groups (Scheme 3.12) vary widely with the structure
of the remainder of the molecule. One principle of significant importance in determining acidity
is that any factor that stabilizes the anion of an acid relative to the acid itself increases the
strength of the acid.
—O—H, —S—H, N—H, and —C—H
SCHEME 3.12
1. Acidity of O—H groups

An alcohol e.g., ethanol (pKa = 16) is a weak acid compared to a carboxylic acid e.g., acetic acid
(pKa = 4.8). The resonance stabilization is not available to an alkoxide ion as is available to
carboxylate anion (see Schemes 2.16 and 2.17).
One may account the acid-strengthening effect of the carbonyl group due to the difference
in electronegativity between carbon and oxygen. There is a partial positive charge on the
carbonyl carbon which induces a polarization of electrons in the O—H bond away from hydrogen.
This electron-withdrawing inductive effect of the carbonyl group weakens the O—H bond to
help the ionization of a carboxylic acid compared with an alcohol. (i.e., CH 3COOH and
CH3CH2OH).
Electron-withdrawing substituents near the carboxyl group increase the acidity of
carboxylic acids. This is seen in the acidities of acetic acid and the halogen-substituted acetic
acids. As the electronegativity of the halogen increases, its inductive effect increases (–I effect.:
I < Br ~ Cl < F) and the strength of the halogen-substituted acid increases. Fluoroacetic acid as
expected is the strongest of the monohalogenated acetic acids (Scheme 3.13). Thus a halogen
atom in chloroacetic acid stabilizes the chloroacetate ion which is formed on proton loss by
dispersing its negative charge. The negative charge is more spread out in the chloroacetate ion
since it resides partially on the chlorine atom. The dispersal of charge makes a species more
stable. An even stronger electron-withdrawing substituent such as nitro group (NO2) enhances
the acidity of a carboxylic acid even more. The pKa of nitroacetic acid (NO2CH2COOH) is 1.68,
while that of chloroacetic acid ClCH2COOH is 2.9.
CH3CO2H ICH2CO2H BrCH2CO2H CICH2CO2H FCH2CO2H

Acetic acid Iodoacetic acid Bromoacetic acid Chloroacetic acid Fluoroacetic acid
pKa 4.76 3.18 2.90 2.86 2.59
SCHEME 3.13
Multiple halogen substitution increases the acidity further (Scheme 3.14). Trichloroacetic
acid, the strongest of the three acids, is a stronger acid than H3PO4.
CICH2CO2H Cl2CHCO2H Cl3CCO2H
Chloroacetic acid Dichloroacetic acid Trichloroacetic acid
pKa 2.86 1.48 0.70
SCHEME 3.14
The inductive effect of halogen substitution falls off rapidly with distance from the
carboxyl group (Scheme 3.15). Electron releasing substituents intensify the negative charge to
destabilize the anion and thus decreases acidity (Scheme 3.16).
Cl Cl Cl
CH3CH2CH2CO2H CH2CH2CH2CO2H CH3CHCH2CO2H CH3CH2CHCO2H

Butanoic acid 4-chlorobutanoic acid 3-chlorobutanoic acid 2-chlorobutanoic acid
pKa 4.82 4.52 3.98 2.83
SCHEME 3.15
H—CO2H CH3—CO2H CH3—CH2—CO2H (CH3)3C—CO2H

pKa 3.77 4.75 4.88 5.05
Alkyl groups are acid-weakening to an extent depending on their + I effects:

(CH3)3C > CH3—CH2 > CH3 > H
SCHEME 3.16
In case of alcohols (Scheme 3.17), the acidity decreases (pKa increases) from methanol
to primary, secondary and then finally tertiary systems. This has been assigned to steric
H H H 3C H 3C
H——OH > H3C——OH > H3C——OH > H3C——OH
H H H H 3C
CH3OH > primary > secondary > tertiary

Strongest acid Weakest acid
Relative pKa values of alcohols (in solution)

SCHEME 3.17
disruption of solvation and to hydrogen bonding in the alkoxide. Both solvation and hydrogen
bonding stabilize the negative charge on oxygen. Any interference with these processes leads
to an increase in pKa. The smaller the alkoxide ion the easier it is for the solvent molecules to
approach and stabilize it. (Scheme 3.18, also see Scheme 3.33a).
Solvent
SO
SO
H3C H
LV E N T
LV E N T
Difficult to C C Easy to
– H –
solvate H3C O O solvate
CH3 H
Solvent molecules can easily approach a smaller

alkoxide ion to stabilize it.
SCHEME 3.18
Electron withdrawal (–I effect) by the halogen also stabilizes the negative charge on
the alkoxide oxygen by electrostatic attraction. Thus, both 2-chloroethanol and 2, 2, 2-
trifluoroethanol are more acidic (pKa 14.3 and 12.4 respectively see Scheme 3.19) than ethanol
(pKa= 15.9).
d– F
– d+ –
Cl—CH2—CH2—O:
: :
F—C—CH2—O
F
The alkoxide ion
(2, 2, 2-trifluoroethanol)
SCHEME 3.19
Compared to ethanol, phenol is more acidic (pKa = 9.95). When phenol ionizes, the
phenoxide ion is a resonance hybrid (Scheme 3.20).
: O: –
:
OH H+ : O: : O: : O:
:– –:
:
–
Phenol
pKa 9.95
Phenoxide ion
SCHEME 3.20
Ring substituents have marked effects on the acidities of phenols by exerting both
inductive and resonance effects. The inductive effect is due to electron polarization caused by
differences in the relative electronegativities of bonded atoms and is relayed through sigma
bonds. Consider the relative acidities of alkyl phenols and halophenols in terms of inductive
effects. p-Cresol is a weaker acid than phenol, while m-chlorophenol is a stronger acid than
phenol (Scheme 3.20a). The alkyl substituents are ‘‘electron-releasing’’ toward the aromatic
ring. Because they are electron-releasing, they destabilize phenoxide ion-contributing resonance
structure and reduce the acidity of alkyl substituted phenols (Scheme 3.20a). The inductive
effect of the halogens operates in opposite direction than that of alkyl substituents. Because
the halogens are more electronegative than carbon, they withdraw electron density from the
aromatic ring and thereby stabilize the phenoxide ion and enhance the acidic-strengthening
effect in halophenols. Both inductive and resonance effects are operative in nitrophenols. In
m-nitrophenolate anion the negative charge is stabilized by the inductive effect of the electron-
withdrawing nitro group therefore, m-nitrophenol is a stronger acid than phenol (Scheme 3.20a).
OH OH OH OH OH
:O:
Cl NO2 –
:
CH3 NO2
Phenol p-cresol m-chlorophenol m-nitrophenol p-nitrophenol
CH3
pKa 9.95 pKa 10.17 pKa 8.85 pKa 8.28 pKa 7.15 A
SCHEME 3.20a
The negative charge of the p-nitrophenolate anion is stabilized both by the inductive
effect as well as a resonance effect. Additional delocalization of charge, beyond to that available
in the phenolate anion and in the m-nitrophenolate anion is possible for the p-nitrophenolate
anion. This extra stabilization of the conjugate base is reflected in the greater acidity of
p-nitrophenol. (Scheme 3.20b). Increasing the number of nitro groups on phenol enhances the
acidity, picric acid (2, 4, 6-trinitrophenol) with pKa 0.38 is a strong acid, even stronger than
phosphoric acid (H3PO4) and is comparable with trifluroacetic acid. (Scheme 3.20b).
: : : : : : OH
: : O O O
O2N NO2
O H
:–
: O:
:
–
NO2
N+ NO2 +N N+
:
– –
:
O : :O : :O : 2, 4, 6-trinitrophenol
: :O : :O
:
(Picric acid)
:
– – –
pKa 0.38
SCHEME 3.20b
The negative charge of the carboxylate ion is shared by the two carboxylate oxygen
atoms and is not effectively delocalized by the aromatic ring (Scheme 3.21). In the phenoxide
ion even though the negative charge is delocalized by the aromatic ring, benzoic acid is a
stronger acid than phenol. The negative charge in benzoate ion, is equally shared by two
electronegative oxygen atoms while in the phenoxide ion most of the negative charge resides
only on the single oxygen atom.
:O: –
:
O:
:
—C—O: – O:
: :
—C
:
SCHEME 3.21
Since the benzene ring is not involved in resonance stabilization of the carboxylate group,
substituents on a benzene ring influence acidity mainly by the inductive effect. An electron-
withdrawing group e.g., the —NO2 group, that is substituted either in the meta or the para
position increases the acidity of a benzoic acid while an electron-releasing group in the same
positions decreases acid strength (Scheme 3.22).
O O O
O2N— —COH —COH CH3— —COH
pKa 3.4 4.2 4.4
SCHEME 3.22
For nitrosubstituted benzoic acids, the ortho isomer is the most acidic pKa = 2.17 (The
pKa of p isomer is 3.4, Scheme 3.22). A nitro group withdraws electrons inductively. It also
withdraws electrons via resonance provided it is ortho or para to the COOH group. The ortho
substituent is far stronger due to greater inductive electron withdrawal from a closer position.
EXERCISE 3.3
Which of the two benzoates (I or II, Scheme 3.22a) will show a faster rate of
ionization.
G
G
O +
+ –
O OOC
(I) G = NO2, (II) G = CH3
SCHEME 3.22a
ANSWER. The substituent which stabilizes the benzoate ion will make the benzoic
acid more acidic (decreased pKa). A nitro group is an electron-withdrawing group
and it increases the acidity of a benzoic acid. Thus since NO2 group stabilizes the
benzoate ion with its presence, the rate of ionization will go up, consequently (I)
will display a faster rate of ionization. Methyl ion is an electron-releasing group,
it will make the benzoate ion less stable to lower the rate of ionization.
2. Acidity of sulphonic acids

Benzenesulphonic acid and its derivatives e.g., p-toluene sulphonic acid are useful as strong
acid catalysts in organic synthesis, as useful alternatives to sulphuric acid for, while being
strong acids they do not bring about the side reactions, e.g., oxidation and sulphonation which
is characteristic of sulphuric acid. The strong –I effect of sulphone group (-SO2-, sulphur is
slightly more electronegative than carbon, and thus sulphonate anion is stabilized more than
the carboxylate anion) and greater delocalization of the charge in the sulphonate anion compared
to that in the carboxylate anion makes sulphonic acids very much stronger than carboxylic
acids (Scheme 3.23).
—SO3H —COOH
Benzenesulphonic acid Benzoic acid

pKa –6 pKa 5
O O– O –O
– +2 –
C6H5—S—O C6H5—S O C6H5—S O C6H5—S—O
O O O– –O
The sulfonate ion has three equivalent resonance forms
O O–
–
C6H5—C—O C6H5—C O
The carboxylate ion has two equivalent resonance forms
SCHEME 3.23
Super Acids
Pure sulphuric acid is a stronger acid than sulphuric acid in water since aqueous
sulphuric acid is in fact H3O+. Super acids are defined as compounds which are
even stronger acids than 100% H2SO4. An example of a superacid is fluorosulphonic
acid. The inductive effect of the electronegative fluorine makes this a stronger acid
than sulphuric acid. This super acid is made further stronger on addition of a
Lewis acid e.g., SbF5. Antimony pentafluoride complexes with the conjugate base
of fluorosulphonic acid, decreasing its basicity. This mixture, termed magic acid
is very strong and can protonate extremely weak bases e.g., electron pair of a carbon-
carbon pi bond (Scheme 3.23a). The carbocation thus generated is stable enough
in the solution of magic acid to be studied.
O O
H—O—S—O—H F—S—O—H
O O
Sulphuric acid Fluorosulphonic acid
H 3C O H 3C O
+ –
C CH2 + H—O—S—F + SbF5 C—CH3 + F—S—O—SbF5
H 3C O H 3C O
Very Lewis acid A carbocation
weak base
SCHEME 3.23a
G. Olah received Nobel Prize (1994) for this work on carbocations and superacids.
3. Acidity of N—H groups

Because nitrogen is much less electronegative than oxygen, the pKa e.g., of an amide is more
than ten units larger than that of a carboxylic acid. Amides with one or two protons on the
nitrogen are deprotonated at nitrogen to form an amidate ion which is resonance stabilized.
The amidate ion is synthetically useful nucleophile, which is initially formed during Hoffmann
rearrangement (see, Scheme 15.15). When N—H group is bonded to two carbonyl groups, its
acidic properties are enhanced because the negative charge of the conjugate base is
delocalized over both oxygens and the nitrogen. The pKa of phthalimide is 8.3 and in aqueous
:O : O:– :O
:
O
–
:OH
: :
:N—H :N:– N: N:
O :O :O :O : –
:
Phthalimide Phthalimide anion

SCHEME 3.24
basic solution, the imide is converted almost completely into the anion (Scheme 3.24). Use is
made of the acidity of imides in a method for forming C—N bonds e.g., in Gabriel synthesis of
amines. Phthalimide anion has nucleophilic properties and can enter into displacement reactions
with alkyl halides.
4. Acidity of C—H groups
The sp3 C—H bonds are less acidic than N—H bonds so that strong bases must be used to
break them. Allyl cations and radicals are stabilized by resonance (see, Scheme 2.11). The sp3
hybridized C—H bond in propene (pKa = 40) is more acidic than in propane (pKa = 50). The
allyl anion formed by deprotonation of propene is stabilized by resonance (Scheme 3.25). When
the conjugation of the allyl ion is extended further, the additional resonance contributors further
stabilize the anion. The deprotonation of 1, 3-pentadiene (CH2 CH—CH CH—CH3, pKa = 33)
is thus easier when compared to propene (Scheme 3.25).
–
H :B
– – – – –
Propene Allyl anion The pentadienyl anion

Allyl anion, formed by the
deprotonation of propene
SCHEME 3.25
An anion formed from deprotonation of a C—H bond adjacent to a carbonyl group

(α-proton) is also stabilized by resonance (Scheme 3.26).
O O O–
H H H
H3C C H3C C– H3C C
H H : B– H H
Ketone Enolate anion
SCHEME 3.26
The resulting anion is stabilized not only because of delocalization as in the case of allyl
anion, but also because one of the resonance contributors has negative charge on the more
electronegative oxygen atom. Thus the pKa values of aldehydes and ketones (19–21) are not
only much lower than those in alkanes (Scheme 3.27) but much lower than the pKa values of
H
O O O O O
CH2
H H H H H H CH2
A hydrocarbon A ketone A 1, 3-diketone
(pKa 51) (pKa 19) (pKa 9) (I)
SCHEME 3.27
ethene (pKa = 44) and ethyne (pKa = 25), but higher than those of alcohols (pKa = 15–18). When
two carbonyl groups are adjacent to the same carbon atom as in 1, 3 relationship (in β-diketones
deprotonation gives an anion with charge delocalization over three atoms (two oxygen atoms
and one carbon atom) much the same way as in the pentadienyl anion. (Scheme 3.28). Other
β-dicarbonyl compounds are β-keto esters (RCOCH2COOR) and β-diesters (ROCOCH2COOR).
The anion resulting from deprotonation of a 1, 3-diketone is more stable than a simple enolate
anion, and as a result, 1, 3-diketones (and other 1, 3-dicarbonyl compounds) are more acidic
than simple ketones. However, the effect of the second carbonyl group on acidity is not as great
as that of the first. The 1, 3-diketone (I, Scheme 3.27) lacks the normal acidic properties of a
1, 3-diketone, since the corresponding enolate would have a bridgehead double bond (Bredt
rule violation, see Scheme 1.37).
O O O O –O O O O–
–
H H H H H
: B–
Resonance structures of the enolate anion of a 1, 3-diketone
SCHEME 3.28
Generation of aromaticity can significantly promote the loss of a proton. Deprotonation

of cyclopentadiene generates the cyclopentadienyl anion, which contains six (that is, 4n + 2π)
electrons in a Hückel aromatic system. The pKa of cyclopentadiene (16) is much lower than
that of 1, 4 pentadiene (40) and is, in fact, very close to that of water (15.7), despite the cleavage
of a C—H rather than an O—H bond (Scheme 3.29). However, 8π electron cycloheptatrienyl
anion is very difficult to prepare. Thus cycloheptatriene is much less acidic than cyclopentadiene.
The decreased acidity is due to the fact that the cycloheptatrienyl anion with 8π electrons is
not a stable Hückel aromatic system.
When the C—H bond is adjacent to one group of –M type; pK values lie in the range
10–20. Reactions involving anions derived from these substrates are the aldol condensation
( >CH—CHO and >CH—COR), the Claisen condensation ( >CH—CO2R) and the Thorpe reaction
( >CH—CN). When the C—H bond is adjacent to two groups of –M type as in ethyl acetoacetate,
CH3COCH2CO2Et, and diethyl malonate, CH2(CO2Et)2, the pK values of such compounds are
in the range 4–12. When the C—H bond is part of cyclopentadiene or a derivative, the compounds
are acidic because the derived anion, having six π-electrons and fulfilling the criteria for
aromaticity, is strongly resonance stabilized (see, Scheme 3.29).
H H :B–
H
H H H
–
–
pKa = 40
Cyclopentadiene Aromatic anion
has a pKa of 16
H H :B–
–
:
Cycloheptatriene Cycloheptatrienyl anion

a pKa of about 40 antiaromatic
SCHEME 3.29
Carbonyl is one of the number of groups of –M type which have a marked acid promoting
influence. The cyano group (–C N) and the nitro group (–NO2) also withdraw electrons and
cause α-hydrogens to be somewhat acidic. The resulting carbanions are stabilized by resonance
(Scheme 3.30).
:
:
—C—C N —C—C N: C C N : + B: H
:
–
H B :–
O:–
:
:
:
O O
:
+
+ B: H
: : :
: : :
—C—N —C—N C N
+ O: – :– O:– + : –
:O
:
H B :–
SCHEME 3.30
The α-hydrogen atoms to an alkyl side chain at the 2 or 4 (α or γ) position of a pyridine

ring are comparable in acidity with methyl ketones and therefore, readily undergo base catalysed
reactions. Thus, reaction of a carbonyl group with the alkyl anion formed by base provides a
method for extending the pyridine side chain as in the case of γ-picoline. The acidity at this
position is due to the formation of a resonance stabilized anion with negative charge on nitrogen
(Scheme 3.30a).
–
CH3 CH2Na+ CH CHC6H5
C6H5CHO
+ NaOH + H2O
N N N
g-picoline
– : CH
2 CH2 CH2 CH2
–: :–
–
:
N N N N
:
Anion from g-picoline
SCHEME 3.30a
The enhanced acidity of the hydrogen atoms of an alkyl side chain at α positions is also
due to the delocalization of negative charge in the intermediate anion onto the ring, particularly
onto the nitrogen (Scheme 3.30b).
– –
–
: :
N CH2 N CH2 N CH2 –N CH2

:
SCHEME 3.30b
However, the removal of a proton from β-picoline gives only a higher energy anion with
negative charge only on carbons and none on nitrogen.
The conjugate base of 1, 3-dithiane is valuable in synthetic applications as a nucleophile.
The anion is produced by deprotonation of 1, 3-dithiane using n-butyl lithium (Scheme 3.30c).
1, 3-dithiane is a weak proton acid (pKa = 32). The hydrogens on the methylene group positioned
between two sulphur atoms in 1, 3-dithiacyclohexane are relatively acidic, since the negative
charge in the carbanion is stabilized by delocalization to each S by p-d π bonding. A 1, 3-dithiane
can be prepared by the reaction of 1, 3-propanedithiol with an aldehyde (HCHO in this case).
Among the many synthetic uses, aldehydes e.g., may be prepared by alkylating 1, 3-dithiane at
C-2 followed by hydrolysis of the resulting thioacetal (see Schemes 7.31–7.34).
O
SH SH BuLi R—X Hg 2+
C S S S S – S S RCHO
BF3 –X H2O
H H C C: – SN2 H R
H H
H
1, 3-dithiane Anion
pKa = 32
SCHEME 3.30c
(E) Effect of Hydrogen Bonding

When an acidic hydrogen is involved in a hydrogen bond with another atom in the same molecule
then the strength of the acid is decreased. It is more difficult for a base to remove the proton
since the hydrogen bond must also be broken along with sigma bond to the hydrogen. However,
this effect is complicated by the inductive effect of the group involved in the hydrogen bond.
The acetyl group is electron withdrawing and its location on the benzene ring opposite the
carboxylic acid group increases the strength of this acid in comparison to benzoic acid (Scheme
3.31). However, when this group is present adjacent to COOH group it leads to an acid weakening
effect. Infact its pKa now becomes almost similar to that of benzoic acid. This is due to acid
weakening effect of the hydrogen bonding.
O O O O—H
Intramolecular
COH COH C hydrogen bond
O
CCH3
Benzoic acid o-Acetylbenzoic acid

pKa = 4.19 CCH3 pKa = 4.13
O
p- Acetylbenzoic acid
pKa = 3.70
SCHEME 3.31
3.4 BASES
Nitrogen is the most important basic element in uncharged bases. An amine is nucleophile
since its lone pair of nonbonding electrons can form a bond with an electrophile. An amine also
behaves like a base by accepting a proton from a proton acid (I, Scheme 3.32). A convenient
expression for relating basicities is a quantity called the basicity constant Kb or its negative
logarithm pKb. When an amine dissolves in water, the equilibrium (Scheme 3.32) is established.
The larger the value of Kb (or the smaller the value of pKb), the greater is the tendency of the
amine to accept a proton from water and, thus, the greater will be the concentrations of RNH3+
and OH– in the solution. Larger values of Kb, therefore, are associated with those amines that
are stronger bases, and smaller values of Kb are associated with those amines that are weaker
bases. (Just the opposite is true for values of pKb). A structural feature which tends to stabilize
the ammonium ion (relative to the free amine) makes the amine a stronger base. A structural
feature which stabilizes the free amine (relative to the ammonium ion) makes the amine a
weak base.
+ –
:
RNH2 + HX RNH3 + X : ... (I)
Kb + [RNH3+ ] [OH–]
–
:
RNH2 + H2O RNH3 + OH Kb = pKb = – log Kb

[RNH2]
SCHEME 3.32
Strength of Bases in Terms of their Conjugate Acids

Amines e.g., have very high pKa values and therefore, these do not behave as acids.
Ammonia also has a high pKa(Scheme 3.32a). Thus amines behave as typical
organic bases. Instead of specifying
the strength of a base in terms of its CH3NH2 NH3
pKb value, it is convenient to express Methylamine Ammonia
the strength of its conjugate acid and pKa = 40 pKa = 36
indicate it by its pKa value. Thus the
stronger the acid, the weaker is its +
CH3NH3 CH3CH2NH3
+
conjugate base. Protonated
Protonated methylamine Protonated ethylamine
methylamine is a stronger acid than pKa = 10.7 pKa = 11.0
protonated ethylamine and this
reflects that methylamine is a weaker
SCHEME 3.32a
base compared to ethylamine.
3.5 RELATION BETWEEN STRUCTURE AND BASICITY

(A) General Discussion
– –
The anions, e.g., NH2 and EtO and neutral molecules with at least one unshared pair of
electrons e.g., NH3 and EtOH represent the common bases. For the former types, the basicity
is weakened by any factor which stabilizes the negative charge of the anion, while for the
latter, the basicity is increased by any factor which stabilizes the positive charge on the
conjugate acid of the base. Anionic bases are far more strong than their neutral analogues
(e.g., NH2– >>NH3).
In the case of anionic bases the charge is generally associated with oxygen, nitrogen or
carbon. The electronegativities of these elements follow the order O > N > C, the order of
– – –
basicities is therefore, R3C > R2N > RO . Thus, amide ion is a far stronger base than hydroxide
–
ion, and methide ion (CH3 ) is so high in energy that it does not exist in organic media. However
–
in Ph3C where the negative charge is delocalized by the aromatic rings is more stable and is
used (as sodium triphenylmethyl) in some reactions which need a particularly powerful base.
– – – –
Basicities of oxy-anions follow the order: (CH3)3CO > CH3O > PhO > CH3CO2 , and these are
based on the principles which govern acidity: t-butoxide ion is a stronger base than methoxide
ion since the three electron-releasing methyl groups in the former destabilize the negative
charge; phenoxide ion is a weaker base than the alkoxide ion because the charge is delocalized
over the aromatic ring; and acetate ion is still weaker because the charge delocalization by
oxygen is much more effective.
(B) Substitution by Alkyl Groups

If one examines the pKb values of the amines (Scheme 3.33) it is seen that most primary
aliphatic amines (e.g., methylamine and ethylamine) are somewhat stronger bases than
ammonia (Recall that decreasing value of pKb indicate increasing base strength, just as the
higher the pKa, the weaker the acid). One may account for this on the basis of the electron
donating ability of an alkyl group. An alkyl group releases electrons, and it stabilizes the
ammonium ion that results from the acid-base reaction by dispersing its positive charge. It
stabilizes the ion to a greater extent than it stabilizes the amine. Thus in gas phase, the basicities
of these amines increase on methyl substitution i.e., (CH3)3 N > (CH3)2 NH > CH3NH2 > NH3
and thus the trend is regular.
:
NH3 CH3NH2 CH3NHCH3

pKb = 4.74 3.36 3.27
Increasing basicity
H
+
:
R N—H H—X R—N—H + X: –
H H
By releasing electrons, R
stabilizes the ammonium ion
through dispersal of charge
SCHEME 3.33
Interestingly, however, in aqueous solution the order of basicities is different and it is

found that instead trimethylamine (pKb 4.19) is a weaker base than dimethylamine (pKb 3.27).
In gas phase there is no solvation and only the stabilizing effect of methyl group(s) remains
and each replacement of hydrogen with a methyl group has its stabilizing effect and therefore,
the trend of basicities is regular. The ammonium ion is also stabilized by solvation in the
presence of solvent (Scheme 3.33a). Trimethylamine is more hindered and its ammonium ion
is less stabilized by solvation. Thus, these effects operate in different directions. In solution an
alkyl group effects the stability of the ammonium ion in two ways it stabilizes by dispersing
the charge and also it destabilizes the ammonium ion by interfering with solvation.
H
+
H3C—N—H
H H
+ H H Hydrogen bonding
:
Stabilization with a H3C—N O
providing stability
:
polar solvent via H
dipole-dipole H
interaction H—OH
Stabilization of an ammonium ion by solvation
SCHEME 3.33a
(C) Resonance Effects

Aromatic amines (the anilines and their derivaties) are much weaker bases than the simple
aliphatic amines. This reduced basicity is due to resonance stabilization of the nonbonding
electrons in the free aromatic amine. Thus in aniline, the lone pair of nonbonding electrons on
nitrogen is stabilized by overlap with the p orbitals of the ring (Scheme 3.34). On accepting a
proton aniline is converted to an anilinium ion (Scheme 3.35) and now one can write only two
resonance structures for the ion.
Cyclo-C6H11NH2 C6H5NH2 p-CH3C6H4NH2

pKb = 3.36 9.42 8.92
Cyclohexylamine Aromatic amines
nonaromatic amine
+ + +
:
NH2 NH2 NH2 NH2 NH2
:– –:
–
:
SCHEME 3.34
+ +
NH3 NH3
+ –
:
C6H5NH2 + H2O C6H5NH3 + OH

Anilinium ion
SCHEME 3.35
Thus aniline is stabilized in comparison to the ion, and aniline is not as basic as the
aliphatic amines.
Electron-releasing groups with +I effect e.g., alkyl groups increase the basicity of
aromatic amines, while electron-withdrawing groups e.g., halogen, nitro, carbonyl decrease
their basicity. Decrease in basicity by halogen substitution is due to the electron-withdrawing
inductive effect of the electronegative halogen. Decrease in basicity due to the presence of
–NO2 on the aromatic ring reflects a combination of inductive and resonance effects.
The basicity-decreasing effect of nitro substitution in the 3 position (Scheme 3.35a) is
due to its inductive effect, whereas nitro substitution in the 4 position is due to both inductive
as well as resonance effects. In the case of para substitution (and ortho substitution as well),
delocalization of the lone pair on the amino nitrogen involves not only the carbons of the
aromatic ring but also oxygen atoms of the nitro group.
O2N
: –:
:
O O
+
:
:
NH2
:
N—
+ :
—NH2
:
N
+
NH2
3-nitroaniline – O: – O:
:
:
(pKb 11.5) 4-nitroaniline
(pKb 13.0)
SCHEME 3.35a
One easily understands as to why compared with N, N-dimethylaniline (I, Scheme 3.35b)
2, 6-dimethyl N, N-dimethylaniline (II) is much more basic. The extended π bonding between
the amino nitrogen and the ring can be attained (base weakening structural feature) only if
the σ bonds on N attain coplanarity with the ring and its ortho bonds, as is so in the case of
(I, Scheme, 3.35b). The presence of bulky substituents in the ortho position hinders the
attainment of planar geometry. Due to this steric inhibition of resonance (II, Scheme 3.35b) is
a stronger base than I (see also Scheme 2.9).
H CH3
CH3 CH3
+
–:
:
N —N
CH3 CH3
H CH3
(II)
(I) Steric inhibition of resonance
SCHEME 3.35b
Pyrrole is a very weak base (pKb ~ 15). Pyrrole is aromatic because the lone pair of
electrons on nitrogen is located in a p orbital, and these electrons contribute to the aromatic
sextet. Pyrrole is thus extremely non-basic. Very strong acid is required to bring about
protonation which does not occur on nitrogen but on C-2. Protonation at nitrogen gives an
ammonium ion with no resonance stabilization, while protonation at the α-carbon (Scheme 3.36)
gives a cation which can be described by three resonance forms.
– +
–X
H—X : H H H
: :
+ vs
+ H H +
:
:
N N H N N N
H H H H H H
Pyrrole aromatic Not aromatic
(lone pair in p system)
Pyrrole is protonated on carbon and not nitrogen
SCHEME 3.36
Amides (pKb ~ 14) are far less basic and even less basic than aryl amines. The lower
basicity of amides than amines is explained by resonance. An amide is stabilized by resonance
involving the nonbonding pair of electrons on the nitrogen atom, and an amide protonated on
its nitrogen atom does not display this type of resonance stabilization (Scheme 3.37). A more
:O : O :– : O :– :O : O :–
:
:
+ + +
:
R—C—NH2 R—C—NH2 R—C NH2 R—C—NH3 R—C — NH3

+ +
Amide N-protonated
Larger resonance stabilization amide
Smaller resonance stabilization
SCHEME 3.37
important factor to account for amides being weaker bases than amines is the powerful electron-
withdrawing effect of the carbonyl group of the amide. This means that the equilibrium
(II, Scheme 3.38) lies almost to the left as compared to reaction (I, Scheme 3.38). The nitrogen
O O
+ – + –
:
R—C NH2 + H2O R—C NH3 + OH R NH2 + H2O R NH3 + OH (II)

(I)
SCHEME 3.38
atoms of amides are so weakly basic that if an amide accepts a proton, it does so on its oxygen
atom. Protonation on the oxygen atom occurs even though oxygen atom (because of their greater
electronegativity) is typically less basic than nitrogen atom. If an amide accepts a proton on its
oxygen atom, resonance stabilization involving the nonbonding electron pair of the nitrogen
atoms is still operative (Scheme 3.39).
+
:
:OH :OH :OH

+
:
R—C—NH2 R—C—NH2 R—C NH2

+
SCHEME 3.39
(D) Hybridization Effects

The study of terminal alkynes showed that electrons are held more tightly by orbitals with
more s character. This principle is also used to explain the relative basicities of unsaturated
amines. Pyridine is a weaker base than the simple aliphatic amines. In pyridine the nonbonding
electrons occupy a sp2 hybrid orbital with greater s character (Scheme 3.40) and has more
tightly held electrons than those in the sp3 orbital of an aliphatic amine, therefore, pyridine’s
nonbonding electrons are not that available for bonding to a proton. Since pyridine retains its
aromaticity upon protonation, it is even more stronger base than pyrrole (Scheme 3.36). The
nitrile’s lone pair occupies an sp-hybridized orbital with 50 per cent s character. This orbital is
close to the nucleus and these electrons are tightly bound and relatively unreactive to make it
a very weak base.
H
2 sp3
sp hybridized sp
N :
N :
CH3—C N :
Acetonitrile Pyridine Piperidine
pKb = 24 pKb = 8.75 pKb = 2.88
SCHEME 3.40
Consider, for example guanidine (Scheme 3.41), which probably is the strongest, organic
nitrogen containing base (Kb = 1), as strong as the alkali metal hydroxides. Considering the s
character, the N (sp3) of NH2 has less s character compared with N (sp2) of the imino group
(= NH). However, actually it is the imino nitrogen which is protonated, since this would lead to
the formation of a symmetrical resonance stabilized system with three equivalent contributing
structures. The delocalization energy is therefore large and the conjugate acid formed by
guanidine is unusally stable.
H2N +
:
:
H2N +
H 2N H2N
H +
:
:
:
C NH C NH2 C NH2 C NH2

H 2N : H 2N : H2N: H 2N +
Guanidine is a
strong base (Kb 1)
SCHEME 3.41
(E) Some Typical Bases and Their Reactions

The amount of enolate formed from a carbonyl compound depends on the pKa of the carbonyl
compound and the base used to remove the α-hydrogen. Thus, when hydroxide ion (the pKa of
its conjugate acid is 16) removes an α-hydrogen from cyclohexanone (pKa = 17), only a small
amount of the enolate is formed since hydroxide ion is a weaker base than the base being
formed (I, Scheme 3.42). However, the use of strong non-nucleophilic bases like LDA (pKa = 35)
allows the conversion of carbonyl compounds (pKa of α protons 20–25) completely to enolate
anions (nucleophiles). This may be necessary in several situations e.g., during aldol condensation
(see Scheme 6.9) when the carbonyl compound has no chance to condense with itself. Moreover,
generation of enolates with LDA provides a useful technique to alkylate ketones regioselectively
(Scheme 3.42a, for details see Scheme 3.43d).
–
O O O
–
–
+ HO + H2O (I)
pKa = 17 0.1% pKa = 16

(Enolate)
–
O O O
–
+ LDA + DIA (diisopropylamine) (II)
pKa = 17 100% pKa = 35
LDA is a base of choice for converting a carbonyl compound completely

to an enolate, before it reacts with an electrophile
SCHEME 3.42
+
Li –
O O O
H 3C H 3C H 3C CH3
LDA CH3—I
SCHEME 3.42a
Alkylation of the α-carbon of a carbonyl compound is an important reaction. Alkylation

is carried out by first removing a proton from the α-carbon with LDA and then adding the
appropriate alkyl halide. The reaction works best with primary alkyl halides (being an SN2
reaction, Scheme 3.42a).
Dehydrohalogenation of an alkyl halide gives a mixture of alkenes in which either the
more substituted (more stable) or less substituted alkene may be formed as the major product
(Scheme 3.43). The steric bulk of the base is partly responsible for this behaviour. For the
bulky t-butoxide ion it is easier to remove a more exposed (1°) hydrogen atom than the internal
(2°) hydrogen atom.
CH3
ethoxide ion
CH3CH C (major product)
CH3 CH3
2-methyl-2-butene
CH3CH2C—CH3
Br CH2
2-bromo-2-methylbutane CH3CH2C (major product)
tert-butoxide CH3
ion
2-methyl-1-butene
SCHEME 3.43
Formation of Carbanionic Nucleophiles (Role of Very Strong Bases)

Several structural features make a proton attached to a carbon acidic which can
be removed by a base. Two such structural features are in phenylacetylene and
acetophenone. For the proton removal one chooses a base with a higher pKa than
the pKa of the proton to be removed in order to achieve a complete conversion to
carbanionic nucleophile. The pKa values are reviewed (Scheme 3.43a).
O O O
C C C—H
CH3 H H
pKa = 21 9 25
–
N
– –
CO3 RO Bu—Li KH
(LDA)
pKa = 12 15-19 35 > 35
SCHEME 3.43a
Significantly several bases e.g., BuLi can act as nucleophiles. If the structural
feature which makes the C—H proton acidic is itself an electrophile then a
nucleophilic base cannot be ued. Butyl lithium (pKa > 45) converts phenylacetylene
(pKa ~ 25) to its conjugate base by proton removal but, it reacts as a nucleophile
with the carbonyl group of acetophenone although the α protons of acetophenone
have pKa = 21 and are thus more acidic than the terminal proton in phenylacetylene
(Scheme 3.43b).
—BuH – +
C C—H + BuLi C C Li
pKa = 25
– +
O O Li
C + BuLi CH3
Bu
CH3
pKa = 21
SCHEME 3.43b
It is to solve such nucleophilicity problems that hindered and very strong bases
like LDA are used for the removal of acidic protons but themselves these are poor
nucleophiles. Thus LDA can remove a proton from acidic C—H bond, but it does
not attack the carbonyl group or other electrophilic centers.
3.6 SYNTHETIC APPLICATIONS OF LITHIUM DIISOPROPYLAMIDE (LDA)

(A) Preparation
It is prepared easily by adding butyl lithium to diisopropylamine (DIA) at –78°C in THF
(Scheme 3.43c).
CH3 CH3 CH3 CH3

– + THF –
CH3CHNHCHCH3 + CH3CH2CH2CH2Li CH3CHNCHCH3 + CH3CH2CH2CH3
–78°C +
Li
Diisopropylamine Butyllithium Lithium diisopropylamide Butane
pKa = 35 LDA pKa ~ 50
SCHEME 3.43c
(B) Enolate Regiomers

With an unsymmetric ketone, reaction with excess LDA at –78°C removes the proton from the
less highly substituted α-carbon to give a kinetic enolate (Scheme 3.43d). The less substituted
α-position has slightly more acidic protons, thus both steric and electronic factors lead to the
formation of kinetic enolate. The enolate with more highly substituted double bond, the
thermodynamic enolate is however, more stable. If a slight excess of ketone is used around
room temperature 25°C (instead of excess LDA) or trace of protic impurities are present, an
equilibrium is established to form thermodynamic enolate.
CH3 CH3
LDA ketone
or
H—X
O O– O–
Kinetic enolate Thermodynamic enolate
SCHEME 3.43d
The kinetic or thermodynamic enolates can be captured as enol trimethylsilyl ethers,

purified and regenerated (see, Scheme 6.5) for use in aldol condensations.
(C) Synthesis of Alkynes

Successive E2 eliminations can be carried out on geminal or vicinal dihalides for their conversion
into alkynes. The first elimination gives a vinyl halide and then to form an alkyne a powerful
base is needed to carry out the second dehydrohalogenation reaction. Previously NaNH2 in
liquid ammonia was employed, now LDA is the common base used (Scheme 3.43e) and both
the steps can be carried out with LDA itself.
H – +
Br – + (i-C3H7)2N Li
(CH3)3CO K Br
LDA
Ether–THF, 0–25°C THF, –25°C
Br H
H Cyclooctyne
SCHEME 3.43e
(D) Enolates from Esters

As expected enolates from esters can be generated which can be then alkylated (Scheme 3.43f).
– +
O O Li O
– +
(i-C3H7)2N Li CH2 CHCH2Br CH2CH CH2
O O O
Tetrahydrofuran Hexamethylphosphoric
–78°C triamide –78°C
Lactone of
4-hydroxybutanoic
acid
SCHEME 3.43f
(E) Synthesis of Fused Rings

Intramolecular alkylation reactions of enolate anions are used in the synthesis of fused rings.
Thus e.g., the cyclization of a disubstituted cyclopentane gives two different fused ring
compounds depending on whether the reaction conditions favour the formation of kinetic enolate
or the thermodynamic enolate (Scheme 3.43g).
O CH3 –
O K+ O
C
– + CCH3
C (CH3)3CO K
CH3
–KBr
CH2CH2CH2—Br CH2CH2CH2Br
Thermodynamic enolate
LDA –78°C
– +
O O Li
–LiBr C
CH2
CH2CH2CH2—Br
Kinetic enolate
SCHEME 3.43g
EXERCISE 3.4
Predict the product from the reaction (Scheme 3.43h) at two different temperature
conditions?
CH3 CH3
O
– + – +
(1) (CH3CH)2N Li CH2 (1) (CH3CH)2N Li
25°C –78°C
(2) CH3I (excess) (2) CH3I (excess)
SCHEME 3.43h
ANSWER. At lower temperature, kinetic enolate is exclusive which gives the

corresponding alkylated product (Scheme 3.43i). At higher temperature
(equilibrium conditions) the major product is derived from thermodynamic enolate.
– + – +
O Li O O Li O
C6H5—CH2 C6H5—CH2 CH3 C6H5—CH2 C6H5—CH2
CH3
Kinetic enolate Thermodynamic enolate
SCHEME 3.43i
The alkylations of enolates (see Scheme 3.42a) are typically SN2 reactions which work
well with primary alkyl halides/CH3I. Recall that enolates are strong bases and use of secondary
and tertiary alkyl halides leads to predominant elimination. One can work successfully with
tertiary halides by using silyl enol ethers (see Scheme 6.43b).
3.7 ACID-BASE REACTIONS

In general, acid-base reactions always favour the formation of the weaker acid and the weaker
base. The reason for this is that the outcome of an acid-base reaction is determined by the
position of an equilibrium. Acid-base reactions are thus under equilibrium control to favour
the formation of the most stable (lowest potential energy) species. The weaker acid and weaker
base are more stable (lower in potential energy) than the stronger acid and stronger base.
Thus phenol reacts with sodium hydroxide to form water soluble salts, while it does not react
with a weaker base like sodium bicarbonate (Scheme 3.44).
This concept is used in the synthesis of deuterium and tritium labeled compounds often
needed in the study mechanism of organic reactions (Scheme 3.44). Similar reactions involve
the replacement of the α-hydrogen by deuterium via a carbanion formation (Scheme 3.45). The
reaction occurs when an aldehyde or a ketone is dissolved in deuterium oxide containing sodium
deuteroxide as the base. These isotopic exchange studies provide a strong evidence for
α-carbanion formation.
– +
OH + NaHCO3 O Na + H2CO3
Phenol Sodium Sodium Carbonic acid

pKa = 9.95 bicarbonate phenoxide pKa = 6.36
(weaker acid) (weaker base) (stronger base) (stronger acid)
– +
OH + NaOH O Na + H2O
Phenol Sodium Sodium Water

pKa = 9.95 hydroxide phenoxide pKa = 15.7
(stronger acid) (stronger base) (weaker base) (weaker acid)
CH3 CH3
– + hexane –
CH3CH: Li + D2O CH3CH—D + OD
Isopropyllithium (Stronger acid) 2-deuteriopropane (Weaker base)
(stronger base) (weaker acid)
SCHEME 3.44
O O Strong base O
– k2 k2 –
: :
: :
: :
R—C—C— + : OD R—C—C— + H—OD R—C—C— + : OD
:
–
H D
: :
D—OD (serves as acid)
SCHEME 3.45
3.8 THE EFFECTS OF THE SOLVENT ON ACID AND BASE STRENGTH

One has already seen that inductive stabilization and steric hindrance of solvation act in opposite
directions in the case of amines. These results are helpful in explaining the basicity of amines.
A solvent can exert considerable influence on acid and base strengths by differential solvation.
In the gas phase where the solvation effects are absent the basicity order of amines toward the
proton are R3N > R2NH > RNH2 > NH3. This change in their basicities in the gas phase can
now be explained by the electron donating effect of alkyl groups.
A more important aspect of the effect of solvent deals with its orientation (i.e., entropy
change) when an acid or a base is converted into its conjugate. If one considers the effect of a
solvent on acidity, it is seen that in the absence of a solvent (i.e., in the gas phase) most acids
are far weaker than these are in solution. Acetic acid in gas phase has a pKa of about 130.
When one considers the conversion of CH3COOH to CH3COO– in aqueous solution, one deals
with solvation of both CH3COOH and CH3COO– by water via hydrogen bonding. The solvent
molecules arrange themselves around the CH3COO– group in a much more orderly fashion
than they arrange around the CH3COOH itself (the hydrogen bonding to CH3COO– is far more
stronger than to CH3COOH since the water molecules are more attracted to the negative
charge). Thus on this ionization, there is decrease in entropy (loss of freedom, solvation of a
species decreases the entropy of the solvent). Recall that it is only the positive entropy change
(from order to disorder) which makes a negative contribution to ∆G° and is energetically
favourable for the formation of products (see, Scheme 4.9). Thus the entropy change (∆S°) for
the ionization of acetic acid is negative i.e., the –T ∆S° term in equation ∆G° = ∆H° – T ∆S°
leads to an acid-weakening positive contribution to ∆G°. A fact which has been proved
experimentally from the thermodynamic values for the dissociation of acetic acid and its
comparison with chloroacetic acid. In the case of simple aliphatic and halogenated aliphatic
acids in aqueous solutions at room temperature, it has indeed been shown, that entropy (T ∆ S)
usually contributes much more to the total free energy change ∆G compared to enthalpy ∆H.
Resonance and electron withdrawing effects of functional groups in RCOOH, effect its acidity
in two distinct ways. These groups effect the enthalpy (electron withdrawal increases the acidity
by stabilizing RCOO– by dispersing charge) and also the entropy.
Chloroacetic acid is a stronger acid compared to acetic acid and this increased acidity is
due to the presence of electro-withdrawing chlorine atom. This electron withdrawal helps to
spread the negative charge all over the chloroacetate ion. The chlorine atom therefore, makes
the chloroacetate ion ClCH2COO– less prone to bring about an ordering of the solvent compared
to CH3COO–, since it now requires less stabilization through solvation (i.e., during the ionization
of ClCH2COOH, the solvent molecules have much more freedom and consequently a higher
entropy).
3.9 LEVELING EFFECT

The acid strengths of two strong acids, HY and HX cannot be compared in H2O. Strong acids,
especially in dilute solutions are practically completely ionized in H2O, consequently the only
acid present is H3O+. This is known as the leveling effect. It is necessary to compare them in a
solvent which is much less basic than water so that an equilibrium is established with both the
unionized acids and their conjugate bases present. The solvent of choice is 100% (glacial) acetic
acid (Scheme 3.46).
+ – – +
HX + H2O H 3O + X HX + HOAc X + H2OAc
In H2O In HOAc
Leveling effect of solvent

SCHEME 3.46
3.10 HARD AND SOFT ACIDS AND BASES

A qualitative classification is used to characterize the acidity and basicity of Lewis acids and
bases. Hard acids (electron pair acceptors) generally have a small electron acceptor site of high
positive charge and do not possess unshared pairs of electrons in their valence shells. Hard
acids are characterized by high electronegativity and have less polarizable sites examples are:
H+, BF3, CO2, SO3, Li+, Na+. Hard bases (electron pair donors) are generally difficult to oxidize
and have no empty low energy orbitals available. Hard bases are characterized by a highly
electronegative donor atom of low polarizability. Example are: H2O, OH–, ROH, RNH2, F–. Soft
acids are characterized by a large electron acceptor atom of high polarizability (e.g., BH3, Br2,
I2, Cu+, Ag+, Pd2+).
Soft bases (e.g., CN–, C2H4, C6H6, H–, CO, R2S) normally have electrons which are easily
removed by oxidizing agents and have empty orbitals of low energy. Soft bases are characterized
by a polarizable donor atom. Soft bases combine best with soft acids whereas hard acids combine
best with hard acids. BH3 (a soft acid) forms more stable complexes with soft bases like carbon
monoxide and olefins than with hard bases. On the other hand, the hard acid-hard base complex
BF3. OR2 is more stable than BF3. SR2, a hard acid-soft base complex. In BF3, boron is largely
B3+ because of the electronegative fluorines, hence BF3 is hard; in BH3, boron is largely neutral,
hence BH3 is soft. The softer bases react best in displacement reactions, thus the attacked
carbon in an alkyl halide RX must also be soft like.
PROBLEMS
3.1 How one explains the acidity of nitromethane (CH3NO2, pKa = 10.2)?
3.2 Comment on the acidity of C—H bond in a haloform.
3.3 Why amidines are far stronger base than amines?
3.4 Write the structure of the intermediate and the product formed by the based catalysed
(NaNH2) reaction of the following pyridine with methyl iodide.
CH3
CH2CH3
3.5 Why the following reaction proceeds under milder conditions compared to the one in
Scheme 3.30a?
N
H
+ OH
–
I N CH3 N CH2CH—
+
CHO CH3
CH3
3.6 Why isocyanic acid, HN C O, and cyanic acid, N C–OH, have the same conjugate
base?
3.7 Which out of the following pair is more basic?
(I) 4-cyanoaniline and 4-nitroaniline
(II) Diethylamine and pyrrolidine
(III) Amine and alcohol
(IV) o-chloroaniline and p-chloroaniline.

3.1 Loss of proton gives an anion whose charge is delocalized onto the oxygen atoms of the
nitro group.
: O: – :O:–
:
: O:
– + + – +
: CH2—N CH2 N : CH2 N
: O: : O: : O:
– –
:
Resonance contributors for the carbanion from nitromethane
3.2 This bond is acidic, since the conjugate base is stabilized both by the inductive effects of
three halogen atoms and by charge-delocalization, for the halogens (other than fluorine)
have unfilled and relatively low-lying d orbitals. These anions, by loss of a halide ion,
give carbenes which are reactive intermediates.
– –
Cl –
Cl Cl Cl Cl Cl Cl Cl
:
C C C C
–
Cl Cl Cl Cl
3.3 Because both the base and its conjugate acid are resonance-stabilized, the stabilization
energy of the latter, whose principle canonical structures are equivalent, is greater than
that of the former, in which one of the corresponding structure is dipolar and of high
energy.
+ +
NH2 NH2 NH2 NH2
R—C R—C R—C R—C
– +
NH NH NH2 NH2
Amidine
3.4 Only the hydrogens of the alkyl group either in 2- or 4-position are acidic.
–
:
CH2 CH2CH3
CH2CH3 CH2CH3
CH3I
N N
3, 4-diethylpyridine
3.5 This is due to enhancement of the side chain acidity in the N-alkylpyridinium compound.
3.6 The loss of proton from both the acids gives the conjugate bases which in fact are the
contributing structures of the same resonance hybrid.
+
–H – – –H+
O: :N C O: :N O: :N O: H
:
: :
: :
HN C C C
d– d–
:N C O:
:
Hybrid
+ NH2 + NH2
3.7 (I) 4-Cyanoaniline. In 4-nitroaniline, the base weak-
ening electron delocalization is more effective, the
negative charge here ends up with more
electronegative oxygen than with the CN group
where it ends up with less electronegative nitrogen. C
–
N
–
O O
:N –
:
(II) Diethylamine pKb = 3.01 is a weaker base than

nonaromatic heterocyclic amine pyrrolidine
pKb = 2.73. In the later the alkyl groups are ‘‘tied
CH3CH2NHCH2H3
back’’ away from the unshared electrons of the
N
nitrogen. This infact is the case with nonaromatic Diethylamine
H
heterocyclic amines which are more basic compared Pyrrolidine
with open chain secondary amines of same size.
(III) Amines are much stronger bases compared + +

with alcohols. One can focus not on the NH4 OH3
basicity of the amine, but on the bronsted Ammonium ion Oxonium ion
acidity of its conjugate acid, the ammonium
pKa = 9.2 pKa = – 1.7
ion. In case the ammonium ion is a strong
acid, the related amine must be a weak +
N(CH3)4 Cl
– +
O(CH3)3 BF4
–
base. This is due to the fact that oxygen is
Tetramethylammonium Trimethyloxonium
more electronegative atom compared to chloride, a stable solid fluoroborate, very
nitrogen and thus can accomodate the reactive
negative charge much better.
(IV) The inductive effect of chlorine in the ortho position is more (being closer to the
amino group) than when it is present in the para position. Thus the more effective
inductive effect removes more electron density from nitrogen and therefore ortho
isomer is the weaker base.
CHAPTER 4 +
C 120°
.
Organic Reactions and the
:
C
–
C
Determination of their
Mechanisms
Most organic reactions can be placed in one of the six classes:
1. Substitution,
2. Addition,
3. Elimination,
4. Rearrangement,
5. Pericyclic reactions, and
6. Complex reactions.
Each of these terms describes an operation which occurs during a reaction on an organic
compound. The organic compound undergoing structural or functional group changes is called
a reactant or a substrate. A detailed and a stepwise description of the pathway by which
reactants are converted to products is termed as the reaction mechanism. An acceptable
mechanism has to account not only for structural changes and stereochemical outcome but the
energy changes as well that take place at every stage of the reaction.
4.1 MECHANISTIC CLASSIFICATION

(A) Substitution Reactions
In a substitution reaction one atom, ion or a group is substituted in a reactant by another. The
substituting species may be either a nucleophile, an electrophile or a free radical. Typical of
the aliphatic substitution reactions are SN2 type (Scheme 4.1). Aromatic electrophilic and
nucleophilic substitutions represent a typical class of their own. The species that attacks a
d+ d– –
–
: :
: :
: :
: :
HO : + CH3CH2—Br : CH3CH2—OH + : Br :
Hydroxide ion Bromoethane Ethanol The sigma-bond electrons
nucleophile (Nu : – ) leave with the halogen.
–
CH3O :–
: :
: :
: :
: :
+ CH3CH2CH2—Cl : CH3CH2CH2—OCH3 + : Cl :
Methoxide ion 1-chloropropane Methyl propyl ether
Nucleophilic SN2 substitution reactions
SCHEME 4.1
122
Organic Reactions and the Determination of their Mechanisms 123
reactant e.g., an alkyl halide (Scheme 4.1) in a substitution reaction is called a nucleophile
Nu:– (literally, “nucleus lover”). A nucleophile is generally any species that is attracted to a
positive center and a nucleophile is a Lewis base. Most nucleophiles are anions while some
neutral polar molecules like H2O, CH3OH, and CH3NH2 which have unshared electrons can be
used to form sigma bonds and act as nucleophiles. Substitutions by nucleophiles are called
nucleophilic substitutions, or nucleophilic displacements.
The opposite of a nucleophile is an electrophile E+ (“electron lover”). An electrophile is a
species that is attracted toward a negative center and thus an electrophile represents a Lewis
acid, such as H+ or ZnCl2.
Substitution on an aromatic ring is almost always the result of electrophilic reactions
(Scheme 4.1a). Here the aromatic stabilization dictates the reaction mechanism which is
substitution rather than addition. A large amount of resonance energy would have been lost if
instead of substitution, addition had occurred. In this example, the electrophile substitutes for
E H E
+
+ +
+ E + Nu : + NuH
Electrophilic aromatic substitution
SCHEME 4.1a
a proton and an example is that of nitration of benzene with HNO3/H2SO4. However, other
groups can also leave during electrophilic aromatic substitution.
An electrophile can form a bond to an aromatic carbon atom already having a substituent
other than hydrogen and the loss of that substituent results in Ipso substitution. Ipso
substitution is limited to those reactants in which the group originally on the ring can be
somewhat a good leaving group (Scheme 4.1b, also see Scheme 4.3g).
CH3 CH3 CH3 CH3

NO2
– Ac2O
+ NO+
2 AcO + + + CH2 CHCH3
NO2
CH(CH3)2 NO2 CH(CH3)2 CH(CH3)2
1-isopropyl-4- Nitronium 10% 80% 10%

methylbenzene acetate (Ipso substitution)
(p-cymene)
Ipso electrophilic aromatic substitution
SCHEME 4.1b
Generally aromatic compounds undergo electrophilic substitution, however, nucleophilic

substitution is also an important reaction. The early industrial processes for the formation of
phenol and aniline (Scheme 4.1c) were nucleophilic substitution reactions.
Cl NH2
High pressure
+ NH3
300°C
Chlorobenzene Aniline
Nucleophilic aromatic substitution
SCHEME 4.1c
Nucleophilic aromatic substitution may involve addition of the nucleophile to the aromatic
ring followed by loss of a leaving group. This sequence is reminiscent of nucleophilic substitution
on carboxylic acid derivatives. Other reactions are believed to involve an aromatic cation or in
some cases by initial 1, 2-elimination. The common to all the processes is that the aromaticity
is retained in the product.
One mechanism of nucleophilic aromatic substitution is in (Scheme 4.1d). Here an amine
acts as a nucleophile and the substrate is chlorobenzene substituted with an electron with
drawing group like a nitro group. The reaction, however does not take place with chlorobenzene
itself under similar conditions. The nitro group, evidently, lowers the activation energy of the
reaction by stabilizing the negative charge generated by the addition of nucleophile to the
aromatic ring. A series of resonance structures can be drawn to show this stabilization. Loss of
chloride completes the substitution reaction. By analogy with the mechanism of electrophilic
aromatic substitution, an addition-elimination mechanism looks reasonable for nucleophilic
aromatic substitution (Scheme 4.1d).
Cl
:
CH3NH2
N+
–: :
:
O O:
:
Reactant
+ + + + CH3NH
CH3NH2 Cl CH3NH2 Cl CH3NH2 Cl CH3NH2 Cl
– – :
–HCl
:
–
N+ N+ N+ N+ NO2
: :
: :
– :O O :– – :O
: :
: :
: :
– :O – :O O: O:
O
:
Product
SCHEME 4.1d
(B) Addition Reactions

Addition reactions involve an increase in the number of groups attached to the substrate and
thus a decrease in the degree of unsaturation of the substrate. Addition reactions are the
reverse of elimination reactions. Generally an addition involves the gain of two groups or
atoms (one electrophile and one nucleophile) at each end of a π bond (1, 2-addition) or ends of
π system (e.g., 1, 4 or 1, 6-addition). There are, however, examples of addition to certain highly
reactive σ bonds (e.g., cyclopropane additions).
Consider the electrophilic addition to an alkene where the π electrons (like that of a
benzene ring) present an electron-rich region of potential reactivity. The first step is addition
of an electrophile to an unsaturated carbon atom of an alkene (Scheme 4.2). The carbocation
derived from the alkene usually adds a nucleophile to give the product of overall addition (the
intermediate generated from the aromatic substrate on the other hand loses a cation and the
product of substitution is formed see Scheme 4.1a).
+ + Nu : –
C C + E C C E Nu C C E
Alkene Carbocation Product

Electrophilic addition to an alkene
SCHEME 4.2
(C) Elimination Reactions

An elimination reaction proceeds via the removal of two atoms or group from the same molecule.
In most of the cases (Scheme 4.3) the loss is from adjacent atoms so as to form a new double or
triple bond. Some nucleophiles e.g., –OH and –OR, are also strong bases. A tertiary alkyl halide
is unable to undergo an SN2 backside displacement because of steric hindrance; however, when
heated with a strong base, usually K+ –OH dissolved in ethanol, a tertiary alkyl halide undergoes
an elimination reaction to yield an alkene. This elimination proceeds by a different path from
that of the E1 mechanism and is termed E2 elimination. An E2 reaction is a one step reaction,
like an SN2 reaction. The strong base abstracts a proton from the alkyl halide, the electron pair
forms a pi bond, and the halide ion leaves, all in one step.
CH3 CH2
– E2 –
CH3C—Cl + OH CH3C + H2O + Cl
CH3 CH3
t-butyl chloride Methylpropene
:
HO :
– H – +
d–
: :
HO : 1 The OH abstracts H
:
HO : + 2 The two electrons form a pi bond

1 –
H—CH2 H CH2 CH2 3 The Cl leaves with the pair of sigma
2 d– electrons
–
: :
: :
: :
CH3C—Cl : CH3C Cl : CH3C + : Cl : E2 reaction rate = k [Base] [RX]

3
CH3 CH3 CH3
Mechanism of E2 elimination
SCHEME 4.3
A reaction proceeding by an E2 mechanism is a bimolecular elimination because two

particles (–OH and RX) are involved in the transition state of the only step (thus the rate-
limiting step) of the reaction.
Nucleophilic Aromatic Substitution—An Example of Elimination-Addition

Mechanism—Benzyne Formation
Reaction of chlorobenzene with sodamide in liquid ammonia at –33°C gives aniline.
Chlorobenzene labelled with 14C at the position bearing chlorine gives an equimolar
mixture of unrearranged and rearranged products and this along with other
evidence, shows the formation of a symmetrical species a benzyne. Benzyne is formed
from chlorobenzene by an E2-type elimination and adds the nucleophile to give
aniline (Scheme 4.3a).
14 NH2
14 Cl 14
E2 NH3
– like
H NH2 14
NH2
SCHEME 4.3a
This facile reaction is due to the strong basicity of amide ion while hydroxide ion,
which is a much weaker base, reacts with chlorobenzene only at 340°C to give
phenol via benzyne. Bromobenzene and iodobenzene react in a similar fashion
while fluorobenzene does not yield benzyne directly with base due to greater strength
of C—F bond.
EXERCISE 4.1
Why 2, 6-dimethylchlorobenzene does not undergo
Cl
a nucleophilic aromatic substitution (Scheme 4.3b).
H 3C CH3
ANSWER. The reactant does not have a H atom NaNH2
in the β-position to the halogen and therefore,
NH3 (l)
benzyne cannot be formed via the elimination
reaction. SCHEME 4.3b
(D) Molecular Rearrangements

Most of the molecular rearrangements involve the migration of an atom or a group from one
atom to another. The type of migration depends on the number of electrons the migrating
atom or group carries with it. The most common type are 1, 2 rearrangements in which the
migrating group moves to the adjacent atom with its bonding pair of electrons. The electron-
deficient carbocation attracts electron density from adjacent bonds which are rendered weak.
The ready loss of a proton to a basic solvent molecule can lead to elimination. In some systems,
another important side reaction, rearrangement can occur. The hydrogen attached by the
weakened bond with its bonding electrons can move to the cationic center, to create a new
carbocation (Scheme 4.3c).
+
Loss of H
—C C— (Elimination)
Basic solvent
H molecule Alkene
+
—C—C—
H
or A hydride (H : ) shift +
—C—C— (Rearrangement)
H
Migration of H with its
+ bonding electron pair New carbocation
—C—C—
A rearrangement involves a change in the way the atoms are connected.

A carbocation rearrangement may involve a 1, 2-hydride
shift, a 1, 2-methyl shift or migration of a ring residue
SCHEME 4.3c
During a rearrangement (Scheme 4.3c) the positive charge moves to the carbon to which
the hydrogen was originally attached. Such rearrangements are particularly important when
the new carbocation is more stable than the initially formed carbocation, but the rearrangement
still occurs even if the two carbocations have comparable stability. These reactions are commonly
observed for secondary carbocations but almost never involve primary carbocations. In primary
systems it is the SN2 process which is generally favourable and the highly unstable primary
carbocation is never formed. Rearrangements are less common in tertiary systems.
An example of a carbocation rearrangement is during the reaction of 3-methyl-2-butanol
with HBr when the only product formed is 2-bromo-2-methylbutane. The intermediate sec-
carbocation rearranges much faster compared to its reaction with bromide ion (Scheme 4.3d).
+
H H OH2
+
H
CH3C—CHOHCH3 CH3C—CHCH3
CH3 CH3
3-methyl-2-butanol
–H2O
Br H H
HBr + +
(CH3)2CCH2CH3 CH3C—CHCH3 CH3C—CHCH3
2-bromo-2-methyl- CH3 CH3
butane
Secondary carbocation Tertiary carbocation
rearrangement (more stable)
SCHEME 4.3d
EXERCISE 4.2
Explain as to why 2-pentanol and 3-pentanol on reaction with HBr give the mixture
of 2-and 3-bromopentane (Scheme 4.3e)?
HBr
CH3CH2CH2CHOHCH3 CH3CH2CH2CHBrCH3 + CH3CH2CHBrCH2CH3
Major Minor
HBr
CH3CH2CHOHCH2CH3 CH3CH2CH2CHBrCH3 + CH3CH2CHBrCH2CH3
Minor Major
SHCEME 4.3e
ANSWER. In both cases a secondary carbocation is formed and their rate of
equilibration is not complete. The rate of reaction of the bromide ion with
carbocation is comparable to the rate of rearrangement (Scheme 4.3f).
H
–
+ Br
CH3CH2CH2CHCH3 CH3CH2CHCHCH3 CH3CH2CH2CHBrCH3
+ OH
2
–
+ Br
CH3CH2CHCH2CH3 CH3CH2CHCHCH3 CH3CH2CHBrCH2CH3
+ OH H
2
SCHEME 4.3f
Rearrangement During Ipso Attack

In a monosubstituted benzene the orientation is discussed in terms of attack at the
ortho, meta or para position, however, attack at the position bearing the substituent
(called ipso position) may also occur. The ipso attack has been generally studied
in nitration reactions. The arenium ion can loose the substituent as a cationic
species and the end result is aromatic substitution with a leaving group other
than H. The electrophilic group (NO2+) may also undergo a 1, 2-migration followed
by loss of proton. This migration occurs in those cases where the substituent already
present on the ring is not a good leaving group (Scheme 4.3g). On rearrangement
of the electrophile a proton becomes available which is lost to give normal
substitution product.
Thus an electrophile can form a bond to an aromatic carbon atom to which a
substituent other than hydrogen is already attached and the process is ipso addition
which is the first step of ipso substitution. The loss of that substituent leads to ispo
substitution.
CH3 CH3 NO2 CH3 CH3

NO2 NO2
+
+ – Ac2O –H
+ NO2 AcO + + H
CH3 CH3 CH3 CH3

1, 4-dimethylbenzene Ipso addition Rearrangement Normal
(p-xylene) substitution
product
SCHEME 4.3g
(E) Pericyclic Reactions

Several reactions and rearrangements may however, follow pericyclic mechanisms (see
Chapter 17).
(F) More Examples of Complex Reactions

Complex reactions can be combination of substitution, addition, elimination and rearrangement
reactions, some of these had already been discussed. In all cases reactions may be broken
down into a series of steps each involving one of these basic reactions. Consider for example,
the Friedel-Crafts alkylation of benzene with 1-chloropropane (Scheme 4.4). It is an electrophilic
substitution reaction, where the electrophilic carbocation or polarized haloalkane attacks the
benzene ring followed by the loss of a proton. In reaction mixtures carbocations are capable of
rearrangement i.e., a change of structure, if these can yield more stable carbocations. Thus,
the polarized primary haloalkane (a potential carbocation) shifts a hydride ion H:– to the adjacent
positive carbon to yield the more stable secondary carbocation (Scheme 4.5).
AlCl3
+ CH3CH2CH2Cl CH(CH3)2
1-chloropropane Mainly
isopropylbenzene
SCHEME 4.4
H
d+ d– + –
CH3CH—CH2 Cl AlCl3 CH3CH—CH3 + Cl—AlCl3
1-chloropropane polarized Isopropyl cation

a 2° cation
more stable
SCHEME 4.5
SN1 substitution reactions of alkyl halides are accompanied by elimination reactions

and these yield alkenes. These reactions are called dehydrohalogenation reactions. In these
elimination reactions, the nucleophile acts as a base—a proton acceptor. This elimination
reaction proceeds by an E1 mechanism (elimination, unimolecular). The first step in an E1
reaction is the ionization of the alkyl halide, (as in reaction by the SN1 path). The first step in
E1 elimination is the spontaneous dissociation of the alkyl halide to give an intermediate

carbocation in the slow rate limiting step. The second step in an E1 reaction is the loss of a
proton (H+) to the solvent. The electrons in the C—H bond are used to form a pi bond. The
product is a stable uncharged alkene (Scheme 4.6).
CH3 CH3 CH2
CH3CBr + H2O CH3COH + CH3C
CH3 CH3 CH3

t-butyl bromide t-butyl alcohol Methylpropene
(70%) (30%)
slow + –
: :
(CH3)3C—Br : (CH3)3C : :
+ : Br : Step 1 Ionization
CH3 CH3
+
CH3C—CH2 fast
CH3C CH2 + H—Solvent+ Step 2 Loss of H
+
H
Solvent
SCHEME 4.6
4.2 NUCLEOPHILES AND ELECTROPHILES

The nucleophile (“nucleus lover”) is an electron rich ion or molecule that reacts at a positively
charged site in a compound. Nu:– represents a negatively charged nucleophile e.g., HO–, RO–,
X–, CN– and Nu represents an uncharged nucleophile e.g., H2O, ROH. An electrophile
(E, “electron lover”) may be electrically neutral BF3 or AlCl3 or positively charged like H+, Br+,
NO2+. Both BF3 and BH3 are Lewis acids, they do not have a positive charge but have empty 2p
orbitals and react like cations (electrophiles, see Scheme 1.4a). To form the bromonium ion, a
pair of nonbonding electrons on bromine (the nucleophile) attacks the empty p orbital on the
positive carbon (the Lewis acid) to form a normal, two-electron bond, (Scheme 4.6a). In an
ionic reaction a nucleophile (Nu:) shares an electron pair with an electrophile (E) in the process
of bond formation (Nu: + E → Nu—E). Thus nucleophiles are Lewis bases; i.e., electron pair
donors and electrophiles are lewis acids, i.e., electron pair acceptors.
: :
: Br—Br :
: :
Lewis acid Nucleophile :

Br :+
:
:Br :
:
Bromine
+
C C – C C C——C
– :Br :
: :
Cyclic
Empty p orbital on bromonium ion
Alkene double the positive carbon
bond
SCHEME 4.6a
4.3 ELECTRON MOVEMENT

When a bond breaks homolytically, each bonded atom retains one of the bond’s two electrons.
In contrast, when a bond breaks so that one of the two atoms retains both electrons, one says
that heterolytic cleavage has occurred. Homolytic cleavage forms free radicals, while heterolytic
cleavage forms ions. A heterolytic cleavage is sometimes called an ionic cleavage. A curved
arrow is used to show the movement of the electron pair in an ionic cleavage. Half-arrows
show the separation of the individual electrons in a homolytic cleavage (Scheme 4.7). Energy
is released when bonds are formed, and energy is always consumed when the bonds cleave.
–
2 : Cl.
: Cl:Cl : +
: :
: :
: :
: :
: :
(CH3)3C—Cl : (CH3)3C + : Cl:
Homolytic cleavage Heterolytic cleavage

(free radicals result) (ions result)
SCHEME 4.7
4.4 EQUILIBRIA AND FREE ENERGY

All chemical reactions are reversible and reactants and products interconvert to different
degrees. When the concentrations of reactants and products do not undergo a change, the
reaction is said to be in a state of equilibrium. In several cases, equilibrium lies largely (say,
more than 99.9%) to the side of the products. When this happens the reaction is said to have
gone to completion. (In such cases, the arrow indicating the reverse reaction is usually
ommitted). Equilibria are described by equilibrium constant, K. To find an equilibrium constant
one divides the product of the concentrations of the components on the right side of the reaction
by the product of the concentrations of the components on the left, all given in units of mole
litre–1. A large value for K shows that a reaction will go to completion and has a large driving
force.
Some chemical equilibria are:
K [B]
A B K=
[ A]
K [C ]
A+B C K=
[ A] [ B]
K [C] [ D]
A+B C+D K=
[ A] [ B]
The value of K is determined by the change in free energy (sometimes called Gibbs free
energy) that accompanies the reaction. Free energy is represented by G, and the change (∆) in
free energy of reactants and products in their standard states (25°C, 1 atm) is represented by
∆G°. The relationship between ∆G° and K is in the expression (eq. I, Scheme 4.8).
–1
DG° = – RT ln K = – 2.303 RT log K (in kcal mol ) (I)
DG° = (Free energy of products) – (Free energy of reactants)

R = 1.986 cal/deg-mol (8.309 J/deg-mol), the gas constant
T = Temperature in degrees kelvin
–1
DG° = –1.36 log K (in kcal mol ) (II)
SCHEME 4.8
When a reaction “goes to completion” or has “a large driving force”, a certain amount of
energy is released. A negative value of ∆G° shows a release of energy. It follows that a large
value for K indicates a large favourable free energy change. At room temperature (25°C, 298 K),
the equation (I, Scheme 4.8) becomes (eq. II, Scheme 4.8), and from this expression, an
equilibrium constant of 10 would have a ∆G° of –1.36 kcal mol–1, and conversely, a K of 0.1
would have a ∆G° = +1.36 kcal mole–1. Because the relation is logarithmic, doubling the ∆G°
value increases the K value exponentially. When K = 1, starting reactants and products are
present in equal concentrations and ∆G° is zero.
4.5 FREE ENERGY CHANGE IN RELATION TO BOND STRENGTHS AND DEGREE

OF ORDER IN A SYSTEM
The Gibbs standard free energy may be dissected into enthalpy and entropy components ∆H°
and ∆S° respectively (Scheme 4.9).
DG° = DH° – TDS°
DG° = (Free energy of products) – (Free energy of reactants)

DH° = (Enthalpy of products) – (Enthalpy of reactants)
DS° = (Entropy of products) – (Entropy of reactants)
SCHEME 4.9
The enthalpy change ∆H° is defined as the heat of a reaction at constant pressure.
Enthalpy changes in an organic chemical reaction relate mainly to changes in bond strengths
during the course of the reaction. The value of ∆H° = ∆H° for bonds being broken –∆H° for
bonds being formed.
The values of ∆H° can be calculated from bond dissociation energies (Table 1.2). Since
values of ∆H° are easy to calculate organic chemists therefore, evaluate reactions from this
quantity.
When weaker bonds are broken and stronger bonds are formed, heat is released and the
reaction is then exothermic (negative value of ∆H°). In an exothermic reaction, the enthalpy
term contributes to a favourable negative value of ∆G°. However, if stronger bonds are broken
and weaker bonds are formed then energy is consumed in the reaction which becomes
endothermic (positive value of ∆H°). In an endothermic reaction, the enthalpy term contributes
to an unfavourable positive value of ∆G°.
The value of ∆H° for the chlorination of methane is about –25 kcal/mol (105 kJ/mol).
Thus it is a highly exothermic reaction, with the decrease in enthalpy serving as the primary
driving force. Another example of an exothermic reaction is the combustion of methane, (the
main component of natural gas), to carbon dioxide and water. This process has a ∆H° value of
–213 kcal mol–1 (CH4 + CO2 → CO2 + H2O). The exothermic nature of this reaction is due to
very strong bonds formed in the products. The entropy change ∆S° provides a measure of the
changes of the order of a system or freedom of motion of a system. Reactions tend to favour
products with the greatest entropy, since there is a negative sign in the entropy term of the
free-energy expression. A positive value of ∆S° thus indicates that the products have more
freedom of motion than the reactants, contributes to a favourable (negative) value of ∆G° (see,
Sec. 3.6).
In most of the situations the enthalpy change is much larger than the entropy change,
and the enthalpy term dominates the equation for ∆G°. Therefore, a negative value of ∆S° does
not for sure mean that the reaction has an unfavourable value ∆G°. The formation of strong
bonds (the change in enthalpy) is usually the most important component in the driving force
for a reaction.
For example, consider the chlorination of ethane with chlorine to give chloroethane and
hydrogen chloride. The reaction (Scheme 4.10) has a ∆H° of –28 kcal mol–1 and only a small
∆S° of +0.5 e.u. (“entropy units”). This shows that at room temperature (298 K) the contribution
of – T ∆S° to ∆G° is only on the order of – 0.15 kcal mol–1 i.e., almost negligible. The considerable
driving force for the chlorination lies largely in the large negative value of ∆H°.
–1
CH3CH3 + Cl2 CH3CH2Cl + HCl DH° = – 28 kcal mol
Chloroethane DS° = + 0.5 e.u.
SCHEME 4.10
The activation energy of a reaction is composed of an enthalpy contribution, to which

ring strain adds a positive (unfavourable) increment, and an entropy contribution, which is
almost entirely influenced by the proximity of the reacting centers and relative rigidity of the
transition state. These two factors display systematically variation however, in opposite
directions from smaller to larger rings. At first sight, it may look surprising that usually, three
membered rings are formed faster than four-membered rings. An example is of Williamson
synthesis of cyclic ethers via intramolecular S N2 reaction on halo alcohols (Scheme 4.10a).
–
OH – O O
OH –
+ Cl
Cl Cl
4-chlorobutanol An alkoxide intermediate tetrahydrofuran

(THF)
Intramolecular SN2 reaction—the Williamson synthesis
SCHEME 4.10a
A comparison of the relative rates of cyclic ether formation reveals that three membered rings
(epoxides) form quickly. Thus the preparation of an epoxycyclopropane from a 2-bromo-alcohol
is entropically highly favourable, since the nucleophile and the leaving group are as close to
each other as possible. Although the ring strain is worst in this case. The transition state
energy is relatively small, since a favourable entropy contribution allows relatively a rapid
ring formation.
On increasing the chain of a halo alcohol, the reacting centers fall apart (unfavourable
entropy factor) which contributes more flexibility (degrees of freedom) to the substrate. This
flexibility has to be given up in the transition state of ring closure. Moreover, five-membered
rings are formed easily. (The relative rates of cyclic ether formation with respect to ring size
are 3 ≥ 5 > 6 > 4 ≥ 8). In the formation of five-membered ring, compared to e.g., a four-membered
ring, though the reacting centers are far apart in the former, however, the unfavourable strain
contribution to the enthalpy of activation is largely decreased. Five-membered rings form faster
than six-membered rings, although the six-membered rings are almost strain free. In this case
the relative greater distance between alkoxide and electrophilic carbon and consequently greater
degree of freedom of the chain reflects on this.
The more negative the ∆H°, the more positive the ∆S°, the more negative the ∆G°, the
more exothermic (favourable) will be the reaction. While dealing with conformational changes
one discusses the total changes in free energy that occur (∆G°). However, while discussing
most chemical reactions involving bond breaking and forming, one normally discusses changes
in enthalpy (∆H°). In many organic reactions, the entropy change is most often very small in
relation to the change in enthalpy then the relationship holds: ∆G° ≅ ∆H°.
In cyclohexane e.g., because of its relatively increased rigidity, there are fewer degrees
of vibrational and rotational freedom compared to a straight-chain hexane. Ring opening
therefore, means a gain in entropy and ring closing a loss.
4.6 REACTION RATES

Reaction rates usually depend on the concentrations of the reactants. When the concentrations
of the reactants is large they will collide more often and the greater will be the chance of
reaction. The concentration of reactants influences the rate of a reaction. Consider the addition
of reagent A to reagent B to give C (A + B → C). In many transformations of this type, it is
observed that increasing the concentration of either reactant increases the rate of the reaction.
In some cases, the transition state is formed as the result of collision of molecules A and B. The
rate is then expressed (eq. I, Scheme 4.11). In this equation the proportionality constant, k, is
also called the rate constant of the reaction. The initial rate equals the rate constant when the
two starting materials are at one molar concentration. A reaction for which the rate depends
on the concentrations of two molecules in this way is termed second order.
There are processes whose rate depends on the concentration of only one of the reactant,
such as in the reaction (A → B, eq. II, Scheme 4.11). A reaction of this type is called first order.
Rotation around a carbon-carbon bond follows such a rate law.
–1 –1
Rate = k [A][B] in units of moles l sec (I)
–1 –1
Rate = k [A] in units of moles l sec (II)
SCHEME 4.11
4.7 THE TRANSITION STATEACTIVATION ENERGY

A reaction which proceeds with a negative free energy change is called exergonic, and the one
which proceeds with a positive free energy change is termed endergonic. The reaction between
methyl chloride and hydroxide ion in aqueous solution is a very favourable exergonic process
(at 60°C (333 K), ∆G° = –24 kcal mol–1. The equilibrium constant for the reaction is extremely
large (near 1016). Even then a dilute solution of methylchloride in aqueous base requires weeks
to approach the position of equilibrium. Many factors must contribute together for the reaction
to occur. These are:
• Reactants must have adequate energy to collide.
• The reactants must come together in a proper orientation favourable for reaction
(i.e., the specific orientation in the reaction of methylchloride with hydroxide ion in
the SN2 reaction).
• Sufficient energy must be available to break the bonds undergoing change. If e.g.,
covalent bonds are broken in a reaction, the reactants must go up an energy hill first,
before they can go downhill. This will be true even if the reaction is exergonic.
The configuration of reactants in which all the stringent requirements for an effective
collision are met is commonly known as the transition state (activated complex), a hypothetical
description of the atoms at the point of highest energy along the reaction pathway. By contrast,
intermediates are capable of detection and in some cases even isolation. One cannot isolate
transition states or even detect them. However, the reaction intermediates like a carbocation
can not only be detected but can be even isolated.
Thus in short, just because a reaction has a negative ∆G° does not necessarily mean that
it will take place during a reasonable period of time. A negative ∆G° is a necessary however,
not a sufficient condition for a reaction to occur spontaneously. For a reaction to take place the
transition state must be attained and energy must be supplied to the reactants for this purpose.
This energy, the difference between the free energy of the reactants and of the transition
state, is the free energy of activation ∆G‡. It is this activation energy that controls the rate of
a chemical reaction. Typical organic reactions have activation energies of 10–50 kcal/mol
(40–200 kJ/mol) and for these to occur free energy of activation ∆G‡ must be added.
4.8 TRANSITION STATE THEORYMEASUREMENT OF ACTIVATION ENERGY

The transition state theory of rates of reactions makes as assumption in an elementary reaction
the reactants must pass through a transition state. The reactants are in equilibrium with an
activated complex, e.g., for a bimolecular reaction (Scheme 4.12).
A+B AB‡ Products AB‡ is an activated complex at the transition state.
SCHEME 4.12
One usually measures a somewhat different energetic barrier to reactions in the

laboratory i.e., the Arrhenius activation energy Ea. Values of Arrhenius activation energies
are related to the enthalpies of activation ∆H‡, (eq. I, Scheme 4.13). Enthalpies of activation
are related to free energies of activation ∆G‡ (eq. II, Scheme 4.13). In most of the situations the
values of Ea is an acceptable approximation of ∆G‡.
The Swedish Chemist Arrhenius found the dependence of reaction rate on temperature
at which the reaction is carried out. For chemical reactions the measurement of the variation
of the rate of reaction at a number of different temperatures helps in calculating activation
energy Ea, from the Arrhenius equation (Scheme 4.14), where k is the rate constant and A is a
frequency factor for that reaction. The activation energy, Ea, is related to the activation enthalpy
∆H‡ (Scheme 4.13).
‡ ‡ ‡ ‡
Ea = DH + RT (I) DG = DH – TDS (II)
SCHEME 4.13
Any reaction (with an activation energy) is faster at higher temperatures, as may be

readily derived from the Arrhenius equation. When the temperature increases, a larger fraction
of molecular collisions have enough kinetic energy for the reaction to occur and this increases
the reaction rate. A typical distribution of energies for a collection of molecules at two
temperatures where T2 > T1 is shown (Scheme 4.15). The activation energy for a hypothetical
reaction is marked as Ea. The number of molecules with sufficient energy for reaction is given
by the shaded areas, which is much greater at T2 i.e., the higher temperature. Since there are
more molecules with energies sufficient for reaction to occur, at higher temperature, the reaction
is faster. A rule of thumb is that with an increase of 10°C in temperature the reaction rate
approximately doubles.
k is a rate constant
Ea is the energy of activation
–Ea /RT
k = Ae T is the absolute temperature
R is the gas constant
A is a constant known as the pre-exponential factor
Arrhenius equation
The Arrhenius equation is generally used
to determine energies of activation from rate data
SCHEME 4.14
(T1)
Ea, the Arrhenius The distribution of energies at two temperatures,
with a given
Fraction of
molecules
activation energy T1 and T2 (T2 > T1 ). The number of collisions with

energy
energies greater than the free energy of activation

(T2) is shown by shading the area under each curve
‡
Ea = DH + RT
Energy
SCHEME 4.15
4.9 REACTION PROFILE DIAGRAMS

Organic chemists generally represent the course of a reaction through an energy profile diagram.
The interpretation of a simple SN2 reaction is shown in (Scheme 4.16) which throws light on
the concepts of transition state and activation energy. This is the usual energy profile diagram
for a one step reaction without an intermediate. For the reaction to occur, free energy of
activation ∆G‡ must be added.
The vertical axis of the energy profile depicts the total free energy of all the species
involved in the reaction. The horizontal axis is called the reaction coordinate which reflects
the progress of the reaction, going from the reactants on the left to the products on the right
and usually considered to be related to the changes in molecular geometry e.g., bond angle and
bond length. The SN2 reaction has only one transition state and no intermediate. The transition
state has a definite geometry and charge distribution and has no finite existence. The system
at this point is termed an activated complex. In the transition state theory the starting materials
and the activated complex are in equilibrium and then the equilibrium constant is designated
by K‡. Thus the rate constant of the reaction is dependent only on the position of the equilibrium
between the starting materials and the activated complex, i.e., on the value of K‡ (∆G‡ = – 2.3
RT log K‡). The interpretation of such figures can be explained by reference to (Scheme 4.16).
The reaction represented will proceed spontaneously as the activation energy is relatively
small and the free energy of the products is lower compared to that of the reactants.
‡
H H H H H
H
– d– d–
HO :
: :
–
C—Cl : + : Cl :
: :
: :
: :
: :
Cl :
: :
HO C HO—C
H H H
–
Backside attack of Nu : SN2 transition state Loss of leaving group
DG ‡ = 24.5
–1
kcal mol
–
HO + CH3Cl
Reactants
Energy
Free- DG° = – 24
–1
energy kcal mol
change
–
CH3OH + Cl
Products
Reaction coordinate
A potential energy diagram for the reaction of methyl chloride with hydroxide
SN2 mechanism, backside attack with inversion
SCHEME 4.16
By contrast, a reaction which has a high activation energy will take place very slowly at
normal temperatures. Thus the SN2 reaction of a sterically hindered secondary bromide will
raise the energy of the transition state (compared with unhindered methyl bromide) and
consequently the reaction will become slow.
Entropy of activation ∆S‡ (difference in entropy between the starting compounds and
the transition state) gains importance (see Scheme 4.13, eq. II) when the reacting molecules
have to approach each other in a defined orientation for the reaction to occur. Consider the
elimination reaction of an acyclic alkyl chloride with hydroxide ion to give an alkene. Under
the usual E2 reaction conditions it is essential that OH– be near the hydrogen, moreover the
hydrogen must also be oriented anti to the chlorine atom (Scheme 4.17). For the success of this
elimination, the reactants therefore, must surrender the freedom normally associated with
them. This leads to a considerable loss of entropy i.e., ∆S‡ is negative.
1 2
– R R
HO R R
–
H C C + H2O + Cl
Cl 1 3
2 3 R R
R R
SCHEME 4.17
The reaction profile of a particular reaction can be altered by the use of a catalyst.
A catalyst is a species that can change the reaction mechanism and thereby lower the activation
energy by providing an alternative, lower energy pathway. A catalyst can therefore, increase
the rate of a reaction but can have no effect on the equilibrium constant. At the end of a
reaction a catalyst is recovered chemically unchanged.
The mechanistic description of some reactions may involve more than one steps. Reactions
with intermediates are two step (or more) processes. In these reactions e.g., in nucleophilic
substitution of chloride by hydroxy in tertiary-butyl chlordie (SN1 reaction), there are two
transition states, each with an energy higher than the carbocation intermediate (Scheme 4.18).
In such a reaction, one sees an energy “well” and deeper the well the more stable is the
intermediate. The first step (Scheme 4.18) is the formation of an unstable carbocation
intermediate. This high energy intermediate reacts with water i.e., the nucleophile in a rapid
second step to afford the protonated alcohol. The step 3 in the solvolysis of an alkyl halide, is
the loss of a proton by a protonated alcohol. This reaction is an acid-base reaction and is not
actually part of the SN1 mechanism. The SN1 path is a two-step sequence: (1) ionization of the
alkyl halide to yield the intermediate carbocation and (2) combination of the carbocation with
the nucleophile. The energy, profile diagram displays two energy maxima and the transition
state associated with the formation of the carbocation and the transition state for the formation
of the protonated alcohol i.e., the formation of the new carbon-oxygen bond.
4.10 THE RATE DETERMINING STEP

In a multistep reaction, every step has its own characteristic rate. There can be only one
overall reaction rate however, which is determined by the rate-determining step. In general,
the highest-energy step of a multistep reaction is the “bottleneck”, and it determines the
overall rate. On an energy profile diagram the step involving formation of the highest energy
transition state is designated as the rate determining step. In the reaction of methyl chloride
with hydroxide the single step must be the rate controlling step (Scheme 4.16). In the two-step
reaction (Scheme 4.18) the first step is rate-controlling.
CH3 CH3 CH3 CH3

slow fast + fast +
+
: :
:
CH3—C—Cl CH3—C + H2O : CH3—C OH CH3—C OH + H3O :
CH3 CH3 CH3 H CH3

H2O :
:
–
C—Cl bond breaks to give a + Cl Nucleophile attacks
carbocation intermediate the carbocation
Proton transfer
Mechanism of the SN1 reaction
Rate determining transition state

Transition state
‡
‡
‡
G (kcal/mol)
DG
Intermediate
(Reactants)
DG°
Products
Reaction coordinate
Reaction coordinate diagram for an SN1 reaction
SCHEME 4.18
4.11 THERMODYNAMIC AND KINETIC CONTROL
When more than one product is formed during a reaction, the product which is
formed most rapidly is called the kinetic product while the most stable product is
called the thermodynamic product. Kinetically controlled reactions produce kinetic
product as the major component, while thermodynamically controlled reactions
produce thermodynamic product as the major component.
Under reversible reaction conditions the ratio of possible products is determined by the
relative stability of each product which is measured by its standard free energy (∆G°). The
composition of the equilibrium mixture does not depend on how fast (∆G‡) each product is
formed in the reaction. This is termed thermodynamic (or equilibrium control). On the other
hand when the quantity of each possible product is determined by how fast each product is
formed and is not a function of the relative stability ∆G° of each product, one calls it kinetic
control. Consider the addition of HBr to 1, 3-butadiene which gives two products both derived
from a common intermediate (Scheme 4.18a).
The common
allylic carbocation
(intermediate)
‡ the 1, 4
‡ the 1, 2
Ea
1, 4
Ea
1, 2
Potential energy
DH°1, 2
DH°1, 4
Br
1, 2-product Br
(formed faster) 1, 4-product
(more stable)
Reaction coordinate
Reaction coordinate diagram for HBr addition to 1, 3-butadiene
+ HBr
Br
+ +
Br
Common intermediate
The 1, 2-addition The 1, 4-addition
kinetic product thermodynamic product
At –80° : 80% 20%

At +40° : 20% 80%
SCHEME 4.18a

• The reaction proceeds through the same common intermediate which is a resonance-
stabilized allylic cation that both products have in common. The formation of this
intermediate is the first step of the reaction.
• Under sufficiently low temperature conditions, – 80°C (mild conditions) the reaction
is irreversible and HBr adds to 1, 3-butadiene to give 1, 2-addition product as the
major component. The reaction-energy diagram for the second step of this addition is
in (Scheme 4.18a, recall that organic chemists analyze reactions by considering ∆H°).
The transition state for 1, 2-addition has lower energy than transition state for
1, 4-addition, consequently 1, 2-addition is associated with a lower activation energy
(Ea). The 1, 2-addition occurs by the attack on the more highly substituted carbon
(one may note here, that the less stable product has a more stable transition state).
• The attack by bromide on the allylic cation represents a highly exothermic process
and therefore, the reverse reaction has a large activation energy. At low temperatures
(–80°C) enough energy is available and the reactants overcome the energy barrier for
the first step of the reaction to form the intermediate, the resonance-stabilized allylic
cation. Moreover, enough energy is also available for the intermediate to yield two
addition products.
• At low temperature (– 80°C), however enough energy is not available for the reverse
reaction and the product which is formed faster (the 1, 2-product) predominates.
• At higher temperature (40°C), however, enough energy is available for the products
to go back to the intermediate i.e., for the reverse reaction to occur. At 40°C an
equilibrium is set up and the most stable species predominate which is the 1, 4-product.
4.12 APPLICATIONS OF KINETIC PRINCIPLES

(A) Hammond Postulate
The precise structure of an intermediate is far better understood than the transition state.
Often it is helpful to regard an intermediate as a model for the transition state which reflects
on the rate of a reaction. Thus the transition state may have some character of the intermediate
formed in a reaction. The Hammond postulate states that the structure of the transition state
for a reaction step is closer to that of the species (reactant or product of that step) to which it is
closer in energy. Recall the application of Hammond postulate to explain regioselectivity of
bromination versus chlorination.
Consider Markovnikov’s rule (a regioselective reaction), it states that during ionic addition
of an unsymmetrical reagent (e.g., HX) to a double bond, the positive portion of the adding
reagent attaches itself to that unsaturated carbon so as to give the more stable carbocation as
an intermediate. As an example to explain Hammond’s postulate, consider the addition of HBr
to propylene (Scheme 4.18b). Of the two possible products, II predominates (Markovnikov’s rule).
+ Br
– d+
CH3—CH2—CH2 CH3—CH2—CH2Br CH3—CH CH2
1° 1-bromopropane
A (not formed) H
(I)
CH3CH CH2 + H
+ Br d–
Propylene Transition state (C)
+ Br
– d+
CH3—CH—CH3 CH3—CH—CH3 CH3—CH CH2
2°
B Br H
2-bromopropane d–
(actual product) Br
(II)
Transition state (D)
SCHEME 4.18b
The rate-determining step in the addition is the protonation of one of the carbon atoms
of the double bond the give a carbocation which then reacts rapidly with the anion Br– from
HBr. One of two such carbocations A or B may be formed in competing ways. The secondary
ion B is however, more stable. The rate of formation of these two ions is not immediately
dependent on their stabilities, but rather on the relative free energies of the transition states
for carbocation formation. The detailed structures of the transition states are uncertain; the
new C—H bond is partly formed at the transition state, however, to an unknown extent. But
one knows that the carbocations have relatively high free energies compared with the reactants
(Scheme 4.18b) and there is thus a smaller change in energy when the transition states are
transformed into the intermediate carbocations than when they revert to the reactants.
Therefore, one may conclude that there is a smaller reorganization of the molecular geometry
in passage from transition state to intermediate than in passage from transition state to
reactants. Thus the transition states have resemblence to the carbocations which arise from
them. The two transition states may be represented as (C and D, Scheme 4.18c). One therefore,
concludes that the factors which determine the relative stabilities of the carbocations are also
effective in determining the relative stabilities of the transition states and therefore, the more
stable of the two ions is formed the faster and corresponds to a lower maximum on the energy
profile.
d+
CH3—CH CH2
d+
H CH3—CH CH2
d–
Br H
(C) d–
Br
Less stable (D)
Higher-energy
intermediate
transition state
Lower-energy
+ transition state More stable
CH3CH2CH2 intermediate
G –
Br
+
CH3CH2CH2
‡
DG° DG° ‡ –
Br
CH3CH CH2 CH3CH CH2

CH3CH2CH2—Br
+ HBr + HBr (CH3)2CH—Br
Slower reaction Faster reaction
Reaction coordinate
Energy profiles—the addition of HBr to propylene
SCHEME 4.18c
(B) The Effect of Solvent on Rate of a ReactionStabilization of Transition State

The nature of the solvent affects the rate of a reaction
CH3
almost always. If one considers again the solvolysis of R
d– d+
d+
t-butyl chloride (see Scheme 4.18, the rate determining O: C Br H—O
step is the formation of the carbocation intermediate), H CH3 CH3 R
two characteristics of the solvent have their role in
determining the relative free energies of reactant and SCHEME 4.18d
the transition state and consequently the rate of reaction. Firstly, energy is needed to separate
the unlike charges and therefore, the reaction rate increases with the dielectric constant.
Secondly the solvating power of the solvent plays an important role, since the transition state
can be stabilized by solvation of the developing positive and negative ions. This solvation is
significant with water and other hydroxylic compounds e.g., alcoholic solvents. The electron-
rich hydroxylic oxygen solvates the developing carbocation (Scheme 4.18d) while the developing
chloride ion is solvated by hydrogen bonding to the hydroxylic hydrogen (also see Scheme 5.15).
Polar aprotic solvents like DMSO and DMF are less effective solvents in this case, since they
can only stabilize cations (see, Scheme 5.14). As a result the rate of solvolysis of t-butyl chloride
increases in water and other alcoholic solvents, since the transition state is stabilized by solvation
of both the developing positive and developing negative ions.
The following points may be noted.
• In the SN1 reaction (Scheme 4.18d) the transition state is more polar (with more
charge separation) than the reactant, therefore, a change to a more polar solvent
stabilizes the transition state far more than it stabilizes the reactant. The rate of SN1
reaction is very fast in a more polar solvent.
• In an SN2 reaction, with a nucleophile with a negative charge, this charge is more
dispersed in the transition state (the transition state is a much larger ion). In the
nucleophile however, the charge is more concentrated and it is thus more effectively
solvated and stabilized compared to the transition state. Thus the rate of an SN2
reaction involving a negative nucleophile occurs more slowly when the anion solvating
power of the solvent increases (Scheme 4.18e). In such cases the use of aprotic solvents
e.g., DMSO, DMF or acetone which cannot form a hydrogen bond with the nucleophile
(no H bonded nitrogen or oxygen in these solvents is available) increase the reactivity
of the nucleophile and thus enhance the rate of SN2 reaction. For example, the reaction
Cl– + CH3I → CH3Cl + I– is a million time faster in an aprotic solvent like DMSO
compared to a protic solvent like methanol.
– d– d–
Nu: + C—L Nu C L
Reactants Transition state

(more polar) (less polar)
SCHEME 4.18e
• When in an SN2 reaction, the nucleophile is neutral (Scheme 4.18f). The transition
d+ d–
Nu: + C—L Nu C L
Reactants Transition state

(less polar) (more polar)
SCHEME 4.18f
state in such cases involves the generation of opposite charges (Scheme 4.18f). Employing a
solvent like an alcohol solvates both positive and negative charges of the transition state, thus
the reactions are faster in protic solvents than in aprotic solvents.
EXERCISE 4.3
How the rate of the reaction (Scheme 4.18g) with the shown transition state will be
effected by using solvents with increasing solvating power?
– +
– + d d
HO + (CH3)3S HO—CH3 + (CH3)2S HO CH3 S(CH3)2
Transition state
SCHEME 4.18g
ANSWER. The unlike charges of the reactants are partially neutralized in the
transition state. Thus such reaction occurs more slowly with the increasing
solvating power of the solvent.
EXERCISE 4.4
Consider the transition state involved during the reaction (ipso) of bromobenzene
with an alkoxide ion (Scheme 4.18h). Why the reaction with t-butoxide ion in DMSO
is very fast when compared to that in t-butanol where the rate is extremely slow?
–
d
Br RO Br RO Br OR
– –
RO –Br
d– –
Transition Intermediate Product

state
SCHEME 4.18h
ANSWER. t-butanol solvates the anion strongly while DMSO cannot provide
similar stabilization and in DMSO as solvent the nucleophile (CH3)3CO– is
essentially free to take part in the reaction.
4.13 THE CURTIN-HAMMETT PRINCIPLEIMPORTANCE OF TRANSITION STATE

Consider examples of anti E2 elimination (see Schemes 12.13 and 12.14) which may be
stereoselective or stereospecific. Consider the stereoselective elimination (Scheme 12.13). The
Curtin-Hammett principle implies that in a chemical reaction that gives one product from one
conformer and a different product from another conformer (provided the products do not
interconvert while the two conformers are rapidly interconverting relative to the rate of product
formation). The product composition is not determined by the relative populations of the ground
state conformations but depend almost entirely on the relative energies of the representative
transition states involved (Scheme 4.18i). There are three possible staggered conformations
(I–III, Scheme 4.18i). Only the conformations (I and II) have H and Br in trans-coplanar
orientation for E2 elimination, the transition state from conformer (I) gives the minor product,
since the transition state is of higher energy (compared to the transition state from conformer II)
due to repulsive forces between the two methyl groups.
– –
d d
Br Br Br Br
H CH3 H 3C H H 3C
H CH3 H
CLASH
H CH3 H CH3 H CH3 H CH3
H H H H
–
d (I) (II) d–
Base Base
Transition state Transition state
Br
H H H 3C
H CH3 H
H H CH3 H
CH3 CH3
CH3
cis-2-butene trans-2-butene
(minor product) (III) E-2-butene
(major product)
SCHEME 4.18i
4.14 MICROSCOPIC REVERSIBILITY

At equilibrium individual molecular processes and the exact reverse of these processes have
an equal probability of occurring. If a certain number of molecules follow one path (of many
possible paths) in the forward direction, the same number follow that path in the reverse
direction. Microscopic reversibility is also known as the Principle of Detailed Balancing. In the
reaction (Scheme 4.18j) if B is an intermediate in going from A to C, then under the same
conditions B must be an intermediate in going from C to A. Consider e.g., a step from the chain
reaction during chlorination of CH4. The attack by Cl • on methane molecule gives a methyl
radical and HCl (Scheme 4.18j) via a transition state in which the methyl group begins to
flatten out from its original tetrahedral arrangement [subsequently methyl radical gives methyl
chloride on reaction with chlorine]. The same mechanism is involved during the reverse process,
•
HCl + CH 3 → CH 4 + Cl , during which the carbon of the methyl radical attacks the hydrogen
of HCl from the side opposite the H—Cl bond and the C—H bond begins to form.
A B C
‡ H H
H H
.
H C—H .Cl H C H Cl C H—Cl
H H H
SCHEME 4.18j
4.15 METHODS OF DETERMINING MECHANISMS

(A) Identification of Products
A mechanism proposed for a reaction must account for all the products as well as for their
relative proportions. Olefinic double bonds react with peracids to give epoxides and the reaction
is an electrophilic attack on the olefin. Electron-releasing groups in the olefin and electron
attracting groups in the peracid facilitate the reaction. The epoxidation reaction is first order
with respect to the olefin and the peracid i.e., it is a bimolecular process. One may, therefore,
H C+
C : O: —C —C
+
: :
: :
: :
—C—OH O + OH2 O
C : O:
—C H —C
: :
Alkene C O
A carbocation Epoxide
R
intermediate
Peracid (not involved)
:O:
:
+OH
:OH
:
H H
H
C C C+ C C—C C—C
H H H H H
R
R R R R R R
R
Alkene Carbocation cis-epoxide
Rapid
rotation
:O:
:
+OH
:OH
:
R
C+ C C—C C—C
H R H R H
H
R H R H R
Carbocation trans-epoxide
SCHEME 4.19
suggest an ionic mechanism (Scheme 4.19). A mechanism involving a carbocationic intermediate

is however, not operative, since the initially formed carbocation would undergo a rapid rotation
to yield a mixture of cis an well as trans-epoxides. The epoxide formation however, retains the
stereochemical relationships present in the reacting alkene and the epoxidation reaction is
found to be stereospecific. Thus cis-2-butene gives only cis-epoxide while trans-2-butene gives
only trans-epoxide. A reaction in which the two new bonds are formed at the same time cannot
change the stereochemical relationships of the groups in the original alkene. Thus the
stereospecificity of the reaction indicates that ring formation occurs essentially in one step
and does not involve a free carbocation. The currently accepted mechanism is a one step syn
addition which involves transfer of the oxygen atom β to the carbonyl group from the peracid
to the carbon-carbon double bond (Scheme 4.19a). Moreover, a large negative entropy of
activation also supports the concerted mechanism.
R O
C
O R OH
O b H CH2Cl2
O C—C + C
H H H H
H 3C CH3 O
C C
H3C CH3
One step syn-addition of a peracid to an alkene
SCHEME 4.19a
(B) Detection of Intermediates

1. Direct Isolation
In several reactions an intermediate can be isolated either by using mild conditions or by
stopping the reaction after a short time. In e.g., Hoffmann rearrangement an acid amide is
converted to an isocyanate and then to an amine on treatment of the amide with bromine in
alkaline solution. The overall reaction formally consists of decarboxylation of an amide. In
support of the mechanism (Scheme 4.19b) the involvement of an isocyanate intermediate has
been suggested.
O
Br2/NaOH –
OH
:
R—C—NH2 R—N C O: RNH2

H2O H2O
Isocyanate
Hoffmann rearrangement
SCHEME 4.19b
The detailed mechanism is given (see Scheme 5.15). In a related curtius rearrangement
an isocyanate has indeed been isolated (see Scheme 5.17).
EXERCISE 4.5
Why Hoffmann rearrangement is limited to amides of the type RCONH2?
ANSWER. Unless two H atoms are present on nitrogen of an amide, the isocyanate
intermediate cannot be formed (Scheme 4.19c).
O
– – –
OH OH – –Br
: :
R—CONH2 RCONHBr R— C—N—Br RN C O

Br2
Primary amide Step 1 Isocyanate
Step 2
SCHEME 4.19c
Removal of first H gives N-bromoamide while removal of second H gives a bromo

amide anion which undergoes a molecular rearrangement.
Application of Host-guest chemistry forms the basis of isolation of benzyne at low

temperature inside the molecular container called a hemicarcerand. The incarcerated benzyne
was sufficiently stable for NMR spectral measurements, before it ultimately underwent a Diels-
Alder reaction with the host container molecule.
2. Spectroscopic Determination
The involvement of a nitronium ion (NO2+) in the electrophilic nitration of benzene was found
on the basis of its detection by Raman spectroscopy (Sec. 8.2).
Benzyne is a reactive intermediate and as represented is strained acetylene in which
the acetylene bond is badly bent. Some of its IR and 13C NMR spectra (see Scheme. 4.50)
confirm these observations.
3. Trapping
An intermediate can be identified by trapping it by the addition of a compound with which it is
known to react. This is the way, benzynes are identified, since these react with dienes in the
Diels-Alder reaction. Thus during the diazotization of anthranilic acid in the presence of furan
a Diels-Alder adduct is isolated (Scheme 4.19d).
O O
C – C – –CO
O diazotization O 2 O
O
+ + –N2 Furan
NH3 N
N Benzene Diels-Alder adduct
Anthranilic acid (trapped in situ)
:
SCHEME 4.19d
4. Indirect Evidence
.
Intermediates may also be detected from indirect evidence. Thus when free radicals (R ) are
involved, often a chain-reaction mechanism operates, which is easily recognizable
(see Scheme 16.23). However, if carbocations (R + ) are involved, the result is often
rearrangements in the carbon skeleton of the starting materials. Consider the general reaction
of the formation of one alkyl halide from another alkyl halide. Reaction between bromoethane
and sodium iodide (eq. I, Scheme 4.20), gives iodomethane and Br– (as e.g., NaBr) as the only
two products. When this reaction is carried on 1-bromopropane; 1-iodopropane is the exclusive
product (ignoring NaBr). There is no rearrangement to produce, for example, 2-iodopropane.
Thus carbocations are not involved in the mechanism (Scheme 4.20) and 1-iodopropane is not
formed via the 1° carbocation. In case 1° carbocation was formed, it would have rearranged to
the more stable 2° carbocation from which some 2-iodopropane should have been formed. The
reaction therefore, must be proceeding through a concerted (one step) mechanism
(SN2 mechanism).
– – SN2
: :
: :
CH3—Br + : I : CH3—I + :Br : (I) CH3CH2CH2—Br – CH3CH2CH2—I
I
1-bromopropane 1-iodopropane
(n-propyl bromide) (n-propyl iodide)
(actual product)
+
CH3CH2CH2
1° Carbocation
Rearrangement
CH3CHCH3 CH3CHCH3
+
I
2° Carbocation 2-iodopropane
(isopropyl iodide)
(not formed)
SCHEME 4.20
(C) Stereochemical Evidence

When a reaction gives products which can exist in more than one stereoisomeric form, their
identification throws much light on the mechanism. The SN2 reaction mechanism involves a
one-step backside displacement of a leaving group by a nucleophile. It is a bimolecular reaction
since two particles (molecules or ions) are involved in the transition state of the slowest (rate
determining) reaction step, which is the only step in this reaction.
In the reaction of methyl chloride with hydroxide ion, one cannot detect inversion of
configuration because both the starting material and the product are achiral. When a pure
enantiomer of a chiral alkyl halide is used as the starting material, the inversion can be detected
due to the change in configuration. These data show that SN2 displacements to proceed by the
one step backside attack by the nucleophile on the substrate (Scheme 4.21).
R¢ R¢ Br H H OH
–
HO:
: :
– –
NuC: H C—LG NuC—C + : LG C C
H (SN2)
R R (R)-2-bromobutane (S)-2-butanol
Back-side attack LG = Cl, Br, I SN2 Mechanism
(inversion of configuration
One enantiomer of a
chiral alkyl halide
SCHEME 4.21
When an SN2 reaction occurs at a stereogenic carbon, the configuration of that carbon is
inverted in the product. SN1 reaction, on the other hand, is unimolecular (kinetic evidence)
and a two step sequence involving an intermediate formation of a planar carbocation. Thus
such a reaction at the stereocenter of an optically active alkyl halide should lead to racemization
(Scheme 4.22). Racemization is indeed observed by the expected attack of the nucleophile on
either side of the planar achiral carbocation.
R
R NuC—C
– – H
slow NuC : R NuC: (a)
H C—LG R
+
C Fast SN1 Mechanism
R a b
–
R
R H : LG (b)
One enantiomer of C—NuC
a chiral alkyl halide Achiral, trigonal H
planar carbocation R
Racemization
Br OH OH
+
SN1
(R)-2-bromobutane (R)-2-butanol (S)-2-butanol
(Racemic mixture)
SCHEME 4.22
A cycloalkene adds bromine to yield only a trans-1, 2-dibromocycloalkane. This shows

the anti mode of addition via a bridged ion intermediate. A carbocation intermediate should
have given products of both syn as well as anti addition (Scheme 4.23).
+
Br
Br H
H H + Br (Actual mechanism)
H Br
H Br H
Br –
trans-1, 2-dibromocyclohexane
A bridged bromonium ion (a racemic mixture)
Br– could attack either C but only from the side opposite
the bridge, bcause the bridge blocks the other side
Br2
–
Br
Br Br Br
Cyclohexene Br + H (Hypothetical
+ mechanism)
H H H
– H H Br
Br
(A carbocation intermediate) Cis Trans
– Not observed
Br could attack from
above or below
SCHEME 4.23
(D) Kinetic Isotope Effects

Chemists use different experimental techniques to reach at the most plausible mechanism for
a reaction. The mechanisms of the SN1, SN2, E1, and E2 reactions are based on a knowledge of
the rate law of the reaction, the relative reactivities of the reactants, and the structures of the
products formed.
Another powerful experimental evidence to investigate the mechanism of a reaction is

the deuterium kinetic isotope effect—the ratio of the rate constant observed for a compound
having hydrogen to the rate constant observed for a related compound in which one or more of
the hydrogens are replaced by deuterium, an isotope of hydrogen.
kH Rate constant of H-containing reactant
Deuterium kinetic isotope effect = = .
kD Rate constant for D-containing reactant
Because isotopic substitution has only a very small effect on the chemical behaviour of a
compound, the isotopically modified compound undergoes the same reactions and follows the
same mechanisms as its parent compound. Thus although the chemical properties of deuterium
and hydrogen are similar; but, a C—D bond is about 1.2 kcal/mol (5 kJ/mol) stronger than a
C—H bond. It is thus more difficult to break a C—D bond than a related C—H bond.
At a given temperature the rate of reaction for a compound containing a heavy isotope is
slower than the compound with a lighter isotope. This holds only if breaking of that bond is
involved at the transition state of the rate-determining step. If breaking of this bond occurs
prior to or after the rate-determining step, isotopic substitution does not lead to a large change
in the rate. This effect is most pronounced for hydrogen/deuterium, which has the largest
mass difference of any isotopic pair. When a bond to hydrogen (or deuterium) cleaves in the
rate-determining step, then kH/kD values of 2–8 are observed and are called primary kinetic
deuterium isotope effects.
When the C—H(D) bond does not break in the rate-determining step, there are sometimes
smaller effects on the rate resulting from isotopic substitution that are called secondary kinetic
deuterium isotope effects. The kH/kD values are 1 – 1.3 for these effects. When a kinetic deuterium
isotope effect is larger than about 1.5, it is a primary kinetic deuterium isotope effect to show
that C—H(D) bond breaks in the rate-determining step. If a kinetic deuterium isotope effect is
found to be between 1 and 1.5, it is a secondary kinetic deuterium isotope effect to indicate
that C—H(D) bond cleavage is not involved in the rate-determining step.
This helps in determination of mechanism. In the bromination of acetone (Scheme 4.24),
the rate-determining step is the tautomerization of acetone which involves cleavage of a
C—H bond. In case this mechanistic assignment is correct, one should observe a substantial
isotope effect on the bromination of deuterated acetone. Indeed kH/kD was found to be around 7.
This is a primary kinetic deuterium isotope effect to indicate that removal of a proton is involved
in the rate determining step. The base promoted bromination of ketones is a second order
: O: : O: –
:
H kslow
+ H2O
CH3 H CH3 CH2
Only Curite H
Acetone Proton removal and enolate
– formation are rate-determining
OH
–
:
: O: : O:
Br—Br kfast
Br + Br –
CH3 CH2 CH3 CH2
Base-promoted bromination of ketones
SCHEME 4.24
process, first order in ketone and first order in base (rate = k [ketone] [base]). The bromine
concentration does not appear in the rate law. The lack of rate dependence on bromine requires
that bromine is added to the molecule after the rate-determining step. A mechanism in keeping
with these facts is proton removal and enolate formation as the rate determining steps.
Several mechanisms get support from kinetic isotope effect. Some of these are, oxidation
of alcohols with chromic acid (see Scheme 13.1) and electrophilic aromatic substitution (see
Scheme 8.6). An example of a secondary isotope effect is given (Scheme 4.25), where it is sure
that the C—H bond does not break at all in the reaction. Secondary isotope effects for kH/kD
are generally between 1.0–1.5.
(CZ3)2CHBr + H2O (CZ3)2CHOH + HBr
The solvolysis of isopropyl bromide

where Z = H or D, kH /kD is 1.34.
Secondary isotope effect
SCHEME 4.25
The substitution of tritium for hydrogen gives isotope effects which are numerically
larger (kH/kT = 16).
E2 elimination like SN2 process takes place in one step (without the formation of any
intermediates). As the attacking base begins to abstract a proton from a carbon next to the
leaving group, the C—H bond begins to break (see Scheme 4.3), a new carbon-carbon double
bond begins to form and leaving group begins to depart. In keeping with this mechanism
(Scheme 4.3), the base induced elimination of HBr from (I, Scheme 4.25a) proceeds 7.11 times
faster than the elimination of DBr from (II). Thus C—H or C—D bond is broken in the rate
limiting step. If it was not so, there would not have been any rate difference.
– kH –
CH2CH2Br + CH3CH2O CH CH2 + Br + CH3CH2OH (I)
CH3CH2OH
fast
(I)
– kD –
CD2CH2Br + CH3CH2O CD CH2 + Br + CH3CH2OD (II)
CH3CH2OH
slow
(II)
SCHEME 4.25a
No deuterium isotope effect is observed in E1 reactions since the rupture of C—H

(or C—D) bond occurs only after the rate limiting step, rather than during it. Thus no rate
difference can be measured between a deuterated and a non-deuterated substrate.
EXERCISE 4.6
The reactions (Scheme 4.25b) may follows the E2 mechanism, however, these occur
at almost identical rates. What conclusion one can draw from these rate data?
Cl
EtOH
Ph—CH—CH3 Ph—CH CH2 + Substitution products
H2O
Cl
EtOH
Ph—CH—CD3 Ph—CH CD2 + Substitution products
H2O
SCHEME 4.25b
ANSWER. Since the rate of reaction of the undeuterated compound is almost

similar to that of the deuterated analog, indicates that the C—D bond is not cleaved
in the rate-determining step. Therefore, this reaction is not proceeding by an E2
mechanism.
Consider the electrophilic nitration of benzene using acetyl nitrate whereby a hydrogen
on benzene ring is replaced by a nitro group (Scheme 4.25c). The reaction is second order
overall, first order in benzene, and first order in the nitrating agent, rate = k[C6H6] [acetyl
nitrate]. When fully deuterated benzene is used then kH/kD = 1 to prove that nitrating agent
attacks the benzene ring in the rate-determining step, and the C—H bond cleavage does not
occur in the rate-determining step. The formation of nitrobenzene does require the loss of
hydrogen, and its loss does not take place in the rate-determining step of the reaction but after
the rate-determining step.
H NO2
O
+ kslow
+ –
N OAc + CH3CO2
–
O
CH3CO2–
H NO2 NO2
kfast
+ + CH3CO2H
SCHEME 4.25c
(E) Kinetic Evidence

When one determines the kinetics of the reaction between e.g., bromomethane and sodium
iodide, the rate expression derived from the experimental data (Scheme 4.26) is obtained. The
rate of the reaction depends on the concentration of both reactants therefore, both are involved
in the rate-determining step.
– – –
: :
: :
: :
CH3—Br + : I: CH3—I + :Br : Rate = k [CH3Br] : I:
SCHEME 4.26
This is consistent with our earlier findings. It appears that the reaction is a one-step
process with no detectable intermediates, it follows that both reactants must be involved in
one step. The kinetic evidence, thus provides added evidence to the original assignment of
mechanism.
(F) Isotopic Labelling

Working with molecules which are isotopically labelled followed by the tracing the path of
reaction gives useful information on mechanism. Thus e.g., the alkaline hydrolysis of esters
labelled with 18O helped to prove that the mechanism is bond cleavage between oxygen and
the acyl group (Scheme 6.58). The benzyne mechanism for nucleophilic aromatic substitution
is supported by isotopic labelling experiments (see Schemes 9.13 – 9.15).
(G) Crossover Experiments

Intra- or intermolecular nature of a rearrangement can often be demostrated by carrying out
the reaction on a mixture and then analyzing the products. For example, when the Hoffmann
reaction (RCONH2 RNH2), was carried out on a mixture of C6H4DCONH2
(3-deuteriobenzamide) and C6H4CO *NH2 (15N-benzamide) mixed anilines could not be isolated.
Thus the migrating group does not separate during the rearrangement (Scheme 15.16a).
4.16 REACTIVE INTERMEDIATES

Synthetic intermediates are stable products which are prepared, isolated and purified and
subsequently used as starting materials in a synthetic sequence. Reactive intermediates, on
the other hand, are short lived and their importance lies in the assignment of reaction
mechanisms on the pathway from the starting substrate to stable products. These reactive
intermediates are not isolated, but are detected by spectroscopic methods, or trapped chemically
or their presence is confirmed by indirect evidence.
(A) Carbocations
Carbocations are the key intermediates in several reactions and particularly in nucleophilic
substitution reactions.
1. Structure
Generally, in the carbocations the positively charged carbon atom is bonded to three other
atoms and has no nonbonding electrons. A carbocation is an sp2 hybridized carbon with a
planar structure and bond angles of about 120°. There is a vacant unhybridized p orbital which
e.g., in the case of CH3+ lies perpendicular to the plane of C—H bonds (Scheme 4.27).
Triphenylmethanol reacts like any other alcohol with a strong aid fluoroboric acid to
give a stable salt-triphenylmethyl fluoroborate containing the triphenylmethyl cation. This
cation is propeller shaped through the central carbon and the three ring carbons connected to
it lie in a plane (the three phenyl rings are at an angle of 54° to the plane of the trigonal
carbon). The three benzene rings cannot be in the same plane as a result of van der Walls
Empty p orbital
+
–H2O C
+ 120° (C6H5)3C—OH + HBF4 –
C BF4
Triphenylmethanol Fluorobric acid
Carbocation planar Triphenylmethyl fluoroborate

2
sp hybridized propeller shaped
–
BF4
H +
+ (C6H5)3CBF4 + H + (C6H5)3C—H
H
Triphenylmethyl cation Triphenylmethane
Cycloheptatriene (less stable) Cycloheptatrienyl cation
(tropylium ion)
SCHEME 4.27
repulsions between the ortho hydrogens. The triarylmethyl cations are particularly stable due
to the conjugation with the aryl groups which delocalize the positive charge. The triphenylmethyl
cation reacts with cycloheptatriene to form the cycloheptatrienyl cation (tropylium ion) by
abstraction of a hydride ion, the triphenylmethyl cation is converted to triphenylmethane in
the process. The cycloheptatrienyl cation (an aromatic ion) is more stable than the
triphenylmethyl cation, thus providing the driving force for its formation.
2. Stability
There is an increase in carbocation stability with additional alkyl substitution (Scheme 4.28).
Thus one finds that addition of HX to three typical olefins decreases in the order (CH3)2 C CH2
> CH3—CH CH2 > CH2 CH2. This is due to the relative stabilities of the carbocations formed
in the rate determining step (Scheme 4.28) which in turn follows from the fact that the stability
is increased by the electron releasing methyl group (+ I), three such groups being more effective
than two, and two more effective than one.
CH3
+ +
CH3 C+ > CH3—CH—CH3 > CH2—CH3 Stability of carbocations 3° > 2° > 1° > CH3+
CH3
SCHEME 4.28
Further, a structural feature which reduces the electron deficiency at the tricoordinate
carbon stabilizes the carbocation. When the positive carbon is in conjugation with a double
bond, the stability is more. This is so, because due to resonance the positive charge is spread
over two atoms instead of being concentrated only on one. This explains the stability associated
with the allylic cation. The benzylic cations are stable, since one can draw canonical forms as
for allylic cations (Scheme 4.29). Among the allylic and benzylic cations the relative stabilities
are as expected (Scheme 4.29). An alkyl halide can be detected by reacting it with AgNO3
in ethyl alcohol under SN1 conditions when a precipitate of silver halide is formed
(eq. A, Scheme 4.29, the mechanism is SN1 since ethanol is polar and no other strong nucleophile
is present). Keeping the carbocation stability in mind compound (I) as expected forms a
precipitate immediately as compared to (II) since the carbocation from (I, Scheme 4.29) is a
resonance stabilized benzylic cation.
+ +
R—CH CH—CH2 R—CH—CH CH2
An allylic cation
+
+
CHR CHR + CHR CHR
+
A benzylic cation
+ + +
CH2 CH—C—R > CH2 CHCH—R > CH2 CHCH2
R
Tertiary allylic cation Secondary allylic cation Allyl cation
+ + +
—C—R > —CH—R > —CH2
R
Tertiary benzylic cation Secondary benzylic cation Benzyl cation
Increase in stabilities
+ – C2H5OH + C2H5OH
RX + Ag NO3 AgX(S) + R R—OC2H5 (A)
Cl Cl
C6H5—CH—CH3 CH3—CH—CH3
(I) (II)
SCHEME 4.29
Aromaticity provides further stability to a carbocation when the vacant p orbital is part
of the conjugated cyclic system. This aspect is completely discussed in Chapter 2. One may
note that cyclopropenylium and cycloheptatrienylium ions are stable carbocations (Scheme
4.29a). The cyclic conjugated antiaromatic system e.g., cyclopentadienylium ion is relatively
more stable than a methyl cation, but it is far less stable than its aromatic analogs.
+ +
+
+
Relative to CH3 (kcal/mol) 91 114 56
SCHEME 4.29a
The benzyl cation stability is affected by the presence of substituents on the ring. Electron
donating p-methoxy (Scheme 4.29b) and p-amino groups stabilize the carbocation by 14 and
26 kcal/mole, respectively. The electron withdrawing groups like e.g., p-nitro destabilize by
20 kcal/mol.
H + H H H H + H H + H
C C C C
+
OCH3 +OCH3 N
+
N
+
– –
O O– O O
SCHEME 4.29b
A hetero atom with an unshared pair of electrons when present adjacent to the cationic
center strongly stabilizes the carbocation (Scheme 4.30). The methoxy-methyl cation has been
R R
+
: :
: :
:
R—C—O—Me R—C O—Me R—C O R—C O+
+ +
SCHEME 4.30
–
obtained as a stable solid CH3O+CH2 SbF6. Similarly acyl cations RCO+ have been prepared
and acetyl cation CH3CO+ is almost as stable as t-butyl cation. These ions are also stabilized by
resonance, however the positive charge is largely located on carbon.
It is for this reason that a primary halide (I, Scheme 4.30a) reacts very fast under SN1 conditions.
This is due to the resonance stabilization of the carbocation formed after the loss of Cl. The
carbocation has a resonance structure (III) where the octet rule is satisfied on all atoms and
this structure provides very large resonance stabilization.
+ +
: :
CH3—O—CH2—Cl CH3—O—CH2 CH3—O CH2

:
(I) (II) (III)
SCHEME 4.30a
Alcohols are protected to prevent their further reaction in synthesis and use of acetals
e.g., tetrahydropyranyl (THP) derivatives which are made from reaction with dihydropyran
and an acid catalyst are useful for this purpose (Scheme 4.30b). Protonation of dihydropyran
gives a carbocation which is highly stabilized since the positive charge is located on a carbon
next to oxygen atom. The nucleophilic alcohol then attacks this carbocation and loss of proton
gives the THP derivative.
: :
+ (1) ROH
H
+ + (2) –H+ R
: :
: :
O O O O O
:
Dihydropyran Resonance stabilized carbocation THP derivative
SCHEME 4.30b
EXERCISE 4.7
How the following relative rates of solvolysis (Scheme 4.30c) under SN1 conditions
can be explained?
CH3OCH2CH2Cl CH3CH2CH2CH2Cl CH3CH2OCH2Cl

9
SN1 solvolysis 0.2 1.0 10
(relative rates)
SCHEME 4.30c
ANSWER. The fastest rate of solvolysis in the case of chloromethylethyl ether is
due to the specially stabilized carbocation which is formed after the loss of chlorine
atom. 2-Chloroethylmethyl ether reacts the slowest since the derived carbocation
in destabilized due to adjacent partially positive carbon atom (Scheme 4.30d).
d– d+ d+ +
CH3—O—CH2—CH2—Cl CH3—O—CH2—CH2
Destabilizing
factor
SCHEME 4.30d
EXERCISE 4.8
3-Butyne-1-ol can be made as shown (Scheme 4.30e), an acetylide ion is both a
strong base and a good nucleophile. How 3-hexyn-1, 6-diol can be mode?
O
NaNH2 – + (1) CH2—CH2
CH CH CH C Na CH CCH2CH2OH
NH3(l) (2) H2O
3-butyn-1-ol
SCHEME 4.30e
ANSWER. Due to the acidity of OH group which will interfere with the formation
of acetylide ion in base, the hydroxyl group must first be protected (Scheme 4.30f).
O NaNH2
HC CCH2CH2OH +
HC CCH2CH2O O Na+ –C CCH2CH2O O
H NH3 (l)
3-butyn-1-ol Hydroxyl group O
protected as
THP derivative (1) H2C—CH2
(2) H2O
+
H3O
HOCH2CH2C CCH2CH2OH HOCH2CH2C CCH2CH2O O
SCHEME 4.30f
Cyclopropylmethyl cations (I, Scheme 4.31) are even more stable than the benzyl cations.
This stability increases with every cyclopropyl group and consequently tricyclopropylmethyl
cation (II, Scheme 4.31) is even more stable than the triphenylmethyl cation. This special
stability is a result of conjugation between the bent orbitals of the cyclopropyl rings (see
Scheme 1.2a) and the vacant p orbital of the cationic carbon (III, Scheme 4.31).
CH3 H
H
C+ C +
+
H H
CH3 C
(I) (II) H
Cyclopropylmethyl cations
H
H
(III)
Cyclopropylmethyl cation
SCHEME 4.31
Participation of the cyclopropyl ring is reflected in the solvolysis of cyclopropylcarbinyl

tosylate (I, Scheme 4.31a), which proceeds 106 times faster than solvolysis of the tosylate of
2-methyl-1-propanol (II). This is due to special stability which the cyclopropyl group imparts
to the adjacent carbocationic center. However, cyclopropylcarbinyl cations undergo opening of
the strained three membered ring to give a homoallylic cation (IV) and a cyclobutyl cation (V).
+ +
OTs OTs CH2 + +
(I) (II) (III) (IV) (V)
SCHEME 4.31a
Oxaspiropentanes (I, Scheme 4.31b) can be prepared by the reaction of ketones with
sulphur stabilized cyclopropyl ylides (see Scheme 7.26a). These oxaspiropentanes on treatment
with acid give a cationic carbon conjugated to the cyclopropyl ring (II) which undergoes
rearrangement via ring opening.
H
O O
O + OH +
H + + —H
(I)
SCHEME 4.31b
That the carbocations are planar is shown by the fact that these are difficult or
impossible to form at bridgeheads, where they cannot be planar. Thus, t-chloride,
1-chloroapocamphane is inert to SN1 substitution. The cause of inertness is due to the
presence of a rigid bridged system which prevents rehybridization to a planar sp2 carbon.
When the structure is flexible, the bridgehead carbocations can be prepared. Thus the
bridgehead bromide, 1-bromoadamantane (II, Scheme 4.32) undergoes solvolysis. In fact
(III) has been prepared as the SF6– salt. The unstability of bridgehead carbocation
(IV, Scheme 4.32) which has also been prepared in super acid solution at – 78°C is due to
stability gain from the conjugation with the three cyclopropyl groups.
+
Br +
Cl
The 1-trishomobarrelyl cation
(I) (II) (III)
SCHEME 4.32
The stability order of a carbocation is explained by hyperconjugation (see Scheme 2.44).

In vinyl cations (CH2 C+H), resonance stability lacks, completely and these therefore are
very much less-stable. Such cations may be the intermediates in solvolysis reactions, however,
the simple vinyl cations have not been directly observed (see Scheme 5.18a).
A carbocation is planar with an empty p orbital. A phenyl cation is very unstable and
the p orbital is full (the part of the aromatic ring) and the empty orbital is an sp2 orbital which
is outside the ring. Thus normally e.g., bromobenzene does not undergo SN1 reaction since it
would involve the formation of a highly unstable phenyl cation. However, significantly, the
phenyl cation can be formed and captured by heating a diazonium salt which involves the loss
a best leaving group—a molecule of nitrogen (Scheme 4.32a, see also Scheme 4.32e).
+
Br + N N + OH
+
– heat –H
Cl H 2O
2
Empty sp orbital A diazonium salt A phenyl cation
SCHEME 4.32a
3. Generation and Fate

The carbocations are formed as reactive intermediates in a variety of reactions. Thus during a
direct ionization, a group attached to the carbon atom leaves with its pair of electrons to give
a carbocation (see Scheme 4.6). After its formation, a carbocation may rearrange to give other
more stable carbocation (see Scheme 4.5), may react with a charged or an uncharged nucleophile
(see Scheme 4.22) or may lose a proton from the adjacent atom (see Scheme 4.6).
The following points may be noted regarding methods of preparation of carbocations
and the reactions undergone by them.
• By the addition of an acidic reagent (HX) to an alkene (Scheme 4.32b), to form a more
stable carbocation followed by its trapping with X–.
+
PhCH2CHCH3
A secondary carbocation +
HBr Addition of H so as
PhCH CHCH3
:
: Br : to form a more stable
–
:Br :
: :
+ of the carbocations.
PhCHCH2CH3 PhCHCH2CH3
A secondary
benzylic carbocation
+ + +
Relative stabilities —C—R —CH —CH2
R R
Tertiary benzylic cation Secondary benzylic Benzylic cation
(most stable) cation
SCHEME 4.32b
• By treatment of an alcohol with an acidic reagent e.g., HCl (Scheme 4.32c). The reactant
(I) gives an onium salt which gives a 3° carbocation (A) by the loss of water. The relief
CH3 Cl
H H CH3 H CH3
+ + CH3 CH3
–
C—OH + HCl OH2 –H2O + Cl
CH3 CH3
CH3 CH3 CH3
(I) (A) (B)
SCHEME 4.32c
of ring strain provides the driving force to give a less stable 2° carbocation (B) which
is trapped by Cl– to give the product. A similar situation obtains when the alcohol
(I, Scheme 4.32d) is treated with HCl. The initially formed secondary carbocation (II)
is trapped by chloride ion to directly give the SN1 product (III). The carbocation (II)
rearranges to the more stable benzylic cation (IV) by involving a 1, 2-hydride shift
and finally the rearranged product (V).
1, 2-H shift
–
Cl
H 3C + H3C
Cl
H H
(IV) (V)
HCl
H 3C –H2O H 3C More stable benzylic carbocation
H H
+
OH
(II)
(I) (Carbocation)
–
Cl H3C H
Cl
(III)
SCHEME 4.32d
• Amine (I, Scheme 4.32e) on reaction with nitrous acid (HNO2 give a diazonium salt
which readily decomposes to a cation which subsequently undergoes ring enlargement
(Scheme 4.32e).
+ + +
OH O
HO CH2NH2 HO CH2—N N HO CH2—N N
–N2 +
–H
HONO Migration of
ring residue
(I) Diazonium ion
(A ring enlargement)
SCHEME 4.32e
• Epoxides on reaction with acid generate carbocations which may also undergo a
rearrangement (Scheme 4.32f).
+
OH O
H3C O H3C OH H3CC CH3 H3CC CH3
CH3 + + CH3
H
+
Migration of –H
Via acid catalyzed ring residue
ring opening of an
epoxide
(A ring contraction)
SCHEME 4.32f
• Aldehydes and ketones on treatment with acid catalyst yield the oxygen stabilized
cation (Scheme 4.32g). These cations can be stabilized on treatment of an aldehyde or
a ketone with boron trifluoride.
+ + – –
O + O—H O—H O O BF3 O BF3
H BF3
1 1 1 1 1 1
R R R R R + R R R R R R + R
SCHEME 4.32g
• Resonance stabilized acylium ion can be generated by the removal of chlorine from
an acid chloride with Lewis acids e.g., aluminium chloride (Scheme 4.32h). The acylium
ion e.g., can attack the pi bond of benzene ring to yield an aryl ketone in Friedel
Crafts acylation reaction.
O O O+ C
AlCl3 – R
+
AlCl4
R Cl R R
Acylium ion
SCHEME 4.32h
• Primary reactants undergo S N2 displacement reaction rather than generating

carbocations and subsequent rearrangement (Scheme 4.32i).
H H
+ + –
Br
CH3CH2CHCH2 CH3CH2CHCH2—OH2 CH3CH2CH2CH2—Br
Protonated
primary alcohol
SCHEME 4.32i
Recall the steric requirements of SN2 reactions. In the case of isobutyl alcohol a reaction
with HBr/H2SO4 gives isobutyl bromide as the major product and t-butyl bromide is formed as
a result of the formation of t-butyl cation formed via rearrangement (Scheme 4.32j). However,
the neopentyl type of systems with a quaternary carbon next to the alcohol carbon display
complete rearrangement. SN2 reactions on such systems are completely hindered and thus the
rearrangement reaction becomes the dominating reaction (Scheme 4.32j).
H H
– + –H2O + –
Br Br
(CH3)2CHCH2Br CH3CCH2—OH2 CH3CCH2 (CH3)3CBr
(major product) (minor product)
CH3 CH3
CH3 CH3 Br
+ –H2O + –
Br
CH3CCH2—OH2 CH3CCH2 (CH3)2CCH2CH3
CH3 CH3
SCHEME 4.32j
Methods have been developed by Olah for preparing carbocations under conditions where
they are stable enough to be studied by 1H NMR spectroscopy. In liquid sulphur dioxide, alkyl
fluorides react with the Lewis acid antimony pentafluoride to give solutions of carbocations
(I, Scheme 4.33). The 1H NMR spectrum of tert-butyl fluoride in liquid sulphur dioxide displays
the nine protons as a doublet centered as δ 1.35. On adding antimony pentafluoride to the
solution, the doublet at δ 1.35 is replaced by a singlet at δ 4.35. Both the change in the
splitting pattern of the methyl protons and the downfield shift are in keeping with the formation
of a tert-butyl cation (II, Scheme 4.33). On treating a solution of isopropyl fluoride in liquid
sulfur dioxide with antimony pentafluoride a more remarkable downfield shift is seen
(III, Scheme 4.33).
liq. SO2 + –
R—F + SbF5 R SbF6 (I)
Solutions of carbocations
liq. SO2 + –
(CH3)3C—F + SbF5 (CH3)3C SbF6 (II)
d 1.35 d 4.35
Doublet Singlet
+ –
(CH3)2—CHF + SbF5 (CH3)2—CH SbF6 (III)
d 1.23 d 4.64 d 5.03 d 13.50
(quartet) (multiplet) (doublet) (septet)
SCHEME 4.33
The tropylium ion and cyclopropenyl ions (see Schemes 2.34 and 2.37) are examples of
cations stabilized by being part of a delocalized aromatic system. These cations are aromatic
due to Hückel’s rule.
(B) Carbanions
1. Structure
A carbanion possesses an unshared pair of electrons and thus represents a base. A best
description is, that the central carbon atom is sp3 hybridized with the unshared pair occupying
one apex of the tetrahedron. Carbanions would thus have pyramidal structures similar to
those of amines. It is believed that carbanions undergo a rapid interconversion between two
pyramidal forms (Scheme 4.34).
:
The two possible forms are

– rapidly inverting carbanion
C C–
(pyramidal).
:
SCHEME 4.34
There is evidence for the sp3 nature of the central carbon and for its tetrahedral structure.
At bridgehead a carbon does not undergo reactions in which it must be converted to a carbocation.
However, the reactions which involve carbanions at such centers take place with ease, and
stable bridgehead carbanions are known. In case this structure is correct and if all three R groups
on a carbanions are different, the carbanion should be chiral. All reactions therefore, which
involve the formation of chiral carbanion should give retention of configuration. However, this
never happens and has been explained due to an umbrella effect as in amines (Scheme 4.34).
Thus the unshared pair and the central carbon rapidly oscillate from one side of the plane to
the other.
2. Stability and Generation
The Grignard reagent is the best known member of a broad class of substances, called
organometallic compounds (Chapter 7) where carbon is bonded to a metal: lithium, potassium,
sodium, zinc, mercury, lead, thallium—almost any metal known. Whatever the metal, it is less
electronegative than carbon, and the carbon-metal bond like the one in the Grignard reagent
(Scheme 4.35) is highly polar. Although the organic group is not a full-fledged carbanion—an
anion in which carbon carries negative charge, it however, has carbanion character.
Organometallic compounds can serve as a source from which carbon is readily transferred
with its electrons. On treatment with a metal, in RX the direction of the original dipole moment
is reversed (reverse polarization). Thus, metallation turns an electrophilic carbon into a
nucleophilic center (also see Sec. 7.5B, Scheme 7.31, i.e., umpolung).
d+ d– d– d+
CH3CH2CH2CH2—Br + 2 Li CH3CH2CH2CH2—Li + LiBr
n-butyl bromide n-butyllithium
a carbanion like species
SCHEME 4.35
Acetylene is ionized on treatment with amide ion in liquid ammonia to form a sodium
acetylide; this has a little covalent character and may be regarded as a true carbanion (see
Scheme 3.11). This property is used in making substituted alkynes by reaction of an acetylide
anion with an alkyl halide via an SN2 reaction. The stability order of carbanions points to their
high electron density. Alkyl groups and other electron-donating groups in fact destabilize a
carbanion. The order of stability is the opposite of that for carbocations (Scheme 4.35a) and
R R H H
Most + + + + Least
stable R—C > R—C > R—C > H—C stable
R H H H
Tertiary Secondary Primary Methyl
carbocation carbocation carbocation cation
Relative stabilities of carbocations
R R H H
Least – – – – Most
stable R—C : > R—C : > R—C : > H—C : stable
R H H H
Tertiary Secondary Primary Methyl
carbanion carbanion carbanion anion
Relative stabilities of carbanions

SCHEME 4.35a
free radicals, which are electron deficient and are stabilized by alkyl groups. Based on this
stability order it is easy to understand that carbanions that occur as intermediates in organic
reactions are almost always bonded to stabilizing groups. An important method of preparation
thus involves a loss of proton from a haloform to afford a stabilized carbanion (Problem 3.2).
Another factor which leads to stability is resonance e.g., a carbonyl group stabilizes an adjacent
carbanion via overlap of its pi bond with the nonbonding electrons of the carbanion. Carbanions
generated from carbonyl compounds are often called enolate anions. Among other functional
groups which exert a strong stabilizing effect on carbanions are nitro and cyano groups. Thus
carbanions can be generated from substrates with a C—H bond adjacent to a carbonyl, C N
or NO2 groups (see Schemes 3.26 and 3.30).
The second row elements, particularly phosphorus and sulphur stabilize the adjacent
carbanions. A very important nucleophilic carbon species constitute the phosphorus and sulphur
ylides. The preparation of ylides is a two stage process, each stage of which belongs to a familiar
reaction type: nucleophilic attack on an alkyl halide, and abstraction of a proton by a base
(Scheme 4.36).
–
Br
SN 2 + Bu—Li + –
:
Ph3P: + CH3—Br Ph3P—CH3 Ph3P—CH2 Ph3P CH2
Methyltriphenylphosphonium Ylide
Triphenylphosphine salt carbanion like
species
SCHEME 4.36
The phosphorus ylides (used in Wittig reaction) have hybrid structures, and it is the
negative charge on carbon i.e., the carbanion character of ylides which is responsible for their
characteristic reactions (see Scheme 7.9). The sulfur atoms also stabilize carbanions and as a
last example of formation and reactivity of an acyl anion equivalent is in (Scheme 4.36a).
O O
HS SH BuLi
propane S S S S :–
H3C H
dithiol
:
–
H3C H H3C
Substrate
Thioacetal Dithiane anion
(a carbanion)
+
SN 2 H /HgCl2 O
+ R—X
S S S S H2O
Primary H 3C R
– alkyl halide
:
H3C H3C R
Product
SCHEME 4.36a
The proton(s) on the carbon bearing two sulfur atoms is acidic (pKa = 31) and can be
removed with a strong base like n-butyl lithium to afford a stable carbanion. This carbanion is
a strong nucleophile and displays SN2 reactivity (also see Scheme 3.30c).
When a double or triple bond is located α to the carbanionic carbon, the ion is stabilized
by resonance as in the case of benzylic type carbanions (Scheme 4.37). Thus toluene is more
acidic (pKa = 41) than alkanes (ethane, pKa = 50).
–
:
CH2 CH2 CH2 CH2
:– –:
:
Resonance in benzylic carbanion
SCHEME 4.37
3. Properties
Carbanions are nucleophilic and basic and in this behaviour these are similar to amines, since
the carbanion has a negative charge on its carbon, to make it a powerful base and a stronger
nucleophile than an amine. Consequently, a carbanion is enough basic to remove a proton
from ammonia (see Scheme 3.11).
EXERCISE 4.8a
Alkyl fluorides undergo E2 dehydrohalogenation to give less substituted alkene
(Hoffmann regioselectivity) as the major product unlike E2 dehydrohalogenation
of alkyl chlorides, alkyl bromides and alkyl iodides. Explain giving an example.
ANSWER. E2 dehydrohalogenation of alkyl fluorides involves a carbanion-like
transition state and thus carbanion stability has to be considered (Scheme 4.37a)
–
d
OCH3
F H
– —CH3OH
CH3CHCH2R + CH3O CH2CHCH2R
– – CH2 CHCH2R
CH3OH d —F
Methoxide (major product)
ion F
(more stable)
Carbanion-like transition state leading to

less substituted alkene
–
d OCH
3
CH3CHCHR CH3CH CHR

–
d 2-pentene
F Minor product
(less stable)
Carbanion like transition state
leading to more substituted alkene
SCHEME 4.37a
Fluoride ion is the strongest base and therefore, the poorest leaving group. Thus
when a base starts removing a proton from an alkyl fluoride there is less tendency
for the fluoride ion to leave and negative charge develops on the carbon losing the
proton. The transition state resembles a carbanion (Scheme 4.37a) rather than an
alkene. To determine which of the carbanion-like transition states is more stable,
one must determine which carbanion would be more stable. When a hydrogen and
a chlorine, bromine, or iodine are eliminated from an alkyl halide, the halogen
starts to leave as soon as the base begins to remove the proton. A negative charge
therefore, does not build up on the carbon that is losing the proton. The resulting
transition state then resembles an alkene rather than a carbanion.
(C) Free RadicalsAn Introduction (For Details see chapter 16)

1. Structure and Geometry
A free radical is a species which has one or more unpaired electrons. In the species where all
electrons are paired the total magnetic moment is zero. In radicals, however, since there are
one or more unpaired electrons, there is a net magnetic moment and the radicals as a result
are paramagnetic. Free radicals are usually detected by electron spin resonance (esr), which is
also termed electron paramagnetic resonance (epr, see Scheme 2.22).
Simple alkyl radicals have a planar (trigonal) structure, i.e., these have sp2 bonding
with the odd electron in a p orbital. The pyramidal structure is another possibility (Scheme 4.38),
.
C or C C
rapidly
inverting
.
Planar Very shallow pyramid
Methyl radical is planar while the trifluoromethyl radical is pyramidal.

. .
The oxygenated species CH2OH and CMe2OH lie somewhere in between.
SCHEME 4.38
when the bonding may be sp3 and the odd electron is in an sp3 orbital. The planar structure is
in keeping with loss of activity when a free radical is generated at a stereocentre. On adding
HBr to 2-methyl-l-butene in the presence of peroxide, the product has a single stereocenter.
However, equal amounts of the R and S enantiomers are obtained. The product is a racemic
mixture (Scheme 4.39). The carbon atom in the radical intermediate that bears the unpaired
electron is planar and sp2 hybridized. This means that the three substituents bonded to it are
all in the same plane. Consequently, the R enantiomer and the S enantiomer will be obtained
in equal amounts, because HBr has equal access to both sides of the achiral radical (Scheme
4.39). Unlike carbocations the free radicals can be generated at bridgeheads to show that
pyramidal geometry for radicals is also possible and the free radicals need not be planar.
CH3 CH3
peroxide
CH3CH2C CH2 + HBr CH3CH2CHCH2Br
A
2-methyl-1-butene 1-bromo-2-methylbutane
.
.
CH3
CH3 H
CH3CH2—C H—Br
C C
CH2Br CH2Br .
CH3CH2 H CH3
2
CH2Br CH3CH2 Bridgehead radicals
sp
SCHEME 4.39
2. Stability
As in the case of carbocations, the stability of free radicals is tertiary > secondary > primary
(see Scheme 4.35a) and is explained on the basis of hyperconjugation (see Scheme 1.4i). The
stabilizing effects in allylic radicals (see Scheme 2.11) and benzyl radicals (Scheme 4.40), is
due to resonance structures. The strength of the bonds between the same atoms can give an
idea about the stability of the radicals formed by their homolysis. The following points may be
noted:
• The strength of C—H bonds decrease in R—H when R changes from primary, secondary
and tertiary. Thus tertiary alkyl radicals are the most stable.
• A C—H bond next to conjugating groups like allyl or benzyl are very weak, thus allyl
and benzyl radicals are more stable than even alkyl radicals.
• The C—H bonds to alkenyl or phenyl groups are strong thus a vinyl or a phenyl
radical is less stable than an alkyl radical.
.
. Br :
: :
CH2—H CH2 CH2 CH2 CH2

. .
–HBr
.
Formation of a resonance stabilized benzyl radical
.
: :
: :
CH2 + :Br—Br : CH2Br
.
–Br
Benzyl radical Benzyl bromide
SCHEME 4.40
The triphenylmethyl type radicals are no doubt stabilized by resonance (Scheme 4.41),
however, the major cause of their stability is the steric hindrance to dimerization (also see
Schemes 16.3 and 16.3a). The dimeric product is a cyclohexadiene derivative (Scheme 4.42,
also see, Scheme 16.2).
C. C C
. .
Free triphenylmethyl radical
SCHEME 4.41
H
2 Ag .
2Ph3CCl 2Ph3C Ph2C + 2 AgBr
Triphenylmethyl CPh3
radical,
yellow Dimer colourless
SCHEME 4.42
3. Generation and Properties

These are discussed in detail in Chapter 16. It may be sufficient here to mention that free
radicals are formed on thermal and photochemical cleavage. Thus azo and peroxy compounds
on heating give free radicals (Scheme 4.42a).
O O O
D
2 R.
:
:
heat . –2CO2 . R—N N—R

PhC—O—O—CPh 2PhC—O 2Ph –N2
An azo compound
Benzoyl peroxide
Me Me Me Me
heat . .
Me—C—N N—C—Me N2 + 2Me—C C C N
CN CN Me
C N
AIBN
(azobisisobutyronitrile)
SCHEME 4.42a
The energy of light of 600–300 nm (48–96 kcal/mol) is around the order of magnitude of
.
covalent bond energies. Thus on photochemical reaction, chlorine gives radicals (Cl2 → 2Cl ).
For further details on methods of preparation (see, Schemes 16.5–16.6).
• AIBN is a source of relatively unreactive, nitrile stabilized radical. This radical is
employed when weaker bonds (e.g., Sn—H) are to be cleaved.
• Peroxides, however generate highly reactive RO• radicals and thus can abstract
hydrogen from any position leading to loss of selectivily.
Some of the more general radical reactions are depicted (Scheme 4.42b), further details
are in chapter 16.
H
.
R. .R R—R R. + R¢CH—CH2 R—H + R¢CH CH2
Coupling Disproportionation
. C— .
R. + H—C— R—H + R. + C C R—C—C
Abstraction Addition
O
.
R.
Radical may fragment to a smaller
R—C—O : + CO2 radical and a neutral molecule. This
:
process is reverse of addition.

Fragmentation
SCHEME 4.42b
(D) Carbenes
Carbenes are neutral intermediates having bivalent carbon, in which a carbon atom is covalently
bonded to two other groups and has two valency electrons distributed between two nonbonding
orbitals. When the two electrons are spin paired the carbene is a singlet, if the spins of the
electrons are parallel it is a triplet (Scheme 4.43).
1. Structure
A singlet carbene is thought to possess a bent sp2 hybrid structure in which the paired electrons
occupy the vacant sp2 orbital. A triplet carbene can be either bent sp2 hybrid with an electron
in each unoccupied orbital, or a linear sp hybrid with an electron in each of the unoccupied
p-orbitals. It has however, been shown that several carbenes are in a non-linear triplet ground
state. However, the dihalogenocarbenes and carbenes with oxygen, nitrogen and sulphur atoms
attached to the bivalent carbon, exist probably as singlets. The singlet and triplet states of a
carbene display different chemical behaviour. Thus addition of singlet carbenes to olefinic
double bonds to form cyclopropane derivatives is much more stereoselective than addition of
triplet carbenes (see Schemes 11.13a and 11.13b).
A
R
C: R R
B R R R
A carbene
Singlet Triplet
SCHEME 4.43
2. Generation
Carbenes are obtained by thermal or photochemical decomposition of diazoalkanes. These can
also be obtained by α-elimination of a hydrogen halide from a haloform with base, or of a
halogen from a gem dihalide with a metal (Scheme 4.44).
hv D
RCHN2 [RCH : ] + N2 N2CHCO2C2H5 [ : CHCO2C2H5] + N2
–
B: – –
CHCl3 BH + : CCl3 : CCl2 + Cl + BH
SCHEME 4.44
3. Reactions
These add to carbon double bonds (see Schemes 11.13a and 11.13b) and also to aromatic systems
and in the later case the initial product rearranges to give ring enlargement products
(Scheme 4.45, see also exercise 8.8).
– D
: CH2—N N N2 + : CH2
Diazomethane
H2C CH2
carbene
:
CH2 electrocyclic
rearrangement
Benzene Norcaradiene Cycloheptatriene

intermediate
SCHEME 4.45
Benzvalene can be prepared by the reaction of lithium cyclopentadienide with a carbene

prepared in situ from dichloromethane and methyl lithium (Scheme 4.45a). Carbenoids—
organometallic or complexed intermediates which, while not free carbenes afford products
expected from carbenes are usually called carbenoids (Scheme 4.45b).
H2CCl2 + H3CLi
(H3COCH3)
C
:
– +
H Li
Lithium cyclopentadienide Benzvalene
SCHEME 4.45a
diethyl ether
CH2I2 + Zn ICH2ZnI
Cu
Iodomethyl zinc iodide
(a carbenoid)
SCHEME 4.45b
When a carbene is generated on a three membered ring, allenes are formed by

rearrangement (Scheme 4.46). However, a similar formation at a cyclopropyl-methyl carbon
gives ring expansion (Scheme 4.46, see also Scheme 10.22). Carbenes are also involved in
Reimer-Tiemann reaction (see Schemes 8.52 and 8.53 and exercise 8.8).
R R
Br alkyllithium
:
: RCH C CHR CH2
Br
R R Allene
Carbene
1, 1-dihalocyclopropane Carbene
SCHEME 4.46
(E) Nitrenes
1. Structure and Generation
The nitrenes R—N represent the nitrogen analogs of carbenes and may be generated in the
singlet ( R—N:) or triplet state ( R—N. .). A nitrene can be generated via elimination (Scheme 4.47),
:
or by the thermal decomposition of azides (R—N N+ N– RN + N2).
Base –
R—N—OSO2Ar R—N + B—H + ArSO2O
H
SCHEME 4.47
2. Reactions
In their chemical behaviour, nitrenes are similar to carbenes. Nitrenes, (in particular acyl
nitrenes) get inserted into some bonds e.g, a C—H bond to give an amide (Scheme 4.48).
Aziridines are formed when nitrenes add to C C bonds (Scheme 4.48). Alkyl nitrenes do not
display the typical reactions shown in Scheme 4.48, however, these undergo an instant
rearrangement (Scheme 4.49).
H R
R¢—C—N + R3CH R¢—C—N—CR3 R—N + R2C CR2 N

Insertion Addition
R2C CR2
O O
Acyl nitrene Aziridine
SCHEME 4.48
: :
R—CH—N RCH NH
H
Alkyl nitrene rearrangement
SCHEME 4.49
(F) Arenium Ions

A considerable amount of experimental evidence indicates that electrophiles attack the π system
of benzene to form a delocalized non-aromatic carbocation known as arenium ion or sometimes
a σ complex (see Schemes 8.2 and 8.4). CMR spectroscopic evidence is available in favour of
σ complex.
(G) Benzyne
It is a reactive intermediate in some nucleophilic aromatic substitutions. It is a benzene with
two hydrogen atoms removed (see Sec. 9.3 and 9.4). It is usually drawn with a highly strained
triple bond in the six membered ring. Benzyne intermediate has been observed spectroscopically
and trapped (see Scheme 9.16a).
Benzyne is too reactive to be isolated and is observed only spectroscopically. Photolysis
of benzocyclobutenedione gives benzyne. Although benzyne is usually represented as a
cycloalkyne (Scheme 4.50), its triple bond exhibits an IR stretching frequency of 1846 cm–1
which is intermediate between the double (ethene, 1655 cm–1) and triple (ethyne, 1974 cm–1)
bonds. The 13C NMR values for these carbons (δ = 182.7 ppm) are also not of pure triple bonds.
This evidence shows a contribution by a cumulated triene resonance structure. This bond is
however, weak due to poor p orbital overlap in the plane of the ring (see Scheme 9.15).
O
–2 CO
hv, 77 K
O
Benzyne
Benzocyclobutene-1, 2-dione
SCHEME 4.50
PROBLEMS
4.1 Why the addition of HCl to the following olefin takes place in the opposite manner as
predicted by Markonikov’s rule (i.e., the hydrogen atom of HX adds to that carbon which
has the greatest number of hydrogens?
CH2 CH—CO2Et + HCl CH2Cl—CH2—CO2Et
4.2 Considering H and S terms, how one can predict the favoured direction of the reaction
.
R:R 2R ?
4.3 Why compared to the slow esterification of acetic acid with methanol in the absence of
an acid catalyst, the lactonization of 4-hydroxy-butyric acid is almost spontaneous?
4.4 Why the synthesis of larger rings is usually impeded?
4.5 Indicate if the following statements are true or false:
(a) More stable species have lower energy.
(b) In case products are favoured at equilibrium ∆G° is negative while Keq is larger than 1.
(c) With a smaller rate constant, the reaction is fast.
(d) The products formed with stronger bonds and with larger freedom of motion causes
∆G° to be negative.
(e) Bond are only partially formed in a transition state while in intermediates the bonds
are fully formed.
4.6 Write a mechanism for the following conversion:
CH2 CH3
H+ /H2O
H3C
H3C CH3
CH3

4.1 Of the two possible intermediate I and II, I is of lower energy than II. In, II the positive
charge is adjacent to the strongly electron withdrawing carboethoxy group.
+ +
CH2—CH2—CO2Et CH3—CH—CO2Et
(I) (II)
.
4.2 An molecule R—R gives two R radicals and their greater randomness makes ∆S positive
and favourable for reaction. However, this term is much smaller compared to large
unfavourable positive ∆H, this favors the reverse reaction when R—R is more stable
than two radicals. Consequently ∆G is positive and the reverse reaction is favoured.
4.3 The rate determining step in each case is the formation of the new C—O bond, and in
the transition state this bond is partially formed. Thus the ∆H‡ terms are same in
magnitude in both cases. In the esterification case, the passage to the transition state
requires two molecules coming together to form one compound, thus ∆S‡ is large and
negative compared with the lactonization reaction. Therefore, ∆G‡ is smaller for
lactonization, consequently this process occurs faster.
–
d d
–
O O CH2—CH2 CH2—CH2
O O
CH3—C—OH CH3—C—OH C C
d+
CH3OH + CH2—OH OH CH2 O OH
Od
H
CH3 H
4.4 This is due to the involvement of adverse entropy effects, eclipsing and other strain
factors during the formation of larger rings.
4.5 (a) true; (b) true; (c) false; (d) true; (e) true.
CH2 CH3 CH3 CH3
+
+
H+ –H3O
4.6
+
H3C H 3C
H3C CH3 H 3C CH3 H
CH3 CH3
H 2O :
:
CHAPTER 5 O
CH3
C Cl
H
Aliphatic Nucleophilic
H H
Substitution and its Synthetic

Applications
5.1 INTRODUCTION
In the nucleophilic substitution reactions a group attached to a carbon is replaced by another
group which may involve several mechanisms. Bimolecular nucleophilic substitution SN2 along
with its unimolecular counterpart are the most important and involve reactions of alkyl halides,
– –
alcohols, and related compounds. Good nucleophiles ( OH, CH3O ) encourage SN2 reactions,
while poor nucleophiles (H2O, CH3OH) encourage SN1 reactions.
Competition between SN1 and SN2 Reactions

• SN2 reaction has high synthetic value since it leads to a single substitution
product. An SN1 reaction has a far less synthetic value since it leads to two
substitution products if the leaving group is bonded to a stereogenic carbon.
• An SN1 reaction is further complicated by carbocation rearrangements.
• An SN1 reaction pathway (the initial species formed is a carbocation) is favoured
when the carbocation is stabilized (tertiary or resonance stabilized carbocations),
and the solvent is polar (to stabilize the transition state).
• The SN2 pathway (a concerted pathway) is favoured when the electrophilic carbon
is not sterically hindered and the solvent is aprotic (to make the nucleophile
more reactive).
• The rate law for the reaction of a reactant e.g., an alkyl halide that can display
both SN2 and SN1 reactions simultaneously is the sum of the individual rate
laws.
Rate law (SN2 reaction) = k2 [alkyl halide] [nucleophile]
Rate law (SN1 reaction) = k1 [alkyl halide]
Contribution to the rate Contribution to the rate

via an SN2 reaction via an SN1 reaction
Rate = k2 [alkyl halide] [nucleophile] + k1 [alkyl halide]
176
Aliphatic Nucleophilic Substitution and its Synthetic Applications 177
Thus on increasing the concentration of the nucleophile increases the rate of an

SN2 reaction but the rate of an SN1 reaction is not effected.
• The outcome of an SN2 reaction on a chiral substrate is inversion of configuration
relative to the configuration of the reactant. The SN1 reaction on the other hand
gives one product of retained configuration while the other with inverted
configuration relative to the configuration of the reactant (Scheme 5.1).
CH3CH2 – CH2CH3
OH
C—Cl HO—C (Inversion of configuration)
H SN 2 H
H 3C CH3
(S)-2-chlorobutane (R)-2-butanol
Ph Ph Ph
: :
: :
: :
C—Cl : + H2O:
:
C—OH + HO—C (Racemization)

H SN 1 H H
H 3C H 3C CH3
(S)-1-chloro-1-phenylethane (S)-1-phenylethanol (R)-1-phenylethanol
50% 50%
SCHEME 5.1
Substitution reactions face a competition from elimination reactions, since all nucleophiles
are also bases. This is seen e.g., with a secondary alkyl halide with cyanide ion (Scheme 5.2).
H H N H
Br C Br H
C Substitution C Elimination
–
:CN –Br – –HCN
Cyanide H H
H –
ion :CN
SCHEME 5.2
The nucleophilic substitution at the saturated carbon is the alkylation of the nucleophile.
The nucleophile forms a bond to a saturated carbon atom from which a leaving group departs.
These substitutions provide very useful synthetic pathways and an example is the preparation
of methyl esters from carboxylic acids. Diazomethane in the presence of a proton source is
converted into a very reactive methylating agent. The high reactivity is due to the presence of
an excellent leaving group, gaseous nitrogen (Scheme 5.2a).
– +
O :CH2—N N:
C H – +
H 3C O + – CH3COO CH3—N N CH3COOCH3 + N N
N:
:
CH2 N
Acetic acid Diazomethane (SN2 reaction) Methyl acetate Nitrogen
SCHEME 5.2a
The balance between the nucleophilic and basic characters of a reagent is greatly
dependant on the size of the orbital containing the lone pair of electrons, and thus the
polarizability of these electrons. The reagents with highly polarizable centers of electron density
e.g., halide ions are better nucleophiles than bases as these prefer to attack carbon (substitution)
rather than the considerably smaller proton (elimination). Thus, I– is the most nucleophilic of
the halide ions and is the least basic, (and H—I is the strongest of the halogen acids). On the
other hand, the high concentration of electron density in N H 2− , OH − , C N–, and –C C—H
makes these reagents good bases and only moderately active nucleophiles.
It is important to select the reagents which will give substitution products in high yield
with less elimination, the nature of the nucleophile reflects on the desired outcome of the
substitution reaction. To convert an alkyl halide to an alcohol, the nucleophile must be OH– or
H2O. It is therefore, sometimes difficult to achieve only substitution, without a competing
elimination reaction. The following points may be noted:
• Alcohols can be synthesized from alkyl halides by the use of either water or hydroxide
ion as the nucleophile (Scheme 5.2b).
– –
H—O:
: :
: :
+ R—L R—OH + :L
SCHEME 5.2b
• Good yields are obtained from SN2 reactions of hydroxide ion with secondary alkyl
halides that are allylic, benzylic, or adjacent to a carbonyl group (Scheme 5.2c).
Cl NaOH OH
H 2O
SCHEME 5.2c
• Hydroxide ion is not normally employed as a nucleophile with unactivated secondary

halides and never with tertiary halides due to competing E2 elimination reactions.
For these reactants replacement of the halide with OH can be accomplished by using
water as a nucleophile and SN1 conditions (Scheme 5.2d).
H 2O :
:
+ R—L R—OH + H—L
CH3
H2O
CH3 CH3CH2—C—OH (65%)
CH3CH2—C—Br CH3
CH3
CH3
NaOH
2-Bromo-2-methylbutane
CH3CH2—C—OH + Elimination
H2O products
CH3
(1 %) (99 %)
SCHEME 5.2d
EXERCISE 5.1
Which of the following routes (Scheme 5.2e) is suitable for the synthesis of ethyl
isopropyl ether?
CH2CH3
Br O
H 3C
– (I) (II) –
CH3CH2O + CH3—CH—CH3 CH3CHCH3 CHO + CH3CH2—Br
H 3C
Ethoxide ion 2-bromopropane Ethyl isopropyl ether Isopropoxide ion Bromoethane
SCHEME 5.2e
ANSWER. The route (II) using the primary halide. In either route, the base
employed is an alkoxide which is a strong base. In route (I) therefore, using a
secondary alkyl halide would mean that the major reaction would be E2 elimination
rather than SN2 substitution.
The conversion of alcohols into alkyl halides is another important substitution reaction.
As seen in E2 eliminations, a hydroxy group is not displaced as its anion, it being of high
energy. Consequently alcohols are inert to nucleophiles, unless special conditions are employed.
Thus a hydroxyl group can be displaced from an alcohol, when it is protonated using a strong
acid and the process termed as electrophilic catalysis (Scheme 5.3).
+ –
: :
: :
: :
CH3(CH2)2CH2OH + H—Br : CH3(CH2)2CH2OH2 + :Br :

1-butanol
+ SN2
: Br : – + CH3(CH2)2CH2—OH2
: :
CH3(CH2)2CH2Br + H2O
1-bromobutane
95%
Substitution at primary carbon
+ +
: :
: :
(CH3)3COH + H—Br : (CH3)3C—OH2 (CH3)3C + H2O

2-methyl-2-propanol
(tert-butyl alcohol)
+ – SN 1
: :
(CH3)3C + : Br : (CH3)3CBr
(tert-butyl bromide)
85%
Substitution at tertiary carbon
SCHEME 5.3
Sulphonate esters, e.g., p-toluenesulphonate esters known as tosylates (represented as

–OTs in structures) are excellent leaving groups and react very much like alkyl halides in both
SN1 and SN2 reactions (Scheme 5.4). In fact p-toluenesulphonate ion is about 100 times better
than a chloride ion as a leaving group. Another related ester is methane sulphonate ester.
During tosylate formation from an alcohol, the C—O bond of the alcohol remains intact and
the alcohol, (as its tosylate ester) retains its stereochemical configuration. As expected during
the SN2 reaction on a tosylate the inversion of configuration is observed (Scheme 5.4).
The inversion of configuration was confirmed from the ester prepared from the parent
alcohol by reaction with acetyl chloride (this ester has the same relative configuration as the
alcohol or its tosylate ester) and comparing its [α] with that prepared by the acetolysis of the
O O
– –
R—O—S— —CH3 ROTs O—S— —CH3 OTs
O O
A sulphonate ester of alcohol A very good leaving group
(alkyl tosylate)
pyridine
ROH + TsCl ROTs
An alcohol Tosylchloride A tosylate ester
Cl—S— —CH3
H O
H O
CH3(CH2)5 CH3(CH2)5
p-toluenesulphonylchloride
: :
C—OH C—O—S— —CH3

pyridine
H 3C – H 3C
OAc O
An alcohol (2 octanol) (A tosylate ester)
(retention of configuration)
Pyridine Cl—C—CH3 Acetone SN2

O
H O O H
CH3(CH2)5 (CH2)5CH3
–
C—O—C—CH3 H3C—C—O—C + OTs
H 3C CH3
[a] = + 0.84 [a] = – 0.83
(Retention of configuration) (Inversion of configuration)
– –
H: R—L RH + :L (I)
(from LiAlH4) Hydrocarbon
SCHEME 5.4
tosylate (SN2 reaction). Conversion of an alcohol to its hydrocarbon via reduction of its tosylate
occurs via SN2 attack by a hydride ion, H– : on the tosylate (eq. I, Scheme 5.4).
Complexation with the oxygen of hydroxyl group by adding Lewis acid, ZnCl2 creates an
even better leaving group than that formed by protonotion of the oxygen. The complex either
reacts with the nucleophile by SN1 or SN2 mechanism (Scheme 5.5).
CH3 –ZnCl CH3 CH3CH2CH2

–
2 ZnCl2
:
H—C—O + H—C + C—O+
SN1
:
: :–
: :
CH3 H CH3 Cl H H
SN2 H
HCl + –
CH3CH2CH2CH2OH + ZnCl2 CH3CH2CH2CH2—O ZnCl2
H
1-butanol
–
: Cl : – + CH3CH2CH2CH2—O+ ZnCl2
: :
CH3CH2CH2CH2Cl
H
1-chlorobutane
SCHEME 5.5
Chloroalkanes can be made the same way as bromoalkanes (see Scheme 5.3) using
hydrochloric acid, but hydrochloric acid is not as reactive with alcohols as is hydrobromic acid.
Hydrogen chloride is a weaker acid than hydrogen bromide and formation of the protonated
alcohol (an oxonium ion) is less favourable with HCl as the reagent. Moreover, chloride is a
poorer nucleophile than bromide and thus the displacement step is also less favourable. A
Lewis acid e.g., zinc chloride is often added to bring about an enhancement of the reaction of
alcohols with HCl (Scheme 5.5).
SN1 reactions involve the formation of carbocations, therefore rearrangements are often
observed during these reactions. SN2 reactions being one step processes give no possibility of
rearrangement. Thus neopentyl bromide on boiling with ethanol (gives a rearrangement product
(Scheme 5.6).
CH3 CH3
+ –
: :
: :
CH3—C—CH2—Br : CH3—C—CH2 + : Br :
CH3 CH3
Neopentyl bromide Unstable primary
carbocation
CH3 H CH3 H CH3

+
–H
: :
CH3—C C—Br : CH3—C C—H CH3—C—CH2—CH3

+
CH3 H CH3 O—CH2CH3
CH3CH2OH
Ethanol Tertiary Rearranged product
carbocation
SCHEME 5.6
5.2 SYNCHRONOUS SUBSTITUTIONSN2 PROCESS

(A) MechanismSN2 Process
The mechanism of an SN2 reaction is a concerted one step process without an intermediate and
involves backside displacement of the leaving group by a nucleophile (see Scheme 5.4). The
configuration at the carbon atom undergoing substitution inverts (Walden inversion) since the
nucleophile approaches along a line diametrically opposite the bond to the leaving group. This
stereochemical outcome of the reaction points to a transition state (Scheme 5.7) in which the
carbon undergoing substitution involves a temporary rehybridization from sp3 to sp2 and finally
back to sp3, sp2-hybridized carbon has a p orbital perpendicular to the plane of the bonds which
partly overlaps with an orbital of the leaving group as well as with that of the incoming
nucleophile.
2
sp hybridized
with p orbital
3
sp hybridized ‡
R – R – R
– d d
–
Nu : C X Nu C X Nu C + :X
H H H
D D D
3
sp hybridized
(transition state)
S configuration R configuration
(Nu and X of same priority)
SCHEME 5.7
Thus the SN2 reaction transition state with a given reactant may be represented properly
(Scheme 5.7a).
–
–
d
– d
: :
: I: Br Br
:
H : I:
H H CH3 H CH3
SN 2 –
: :
I: OH
CH3 H
: I: SN2
:
–
d H 3C H CH3
CH3 d
– OH
(transition state)
(transition state)
SCHEME 5.7a
(B) Structure of the Substrate

The rate of direct displacement i.e., an SN2 reaction is highly sensitive to the steric bulk of the
substituents present on the carbon undergoing this reaction. As expected the degree of
coordination increases at the reacting carbon atom and from the steric point of view, the optimum
substrate would be CH3—X. Each replacement of hydrogen by a more bulky alkyl group should
decrease the rate of reaction. Consequently, the order of reactivity of alkyl groups is expected
to be methyl > primary > secondary > tertiary and this is observed. Table 5.1 gives the relative
rates of typical SN2 reactions. Methyl halides react most rapidly and tertiary halides react so
slowly as to be unreactive by the SN2 mechanism. It may be noted that in E2 reactions the
order of reactivities (see Scheme 12.11) is the opposite to this, therefore, the SN2/E2 ratio is
largest for a primary halide while it is least for a tertiary halide and this is seen during the
reactions of alkyl bromides with ethoxide ion in ethanol at 55°C (Table 5.1). Thus tertiary
halides do not give any significant yield in the SN2 reactions. One fails to prepare e.g., t-butyl
cyanide from t-butyl chloride and cyanide ion as the product is derived only from elimination,
(CH3)2C CH2.
Table 5.1: Relative rates of reactions

of alkyl halides in SN2 reactions CH3—CH2—Br CH3—CH2—OEt + CH2 CH2
Almost exclusive 10%
Relative
Substituent Compound
rate CH3
Methyl CH3—X 30 CH—Br (CH3)2CH—OEt + CH3—CH CH2
1° CH3—CH2—X 1 CH3 20% Predominant
2° (CH3)2CH—X 0.02
CH3
3° (CH3)3C—X 0
CH3—C—Br (CH3)2C CH2
(only product)
CH3
Neopentyl halides being primary halides are also unreactive in SN2 reactions. This
situation shows that steric hindrance effects operate even if the β-carbon is substituted by
alkyl groups. A general statement is therefore, that SN2 type displacements are retarded by
increased steric repulsions at the transition state. In substrates of the type R—CH2—X, where
X is a leaving group, showed that steric effects of R are the dominant factor in determining
rates (good yields of neopentyl iodide can be obtained via Grignard reagent, see Scheme 7.82).
The bulky substituents on or near the carbon atom undergoing SN2 reaction hinder the approach
of the nucleophile to a distance within bonding range. In an extreme case within the series i.e.,
in neopentyl system (compared to methyl), the approach of the nucleophile along the line of
the C—X bond is hindered by a methyl group, whatever geometry is attained by rotation about
the single bonds (Scheme 5.8).
Hindrance to the approaching

CH3
nucleophile CH3
H H
H C
– –
Nu: C—X Nu: C—X
CH3
H H
Backside attack, Methyl halides Neopentyl halides
relatively unhindered
Steric effects in acyclic systems in the SN2 reaction
SCHEME 5.8
The halocycloalkanes show considerable rate differences during SN2 reactions depending
on the size of the ring (for detailed discussion (see Table 1.1). Halocyclohexanes although
seemingly more capable of attaining sp2 hybridization at the reacting carbon are however,
slower in SN2 reaction (see Table 1.1). When a nucleophile approaches an equatorial halide, it
faces an inhibiting effect i.e., steric hindrance by the two axial hydrogens at C-3 and C-5 carbons
(Scheme 5.9). In a conformation where the leaving group is axial, then its exit itself faces steric
hindrance.
Steric Exit of iodide faces

hindrance steric hindrance
Incoming iodide (nucleophile) is –
– blocked somewhat by the axial Nu:
: I:
: :
: I:
:
H H carbon-hydrogen bonds H
H H
I:
: :
H
– Br
: I:
: :
A bridgehead halide
Slow SN2 displacement Slow SN2 displacement (SN2 reaction impossible)
SCHEME 5.9
A bridgehead halide is inert since the three bridges prevent the backside attack necessary
for SN2 reaction. Moreover, inversion of such a system is impossible.
Epoxides are most important three-membered heterocycles which undergo reactions
with nucleophiles such as hydroxide ion or alkoxides. The nucleophile attacks the less hindered
carbon as expected from an SN2 attack (1° > 2° > 3°) and the alkyl group is transferred with a
heteroatom in the β-position (Scheme 5.9a).
–
O O OH
SN 2 H+
CH3—C—CH2 CH3CHCH2OCH3 CH3—CH—CH2—OCH3
H –
OCH3
SCHEME 5.9a
The C—O bond of an epoxide is weaker than those of other ethers due to strained three
membered ring. Organolithium and organomagnesium compounds, therefore, act as
nucleophiles in SN2 reactions with epoxides and otherwise these reagents are normally poor
nucleophiles and being very strong bases promote elimination reactions (see Scheme 7.78).
(C) Nucleophiles and their Relative Nucleophilic StrengthNucleophilicityPolarizability of an Atom

The rate of an SN2 reaction is directly related to the effectiveness of the nucleophile in displacing
the leaving group. As a consequence, of a pair of nucleophiles containing the same reactive
atom e.g., methanol and methoxide ion, the species with a negative charge is the more powerful
nucleophile. Put in other words, of a base and its conjugate acid, the base is always more
–
nucleophilic. Therefore, OH is a stronger nucleophile than H2O, SH– a stronger nucleophile
than (CH3)2 SH and NH 2− is stronger nucleophile than NH3. This finding is reasonable as a
stronger bond between the nucleophilic atom and carbon would lead to a more stable transition
state and thus a reduced activation energy. Because the SN2 reaction is concerted the strength
of the partially formed new bond will be reflected in the energy of the transition state; the
more negative the attacking species, the faster will be the reaction.
There seems to be a good correlation between basicity and nucleophilicity. However, it
would be a mistake to explain that methoxide is a much better nucleophile since it is much
more basic. Basicity and nucleophilicity are two fundamentally different properties. Basicity
(a measure of a thermodynamic phenomenon) is defined by the equilibrium constant for

abstracting a proton (Scheme 5.10). On the other hand, nucleophilicity (a measure of a kinetic
phenomenon) is defined by the rate of attack on an electrophilic carbon.
Nucleophilicity
Basicity
Keq
– Kr –
– H—A B—H + A : – —C—X B—C— + X:
Base : Base:
SCHEME 5.10
The hydroxide ion (OH–) is a stronger base than a cyanide ion (CN–); at equilibrium it
has a greater affinity for a proton (the pKa of H2O is ~ 16, whereas the pKa of HCN is ~ 10).
However, cyanide ion is a stronger nucleophile, i.e., it reacts more rapidly with a carbon having
a leaving group than a hydroxide ion. In both cases (Scheme 5.10) however, a new bond is
formed. When the new bond is to a proton, the species has reacted as a base; in case the bond
is to a carbon it has reacted as a nucleophile. Moreover, since nucleophilicity is used to describe
trends in the kinetic aspects of reactions, the relative nucleophilicity of a given species may
differ from substrate to substrate.
A sterically bulky nucleophile is less reactive than a
smaller one. An SN2 reaction is not only sensitive to the CH3
bulky groups on the electrophile, but to the bulky groups – –
CH3CH2O CH3CO
on the nucleophile as well. This is due to nonbonded
repulsions which would develop in the transition state. Unhindered CH3
Thus although t-butoxide ion is a stronger base than ethoxide ion
Hindered
better nucleophile
ethoxide ion, but the bulky t-butoxide is a weaker tert-butoxide ion
nucleophile. Basicity is little effected by steric hindrance, stronger base
since the attack is on an unhindered proton. The strength
of a base depends only on how well the base shares its SCHEME 5.11
electrons with a proton (Scheme 5.11).
Nucleophilicity decreases on going from left to right in the periodic table. This follows
the increase in electronegativity from left to right. Thus high electronegativity is unfavourable,
due to tightly held electrons which are therefore, relatively less available for donation to the
substrate for SN2 process. Thus OH– is more nucleophilic than F–; NH3 is more nucleophilic
than H2O.
Nucleophilicity increases going down the periodic table i.e., Br– is more nucleophilic
than Cl– and SH– is more nucleophilic than OH–. For the halide ions the nucleophilic reactivities
follow the order:
I– > Br– > Cl– > F–
Thus I– is the best nucleophile while F– is poorest. This order is the reverse of the basicity
order of the halide ions:
F– > Cl– > Br– > I–
Thus one finds that the correlation between basicity and nucleophilicity does not hold
for the halides. Down a column in the periodic table the atoms become larger. Thus one has
more electrons at a greater distance from the nucleus. These electrons are rather loosely held
and the atom with this situation is more polarizable. The increase in polarizability leads to an
ease of the distortion of the electron cloud of the attacking atom of the nucleophile to allow far
more effective overlap in the transition state, with the back lobe of the slowly rehybridizing
sp3 hybrid used to maintain bonding to the leaving group. For these very reasons the basicity
of the larger elements is relatively poor than smaller elements as the overlap with the hydrogen
1 s orbital is poor. Thus, one can use successfully the extent of polarizability to explain as to
why I– is a better nucleophile than F– (Scheme 5.12). It is only with I– that the partial bond
formation begins at relatively large distances as the electron cloud of the nucleophile gets
‘‘pulled’’ to the carbon atom where the SN2 reaction occurs. Thus the activation energy of the
substitution is decreased. This however, is not the case with F– which has tightly bound electrons
More bonding
‡
H H –
d
C—X C X –
The larger I is more polarizable than a
– H H H fluoride ion. Thus, the relatively loosely
I H held electrons of the iodide ion can
(transition state) overlap even when farther away with
the orbital of carbon undergoing
Iittle bonding nucleophilic attack. The tightly bound
electrons of the fluoride ion cannot
‡
H start to overlap until the atoms are
H – closer together.
d
C—X C X
– H H H
F H
(transition state)
SCHEME 5.12
that cannot begin to form a C—F bond until the atoms are very close together. One may
appreciate that the degree of nucleophilicity increases on going down in the periodic table
even for uncharged nucleophiles i.e., H2 Se > H2S > H2O and PH3 > NH3. In these cases
particularly, the fact that the increasing polarizability improves nucleophilic power explains
the nucleophilicity trend. In these uncharged nucleophiles, the solvent effects must, however,
be less pronounced.
Synthesis of amines involves the reaction of nucleophiles like NH3 or an amine on alkyl
halides or sulphonate esters in an SN2 reaction (Scheme 5.12a). The product of the reaction
with ammonia or an amine is an amine salt. The free amine is isolated on treatment with a
base such as NaOH.
CH3 CH3
SN2 +
H3N : + CH2—Br : H3N—CH2 / Br–
: :
Ammonia Bromoethane Ethylammonium bromide

(an amine salt)
+ – – –
: :
CH3CH2NH3 Br + : OH
:
CH3CH2NH2 + H2O + Br
Ethylamine
SCHEME 5.12a
The order of reactivity of alkyl halides is typical for SN2 reactions: CH3X > 1° > 2°.
Tertiary alkyl halides react with ammonia or amines to give elimination products.
A disadvantage of this route to amines is that the product amine salt can exchange a
proton with the starting ammonia or amine (Scheme 5.12b). This leads to two or more nucleophiles
– –
CH3CH2NH3+ Br + NH3 CH3CH2NH2 + NH4+ Br
(also a nucleophile)
SCHEME 5.12b
competing in the reaction with the reactant. Recall that a primary amine is a stronger base
and a stronger nucleophile than is NH3. For these reasons e.g., methyl iodide and ethylamine
in basic solution lead to quaternary ammonium iodide as the final product (Scheme 5.12c).
K2CO3
+
:
CH3CH2NH2 + CH3—I CH3CH2NH2CH3 CH3CH2NHCH3
:
–
I
CH3—I
CH3
+ K2CO3
CH3—I +
:
CH3CH2NCH3 CH3CH2NCH3 CH3CH2NHCH3

– –
CH3 I CH3 CH3 I
SCHEME 5.12c
EXERCISE 5.2
How an alkyl halide reacts with the azide ion? How this method can be used to
synthesise primary amines?
ANSWER. Azide ion is a very good nucleophile which reacts with an alkyl halide
to give an alkyl azide. An alkyl azide is not however, nucleophilic and its catalytic
hydrogenation gives the primary amine in good yield (Scheme 5.12d).
+ – + – H2
CH3CH2CH2Br + Na :N N N: CH3CH2CH2N3 CH3CH2CH2 NH2+ N2
Pt
:
Sodium azide
SCHEME 5.12d
EXERCISE 5.3
Explain the Gabriel synthesis of a primary amine.
ANSWER. In phthalimide the electron pair on the nitrogen is neither basic nor
nucleophilic (due to resonance). Recall that the hydrogen on nitrogen is very acidic
and can be removed by a base to yield phthalimide anion which is a good
nucleophile. Reaction with an alkyl halide gives an N-alkylphthalimide which
does not alkylate further. Hydrolysis then produces the alkylamine (Scheme 5.12e).
–
OH
O – O O
OH
:– R—CH2—Br
:
:
N—H N: N—CH2R
O O O
Phthalimide
O H2O
–
O
+ H2N—CH2R
O–
Primary amine
O
SCHEME 5.12e
(D) Nucleophilicity and Solvent Effects

Nucleophilicity is impeded by solvation. A molecule of a solvent e.g., water or an alcohol (protic
solvent) can form hydrogen bonds to an anionic nucleophile (Scheme 5.13). Smaller anions
(concentrated charge) are more strongly solvated than larger ones. This phenomenon, therefore,
–
: :d
O CH3 d+ CH3
:
H H S
+ +
d d –
+ + d :O
d d
:
H H CH3 – CH3
+ d d
+
d :
–
–
: d d +
:S O: :O S:
–
:
O O: Na X
: –
: :
–
:X: CH3 d Anion is
H H CH3
+ – essentially
d O:
+
:
d d free
+ +
d d d
+
H H S
:
: O: –
CH3 CH3
d
Protic solvent e.g., H2O DMSO can solvate a cation better
solvates the anion than it can solvate an anion
DMSO is a polar aprotic solvent and dissolves many

organic compounds and salts. Nucleophiles are less solvated
and are more free to react.
SCHEME 5.13
creates a solvent induced barrier to attack at the substrate. For a solvated anion to act as a
nucleophile in an SN2 reaction energy is required to ‘‘strip off’’ some of the solvent molecules.
This energy is much larger in the case of a small strongly solvated ion e.g., F– as compared to
I–. Consequently an iodide ion is a better nucleophile than fluoride ion in protic solvent in an
SN2 reaction. Table 5.2 lists some common nucleophiles which are listed in decreasing order of
nucleophilicity in protic solvents e.g., water or alcohol. It is found that when benzyl tosylate
Table 5.2: Some common nucleophiles
Strong nucleophiles Weak nucleophiles

– –
SH F
–
I H2O
(CH3CH2)2NH CH3OH
–
:C N
(CH3CH2)3N
–
OH
–
CH3O
Moderate nucleophiles
– –
Br –, NH3 , Cl , OAc
is heated in methanol, then benzyl methyl ether is formed (Scheme 5.13a). On adding bromine
to the reaction, the reaction rate does not change but, now benzyl bromide is formed. It is an
SN1 reaction, therefore, the rate does not depend on nucleophile. Bromide ion is a better nucleophile
CH3OH
PhCH2—OCH3
PhCH2—OTs
–
Br
CH3OH
PhCH2—Br
SCHEME 5.13a
than methanol and in the presence of this ion the product is benzyl bromide and not benzyl
methyl ether.
Several aprotic solvents e.g., dimethylsulphoxide (DMSO) and dimethylformamide (DMF)
(Scheme 5.14) are used. An aprotic solvent is not a hydrogen bond donor since it does not have
a hydrogen attached to an oxygen or to a nitrogen. Thus they do not solvate anions to any
appreciable extent. Consequently with anionic nucleophiles, reaction rates are far greater in
the polar aprotic solvents. There is lack of
stabilization of these nucleophiles by hydrogen –
The d is on the surface
bonding, these are therefore, almost ‘‘naked’’ to be –
of the molecule
d
highly reactive as nucleophiles. Fluoride ion, O
therefore, is a better nucleophile in DMSO than in –
S+ Od
water during an SN2 reaction. H3C d CH3
A polar aprotic solvent dissolves ionic C
+
compounds and it solvates cations, the way similar + H d N—CH3
The d is not
to protic solvents by orienting the negative end of accessible CH3
its dipole around the cation (Scheme 5.14). It is Dimethylsulphoxide N, N-dimethylformamide
however, unable to solvate the anion by H-bonding. DMSO DMF
Moreover, methyl groups in the case of DMSO
SCHEME 5.14
shield the S which is the positive end of the dipole, this prevents the solvation of the anion, and
same is the case with DMF.
Consider the SN2 reaction on methyl iodide by a Br– and an uncharged nucleophile
Me3N (Scheme 5.15) in an alcohol. In the reaction of Br– the nucleophile is solvated by hydrogen
R H H
– + –
d d
–
d d
: Br :– H—O
: :
+ CH3I Br C I Me3N + CH3I Me3N C I
H H H H
Slower reaction in a polar protic solvent, Faster reaction in a polar protic solvent,
the nucleophile is solvated and not free. both +ve and –ve charges are stabilized.
SCHEME 5.15
bonding. Thus the rate of an SN2 reaction involving a negative nucleophile is slower in a more
polar solvent. The transition state, however, behaves as a much larger ion and is thus much
less stabilized by hydrogen bonding. In the case of neutral reactants a passage to the transition
state involves the generation of opposite charges. Consequently the transition state is stabilized
more than the reactants as the solvent is changed to more polar one. Thus the rate of an SN2
reaction involving a neutral nucleophile is faster in a more polar solvent.
EXERCISE 5.4
(a) Explain whether the reaction of 1-chloropropane with NH3 would be faster in
CH3OH/80% H2O or in CH 3OH 40%/60% H 2O. (b) Whether the reaction of
1 chloropropane with CN– will be faster in EtOH or DMSO.
ANSWER. (a) This is an SN2 reaction and the reactants are neutral, the transition
–
Cl d
state, CH3—CH2—CH2Cl + NH3 CH3CH2CH2 is polar. The reaction will be
NH3
+
d
faster in a more polar solvent. Since water is more polar than CH3OH, so the
reaction will be faster in 20% CH3OH/80% H2O.
(b) Reaction is faster in DMSO.
(E) Leaving Groups

A good leaving group is the one which becomes a stable ion after its departure. As most leaving
groups leave as a negative ion, the good leaving groups are those ions which stabilize this
negative charge most effectively. The weak bases do this best, thus the best leaving groups are
weak bases. In an SN2 reaction the leaving group begins to gain negative charge as the transition
state is reached. The more the negative charge is stabilized, the lower is the energy of the
transition state; this lowers the energy of activation and thereby increases the rate of reaction.
The weak bases are the best leaving groups since weak bases are stable bases, since
these can readily hold on to electrons which were earlier shared with a proton. Moreover, a
weak base is not bonded as strongly to the carbon as would be the case with a strong base and
consequently a weaker bond is more easily broken. When one considers SN2 reactions on the
similar reactants but with different leaving groups (Scheme 5.15a) one finds that I– is the best
leaving group while F– is the worst. This is in keeping with the above discussion. One may also
remember that larger atoms can better stabilize their negative charge.
Leaving Relative rates

Reactant
group of reaction
– –
HO + CH3CH2I CH3CH2OH + I 30,000
–
HO + CH3CH2Br CH3CH2OH + Br – 10,000
– –
HO + CH3CH2Cl CH3CH2OH + Cl 200
– –
HO + CH3CH2F CH3CH2OH + F 1
– – – –
I < Br < Cl < F
Weakest base, most stable Strongest base, least stable

base, best leaving group base, worst leaving group
Cl Br
(I) (II)
SCHEME 5.15a
An alkyl chloride or bromide reacts with NaI in acetone under SN2 mechanism due to
the presence of a strong nucleophile I– and an aprotic solvent acetone. NaCl/NaBr formed is
not soluble in acetone and therefore, the appearance of a precipitate in a test for alkyl chloride
or bromide. As expected the compound (II, Scheme 5.15a) gives a precipitate immediately
since bromide ion is a better leaving group than chloride ion.
Sulphonic acids, R SO2OH are similar to sulphuric acid in acidity and the sulphonate
ion RS O 3− is a very good leaving group. Alkyl benzenesulphonates, alkyl p-toluenesulphonates
are therefore, very good substrates in SN2 reactions (see Scheme 5.4).
The triflate ion (CF3SO3–) is one of the best leaving groups known, it is the anion of
CF3SO3H which is a strong acid much stronger than sulphuric acid.
Recall that an alcohol can be converted into an alkyl halide on treatment with a hydogen
halide (see Schemes 5.3 and 5.5). A hydrogen halide protonates the alcohol as well as provides
the nucleophile for the reaction. Other alternative could be the conversion of an alcohol into its
sulphonate ester followed by an SN2 substitution employing a halide nucleophile (Scheme 5.15b).
Ph Ph
OH (1) TsCl, pyridine Br
Ph (2) LiBr, acetone Ph
OTs Br
DMSO
+ NaBr + NaOTs
SCHEME 5.15b
The sulphonate ester method requires two steps for the conversion of an alcohol into an
alkyl chloride. A one step method employs the use of a reagent thionyl chloride (SOCl2) or a
phosphorus trihalide e.g., PBr3. These reagents convert the OH group of an alcohol into good
leaving groups chlorosulphite and bromophosphite groups respectively (Scheme 5.15c). These
reagents replace the H of the alcohol group which makes the oxygen a weaker base and a
better leaving group. Chloro-and bromoalkanes are generally used as reaction intermediates
and since alcohols are widely available, the role of SOCl2 and PBr3 for their one step conversion
into alkyl halides is synthetically very important. The mechanism may be SN1 or SN2 depending
O O O
+ –
Cl –
:
: :
: :
CH3—OH + Cl—S—Cl CH3—O—S—Cl CH3—O—S—Cl CH3Cl + SO2 + Cl

Thionyl H
chloride A chlorosulphite group
N
:
Br
+ –
Br
CH3CH2Br + –OPBr2
:
: :
: :
CH3CH2—OH + P—Br CH3CH2—OPBr2 CH3CH2—OPBr2
Br H
A bromophosphite group
Phosphorus
tribromide
N
:
SCHEME 5.15c
on the structure of the compound. Pyridine is often used as a solvent to avoid the build up of
HCl or HBr.
Role of triphenylphosphine and bromine in the conversion of alcohols into their bromides
is more selective and occurs under milder conditions (see Scheme 7.18).
EXERCISE 5.5
Explain the stereochemical outcome of the reactions of the same chiral alcohol in
reactions (I and II, Scheme 5.15d).
R R R R
1. TsCl/pyridine 1. PBr3/pyridine
R¢ OH – CH3O R¢ R¢ OH – R¢ OCH3
2. CH3O 2. CH3O
H H H H
(I) (II)
SCHEME 5.15d
ANSWER. In reaction (I) only one SN2 reaction is involved i.e., attack of CH3O–
on the alkyl tosylate formed in the first step, thus the ether has the opposite
configuration to that of alcohol. In (II) two SN2 reactions are involved first is the
attack of Br– on bromophosphite followed by attack of CH3O– on the resulting
alkyl halide, thus the parent configuration is retained.
EXERCISE 5.6
What synthetic strategy one can use to obtain a high yield of 2-butanol from
2-bromobutane?
–
ANSWER. One cannot use OH with a secondary reactant since it being a strong
base, more of elimination will occur. One therefore, must modify the reagent suitably
–
and replacing the H of OH by acetyl group (CH3CO) will decrease the basicity in
the acetate ion (resonance stabilization). One thus uses acetate anion in place of
–
OH ion as the nucleophile in the SN2 reaction using an aprotic solvent like DMSO.
The acetate ester is formed in an SN2 reaction in high yield which is then hydrolyzed
–
OH /H2O in a separate step (Scheme 5.15e).
Br OAc OH
–
DMSO OH/H2O
CH3—CH2—CH—CH3 CH3—CH2—CH—CH3 CH3—CH2—CH—CH3
Step 1 ester
SN 2 hydrolysis 2-butanol
–
OAc
SCHEME 5.15e
(F) Electrophilic and Nucleophilic Catalysis

SN2 reaction rates can be increased both by electrophilic and nucleophilic catalysis. A hydroxyl
group can come off from an alcohol easily by adding a strong acid in a process termed electrophilic
catalysis. In the case of alkyl halides, silver ion and mercury (II) ions are suitable, as these
form strong bonds with halide ions. In case, when the nucleophile is weak and the leaving
group is poor, reaction rates can be enhanced by the addition of iodide ion as a nucleophilic
catalyst. Thus the SN2 displacement (I, Scheme 5.16) is successfully catalysed since iodide ion
is both a stronger nucleophile compared with pyridine and a better leaving group than acetate
as shown (II, Scheme 5.16).
CH3
+ –
N: CH2—OAc N—CH2CH3 + AcO (I)
CH3 CH3
–
– –AcO + –
I CH2—OAc I—CH2 :N CH3CH2— N + I (II)
SCHEME 5.16
(G) The Role of Crown Ethers

Nucleophilic reactivity is increased in the presence of a suitable crown ether (see Scheme
1.20). The crown ether [18]-crown-6, e.g., coordinates very effectively with potassium ions.
Salts like KF, KCN and CH3 COOK which are otherwise insoluble in non-polar solvents like
benzene, in the presence of [18]-crown-6 dissolve in it. Thus, the situation in the organic phase
is the presence of relatively unsolvated anions to carry out nucleophilic substitution on an
organic substrate. For example, KF which is both insoluble in benzene and unreactive to organic
halides, brings about an efficient nucleophilic displacement on a halide in the presence of
[18]-crown-6 (Scheme 5.17). The role of a crown ether here is of a catalyst which brings the
anion into the organic phase, and the process is termed phase transfer catalysis.
O
O O
+ –
+ – [18]-crown-6 + – K F
C6H5CH2Cl + K F C6H5CH2F + K Cl
acetonitrile O O
(100%)
O
A crown ether complex of potassium
ion (soluble in organic solvents)
SCHEME 5.17
(H) SN2 Reactions with Allylic, Vinylic and Other Systems

The allylic systems are prone to react by SN1 mechanism since these form delocalized allylic
carbocations easily (see Schemes 2.11 and 2.18). However, the synthetic utility of these reactions
is limited due to the allylic shift of the double bond. It is possible to have suitable reaction
conditions under which allylic bromides react cleanly (without rearrangement) by way of the
SN2 mechanism. Thus allyl bromide undergoes bimolecular substitution about 40 times faster
than n-propyl bromide. In the case of allylic system, the transition state receives resonance
stabilization through conjugation with the p orbitals of the pi bond, (Scheme 5.18). The electronic
structure of this transition state resembles the structure of the allyl anion. The stabilization of
the transition state via the conjugation with the p orbital which is momentarily generated on
the reacting carbon atom lowers the activation energy of the system, increasing the reaction
rate.
Haloalkenes, in which the halogen is directly attached to the unsaturated carbon and
phenyl halides display exceptionally low reactivity either by SN1 or SN2 mechanism. Thus
while n-propyl chloride (CH3CH2CH2Cl) undergoes rapid substitution with potassium iodide
in acetone, 1-chloropropene (CH3CH CHCl) is inert. Simple alkenyl halides e.g., vinyl chloride
(CH2 CHCl) also do not form carbocations readily. This is due to the increased strength of the
vinyl halogen bond (see Scheme 2.15) in vinylic and phenyl halides. Moreover, the electrons of
the double bond of benzene ring repel the approach of the nucleophile from the backside to be
unreactive by SN2 mechanism.
–
–
Nu : Nu
H
:
H H Nu
H H
C C H
C C H C
H H C H C
C H C H
Br H H H
–
: Br :
: :
: Br :
: :
transition state
SN2 reaction on allyl bromide
–
– Nu
Nu :
:
H Nu
CH3CH2 H H
C CH3CH2 C C
H H
CH3CH2 H
Br
–
: Br :
: :
: :
: Br :
transition state
SN2 reaction on n-propyl bromide
SCHEME 5.18
Thus SN2 attack at sp2 carbon does not occur and as said the failure is for the reasons
that since the C—Br bond is in the plane of the ring the nucleophile shall have to be in the
benzene ring to invert the carbon atom in an impossible way (Scheme 5.18a).
SN1 type of solvolysis leading to vinylic cations can however, be carried out on suitable
substrates provided one has an efficient leaving group like triflate anion OTf – (CF3SO2O–,
which is a super leaving group) and the vinylic group contains electron releasing groups
(Scheme 5.18a).
Triflate (a ‘‘super’’
leaving group) Br
+
C C – C C – HO
–OTf OH
OTf
SN2 reactions do not take
A vinylic triflate A vinylic cation place at sp2 carbons
SCHEME 5.18a
Organocuparate Reagents and their Reactivity toward

Alkenyl and Aryl Bromides
Grignards reagents and organolithium compounds (see Chapter 7) are reactive
toward carbonyl compounds but do not react with organic halides to give new
carbon-carbon bonds. The Gilman reagents-dialkylcuparates provide a useful
alternative. These reagents react with alkyl (primary or secondary) bromides and
iodides by the displacement of the halide ion in a process known as coupling
reaction. Significantly Gilman reagents also react with alkenyl and aryl bromides
and iodides (Scheme 5.18b) to show that reactions are not SN2 reactions. It seems
that electron transfer process are involved.
Br CH3
(CH3)2CuLi (CH3)2CuLi
Br CH3
SCHEME 5.18b
5.3 SUBSTITUTION BY IONIZATION SN1 MECHANISM

(A) Mechanism SN1 Process
This reaction involves an ionization mechanism which proceeds by rate determining heterolytic
dissociation of the substrate to a tricoordinate carbocation (Scheme 5.18c) and a leaving group.
This dissociation is followed by a rapid combination of the highly electrophilic carbocation
with a Lewis acid present in the medium. A free energy diagram for the SN1 reaction of tert-
butyl chloride and water is shown (Scheme 4.18).
CH3 CH3 CH3 CH3
SN 1 +
H3CCCH2Cl H3CCCH2Cl H3CCCH2Cl H3CCCH2Cl
:
Cl H2O: + :O—H OH
1, 2-dichloro-2-methylpropane
:
H H 2O : Product
Reactant
SCHEME 5.18c
Out of two chlorine atoms in the reactant (Scheme 5.18c), only one is replaced by the
hydroxy group because it is an SN1 reaction and only the chlorine atom bonded to a tertiary
carbon is replaced. Water then acts as a nucleophile.
(B) The Effect of the Structure of the Substrate on SN1 Reactions

The major structural features necessary for a substrate to undergo SN1 substitution is the
presence of substituents which stabilize the carbocation derived from it. These are the
substituents which have +I and +M effects. Among alkyl halides, for all practical purposes
only tertiary halides react by SN1 mechanism. A tertiary carbocation being stabilized by three
electron releasing group (see Scheme 4.28). Allylic and benzylic halides can also react by an
SN1 mechanism since these substrates can form relatively stable carbocations (Scheme 5.18d).
+
CH2 CH2 CH2 CH2
+ +
CH2 CH—CH2 CH2—CH CH2 + +
Allyl carbocation
+
Benzyl carbocation
SCHEME 5.18d
Aliphatic Nucleophilic Substitution and Its Synthetic Applications 197
The benzyl cation is almost as stable as an allyl cation and in benzyl cation as well, the
positive charge is delocalized around the ring (Scheme 5.18d). Recall that an unsymmetrical
allylic cation is attacked by the nucleophile at both ends and the regioselectivity is determined
by steric hindrance (see Scheme 2.18). In the case of a benzyl cation the attack is almost
always in the side chain.
Another point of interest is that due to high instability of a phenyl cation, phenyl halides
show a retarded SN1 activity, but for when the leaving group is very good as nitrogen in a
diazonium salt (see Scheme 4.32a).
Methyl chloromethyl ether, with ether group of +M types is hydrolysed fast in water.
The intermediate formed after heterolytic dissociation being the delocalized carbocation
(oxonium ion, Scheme 5.19).
–
–Cl + + H2O
CH3O—CH2—Cl CH3O—CH2 CH3O CH2
+M type group
H
+
CH3O + CH3O + CH3O +
–H H –H
CH—H CH—H CH—H CH2 O + CH3OH
+
H 2O HO O
A hemiacetal
H
SCHEME 5.19
B strain and I strain effects are observed in many substrates and these effect the rate of
SN1 reactions. When e.g., in a tertiary alkyl halide (R3Cl), one or more R groups are highly
branched like e.g., t-butyl, the ionization is facilitated by relief of steric crowding in going from
the tetrahedral ground state to the transition state for ionization and finally to the carbocation.
This strain which may be present in a suitable substrate is called B strain3 (for details see
Scheme 1.36).
Similarly I strain effects SN1 solvolysis rates in some cyclic compounds (see Scheme 1.36).
Nucleophilic SN1 substitutions at bridgeheads is impossible or very slow, since a rigid
bridged system prevents rehybridization to a planar sp2 carbon. However, when such a structure
is flexible the SN1 reactions can take place, since now the bridgehead carbocation can be
generated (see Scheme 4.32).
(C) Nucleophilicity
The rates of SN1 reactions are independent of the nature or concentration of the nucleophile,
since it does not participate in the rate determining step.
(D) Solvent Effects on SN1 Reactions

The majority of the substrates in SN1 reactions are neutral. In these cases, the more polar the
solvent, the faster the reaction. There is a greater charge in the transition state than in the
starting substrate (see Scheme 4.18). A polar protic solvent e.g., will largely increase the rate
of ionization of an alkyl halide, since it can solvate cations and anions. The solvation stabilizes
the transition state (leading to the intermediate carbocation and halide ion) more than it does
the reactants, consequently the free energy of activation is lower.
(E) The Nature of the Leaving Group

In either SN1 or SN2 reaction, the leaving group begins to acquire a negative charge as the
transition state develops. Thus the effect of the leaving group is the same as studied earlier for
SN2 mechanisms.
(F) Stereochemical Outcome of SN1 Reactions

The reactions at a stereocenter of an optically active alkyl halide lead to recemization due to
the intermediate formation of a planar, achiral carbocation (see Scheme 4.22). However, the
enantiomers are not normally formed in equal quantities, the major enantiomer has the opposite
configuration to that of the substrate, i.e., inversion predominates over retention. The
carbocation R+ and the leaving group X– exist for a while as an ion pair R+ X–, consequently X–
part of the ion pair shields the side of the carbon atom to which it was attached. The incoming
group therefore has a more chance to attack the other side.
5.4 SN1 8-4575 SN2 REACTIONS

SN1 mechanism operates with those reactants which can form relatively stable carbocations.
The use of weak nucleophiles and highly ionizing solvents favour SN1 mechanisms. Thus, in
the case of solvolysis of tertiary halides in the presence of highly polar solvents, SN1 mechanisms
are significant. During solvolysis, the nucleophile is weak, it being a neutral molecule (the
solvent) rather than an anion.
SN2 mechanisms operate with relatively unhindered alkyl halides, (tertiary halides do
not react by SN2 mechanism) by using strong nucleophiles, a polar aprotic solvent and a high
concentration of the nucleophile.
Some Preparatively Useful SN2 and SN1 Reactions—Alkylations

• Hydride nucleophiles from LiAlH4 or NaBH4 convert primary and secondary
substrates into hydrocarbons via SN2 mechanism (see Scheme 5.4).
• Carboxylate ion is the nucleophile during methyl ester formation from carboxylic
acids from diazomethane (see Scheme 5.2a).
• O-Nucleophiles Na+ OR– bring about Williamson ether synthesis –SN2 reaction.
Since the base is strong, a secondary substrate may lead mostly to elimination.
Generally two routes may be available for the synthesis of the same product (see
Scheme 5.2e). SN1 conditions of solvolysis with substrates other than primary
give good yield of ethers (RL + HOR′ → ROR′).
• Carboxylate ion, a weak base gives good yield of esters when the substrate is
secondary under SN2 conditions (see Scheme 5.15e).
• Hal-nucleophiles convert alcohols in to alkyl halides ROH + HX → RX.
The reaction takes an SN1 path unless the substrate is primary. Reaction with
HCl requires ZnCl2 for primary and secondary alcohols (See Schemes 5.3 and
5.5). Conversion of the OH group of an alcohol into a good leaving group and
subsequent reaction with a halide ion X– gives an alkyl halide (SN2 conditions,
see Scheme 5.4)
• A one step procedure to convert an alcohol into an alkyl halide is reaction with
thionyl chloride, phosphorus tribromide and phosphorus triiodide (see
Scheme 5.15c).
• Amines can be prepared by using nucleophiles like NH3, an amine, an azide ion
or phthalimide anion (see Schemes 5.12a–5.12e).
• In subsequent chapters one will find the preparatively important SN2 reactions
e.g., ketones, esters and nitriles can be alkylated (alkylation at the α-carbon) to
form a new C—C bond (Scheme 5.19a).
–
: O:
:
O O O
LDA/THF RCH2—Br CH2R –

–
: + Br
SN 2
Enolate anion
SCHEME 5.19a
The first step is the removal of a proton from the α-carbon of a carbonyl compound
with a strong base LDA. Since the alkylation step is an SN2 reaction it works
best with primary alkyl halides.
Alkylation can also be carried out at the α-carbon via an enamine which is a
very good carbon nucleophile like an enolate. Here again the alkylation step is
an SN2 reaction which therefore, works very well with methyl halides or primary
alkyl halides (Scheme 5.19b).
O N: N+ O
catalytic CH3 CH3
+ CH3—Br
H HCl
+ +
H2O
N N
H +
An enamine H H
SCHEME 5.19b
The role of carbon nucleophiles CN– and RC C – is explained (see Schemes
3.11b and 5.2) and these provide useful methods to make C—C bonds.
Phosphorus nucleophiles e.g., triphenylphosphine react via an SN2 reaction with
an appropriate alkyl halide to yield a phosphonium ylide needed during Wittig
and related reactions. A proton on the carbon adjacent to the positively charged
phosphorus atom is sufficiently acidic (pKa = 35) for removal with a strong base
like butyl lithium (Scheme 5.19c).
– +
SN 2 + CH3CH2CH2CH2Li + –
:
(C6H5)3P : + CH3CH2—Br (C6H5)3P—CH2CH3 (C6H5)3P—CHCH3

Triphenylphosphine – A phosphonium ylide
Br
needed for Wittig
reaction
SCHEME 5.19c
Lastly mention may be made of sulphur nucleophiles HS– or RS– which are
weak bases, but good nucleophiles and give good yields with primary and
secondary substrates (Scheme 5.19 d)
(R—L + HS– R—S—H).
SCHEME 5.19d
5.5 OTHER ALIPHATIC SUBSTITUTION PATHWAYS

(A) The SN2′′ and SN1′′ Reactions
Allylic substrates undergo substitution with the migration of the double bond and is called
SN2′ reaction. (see Schemes 2.20 and 2.21). These reactions normally take place when the SN2
mechanism is sterically hindered. In the substrate (Scheme 5.20), the SN2 process is suppressed
by steric factors and SN1 process is suppressed by using a reagent of high nucleophilic activity
and a solvent of low ionizing power. The substrate, α, α-dimethylallyl chloride undergoes an
SN2′ process with sodium thiophenoxide in ethanol to give the rearranged product in high
yield. SN1′ reactions are discussed in Scheme 2.18.
Cl
– The SN2¢, i.e., a bimolecular nucleophilic
Me2C—CH CH2 SPh Me2C CHCH2SPh + NaCl substitution with allylic rearrangement.
Steric factors
SCHEME 5.20
(B) The SE2 Reaction

A carbon can undergo substitution electrophilic, bimolecular termed as SE2 reaction when it is
attached to strongly electropositive atoms i.e., metals. Thus the bromination of an organo-
mercurial occurs with retention of configuration at carbon (Scheme 5.21). This is in contrast to
the inversion of configuration which is typical of the SN2 reaction.
R Br—Br R
SE2
C—HgBr C—Br + HgBr2
R¢ R² R¢ R²
An organo-mercurial Retention of configuration at carbon
SCHEME 5.21
(C) The SN1 Process

An alcohol may be converted into an alkyl chloride from the reaction of the alcohol with thionyl
chloride either in ether solution or in the presence of pyridine. In the presence of ether, the
chlorosulphite first formed decomposes via an intimate ion pair (Scheme 5.22). The ion pair
collapses to give the alkyl chloride with the retention of configuration.
In the presence of pyridine, a chloride ion is liberated which then brings about an SN2
displacement on the chlorosulphite and now the configuration at the sterocenter gets inverted
(Scheme 5.23). In a solvent like diethyl ether most of HCl in lost as a gas and the chloride for
substitution comes from chlorosulphite. In the presence of pyridine, pyridinium hydrochloride
brings about an SN2 reaction. This reaction shows as to how reaction conditions can change the
stereochemical outcome of a reaction.
Cl
CH3CH2
CH3CH2 CH3CH2 S O Cl CH3CH2
SOCl2 ether +
C—OH C—O C S O C—Cl + SO2
H –HCl H H H
:O:
CH3 CH3 CH3 CH3
:
–
(S)-2-butanol The chlorosulphite ester A closely associated ion pair (S)-retention
of configuration
An SN1 reaction (substitution, nucleophilic, internal) with retention of configuration
SCHEME 5.22
Cl
+ CH3CH2 S O CH3CH2
N
:
– C—O: Cl—C + SO2

H Cl H
H
Pyridine HCl CH3 CH3
Inversion of configuration
A normal SN2 reaction
SCHEME 5.23
(D) Nucleophilic Substitution at a Bridgehead

When the leaving group e.g., at [2.2.1] bridgehead is such that it cannot function as a
nucleophile i.e., to come back once it has gone, then a nucleophilic substitution can occur.
Thus (I, Scheme 5.24) undergoes substitution with chlorobenzene as the nucleophile to
give (II).
PhCl
+ CO2 + BF3 + AgCl + HF
AgBF4
O
Cl
C O
Cl
(I) (II)
SCHEME 5.24
(E) The SET Mechanism

In some nucleophilic reactions where SN1 mechanism is highly probable, it has been proved by
esr determination of intermediate that free radicals are infact involved. In such a mechanism
a carbocation is a good electron acceptor and the nucleophile a good electron donor. The
mechanisms are named SET (single electron transfer) mechanisms, e.g., the reaction between
trimethyl cation and t-butoxide ion (Scheme 5.25).
+
Ph3C. + t-BuO .
–
Ph3C + t-BuO t-BuOCPh3
SCHEME 5.25
5.6 THE ROLE OF ION PAIRS

The SN1 mechanism involves the intermediate formation of a carbocation, it is planar and the
nucleophile, therefore, should attack from either side of the plane with equal facility to give
complete racemization. This result has been found in most first order substitutions (see
Scheme 4.22), in many others, one finds that there is inversion to the extent of 2–20%. Thus, in
some SN1 reactions some of the product does not come from the carbocation but rather from
ion pairs (Scheme 5.26).
– – –
RX R+ X R+ X R+ + X
An intimate, contact A solvent Dissociated ions
or tight ion pair separated each surrounded by
asymmetry ion pair molecules of solvent
maintained
–
X is called the counterion
SCHEME 5.26
The reaction products can be formed by attack by the nucleophile at any stage. In case
the products arise from tight ion pair one expects inversion of configuration. This is because in
the case of tight ion pair R+ is not completely free, there is still significant bonding between R+
and X– and asymmetry of the substrate is reasonably maintained to a considerable extent. As
a consequence in tight ion pair, X– solvates the cation on the side of its departure and therefore,
it can only get solvation from the solvent molecules from the opposite side. This process will
lead to inversion of configuration. In case the product arise from the solvent separated ion pair
extensive racemization will result since here the stereochemistry is not maintained as tightly
as in intimate ion pair. The product from the dissociated cation R + will give complete
racemization. Thus in summary the following points may be noted:
Consider the reaction of optically pure 1-phenylethyl chloride of (S) configuration with
water in aqueous acetone (Scheme 5.27) which as a whole shows first order kinetics (SN1
reaction). The 2% net inversion of configuration of the substrate is due to the involvement of
an ion pair mechanism (Scheme 5.28). In the initially formed intimate ion pair the carbocationic
part is solvated on the side opposite to the leaving group and the product from these species
will have inverted configuration. Thus many SN1 reactions involve the formation of ion pairs.
• An ion pair is a closely associated cation and an anion and behaves as a single unit.
• In a tight ion pair, the individual ions retain their stereochemical configuration.
• A solvent separated ion pair has its ions separated by solvent molecules and the ions
may and may not retain their stereochemical configuration.
H H H
C 6H 5 C—Cl + H2O C 6H 5 C—OH + HO—C C 6H 5
CH3 CH3 CH3

S-1-phenylethyl chloride (S) (R)
(optically pure) Retention Inversion
Rate = k[RX] 1-phenylethanol 98% Racemization

2% Net inversion
SCHEME 5.27
C 6H 5 H
H H
slow – fast –
:
C 6H 5 C 6H 5 C+ : Cl :
: : C+ (: OH2)n
: :
C—Cl : Cl :
:
:
H 2O : 98% (H2O:)n
CH3 CH3 CH3
Intimate ion pair Dissociated carbocation
(chiral) 2
(symmetrically solvated sp cation)
moderately
fast fast
– –
H + Cl H H + Cl
– + C6H5 C6H5 C 6H 5
Cl + H2O—C H2O—C + C—OH2
+ +
CH3 CH3 CH3
Inversion Racemization
(2%) (98%)
SCHEME 5.28
Other evidence also proves the formation of ion pairs. When 2-octyl brosylate (labelled
at the sulphone oxygen with 18O) was subject to solvolysis, the unreacted brosylate isolated
from various stages of solvolysis had the 18O considerably (but not completely) scrambled
(Scheme 5.29).
18 –
O O O O O
18 + – + +
R—O—S—Ar R— O—S—Ar R O—S—Ar R O S—Ar R O S—Ar
O O O –O O
2-octyl brosylate An intimate ion pair the three oxygens become equivalent
18
labelled at the sulphone oxygen with O
SCHEME 5.29
In this case the reaction involves the formation of an intimate ion pair, where the three
oxygen atoms become equivalent. It may be remembered that an ion pair can recombine to
afford the original substrate (an internal return, Scheme 5.29).
The addition of an inert salt like NaClO4 or LiBr at a very low concentration to the
solution of some substrate undergoing solvolysis leads to an initial large rate increase. This rate,
subsequently falls off to become a normal ionic strength effect and the effect is called special
salt effect. In the absence of the added salt, the solvolysis proceeds with intimate ion pair
formation with considerable return to the starting substrate. The ClO4– or Br– exchanges with
the leaving group to prevent this return. Consequently the amount of the solvent separated
ion pair that could have returned to the substrate is reduced. This leads to an overall increase
in the reaction rate.
5.7 NEIGHBOURING GROUP PARTICIPATION AND NONCLASSICAL

CARBOCATIONS
One has seen that nucleophilic substitution take place with racemization or with inversion of
configuration. However, in several cases such reactions occur with overall retention of
configuration. One factor which leads to retention of configuration during a nucleophilic
substitution is neighbouring group participation. The neighbouring group is an electron rich
substituent (Z:, Scheme 5.30) present in the proper position for backside attack i.e., anti attack
to the leaving group (X). The process infact is a two step process. In the first step (Scheme 5.30)
Neighbouring group
Z: R¢ Z
+
step 1 –
R—C C—R R—C C—R¢ + X The neighbouring group mechanism
two SN2 substitutions, each brings
R X R R about an inversion the configuration at
The leaving group a stereogenic carbon. Configuration is
retained and not inverted or racemized.
+
Z Z: R¢
step 2
R—C C—R¢ R—C C—R
R R External nucleophile R Y
Y:
SCHEME 5.30
the neighbouring group (acting as an internal nucleophile) attacks carbon at the reaction center
(SN2 attack) and the leaving group is lost to give a bridged intermediate. This is then attacked
in the second step by an external nucleophile (Y:, another SN2 attack) and the internal
nucleophile goes back to where it came from, the net result is two consecutive SN2 reactions
leading to retention of configuration at the reacting carbon.
A graphic example of neighbouring group participation is found in the conversion of
2-bromopropanoic acid into lactic acid (Scheme 5.31). In the presence of concentrated sodium
hydroxide, (S)-2-bromopropanoic acid (shown as its ion, Scheme 5.32) undergoes a bimolecular
displacement with inversion of configuration as expected from the normal SN2 reaction. The
same reaction when carried out in the presence of Ag2O and a low concentration of hydroxide
ion, however, occurs with retention of configuration (Scheme 5.32). The reaction now involves
two steps, in the first step the carboxylate group acts as a neighbouring group to displace
bromide ion via backside attack on the stereocenter. The silver ion here acts as an electrophilic
catalyst and aids the removal of bromine. In the second step, the α-lactone is attacked by a
water molecule. Both the steps involve an inversion of configuration on the attacked carbon.
Thus, the net result of two inversions in two steps is an overall retention of configuration.
–
–
CO2 CO–2 COO
– –
– d d
CH3CHCO2H CH3CHCO2H OH + C—Br OH C Br HO—C
H –Br – H
Br OH CH3 H CH3 CH3
2-bromopropanoic Lactic acid (S)-2-bromopropanoate (R)-lactate ion

acid ion inversion of
configuration
The normal stereochemical result for an SN2 reaction
SCHEME 5.31
–
:O
: :
O O O
–
C d C C
:O :O
:
:
C C d
– C + AgBr
H Br Br H
CH3 H CH3 CH3
Ag+ Ag+
An a-lactone
Step 1 Configuration of the stereocenter inverts
O O O
–
:O
: :
C d– C C
:O :O
:
: :
:OH2O
:
C C + C
d +
H OH2 H OH + H
CH3 H CH3 CH3
Step 2 Configuration of the stereocenter inverts again
SCHEME 5.32
When the neighbouring group participation operates during the rate determining step
of a reaction, the reaction rate is usually markedly increased. This effect is then termed
anchimeric assistance. Sulphur atoms act as powerful nucleophiles and the participation of
sulphur as a neighbouring group is common. On reaction with water both hexyl chloride
(I, Scheme 5.33) and 2-chloroethyl-ethylsulphide (II) give their corresponding alcohols.
Relative
rate H2O
: :
: :
Cl : OH
(I)
1
: :
: :
Cl : H2O OH
~700
: :
: :
S S
(II)
SCHEME 5.33
However, the rate of reaction of sulphur containing compound (II) is much greater than
that of the alkyl chloride. The reaction in the case of (I) is a simple SN2 displacement of chloride
with water, while in the case of sulphide, it is the sulphur atom, which displaces the leaving
group and acts as a neighbouring group. The intramolecular reaction (as expected) is much
faster than the intermolecular reaction. The initial product from (II) is an episulphonium ion
which is then opened by second SN2 displacement (now intermolecular) to give the product
(Scheme 5.34).
Thus a neighbouring group participation is the intramolecular involvement of one
functional group in the reaction at other functional group. Anchimeric assistance is the increase
in the reaction rate in the rate determining step of the reaction.
: :
H + H :Cl :
:
H2O :
:
:O :OH
SN2
: :
+ HCl :
: :
Cl :
(I)
Operation of a normal SN2 reaction
– +
: :
: :
S –Cl –H OH
:
: :
S
: :
Cl : S
+
:
(II) : OH2
Episulphonium ion
Operation of neighbouring group effect
SCHEME 5.34
In a 1, 2-disubstituted cyclohexane derivative, for the neighbouring group participation

to be operative the groups have to be anti to each other i.e., diaxial as in (I, Scheme 5.35).
A ring flip may be necessary to bring about such an arrangement of the groups. Consider the
acetolysis of cis and trans isomers of 2-acetoxycyclohexyl tosylate (Scheme 5.36) which give
the same product (I).
Z
H
H
H Z
X
X H
(I) (II)
SCHEME 5.35
The cis isomer reacts via a direct SN2 mechanism and the trans isomer reacts (about 700
times faster) via neighbouring group participation by involving an acetoxonium ion (A, Scheme
5.36). This acetoxonium ion (A, the resonance hybrid structure) from the trans isomer is,
symmetrical achiral (Scheme 5.37) and can be attacked by the acetate ion at either of the two
equivalent carbons shown by arrows. Thus, if one starts with an optically active trans isomer,
the net result is the formation of a racemic mixture of diacetates.
–
OAc
OTs OAc
OTs
OAc O O H
H
C +C CH3
O CH3 O OAc
(A)
Trans-2-acetoxycyclohexyl tosylate Acetoxonium ion
Neighbouring group participation
OTs H H
–
H OAc OAc OAc
OAc SN2 OAc OAc
H H H
Cis-isomer (I) (I)
Normal SN2 displacement
SCHEME 5.36
CH3
: :
: :
:
O+
ã
O O
C
C—CH3 C—CH3
:O:
ã
: :
: :
OTs O+ O
:
(A)
Symmetrical achiral
SCHEME 5.37
Among the norbornyl derivatives (on acetolysis) the anti tosylate (III, Scheme 5.38)
reacts 1011 times faster than (I) while (II) has 104 times reactivity compared to (I).
H OTs TsO H OTs

H
(I) (II) (III)

4 11
Rates = 1 10 10
SCHEME 5.38
The fastest rate of acetolysis of anti-tosylate (III) compared to (I, Scheme 5.38) proves
the removal of the tosyl group (the rate determining step) with strong anchimeric assistance
by the double bond. The resulting non-classical carbocation i.e., bridged ion can only react with
acetate ion from the side opposite to the neighbouring group, with retention of configuration
(Scheme 5.39). In the syn-isomer (II, Scheme 5.38) the rate is slower because the double bond
is not properly situated for participation. Thus this isomer dissociates without anchimeric
assistance to give a homoallylic carbocation which rearranges to allylic carbocation
(V, Scheme 5.40) and this reacts to give an acetate. The high reactivity (104 times) of (II) than
(I) may be because of participation of σ electrons of two allylic 1, 6 and 4, 5 bonds.
Thus the bridged cation (Scheme 5.39) is an unusual situation which involves three-center
two-electron bonding such species are called non-classical carbocations.
OTs OAc
7 –
AcO
1
6 – +
– OTs
2
4
5
3
Anti-7-norbornenyl Bridged cation Anti-acetate

tosylate (Non-classical carbocation)
(III)
Involves three-centre two-electron bonding
SCHEME 5.39
–
TsO +
1
+
6 +
4
5
CH3CO
–
AcO O
(IV) (V)
SCHEME 5.40
EXERCISE 5.7
A 2-thiosubstituted chlorocyclohexane reacts with aqueous solution of ethanol to
give an alcohol and an ether due to presence of two nucleophiles water and alcohol.
Explain why this rate of reaction is 70,000 times faster when the thio substituent
is trans placed to the chloro substitutent?
ANSWER. The thio substituent acts as an intramolecular nucleophilic catalyst
and provides anchimeric assistance. It displaces the chloro substituent by the back
side attack on the carbon with chloro substituent. Back-side attack requires both
substituents to be diaxial. Subsequent attack by water or ethanol on the sulphonium
ion is fast as the positively charged sulphur is a very good leaving group and
cleavage of the three-membered ring releases strain (Scheme 5.41).
Cl OH OC2H5
SC6H5 SC6H5 SC6H5
C2H5OH
+ + HCl
H2O
C6H5 C 6H 5
C 6H 5
:S: :S:
+ S:
– +
–Cl –H +
+ H
H 2O :
:
Cl OH
SCHEME 5.41
Evidence has been presented that C C acts as a neighbouring group and that a non
classical carbocation (a bridged cation) may be formed. Evidence is also available to show that
a suitably located C—C in a substrate can also participate in the departure of the leaving
group and non-classical carbocations may be involved.
During the acetolysis of exo- and endo- norbornyl tosylates (Scheme 5.42) it is found
that (a), the solvolysis of exo isomer is 350 times faster than the endo isomer; (b), both the
isomers give only the exo acetate; (c), and optically pure exo-tosylate gives 100% racemic product
while an optically pure endo tosylate gives 93% racemic exo-acetate. These observations are
explained:
OTs
H
exo
HOAc
+ AcO
OAc
H H
H Enantiomers
exo-2-norbornyl acetate
endo OTs
SCHEME 5.42
• In the exo isomer the 1, 6 σ bond is suitably located to act as a neighbouring group to
lend anchimeric assistance via backside attack to give directly a non-classical
carbocation (I, Scheme 5.43) which is more stable than the carbocation (II, Scheme 5.44)
formed initially in the case of endo-isomer. The endo-isomer on the other hand first
gives a carbocation (II, Scheme, 5.44) which subsequently forms the same non-classical
carbocation.
Rotate
7
ã
5
4 4
ã
5 3 3 6 7
1 2 OTs = +
6 +
2 1
H (I)
Achiral
Exo-tosylate
(optically active)
add add
deprotonate + deprotonate
H H
or
OAc OAc
HOAc
OAc + AcO
H H
A pair of enantiomers (a racemic mixture)
SCHEME 5.43
• The attack occurs from the exo-side due to the cage structure of the non-classical
carbocation intermediate (I, Scheme 5.43). Moreover, the attack must occur from the
direction opposite that of bridging interaction and this is exo-direction.
• Recall that a non-classical carbocation involves a three-center two-electron bonding.
In a common case three carbon atoms are involved, two of which are bonded by a
σ bond while the third is bonded to the other two by a two-electron three-center bond.
• The non-classical carbocation intermediate (I, Scheme 5.43) is achiral having a plane
of symmetry passing through C-4, C-5, C-6 and midpoint of the C-1 and C-2 bond.
The C-6 has two hydrogens and is pentacoordinate and is the bridging atom in the
cation. Thus the attack at both C-1 and C-2 is equally likely which gives equal amounts
of enantiomeric acetates—a racemic mixture.
In the case of endo-tosylate, till (II, Scheme 5.44) collapses to (I), it will give one
enantiomer in excess to explain 93% formation of racemic acetate.
Bridging provides only stabilization. If other forms of stabilization are available, ions
will then be open classical species. 13C NMR spectroscopy is used to distinguish between
equilibrating structures and bridged species. Thus 2-phenylnorbornyl cation (III, Scheme 5.44)
has the classical structure. This benzylic cation is stabilized by π-electrons of the benzene ring
and thus bridging is not involved. Firstly consider the resonance-stabilized carbocation
(Scheme 5.45), the two carbons (shown by dots) which share the positive charge as expected
are almost equivalent. In equilibrating ionic structures (two independent ions) such carbons
differ by about 100 ppm.
H +
+ +
OTs
(II) (I) (III)
Endo tosylate Classical (the bridged ion)
(optically active) carbocation Open unbridged
carbocation
(classical carbocation)
SCHEME 5.44
D X D + H D + H D H
+
superacid
Practically no difference for the

two carbons that share the
13
positive charge C NMR
SCHEME 5.45
That 2-norbornyl cation is a bridged species has been shown by detecting it in a highly
polar but non-nucleophilic solvent (super acid media, SbF5-SO2). The 13C NMR showed very
similar signals for both the deuterated as well as undeuterated positively charged carbons
(Scheme 5.46). This evidence excludes the formation of an equilibrating pair of cations where
the two boldly shown carbons should have displayed widely separated signals in 13C NMR.
Very similar signals are

13
H displayed in the C NMR
+
D
Bridged structure
OTs
H
D
H
+
+
H
D Equilibrating pair D
of cations
SCHEME 5.46
Certain properties of a cyclopropane ring are similar to that of an olefin. Cyclopropane

rings in particular and cyclobutane ring generally display rate enhancements when these are
suitably placed in a substrate. Thus cyclopropyl-methyl and cyclobutyl substrates undergo
hydrolysis abnormally rapidly to yield the same products which include cyclopropyl methyl,
cyclobutyl and homoallylic compounds (Scheme 5.47). Their formation is due to the intermediate
formation of a non-classical cation (Scheme 5.47). In cyclic systems related to norbornyl system
CH2Cl
OH
CH2OH + + CH2 CHCH2CH2OH
48% 47% 5%
H
Cl
+ + + +
CH2
The formation of a common non-classical intermediate

SCHEME 5.47
the presence of a suitably placed cyclopropyl group acts as a neighbouring group. Thus (II,
Scheme 5.48) reacts 1014 times faster than I. It has been suggested that in (II, Scheme 5.48)
and other cyclopropyl derivatives which display rate enhancement, the developing p orbital of
the carbocation is orthogonal to the participating bond of the cyclopropane ring.
ArCOO H OCOAr
H
(I) (II)
Ar = p-NO2C6H4
SCHEME 5.48
5.8 NUCLEOPHILIC SUBSTITUTION AT SILICON

(For details see Scheme 7.36).
PROBLEMS
5.1. A factor which stabilizes an anion would be generally expected to reduce or enhance the
rate of an nucleophilic substitution?
5.2. The free energies of activation for reaction of nucleophiles with CH3I at 25°C in methanol
and in DMF are given. How do you explain the relative nucleophilicities of the halide
ions and thiocyanate ion?
Nu:– DMF CH3OH
Cl– 16.9 25.0
Br– 17.3 23.0
SCN– 19.0 22.0
I– 20.9 18.0
5.3. Why displacement of cyanide is never observed? Why azide and acetate ions are poor
leaving groups?
5.4. Why an alcohol reacts with a halide ion only in the presence of a strong acid?
5.5. Why α-carbonyl substituted substrates like Br CH2COCH3 and BrCH2COO Et react
more readily than the corresponding alkyl halides?
5.6. Why CH3OCH2Cl reacts with iodide ion in acetone several thousand times faster than
CH3Cl?
5.7. Why the inversion of configuration is much more during the solvolysis of C6H13CH(CH3)Cl
than C6H5CH (CH3)Cl?
5.8. Why the following allylic and benzylic halides react only by SN1 process and not by SN2
mechanism? Why both SN1 and SN2 mechanisms operate when R′ H or R R′ H?
R R
—C C—CX ArCX
R¢ R¢
Allylic Benzylic
5.9. Trans-2-chlorocyclohexanol gives epoxycyclohexane in high yield on reaction with base

however, the cis-isomer does not react this way. Explain.
OH OH
Cl
Cl
trans cis
5.10. Why the epoxide (I) reacts with acidic methanol to give a optically pure
Me
mixture of II and III (see under answer 5.10) and no racemization is
observed? Et—C
O
H 2C
(I), (R)
5.11. Explain the outcome of the following reaction.
– 14 14 14
MeO + H2 C—CHCH2Cl MeO CH2CH—CH2 + H2 C—CHCH2OMe
O O O
Not formed
5.12. Compound I reacts as shown. Explain.
1. TsCl in Py HBr
2. LiBr in acetone ZnBr2
CH2Br CH2OH Br
(II) (I) (III)
5.13. The following nucleophilic substitution reaction proceeds with a rearrangement. When
the reactant is optically active the product is also optically active. Explain.
Cl CH2OH
CH3CH2 CH3CH2
NaOH
NCH2CHCH2CH3 NCHCH2CH3
H 2O
CH3CH2 CH3CH2
5.14. 2-Methyl but-3-en-2-ol reacts easily to yield almost exclusively one product through the
unsymmetrical allylic carbocation intermediate. Explain.
+ –
HO HBr H2O + Br
Br
2-methylbut-3-en-2-ol (I)
[Hint: Though the allylic carbocation (I) is unsymmetrical and resonance stabilized it is
attacked by the nucleophile almost exclusively at the less substituted end predominantly.
Compare with the explanation in Scheme 2.18.]

5.1. Reduce the rate.
5.2. Considering the halide ions, the smaller chloride is more hydrogen bonded in methanol
compared to the larger halide ions. Generally nucleophiles (e.g., SCN–) with second row
and larger atoms are less hydrogen bonded in hydroxylic solvents.
5.3. HCN is a weak acid (pKa = 10). Similarly hydrazoic acid (HN3) and acetic acid (CH3COOH)
are also weak acids (pKa’s of 5.8 and 4.8 respectively).
5.4. The hydroxide ion is a strong base and thus cannot be a leaving group. The acid protonates
the hydroxyl group, and then the leaving group is water a much weaker base than a
hydroxide ion.
5.5. In the case of carbonyl derivatives the transition states are stabilized by interaction of
the p orbital on the carbon undergoing displacement with the adjacent pi system.
5.6. In case of the α-alkoxy compound the transition state (SN2) is stabilized via the interaction
of the p orbital on the carbon undergoing substitution with the (filled) oxygen 2p orbital.
5.7. It depends on the relative stability of the carbocation and subsequent ion-pair formation.
In the case of phenyl containing substrate, the positive charge on the carbocation is
delocalized on to the aromatic ring.
5.8. As with tertiary halides, the steric hindrance associated with the presence of three alkyl
groups on the carbon having the halogen prevents these tert allylic and benzylic halides
from undergoing SN2 displacements. These, however, can react only by SN1 process.
However, with primary and secondary allylic and benzylic halides SN2 displacements
are possible. The primary and secondary allylic and benzylic halides react by SN1
mechanism due to stability associated with the allylic carbocation.
5.9. In the conformation of a 1, 2-trans cyclohexane either the groups can be diaxial or
diequatorial. In the diaxial conformation (anti-coplanar conformation) nucleophilic O–
displaces Cl via a backside attack (neighbouring group participation).
–
O
—Cl
– O
Cl Cyclohexene oxide
In a 1, 2-cis-cyclohexane one group must be axial and the other equatorial. In one
conformation Cl and H are diaxial and this situation can lead to elimination i.e.,
dehydrochlorination to give a vinyl alcohol which finally gives a ketone (compare this
situation with that in Scheme 12.15).
H OH O
OH
H H
Cl Cyclohexanone
5.10. The compound I arises from the SN2 attack on the less substituted carbon of the
protonated epoxide without disturbing the stereocenter.
Me Me Me
Et Me
MeOH
Et—C—OH SN 2 Et—C + MeOH C+ —H
+ MeO—C—Et
+ OH OH
–H SN1
MeO—CH2 H 2C H 2C CH2OH
(R) (S)
(II) (III)
The compound (III) is obtained via SN1 attack on the intimate ion pair which occurs
with inversion of configuration (compare with Scheme 5.28).
5.11. The reaction is initiated by an SN2 displacement on less substituted carbon of the epoxide.
The alkoxide ion then acts as a neighbouring group to displace Cl– by another SN2 reaction.
14
CH3O CH2CHCH2—Cl
–
O
5.12. Neopentyl system is present in I, II is formed (SN2) since (Br–) does not face steric
hindrance (ring residues on bridgehead carbon are tied back). The loss of OH– as H2O
gives a 1° carbocation, the bridge methylene then migrates to give a 3° bridgehead
carbocation (a flexible system) which picks up Br– to give III.
5.13. An internal SN2 reaction gives a three membered ring intermediate. This is then attacked
by hydroxide at the less hindered site.
–
OH Less hindered site
CH3CH2 Cl CH3CH2 CH3CH2 CH2OH

CH2
SN2; internal
:
NCH2CHCH2CH3 N NCHCH2CH3
nucleophile +
:
CH3CH2 CH3CH2 CH CH3CH2
CH2CH3
CHAPTER 6 O
—H
Li
N O
Li
Common Organic
Reactions and their Mechanisms
6.1 BASE CATALYSED REACTIONS (FORMATION OF CARBON-CARBON BONDS)

(A) Enolates are Important Nucleophiles
In base catalysed reactions negatively polarized carbon reacts with the electrophilic carbon of
carbonyl groups, alkyl halides and related compounds. The role of the base is to abstract a
proton from a C—H bond which is adjacent to one or more groups of –M type to afford a
carbanion. The group of –M type stabilizes the anion (see Schemes 3.25 and 3.26). Because of
its relation to enol, the resonance stabilized anion is called an enolate ion which has two
chemically different sites with a partial negative charge (an ambident nucleophile).
–
O O O d– O
– d–
CH3—C—CH2 CH3—C—CH2 CH3—C CH2 CH3—C CH2
:
–
H :B
Carbonyl compound Base Enolate anion resonance contributors Resonance hybrid
This site reacts as

an alkoxide ion
This site reacts as a carbanion

d– O
d–
CH3—C CH2
SCHEME 6.1
The enolate ions are capable of reacting at two sites (Scheme 6.1); as alkoxide ions and
as carbanions. Thus when an enolate is treated with chlorotrimethylsilane, silylation occurs
exclusively at the oxygen atom (Scheme 6.2). The silylation is a nucleophilic substitution at
the silicon atom by the oxygen atom of the enolate. The formation of enol trimethylsilyl ether
is a highly exothermic process. The oxygen-silicon bond thus formed is much stronger than a
carbon-silicon bond. Consequently, the free energy of activation for reaction at the oxygen
atom is lower than that for the reaction at the α-carbon. Silylation has its importance in several
organic reactions. Thus electrophiles particulary silicon halides react at the oxygen atom to
give silyl enol ethers (in a process called silylation).
216
Common Organic Reactions and their Mechanisms 217
CH3
CH3 O
Cl—Si reaction
CH3 H+ CH3—C—CH3
at C
Carbonyl
+ –
Li O O compound
–
:
CH3—C CH2 CH3—C—CH2
Enolate anion resonance contributors
reaction at O
OSi(CH3)3
CH3—C CH2
Silylenol ether
SCHEME 6.2
An enolate reacts as a carbanion with alkyl halides (Scheme 6.3) to give C-alkylation.
One may appreciate that such SN2 reactions are successful only with primary alkyl, primary
d – O Li + O CH2R²
d– SN 2
R—C CHR¢ + R²CH2—X R—C—CHR¢
C-alkylated
C—C bond formation via the product
reaction of a lithium enolate
with alkyl halides
SCHEME 6.3
benzylic and primary allylic halides. As enolates are strong bases, with secondary and tertiary
halides the major course taken by the reaction is elimination (Scheme 6.3a). Thus enolate ions
are useful nucleophiles which are readily alkylated by primary alkyl halides (Scheme 6.3).
The enolate ion being a relatively stronger base can involve itself into
O O– Li + O
Br
LDA + –
+ + Li Br
THF
SCHEME 6.3a
E2 eliminations with secondary and tertiary alkyl halides (Scheme 6.3a). Another significant
limitation is with aldehydes which cannot be alkylated as ketones (see Scheme 6.3). This aspect
is discussed in detail in Schemes (6.46a and 6.46b).
The extent of enolate formation depends on the strength of the base used. When the
base is weaker than the enolate itself, then the equilibrium lies to the left (eq. I, Scheme 6.4).
– +
O O d Na
+ – d–
CH3—C—CH3 + Na OH CH3—C CH2 + H2O (I)
Weaker acid Weaker base Stronger Stronger acid

pKa = 20 base pKa = 16
O d– O Li +
– + d–
CH3—C—CH3 + (i-C3H7)2N Li CH3—C CH2 + (i-C3H7)2NH
Stronger acid Weaker base Weaker acid (II)
pKa = 20 Stronger base pKa = 38
LDA
SCHEME 6.4
However, when a very strong base (LDA) is employed, the equilibrium lies far to the right
(eq. II, Scheme 6.4, for this reasoning (see Scheme 3.42).
In an unsymmetrical ketone like 2-methylcyclohexanone there are two active sites and
one can expect the formation of two possible enolates (I and II, Scheme 6.5). Of these,
(I, thermodynamic enolate) with more substituted double bond is the thermodynamically more
–
HO
O O–
H
Me Me
weak base More highly substituted
protic solvent double bond
2-methylcyclohexanone Thermodynamic enolate

(more stable)
(I)
– +
(i-C3H7)2N Li
Less substituted
O Less hindered O– Li + double bond OSi(CH3)3
H
Me Me Me
DME (CH3)3Si—Cl
H
Kinetic enolate
formed faster
(II)
Kinetic versus thermodynamic deprotonation of unsymmetrical ketones
SCHEME 6.5
stable enolate. This enolate will be formed predominantly under conditions which allow the
establishment of an equilibrium (use of a weak base in a protic solvent). The enolate (II, kinetic
enolate, with less substituted double bond) is usually formed faster since the CH2 group is
sterically more accessible than the methyl substituted CH. Thus the kinetic enolate is formed
predominantly when the reaction is kinetically controlled. This can be achieved by employing
a sterically hindered base (LDA) which rapidly removes the proton from the less substituted
α-carbon of the ketone. One can capture this enolate ion by reaction with chlorotrimethylsilane
as the enol trimethylsilyl ether. This ether can be purified and converted back to the enolate
(Scheme 6.6) by either reacting it with fluoride ions, making use of the very strong Si—F bond
Si—F bonds are very strong

O—Si(CH3)3 O–
Me – Me
F
+ (CH3)3SiF
Kinetic enolate
– +
O—Si(CH3)3 O Li
Me – + Me
CH3 Li
+ (CH3)3Si—CH3
SCHEME 6.6
(594 kJ mol–1), or by treatment with methyl lithium. Using this information one can, therefore,
alkylate a ketone in a regioselective way (Scheme 6.7). The lithium enolate formed from
2-methylcyclohexanone e.g., can be methylated with methyl iodide. Lithium enolates have
their utility in directed aldol reactions (see Scheme 6.12).
O Li + O– O
Me Me Me CH3
LDA CH3—I
+ LiI
DME
SCHEME 6.7
EXERCISE 6.1
How a β-dicarbonyl compound with pKa ~ 10–14 or a nitro compound pKa ~ 9–12
can be converted into its conjugate base ?
ANSWER. With these substrates weaker bases e.g., alkoxides (pKa ~ 17) can be
employed to convert the material completely to its conjugate base. Aprotic conditions
are thus no longer needed. However, a common practice to convert dicarbonyl
compounds to their enolates in a clean, controllable manner is to use sodium hydride
in dry THF (Scheme 6.7a).
+
Na
O O O O
–
NaH
R R R R
THF
H H H
SCHEME 6.7a
(B) Regiospecific Generation of Enolates

Recall that one can either make a kinetic enolate or a thermodynamic enolate by choosing
proper conditions. Advantage is taken of the fact that LDA removes preferentially a proton
from the less substituted α-position to give a kinetic enolate. The most stable enolate is however,
the thermodynamic enolate. The enolate formation may become reversible and the product
formed then will be the one derived from thermodynamic enolate. Enolate formation may
become reversible e.g., by the use of a less hindered base like KH. The equilibrium between
the enolates can also be established on using excess of ketone and if traces of protic inpurities
are present. Thus carefully controlled conditions are required to prevent a possible equilibration
(Scheme 6.7b).
LDA excess ketone

or
protic impurities
O O– O–
(Kinetic enolate) (Thermodynamic enolate)
SCHEME 6.7b
Several alternatives are employed for the synthesis of compounds involving enolates
which could avoid the reaction becoming reversible and one such alternative employs acetoacetic
ester (see Scheme 6.18a). As a second approach, the unsymmetrical ketone is converted into
its N, N-dimethylhydrazone and it is the geometry of this hydrazone which plays an important
role in directing the base to least hindered α-position. The dimethylamino group points away
from the more substituted carbon and coordinates with the lithium ion of butyl lithium (Bu– Li+)
the base normally employed in this reaction. The hydrolysis of the hydrazone after the reaction
regenerates the carbonyl product and thus the result is the same as working with the kinetic
enolate (Scheme 6.7c).
CH3
H3C N
:
O + N N—N(CH3)2 O
Li Bu –
H CH3 CH3 CH3 CH3
(1) NH2 N(CH3)2 –: 1. CH3I
H 3C
– +
(2) Bu Li 2. HCl/H2O
SCHEME 6.7c
(C) Aldol Condensation

When a dilute base is used, a condensation reaction involving two molecules of carbonyl
compound occurs (Scheme 6.8). The process is the addition of the nucleophilic carbanion enolate
(usually of an aldehyde) to the C O of its parent compound and is termed an aldol condensation
(Scheme 6.9). In a mixed aldol addition, the carbanion enolate adds to the C O of the molecule
O OH O O OH O
aldol aldol
—C—C—H —C—C—C—C—H —C—C—R —C—C—C—C—R
condensation g b a condensation
H H H H H R
Aldehyde b-hydroxyaldehyde Ketone b-hydroxyketone
2 moles 2 moles
SCHEME 6.8
–
O:
:
:O:
:
O
– –
:
CH3CH + OH CH2CH CH2 CH + H2O
Resonance structures
for the enolate ion
O: :O:–
:
O O OH O
CH3CH + – CH CH
2 CH3CH—CH2CH CH3CHCH2CH + OH –
:
H2O
An electrophile A nucleophile Alkoxide ion 3-hydroxybutanol
(b-hydroxyaldehyde)
Mechanism of aldol condensation
SCHEME 6.9
other than its parent. Aldols as such are not always isolated from the condensation, and
dehydration is brought about by base (Scheme 6.10). Intramolecular aldol reactions are used
to make five and six membered cyclic enones (Scheme 6.10a). Three and four membered rings
(strain) are not formed by this method due to strain and in these cases intermolecular reaction
is favoured.
O O OH O O
–
OH
—C—H + CH3—C—H —CH—CH2—C—H —CH CH—C—H
H 2O
Benzaldehyde Acetaldehyde Unstable 3-phenylpropenal

(cinnamaldehyde)
SCHEME 6.10
O O R O R
R
H –
– H OH
:
– R¢
R¢ OH
O OH R¢
Enolate of 1, 4-diketone Aldol product A cyclopentenone
SCHEME 6.10a
(i) Aldol reaction under ordinary conditions

The aldol reaction, when conducted under ordinary conditions often gives a mixture of products,
due to two reasons. Firstly e.g., if each of the two aldehydes has an α-hydrogen atom, the
condensation can give each of four products. This is due to the fact that each aldehyde can give
an enolate and each can act as a carbonyl component. Secondly an aldol reaction can generate
two stereocenters, thus it can lead to four possible stereoisomeric products (Scheme 6.11), two
syn or erythro products and two anti or threo products. Thus it may be necessary to control the
stereochemistry of the reaction. This requires both diastereoselection i.e., if (±)-I (Scheme 6.11)
or (±)-II (Scheme 6.11) will be the favoured product, as well as enantioselection i.e., for a given
diastereomer, whether the product will be (+)- or the (–)-epimer. The system of nomenclature
is based on the main carbon chain which is drawn in the extended zig-zag form. The isomer, in
which the two substituents at C-2 and C-3 are disposed in the same direction towards or away
from the observer is called syn (or erythro) and the other anti (or threo).
O OH O OH
R¢ R² + R¢ R²
O O R R
+ (I)
R¢ H R² (±)-anti (threo)
R
O OH O OH
R¢ R² + R¢ R²
R R
(II)
(±)-syn (erythro)
SCHEME 6.11
(ii) Use of preformed enolates in aldol reactions (directed aldol reactions)

A disadvantage while carrying out a crossed aldol reaction (i.e., a mixed aldol reaction) is that
more than one product is formed, when each of the carbonyl compound contains an active
hydrogen. Under these situations one then directs an aldol reaction to follow a particular
regioselectivity. One generates a kinetic enolate using LDA (see Scheme 6.5). This process
ensures the complete formation of an enolate of one of the components (where the proton has
been removed from the less substituted α-carbon, i.e., from the position with larger number of
α-hydrogens, Scheme 6.12). Thus in such a case, the mixed aldol reaction occurs specifically at
one of the two α-positions and the ketone (I, Scheme 6.12) reacts as shown. Under ordinary
conditions, this ketone would have reacted to afford a mixture of products (Scheme 6.13).
When the addition of the preformed enolate to the second carbonyl component is rapid and the
carbonyl component is added after the enolate formation the product is predictable and not a
mixture (Scheme 6.12).
– +
O O Li
LDA, THF
CH3CH2—C—CH3 CH3CH2C CH2 Step 1, formation of the enolate.
–78 °C
(I) The kinetic enolate
O– Li + O O– Li+ O OH
step 2 H2O
CH3CH2—C CH2 + CH3CHO CH3CH2CCH2CHCH3 CH3CH2CCH2CHCH3
A directed aldol reaction

SCHEME 6.12
O– O– O OH CH3CHCCH3
CH3CHO
CH3CH2—C CH2 + CH3CH C—CH3 CH3CH2CCH2CHCH3 + CHCH3
Kinetic enolate Thermodynamic
enolate
OH
A crossed aldol reaction carried out in the classical way
SCHEME 6.13
(iii) The stereochemical course of the reaction—Diastereoselection

The following points may be considered:
• The aldol reaction creates two stereocenters from achiral starting materials and in a
most general case, there are four stereoisomers of the aldol product (Scheme 6.11).
Thus syn or anti diastereomers are produced, each as a pair of enantiomers.
• Regarding the stereochemistry of the reaction, therefore, one has to control
diastereoselection i.e., whether (racemic) syn or (racemic) anti product is formed as
the major product. Secondly one has also to aim at enantioselection i.e., formation of
one of the four possible stereoisomers.
• Diastereoselectivity in the aldol reaction is achieved by employing the enolate of desired
stereochemistry (E or Z).
• Enolates are generated e.g., from a ketone and a base in the presence of chloro-
trimethylsilane when the enolated are trapped as silyl enol ethers. These are separated
and purified by chromatography and then converted into pure (Z)- or (E)-enolate
with fluoride ion (see Schemes 6.5 and 6.6).
• Methods are available to produce either E or Z enolates in pure forms.
• Z enolates give mainly 2, 3-syn aldols while the E-enolates give the 2, 3-anti aldols
(Scheme 6.14).
OLi HO O OLi HO O
1
R 2 2
RCHO + R RCHO + R
R R2 R R2
1
R 1 R R1
(Z)-Enolate
syn (or erythro) (±) pair (E)-Enolate anti (or threo) (±) pair
Specifically pure (E)-or (Z)-enolates can be made. Aldehydes react with

(Z)-enolates to give 2, 3-syn aldols and (E)-enolates give the 2, 3-anti aldols.
SCHEME 6.14
• The diastereoselectivity is explained by involving a six-membered chair like transition

state between the reactants i.e., an enolate of defined geometry and the carbonyl
compound e.g., an aldehyde.
• Greater diastereoselectivity in aldol reactions is achieved by employing boron enolates
as the carbon nucleophiles. The boron-oxygen bonds are shorter than lithium-oxygen
bonds, and consequently the steric interactions in the chair like transition state are
magnified to result in greater stereoselectivity. Z-vinyloxyboranes e.g., are readily
prepared by reacting ketones with a dialkylboron–trifluoromethanesulphonate
(triflate) and a mild base diisopropylethylamine (in these enolates the boron atom is
bonded to the oxygen atom of the ketone) and these react with aldehydes to give syn
aldol in high yield (Scheme 6.14a). 3-Pentanone by this method gives Z and E enolates
in a ratio of > 99 : 1 and subsequent reaction with benzaldehyde gives the syn and
anti aldols in a ratio > 97 : 3 (The same condensation when carried out with lithium
enolates gave a ratio of only 80 : 20).
Bu2BOTf, BBu2
O O OH O OH O
EtN(iPr)2
Et2O, –78°C PhCHO Ph Ph

> 99 : 1 CH3 CH3
(Z)-Enolate
(> 97% syn) anti
Minor product
SCHEME 6.14a
• The diastereoselectivity is achieved by the reaction (i.e., formation of the new C—C
bond) proceeding via a chair like six membered transition state in which the ligated
metal atom is bonded to the oxygen atom of the aldehyde as well to that of the enolate.
If the geometry of the enolate is fixed, the only variable is the orientation of the
aldehyde, and therefore, one deals with transition states of different stabilities. With
Z enolate one of the transition states (III, Scheme 6.15) is disfavoured due to 1,
3-non-bonded interactions between the substituents and thus the reaction takes place
largely via transition state (II, Scheme 6.15) to give syn aldol. Similar arguments
show that the reaction with the E-enolate proceeds preferentially through the
transition state (IV, Scheme 6.15).
2
R OBR2
1
(Z)-enolate
R CHO +
3
R
(I)
2 2 2 2
R R R R
1 3 1 3
R R H O H O R R
1
R O H O
BR2 BR2
HO O 3 1 3 HO O
H R R R
Syn product major
(II) CLASH
More stable (III) Anti
chair like (minor)
transition states
OBR2
1
(E)-enolate
R CHO +
2 3
R R
2 H 2
R H R
2 2
1 3 R O R O 1 3
R R R R
1
H O R O
BR2 BR2
HO O 1 3 3 HO O
R R H R
(iv) Anti product (major)
Syn CLASH More stable chair like
transition state
SCHEME 6.15
During reactions with lithium enolates the size of the substituents R1 and R2 explains
selectivity, larger the size of R2 (Scheme 6.14), the greater the selectivity. Thus in the case of a
ketone CH3CH2COR, the Z enolate is generally formed the faster of the two, if the group R has
reasonable size. The reason for this effect is that the methyl group has an eclipsing relationship
with oxygen in the Z isomer, but with the bulkier R group in the E-isomer. This factor due to
the steric strain is reflected in the transition states leading to their formation. Thus when R is
very bulky e.g. t-butyl as in 2, 2-dimethyl-3-pentanone, the selectivity is very high (Scheme
6.16). The selectivity gets less pronounced when the size of group R is reduced, 3-pentanone
under similar conditions gives a mixture containing 30% of the anti isomer.
OH O
– +
C4H 9-t (i-C3H7)2N Li C4H9-t C6H5CHO
C6H5 R
(LDA) – +
O O Li CH3
2, 2-dimethyl- The Z-enolate > 98% syn
3-pentanone
SCHEME 6.16
Strong Non-Nucleophilic Bases

Unlike in the past, now enolate nucleophiles are made by using very strong and
non-nucleophilic bases (Scheme 6.16a). These bases have pKa > 35 and convert
Si(CH3)3
K—N K—H
Li—N Si(CH3)3 NaNH2
Potassium Hexa Potassium hydride

Lithium diisopropyl Methyl Disilylamide Sodium amide
amide KHMDS
LDA
SCHEME 6.16a
carbonyl compounds with α protons that have pKa 20–25 completely to their enolate
anions. A carbonyl compound is completely converted into a stable nucleophile
and thus cannot condense with itself. This is the key to success of a reaction e.g.,
aldol condensation (see Scheme 3.43d).
(D) Other Reactions Resembling Aldol Condensations

(i) The Claisen-Schmidt reaction
Ketone enolates react with aldehydes effectively, however, aldehyde enolates donot
undergo crossed aldol condensation with most ketones but on the other hand
undergo self condensation.
This is a crossed aldol reaction when ketones are used as one component (Scheme 6.17)
and bases like sodium hydroxide are used. Under these basic conditions ketones do not self
condense appreciably since the equilibrium is unfavourable (see retroaldol reaction, Scheme 6.20).
O O– O
CH3COCH3 + OH
–
H2O + CH3CCH2 :– CH3C CH2
C6H5CHO
C6H5CH CHCCH3
4-phenyl-3-buten-2-one
Claisen-Schmidt reaction
SCHEME 6.17
This difference can be understood by considering the following discussion. In the dimerization
of acetaldehyde to give aldol (Scheme 6.9), the kinetics show that the first step i.e., the generation
of the enolate is rate determining. In the self condensation of acetone to yield diacetone alcohol
(Scheme 6.20), the kinetics show, that in this closely related reaction, the rate determining
step is instead the reaction of the enolate with a second molecule of acetone. The reason for
this difference is that the carbonyl group in acetone is less rapidly attacked by nucleophiles
(i.e., the carbonyl carbon atom of a ketone is less positive) as compared to acetaldehyde. This is
due to the fact that the methyl group due to its +I effect renders the adduct from acetone (and
therefore, the preceding transition state) less stable. Moreover, the carbonyl group of acetone
is more hindered. One may note that the C—C bond forming step in aldol condensations is
facilitated by groups with –I effect on the carbonyl component and retarded by electron releasing
groups.
An example of Claisen-Schmidt reaction is found in the synthesis of pseudoionone
(Scheme 6.18) from the naturally occuring geranial and acetone. Pseudoionone is used in the
commercial synthesis of vitamin A.
O
CHO O
C2H5ONa
+ CH3CCH3
C2H5OH
–5°C
Geranial Acetone Pseudoionone
The Claisen-Schmidt reaction

SCHEME 6.18
Enolates and Other Nucleophiles—Alkylation of β-Dicarbonyl Compounds

• Regiospecific formation of kinetic or thermodynamic enolates from ketones can
be directly achieved by using a strong base which is a relatively poor nucleophile
e.g., LDA, KHMDS or KH.
• For the removal of a proton attached to a carbon, a base with a higher pKa than
the pKa of the proton to be removed is employed so that a complete conversion to
carbanionic nucleophile is achieved (see Scheme 3.42).
• Thus one can either form a kinetic or a thermodynamic enolate from a ketone.
• The regiospecificity in the product can be forced by using an older but useful
strategy. In order to make a methyl ketone, enolate anion could be generated
from acetone itself (pKa = 20) followed by the addition of an alkyl group from
R—X via SN2 reaction. Enolate anion of acetone requires the use of a very strong
base to generate it and more importantly its high reactivity gives low yield of
the desired product.
• One thus works with a different strategy, and uses a synthetic equivalent enolate
anion of acetone (Scheme 6.18a) which is the enolate anion of ethylacetoacetate
(ethyl acetoacetate pKa 10, gives its enolate ion by using a moderate base e.g.,
NaOEt, however, the usual practice is to use NaH, pKa > 35).
• The resulting nucleophile (as an enolate) is then used to form a new carbon-
carbon bond.
O O O Enolate anion of
ethyl acetoacetate is
C – C – C the synthetic
:
H3C CH2 CH3 CH OEt equivalent of enolate
anion of acetone.
Enolate anion Enolate anion of
of acetone ethyl acetoacetate
Temporary ester group

–
O O O O O
+ –
:
CH3 Cl CH2 OEt OEt H 3C OEt

H H
Acid chloride Ester enolate Acidic
More acidic
(Ethyl acetoacetate)
–
removal of a proton OEt
from a-carbon or NaH
O O O O
–
:
R—X
H 3C OEt CH3 OEt
LiOH H R SN2
H
(Hydrolysis) (A)
O O O
D
CH3 OH H3C + CO2
H R
R
Decarboxylation
Substituted acetone with temporary

ester group removed
SCHEME 6.18a
• Ethyl acetoacetate can be prepared by reacting an acid chloride with the ester
enolate by Claisen type condensation. More acidic proton is removed and the
enolate (A, Scheme 6.18a) thus formed can be used to create new carbon-carbon
bond. After having guided the regioselectivity of the specific enolate anion
formation, this ester grouping of the system is removed by hydrolysis followed
by decarboxylation of the resulting β-keto acid (for mechanism of decarboxylation
of a β-ketoacid (see) Scheme 6.52).
–
• One may recall the role of more stable acetate anion (OAc ) as a synthetic
equivalent of OH– (see Scheme 5.15e) and the use of conjugate base of phthalimide
as the synthetic equivalent of amide ion for the synthesis of primary amines
(see Scheme 5.12e).
(ii) Condensation with nitro alkanes and nitriles

The α-hydrogens of nitro alkanes are much more acidic (pKa = 10) than those of aldehydes and
ketones (see Scheme 3.30). Such nitro alkanes with α-hydrogens undergo base catalysed
condensations with aldehydes and ketones in a way similar to aldol condensation (eq. I,
Scheme 6.19). Similarly, nitriles (see Scheme 3.30) also display aldol type condensations (eq. II,
Scheme 6.19).
O
–
OH
C6H5CH + CH3NO2 C6H5CH CHNO2 (I)
Benzaldehyde Nitromethane
O
EtO– /EtOH
C6H5CH + C6H5CH2CN C6H5CH C—CN (II)
Benzaldehyde Phenylacetonitrile
C 6H 5
SCHEME 6.19
(E) The Retro-Aldol Reaction

The aldol reaction is reversible. Thus when diacetone alcohol (product of self condensation of
acetone, Scheme 6.20) is heated with a strong base, the aldol addition is reversed. Infact one
then gets an equilibrium mixture which consists largely of acetone. This type of reaction is
called retro-aldol reaction.
–
OH O O O O O O
– –
HO – OH
:
CH3C—CH2CCH3 CH3C—CH2CCH3 CH3C + CH2CCH3 CH3—C—CH3

H2O H2O Acetone
CH3 CH3 CH3 (99%)
Diacetone alcohol
(1%) A retro-aldol reaction
SCHEME 6.20
(F) The Claisen Reaction

The Claisen reaction (different from Claisen ester condensation) is a base catalysed reaction
between an aldehyde which does not have an active hydrogen and an ester which contains an
active hydrogen. Thus e.g., benzaldehyde condenses with ethyl acetate in the presence of sodium
ethoxide to give ethyl cinnamate in high yield (Scheme 6.21).One may note that carbonyl in an
aldehyde is more reactive towards nucleophiles when compared to the carbonyl group of an
ester. The aldehydes with α-hydrogen atoms are not suitable partners for this reaction since
these would prefer to undergo self condensation.
– – C6H5CHO C6H5
:
EtO H—CH2CO2Et EtOH + CH2CO2Et CO2Et

Ethyl acetate Ethyl cinnamate
The Claisen reaction
SCHEME 6.21
(G) The Reformatsky Reaction

This is a crossed condensation reaction, and leads to aldol type products. The Reformatsky
reaction involves the addition of an organozinc reagent to the carbonyl group of an aldehyde or
ketone. This reaction extends the carbon skeleton of an aldehyde or a ketone and yields
β-hydroxy esters. In this regard the mechanism of Reformatsky reaction (Scheme 6.22)
resembles a Grignard reaction e.g., with a ketone (Scheme 6.23). The organozinc reagent is
less reactive than a Grignard’s reagent, therefore a nucleophilic addition to the ester group
does not occur.
Zn:
– +
O O O [ZnBr]
Zn Br
BrCH2COEt
ether EtO EtO
Zinc salt of an
enolate anion
ZnBr
– +
O [ZnBr] O O O OH O
H2O
+
EtO OEt OEt
b-hydroxyester
The Reformatsky reaction
SCHEME 6.22
On simply treating a mixture of a ketone and an ester with base does not lead to a
synthetically useful product. A ketone is more acidic as well as more electrophilic than the
ester. Thus, this combination leads only to the aldol condensation of the ketone. The problem
is solved by having an ester enolate anion to act as a nucleophile to attack a ketone or an
aldehyde. The ester enolate anion is formed first, in the absence of the ketone, by reduction of
an α-bromoester with zinc (α-bromoacid is prepared by Hell Volhard Zelinski reaction is
esterified to α-bromoester) Reformatsky reaction is not a base catalysed condensation. It
resembles a Grignard reaction with a ketone (Scheme 6.23). The enolate attacks the ketone
more rapidly compared to its ester precursor.
– + +
d d H3O
R: MgX + C O R—C—OMgX R—C—OH
The addition of Grignard reagent to a carbonyl compound
SCHEME 6.23
(H) The Perkin Reaction

The reaction is used for the synthesis of α, β-unsaturated acids, and is an aldol type condensation
between an aromatic aldehyde (ArCHO) and a carboxylic acid anhydride (RCO)2O catalysed
by a carboxylate ion (the potassium salt of the carboxylic acid, RCOOK). The anhydride gives
the enolate by reacting with basic carboxylate ion (Scheme 6.24).
CH3 O CH3 –
O
O O O O
C C
– –
:
CH3COCCH3 + AcO CH2COCCH3 + AcOH O O O O
:
–
O Ar—CH C Ar—CH C
O
H CH2 O CH2
AcOH
OAc
–
CH CHCOOH CH—CH—CO2
H
–
The Perkin reaction AcO
SCHEME 6.24
(I) The Stobbe Condensation

This is a condensation between dialkyl succinates and ketones in the presence of bases like
NaOEt. Mechanistically the enolate from the ester adds to the carbonyl group of the ketone
(Scheme 6.25). One may compare this situation with that in Claisen ester condensation where
in the presence of a base, the enolate from the ketone displaces alkoxide ion from the ester. In
the Stobbe condensation, the condensation product (I, Scheme 6.25) undergoes cyclization to
give a lactone intermediate, the oxygen anion of the adduct (I, Scheme 6.25) acting as an
internal nucleophile facilitates the hydrolysis of one of the ester groups. The lactone then
undergoes elimination (E1 or E2) to give a carboxylate salt. The net result is the attachment of
a three carbon chain to the ketonic carbon atom.
COOEt H Base
COOEt
–: R2C—CH R2C—C—COOEt R
CH aldol OEt E1
R 2C O+ –O CH2 O CH2
or E2
R—C CCH2COOH
CH2 C
C
COOEt
COOEt EtO O O
(I)
The Stobbe condensation
SCHEME 6.25
( J) Darzens Reaction
Aldehydes and ketones condense with α-haloesters in the presence of bases to give α, β-epoxy
esters called (glycidic esters). The reaction called Darzens condensation involves the addition
of the enolate to the carbonyl group to give an oxyanion (Scheme 6.26), this displaces the
halide ion by an internal SN2 reaction. On alkaline hydrolysis, these esters give glycidic acids
which undergo a decarboxylative rearrangement when warmed in the presence of acids
(Scheme 6.27) to give an aldehyde if R3 H or a ketone if R3 alkyl group. Thus the eventual
outcome of such a reaction is to extend the chain by one carbon.
1
R
O
2 Cl
– R
– 1 2
:
CH2CO2Et + B: CHCOOEt R R C—CHCO2Et
–BH
Cl Cl : O:
–
:
a-Haloester
–
–Cl
1 2
R R C¾¾CHCO2Et
O
An a, b-epoxy-ester (glycidic ester)
The Darzens reaction
Darzens reaction involves the reaction of an
a-halo ester with an aldehyde or a ketone in an
aldol type reaction to give a glycidic ester
SCHEME 6.26
1 1 1 3 1
R O H
+ R O + R R R
3 3 –H 3
C CR —C + C CR —C –CO2
C C CHCOR
–H
2 O OH 2 O+ O—H 2 OH 2
R R R R
H
SCHEME 6.27
When t-butyl glycidates are used, the ester on pyrolysis eliminates isobutene to give an
aldehyde or ketone (Scheme 6.28).
H
1 O CH2 1 1 3 1
R R R R R
3 3 3
C CR —C CMe2 Me2C CH2 + C CR CO2H C C CH—COR
2 O O Isobutene 2 O 2 OH 2
R R R R
t-butyl glycidate
SCHEME 6.28
(K) The Knoevenagel Reaction

The condensation of aldehydes and ketones, usually not containing an α-hydrogen with
compounds having an active methylene group (i.e., a methylene bonded to two groups of –M type)
like malonic ester can take place even with a weaker base to give a sufficient concentration of
the enolate ion. In reactions where amines like piperidine are used, are termed Knoevenagel
condensation (Scheme 6.29). The initially formed condensation product (I), then undergoes a
COOC2H5 CO2C2H5
: N—H + NH2 +
+ –:
CO2C2H5 CO2C2H5
Piperidine Malonic ester
:B
R H H H
CO2C2H5 CO2C2H5
C + : R—CH—C—COOC2H5 R—CH—C—COOC2H5 R
–
CO2C2H5 CO2C2H5
O –O COOC2H5 OH COOC2H5
(I) Base-catalysed elimination
B = Piperidine
The Knoevenagel reaction
SCHEME 6.29
base catalysed elimination (Scheme 6.29). When malonic acid is employed, one of the carboxyl
group gets eliminated. Thus using benzaldehyde and malonic acid, one ends up with cinnamic
acid in high yield. (Scheme 6.30). In some cases it is possible for the second molecule of the
OH
B: –CO2
PhCH O + CH2(COOH)2 Ph—CH—CHCOOH PhCH CHCOOH
Benzaldehyde Malonic acid Cinnamic acid
C O
–O
SCHEME 6.30
active methylene compound to add to the C C bond of the product of Knoevenagel reaction
(Scheme 6.31) via Michael reaction (for Michael reaction see Scheme 6.32). The Knoevenagel
R2NH –
CH2(COOEt)2 : CH(COOEt)2
H – +
R2NH2 HO CO2Et CO2Et
–H2O
:
O CH(CO2Et)2 H 2C
H CO2Et CO2Et
Initial Knoevenagel reaction
– CO2Et + EtOOC CO2Et

R2NH2
:
(COOEt)2CH H2C
CO2Et EtOOC CO2Et
Michael addition process
SCHEME 6.31
reaction ends up with the elimination of water from the initially formed alcohol with a base.
The mechanism of loss of water is of E1cb type. The Knoevenagel reaction has more synthetic
value with aromatic aldehydes than aliphatic aldehydes. The addition to the C C of the product
from an aromatic aldehyde should be less likely due to loss of conjugation of the aromatic
system.
(L) The Michael Reaction

This is a conjugate addition of enolate ions to α, β-unsaturated carbonyl compounds i.e., to
activated olefins (Scheme 6.32). Like other nucleophiles, the enolates do not react with simple
olefins. The name Michael reaction is infact applied to a reaction between enolate forming
component and an alkene which is not only activated by conjugation to a carbonyl group but to
other groups of –M type e.g., ester, cyano, nitro and nitrile. With these structural features, the
anion (I, Scheme 6.32) formed after addition (and thus the preceding transition state) is
stabilized sufficiently by the delocalization of the charge on to an electronegative element and
the addition therefore, occurs at a practicable rate.
CH3 O CO2C2H5 CH3

C2H5ONa
CH3C CHCOC2H5 + CH2 CH3C—CH2CO2C2H5
CO2C2H5 CH(CO2C2H5)2
Michael addition
CO2C2H5 CO2C2H5
– –
C2H5O: + H—CH C2H5OH + :CH Step 1
CO2C2H5 CO2C2H5
–
:
CH3 O CH3 :O:
CH3—C CH—C—OC2H5 CH3—C— CH C—OC2H5 Step 2

:
– CH(CO2C2H5)2
CH(CO2C2H5)2
(I)
Conjugate addition of the anion
to the a, b-unsaturated ester
CH3 CH3 O
+ –
H
:
CH3—C— CH2—CO2C2H5 H3C—C— CH—C—OC2H5 Step 3
CH(CO2C2H5)2 CH(CO2C2H5)2
Mechanism of Michael addition
SCHEME 6.32
(M) Robinson Annulation

This ring forming reaction makes use of the Michael and aldol reactions and allows a six
membered ring to be appended to a preexisting carbonyl group. The method is thus used to
prepare cyclohexenone derivatives (Scheme 6.33).
NaOEt, EtOH
+
O O O
Robinson annulation
SCHEME 6.33
The first step is the formation of an enolate ion (II) from the ketone (I, Scheme 6.33a)
which under the conditions of the reaction (use of OEt–) is a thermodynamic enolate in this
example. This enolate ion then undergoes a Michael reaction with an unsaturated ketone, e.g.,
methyl vinyl ketone. The enolate ion (III) from the diketone intermediate thus formed undergoes
an intramolecular aldol condensation to produce the six membered ring (Scheme 6.33a). Note
that the enolate ion (III) is isomerized to its isomeric enolate. Recall that aldol reaction is
reversible, the formation of a six membered ring exclusively is an example of kinetic as well as
thermodynamic control since the more stable product is formed fastest.
NaOEt, EtOH
–O –O –O
:
O
:
:
:
: O : : O
:
:
:
(I) (II) (III)

Thermodynamic
enolate Michael condensation –
OEt,
EtOH
–
OEt
(E1cb)
–O
:
O O : O
:OH
:
:
:
(IV)
Intramolecular aldol condensation
Mechanism of Robinson annulation
SCHEME 6.33a
EXERCISE 6.2
Why during the enolate formation from the diketone (I, Scheme 6.33b) out of several
protons in the α-position, the removal of Ha is preferred ?
ANSWER. It is only then that a stable six membered ring will be formed for other
alternatives, the product would be either strained four membered ring or a strained
bridged product.
O
–Ha
O
Hc
–Hb
O H O
a
Hb HO CH3
(I) –Hc
O
OH
SCHEME 6.33b
(N) The Claisen (Ester) Condensation

On treatment with bases like sodium ethoxide, esters with α-hydrogen undergo self
condensation; termed Claisen (ester) condensation (Scheme 6.34). The mechanism involves
the conversion of one molecule of ester to a nucleophile by the base while the second molecule
serves as a substrate (Scheme 6.34). The Claisen condensation reaction involves a series of
equilibria i.e., each step in the condensation is reversible. One may note that the formation of
the new carbon-carbon bond is not thermodynamically favourable. The formation of the
α-carbanion (ester enolate anion, Scheme 6.34) is not a favourable equilibrium reaction as
alkoxide is a weaker base than the enolate and consequently only a low concentration of enolate
forms. Attack of the α-carbanion on the second molecule of ester (acylation step), however,
gives the product. This reaction is predicted to have an equilibrium constant around 1 and is
reversible. In the final step 4, β-keto ester reacts with the alkoxide generated from substitution
to give
O
–
O CH3C—OEt O O
Step 1 –
:
CH3COEt HOEt + CH2COOEt CH3C—CH2COEt

–
OEt Step 2
OEt
Step 3
– OEt Step 4
:
+
H –
Acetoacetic ester CH3COCH2CO2C2H5 + OEt
O O Acetoacetic ester
The equilibrium driving step (I)
The Claisen condensation

SCHEME 6.34
the enolate anion of the product (I, Scheme 6.34). The equilibrium reactions are shifted toward
this anion due to its stability since two carbonyl groups stabilize the common α-carbanion. The
neutral β-keto ester product is isolated via acidification of the reaction mixture.
EXERCISE 6.3
Why the ester (A, Scheme 6.34a) does not give the expected Claisen ester
condensation product ? How one can obtain this condensation product ?
H3C O H3C O CH3 O

NaOEt
2 CH3CHCOEt CH3CHC—C——C—OEt
(A)
CH3
H not available to shift
equilibrium of step 4 as
in Scheme 6.34
SCHEME 6.34a
ANSWER. The alkoxide ion used as the base is much weaker than the enolate
formed in step 1 of Claisen ester condensation. The equilibria for the first three
steps (see Scheme 6.34) are not favourable. In fact step 4 is key to the success of the
reaction. This condensation product (Scheme 6.34a) can be made if a powerful
base KH is used, since now the enolate ion formed in the first step on the product
side is weaker than the base on the reactant side of the equation.
(O) The Dieckmann Reaction

It is an intramolecular Claisen condensation by way of which certain cyclic ketones can be
obtained. It is most successful on diesters of C6 and C7 dibasic acids, where it gives the high yields
of cyclic β-keto esters (Scheme 6.35). The primary driving force of the Dieckmann condensation
(thermodynamically favourable) as with the Claisen condensation (see Scheme 6.34) is the
–
O O O O
CH3O OCH3 CH3O OCH3

H H – H
:Base
Especially acidic –
:
O O :O:
H
–
CH3O + CH3O CH3O CH3O
O
O CH3O
CH3O
:O:
–
:
Dieckmann condensation
SCHEME 6.35
formation of the anion of the product β-ketoester (not shown) by deprotonation of the hydrogen
bonded to the carbon between two carbonyl groups (shown by an arrow) of the product
β-ketoester. The diesters of shorter chain dibasic acids due to the strain that would result in
the formation of small rings react differently. Thus ethyl succinate undergoes an intermolecular
condensation between two molecules to give a cyclohexanedione system (Scheme 6.36).
CO2C2H5 CO2C2H5
–
HC : OC2H5 CH
H2C C O – H2C CO
–2EtO
O C CH2 OC CH2
–
OEt : CH CH
CO2C2H5 CO2C2H5
SCHEME 6.36
(P) The Thorpe Nitrile Condensation

In the Thorpe reaction, the α-carbon of one nitrile molecule (a carbanion source) adds to the
CN carbon (acceptor site) of the another molecule. The C NH bond that results can be
hydrolyzed to get β-keto nitriles (Scheme 6.37).
H CH3CH2C N: CN
base –
:
CH3—C—C N: CH3—C—C N: CH3CH2C—CHCH3

–H+
–
H H :N
:
H2O
CH3 NH CH3
H2O
NH3 + CH3CH2C—CHCN CH3CH2C—CH—CN
An iminonitrile
O
The Thorpe reaction
SCHEME 6.37
(Q) The Benzoin Condensation

This reaction is the cyanide ion catalysed intermolecular condensation of an aromatic aldehyde
to give an acyloin. The condensation of benzaldehyde gives benzoin (Scheme 6.37a). The aromatic
aldehydes do not form cyanohydrins, but the cyanide addition product, by base abstraction of
a proton gives a carbanion. This reacts with a second molecule of the aldehyde. Thus benzoin
condensation involves the reaction of two molecules of aldehyde (normally aromatic) in the
presence of cyanide ion to give a benzoin (an α-hydroxyketone) which is also called an acyloin.
In benzoin condensation (recall that benzoin condensation resembles an aldol and

Cannizzaro processes) cyanide ion is needed for the success of the reaction, however, it is
regenerated at the end of the reaction (Scheme 6.37a).
KCN
2C6H5CHO C6H5CHOHCOC6H5
Benzaldehyde Benzoin
– –
O O OH OH O
:– C6H5CHO
C6H5C + CN C6H5C—CN C6H5—C—CN C 6H 5 C C—C6H5
:
–
H H A carbanion CN H
–
O OH O OH
–
–CN
C6H5C CC6H5 C 6 H 5C CC6H5
H CN H
Mechanism of the benzoin condensation
SCHEME 6.37a
The success of the reaction is due to the cyanide ion. Firstly it is a reactive nucleophile
and secondly it has the capacity to delocalize the negative charge on the carbanion. Thus the
carbanion formation is assisted. Moreover, with aromatic aldehydes (unlike aliphatic aldehydes)
the negative charge of the carbanion is further delocalized on the aromatic ring (Scheme 6.37b)
and this factor provides the extra driving force for the reaction.
OH OH OH OH
–H+
H – –
CN C
N – N
N
SCHEME 6.37b
6.2 STORK ENAMINE REACTIONS (FORMATION OF CARBON-CARBON

BONDS)REACTION OF AN ENAMINE WITH REACTIVE ELECTROPHILES
The name enamine usually refers to α, β-unsaturated amines. These can be prepared by reaction
of an aldehyde or a ketone which contains at least one α-hydrogen atom and a secondary
amine under acid catalysis (Scheme 6.38). More stable enamines are those derived from ketones
rather than aldehydes. Moreover, the enamines derived from cyclic secondary amines
(Scheme 6.39), are further more stable, than a acylic secondary amines.
O OH R R
:
:
:
C + HN—R —C—C—N N + H2O
—C R C C R
R H
H A secondary
amine
Enamine
Aldehyde or ketone
with an a-hydrogen
Enamine formation
SCHEME 6.38
O
+
H
O + HN N:
N N N –H2O
H H H An enamine
Pyrrolidine Piperidine Morpholine
SCHEME 6.39
Primary amines also form enamines, however, in their case, enamine-imine tautomerism
is possible. The equilibrium lies virtually completely on the imine side, it being more stable
than enamine (Scheme 6.40). Thus an enamine from a primary amine cannot be isolated and
used in synthesis.
The detailed mechanism of the formation of an imine and an enamine involving

the nucleophilic attack of a primary and secondary amine respectively on the
carbonyl carbon of an aldehyde or a ketone is detailed (see Scheme 11.15).
Enamines are represented as resonance hybrids of two canonical structures (Scheme 6.40)
and are closely related to the enolates derived from ketones. In fact these are N analogs of an
enol. An examination of the resonance structure (II, Scheme 6.40) shows that β-carbon is a
nucleophilic center.
+
:
R—NH2
N N
CH—C O C C—NH— CH—C N—
:–
Enamine Imine
Enamine from a primary amine cannot be isolated

(I ) (II) Nucleophilicity on
Enamine carbon
SCHEME 6.40
Thus enamines have a β-carbon with carbanionic character and can act as a nucleophile,
and display alkylation and acylation reactions. The product iminium salt is hydrolyzed to the
ketone. The net result of the entire sequence is the alkylation of the ketone in the α-position
(Scheme 6.41). Enamines can thus be alkylated (Scheme 6.41) and these are SN2 reactions,
the alkylating agents have to be from, methyl, primary, allylic and benzylic halides.
–
Br
+
:
O N N O
N H H + H
H SN 2 H3O
CH2—Br CH2Ph CH2Ph +
cat H + +
N
Enamine Ph Alkylated iminium salt Alkylated ketone H H
Benzyl bromide
SCHEME 6.41
Acylation of an enamine is used for the synthesis of a β-diketone (Scheme 6.42) which
can be further used as synthetic intermediates in more complicated compounds.
– –
: : + Cl – + O Cl O
:
O:
: :
N O N N O
+
C C—CH3 H3O C—CH3
H Cl—C—CH3
CH3
H H H
Enamine Acyl chloride Intermediate Acyl iminium salt b-diketone
SCHEME 6.42
Enamines display Michael type condensation and behave as addenda to α, β-unsaturated

ketones, esters and cyanides etc. (Scheme 6.43).
+
:
N N
H CH2 CH—CO2Et CH2—CHCO2Et
–
:
N O
CH2CH2CO2Et + CH2CH2CO2Et
H3O
H
SCHEME 6.43
Some Problems of Working with Enamines—Enamines

are Alkylated by Reactive Electrophiles
Among the three important enol equivalents mention may be made of (1) enamines,
(2) silyl enol ethers and (3) azaenolates. The following points may be noted:
• Alkylation of ketones is best carried out by employing lithium enolates (see
Scheme 6.3).
Since enolates are very strong bases, secondary and tertiary halides undergo
predominant E2 elimination (see Scheme 6.3a)
• Lithium enolate formation is however, not satisfactory with aldehydes since
aldehydes are highly electrophilic. Even the use of LDA (– 78°C) is not fast
enough to avoid self condensation between the forming lithium enolate and
unreacted aldehyde.
• Thus aldehydes (and ketones) are best alkylated via their enamines which are
stable powerful nucleophiles and are specific enol equivalents (see Scheme 6.41).
• Specifically for alkylating aldehydes (and also for ketones) one uses aza-enolates
(see Schemes 6.46a and 6.46b).
• Using a simple and less reactive alkylating reagent e.g., CH3I, reaction with an
enamine occurs at N instead of C to yield a quaternary ammonium salt which
on hydrolysis gives back the starting reactant and therefore, the yields of the
desired product are low (Scheme 6.43a). Thus more reactive alkylating agents
e.g., benzyl halides, allylic halides and α-chlorocarbonyl compounds work best
with enamines.
+
N: N O
R—X R H3O+ R
, R or R
C-alkylation
X X X
O
Enamine Alkylated carbonyl With active alkylating agents
compound
+
N: N O
Me—I R
H3O+
+ R—CH2—X
N-alkylation
N
Me With simple alkyl halides
Enamine Quaternary Starting
ammonium material
salt
SCHEME 6.43a
Alkylation of Ketones via Silyl Enol Ethers—Silyl Enol Ethers are

Alkylated with SN1 Reactive Electrophiles
Compared to enamines which are potent neutral nucleophiles, silyl enol ethers are
comparatively less reactive (less nucleophilic) and need a more powerful electrophile
e.g., a tertiary carbocation. One has already seen (see Scheme 6.43a), that secondary
and tertiary alkyl halides are not suitable alkylating agents for use with enamines
or lithium enolates since elimination will be a predominant reaction. Thus tertiary
alkyl halides work as very good alkylating agents for silyl enol ethers (Scheme
6.43b). The enolate is converted into its silyl enol ether which reacts with a
carbocation generated from a tertiary alkyl halide in situ with a Lewis acid e.g.,
SnCl4 or TiCl4.
Cl
+ TiCl4 + + TiCl5
2-chloro-2-
methylbutane
–
SiMe3 Cl
+
:
O : OSiMe3 O O
Me3 SiCl +
Et3N
Silyl enol ether
SCHEME 6.43b
An unsymmetrical ketone can react at two sites and the enamine formation occurs
predominantly at the less substituted position (Scheme 6.44). The stabilization in an enamine
is due to interaction of the alkene π-system with the unshared electron pair in a p orbital on
nitrogen (compare with data in Scheme 3.35b). Consequently a coplanarity of the bonds on the
unsaturated carbon atoms and those to nitrogen is favoured. This coplanarity shown by bold
lines can be achieved in (I, Scheme 6.44) but not in II due to steric repulsions. In structure
(I, Scheme 6.44), the methyl group adopts a quasi-axial conformation so that steric interaction
with the amine moiety can be avoided. In structure (II), however, there is a serious steric clash
(A1,3 strain) which makes it unstable. Thus the enamine from 2-methyl cyclohexanone gives
the C-alkylation predominantly on the less substituted carbon (Scheme 6.44). The formation
of least substituted enamine minimizes steric interactions to maximize the planarity of
N—C C moiety and hence the overlap of the nitrogen lone pair with the alkene.
H H
O N N
H H
H N H
–H2O
+ + H N H H
N H H H C—H
H Major Minor H
C—H
product product
H
(I) (II)
SCHEME 6.44
EXERCISE 6.4
Which of the two enamines will be formed preferentially from the tetralone
(I, Scheme 6.45)?
O N N
TsOH
+ N
(I) H (II) (III)
SCHEME 6.45
ANSWER. Conjugated anamine (II) is formed exclusively at the expense of the
non-conjugated isomer (III).
EXERCISE 6.5
Show by drawing structures that enamines are closely related to the enolates derived
from ketones.
ANSWER. Enamines are the nitrogen analogues of enols (Scheme 6.46). Thus
working with an alkylation of an enamine is the conversion a carbonyl compound
R R
– +
N N – –
O O
R R
Enamine Enolate
SCHEME 6.46
to another carbonyl compound and the overall process is as if an enolate is
alkylated (see Scheme 6.41).The advantage of working with an enamine is that
no strong base or an enolate is involved and the problem of self condensation
is eliminated.
Aza-Enolates—A Summary of Enol Equivalents for

Alkylation of Aldehydes and Ketone
Recall the following observations:
• Ketones can be best alkylated by using their lithium enolates (see Scheme 6.7).
• Enamines are formed by reacting an aldehyde or a ketone with a secondary
amine. Enamines can then react with SN2 reactive haloalkanes (with reactive
alkylating reagents i.e., allylic halides, benzylic halides and α-halocarbonyl
compounds the yields are indeed high) to yield alkylated aldehydes and ketones
(see Scheme 6.41).
• Silyl enol ethers derived from aldehydes and ketones can be alkylated with SN1
reactive electrophiles e.g., tertiary, allylic or benzylic alkyl halides (see Scheme
6.43b).
• There is a difficulty with lithium enolate formation. Aldehydes are highly
electrophilic and even a strong base like LDA (– 78°C) is unable to bring about
fast deprotonation to rule out the aldol self-condensation between the lithium
enolate and the unreacted aldehyde (Scheme 6.46a). Thus enamine of an
aldehyde (where the aldehyde is present in the masked form during enolization)
is instead employed for alkylating an aldehyde.
• As an other alternative one works with aza-enolates and aza-enolate alkylation
of aldehydes is a successful procedure, which is also applicable to ketones. Recall
that enamines can be made by reacting an aldehyde or a ketone with secondary
amines. Reaction with a primary amine gives an imine which on reaction with
a strong base LDA or Grignards reagent gets deprotonated to give an aza-enolate
(Scheme 6.46a).
Self condensation (a problem)
H
base –
R—CH CH—OH R—CH2—C O R—CH CH—O
Enol An aldehyde Enolate
(unstable) (highly electrophilic) (highly nucleophilic)
+
R¢NH2/H
+
cat H –H2O primary
N –H2O amine
H
secondary Acidic proton
amine
H
base –
: :
R—CH CH— N R—CH2—CH N—R¢ R—CH CH—N—R¢

:
Enamine Imine Aza-enolate

(stable nucleophilic) (weakly electrophilic) (highly electrophilic)
Self condensation not a problem
SCHEME 6.46a
• Thus the alkylation of an aldehyde through an aza-enolate is presented

(Scheme 6.46 b).
R—MgBr
Aza-enolate
H MgBr
R¢NH2
R—CH2—CHO R—CH—CH N—R¢ R—CH CH—N—R¢
H+
Aldehyde Imine
C6H5CH2—Cl
Alkylating agent
+
H
R—CH—CHO R—CH—CH N—R¢
H2O
C6H5CH2 C6H5CH2
Alkylated aldehyde
SCHEME 6.46b
6.3 ACID CATALYSED REACTIONS (FORMATION OF CARBON-CARBON BONDS)

(A) Acid Catalyzed Cyclization (Self Condensation of Alkenes)
The pseudoionone prepared by the Claisen-Schmidt reaction (see Scheme 6.18) can be elaborated
to β-ionone during the synthesis of vitamin A. On treatment with BF3 in acetic acid, the ring
closure occurs in pseudoionone (Scheme 6.47).This is a typical acid catalysed cyclization of
dienes, provided one can end up with stereochemically favoured five-or six-membered rings.
O O O
+
+
H
+
Pseudoionone
+
–H
O O
b-ionone
SCHEME 6.47
(B) Carbocations Derived from Aldehydes and Ketones

(i) Prins Reaction
The acid catalysed addition of an olefin to formaldehyde in the presence of an acid is called the
Prins reaction. The net result being the addition of hydroxymethylene group to a double bond.
The reaction gives a 1, 3-diol together with a cyclic acetal (1, 3-dioxan) which is formed from
the diol by the addition of a second molecule of formaldehyde (Scheme 6.48). The mechanism
involves electrophilic attack on both the double bonds. The acid protonates the C O and the
CH2OH CH2OH R
+ + RCH CH2 + CH2O
H H2O
H—C—H H—C—H RCH—CH2 RCH—CH2
alkene –H + –H2O O O
O OH (I) OH
Formaldehyde
SCHEME 6.48
carbocation thus formed attacks the C C. The resulting (I, Scheme 6.48) can add water to
give a diol as shown or it can also undergo a loss of H+ to give an olefin (Scheme 6.48a). Other
examples of Prins reaction include the chloromethylation of phenol with formaldehyde and
HCl (Scheme 6.48a).
CH2OH CH2OH
+ +
–H
R—CH—CH2 RCH CH
(I, Scheme 6.48)
OH OH
Cl CH2Cl
H2CO/HCl H2CO/HCl
ZnCl2 ZnCl2
CH2OH
NO2 NO2
SCHEME 6.48a
(ii) Mannich Reaction

This reaction links together an amine an aldehyde (usually formaldehyde) and the enol of a
ketone i.e., a ketone with an α-hydrogen (Scheme 6.49). Thus the net result of Mannich reaction
+
H
OH
H
+ + –H2O +
:
R2NH + C O H R2N—CH2 R2N CH2

H H Iminium ion
(reactive species)
R R
+ +
–H
R—C—CH3 C CH2 CH2 NR2 C—CH2—CH2NR2
O H—O O
Iminium ion
New bond
A Mannich base
Mechanism of Mannich reaction
SCHEME 6.49
among CH2O, RNH2 and R′COCH3 is the extension of the —CH3 of the ketone by —CH2NHR.
The products of the Mannich reaction are known as Mannich bases and many are useful as
intermediates in synthesis.
The reaction of acetophenone with diethylamine and formaldehyde gives the Mannich
base which can be elaborated to a variety of compounds e.g., on Hoffmann elimination (see
Scheme 15.29) and so on (Scheme 6.50).
H
O O
+ +
H + –H
PhCOCH3 PhC CH2 CH2 NEt2 Ph—CHCH2NEt2
Acetophenone Mannich base
+ – H2
PhCOCH2CH2NHR2 Cl PhCOCH CH2 PhCOCH2CH3
cat
Mannich base Phenylvinyl
(as quaternary salt) ketone
SCHEME 6.50
As seen above (Scheme 6.49) the electrophilic component in a Mannich reaction is the
methyleneiminium ion generated from formaldehyde and a secondary amine. The nucleophile
may be an enol, an activated arene or a π-excessive heteroarene (Scheme 6.50a).
O O
CH2—N O
+
+ CH2 N O
CH2NR2
+
+ CH2 N R2
N N
H H
SCHEME 6.50a
EXERCISE 6.6
Why in indole (see Scheme 6.50a) the reactive species, the iminium ion reacts at
the 3-position and not at position 2?
ANSWER. The 2, 3-benzo derivatives of pyrrole, furan and thiophene react in the
hetero ring. Substitution at the 3-position e.g., in indole generates a transition
state (I, Scheme 6.50b) in which the stabilizing effect of N atom on the transition
state is more and the appropriate resonance structure is benzenoid. The benzenoid
system is disrupted on 2-substitution as shown (II, Scheme 6.50b).
+
CH2 NR2 H CH2—NR2 CH2NR2
H
+
:
N +N N N CH2NR2
H H H H
(I)
(II)
SCHEME 6.50b
The Mannich reaction is an important synthetic pathway in the biosynthesis of alkaloids,

and many such reactions have been duplicated under the laboratory conditions. Thus tropinone
can be synthesized from succindialdehyde, methylamine and acetone (Scheme 6.51).
Me
N
CHO O
CH3
CH2
+ MeNH2 + C O
CH2 Methylamine
CH3
CHO Tropinone
Succindialdehyde Acetone
SCHEME 6.51
(iii) Building Heterocyclic Rings

When the ketonic carbonyl group of a β-keto aryl amide or an aryl ester is protonated, a ring
closure leads to quinolines or coumarins (Scheme 6.51a). In this reaction the keto group is
+
O H OH
+
:
G O G O G O
G NH or O
SCHEME 6.51a
acting as an alkylating agent (A Friedel-Crafts type alkylation) in the presence of a proton

acid. The amidoketone (Scheme 6.51a) can be made by reacting aniline and acetoacetic ester
(Scheme 6.51b).
CH3 O
O –C2H5OH
+
NH2 O OC2H5 NH O
SCHEME 6.51b
6.4 REACTIONS OF CARBOXYLIC ACIDS AND THEIR DERIVATIVES

The carboxyl group (–COOH) containing compounds and their derivatives (e.g., acyl chlorides,
acid anhydrides, esters and nitriles) are one of the basic classes of compounds which are
important both to organic and biochemistry. The derivatives of carboxylic acids are those
functional groups that are converted to carboxylic acids by a simple acidic or basic hydrolysis.
The mechanistic considerations of some of these reactions of these classes of compounds are
discussed here.
(A) Decarboxylation of Carboxylic Acids

The carboxylate ions (RCOO–) of simple aliphatic acids do not decarboxylate readily, however,
.
the carboxyl radicals (RCOO ) undergo a ready decarboxylation. The one electron oxidation of
.
a carboxylate ion (RCOO–) produces a very unstable RCOO radical which decomposes with
.
the loss of carbon dioxide and an alkyl radical. The unstable RCOO radical can be produced by
electrochemical oxidation or by halogenation of a carboxylate ion. The alkyl radical formed on
its decomposition can either be halogenated to the corresponding halo (normally bromo–) alkane
in the Hunsdiecker reaction (see Scheme 16.22) or can couple to an alkane (Kolbe electrolysis,
see Scheme 16.25).
When special groups are present in the molecule, the decarboxylation becomes rapid
enough to be useful synthetically. One such structural feature is the presence of a keto group
in the β-position to the carboxylic acid group. Thus, when such an acid decarboxylates it does
so through a six-membered cyclic transition state (Scheme 6.52). This mechanism is consistent
with the resistance of bridgehead bicyclic β-keto acids (Scheme 6.52) to decarboxylation as the
product would be a highly strained bridgehead olefin.
H H
O O O O
–CO2
C C O C C
b
G CH2 G CH2 G CH3 O OH
Enol Keto form COOH
where G = OH (diacid)
R (b-keto acid)
H (b-aldehyde acid)
Decarboxylation of b-keto acids
SCHEME 6.52
Loss of a bromide ion from the β-position of a carboxylate group occurs readily under
mild basic conditions. The process is decarboxylation accompanied by elimination (Scheme 6.53).
Cinnamic acid dibromide is converted into β-bromostyrene on reaction with hot aqueous sodium
carbonate solution. Dehydrobromination with potassium hydroxide gives the acetylenic
compound phenylacetylene. Bromination of cinnamic acid (Ph CH CH COOH) gives 2,
3-dibromo-3-phenylpropanoic acid in high yield as the starting compound.
Br O
–CO2 Br KOH
Ph O– Ph Ph C CH
Br Phenylacetylene
SCHEME 6.53
Decarboxylation of β-keto acids involves both the free acid as well as the carboxylate
ion. When the carboxylate ion decarboxylates, it forms a resonance stabilized enolate anion
(Scheme 6.54). This carbanion is much more stabler than the anion R CH −2 which would be
formed by the decarboxylation of an ordinary carboxylate ion.
–
:
:
:O : O: :O: :O: :O:
–CO2 – +
– H
: :
:
R—C—CH2—C—O : R—C—CH2 R—C CH2 R—C—CH3
Carboxylic acid anion
SCHEME 6.54
Pyrrole and furan carboxylic acids decarboxylate when heated (eq. I, Scheme 6.55), and
this represents a reaction where during electrophilic aromatic substitution a group other than
hydrogen is displaced. (The reaction starts via ipso attack). The decarboxylation which is
operative when powerful activating substituents are present involves an internal electrophilic
substitution by hydrogen, and a similar process is operative when phenolic acids are
decarboxylated under acid catalysis (eq. II, Scheme 6.55).
O
C –
O + CO2 (I)
+
:
N CO2H N H N
H H H
O
–
CO2H H C—O
HO OH + HO OH HO OH
H
CO2 + (II)
OH O+ OH
H
SCHEME 6.55
Aromatic carboxylic acids containing strongly electron-attracting groups, however,

decarboxylate via the carbanions (Scheme 6.56).
– CO2 +
+ O + –
N CO2H N C N N
H H
O
–
O O
C
–
O2N NO2 O2N NO2 O2N NO2
+
H
NO2 NO2 NO2

SCHEME 6.56
Oxidative decarboxylation of carboxylic acids has been discussed (see Scheme 13.58).
(B) Ester Hydrolysis and Esterification

The conversion of an ester into its acid and alcohol moieties (eq. I, Scheme 6.57) is termed ester
hydrolysis. This hydrolysis can involve cleavage either at the acyl-oxygen or alkyl-oxygen bond
(eq. II, Scheme 6.57). A variety of mechanisms may be involved both depending on the nature
of R and R′ and the conditions of the reaction. The mechanisms of esterification are based on
the principle of microscopic reversibility.
O O
R—C + H 2O R—C + R¢O—H (I)
OR¢ OH
Hydrolysis of a carboxylic ester
O O
1 2 1 2
R —C—OR R —C—O—R (II)
Acyl-oxygen heterolysis Alkyl-oxygen heterolysis
SCHEME 6.57
1. BAC 2 mechanism (ester hydrolysis) [Base-catalysed (B), bimolecular (2) hydrolysis

with acyl-oxygen (AC) cleavage]
This is the most common mechanism for base-catalysed ester hydrolysis and involves
nucleophilic attack by base on the ester to give an unstable tetrahedral intermediate which
then decomposes to the products i.e., an acid and alcohol. The following points proves this
mechanism :
(a) The use of 18O as an isotopic tracer has shown that the base promoted reaction
generally proceeds by acyl oxygen cleavage and this is not dependent on the structure
of the R and R′ groups (Scheme 6.58). Thus the alcohol produced (e.g., ethanol if
ethylpropionate labelled with 18O, C2H5—CO—18O—C2H5 is used) was found to be
enriched in 18O.
O O
–
18 OH 18
where R¢ = 1°, 2°, or 3°
R—C— OR¢ R—C—OH + R¢ OH
or H2O
–
: :
(or RCOO : )
SCHEME 6.58
(b) Chemical kinetics of the alkaline hydrolysis of –

: :
esters is second order, with the rate depending Rate of reaction = k2 [ester] [ : OH ]
on the concentration of both ester and the base
(Scheme 6.59). Thus, the reaction involves the SCHEME 6.59
attack on ester by the base.
(c) Further evidence for the acyl-oxygen fission during basic hydrolysis is stereochemical
in nature. When an optically active ester is employed (Scheme 6.60) and if the BAC2
O O
hydrolysis
CH3CO—CH—CH3 CH3C—OH + HO—CH—CH3
n-C6H13 n-C6H13
Optically active Retention of configuration
SCHEME 6.60
mechanism is operative then the complete retention of configuration of the alcohol

formed is indicative of the formation of the ion RO– (acyl-oxygen fission) i.e., the
bond R—O is never broken thus the mechanism (Scheme 6.61) involving an unstable
tetrahedral intermediate is operative. This mechanism is consistent with the following
–
:O:
:
:O: O
18 – slow 18 fast 18 –
R—C— OR¢ + : OH
: :
: :
: :
: :
: :
R—C— O—R¢ R—C—OH + R¢ O
:
:
OH
:
Tetrahedral intermediate
BAC2
SCHEME 6.61
evidence. When the carboxyl labelled methyl benzoate (Scheme 6.62), undergoes
alkaline hydrolysis in ordinary water and the reaction is interrupted after some time
the unhydrolyzed ester is found to be a mixture (Scheme 6.62). The exchange of 18O
of the labelled ester for ordinary oxygen from the solvent occurs to give the unlabelled
ester (i.e., an exchange product is formed).
18 18
O O O
—C—OCH3 —C—OCH3 + —C—OCH3
Methyl benzoate
18 18 – 18
:
:O : :O : :OH
:
– –
R—C—OR¢ + HO: : OH
: :
: :
: :
R—C—OR¢ + H—OH R—C—OR¢ +

: OH Weak acid
:OH
:
(I) (II)
Strong base
Chemically equivalent
hydroxyl groups
SCHEME 6.62
The initially formed intermediate (I, Scheme 6.62) via the addition of hydroxide ion to
the starting ester is the alkoxide ion, a strong base. This intermediate reacts with water to
give the intermediate (II, Scheme 6.62) having two chemically equivalent hydroxyl groups.
Now the hydroxide ion can attack either of these two equivalent OH groups (Scheme 6.63). In
case the base removes the proton from 18OH group the original intermediate (I, Scheme 6.62)
is reformed which then gives the starting 18O labelled ester (or the hydrolysis products). In
case the base removes the proton from the OH group of the intermediate (II, Scheme 6.63),
then a new intermediate (III, Scheme 6.63) is formed which can either give the ester with no
18O or could decompose to give hydrolysis products.
Thus in summary this mechanism of base catalysed ester hydrolysis involves nucleophilic
attack by base on the ester to yield a tetrahedral ion which rapidly collapses to the products
with consumption of one mole equivalent of base.
1 –:
: :
18
:
: OH OH
R—C—OR¢ or
: OH
2
:
–
: :
: OH
1 (II) 2
18 – 18
:
:O: OH
R—C—OR¢ R—C—OR¢
: OH : O–:
:
(I) (III)
18
:O: :O:
– 18 –
: :
: :
R—C—OR¢ + Other products + OH R—C—OR¢ + Other products + OH

: :
SCHEME 6.63
2. AAC 2 [Acid-catalysed (A) bimolecular (2) hydrolysis with acyl-oxygen (AC) fission]
This is the most common acid catalysed hydrolysis mechanism and involves nucleophilic attack
by water on the protonated ester to give a tetrahedral intermediate (infact, more like
II, Scheme 6.64) which collapses to protonated acid (and then to acid) and alcohol. The
evidence for this mechanism is on the same lines as in the alkaline hydrolysis. The oxygen –18
studies show that the acid catalysed hydrolysis is sensitive to the structure of alkyl group. For
primary and most secondary alkyl groups, the acyl oxygen bond is broken (Scheme 6.64).
On the basis of principle of microscopic reversibility (Scheme 4.18j), the mechanism of
reverse reaction i.e., esterification is thus also contained in the same equilibria (Scheme 6.64).
H2O
+ Water
H
+ +
O OH OH
+
R—C—OR¢ R—C OR¢ R—C—OR¢
Ester
+ OH
2
(I)
+
O OH HO
+ +
H + R—C—OH R—C R—C—OR¢
H
Acid
OH HO
(II)
+ Tetrahedral intermediate
R¢OH
Alcohol
+
Rate = k [Ester] [H3O ] AAC2
Acid catalysed hydrolysis and esterification
O O
+
18 H3O 18
R—C— OR¢ R—C—OH + R¢ OH
where R¢ = 1° or 2°
SCHEME 6.64
3. AAL 1 [Acid-catalysed (A) unimolecular (1) hydrolysis with alkyl-oxygen (AL)

cleavage]
This hydrolysis involves the fragmentation of a protonated ester to give a carboxylic acid and
a carbocation, which is rapidly trapped by water. This mechanism (SN1 type) is operative only
in those cases where R′+ is a relatively stable carbocation. It is observed that for most tertiary
alkyl groups, considerable 18O ends up in the carboxylic acid, to indicate alkyl-oxygen fission
(Scheme 6.65). Thus for esters derived from tertiary alcohols the reaction begins with the
protonation of the ester (Scheme 6.66) and the leaving group is a stable tertiary carbocation.
The carbocation subsequently reacts with water to give an alcohol. In keeping with this
mechanism (Scheme 6.66), when the acid catalysed hydrolysis of t-butyl acetate is carried out
in water enriched with 18O, t-butanol containing 18O was isolated.
O O
+
18 H3O 18
R—C— O—R¢ R—C— OH + R¢OH
Alkyl-oxygen
breakage
where R¢ = 3°
SCHEME 6.65
+
O OH
t + t + t
CH3C—O—Bu + H CH3—C—O—Bu CH3COOH + Bu
+ t t + t +
Bu + H2O Bu OH2 Bu OH + H
AAL1
Common mechanism for t-alcohols
SCHEME 6.66
4. BAL2[Base–promoted (B) bimolecular (2) ester hydrolysis with alkyl-oxygen(AL)

cleavage]
This ester hydrolysis mechanism is operative in rare cases and involves nucleophilic
displacement at the alcohol carbon (Scheme 6.67). The process infact is ester cleavage, thus
methyl benzoate on reaction with sodium methoxide and methanol gives dimethyl ether and
sodium benzoate (Scheme 6.67).
– –
MeO Me—O—OCPh Me2O + PhCO2
The BAL2 mechanism
SCHEME 6.67
5. AAC 1 Ester hydrolysis [Acid-promoted (A) unimolecular (1) ester hydrolysis with
acyl-oxygen (AC) cleavage and esterification]
Esterification and hydrolysis of sterically hindered substrates (esters and acids e.g., mesitoic
acid or its ester) is carried out by dissolving them in concentrated sulphuric acid and subsequent
reaction with water (for hydrolysis) or alcohol (for esterification). The mechanism operates via
the initial addition of a proton to the substrate and subsequent heterolytic fission in the rate
controlling step to give an acylium ion (Scheme 6.68) which then reacts further.
+
+
O
H2O O
CO2H C C
CH3 CH3 CH3 CH3 – H2O CH3 CH3
H2SO4
CH3 CH3 CH3
ROH
H
+
O O
CO2R R C
CH3 CH3 + CH3 CH3
–H
CH3 CH3
SCHEME 6.68
6.5 HYDROLYSIS OF AMIDES

1. Hydrolysis of an Amide in Aqueous Acid
• The acid protonates the carbonyl oxygen increasing the susceptibility of the carbonyl
carbon to nucleophilic attack by water (Scheme 6.69) to give a tetrahedral intermediate.
:
:OH
:
+
O OH
+
H
:
—CNHCH3 —C—NHCH3 —C—NHCH3
HOH
H2O:
:
+
:
Proton transfer from

oxygen to nitrogen
:O H
:
O
+ +
+ H –H +
CH3NH3 —C + CH3NH2 —C—NH2CH3
OH : OH
SCHEME 6.69
• Proton is transferred and an amine is expelled. This amine then reacts with H+ to
give an amine salt.
• The acid hydrolysis of amides follows the mechanism in analogy with ester hydrolysis.
Under acidic conditions, the formation of the tetrahedral intermediate is promoted
(attack by poor nucleophile water becomes feasible). The acid also changes the relative
leaving abilities of the two groups on the tetrahedral intermediate. CH3NH2 is lost
being a weaker base than OH–.
• The formation of the amine salt at the end (NH 4+ ) explains why H+ is a reactant and
not a catalyst and why the reverse reaction does not proceed—although R2NH is a
nucleophile, R2 NH 2+ is not and this ion cannot attack the carbonyl group.
2. Hydrolysis of an Amide in Aqueous Base

• In the hydroxide ion promoted hydrolysis of an amide; OH– rather than water is the
nucleophile. Since OH– is a better nucleophile than water it is better to form the
tetrahedral intermediate (Scheme 6.70).
: O: : O: : O:
:
: O: –
:
:
C R—C—NH2 C C + HNH2
O: –
:
: :
: :
R NH2 R OH R
: OH – :OH
: :
–
:
: NH2
:
SCHEME 6.70
• The two leaving groups on the tetrahedral intermediate are OH– and NH 2− (since
OH– is the weaker base it is more easily eliminated, however, occasionally and more
often NH 2− is ejected).
• When, NH 2− is ejected, the carboxylic acid thus formed immediately loses a proton.
This step is irreversible (the carboxylate ion cannot be attacked by nucleophiles) and
the reaction is driven towards products.
• Since hydroxide ion is consumed in the reaction, it is a reagent and not a catalyst.
PROBLEMS
6.1. On reacting acetaldehyde with a large excess of formaldehyde in the presence of a base,
pentaerythrtcol, C(CH2OH)4 is formed. Suggest a mechanism.
6.2. (a) How one can extend the aromatic ring in (1) to obtain (A)? (b) How a combination of
(II and III) can lead to (B).
R R O
CO2Et
O
Me2CHCHO H2C CHCOCH3
(II) (III)
(I) (A) (B)
6.3. Ethyl 2-methylpropanoate (I) fails to undergo, the Claisen reaction with sodium ethoxide
in ethanol and the possible product (II) is not isolated. Explain.
OEt OEt
O O O
(I) (II)
6.4. Claisen condensation of ethyl 2-methylpropanoate with ethanol and sodium ethoxide is
unsuccessful. The expected Claisen product (see Problem 6.3) is obtained by using a
much stronger base than ethoxide ion and the triphenylmethide ion (Ph3C–, added as
sodium triphenylmethyl).
6.5. Intermolecular condensation between oxalic and glutaric esters under base catalysis
gives five membered ring compounds. Give the mechanism.
6.6. How an α-halo ester reacts with an enamine? Give the mechanism.
6.7. Which major product would be formed by the reaction of enamine from 2-methyl-
cyclohexanone and pyrrolidine and benzyl chloride?
PhCH2Cl
2-methylcyclohexanone
6.8. Explain the way, one may link together, phenol (C6H5OH), formaldehyde (HCHO), and
a secondary amine (R2NH)?
6.9. What evidence goes against the following one step mechanism for the basic hydrolysis of
an ester (BAC2 mechanism)?
O O
– – O
– d d –
HO + R—C—OR¢ HO C OR¢ HO—C + R¢O
R R
Transition state
6.10. What is saponification?

6.11. The alkaline hydrolysis of an ester under B AC2 mechanism has been presented
(Scheme 6.61). The structure of the substrate particularly of the R group (Scheme 6.61)
reflects on the different relative rates of hydrolysis. How one explains these differences?
MeCO2Me ClCH2CO2Me CHCl2CO2Me 1

R R R
Relative rates 1 761 16000
MeCO2Et EtCO2Et isoPrCO2Et 2

Relative rates 1.00 0.47 0.10
Alkaline hydrolysis of esters, the BAC2 mechanism

6.12. Write the reaction sequence for the conversion of diethylmalonate into mono and
disubstituted acetic acids.

6.1. In the case only one of the two components i.e., acetaldehyde has α-hydrogens, thus only
two products could be formed. Moreover, it is only acetaldehyde that can form an enolate
and the carbonyl group in formaldehyde is more reactive toward nucleophilic substitution;
consequently β-hydroxypropionaldehyde predominates. However, this first condensation
product still contains two acidic α-hydrogens and condensation continues until all the
α-hydrogens in acetaldehyde have reacted. The final product (I) like formaldehyde has
no active hydrogen and thus undergoes crossed Cannizzaro reaction (see Schemes 14.79
and 14.80) to give the final product.
O O O CH2OH
–
OH CH2O
CH3—C—H + H—C—H CH2—C—H – CH— CHO
OH
CH2OH CH2OH
b-hydroxy-
–
propionaldehyde CH2O OH
CH2OH
C(CH2OH)4 HOCH2—C— CHO

Pentaerythritol CH2OH
6.2. (a) The stobbe condensation on (1) leads to an attachment of a three carbon chain to the
ketonic carbon atom. This undergoes ring closure via a Friedel-Crafts reaction. Its
reduction and dehydration (gain in aromatic stabilization energy) gives (A).
R R R
CO2Et CO2Et
O
HO2C
(I) O
Stobbe condensation Friedel-Crafts reaction
reduction
R R
CO2Et CO2Et
–H2O
(A) OH
(b) The first reaction is the Michael addition of the enolate anion to methyl vinyl ketone
followed by intramolecular aldol condensation.
O O
H 2C CHCOCH3
Michael –: CH3 H
+ CH3
:
–
Me2C—CHO CHO CHO
aldol
O O O
–
:
CH2
– CHO
O
6.3. This failure reflects on the important of the final enolate anion which directs the
equilibrium to the product. The ester (I) has only one α-hydrogen atom, and the expected
β-keto ester product (II) which would result, is without any hydrogen atoms located
between the carbonyl groups. Thus the final enolate cannot be formed under the reaction
conditions.
6.4. The added Ph3C– ion leads to complete removal of ethanol formed in the reaction EtOH
+ Ph3C– → EtO– + Ph3CH.
O –
CHCO2C2H5 –
CO— CHCO2C2H5
C2H5O—C –2EtO
CH2 CH2
6.5. C2H5O—C CHCO
– 2C2H5 CO CHCO2C2H5
O
6.6. This reaction is similar to enamine alkylations and affords γ-keto esters.
+ O O
:
N O N O
SN 2 H2O
+ Br—CH2COC2H5 CH2COC2H5 –
CH2COC2H5
–Br
Alpha-halo ester
g-keto ester
6.7. Of the two possible enamines (I and II), the enamine (I) will be formed as the major
product (for reasoning see Scheme 6.44 which will lead to III as the final major product.
CH3 CH3 CH3

CH3
H H CH2Ph
1. PhCH2Cl
N O 1. PhCH2Cl
2. H3O + N O
2. H3O +
H CH2Ph (II) 2-benzyl-2-methylcyclo-

(I) 2-benzyl-6-methylcyclohexanone
hexanone
(III)
6.8. This is Mannich reaction, the active hydrogen compound being phenol (the hydrogens
in the o and p positions are active) and the result is amino-alkylation in the ortho-
position which is preferred.
OH OH
H + CH2NR2
R2N CH2
Mannich base
H
6.9. The observed oxygen exchange (Scheme 6.62) is not in keeping with this one step process
(with a transition state as in SN2 reaction).
6.10. This is an irreversible base (e.g., OH–) induced ester hydrolysis, the resonance-stabilized
carboxylate anion shows little tendency to react with the alcohol.
6.11. In series 1, the increasing –I effect of group R accelerates the hydrolysis since a positive
charge on the attached carbon facilitates the attack by hydroxide ion. Moreover, with
the increase in the bulk of R one would expect (series 2), a steric retardation as well.
6.12. The nucleophilic ion after the removal of one of the α-methylene protons undergoes an
SN2 reaction with an alkyl halide to give a C–substituted malonic ester.
O O O O O O–
–EtOH
EtO OEt EtO – OEt EtO OEt
:
H
Mesomeric anion
–
OEt
1
EtO2C SN2
EtO2C EtO2C R
1 1 (1) NaOEt
– R —Br R 2
(2) R Br 2
EtO2C EtO2C EtO2C R
2
1 2 R
R R 2
–CO2 + R O
O OH OH –H
1
R +
H
O O OH R
1 OH
H
Decarboxylation
of a b-keto acid
One may introduce similarly a second different alkyl group, or alternately two identical
alkyl groups can be introduced in a one-step operation by employing appropriate amounts
of reactants. On alkaline hydrolysis and careful acidification an alkyl malonic ester
gives an alkyl malonic acid. The alkyl malonic acids (β-keto acids) undergo
decarboxylation to give the mono- or disubstituted acetic acids.
7
9 H
B
CHAPTER 5
6 4
1
Reagents in Organic Synthesis and

8 2
7 3
Relevant Name Reactions
7.1 ORGANOTRANSITION METAL REAGENTS

(A) Introduction
The organoiron compound ferrocene (see Scheme 2.41) was prepared in 1951. Its unusual
stability as well as bonding (holding iron to carbon) laid a strong foundation for the synthesis
of organic complexes of the transition metals. Structure of ferrocene was elucidated by Wilkinson
who received the Nobel Prize for this work (1973). Many of the transition metal complexes
display extraordinary power as catalysts and selectivity.
The transition metals are defined as those elements which have partly filled d or f-shells,
either in the elemental state or in their compounds. The transition metals react with a variety
of groups or molecules called ligands (L) to yield transition metal complexes. Each ligand is
bonded to the metal by overlap of an empty orbital on the metal with a filled orbital on the
ligand. The bonding is thus covalent, but with considerable polar character which depends on
the extent to which the positive and negative charges on the metal and ligand help to hold
them together.
(B) The Catalytic Effect of Complexes

The ligands present on the metal are not directly involved in the reaction which is catalysed by
a transition metal complex, however, their presence on the metal is indeed necessary. Their
electronic or steric effects, lipophilicity or chirality largely determines the course of a reaction.
Moreover, the ligands bring about the solubility of the complex in organic solvents. The catalytic
effect is exerted by the metal by bringing the substrate and the reagent (e.g., hydrogen and an
alkene during hydrogenation with Wilkinson’s catalyst, Scheme 14.16) close to each other via
bond formation. Transition metal complexes can adopt a variety of geometries depending on
the transition metal and the number of ligands present. Thus rhodium can form complexes
with four ligands and is then square planar. When it forms a complex with five ligands, the
geometry attained is trigonal bipyramidal while the complex holding six ligands is octahedral.
(C) Oxidation Number or Oxidation State (of Central Metal in Coordination Compounds)
This is the charge left on the central metal atom after all the ligands have been removed
(theoretically) in their closed shell electronic configuration.
263
(D) The 18-Electron Rule

The transition metals have a partially filled d-orbital shell with a tendency to surround
themselves with 18 electrons which is an electronic configuration corresponding to an “inert”
rare gas (e.g., 3d10, 4s2, 4p6 for Kr). When the metal of a transition metal complex has 18
valence electrons, it is called coordinatively saturated.
An exception is titanium which is low in available electrons and would be overcrowded
if sufficient ligands were present to give a total of 18. The number of outer shell electrons in
some of the metals are:
Outer shell electrons: 4 6 8 9 10
Metals: Ti Cr Fe Rh Ni
Co Pd
Thus chromium can bond to ligands which provide a total of 12 electrons.
(E) Total Valence Electron Count of the Metal in a Complex

The subtraction of the oxidation state of the metal in a complex from the total number of a
valence electrons of the metal in the elemental state gives the d electron count (dn). The total
electron count of the metal in the complex is obtained by adding the number of electrons
donated by all the ligands to dn. The iron of ferrocene (see Scheme 2.41) has 18 valence electrons
and is therefore, coordinately saturated. One calculates this number as follows:
• Iron has 8 valence electrons in elemental state
• Its oxidation state in ferrocene is +2
• Thus dn = 6
• Each cyclopentadienyl ligand of ferrocene donates 6 electrons to the iron
• Thus for iron the valence electron count is 6 + 2 × 6 = 18
In the rhodium complex Rh[(C 6 H 5) 3 P]3 H 2 Cl (an intermediate in some alkene
hydrogenations Scheme 14.16), the rhodium is coordinatively saturated since the total number
of valence electrons is 18. The oxidation state of rhodium in the complex is +3. The two hydrogen
atoms and the chlorine are each counted as – 1 and the charge on each of the triphenylphosphine
ligands is zero. The removal of all the ligands would leave a Rh3+ ion. The dn for the rhodium
of the complex is 9 – 3 = 6. Each of the six ligands of the complex donates two electrons to the
rhodium in the complex to give the total 18.
(F) The Commonly Encountered Reaction Mechanisms

(i) Ligand Dissociation—Association (Ligand) Exchange
A complex which fulfils the 18 electron rule must necessarily dissociate (by the loss of a ligand
with a pair of electrons to give a complex in which the metal has only 16 electrons and it
becomes coordinatively unsaturated) before it can associated (coordinate) to become
coordinatively saturated again.
In this process there is no change in the oxidation state of the metal, but only its electron count
changes. A ligand substitution can take place by the dissociation of one ligand and the association
of another (Scheme 7.1).
Reagents in Organic Synthesis and Relevant Name Reactions 265
Ph3P I +–
Ph3P CH3
–Li I
Pd(PPh3)4 Pd(PPh3)3 + :PPh3 Pd + H3C—Li Pd
Pd(0) Pd(0) Ph3P Ph Ph3P Ph
(18 electrons) (16 electrons)
Pd(II) Pd(II)
Ligand Dissociation-Association; Ligand Substitution
SCHEME 7.1
(ii) Insertion Reaction

It is the cleavage of a metal-ligand σ bond M—L, in complex A—M—L and the apparent insertion
of a coordinated ligand A between M and L to give M—A—L. Thus the electron count of the
metal decrease by two. These reactions are reversible, and the reverse reaction is called
deinsertion (Scheme 7.1a).
Ar CH2 1, 2-ligand Ar CH2

insertion Curved arrow notation
Br—Pd Br—Pd—CH2CH2Ar Br—Pd nearly approximates
ligand insertion
PPh3 CH2 PPh3 PPh3 CH2
Pd(II) Pd(II)
Ligand insertion
SCHEME 7.1a
(iii) Oxidative Addition—Reductive Elimination

This is the cleavage of a reactant molecule accompanied by addition of one or both its parts to
the central metal atom of the complex. As a result of this, σ bonds are formed between the
metal and the entering ligand(s). This requires formal electron donation from the metal, this
process result in an increase in both the coordination number of the metal as well as in its
oxidation number. Reductive elimination is the reverse of oxidative addition.
An example of oxidative addition is provided by the insertion of Pd into the carbon-
halogen bond of iodobenzene (Scheme 7.1b). Electrons flow from the aryl halide to the metal
Ph3P Ph3P C6H5 L Ar L Ar

Pd + C6H5—I Pd M: X M
Ph3P Ph3P I L L X
Pd(0); Pd(II); Electron pair

(14 electrons complex) (16 electrons complex) in d orbital
Oxidation addition
SCHEME 7.1b
and at the same time from the metal to the aryl halide. Reductive elimination can be exemplified
by the formation of carbon-carbon double bond between two ligands within a nickel complex
(Scheme 7.1c).
H R
Ph3P C C Ph3P H R
Ni H Ni + C C
Ph3P CH3 Ph3P H3C H
Ni(II) Ni(0)
Reductive elimination
SCHEME 7.1c
7.2 SOME TRANSITION METAL ORGANOMETALLIC REACTIONS
(A) Rhodium ComplexesWilkinsons Catalyst (Ph3P)3 RhCl

(i) Decarbonylation of Aldehydes
Wilkinson’s catayst exists in a coordinatively unsaturated 16 electron state. The first step is
therefore, oxidative addition which changes the electron count of the metal by +2. This reaction
is of value when a carbonyl group is needed for activation in a step in a synthetic sequence and
has to be removed subsequently. Decarbonylation with Wilkinson’s catalyst goes through
complexes of the type (I and II, Scheme 7.1d), is an intramolecular reaction and gives a retention
of configuration at a chiral R.
H H
L L L L L
oxidative Dissociation
Rh + RCHO Rh Rh—COR
addition –L
L Cl L COR L
Cl Cl
Wilkinson’s catalyst
(Ph3P)3RhCl, L = Ph3P (18 electrons) (I)
(16 electrons)
tris (triphenylphosphine)-
chlororhodium
Deinsertion
H
L Cl L R
Reductive
Rh + RH Rh
elimination
L CO L CO
Cl
(16 electrons) (II)
(18 electrons)
Decarbonylation of an aldehyde with Wilkinson’s catalyst
SCHEME 7.1d
(ii) Formation of Carbon-Carbon Bonds

Rhodium complexes have also been used in the formation of carbon-carbon bonds (Scheme 7.1e).
CH3
–LiCl PhI
(Ph3P)3RhCl + CH3Li (Ph3P)3RhCH3 (Ph3P)3Rh(CH3)I Ph + (Ph3P)3RhI
Ligand Oxidative Reductive
exchange addition elimination
Ph
SCHEME 7.1e
In the example, the first step involves a ligand exchange by a combination of ligand association-
dissociation step and a methyl group is inserted into the coordination sphere of rhodium. An
oxidative addition then incorporates the phenyl group into the rhodium coordination sphere
and subsequent reductive elimination then joins the methyl group and the benzene ring to
yield toluene in the last step.
(iii) Hydrogenation of Alkenes using Wilkinson’s Catalyst
For details see Scheme 14.16.
(B) Organo Palladium Compounds

(i) The Heck Reaction—Arylation and Alkylation of Olefins
It is a useful reaction for making carbon-carbon bonds. Aryl and alkenyl halides react with
alkenes in the presence of catalytic amount of Pd when the halide is substituted by the alkenyl
group. In this coupling reaction the R group in RPdX (X = halide or acetate) replaces hydrogen
at the less hindered carbon atom of the alkene. R can be aryl or alkenyl and alkyl groups
without a β-hydrogen (e.g., CH3, PhCH2, Me3C—CH2, Scheme 7.1f ). Ethylene is an effective
olefin, with increased substitution the reactivity is lowered thus substitution takes place at
the less substituted side of the double bond.
The species RPdX (e.g., ArPdI) can be made in situ by the treatment of an aryl iodide
with palladium acetate in the presence of a base such an tributylamine or potassium acetate
(ArI “ArPdI”). A reactant can be a simple olefin or it may carry a variety of functional
CH3 CH3
R2C CH2 + ‘‘R¢PdX’’ R 2C CH—R¢ + CH2 CH2
Br CH CH2
Heck reaction
SCHEME 7.1f
groups e.g., ester, carboxyl, phenolic or cyano. Primary and secondary allylic alcohols afford
aldehydes and ketones with double bond migration (Scheme 7.1g).
‘‘PhPdCl’’
CH2 CH—CH2OH PhCH2CH2CHO
SCHEME 7.1g
The Heck reaction is stereospecific and occurs by syn-addition of RPdX (Scheme 7.1h) to
form a π-complex with the alkene and this rearranges to a σ complex by forming a carbon-carbon
bond. The σ complex decomposes by syn-elimination (β-elimination). The sequence of reactions
involves an inversion of configuration of the carbon where substitution takes place (Scheme 7.1i).
PdX
R
RPdX H 2
1 1 R
RPdX + R 2 R
R 2
R 1 H
R
Syn-addition
Rotation
PdX
2 H
H R H 2
–HPdX R
R 1
R 1
R R
Syn-elimination
Mechanism of Heck reaction
SCHEME 7.1h
Thus when an acyclic alkene is employed in the Heck reaction, since internal rotation is possible,
the hydrogen atom on the carbon at which insertion occurs gets eliminated.
C6H5 CH3 C 6H 5 R
RPdX +
CH3
SCHEME 7.1i
EXERCISE 7.1
Explain the mechanism of the Heck reaction (Scheme 7.1j).
Ph
Pd(OAc)2
PhI +
SCHEME 7.1j
ANSWER. In this reaction the alkene double bond in the product is not at the site
of coupling, but is one carbon removed i.e., an allylic shift has occured. The insertion
reaction must be syn since Heck reaction is intramolecular. The insertion complex
(Scheme 7.1k) has the Pd and the phenyl groups as cis-substituents (axial-equatorial
relationship). As the subsequent β-elimination is a syn process, the hydrogen on

the carbon at which the insertion had occured has trans relationship with Pd.
Since internal rotation is prevented by the ring the cis relationship of Pd is available
with a hydrogen on the other β-carbon.
Available for
syn-elimination H
Ph Ph
H
+ L—Pd—Ph
L—Pd
I H
I
Syn-insertion of Syn-elimination
Pd and Ph of Pd and H
SCHEME 7.1k
(ii) Suzuki Reaction
Suzuki reaction is discussed in Scheme 8.26.
(iii) Oxidation of Alkenes to Aldehydes and Ketones—The Wacker Reaction

An alkene e.g., ethylene forms a Pd-alkene complex and is followed by addition of water to this
Pd(II) activated alkene. Subsequently elimination of Pd(0) and a proton affords the enol of
acetaldehyde (Scheme 7.2). Further details are in (Scheme 13.45). The coreagents in this reaction
are CuCl2 and O2 which reoxidize the Pd(0) to Pd(II).
CH2 CH2 CH2—OH HO

II H2O 0 +
+ Pd(II) Pd II
C CH2 + Pd + H CH3CHO
CH2 CH2 CH2 Pd
H
The Wacker reaction
SCHEME 7.2
(C) Octacarbonyldicobalt Complexes

(i) Hydroformylation (Oxo-reaction)
In this reaction an alkene reacts with carbon monoxide and hydrogen in the presence of a
cobalt catalyst HCo(CO)4 at high temperature and pressure to give an aldehyde (Scheme 7.3).
HCo(CO)4
C C + CO + H2 —C—C—
2000 psi, 110–150°C
H CHO
An aldehyde
Hydroformylation
SCHEME 7.3
Metallic cobalt reacts with carbon monoxide to give octacarbonyldicobalt (Scheme 7.3a), which
reacts with hydrogen to give hydridotetracarbonylcobalt which is the active catalyst. The
following are some of the steps of oxo reaction.
1. The alkene replaces one molecule of carbon monoxide from HCo(CO)4 to give the
π complex (I, Scheme 7.3a).
H2
2 Co + 8 CO Co2(CO)8 HCo(CO)4 HCo(CO)3 + CO
Octacarbonyldicobalt Hydridotetracarbonylcobalt Dissociation
(OC)3CoH
HCo(CO)3 + CH2 CH2 CH2 CH2 (OC)3Co CH3
an alkene (I) (II) CH2
(a p complex)
CO
reductive
H elimination (OC)3Co (OC)3Co CH3
H2
CO CH2
O O
An aldehyde (III)
+
HCo(CO)3 Mechanism of hydroformylation
SCHEME 7.3a
2. In the insertion step, the hydrogen migrates from cobalt to one of the doubly bonded
carbons, and the other carbon attaches to cobalt as in (II).
3. The metal alkyl formed above associates with an additional molecule of carbon
monoxide to give (III). This is an important insertion step where a carbonyl group is
inserted between the metal and the coordinated alkyl group. One can also consider
this step as migration of the alkyl group from the metal to the carbon of a coordinated
CO ligand and this is the key step where a carbon-carbon bond is formed.
4. Hydrogen is absorbed. One of the hydrogens migrates to the C O group to give an
aldehyde which leaves the coordinated sphere of the regenerated catalyst.
(ii) Synthesis of Cyclopentenones—Pauson-Khand Reaction
Alkynes react with octacarbonyldicobalt to give complexes where all four π-electrons are involved
in bonding (I, Scheme 7.4). The complexes react with alkenes and carbon monoxide to give
cyclopentenones. Reaction with the alkenes of the type RCH CH2 becomes highly
regioselective (II).
In the Heck reaction, nucleophilic addition occurs to an unactivated olefin in the presence
of catalytic Pd. In the Pauson-Khand reaction a five membered ring can be constructed from
three components, an alkene, an alkyne and carbon monoxide in the presence of cobalt.
CH3
–2 CO Co(CO)3
CH3—C C—CH3 + Co2(CO)8
H 3C
Co(CO)3
(I)
Co2(CO)8 H3C R¢
H3C CH3 + CH2 CH—R¢
CO
H3C
Pauson-Khand reaction (II)
SCHEME 7.4
(D) Compound Derived from Titanium

(i) Coordination Polymerization—Ziegler-Natta Catalysts
The catalytic system discovered by Ziegler and developed by Natta (both Noble Laureates,
1963) consists of a bimetallic coordination complex. These catalysts are made up of a transition
metal salt particularly titanium tetrachloride and a metal alkyl e.g., triethylaluminium
(Et3Al : TiCl4).
The polymerization involves the insertion of the alkene e.g., propylene into the C–Ti
bond (I, Scheme 7.5). The process gives polypropylene where each carbon has the same
configuration with all of the methyl groups on the same side of the polymer backbone. This
CH2CH3
CH3CH2 CHCH3 CH3CH2
Cl Cl CHCH CHCH3
CH2 3
Cl Ti Cl Ti
CH2 CH2
Cl Cl
Cl Cl Cl
(I) (II) Cl Ti
Cl
Cl
(III)
CHCH3
CH2
H 3C H H 3C H CH3 CH3
CH3OH H H
H C C
CH3OTiCl3 + Ti
CH2 CH2 CH2CH3 CH2CH3
n Destruction of the
(Isotactic polypropylene) organometallic bond
by a weak acid
Ziegler-Natta polymerization-isotactatic polypropylene
SCHEME 7.5
regular and constant stereochemistry is called isotactic. This H3C H H3C H

polymer has high density and greater strength compared to H CH3 H CH3
the one made from the radical polymerisation (atactic) which
has a random orientation of substituents. One can modify the
catalyst and make syndiotactic polypropylene with alternate Syndiotactic stereochemistry
of polypropylene
carbons having opposite configuration (Scheme 7.6).
Mechanistically one views the transfer of an ethyl group SCHEME 7.6
from aluminium to form a sigma bond with titanium species
(I, Scheme 7.5). Propylene forms a “pi-complex” (II) with the titanium by interaction of its pi
MOs with a vacant coordination site on the metal. The ethyl group migrates to one carbon of
the double bond of the coordinated propylene while the other carbon forms a sigma bond to the
titanium (III). This creates a vacant coordination site on the metal for the process to occur
again, which results in the formation of isotactic polypropylene—a stereoregular polymer which
is linear without any short or long branches.
(ii) σ-Organotitanium compounds—Comparison with Grignards reagents
These compound of the type (I, Scheme 7.6a) are prepared from titanium tetraalkoxides. In
these reagents the carbon atom bonded to titanium is strongly negatively polarized just like in
a Grignard reagent and thus it acts as a nucleophile. The reagents (I, Scheme 7.6a) are far
TiCl4 RMgX
3 Ti(OR¢)4 4 ClTi(OR¢)3 R—Ti(OR¢)3
or RLi
(I)
SCHEME 7.6a
more selective when compared with Grignards reagents, and react with the carbonyl group of
aldehydes and ketone and do not react with the ester group if present in the same molecule
(Scheme 7.6b). Moreover, the reagent discriminates between an aldehyde and ketone and only the
former is reduced when both are present in the same molecule. Moreover, these σ-organotitanium
O
H3C
1. MeTi(OPr)3
CH3—C—CH2—CH2—COOC2H5 CH2—CH2—COOC2H5
+
2. H H3C OH
SCHEME 7.6b
compounds increase the diastereoselectivity observed with Cram’s rule during nucleophilic
addition with Grignards reagents to aldehydes with diastereotopic faces (Attack at the carbonyl
group of an aldehyde with a neighbouring stereocenter, for details see Scheme 14.81).
(iii) Alkene Metathesis
On heating with different catalysts e.g., tungsten, molybdenum, rhenium or titanium complexes,
alkenes undergo disproportionation reactions. Thus under the influence of a suitable catalyst
e.g., Tebbe reagent, propylene give mainly trans-2-butene and ethylene (Scheme 7.6c).
H
2 CH3—CH CH2 CH3—C C—CH3 + CH2 CH2

Propylene
H
Trans-2-butene Ethylene
Alkene metathesis
SCHEME 7.6c
The Tebbe reagent contains titanium and is prepared from Cp2TiCl2

(Cp Cyclopentadienyl) as shown (Scheme 7.6d). The reactive intermediate being a
metallocarbene complex containing a carbon metal double bond (Cp2Ti CH2).
–
Cp2Ti Al(CH3)2
+
—HCl Cl
Cp2TiCl2 + Al(CH3)3 Cp2Ti Al(CH3)2
Cl The charges in such bridging
halogens and complexes are
not indicated as a convention
SCHEME 7.6d
Alkenes can form metallocycles as two metallocyclobutanes with Tebbe reagent in a

reversible process (Scheme 7.6e). One may also use two different alkenes and e.g., ethylene
reacts with dimeric isobutylene to give neohexene which is a commercial process (Scheme 7.6f ).
H3C
M
M CH2 + CH3—CH CH2 CH3—CH M + CH2 CH2
(M = Cp2Ti) Metallocycle New metallocarbene

(Metallocarbene) (I)
CH3—CH CH2
H 3C H H3C
C M
M CH2 +
C
H CH3 H3C
(II)
Alkene metathesis
SCHEME 7.6e
H3C CH3 Cp2Ti Al(CH3)2 H3C CH3

H 3C Cl H3C CH3
CH3
+ H 2C CH2 CH2 + H2C
H 3C H3C
Neohexene
Dimeric isobutylene Ethylene
SCHEME 7.6f
The mechanism of the reaction involves the intervention of a metallocarbene and a four
membered ring containing a metal (Scheme 7.6e). The metallocyclobutane is thought to undergo
a cleavage across the ring by (A or B, Scheme 7.6g). Cleavage in (I, Scheme 7.6g) across the
ring by (A) gives back the reactants and is thus, unproductive. The cleavage (B) in (I, Scheme
7.6g) gives the original alkene and a new metallocarbene. The new metallocarbene can add the
starting alkene (propylene) to give a new metallocyclobutane(s) which can cleave to give a new
alkene.
A
CH3 H 3C
M M
CH2 CH2 + CH3CH M B CH3CH CH2 + CH2 M
Productive (I) Unproductive
(I)
SCHEME 7.6g
Olefin metathesis represents a new exciting process which has been developed during
the last 15 years for the creation of carbon-carbon double bonds. The process has a base in
Ziegler-Natta catalysts for the polymerization of cyclic olefins. Olefin metathesis involves the
breaking apart of alkenes at the double bond and the pieces get reassembled randomly. The
name metathesis reflects the interchanging of the ends of carbon-carbon double bonds.
EXERCISE 7.2
A catalyst prepared from tungsten hexachloride and ethylaluminium dichloride
is shown to be a metallocarbene complex, (WCl6 + C2H5AlCl2 Cln W = CHCH3 )
On treatment with this catalyst, 2-pentene gives a mixture with 2-butene as one of
the components. Propose a mechanism for this olefin metathesis.
ANSWER. Olefin metathesis is a unique reaction which is successful only with
catalysts prepared from transition metals. The metallocarbene can yield two
metallocyclobutanes. Considering diffferent cleavages across the rings, one can
see that one cleavage B′ in (II, Scheme 7.6h) is productive to yield the desired
product.
WCl6 + EtAlCl2 ClnW CHCH3

Metallocarbene
Cln CH3 Cln CH3

H 3C W W
Cln–W CHCH3 + +
C2H5
H3C C2H5 C2H5 CH3
(I) (II)
B
Cln CH3
W A or B H3C
A Cln—W CHCH3 +
Nonproductive C2H5
H3C C 2H 5
(I)
A¢ Nonproductive
B¢
Cln CH3
W B¢ H3C
A¢ Cln—W CHCH2CH3 +
Productive CH3
C 2H 5 CH3
(II)
SCHEME 7.6h
(E) Role of Iron Compounds and Acyl-Iron Complexes

(i) Stabilization of Cyclobutadiene
Cyclobutadiene is an antiaromatic compound and thus highly reactive. It can, however be
obtained as a complex with Fe(CO)3 when the electron density is withdrawn from the ring by
Antiaromaticity and spectral behaviour of cyclobutadiene has been

discussed in detail in sec. 2.3. Recall that cyclobutadiene is not a square
arrangement, but it gets distorted to attain a rectangle form with short
carbon-carbon double bonds and longer carbon-carbon single bonds. The
distortion leads to minimize the connection i.e., conjugation between the
p orbitals (Scheme 7.6i).
¬¾®
Square delocalized cyclobutadiene Rectangular cyclobutadiene
SCHEME 7.6i
the metal. This cyclobutadiene complex may be viewed as an aromatic duct and it thus undergoes
electrophilic aromatic substitution (Scheme 7.7). This complex of cyclobutadiene from which
cyclobutadiene is released via oxidation with cerium IV undergoes a Diels-Alder reaction
(Scheme 7.7a) followed by photochemical [2 + 2] cycloaddition and base induced ring contraction
(see under answer 10.8) to give cubane.
COR
RCOCl/AlCl3
Fe(CO)3 Fe(CO)3
—HCl
(Stable) (Electrophilic substitution)

SCHEME 7.7
O
O O
Br O
Ce(IV) Br hn Br
+ Fe(CO)3 Br
Br
Br
O
O
KOH
–
OOC
1. SOCl2 –
2. t-BuOOH COO
3. D
2CO2 +
Cubane
SCHEME 7.7a
(ii) Acyl-iron complexes—Direct Conversion of Alkyl Halides to Aldehydes and Ketones

with Collman’s Reagent
The Collman’s regant Na2Fe(CO)4 is made from reacting iron pentacarbonyl Fe(CO)5 with
sodium amalgam in THF. The reagent reacts with an alkyl halide to give the ion R–Fe(CO4)–
(Scheme 7.7b). The reaction of Collman’s reagent with CO in the presence of an alkyl halide
yields an acylated iron complex which reacts with a second alkyl halide to give a ketone.
–NaX – +
Na2Fe(CO)4 + RX R—Fe(CO)4 Na
– R¢X
Na2Fe(CO)4 + RX + CO R—C—Fe(CO)4 RCOR¢
O
Acylated iron complex
SCHEME 7.7b
Interestingly acyl-iron anions can be converted into aldehydes by protonolysis and into
ketones by alkylation. This technique, therefore, provides an alternative to the “reversed
polarity” procedure (umpolung, see, Sec. 7.4d) for the conversion RX RCHO and RCOR′
(Scheme 7.7c).
–
R R¢ R Fe(CO)4 + R H
R¢X H
O O O
SCHEME 7.7c
The ion RFe (CO)4– reacts with Ph3P in the presence of CO (insertion and ligand exchange)
to give a complex which reacts with alkenes and subsequent isomerization and hydrolysis
yields ketones (Scheme 7.7d).
– –
R Fe(CO)3PPh3 R Fe(CO)3PPh3
– CO-Ph3P CH2 CH2
R—Fe(CO)4
O O
CH3 CH3
R + R
H –
Fe(CO)3PPh3
O O
SCHEME 7.7d
(iii) C-Alkylation via Chiral Acyl-iron complexes (an Enantioselective Synthesis of

an Acid)
The cyclopentadienyl triphenylphosphine iron complex with attached acyl units (I, Scheme
7.7e) is used. The following points may be noted.
• Butyl lithium transforms the acyl carbonyl group into the lithium enolate (II) with E
geometry (methyl group on the same side as the enolate oxygen, atomic members of
oxygen and iron are 8 and 28 respectively).
• One of the phenyl groups of PPh3 unit effectively blocks the approach of the electrophile
from CH3I from the Re face at C2 of (II). The alkylation thus occurs from the Si face
(closest to the observer.).
• On one electron oxidation with bromine in water gives an alkylated acid in an
enantiomerically pure form (Scheme 7.7e).
O O O
C C Ph2 C PPh3
PPh3 P CH3
Fe Fe Fe H CH3
BuLi R CH3I R Br2
–
O O Li+ O H2O H2OC R
(I) (II)
SCHEME 7.7e
(F) Chromium Arene Complexes

An arene on heating with chromium hexacarbonyl gives these complexes. The Cr(CO)3 fragment
is highly electron-withdrawing and activates an aromatic system towards nucleophiles. In
these complexes the metal is bound to all six atoms of the aromatic ring and the complexation
removes electron density from the π-cloud. The electron-withdrawing effect of chromium is
comparable to that of a nitro group. The aromatic C—H bond of a Cr complex is acidic due to
electron withdrawing effect of Cr(CO)3 and thus treatment with MeLi or BuLi leads to
deprotonation and the lithiated species then react with electrophiles (Scheme 7.7f). The product
can be released from the complex by mild oxidation usually with cerium IV or also with I2.
CO2
COOH
Cr(CO)3
BuLi I2
H Li I
Cr(CO)3 Cr(CO)3 Cr(CO)3
OH
O
Cr(CO)3
SCHEME 7.7f
Complexed aryl halides undergo displacement by nucleophiles e.g., alkoxide, amines

and stabilized anions (Scheme 7.7g) to give substituted benzenes.
OR
X
– –
RO –X
X – OR
Cr(CO)3 Cr(CO)3 Cr(CO)3
SCHEME 7.7g
Further details of nucleophilic substitution in arenechromium carbonyl

complexes are in sec 9.6.
(G) Use of Nickel and its Complexes

Reductive Coupling of Allyl Halides
Allylic halides can be symmetrically coupled on reaction with nickel carbonyl at room
temperature in a solvent such as DMF, to give 1, 5-dienes (Scheme 7.8).
R R
R—C C—CH2Br R R R R
DMF
+ R—C C—CH2CH2—C C—R + NiBr2 + 4CO
Ni(CO)4
R R De-halogen coupling
R—C C—CH2Br
SCHEME 7.8
The order of halide reactivity is I > Br > Cl. With unsymmetrical allylic halides, coupling
nearly always occurs at the less substituted carbon of the allylic group. A plausible mechanism
may involve reversible dissociation of Ni(CO)4, oxidative addition of the allyl compound to give
a π-allyl complex of the type (I, Scheme 7.8a). The dimerization of this complex via loss of CO
and halogen bridging gives a π-allylnickel bromide (II, Scheme 7.8a), which further reacts to
give the coupled product. As the dimeric nickel complex (II, Scheme 7.8a) brings the coupling
termini into proximity, the method is used intramolecularly for macrocylizations to build
11–20 membered rings in high yield.
Br
Br Ni Ni
2Ni(CO)4
2CH2 CHCH2Br Ni Br
–CO
CO (II)
(I) p-allylnickel bromide
p-allyl complex
[(CH2 CH CH2)NiBr]2 + CH2 CH—Br CH2 CHCH2CH CH2

p-allylnickel bromide
CH CH—CH2Br
Ni(CO)4
(CH2)12
DMF
CH CH—CH2Br
80%
Macrocyclization
SCHEME 7.8a
When the reaction is carried out in a hydrocarbon solvent e.g., benzene, the π-allylnickel
bromide complex is formed which does not couple. Thus unsymmetrical (crossed) coupling can
be achieved by treating an alkyl halide directly with (II, Scheme 7.8a) and even in this case
unsymmetrical allylic groups couple at the less substituted end (Scheme 7.8b). The terpenoid
From Scheme 7.8a R R
R¢X + (II) R¢—CH2—C C—R
SCHEME 7.8b
geranyl acetate can be made this way (Scheme 7.8c). This reaction is of significance, since 1,
5-diene moiety is present in many natural products, consequently the method can be used in
their synthesis.
Br Br
2 Ni(CO)4 OAc
Ni Ni OAc
Br
Br Geranyl acetate
A p-allylnickel bromide
SCHEME 7.8c
(H) OrganocuparatesGilman Reagents
Transition metal organometallic compounds e.g., organocuparates are

derived from a Grignard or organolithium reagent in which the metal ion
(Cu) is a transition metal. They are discussed in sec. 7.7D.
7.3 PHOSPHORUS CONTAINING REAGENTS

(A) Use of Phosphorus YlidesWittig Reaction and its Variants
The Wittig reaction (George Wittig, Nobel Prize 1979) is used primarily for the conversion
of a carbonyl compound to an alkene (Scheme 7.9) using a special class of carbanion reagents
Wittig
C O C C
reaction
Ketone Alkene
– +
SN2 + Bu Li + –
:
Ph3P : + CH3—I Ph3—CH3 Ph3P—CH2
– A phosphonium ylide
I
(or phosphorane)
Triphenylphosphonium
salt
Wittig reaction-generating a phosphonium ylide
SCHEME 7.9
called ylides. A phosphorus ylide is prepared involving two steps, firstly an SN2 reaction between
triphenylphosphine and an appropriate alkyl halide gives a triphenylphosphonium salt. The
proton on the carbon adjacent to the positively charged phosphorus which is sufficiently acidic
(pKa = 35) is then removed by a strong base like butyllithium (Scheme 7.9).
The ylide (nucleophilic carbanion) reacts with the electron-deficient centers like a carbonyl
group to generate a cyclic 1, 2-oxaphosphetane. The cyclic intermediate is thought to get
generated via a [2 + 2] cycloaddition reaction involving four electrons in the transition state.
Decomposition of the cyclic 1, 2-oxaphosphetane eliminates phosphine oxide and brings about
a regiospecific formation of an alkene (Scheme 7.10).
O + O PPh3
R
PPh3
C + R—C CH2 C CH2 + O PPh3
R R : CH2
– R
R
A [2 + 2] cycloaddition
reaction 1, 2-oxaphosphetane
Mechanism of Wittig reaction involving a [2 + 2] cycloaddition
SCHEME 7.10
MECHANISM OF WITTIG REACTION

The negatively polarized carbon in the ylide is nucleophilic and can attack the
carbonyl group (Scheme 7.10a). The result is a phosphorus betaine, a dipolar
species. The betaine is short lived and may not be on the reaction pathway and
rapidly forms a neutral oxaphosphacyclobutane (oxaphosphetane), characterized
by a four-membered ring containing phosphorus and oxygen. This substance then
decomposes to the product alkene. The consideration of a betaine structure is often
invoked to explain the stereochemical outcome of Wittig reaction.
R¢
R¢ R¢
– + RCH—C
:
: :
RCH—P(C6H5)3 + C O RCH—C—R²
R²
Ylide +
(C6H5)3P O:
R² : O:–
:
(C6H5)3P
:
An oxaphosphacyclobutane
(Phosphorus betaine) (Oxaphosphetane)
–(C6H5)3P O
R¢
RCH C
R²
SCHEME 7.10a
(B) Stabilized Phosphoranes for use in Wittig Reactions

Simple phosphoranes (Scheme 7.9) are not only unstable but highly reactive. Thus reactions
involving non-stabilized ylides have to be conducted under anhydrous conditions and in an
inert atmosphere, since these ylides react both with water and oxygen.
The stabilized ylides have a group e.g., a carbonyl group which can share the carbanions
negative charge (II, Scheme 7.11). In such cases the phosphorane can be obtained by treatment
of the phosphonium salt with less strong bases e.g., sodium alkoxides, sodium hydroxide or
even sodium carbonate may be used. Though, such phosphoranes are usually isolable crystalline
compounds, but these have lower carbanionic activity. These react with aldehydes readily but
ketones are frequently not attacked.
–
O O
R
+ – + – +
(C6H5)3P—CH CH2CH3 (C6H5)3P—CH—CCH3 (C6H5)3P—CH CCH3
An unstabilized ylide A stabilized ylide

(I) (II)
SCHEME 7.11
The Wadsworth-Emmons variant of the reaction uses carbonyl activated ylides in which
triphenylphosphine is replaced by triethylphosphite P(OEt)3. Reaction with a bromoester is a
typical SN2 reaction and the product further undergoes another SN2 reaction to create a P O
bond and gives a phosphonate. This process called the Arbuzov reaction provides an important
route to Wadsworth-Emmons reagents (Scheme 7.12).
–
H3C—H2C H3C—H2C Br
O Br O
+
(EtO)2P: + CH2—CO2R (EtO)2P—CH2—CO2R
Triethyl
phosphite O
– –CH3CH2Br
H3C—H2C Br (EtO)2P—CH2—CO2R
+ (A phosphonate)
O
(EtO)2P—CH2—CO2R
Formation of Wadsworth-Emmons reagents via Arbuzov reaction
SCHEME 7.12
The phosphonate obtained from the Arbuzov reaction is deprotonated in a separate step
to give the corresponding carbanion. Much weaker bases compared to those employed in a
Wittig reaction suffice since two electron withdrawing groups are attached to the methylene
group. The resulting carbanion adds readily to the carbonyl groups of aldehydes and ketones
and the steps of mechanism are similar to Wittig reaction (Scheme 7.13). The reactions where
triphenylphosphine is replaced by triethylphosphite are termed Wadsworth–Emmons reactions.
C O
O—P(OEt)2
CH2COOEt base CHCO2Et
—C—CH C CHCO2Et
O P(OEt)2 O P(OEt)2
CO2Et
(A phosphonate) Stabilized +
carbanion
O
Wadsworth-Emmons modification of Wittig reaction O—P(OEt)2
SCHEME 7.13
WITTIG REACTION AND ITS WADSWORTH-EMMONS VARIANT

Simple phosphoranes (phosphorus ylides) as used originally in a Wittig reaction
are highly reactive and unstable (I, Scheme 7.14). More stable phosphoranes (II)
are obtained when an electron withdrawing substituent is adjacent to the anionic
carbon. However, these react with aldehydes but not with ketones. A futher
modification is the Wadsworth-Emmons reagents in which triphenylphosphine is
replaced by triethylphosphite to give reagents of the type (III) which easily add to
ketones as well. These activated ylides are made via Arbuzov reaction, which is
–
O :CHCOOEt O
+ – – + –
:
:
:
Ph3P—CH2 R—C—CH—PPh3 O P(OEt)2 (EtO)2P—CH—CN
(I) or (III) (IV)
+ –
:
Ph3P—C—C N
H
(II)
SCHEME 7.14
general method for making a variety of these activated ylides, other best substrates
are benzylic and allylic halides and compounds with a halogen atom α- to the
carbonyl, nitrile or sulphonyl groups (IV, Scheme 7.14).
EXERCISE 7.3
How can one prepare each of the compounds (Scheme 7.14a)?
R R
CN
C CHPh
R O
R
(I) (II) (III)
SCHEME 7.14a
ANSWER. From retrosynthesis the disconnection for a Wittig reaction to make an
alkene is the double bond between carbon atoms. Generally the ylide component is
the end of the alkene double bond with the less highly substituted carbon atom.
The phosphonate ylides for the synthesis of (I and II) are made by using Arbuzov
reaction.
O
R R (EtO)2 P – CN
(a) Retrosynthesis: CN
:
C O + C
R
R H
O
1. P(OEt)3 (EtO)2 P – CN (I)

(I) Synthesis
:
Br CN C R
2. base
C O
H R
O
O
(b) Retrosynthesis + (C2H5O)2P COCH3
–
:
O C
H
O
1. P(OEt)3 (EtO)2P – COCH3 (II)

(II) Synthesis
:
Br COCH3 2. base
C O
R
C O
Ph3P +– R
+ BuLi
:
(III) Synthesis Ph Ph3P CH2Ph Ph3P CHPh (III)
Br
Br – Ylide
Phosphonium salt
SCHEME 7.14b
MERITS OF WITTIG REACTION

The reaction is the best method to prepare less substituted double bond (the double
bond is placed at the carbonyl group of an aldehyde or a ketone). Thus only one
isomer is formed, the reaction is regiospecific and best method to make a terminal
alkene (Scheme 7.14c), since other methods e.g., E2 reaction will give terminal
alkene only as the minor product.
O CH2 CH3 CH3 CH2

– Br
+ –
:
Ph3P—CH2 OH
+
Wittig E2
reaction
Only product Major product Minor product
SCHEME 7.14c
When methoxymethylene is used as an ylide one can step up a ketone to an aldehyde

with one more carbon atom. The reaction (Scheme 7.14d) involves an acid labile
enol ether (see Scheme 14.37).
O CHOCH3 CHO
+ – +
:
Ph3P—CHOCH3 H3O
Generated from
+
Ph3P—CH2OCH3
– Enol ether
Cl
SCHEME 7.14d
(C) Stereoselectivity in Wittig and Wadsworth-Emmons Reactions
Sterechemistry of Wittig Reaction

The following are the general guidelines:
• The Wittig reaction is E selective with stabilized ylides
• TheWittig reaction is Z selective with unstabilized ylides.
These reactions are ideal for alkene synthesis, however, when the alkene product is capable of
geometrical isomerism a mixture of Z- and E-isomers is often a product. Thus the reactions
are not subject to steric control. It is found that the stereoselectivity depends strongly on both
the structure of the ylide and reaction conditions. Generally, unstabilized phosphoranes give
predominantly the Z-alkene particularly in the presence of polar aprotic solvents and in the
presence of a salt. Stabilized phorphoranes (including Wadsworth-Emmons reagents) on the
other hand give mainly the E-alkene.
The unstabilized phosphorane reacts with an aldehyde and the geometry of the
oxaphosphetane is determined by the steric approach of the phosphorane (ylide). The first step
in the addition is irreversible and the formation of the increased amount of Z-alkene is the
result (Scheme 7.15).
O – O
O
Ph3P R¢
R¢ H H
R¢ H R¢ H
H R H R R H
–
R H
+ +
PPh3 PPh3 Oxaphosphetane (z)-alkene
(major product)
Steric approach of the ylide, the
addition is irreversible
Stereoselectivity in Wittig reaction with unstabilized ylide
SCHEME 7.15
With stabilized phosphoranes, however, the first step in addition is reversible

(Scheme 7.16) and this allows the formation of the more stable oxaphosphetane. Thus an
interconversion to the more stable and thus more abundant isomeric form and a syn-elimination
affords the E-alkene.
O – O
O
Ph3P R¢
R¢ H H
R¢ H R¢ H
H COR H COR H
– ROC
ROC H
+ +
PPh3 PPh3 (Less stable) (z)-alkene
oxaphosphetane minor product
The first step in
addition is reversible
O – O
O
Ph3P R¢
R¢ H H
R¢ H R¢ H
ROC – H ROC H H
H COR COR
+ +
PPh3 PPh3 (More stable) (E)-alkene
oxaphosphetane major product
Stereoselectivity in Wittig reaction with stabilized ylides
SCHEME 7.16
Unlike the formation of Z-alkenes from unstabilized phosphoranes (see Scheme 7.15),
by following the Schlosser modification of Wittig reaction one can end up instead with E-alkenes.
Here the ylide is produced as a lithium halide complex (Scheme 7.17) and alllowed to react
with an aldehyde at low temperature so that the betaine is stable. Treatment with a strong
base such as phenyl lithium gives a β-oxido ylide (a new ylide). Addition of t-butanol protonates
the β-oxido ylide stereoselectively to give the more stable betaine as a lithium halide complex.
On warming, the complex collapses to the E-alkene.
– +
R O Li
– +
R¢CHO + O Li
+ – Ph3P PhLi R¢ H
Ph3P—CHR
– (base) +
Br R¢ –
LiBr Ph3P R
+
Lithium halide Li
complex
t-BuOH
– +
R¢ O Li
+
Ph3P
H –Ph3PO R¢ H
H
—LiBr
R H R
E-alkene
More stable betaine
trans-Selective Wittig reaction-Schlosser variant
SCHEME 7.17
(D) Conversion of Alcohols to HalidesNucleophilic Substitution of Alcohols
Role of phosphorus tribromide (PBr3) for the conversion of alcohols to

bromides has been explained (see Scheme 5.15c).
Use of thionyl chloride and phosphorus halides for the conversion of alcohols into halides is
under vigorous and very acidic conditions. Milder conditions employ a 1 : 1 adduct from
triphenylphosphine and bromine (Scheme 7.18) which converts alcohols to bromides. The alcohol
displaces a bromide ion from the adduct which attacks the alkoxyphosphonium ion in an SN2
reaction.
A 1 : 1 adduct from
PPh3 + Br2 Br2PPh3 triphenylphosphine
and bromine
H H
–
Br2PPh3 + OH O Br
+ HBr
R R +
R¢ R¢ PPh3
Alkoxyphosphonium ion
H H
– SN2
Br O Br + O PPh3
R + R
R¢ PPh3 R¢
Conversion of an alcohol into bromide with Br2PPh3
SCHEME 7.18
Triphenyl dichloride displays the same reactivity to convert alcohols to chlorides.

However, the most convenient method is to generate chlorophonium ions in situ by reacting
trichlorophosphine with a suitable compound from which chlorine can be abstracted without
its bonding pair so as to leave a stable carbanion e.g., hexachloroacetone.
O O
+ –
Ph3P + Cl3CCCCl3 Ph3P—Cl + CCl2CCCl3
+ +
Ph3P—Cl + ROH Ph3P—OR + HCl
Alkoxyphosphonium
ion
– +
Cl + RO—PPh3 RCl + O PPh3
SCHEME 7.18a
A mild method to convert alcohols into iodides is via reaction with triphenylphosphine,
diethyl azodicarboxylate and methyl iodide. The method generates the needed alkoxy
phosphonium ion (which however, cannot be formed by methods discussed in (Schemes 7.18 and
7.18a). The ion then reacts with I– to give alkyl iodide (Scheme 7.18b). Diethyl azodicarboxylate
activates triphenylphosphine for a subsequent nucleophilic attack by the alcohol. After the
initial reaction with Ph3P, CH3I captures the enolate ion (I, Scheme 7.18b) and generates the
iodide ion for SN2 reaction on the alkoxyphosphonium ion.
–
O O CH3
CH3I –
EtOOC—N N—C—OEt EtOOC—N—N C—OEt EtOOC—N—N—COOEt + I
+
Ph3P+
Ph3P :
Ph3P
(I)
(I) Activation of phosphorus and
– H
generation of iodide (I ) HO
+
–H
R¢ R²
O CH3
+ H CH3 EtO—C—N—N—COOEt
Ph3P—O H
+ EtOOC—N—N—COOEt Ph3P—O H
R¢ R²
Formation of
R¢ R²
phosphonium salt
+
Ph3P O H SN2
H I
–
I + Ph3P O
R¢ R² R¢ R²
–
Nucleophilic substitution by I , inversion of configuration
Mitsunobu reaction–conversion of an alcohol into an iodide

SCHEME 7.18b
EXERCISE 7.4
Write the products from the reactions (Scheme 7.18c) with stereochemistry.
CH3
CH3
1. Ph3P EtOOC—N N—COOEt Ph3PBr2
2. CH3I
HO HO
H (I) (II)
SCHEME 7.18c
ANSWER. See Scheme 7.16d. Both reactions are SN2 reactions leading to inversion
of configuration.
Products CH3 CH3
H Br
I From (I) From (II)
SCHEME 7.18d
(E) Conversion of 1, 2-Diols into Alkenes

A 1, 2-diol can be converted into its corresponding olefinic compound via a cyclic thiocarbonate.
Its reaction with triethylphosphite gives the alkene (Scheme 7.18e). The success of the reaction
lies in great affinity of phosphorus for sulphur.
OH O
Thiophosgene O
S —CO2
S : P(OEt)3 + S P(OEt)3
OH O
O
A thiocarbonate
SCHEME 7.18e
(F) Cyclization of Aromatic Nitro Compounds

A great affinity of phosphorus for oxygen is the basis for the reductive cyclization of aromatic
nitro compounds with triethylphosphite (Scheme 7.18f). In this cyclization reaction the oxygen
2P(OEt)3
+ 2(EtO)3PO
NO2 N
H
SCHEME 7.18f
atoms of the nitro group are transferred to phosphorus and the reaction is thought to proceed
via the intermediate formation of a nitrene ( Ar N:).
:
7.4 ORGANOSULPHUR COMPOUNDS: SULPHUR YLIDES

(A) Introduction
The sulphur containing reagents are useful due to the ability of sulphur to utilize 3d orbitals
for bonding and to occur in valence states higher than 2. The S—O bond is strong. Sulphur
containing functional groups stabilize adjacent carbanions to provide carbanionic reagents for
use in organic synthesis.
(B) Sulphur Ylides and their Formation

Just like phosphorus ylides sulphur ylides are also important synthetic reagents and are
prepared from sulphonium salts which in turn are derived from sulphides by treatment with
alkyl halides (Scheme 7.19).
+ –
RR¢S : + R²—X RR¢R²S X
A trialkylsulphonium
Sulphide X = halogen compound
CH3I + – base + –
:
Me2S Me2S I Me2S—CH2 Me2S CH2 (I)
–HX
(I) (a) (b)
A sulphur ylide
R R¢ R R¢
–
:
S: + :C S—C (II)
R R¢ R R¢
(II)
SCHEME 7.19
The abstraction of a proton from the corresponding sulphonium salt (I, Scheme 7.19) is
the most common method, however, a direct method to make a sulphur ylide is via addition of
a sulphide to a carbene (II, Scheme 7.19). The ylides are thought to be stabilized by resonance
with the non-polar contributing forms (i.e., bonding which involves a sulphur 3d orbital). In
sulphur ylides the structure (a, Scheme 7.19) is the major resonance contributor i.e., the sulphur
ylides do not contain appreciable double bond character.
The stabilized ylides (like dialkylsulphoxonium ylides) are stabilized by the oxygen atom
(Scheme 7.20). Nucleophilic dimethyl sulphoxide on reaction with methyl iodide gives the
sulphonium salt which on reaction with a powerful base gives the ylide (sulphoxonium methylide).
O O
– NaH, THF + –
(CH3)2S+ CH3I
:
(CH3)2S O + CH3—I (CH3)2S—CH2

(–HI)
Dimethyl Sulphonium A dialkylsulphoxonium ylide

sulphoxide salt (a stabilized ylide)
SCHEME 7.20
A highly basic sulphur ylide, dimsyl sodium is generated from dimethylsulphoxide

(Scheme 7.21).
NaH –
H3C—S—CH3 H3CS—CH2 H3CS CH2 Na+
(–H2)
–
O O O
Dimsyl sodium
SCHEME 7.21
(C) Reactions of Sulphur Ylides

(i) Reaction with Carbonyl Compounds
Sulphur ylides react with aldehydes and ketones to give epoxides. In this respect they differ
from phosphorus ylides which give alkenes. Sulphur ylides are also nucleophilic and attack
the carbonyl carbon to give sulphur betaine. The first nucleophilic addition step is therefore,
identical to the first step of the Wittig reaction. Sulfur has not that high affinity for oxygen as
phosphorus thus the reaction after sulphur betaine formation follows a different path. The
dimethyl sulphide functions as a very good leaving group, and is displaced by intramolecular
nucleophilic attack of the alkoxide ion leading to the formation of an epoxide (Scheme 7.22).
Thus, the sulphur ylide here (dimethylsulphonium methylide) acts as a methylene transfer
reagent to adds a methylene group to the carbonyl double bond.
+
S(CH3)2
H 3C R¢ R¢ CH2 R¢ An organosulphide,
+ CH2 R2S is a good
–
:
S—CH2 C O C C + S(CH3)2 leaving group in an

1 2
R R O SN2 reaction
H 3C –O R
Dimethylsulphonium An epoxide
methylide
SCHEME 7.22
Epoxides provide an important group of synthetic intermediates and their synthesis

(Scheme 7.23) is one of the most important applications of sulphur ylides. To give an example
+ –
(CH3)2S—CH2 O
O + (CH3)2S
DMSO—THF, 0°C
– +
Ph2C O + H2C—S(CH3)2 Ph2C—CH2 + (CH3)2S
O
SCHEME 7.23
of this synthetic utility, the conversion ( C O CH—CHO ) can be brought about

(Scheme 7.24) since epoxides rearrange to carbonyl compounds on reaction with BF3 (see
Scheme 13.29).
O
–
O O O + CHO
CH2—S(CH 3 )2 O
–
:
CH2—S(CH3)2 BF3
+
– (CH3)2S O
SCHEME 7.24
IMPORTANT SULPHUR YLIDES
O O
+ – – –
:
:
:
(CH3)2S—CH2 (CH3)2S—CH2 CH3S—CH2
Dimethylsulphonium Dimethylsulphoxonium Dimsyl anion
methylide methylide
SCHEME 7.25
Unstabilized sulphonium ylides yield epoxides from α, β-unsaturated ketones, while
stabilized ylides give cyclopropanes. In the absence of double bond both types of
ylide give epoxides.
When a nucleophilic group is located close to the carbonyl group in a reactant then on
reaction with the sulphonium methylide the intermediate epoxides are not isolated and instead
heterocycles are generally obtained. Thus o-aminophenyl ketones (Scheme 7.26) react with
dimethylsulphonium methylide to yield benzopyrroles via the epoxide formation and its
subsequent opening.
R
R O R OH R
C + –
O Me2S—CH2 SN i
(–H2O)
:
NH2 NH2 N N
H H
SCHEME 7.26
A synthetically useful sulphur ylide is cyclopropyl substituted (Scheme 7.26a). This reacts
with carbonyl compounds to give oxaspiropentanes which are strained and undergo several
ring opening reactions. Another example is in (Scheme 4.31b).
R H
O
+ – KOH + – R O H3O
+
O+
(C6H5)2S BF4 (C6H5)2S
R R R R
Oxaspiropentane
O H
O OH HO
R +
–H3O R + H2O R +
R +
R R
A cyclobutanone
R R
derivative
SCHEME 7.26a
EXERCISE 7.5
Write steps of the reaction of cycloheptanone with dimethylsulphonium methylide
followed by NaNH2 and HNO2 .
ANSWER. Epoxide undergoes cleavage with amines to give aminoalcohols. The
nitrous acid deamination will give a ring enlarged product (Tiffeneau-Demjanov
reaction, Scheme 7.26b).
–
NH2
O O HO CH2NH2 O
1 + – + – 8
7 2 1
Me2S—CH2 NaNH2 HNO2 7 2
6 3 6 3
5 4 5 4
Cycloheptanone Cyclooctanone
SCHEME 7.26b
(ii) Camparison in Reactivity Between Dimethylsulphonium Methylide and

Dimethylsulphoxonium Methylide
These two types of sulphur ylides differ in their reactivity with α, β-unsaturated carbonyl
compounds. The more reactive sulphonium ylides react rapidly by 1, 2-addition across the
carbon-oxygen double bond and give epoxides. The less reactive sulphoxonium ylides react
slowly by conjugate addition (1, 4-addition) to give cyclopropanes via Michael addition to the
carbon carbon double bond (conjugate addition Scheme 7.27). The difference probably is due to
two reactions the initially formed betaine can undergo: (i) reversal to starting materials or
(ii) intramolecular nucleophilic displacement. Both reagent react most rapidly at the carbonyl
+ – Ph O
(CH3)2S—CH2
C—CH2 + (CH3)2S
(1, 2-addition)
O1 PhCH CH
PhCH CHCPh
4 3 2
O
+ – O
(CH3)2S—CH2
Ph—CH—CH—C + DMSO
(1, 4-addition)
CH2 Ph
SCHEME 7.27
carbon. With dimethylsulphonium methylide, the intramolecular displacement step is faster

than the reverse of addition leading to epoxide formation (I, Scheme 7.28). The reaction with
more stable dimethylsulphoxonium methylide, the reversal is faster and the product formation
occurs after conjugate addition (II, Scheme 7.28).
O + – O
(CH3)2S O
+ – Fast
(CH3)2S—CH2 + (I)
slow –Me2S
(An alkoxide)
O
O –
O (CH3)2—S O
+
+ –
(CH3)2S—CH2 +
fast
–
O O O
O
– O
+
(CH3)2S—CH2 + + (II)
fast (CH3)2S –DMSO
(An enolate)
SCHEME 7.28
Another difference in these two types of sulphur ylides is the difference in the
stereochemistry of epoxide formation with a cyclohexanone. Both dimethylsulphonium
methylide as well as dimethyloxosulphonium methylide react the same way to give epoxides
on reaction with non-conjugated aldehydes and ketones. These however, differ in their
stereoselectivity with a cyclohexanone (Scheme 7.29). With the sulphonium ylide the epoxide
has the new carbon-carbon bond axial, while with the oxosulphonium methylide this bond is
equatorial. It is suggested that this difference may also be due to reversibility of addition in
the case of the sulphoxonium methylide. The product from the sulphonium ylide is due to the
kinetic preference for axial addition by small nucleophiles. In the case of reversible addition of
the sulphoxonium ylide, product stereochemistry is determined by the rate of displacement
which may be faster for the more stable epoxide.
+ – O
Me2S—CH2
fast
O
Kinetically controlled
epoxide
O O
+ –
Me2S—CH2
slow
Thermodynamically
controlled epoxide
SCHEME 7.29
(iii) Reaction with Dimsylsodium—Synthesis of Complex Ketones

Dimsyl anion is very reactive as a nucleophile and reacts with aldehydes and ketones by
nucleophilic addition to give epoxides, however reaction with esters is a nucleophilic substitution
to give β-ketosulphoxides (I, Scheme 7.30).
–
R R O R
– O – +
:
CH3S—CH2 + C O C C + CH3SO Na
R CH2
O + R¢ CH2—SCH3 R¢
Na
O
+
O Na O O
– –NaOEt 1. NaH
:
C6H5C—OEt + CH2SOCH3 C6H5CCH2SOCH3 C6H5C—CH2

2. BrCH2COOEt
(I) 3. Zn-AcOH CH2COOEt
Acidic a-hydrogens
SCHEME 7.30
A β-ketosulphoxide contains a strongly activated methylene group and the acidic

α-hydrogens can be removed to allow alkylations. Reductive desulphuration (Zn/AcOH) then
gives ketones.
(D) 1, 3-Dithiane AnionsUmpolung (dipole inversion)
For introduction to 1, 3-Dithiane Anions see Scheme 4.36a.
The characteristic reactivity, nucleophilic or electrophilic of an atom or a group can be reversed

temporarily in a process termed umpolung (German for polarity reversal, see Scheme 4.35).
This e.g., is seen in the case of aldehydes when these are converted into the anions of the
corresponding 1, 3-dithiacyclohexanes (1, 3-dithianes). The otherwise electrophilic carbonyl
carbon changes into nucleophilic center. The 1, 3-dithiane anions can be alkylated by a variety
of reagents like, primary and secondary haloalkanes, aldehydes and ketone and epoxides.
A dithiane can be made by the reaction of an aldehyde with 1, 3-propane dithiol with a
Lewis acid catalyst. The hydrogen on the carbon attached to two sulphur atoms can be removed
by reaction with a strong base (Scheme 7.31). After the reaction, the 1, 3-dithiane system can
be reconverted to the carbonyl compound by acid hydrolysis in the presence of mercury (II)
ion.
Dithianes represent very important compounds in organic synthesis since as one goes
from a ketone to a thioacetal the polarity at the functionalized carbon atom is inverted. Recall
that aldehydes are electrophiles at the C O carbon atom but a dithioacetal (a dithiane) after
deprotonation to an anion become nucleophilic at the same carbon atom. This is an example of
umpolung and dithianes represent the most important among the umpolung reagents.
(i) Synthesis of aldehydes (HCHO RCHO)
The carbanion from 1, 3-dithiacyclohexane (I, Scheme 7.31) obtained by condensation of
propane-1, 3-dithiol and formaldehyde can be alkylated by a suitable alkyl halide.
–
d +
O (i) HS(CH2)3SH, H
Electrophilic +
carbon atom d (ii) BuLi
C Nucleophilic
S S
–
carbon atom
R H Cd +
d
umpolung Li
R
O , BF3
2+
SH SH S S BuLi RX Hg
C S S –
S S RCHO
C –X H2O
C: –
H H H H H R
(I)
H
SCHEME 7.31
(ii) Synthesis of ketones (R—CHO RR′ CO)

This can be achieved by working with a dithiane obtained with an aldehyde other than
formaldehyde and following the preocedure as above (see Scheme 4.36a).
(iii) Synthesis of Cyclic Ketones—Cyclobutanone
The carbanion derived from 1, 3-dithiacyclohexane (see I, Scheme 7.31) is alkylated with
3-chloroiodopropane (since iodine is the better leaving group it is selectively displaced) and
the sequence of reactions (Scheme 7.32) gives cyclobutanone at the end.
Cl
I CH2 O
S H S H S H S 2+
BuLi BuLi Hg
a – CH2(CH2)2Cl a
CH2 H2O
+
S H S Li S CH2 S
A dithiane
(cyclic thioacetal)
SCHEME 7.32
EXERCISE 7.6
A 1, 3-dithiane can be converted into a synthetically useful stabilized carbanion
(Scheme 7.33). The corresponding 1, 3-dioxane which has even more electronegative
oxygen atoms around the acetal carbon cannot be converted similarly to the anion
by butyl lithium? Explain.
BuLi BuLi
S S S S O O O O
– –
SCHEME 7.33
ANSWER. The acidifying effect of sulphur is not based on electronegativity. The

sulphur atoms have unfilled valence level d orbitals available which can accept
electron density to stabilize an adjacent anion. One can consider the anion as
being resonance stabilized with the negative charge being delocalized into the
flanking sulphur atoms.
(iv) Synthesis of a α- or β-hydroxy ketone

The nucleophilic 1, 3-dithianyl anions react with another source of electrophilic carbon in the
form of an aldehyde, ketone or an epoxide. For example, reaction with an aldehyde gives an
α-hydroxy ketone (Scheme 7.34) and the dithianyl anion is used as a nucleophile to open an
epoxide ring, the hydrolysis of the resulting hydroxy dithiane gives a β-hydroxy ketone. In the
reaction with an epoxide, it is the less hindered end of the epoxide that is preferentially attacked.
O OH
S R S R + S R 2+
H3O Hg
:– R¢CH O RC—CH—R¢
H2O
S + S CHR¢ S CH(OH)R¢ a-hydroxy ketone
Li
OLi
O OH
S R S CH2CHCH3 + S CH2CH(OH)CH3 2+
O H3O Hg
– RCCH2CHCH3
OLi H2O
S CH3 S R S R b-hydroxy ketone
SCHEME 7.34
7.5 SILICON REAGENTS

(A) Introduction
Several organic reactions involving organosilicon compounds can take place since Si forms
stronger bonds with O and F than does C but weaker bonds with C and H. Moreover the 3p-
electrons of Si do not overlap effectively with the 2p-electrons of C or O. Multiple bonds C Si
and O Si are not, therefore, commonly found in stable molecules.
Silicon is more electropositive than carbon so the carbon-silicon bond is strongly polarized
as shown (I, Scheme 7.34a).This results in alkylsilanes being prone to attack by nucleophilic
reagents. Silicon also has the ability to stabilize α-carbanions, (II, Scheme 7.34a) as well as
β-carbocations (III).
R3Si
+ –
d d – +
Si—C R3Si—C C—C
(I)
a-carbanion b-carbocation
(II) (III)
SCHEME 7.34a
Several chlorosilanes e.g., SiCl 4 and (Me)3SiCl are readily available organosilicon
reagents. These halides undergo a facile nucleophilic displacement to give a variety of useful
synthetic intermediates (Scheme 7.35).
CH3Mgl CH3Mgl CH3Mgl Chlorotrimethylsilane

SiCl4 CH3SiCl3 (CH3)2SiCl2 (CH3)3SiCl
Allyltrimethylsilane
RCH CHCH2MgCl + ClSi(CH3)3 RCH CHCH2Si(CH3)3
Allylmagnesium halide
SCHEME 7.35
(B) Peterson ReactionSynthesis of Alkenes

The Peterson silicon based alkene synthesis may be viewed as silicon version of Wittig reaction
(Scheme 7.35a). Although the use of silicon stabilized carbanions is less common than those
derived from phosphorus or sulphur, there are several significant advantages in steric terms.
–
O
–
C O + C—SiR3 C—C C C
SiR3
The Peterson synthesis—use of silicon stabilized carbanions
SCHEME 7.35a
The reaction can be carried out in two ways. In the first method the reactant e.g., ethyl
α-trimethylsilylacetate has a CH group which is adjacent to both a silicon containing moiety
(which is normally SiMe3) and a –M group displays a base induced reaction with an aldehyde
or ketone to yield the alkene directly (Scheme 7.35b). The driving force for the reaction is the
formation of strong silicon-oxygen bond, which converts the oxygen atom in to a much better
silyloxy leaving group. In this case the more stable olefin isomer is formed because equilibration
occurs in the enolate intermediate.
+
Li –
–
O O O O OSiMe3 O R H
PhLi RCHO
Me3Si Me3Si
OEt –PhH –+ OEt R OEt R OEt
Li H H H CO2Et
SiMe3
a-Silyl anion + – +
Me3SiO Li
SCHEME 7.35b
In the second alternative when the group of –M type is absent in the reactant, one
generates a C-metal bond adjacent to the SiMe3 group. The reagent is therefore,
trimethylsilylmethyl Grignard which adds to the carbonyl group of the reactant to form a
β-hydroxysilane after hydrolysis. In this case the second step in needed to convert
β-hydroxysilane into alkene (since the product alkene is not conjugated). These β-hydroxy
silanes can be formed as diastereomers as threo, erythro form. These are separated and either
of the diastereomers undergoes elimination of the trialkylsilyl group and the hydroxyl group
to yield the alkene. The elimination is carried out under basic (KH) or acidic (H+ or BF3.Et2O)
conditions. Either diastereomer displays over 90% stereoselectivity and can give E or Z alkene,
the elimination being syn under basic conditions and anti under acidic conditions (Scheme 7.35c).
Mg
Me3SiCHCl Me3SiCHMgCl
R R
Source of a-silylcarbanion
Formation of silyl containning Grignard reagent
R¢CHO + Me3SiCHMgCl Me3SiCH—CHR¢
R R OH
b-hydroxysilane
–
OH O
Me3Si Me3Si –
H Me3Si O
H R H R
KH syn R¢
R —C——C—
(base) elimination
R¢ H R¢ H
–H2
b-hydroxysilane H via
(threo isomer) E-alkene
eclipsed
R H
R
Me3Si + The merit of Peterson reaction is in the
HO acid R¢ control of stereoselectivity during
– – H
R¢ H BF3 –HOBF3 elimination of b-hydroxysilane
(Threo isomer) H
staggered (Z)-alkene
SCHEME 7.35c
(C) Silyl Epoxides and their Synthetic Applications to Make Methyl Ketones
A silyl epoxide may be made from ketones by the use of a useful reagent α-chlorotri-
methylsilylmethyl-lithium (II, Scheme 7.35d) which is made from α-chloromethyltrimethylsilane
(I) and s-butyllithium. This reagent (II,Scheme 7.35d) reacts with aldehydes and ketones to
give α,β-epoxysilanes via a chlorohydrin (Scheme 7.35d). These epoxides undergo an acid
catalyzed ring opening and the regioselectivity is dictated by the stabilizing effect of a β-Si-C
bond on a carbocation (see III, Scheme 7.35e). An example is the conversion of an aldehyde
RCHO to a methyl ketone RCH2COCH3 (Scheme 7.35e), which uses a related reagent α-methyl-
α-chlorotrimethylsilylmethyl-lithium (A, Scheme 7.35e).
R
Li O
H –
R H O – O
R¢Li –Cl H R
Me3Si Cl Me3Si Cl Me3Si R
–R¢H
Cl R Me3Si R
(I) (II)
A silyl epoxide
Mechanism of formation of a silyl epoxide from a ketone
SCHEME 7.35d
CH3 H CH3 H CH3 H CH3

+
H
Me3Si—C—Li + R—C—H R—C—C—SiMe3 R—C—C—SiMe3 R—C—C—SiMe3
+
Cl O O +O OH
(A) A silyl epoxide (III)
H
A regioselective acid catalyzed ring
Alkenylsilanes give silyl epoxides opening of epoxide is enforced due to the stabilizing
also by reaction with peracids. effect of a b-Si-C bond on the carbocation
These epoxides serve as masked –
aldehydes and ketones X
–Me3SiX
H CH3
RCH2—C—CH3 R—C C
O OH
SCHEME 7.35e
(D) Synthetic Utility of Vinylsilanes (Alkenyl Silanes)

Vinylsilanes may be prepared by the nucleophilic displacement of halogen from a halosilane
by an organometallic reagent (Scheme 7.36). An electrophile adds to the double
RCH CHMgBr + (CH3)3SiCl RCH CHSi(CH3)3
A vinylsilane
(an alkenylsilane)
+ +
H R H R H R + H R
R E
+ rotation H
E
R¢ R¢ E R¢ E R¢
Si(CH3)3 E
R¢ Si(CH3)3 –
An alkenyl Si(CH3)3 Nu Si(CH3)3
silane
Mechanism of the reaction of a vinylsilane with an electrophile
SCHEME 7.36
bond of a vinylsilane regioselectively at the α-carbon due to stabilization provided by silicon to

a carbocation β to it. This process results in a nucleophilic displacement at silicon to release an
alkene in which the silyl group gets replaced stereospecifically by the electrophile. The reaction
generally occurs with retention of configuration. It has been suggested that retention of
configuration is due to the rotation around the C—C single bond in the carbocation to increase
the stabilization interaction between the unoccupied 2p orbital and the C—Si bonding orbital
(Scheme 7.36). Reaction of a vinylsilane with an electrophile normally requires a Lewis acid
catalyst and some examples are in (Scheme 7.36a).
C2H5 C 2H 5
R R CH3COCl
AlCl3
I2
Si(CH3)3 I Si(CH3)3 COCH3
R¢ –Me3SiI R¢
H H
SCHEME 7.36a
(E) Reactions Involving Allylsilanes

Allylsilanes used for synthesis may be made from allyl halides via. Grignard reagents
(Scheme 7.37). The dominant reaction of the addtion of electrophiles to these allylsilanes is
again the attack of the electrophile at the double bond at the γ carbon due to the stability
R¢ Cl R¢ MgCl R¢ Si(CH3)3
Mg (CH3)3SiCl
R R R
Formation of allyl silanes An allylsilane
SCHEME 7.37
of the β-silyl carbocation. The overall process results in the replacement of the silicon substituent
with an allylic shift of the double bond (Scheme 7.37a). The silyl group is removed via
nucleophilic substitution at silicon. An example of the reaction involving electrophilic attack
on allylic silanes is in (Scheme 7.37b), and probably involves acylium ion as the electrophiles.
b Si(CH3)3 + E + Si(CH3)3 E +
E
NuSi(CH3)3
g a –
Nu
A b-silyl carbocation
Addition of an electrophile to an allylsilane followed by double bond shift
SCHEME 7.37a
CH2 Si(Me)3
CH2 Si(Me)3 O O
+
CH3COCl – –(Me)3SiCl
AlCl4
AlCl3
Acylation of an allylsilane to give a b, g-unsaturated ketone
SCHEME 7.37b
(F) Trapping of Enolate Anions

When e.g., chlorotrimethylsilane is included with the ketone and a base, the enolates
(thermodynamic and kinetic) are trapped as silyl enol ethers, which can be separated by
chromatography and converted to the parent enolates by treatment with fluoride ion
(Scheme 7.38). Silylation, is a nucleophilic substitution at the silicon atom by the oxygen atom
of the enolate, (oxygen-silicon bond that forms in the trimethylsilyl enol ether is very strong
For details of formation and purification of enolates see Schemes 6.5 and
6.6.
– + –
O Li O—Si(CH3)3 O
H 3C H3C –
H 3C
(CH3)3Si—Cl F
+ (CH3)3Si—F
silylation
Kinetic enolate Trimethylsilyl Kinetic enolate
enol ether
SCHEME 7.38
and is much stronger than a carbon-silicon bond). The trimethylsilyl enol ether is converted
back to the enolate on treatment with fluoride ions (nucleophilic substitution) since Si—F
bond is very strong.
A regiospecific α-alkylation of a ketone can be achieved by employing silyl enol ether
intermediates (Scheme 7.38a). The source of fluoride ion is tetrabutylammonium fluoride (C4H9)4
N+ F– (TBAF).
OSi(CH3)3 O
CH3 CH3
1. TBAF
+ PhCHO CHC6H5
2. H2O
O
CH3 OH
OSi(CH3)3 O
CH3 C6H5HC CH3
1. TBAF
+ PhCHO OH
2. H2O
SCHEME 7.38a
Silyl enol ethers are alkylated by SN1-reactive electrophiles with the use
of Lewis acids (see Scheme 6.43 b).
(G) Silyl EtherProtecting Groups

A hydroxyl group may be protected by converting it to a silyl ether group. The most common is
the tert-butyldimethylsilyl ether group [tert-butyl(CH3)2Si—O—R, or TBDMS—O—R], since
it is stable over a pH range of about 4–12. A TBDMS group can be added by reacting the
alcohol with tert-butyl-chlorodimethylsilane in the presence of an aromatic amine (a base such
as imidazole or pyridine). This protecting group can be removed by treatment with fluoride ion
(TBAF, Schem7.39). Conversion of an alcohol to its silyl ether makes it more volatile for
application in analysis by gas chromatography and trimethylsilyl ethers are derivatives of
choice. Trimethylsilyl ether group is however, too labile to solvolysis in protic media for use as
a protecting group. In the case of R—O—TBDMS steric factors increase the stability and
decrease the sensivity to hydrolysis. Reaction of an alcohol with the bulky chlorosilane is rather
slow to be practicable, however imidazole is a far stronger nucleophile than alcohol and
N-t-butyldimethylsilyl-imidazolyl ion (I, Scheme 7.39) thus formed provides an effective
silylating agent and also provides a good leaving group (protonated form of imidazole).
TBDMSCl
t-C4H9(CH3)2Si—Cl ROH
:
Si(CH3)2C4H9–t Si(CH3)2C4H9–t
:
NH N H
+ N
–HCl
+ N
N N +
–H , –
Imidazole H N
– H
F
Regeneration ROH ROSi(CH3)2C4H9–t Protection
SCHEME 7.39
(H) Synthetic Uses of Iodotrimethylsilane

Trimethylsilyl iodide is an electrophilic reagent which forms strong Si—O bonds on reaction
with oxygen nucleophiles and liberates strongly nucleophilic iodide ion. The reagent is often
generated in situ by reacting trimethylsilyl chloride with sodium-iodide.
(i) Cleavage of Ethers
Benzyl and t-butyl systems get cleaved rapidly while secondary systems require longer times.
The reaction involves the initial formation of a silyloxomium ion (I, Scheme 7.40). The direction
Me
d+ d–
: :
Si—I:
Me
Me SiMe3
–
–I + –RI
:
R¢—O: R¢—O: R¢—O—SiMe3 + H2O R¢OH

–
R R I
(I)
Cleavage of ethers with trimethylsilyl iodide
SCHEME 7.40
of cleavage in the case of unsymmetrical ethers is determined by the relative ease of O—R
bond cleavage which may follow either SN2 (methyl, benzyl) or SN1 (t-butyl) processes.
(ii) Cleavage of Esters
Esters are also cleaved via the formation of trimethylsilyl esters which are easily hydrolyzed
with water (Scheme 7.40a).
O +OSiMe O
3
Me3SiI – –R¢I H2O
RCO—R¢ I + RCO—R¢ RCOSiMe3 RCOOH
Cleavage of esters with trimethylsilyl iodide

SCHEME 7.40a
(iii) Reaction with Alcohols

Trimethylsilyl iodide converts alcohols into their iodides and even bridgehead alcohols gives
good yields as seen in the case of adamantan-1-ol. Otherwise inversion of configuration (S N2
mechanism) seems to be operative (Scheme 7.41).
(CH3)3SiI (CH3)3SiI
CH3(CH2)5CH(OH)CH3 CH3(CH2)5CHICH3
OH I CHCl3
(S) (R)
Major
SCHEME 7.41
(iv) Reaction with Ketones

Enolizable ketones react with trimethylsilyl iodide to give silyl enol ethers. Iodine is introduced
in the β or γ- position of the ketone when the reactant is α, β-unsaturated compound or a
cyclopropyl compound (Scheme 7.42).
O OSi(CH3)3 OSi(CH3)3 O
+
(CH3)3SiI – H2O
I
CCl4 CH2I CH2I
O OSi(CH3)3 O
(CH3)3SiI H2O
CH2Cl2, –78° I I
SCHEME 7.42
SELENIUM REAGENTS
SeO2 in allylic oxidation of alkenes (Scheme 13.12), oxidation of C—H groups
(Scheme 13.15), elimination from selenoxides (Schemes 12.32 and 12.33).
7.6 BORON CONTAINING REAGENTS

(A) Introduction
Borane (which exists as the gaseous dimer diborane B2H6) and organic boranes easily add to
C C bonds. The boron atom, subsequently can be removed from these adducts by using several
reagents via reactions which use the ability of the boron atom (which is election poor) to accept
an electron pair. These factors are responsible for synthetic applications of borane.
(B) Hydroboration
The boron-hydrogen bond i.e., the B—H unit adds rapidly and quantitatively to many multiple
bonds including carbon-carbon double bonds, a process known as hydroboration10. With simple
alkenes, a trialkylborane is formed (Scheme 7.43). Diborane is commercially available in the
form of complexes which it forms with ethers.
BH3 RCH CH2 RCH CH2

RCH CH2 RCH2CH2BH2 (RCH2CH2—)2BH (RCH2CH2—)3B
SCHEME 7.43
(C) Mechanism of Hydroboration

The π bond is electron rich and boron, electron poor. The reaction is initiated via the coordination
of BH3 with the π-electrons of the double bond (the participation of the empty p orbital on BH3)
followed by the formation of the carbon-hydrogen bond as in R—CH CH2 (Scheme 7.44), via
a four center transition state. Both the new C—B and C—H are as a result formed from the
same side of the double bond. The addition is dominated by steric considerations. Hydroboration
is regioselective; unlike the electrophilic addition, steric and not electronic factors control the
regioselectivity; the boron generally becomes attached to the less substituted and less sterically
congested carbon. The alkylborane products are normally not isolated but are converted by
subsequent reactions directly into desired products. The most important general reaction of
alkyl-boranes is oxidation with alkaline hydrogen peroxide to give an alcohol (RCH2CH2OH).
–
d H 2B H BH2 H
BH3
H H H H H
C+ C+ C C H—C C
d d R H R R
H H
p complex Less substituted carbon syn-addition
Four center transition state

SCHEME 7.44
In case where stereochemistry may be defined, exclusive syn addition is observed. Thus
addition occurs with syn stereospecificity. Consider 1-methyl-cyclopentene, since BH3 has
B—H bonds, it adds to the double bonds of three molecules of 1-methylpentene to afford a
trialkyl borane (Scheme 7.45). The oxidation of trialkylborane with alkaline hydrogen peroxide
replaces the boron atom with a hydroxyl group in the same stereochemical position. The net
result of hydroboration and oxidation-hydrolysis is the addition of water (hydration) across a
double bond with anti-Markovnikov orientation.
Me Me Me
Me –
BH3/THF H H H2O2/OH H
3
BH2 B OH
H
1-methylcyclopentene
H H H
3
trans-2-methylcyclopentanol
SCHEME 7.45
The alkene reacts at the less hindered side of the multiple bond (Scheme 7.46), there
being a preference for approach of the borane from the less hindered side of the molecule.
BH3 B
3
SCHEME 7.46
(D) Substituted (Sterically Congested) Boranes

Hydroboration of alkenes with borane have several limitations:
(i) Regioselectivity in the hydroboration of terminal alkenes is high, however, it is not
complete (see Scheme 7.48).
(ii) In the case of 1, 2-disubstituted alkenes, there is little discrimination between the
two termini of the double bond (see Scheme 7.48).
(iii) The rates of reaction of borane do not differ with differently substituted double bonds.
Thus one may not achieve selective hydroboration of one double bond in the presence
of other.
(iv) Hydroboration of terminal alkynes proceeds part the desired alkenylborane by the
addition of second molecule of borane.
Most of these difficulties can be solved by using organoboranes formed from an
appropriate alkene and diborane, using control of stoichiometry to terminate the hydroboration
at the desired degree of alkylation. In practice, the number of hydroborations for a given alkene
is strongly dependent on steric effects. The more hindered the alkene, the fewer the number of
possible additions. For example, 2-methyl-2-butene hydroborates only twice, 2, 3-dimethyl-2-
butene only once (Scheme 7.47). These reagents contain one or two B—H bonds; are sterically
congested; less reactive and more selective than borane. Thus one can successfully achieve a
desired regioselectivity between the two carbon atoms of the double bond in an alkene. Diborane
e.g., reacts with the internal alkene (Scheme 7.48) in a completely non-selective fashion, while
with the same alkene disiamylborane (Sia2BH) reacts almost exclusively at the methyl
substituted unsaturated carbon. More example of regioselectivity of diborane and alkylboranes
are given (Scheme 7.48).
CH3
BH3
(CH3)2C CHCH3 [(CH3)2CHCH]2BH Sia2BH
Disiamylborane
CH3
BH3
(CH3)2C C(CH3)2 (CH3)2CHC—BH2 BH2
CH3
Thexylborane
H 9 H
B
B 5
H
H
BH3 H 6 4
1 B
Tetrahydro-
8 2
furan
1, 5-cyclooctadiene 7 3
9-borabicyclo[3.3.1]nonane
(9-BBN)
OH O
BH3
B—H + 2H2
OH O
Catechol Catecholborane
SCHEME 7.47
1-hexene 4-methyl-2-pentene
(a terminal alkene) (a 1, 2-disubstituted alkene)
Disiamylborane 99 97
9-BBN 99.9 99.8
Diborane 94 57 (43% adds at more

substituted carbon)
% of Boron Added at Less Substituted Carbon
SCHEME 7.48
Often one succeeds in the selective hydroboration of one double bond in the presence of
other. Vinyl cyclohexene can be monohydroborated with either disiamyl-borane or 9 BBN and
oxidised to the corresponding alcohol (Scheme 7.49), also see Scheme 13.47. Catecholborane
and 9-BBN are especially useful since these have only one B—H bond and thus one can control
the reaction with an alkene or an alkyne.
CH CH2 B(C5H11)2 CH2—CH2—OH

–
H2O2—OH
+ HB(C5H11)2
Sia2BH
SCHEME 7.49
(E) Isomerization of Organoboranes

Hydroboration is thermally reversible. On heating around 150°C, organoboranes are isomerized
to a mixture in which the major component has boron attached to the terminal carbon atom of
the alkyl group (Scheme 7.50). The process involves a series of eliminations and additions and
is catalysed by diborane. Using this techinque one can convert a readily available internal
alkene to a primary alcohol.
CH2CH3
CH—H
(BH3)2
CH3CH2CH CHCH2CH3 CH3CH2CH B
3-hexene 3
160°
–
OH
CH3(CH2)4CH2—OH [CH3(CH2)4CH2]3B
H2O2
1-hexanol tri-n-hexylboron
Isomerization of organoboranes
SCHEME 7.50
(F) Reactions of Organoboranes from Alkenes

(1) Oxidation
As seen above alkylborane oxidation with alkaline hydrogen peroxide solution gives alcohols.
The reaction is initiated by addition of the HOO– ion to boron (making use of boron’s vacant 2p
orbital) followed by boron to oxygen migration of alkyl groups (Scheme 7.51). When all the
three alkyl groups have migrated, the resulting borate ester is hydrolyzed. The migrating
group retains its configuration in the product.
–
– –OH
: :
: :
– :O—OH
: :
: :
—B + —B—O—OH —B (RO)3B
Hydroperoxide ion
: :
R R O—R
H2O
(RO)3B + 3 NaOH Na3BO3 + 3 ROH
Alkylborane oxidation with alkaline hydrogen peroxide
SCHEME 7.51
More vigorous oxidizing agents effect replacement of boron and oxidation to the carbonyl
level (primary trialkylboranes to aldehydes and of secondary trialkyl boranes to ketones, see
Scheme 13.47).
(2) Enantioselectivity
(i) Enantioselective Hydroboration of Alkenes
Optically active (asymmetric) boranes are prepared e.g., by the reaction of borane with either
(+) – or (–) – α-pinene (Scheme 7.52). These asymmetric boranes are of value in enantioselective
synthesis. Optically active secondary alcohols of high optical purity are made from several
disubstituted Z-alkenes by initial hydroboration with these reagents followed by oxidation
(Scheme 7.53). Ipc2 BH reacts very slowly with (E)-alkenes, but Ipc BH2 can be used effectively.
)2BH BH2
+ BH3
Ipc2BH IpcBH2
a-pinene Diisopinocampheylborane Monoisopinocampheylborane
SCHEME 7.52
R Ipc2B H – HO H
HO /H2O2
+ Ipc2BH R R
R R R
Z-alkene (R, 87% optically pure)
H OH
R 1. Ipc2BH R
R R
2. H2O2, NaOH
(E)-alkene (S, 73% optically pure)
SCHEME 7.53
The chiral reagent (Ipc)2 BH reacts with an alkene like any borane, but since it is chiral,
the two faces of the alkene substrate react differently with the reagent producing tri (organo)
boranes which are diastereomeric of which one predominates. Hydrolysis (oxidative) then gives
a chiral alcohol is good yield and with high optical purity.
(ii) Enantioselective Reduction of Ketones
Boron derivative 9-BBN is prepared by reacting 1, 5-cycloctadiene with BH3. (+) α-Pinene
reacts with 9-BBN to give a chiral adduct (Scheme 7.54) which reduces ketones with a high degree
of enantioselectivity, in some case 100%. It is thought that the adduct transfers a hydride to the
Ph
H
C O
BH B B
Me O
+ H Ph
Me
9-BBN a-pinene
B
HO H + O H
H
Me Ph Me Ph
Enantioselective reduction of ketones

SCHEME 7.54
ketone via. a six-membered boat shaped cyclic transition state, where the larger group on the
ketone (Ph in this example) preferentially lies-away from the α-pinene moiety to make the
steric congestion minimum. The adduct of 9-BBN can be made with both (+)- and (–)- α-pinene
to synthesize both the enantiomers individually.
(3) Protonolysis
The migration of R from boron to an oxygen atom during oxidation of an organoborane with
alkaline hydrogen peroxide is a good way to make alcohols from alkenes via organoboranes.
The R group can also be induced to migrate from boron to a proton. However, the proton
cannot come from any source. Carboxylic acids react with organoboranes to cleave the C—B
bond. When an organoborane is heated with a carboxylic acid, a Lewis acid–Lewis base reaction
occurs between the boron atom (Lewis acid) and the carbonyl oxygen atom of the carboxylic
acid (a Lewis base in this transformation Scheme 7.54a). The reaction proceeds through a six-
membered transition state.
:O: R—H
R R R H R
D
B—R C B– O B O
+
R HO CH2CH3 R O C R O—C
CH2CH3 CH2CH3
SCHEME 7.54a
The protonolysis of a carbon-boron bond is useful in two ways. First, it provides a good
way to introduce deuterium (2H, also denoted by D) into a molecule and an internal alkyne is
converted into a cis alkene (Scheme 7.54b).
H H
CH3 CH3 CH3
BH3, THF CH3CH2COOD
D
H H H
BH2 D
O
BH CH3 CH3
O CH3COOH, D
C C—CH3 C C C C
THF
H B(O2C6H4) H H
SCHEME 7.54b
(4) Carbonylation of Organoboranes

Carbon monoxide forms Lewis acid-base complexes with organoboranes, and these adducts
undergo boron-to-carbon migration of the boron substituents.The reaction can be controlled
and therefore, directed in the migration of one, two or all the three substituents on boron.
Conditions can be defined so that carbonylation of organoboranes can lead to primary, secondary
and tertiary alcohols, aldehydes and open chain, cyclic and polycyclic ketones.
(i) Conversion of Boranes to Tertiary Alcohols
Triallylboranes react with one molecule of carbon monoxide at 125°C in the presence of ethylene
glycol to afford the 2-bora-1, 3-dioxolanes which on oxidation give tertiary alcohols in high
yields. Ethylene glycol helps to intercept the boronic anhydride (Scheme 7.55), which otherwise
forms polymers which are difficult to oxidize. The reaction pathway (Scheme 7.55) involves
three successive intramolecular migrations.
R R R R
– + 1 – 2 3
:
:
R 3B + C O R—B—C O B—C—R B—C—R

+
Reactants R R O O
4
O—CH2 R
H2O2 HOCH2CH2OH
R3COH – R3C—B R—C—B O
HO ethyleneglycol
Product O—CH2 R
The 2-bora-1, 3-dioxolane The boronic anhydride
SCHEME 7.55
(ii) Conversion of Boranes to Ketones and Secondary Alcohols

When the carbonylation of a trialkylborane is conducted in the presence of water, the migration
of the third alkyl group (step 4, Scheme 7.55) is intercepted. The hydrate is formed (Scheme
7.56), this can be oxidized (–OOH) to a ketone or hydrolyzed to a secondary alcohol.
–
OH
R—C—R
O HO OH H2O2
H2O O
R—B—C—R R—B—CR2
–
R OH
R—CH—R
H2O
OH
SCHEME 7.56
The reaction can be used to prepare unsymmetrical ketones by using ‘mixed’

organoboranes prepared from thexylborane (Scheme 7.57). The success of this method depends
upon the thexyl group being noncompetitive with the other groups in migration steps. Thus
the sequential introduction of two alkenes (Scheme 7.57) leads to the synthesis of unsymmetrical
ketones.
CH2CH(CH3)2
BH2 + (CH3)2C CH2 B
H
CH2 CH—CH2CO2C2H5
CH2CH(CH3)2
1. CO
O C
2. H2O2—H2O B
(CH2)3CO2C2H5
C2H5O2CCH2CH2CH2 CH2CH(CH3)2
SCHEME 7.57
By working with appropriate dienes one can end up with cyclic or bicyclic ketones
(Scheme 7.58).
1. CO, H2O
high pressure
+ BH2 B – O
2. H2O2, OH
Thexyl
1. Thex BH2 H H O
2. CO B
3. H2O2—H2O
H H
SCHEME 7.58
(iii) Conversion of Boranes to Aldehydes and Primary Alcohols

When the carbonylation of the trialkylborane is done in the presence of a reducing agent e.g.,
lithium trimethoxyaluminium hydride, the reducing agent intercepts the intermediate after
only one boron-to-carbon migration has taken place (see, Scheme 7.59). This on oxidation
R O H
–
CO LiAlH(OMe)3 H2O2/OH
R 3B R—B—C—R R2B—C—R RCHO
– +
OAl (OMe)3Li
SCHEME 7.59
(route I, Scheme 7.59) gives aldehydes. An inspection of Scheme 7.59 shows that, the method
as such has a disadvantage since only one of the three alkyl groups of the starting trialkylborane
is converted into aldehyde, the others are wasted. This difficulty is solved by hydroboration of
the alkene with 9-BBN. The B-alkyl derivative on reaction with CO in the presence of a reducing
agent is attended with the preferential migration of the alkyl group (there is minimal tendency
of the bicyclic ring to undergo migration) to give high yields of the aldehyde. While working
with B-alkyl-9-BBN, since only the 9-alkyl group migrates, this method, thus converts (high
yields) an alkene to an aldehyde containing one more carbon (R—CH CH2
RCH2CH2CHO, Scheme 7.60).
H OH
Migrating group
B B —CH2CH2R B—CHCH2CH2R
RCH CH2
CO
Reactant – RCH2CH2CHO
LiAl(OMe)3 H2O2/OH
Product
9-BBN 9-alkyl-9-BBN
A dialkylborane
SCHEME 7.60
(5) Cyanidation of Organoboranes

Cyanide ion is isoelectronic with carbon monoxide and a borane reacts similarly to initially
form an adduct with cyanide ion, on reaction with sodium cyanide (Scheme 7.61). Thus this is
another reagent besides carbon monoxide which serves as the electrophilic migration terminus.
The nitrogen atom in the initial adduct is not sufficiently electron attracting to induce migration.
This ability is enhanced by acylation of the cyano group with trifluoroacetic anhydride. Two
alkyl groups are transferred (Scheme 7.61) at low temperature to give ketones by oxidation.
The method has a merit over carbonylation due to low temperature conditions of this reaction.
Moreover, as in the carbonylation reaction, one can avoid the wastage of the alkyl groups by
working with thexylborane. Also the thexyl group does not migrate and unsymmetrical ketones
can be easily obtained.
R R R
R R R C C
– H2O2
CN –
B B—C N CO—O—COCF3 B N B N – R2CO
OH
R R CF3 O C—CF3 O C—CF3
Trifluoroacetic (I)
anhydride
SCHEME 7.61
One can induce the migration of the third group also on (I, R3B, Scheme 7.61) by using
as excess of trifluoroacetic anhydride, to afford tertiary alcohols on oxidation (Scheme 7.62).
R R R R
R CR3
(CF3CO)2O COCF3 H2O2
RB N B– N+ B NCOCF3 – R3COH
OH
O CF3O2C O CF3O2C O
CF3 CF3 CF3
(I, Scheme 7.61)
SCHEME 7.62
(6) Synthesis of Esters

Excellent yields of esters can be obtained by reacting trialkylboranes with e.g., ethyl
bromoacetate, (an α-haloester) in the presence of a base (eq I, Scheme 7.63). The enolate adds
to the organoborane to give a tetracoordinate boron intermediate on which the migration of an
alkyl group occurs with displacement of bromide ion. Hydrolysis of the rearranged product
gives an ester. Similar reactions are displayed by α-haloketone and α-halonitriles. The key
step in this reaction (Scheme 7.63) is again the migration of an alkyl group from boron to
adjacent carbon atom. Only one of the three alkyl groups of the trialkylborane is used in this
reaction. This problem is again solved by using an alkyl derivative of 9-BBN instead of the
trialkylborane thus 9-BBN provides two of the alkyl groups in the borane R3B. By following
this method not only the alkyl group is fully utilized, but the 9-BBN takes no part in alkylation.
R R
– – H2O
:
R3B + CHCO2C2H5 R—B—CHCO2C2H5 R—B—CHCO2C2H5 RCH2CO2C2H5

—R2BOH
Br R Br R (I)
enolate from ethylbromo acetate
SCHEME 7.63
(G) Hydroboration of Alkynes and Reactions of Derived Organoboranes

(i) Synthesis of Z-alkenes
One can make both E-and Z-alkenes from a monosubstituted alkyne. A Z-alkene can be made
by reacting a vinylborane (prepared from monohydroboration of an alkyne) with iodine.
Suzuki Reaction
Hydroboration of an alkyne with catecholborane followed by Pd(O) catalysed coupling
with an aromatic bromide gives cis stereospecificity (also see, Scheme 8.26).
1 2
R R
1 2 1 2
R R H B R R
O
O Ar—Br
O Pd(PPh3)4
H—B
NaOEt H Ar
O
Catecholborane
SCHEME 7.63a
On reaction with iodine an alkyl migration takes place from boron to carbon within an
iodonium ion (Scheme 7.64). Z-alkene is formed via anti elimination after the alkyl group
migration from an anti-periplanar transition state (I, Scheme 7.64). Thus this method, provides
a pathway for the synthesis of a Z-alkene from a monosubstituted alkyne.
O R H R2B H
RC CH + BH C C O C C
O H B H R
Catecholborane O
I2
I –
I R
H H R—B H R H RB H
I
C C C—C R C—C R C—C
H I R—B
R R R H I H I+ R
Z-alkene
Antiperiplanar
arrangement
(I)
SCHEME 7.64
(ii) Synthesis of E-alkenes

For the synthesis of E-alkenes a I-haloalkyne is used. The addition of a dialkylborane gives an
α-halovinylborane (i.e., α-haloalkenylborane). On treatment with methoxide ion, this
intermediate undergoes boron to carbon migration (Scheme 7.65) to afford an alkylated
alkenylborane. Protonolysis gives an E-alkene.
R¢Li Br2
R—C C—H R—C C—Li R—C C—Br
–R¢H –LiBr
–
MeO R
R—B H R H R H
–
syn OMe HOAc
R2BH + BrC CR¢ C C C C C C
Addition Protonolysis
Br R¢ R—B R¢ H R¢
Rearrangement E-alkene
OMe
SCHEME 7.65
EXERCISE 7.7
Depict the outcome of reaction between both a terminal and an internal alkyne
with 9-BBN followed by oxidation with alkaline hydrogen peroxide ?
ANSWER. These are given (Scheme 7.65a).
R R
9-BBN H2O2
RC C –
OH
Internal alkyne H B H OH A ketone
(enol)
1. 9-BBN
RC CH – RCH2CHO
A terminal alkyne 2. H2O2/OH An aldehyde
SCHEME 7.65a
(iii) Synthesis of Conjugated Dienes

The principles used in the synthesis of E- and Z-alkenes can be applied for an appropriate
geometry of the double bond(s) in a conjugated diene. Thus e.g., E, E-dienes can be made as
shown (Scheme 7.66). Hydroboration of a 1-haloalkyne with thexylborane affords a
thexyl-1-chloroalkenylborane. This reacts with another alkyne to give thexyldialkenylborane.
Reaction with methoxide ion induces a rearrangement of alkenyl and protonolysis affords the
diene.
H3C Cl
H3C Cl
R¢ H
H3C Cl + BH2 B-thexyl
Thexylborane H BH-thexyl
R¢
–
OMe
thexyl OMe
H3C AcOH B
R¢ H3C
Conjugated diene R¢
(E, E)-
SCHEME 7.66
(H) Formation of Alkynes from Boranes and Acetylides

Organoboranes alkylate terminal acetylenes, adduct formation occurs between a lithium
acetylide and a trialkyborane. Reaction with iodine involves an electrophilic attack of iodine
on the triple bond thereby inducing a migration of an alkyl group from boron to carbon (Scheme
7.67). This is followed by elimination of dialkyliodoboron.
– + I2
R¢3B + RC CLi RC C—BR¢3 Li RC CR¢
Reactants
I—I R¢ I BR¢2
R—C C—BR¢3 C C R—C C—R + R2BI
–
R R¢ Product
SCHEME 7.67
7.7 ORGANOMETALLIC REAGENTS

(A) Introduction
The compounds of lithium and magnesium are important organometallics, where the metals
are highly electropositive. The polarity of the metal-carbon bond is such so as to place high
electron density on carbon. Thus these reagents are strong sources of nucleophilic carbon.
(B) Grignard Reagents

Organometallic compounds RMgX are called Grignard reagents after the French chemist
Grignard (Nobel Prize 1912). An alkyl halide (RX) with its electrophilic group is converted into
its nucleophilic analog (I, Scheme 7.68) umpolung, reverse polarization as seen in 1, 3-dithianes
(Sec 7.4D). Ether solvent is essential for its formation because the magnesium atom of a Grignard
reagent is surrounded by only four electrons and it needs two more pairs of electrons to form
an octet. The solvent molecules provide these electrons by coordinating (supplying electron
pairs) to the metal. Coordination allows the Grignard reagent to dissolve in the solvent.
The organometallic compounds from when the metal (Li or Mg) donates its valence
electrons to the partially positively charged carbon of the alkyl halide (Scheme 7.68).
More electronegative
+ – than carbon
d d
RCH2—Z
Z is an atom more electronegative than carbon
Electrophile as in alcohols, ethers and alkyl halides
Less electronegative (I)

– + than carbon
d d
RCH2—M
M is a metal e.g., Mg which is less electro-
Nucleophile negative than carbon
: :
Mg O + – – +
magnesium d d Mg d d
RX RMgBr CH3CH2—Br CH3CH2: MgBr
: :
O
: :
Organic halide O
Diethyl ether
Grignard reagent
SCHEME 7.68
(1) Methods of Preparation

In addition to the general method described above, the Grignards reagents are prepared by
metallation of hydrocarbons using a preformed Grignard reagent. When a C—H bond is
significantly acidic i.e., a stable carbanion can be formed, then such a C—H bond reacts with
an organometallic reagent in which the carbon is less electronegative to yield the corresponding
C—Metal derivative. Thus alkynyl Grignards and those from other acidic hydrocarbons e.g.,
cyclopentadiene are made this way (see, Scheme 2.41).
R—C CH + C2H5MgBr R—C C—MgBr + C2H6
SCHEME 7.69
(2) Reactivity
The Grignard reagent is a very powerful base, as a matter of fact this reagent contains a
carbanion. One, therefore, fails to make a Grignard reagent from an organic compound that
contains an acidic hydrogen (any hydrogen more acidic than the hydrogen atoms of an alkane
or an alkene). Thus a Grignard reagent cannot be made from an organic compound containing
an OH group, an NH group, an SH group, a COOH group, an SO3H group —C CH group. The
Grignard reagents are so sensitive to acidic compounds, that even during their preparation all
moisture has to be excluded, otherwise, the Grignard reagent will react with the acidic group
(Scheme 7.70). All OH and NH containing compounds react by replacement of hydrogen. In
+
d
–
d
R H – +
: :
R—H + R¢O: M MgBr + CH3OH + CH3OMgBr

d M
+ :OR¢
:
–
d
SCHEME 7.70
the reaction of Grignard reagents the direction of reaction is such that the magnesium atom is
transferred to a more electronegative atom. This forms the mode of reaction of Grignard
reagents, thus Grignards reagents react at the carbonyl group of aldehydes and ketones to
afford the magnesium derivatives of alcohols, which on treatment with acids give alcohols
(Scheme 7.71). Formaldehyde gives primary alcohols, other aldehydes give secondary alcohols,
while ketones reacts to give tertiary alcohols.
+ –
d d –
:
: :
C O: —C—O: —COMgX
R + MgX R Hydrolyzed to an alcohol

R—MgX
– +
d d
SCHEME 7.71
Alkenyl halides e.g., vinyl bromide are unreactive in nucleophilic substitutions, but these
can be metallated to organometallic reagents, and then these become functional (Scheme 7.71a).
R² R²
Mg/THF
CH2 CHCl CH2 CHMgCl + C O R¢—C—OH
R¢ CH2 CH
SCHEME 7.71a
(3) Reactions of Grignards Reagents

With carbonyl compounds, the addition of Grignard reagents as described above is the basis
for the synthesis of a variety of alcohols. When the carbonyl group carries a substituent which
can act as a leaving group (acyl halides, esters and anhydrides), the initially formed adduct
can break down to regenerate a C O bond and therefore, a second addition of the Grignard
reagent can occur. Thus esters give tertiary alcohols (Scheme 7.72), the reaction probably
begins with addition of the organometallic to the carbonyl function to give the magnesium salt
of the hemiacetal. Rapid elimination regenerates a C O bond for further addition.
1 1 1 1
R R R R
–+ RMgX
XMg—R C O R—C—O MgX C O R—C—OH
Y Y R R
(Y = OR, Cl)
SCHEME 7.72
Acid chlorides are more reactive toward nucleophiles and their reaction with Grignard
reagent can be effectively controlled to give ketones in high yield provided one equivalent of
Grignard reagent is used at –78°C (Scheme 7.73). Grignard reagents also add to nitriles to give
1 1
R R OMgX
+
2 H3O 1 2
C O + R MgX C R COR
2
Cl Cl R
SCHEME 7.73
the magnesium derivatives which are unreactive to further addition and on hydrolysis give
ketones via the unstable ketimines (Scheme 7.74). In these reactions the role of solvents to
increase yield has been reported.
+ +
1 2 1 2 H3O 1 2 H3O 1 2
R CN + R MgX RRC NMgX [R R C NH] R COR + NH3
Ketimine
SCHEME 7.74
EXERCISE 7.8
How primary, secondary and tertiary amides react with a Grignard reagent ?
ANSWER. The principal raction with a primary and a secondary amide is the
removal of acidic proton from nitrogen (Scheme 7.74a). The reaction with a tertiary
amide, however, provides a useful synthesis of carbonyl compounds (ketones). Recall
that –NR2 is a poor leaving group and thus it does not depart from the initially
formed adduct (Scheme 7.74a). The work up with acid provides a very good leaving
group.
– +
XMg—R H—NHCOR¢ RH + R¢CONHMgX
R¢ R¢ R¢ H R¢
– + +
H –R2²NH
XMg—R O R OMgX R O O
NR2² NR2² HNR2² R
+
SCHEME 7.74a
The reaction of a Grignard reagent with ethylorthoformate leads to the formation of an

acetal. The reaction begins with the elimination of one of the alkoxy groups (aided by magnesium
ion acting as a Lewis acid) to generate an electrophilic carbon. The two remaining alkoxy
groups tend to stabilize the resulting carbocationic species (Scheme 7.75). The acetal formed
after the addition is hydrolyzed to an aldehyde.
C 2 H 5O OC2H5 OC2H5
+
–C2H5OMgR RMgX H3O
H—C—OC2H5 – HC + RCH RCHO
–X
C 2 H 5O OC2H5 OC2H5
RMgX Electrophilic Acetal
carbon
SCHEME 7.75
Carboxylic acids are formed by reacting a Grignard reagent with carbon dioxide
(Scheme 7.76).
O
+
– + H 2+
R—MgX + C R—COO MgX R—COOH + MgX + X
O
SCHEME 7.76
Like their alkyl analogs, allyl organometallics function as nucleophiles. Although

structural rearrangements are not encountered with saturated Grignard reagents, allylic
systems give products resulting from isomerization. Allyl Grignard reagents exist in solution
as an isomeric mixture in rapid equilibrium (Scheme 7.77). Reaction of an allylic Grignard
reagent with a carbonyl compound is attended with an allylic shift (shift of the double bond)
and occurs through a six-membered transition stable (Scheme 7.77).
MgX E+ E
+
–MgX
R MgX R R MgX R
Br
MgBr
Mg OH
O CH2 O CH2 H
+ R
R—C R¢ CH2
R
R¢ CH3
R¢ CH3 CH3
Cl
Cl
Mg MgCl
Mg
O O
CH2 O CH2 CH3 CH3
CH2 CH2 CH2OH
CH2 +
H
H
O –
CO2 +
RMgBr H
C
–RH –
N N N H N CO2 N CO2H
H O H H
+ +
MgBr MgBr MgBr
Tautomerization
SCHEME 7.77
Same reactivity is observed with benzylic Grignards. Interestingly pyrrole reacts with a
Grignard reagent at its NH group to yield an N-Mg derivative which then reacts with
electrophiles at the 2-carbon atom (Scheme 7.77). One may note that in the case pyrrole (an
allylic type Grignard) the reaction is however, not assisted by the formation of a six membered
cyclic transition state.
Grignards reagents do not react with acyclic or strain free cyclic ethers. These however,
react with epoxides and the less substituted ring carbon atom of the epoxide is attacked (Scheme
7.78), thus these act as an nucleophiles in SN2 reactions with epoxides.
OH
MgBr O CH2—CH—CH3
1. ether
H2C—CH—CH3
2. H3O+
Cyclohexylmagnesium Methyloxirane 1-cyclohexyl-2-propanol

bromide
SCHEME 7.78
The reaction with epoxides is complimentary to the addition of organometallic reagents

to carbonyl compounds. Thus reaction of formaldehyde with a Grignard reagent or an
organometallic reagent extends the chain of the organometallic reagent by one carbon while
the reaction with ethylene oxide, the chain is extended by two carbon atoms (Scheme 7.78a).
1. CH2 O
R—CH2OH
2. H2O
Extension by
RMgX one carbon
or
RLi O
1. CH2—CH2
R—CH2CH2OH
2. H2O
Extension by
two carbons
SCHEME 7.78a
The epoxide rings are also opened by lithium aluminium hydride, the hydride adds
predominantly to the less hindered side of the epoxide. The initially formed alkoxide is
protonated by water and this provides yet another method for the synthesis of alcohols
(Scheme 7.78b).
CH3 CH3 CH3

– +
O LiAlH4 O Li H2O OH
R R R
S :H –
CH3 CH3
(Optically active) Stereochemistry is lost
SCHEME 7.78b
(4) Stereoselectivity
The reaction of a Grignard reagent with a carbonyl group can create a stereocenter. When
the carbonyl compound already has an adjacent stereocenter, there is predominance of one
of the two possible diastereomers. The results are in keeping with the Cram’s rule (see
Scheme 14.81).
In the case of unhindered cyclohexanones, with Grignard reagents generally there is a
preference for attack from the equatorial direction to give an axial alcohol as the major product
(Scheme 7.79).
O OH Et
EtMgBr Et OH
+
(Major product)
SCHEME 7.79
(5) Limitations—Steric effects
Grignard additions are sensitive to steric effects both in the reacting

carbonyl compound and the Grignard reagent (see Scheme 1.33).
(6) Reactions with elements other than carbon

(i) Thiols can be made by reaction with sulphur (Scheme 7.80), while sulphur dioxide reacts in
a fashion similar to carbon dioxide (Scheme 7.80).
–
+
O +
H + H
RMgX + S R—S—MgX RSH RMgX + SO2 R—S MgX R—S—OH
Thiol O
O
Sulphinic acid
SCHEME 7.80
(ii) Hydroperoxides can be made by reaction with oxygen at low temperature and
acidification of the magnesium derivative of the hydroperoxide (Scheme 7.81).
O2 +
H
Me3C—MgX Me3C—O—O—MgX Me3C—O—OH
t-Butyl hydroperoxide
SCHEME 7.81
(iii) Iodides can be made by reacting with iodine and this provides an useful alternative
to SN2 reaction (see Scheme 5.8). Iodides are prepared from chlorides or bromides via SN2
displacement (treatment with sodium iodide in acetone). This method, however, fails for the
highly hindered neopentyl bromide (see Scheme 5.8). The Grignard reagent prepared e.g.,
from neopentyl chloride on reaction with iodine gives neopentyl iodine in a good yield
(Scheme 7.82).
XMg—R I—I R—I + MgXI

I2
Me3C—CH2Cl Me3C—CH2MgCl Me3C—CH2I
Mg
Neopentyl chloride Neopentyl iodide
SCHEME 7.82
(iv) Derivatives of silicon can be made via Grignard reagents (see Schemes 7.35c and
7.37).
(C) Organolithium and Related Compounds

Organolithium compounds are more strongly nucleophilic than Grignard reagents. Although
generally organolithium compounds show similar reactivity as Grignard reagents, however,
in few instances these distinctly differ from their Grignard counterparts. Here a few such
differences are outlined.
(1) Methods of Preparation
Organolithium compounds are generally prepared by reacting an alkyl halide with lithium
metal. In several cases particularly with aryl and vinyl halides, the reagents are prepared by
metal-halogen exchange (R—Br + BuLi RLi + BuBr). The mechanism is similar to the
formation of Grignards reagents.
(2) Reaction with α, β-unsaturated compounds—1, 2 or 1, 4-addition
Organometallic compounds may add either 1, 2 or 1, 4. In the case of Grignard reagents variable
behaviour is observed depending on the structure of the conjugated system. The main reason
seems to be steric hindrance. In several cases, where Grignard reagent gives predominant
1, 4-addition, the lithium compounds react predominantly by 1, 2-addition (Scheme 7.83). In
fact if one wants to have maximum 1, 2-addition, an organolithium reagent is used. One may
specifically achieve 1, 4-addition by using lithium dialkylcuparates.
Ph O
Grignard reagents
Ph Ph
O Major product
1, 4-addition
Ph Ph OH
Ph
Ph Ph
Lithium compounds
Major product
1, 2-addition
SCHEME 7.83
(3) Reaction with Carbon Dioxide

Unlike a Grignard reagent which gives carboxylic acid on reaction with carbon dioxide, the
reaction with an organolithium compound gives ketones (Scheme 7.84). Organolithium
compounds are much more nucleophilic than Grignard reagents, and therefore, can react with
O Li—R –
R
O OLi +
+ H3O
Li—R C R—C Li C R2CO + 2 LiOH
O R OLi
O
SCHEME 7.84
the intermediate resonance stabilized carboxylate anion. Thus carboxylic acids themselves
can be converted into ketone (Scheme 7.85).
–
CO2 CO—CH3
1. CH3Li
2. H2O—H +
SCHEME 7.85
(D) Lithium DialkylcuparatesGilman Reagents

Lithium dialkylcuparates (referred to as Gilman reagents) are prepared by the reaction of two
equivalents of the corresponding organolithium reagent with cuprous iodide (Scheme 7.86).
These reagents are formally nucleophilic and have the same charge distribution as Grignard
or organolithium reagents.
4Li THF
2CH3I 2CH3Li + 2LiI 2CH3Li + CuI (CH3)2CuLi
–LiI
Organolithium Gilman reagent
reagent
Preparation of an organocuparate (Gilman reagent)
SCHEME 7.86
The following reactions point out the synthetic importance of organocuparates

• Gilman reagents react with an alkyl halide (with the exception of alkyl fluorides) and
one of the alkyl groups of the Gilman reagent replaces the halogen. Thus an alkane
can be formed from two alkyl halides—one alkyl halide is used to form the Gilman
reagent, which then reacts with the second alkyl halide (Scheme 7.87).
– + CH3CH2CH2—I
CH3CH2CH2CH2 Cu Li CH3CH2CH2CH2CH2CH2CH3 + Cu(CH2CH2CH2CH3) + LiI
2 1-iodopropane
Lithium dibutylcuparate Heptane
SCHEME 7.87
• Gilman reagents can be used to prepare compounds that cannot be made by using
nucleophilic substitution reactions. For example, SN2 reactions are not displayed by
vinyl and aryl halides but these react with Gilman reagents to form carbon-carbon
bonds (Scheme 7.88).
I – + CH3
(CH3)2Cu Li
THF, 25°C, 14h
H Br H CH2CH3
THF
C C + (CH3CH2)2CuLi C C
H 3C CH3 H 3C CH3
SCHEME 7.88
• Organocuparates generally do not react with carbon dioxide or other carbonyl

compounds, the way Grignard or organolithium reagents (Scheme 7.89).
Infact organocuparates react only with the most reactive carboxylic acid derivatives
and are particularly useful for the conversion of acid chlorides to ketones
(Scheme 7.89).
O CH3 O Br CH3 CH3C CH2
CH2 C— CuLi CH2 C— CuLi

2 2
0°C
CH3 CH3
Br CH3C CH2
– +
O O Li O
– +
H3C—Cu Li + LiCl
–Cu(CH3) CH3
Cl Cl CH3
CH3
SCHEME 7.89
• Epoxides react with lithium organocuparates to give alcohols with inversion of

configuration at the less substituted carbon atom of the epoxides as in an SN2 process
(Scheme 7.90).
CH3 H 3C
OH
O + R2CuLi
Lithium dialkylcuprate H
H R
SCHEME 7.90
• Organocuparates are highly selective to bring about 1, 4-addition reactions (i.e.,

conjugate addition) with α, β-unsaturated carbonyl compounds (Scheme 7.91). Thus
methylvinyl ketone reacts cleanly to give 1, 4-addition reaction.
CH3
– –
O Cu O –CH3Cu CH3 O H+ CH3
–
(CH3)2Cu H 3C
O
– +
O O Li O
+
(CH3)2CuLi H3O
diethyl ether
– 78°C CH3 CH3
Enolate anion from
conjugate addition
SCHEME 7.91
• Coupling reaction takes place in the presence of oxygen when organocopper reagents
are heated or even at room temperature (Scheme 7.92).
H CH3
H H
O2
CuLi H
H 3C H H3C H
2
O2
Ph2CuLi Ph—Ph
SCHEME 7.92
• Organocuparates involve oxidative addition and reductive elimination during carbon-

carbon bond formation. The reaction between iodobenzene and an organocuparate
e.g., dimethylcuparate to give toluene occurs by the pathway that is not SN2 in
character. The overall mechanism probably consists of two steps (i) oxidative addition
to the metal and the oxidation state of the copper ion increases from +1 to +3 (Scheme
7.93). Once the phenyl ring is bonded to the copper ion, the complex thus formed is
unstable and undergoes reductive elimination forming toluene and a metal containing
species.
I
–
I CH3
+ – III + + –
Li [CH3—Cu—CH3] CH3—Cu—CH3 Li + Li [I—Cu—CH3]
Cu(I) Cu(I)
Cu(III)
Mechanism with an organocuparate
SCHEME 7.93
PROBLEMS
7.1 How can one convert methylenephosphorane into keto-ylides?
7.2 Dichloromethylene (CCl2) obtained by the reaction of base on chloroform CHCl3 is trapped
by triphenyl-phosphine to give an ylide. How this ylide can be converted into a vinylidene
chloride ?
7.3 How can PhCHO be converted into PHCDO?
7.4 How can one transform (I) into (II) and (III) into (IV) by using Wittig reaction?
CHO
CH2 CH(CH2)4CH CH2
CHO
(I) (II)
(III) (IV)
7.5 Write the structure of ylides which can bring about the following epoxidations:
CH3
O O O
O
CH3CH2CH
CH2CH3
(I) (II)
7.6 (a) Which reactants one can use to synthesize the following spirocyclic compound I?
(b) How can you convert II into III, and IV into V?
O
CHO CH2CO2C2H5
(I) (II) (III) (IV) (V)
7.7 Using a Grignard reagent, describe a method to prepare 1-alkenes.

7.8 How one can prepare butane from chloroethane using the Corey-House Synthesis (see
Scheme 7.86)?
7.9 How can one prepare 2-deuteropropane from isopropyl bromide?
7.10 How can one synthesize the following aldehyde CH3(CH2)4CH O
I
7.11 Write the product from the reaction. 2CH2 CHCH2Br + 2Ni(CO)4
Cl
7.12 Write the products of reaction of cyclochexanone with (I) Li—CH Si(Me)3/H+ and (II)
Cl
with(Me)3 SiC—Li/H+ .
CH3
7.13 Write the product from reaction of each compound
CH2SiMe3
SiMe3 SiMe3
AcOH R3CCl (1) RCHO/TiCl4
+
(II) TiCl4 (2) H
(I) (III)

RCOCl + – Ph3P CH2 + –
7.1 Ph3P CH2 [Ph3PCH2COR]Cl Ph3P CHCOR + [Ph3PMe] Cl
Keto-ylide
7.2 Via Wittig reaction with a ketone
Ph3P RR C O
CHCl3 [CCl2] Ph3P CCl2 R 2C CCl2 + Ph3P O
Dichloromethylene Dichloromethylenetriphenyl- A vinylidene
phosphorane chloride
+
1. BuLi H , HgCl2
7.3 HS SH + PhCHO S S
2. D2O
S S
H2O
PhCDO
1, 3-propanedithiol H Ph D Ph
7.4 (I to II). The dialdehyde obtained after ozonolysis of (I) will undergo Wittig reaction to
give yield (II), (III to IV). When (III) is reacted with a bifunctional Wittig reagent (V).
O O Ph3P PPh3
HC(CH2)4CH + (C6H5)3P CH2 (II) (V)
7.5 CH3CH S(CH3)2 CH2 S(CH3)2

(I) (II)
7.6 (a) Cyclohexanone and diphenylsulphonium cyclopropylide.
O
+ –
(C6H5)2S— +
These will react to give an oxaspiropentane which will rearrange on treatment with
acid (see Scheme 7.26a).
(b) (II to III). By the reaction of cyclohexene with 9-BBN to give 9-alkyl-9-BBN (where
the alkyl group is cyclohexyl); followed by its reaction with CO and a reducing agent
(see Scheme 7.60).
(IV to V). This is the synthesis of a substituted acetic acid and can be undertaken as
shown, (see Scheme 7.63). Malonic ester route is another alternative for the synthesis
of substituted acetic acids.
BH3 t-C4H9OK
B + BrCH2CO2C2H5 CH2CO2C2H5
3
7.7 This can be done by using allyl halide with a suitable Grignard reagent or an
organolithium compound.
14
C
CH
H 2C CH2
PhCH2CH CH2
Ph Cl
Li
Alkylation by allylic halides often follows a cyclic mechanism. Thus allyl 1– 14C chloride
reacts with phenyl lithium to afford a major product with labelled carbon at the terminal
methylene group.
1. Li CH3CH2Cl
7.8. CH3CH2Cl
2. Cul
(CH3CH2)2LiCu CH3CH2CH2CH3
Chloroethane Lithium diethylcuprate
D2O
7.9. (CH3)2CHBr + Mg/ether (CH3)2CHMgBr (CH3)2CHD
2-deuteropropane
7.10. Via reaction of the appropriate Grignard reagent with ethyl orthoformate and by the
hydrolysis of the resulting acetal CH3(CH2)4MgBr + HC(OC2 H5)3
I
7.11. 2CH2 CHCH2Br + 2Ni(CO)4 [(CH2 CH CH2)NiBr]2 CH2—CH CH2
7.12 [Hint] For mechanism see schemes 7.35d and 7.35e
(Me)3Si CHO
Cl O
+
Li—CHSi(Me)3 H
O (I)
H3C
H3C C O
O
(II) (Me)3Si +
H
Cl
(Me)3Si—Li
CH3
CH2SiMe3 CH2SiMe3
–
+ OAc
7.13. (I), AcOH
+ Me3SiOAc
–
–OAc
Since proton is the electrophile, only double bond shift occurs.

SiMe3 –Me3SiCl R3C
(II),
OH
SiMe3 (1) RCHO/TiCL4
(III), +
R
(2) H
8
+ –
Cl—Cl—AlCl3
CHAPTER
Electrophilic Aromatic Substitution
Both benzene and an alkene are susceptible to electrophilic attack primarily because of their
exposed π-electrons (Scheme 8.1). However, benzene differs from an alkene in a very different
way, since the closed shell of six π-electrons gives it a special stability. Thus unlike an alkene,
where the carbocation formed after the initial attack of an electrophile undergoes an addition
reaction (Scheme 8.1), the carbocation (arenium ion) from benzene undergoes substitution
reactions by the loss of a proton. This loss of proton restores the aromatic sextet. Thus, e.g.,
cyclohexene reacts to give trans-1, 2-dibromoc-yclohexane. This reaction is exothermic by about
29 kcal (121 kJ) per mole. A similar addition reaction on benzene is endothermic since it leads
to loss of aromatic stability.
E E The more loosely held p-electrons of an

–
+ : Nu alkene attack a strong electrophile to form
+ E a carbocation. Subsequent attack by a
+ nucleophile gives the addition product.
H Nu
H
H H
E E
+ Product less stable than reactant
+ E by ~ 36 kcal/mole (150.6 kJ/mole).
+
Nu:
H H
Nu
Does not form
H
E
E +
+ –H
E
+
SCHEME 8.1
8.1 GENERAL VIEWTHE ARENIUM IONTHE ARENIUM ION MECHANISM

SE2 REACTION
(A) Arenium Ion
In electrophilic substitution reactions, the benzene ring acts as an electron source. The reaction
conditions employed are designed to form an electrophilic species (E+, Scheme 8.2). Once formed,
the electrophile (E+) reacts with an arene e.g., benzene itself to generate a carbocation. For
benzene the structure of the ionic intermediate after attack by E+ is a resonance hybrid of
three resonance contributing structures which can be represented by a single structure showing
the delocalization of charge (Scheme 8.2). This delocalized nonaromatic carbocation is termed
an arenium ion, or often a sigma complex, since the electrophile is joined to the benzene ring
329
via a new sigma (σ) bond. The sigma complex is not aromatic, however, because the sp3 hybrid
carbon atom interrupts the ring of p-orbitals (i.e., the cyclic system of π-electrons is interrupted).
The nature of electrophilic attack is thus highly endothermic (loss of aromaticity). The sigma
complex, consequently regains aromaticity by the loss of the proton on the tetrahedral carbon
atom with the help of a proton-accepting species, a base, B (e.g., Nu–:, to give a substitution
product (Scheme 8.1).
+ H H H H
E E E E
+
+ +
SCHEME 8.2
By using a Kèkule structure one can see that the arenium ion is a hybrid of three allylic
type resonance structures (Scheme 8.2) and each has a positive charge on a carbon which is
ortho or para to the site of electrophilic attack. The rate-determining step in this mechanism is
the step in which the arenium ion is generated (the first step) and not the step in which a
porton is lost from the arenium ion (second step). The breaking of C—D or a C—T bond is more
difficult than the breaking of the C—H bond. If the second step in the reaction mechanism is
the rate-controlling, electrophillic substitution reactions (e.g., nitration) of aromatic compounds
labelled with deuterium or tritium should be slower than those of the unlabelled compounds
(Scheme 8.3). As a matter of fact, no significant change in reaction rate for the labelled compounds
H NO2 T NO2
No difference in rate
when nitro replaces
hydrogen or tritium
+ HNO3/H2SO4 + HNO3/H2SO4 (no significant kinetic
isotope effect).
Benzene-t
SCHEME 8.3
(no significant isotope effect) is observed. Thus, the first step in the mechanism must be the
slower, rate-determining step. Benzene is an extremely weak base and is only slightly protonated
in concentrated H2SO4. Protonation of benzene (see Scheme 8.10) can be detected by carrying
out hydrogen isotope exchange reactions in acid. Benzene in contact with 80% aqueous H2SO4
and tritium over longer periods gives benzene-t when the isotope distributes between the
benzene and the aqueous acid.
The energy profile shown (Scheme 8.4) is in keeping with this type of mechanism. The
arenium ion is a true intermediate lying between transition states 1 and 2. In transition state 1
the bond between the electrophile and one carbon of the benzene ring is only partially formed.
In transition state 2 the bond between the same benzene carbon and its hydrogen is partially
broken. In the slow, rate-determining (step), the aromatic nucleus (benzene) and the electrophile
(E+) come together to form a new bond between them. Because of this bimolecular attack,
electrophilic aromatic substitution is often termed an SE2 reaction, where S stands for
substitution, E for electrophilic, and for the biomolecular nature of the reaction.
Electrophilic Aromatic Substitution 331
Rate-determining
transition state
H E
H E
+
+
Transition state
Intermediate Eact (2)

Eact (1)
H E
Energy
+
H
+
+E
Reactants: E
Step 1 is the slow, rate-determining step
Eact (1) > Eact (2) +
Products: +H
Progress of reaction
SCHEME 8.4
The arenium ion (I, Scheme 8.5) has been isolated as a crystalline compound (m.p.
–15°C) by reacting mesitylene with ethyl fluoride with BF3 as the catalyst at –80°C. On heating
the arenium ion, the normal electrophilic substitution product was reached.
Me Me Me
H Et
–80°C – Heat
+ EtF + BF3 + Et BF4
Me Me Me Me Me Me
Mesitylene Arenium ion intermediate Normal substitution product
(I)
SCHEME 8.5
The simplest of the arenium ions i.e., the benzenonium ion (Scheme 8.6) has been prepared
by the protonation of benzene in HF—SbF5—SO2ClF—SO2F2 at –135°C and has been studied
by 13CNMR spectroscopy. The resonance stabilized carbocation, the benzenonium ion (σ complex)
thus generated (Scheme 8.6) has about +1/3 charge at C-1, C-3 and C-5. In keeping with this
fact these carbons have a greater chemical shift in 13CNMR compared to C-2 and C-4 which
remain uncharged.
186.6
136.9
H H H + H 1 H
–134°C 2 52.2
H H H + H
+ + 3 5
4
178.1 186.6
HF—SbF3—SO2CIF—SO2F2 The benzenonium ion
136.9
13
C nmr chemical shifts (d)
SCHEME 8.6
Another evidence for the formation of σ complexes as intermediates in electrophilic

aromatic substitution is their trapping by nucleophiles. With suitable subtrates an addition is
observed after the electrophile attacks a position which is already substituted (ipso attack),
because now facile rearomatization by deprotonation is blocked. Thus nitration of the alkylated
benzene (I, Scheme 8.7) at 0°C gives a diene (II), with acetate acting as the nucleophile. In
several situations, however, atoms or groups other than hydrogen may be displaced from the
aromatic ring (see, Scheme 8.48d).
CH3 H 3C NO2 H 3C NO2
+ CH3CO2H
+ NO2 +
CH(CH3)2 CH(CH3)2 (CH3)2CH OCCH3

(I) ipso attack O
(II)
SCHEME 8.7
(B) Nitration of Benzene

Nitration of benzene with nitric acid requires sulphuric acid as the catalyst. The nitronium ion
which is the electrophile is obtained when H2SO4 protonates HNO3 (Scheme 8.8). H2SO4 is
also the source of base HSO4– which removes the proton in the second step.
H
+ +
:
: :
HO—NO2 + H—OSO3H O—NO2 NO2 + H 2O

Nitric acid H Nitronium ion
+
–
HSO4
–
HSO4
H NO2
+
+ NO2 + NO2 + H2SO4
Nitration of benzene
SCHEME 8.8
As an evidence for the formation of nitronium ion as the electrophile, a salt e.g., nitronium
perchlorate, NO2+ClO–4 (which is a stable, isolable compound), reacts with benzene to give
nitrobenzene in the absence of sulphuric or nitric acid. Nitric acid shows a peak in its Raman
spectrum which disappears on the addition of sulphuric acid and two new peaks are displayed,
one at 1400 cm–1 due to NO+2 and the other at 1050 cm–1 due to HSO4–.
(C) Sulphonation of Benzene

The sulphonation of benzene is normally carried out with fuming sulphuric acid (sulphuric
acid containing sulphuric trioxide, SO3), however concentrated sulphuric acid (95% H2SO4, 5%
H2O) works for “activated” rings. In either reaction the electrophile appears to be sulphur
trioxide. In concentrated sulphuric acid, sulphur trioxide is generated in the equilibrium
(Scheme 8.9) in which H2SO4 acts as both an acid and a base. Chemical kinetics show that the
rate of sulphonation depends on the concentration of benzene and sulphur trioxide and not
sulphuric acid.
–
2H2SO4 H3O + HSO4 + SO3
Generation of the electrophile, SO3
–
: O: : : : :
:
O O O
:
:
S S+ – S+ S+
:O O: :O O: O O: :O O
:
:
–
:
:
:
:
:
:
Sulphur trioxide powerful electrophile
–
HSO4 HO
H O
Slow Fast
H + SO3 + S + H2SO4
SO3 O
Attack of SO3 on benzene ring Sigma complex Benzenesulphonic acid
SCHEME 8.9
(D) Protonation of Benzene

When a proton acting as an electrophile attacks benzene, the sigma complex can lose either of
the two protons on the tetrahedral carbon. One can prove the formation of such a σ complex
from benzene by using a deuterium ion (D+) rather than a proton to show that the product
contains deuterium atom in place of a hydrogen atom (Scheme 8.10). This is achieved by carrying
out the reaction in the presence of deuteriosulphuric acid (addition of SO3 to D2O to give D2SO4).
H
D
+ D +
D + + H
SCHEME 8.10
(E) Halogenation of Benzene

Bromine and chlorine molecules are not strong electrophiles and do not react with benzene. In
the presence of a Lewis acid however, reaction occurs readily. The role of the catalyst is to
accept a lone pair of electrons from the halogen molecule, which then weakens the Br—Br
bond to provide Br+ the electrophile for electrophilic aromatic substitution. The actual
electrophile is probably the complex formed from the halogen and the catalyst, rather than a
halonium ion e.g., Br+.
+ – + –
:
Br—Br FeBr3 [Br—Br—FeBr3] Br + [FeBr4]

(Complex) Bromonium ion
–
H Br—FeBr3
Br
+ – Br –HBr
Br—Br—FeBr3 + + FeBr3
SCHEME 8.11
(F) Friedel-Crafts AlkylationA Carbon-Carbon Bond Forming Reaction

In the Friedel-Crafts alkylation reaction a hydrogen is substituted for an alkyl group. A
carbocation is generated during the first step of the reaction. There is not enough positive
character on the carbon atom in alkyl halides for reaction with benzene; the catalyst increases
the positive character. Aluminium chloride is the commonly employed Lewis acid.
The electrophile is a carbocation and alkyl fluorides, chlorides, bromides and iodides
can all be used. Vinyl halides and aryl halides cannot be used since their carbocations would be
too unstable if formed. As already said the electrophile may be a carbocation or perhaps more
likely the complex itself (Scheme 8.12).
+ – + –
R—X: AlCl3 [R—X—AlCl3] R + [X—AlCl3]
Carbocation
–
H X—AlCl3
R
+ – R –HX
R—X—AlCl3] + + AlCl3
(Complex)
Friedel-Crafts alkylation of benzene
SCHEME 8.12
Alcohols and alkenes generate these carbocations on their reaction with an acid and
thus these react analogously to alkyl halides. Alkenes can be protonated with HF, the fluoride
ion being a weak nucleophile does not immediately attack the carbocation. Recall that
carbocation is generated following the Markovnikov’s rule (Scheme 8.13) in the protonation step.
CH3—CH CH2 HF +
CH3—CH CH2 CH3—CH—CH3
HF
SCHEME 8.13
There are several drawbacks of the Friedel-Crafts alkylation reaction.

• The carbocations rearrange if such a rearrangement leads to a more stable carbocation.
Thus it is not uncommon for mixtures to be produced. This is seen during alkylation
of benzene with 1-chloropropane in the presence of AlCl3 (Scheme 8.14).
H 1, 2-hydride
shift
CH3CH2CH2Cl + AlCl3 CH3CHCH2 Cl AlCl3 CH3CHCH3
Incipient primary carbocation Cl
AlCl3
CH3CH2CH2Cl
+
AlCl3
Isopropyl benzene Propylbenzene

(major) (minor)
SCHEME 8.14
• Friedel-Crafts alkylations fail when the reactant contains more powerful electron
withdrawing group than halogen. Nitrobenzene is an example which for this reason
is used as a solvent for the reaction.
• Aromatic amines are reactive towards electrophilic attack, but do not undergo
alkylation reactions. AlCl3 forms a coordinate bond with the lone pair of electrons on
the N atom of the amino group. This prevents the complexations of AlCl3 with the
alkyl halide and moreover the amino group is converted into a powerful electron-
+ −
withdrawing group (C6H5 NH2 + AlCl3 C6H5 N H2— A lCl3).
• The electron donating nature of an alkyl group, assists electrophilic attack on the
benzene ring. After the initial alkylation, the product becomes more reactive than
the starting reactant leading to mixed products of alkylation (Scheme 8.15).
CH3 CH3 CH3

CH3
CH3Cl
+ + + Trimethylbenzenes
AlCl3
+ Tetramethylbenzenes
CH3
SCHEME 8.15
• Alkylation is reversible and an alkyl group can migrate from one molecule to other.
This may lead to mixture of products. However, often advantage can be taken to
transfer a tert-butyl group from one arene to another (Scheme 8.16).
C2H5 C2H5 C2H5 C2H5

OH OH
AlCl3, 25°C, 3h
+ +
C(CH3)3 Solvent C(CH3)3
SCHEME 8.16
• Tertiary alkyl groups are most easily introduced during alkylation and depart as well
most readily to give relatively stable carbocations. Thus, t-butyl group has been used
in the protection of most reactive position in a reactant to instead initiate reaction
elsewhere. After the protection, the t-butyl group is removed by adding excess of
benzene to derive the equilibrium in the desired direction (Scheme 8.17).
C(CH3)3 H C(CH3)3 H
HCl—AlCl3
+ + (CH3)3CCl
–
AlCl4
CH3 CH3 CH3 CH3

COCH3 Benzene COCH3
(CH3)3CCl CH3COCl HCl—AlCl3
AlCl3 AlCl3
C(CH3)3 C(CH3)3
Friedel-Crafts alkylation Friedel-Crafts Removal of
(protection of p–position) acylation t-butyl group
SCHEME 8.17
β-keto aryl amides or β-keto aryl esters act as alkylating agents in the presence of
proton acids leading to the synthesis of quinolines or coumarins (see Scheme 6.51a).
(G) Friedel-Craft Acylation Reaction

Acylium cations are generated by the reaction of acid halides with aluminium chloride. The
Lewis acid initially coordinates to the carbonyl oxygen. This complex is in equilibrium with an
isomer in which the aluminium chloride is bound to the halogen. Dissociation then gives the
acylium ion, which is stabilized by resonance, most of the positive charge resides on the carbonyl
carbon (Scheme 8.18). Reagents are not limited to acyl halides, but carboxylic acids, anhydrides
and ketenes are also used.
–
AlCl3
+
:O: :O :O:
+ – + + –
: :
: :
: :
RC—Cl : + AlCl3 RC—Cl : O:
: :
RC—Cl—AlCl3 [RC RC O] + AlCl4
Acylium ion
(I)
(II)
SCHEME 8.18
In the lewis acid catalysed acylation reaction two electrophiles are involved, one is the
oxygen bound complex (I, Scheme 8.18) and the other is acylium ion which attack the benzene
ring (Scheme 8.19). Which of the two is more effective in a particular case depends on the
nature of R (for example, formation of the acylium ion is favoured when R is aromatic, since its
positive charge can be delocalized on to the aromatic ring).
–
AlCl3
+
– O :O
Cl—AlCl3
O H C
R CR
–HCl R + AlCl
C+ + C 3
R O
– + –
O—AlCl3 O—AlCl3 O
–
+O—AlCl
R
3
C C C
Cl –HCl –AlCl3
+ C—R + R R
H
Cl
(I from Scheme 8.18)
SCHEME 8.19
The major disadvantages seen in the case of Friedel-Crafts alkylation are not found
here. Rearrangement in R is never observed and since RCO is a deactivating group, the reaction
stops after one group is introduced. The effect is accentuated by the formation of a strong
complex between the aluminum choride catalyst and the carbonyl function of the product ketone
(Scheme 8.19). This complexation removes the AlCl3 from the reaction mixture and requires
the use of at least one full equivalent of the Lewis acid for the reaction to go to completion.
Aqueous work-up is required to liberate the ketone from its aluminium chloride complex.
One has already seen that use of longer alkyl chains than ethyl is complicating due to
carbocation rearrangements (see Scheme 8.14). Acylium ions, do not rearrange, however, thus
straight chain alkyl groups can be placed on the benzene ring via Friedel-Crafts acylation and
then reducing the carbonyl group to the methylene. Several methods can be used for reduction
O
O CCH2CH2CH3 CH2CH2CH2CH3
1. AlCl3 H2
+ CH3CH2CH2CCl
2. H2O Pd
Acyl-substituted benzene Alkyl-substituted benzene

without rearrangement
in the alkyl chain
SCHEME 8.20
when a ketone carbonyl group is adjacent to a benzene ring it can be reduced to a methylene
group by catalytic hydrogenation (H2/Pd). Reduction of a carbonyl group to a methylene can be
achieved by other methods namely by Clemmensen reduction (Zn/Hg/HCl) or via Wolff–Kishner
reduction (heating with NH2NH2 and base).
Friedel-Crafts acylations have an important role to bring about ring closure provided
the group introduced is in the proper position (Scheme 8.21). With cyclic anhydrides, the product
contains a COOH group in the side chain which can be involved in cyclization by carrying out
an intramolecular Friedel-Crafts acylation.
O O
1. Reduction
O 2. SOCl2 AlCl3
AlCl3
HOOC HOOC
O
a-tetralone
SCHEME 8.21
EXERCISE 8.1
Give the mechanism of formation of acylium ion from a carboxylic anhydride.
ANSWER. It is in (Scheme 8.22).
–
AlCl3
+
:O: :O: :O :O: :O: :O:
+
: :
: :
RC—O—CR + AlCl3 RC—O—CR RC—O—CR

–
AlCl3
: O:
+ + –
: :
: :
[RC O: RC O] + Cl3AlOCR
SCHEME 8.22
EXERCISE 8.2
Why benzene reacts with trimethylacetyl chloride in the presence of AlCl3
to give t-butylbenzene, while anisole reacts to give the normal product
CH3OC6H4CO(CH3)3 ?
ANSWER. Benzene is relatively less reactive and the acylium ion has the time to
break down to CO and stable t-butyl carbocation (Scheme 8.23).
C(CH3)3
AlCl3 + –CO +
(CH3)3CCOCl (CH3)3CCO (CH3)3C +
–H
SCHEME 8.23
EXERCISE 8.3
Write the reagents for the conversion (Scheme 8.24).
O
O
(I) (II)
+ Cl
Br
(III)
Hexylbenzene
SCHEME 8.24
ANSWER. I, AlCl3 (–HCl); II, (1) NaBH4; (2) HBr2; III LiAlH4.
OTHER METHODS TO INTRODUCE STRAIGHT CHAIN

ALKYL GROUPS ON A BENZENE RING
• By using Gilman reagents (see Scheme 7.88) as shown (Scheme 8.25).
Br CH3
+ (CH3)2CuLi + CH3Cu + LiBr
(A Gilman reagent)
SCHEME 8.25
• By using Suzuki reaction. This is a versatile reaction for making carbon-carbon

bonds and involves a palladium catalysed coupling of an organohalide and an
organoborane. The desired organoborane can be made by reacting an alkene
with catecholborane (Scheme 8.26).
O O
CH3CH CH2 + H—B CH3CH2CH2—B
O O
Catecholborane
Cl O CH2CH2CH3 O
Pd(PPh3)4
+ CH3CH2CH2—B NaOH
+ HO—B
O O
An organoborane Propylbenzene
SCHEME 8.26
8.2 ELECTROPHILIC SUBSTITUTION ON MONOSUBSTITUTED BENZENES

ORIENTATION AND REACTIVITY
The reactivity of a monosubstituted benzene (C 6H5—S) and the orientation of incoming
substituent depends on the nature of the substituent (S) already present on the ring. A
monosubstituted benzene on electrophilic substitution may give three possible disubstituted
products (ortho, meta, and para isomers). From the yields of these isomers, it is possible to
separate the substituents into two groups the o, p-directors which give predominantly o, p
products and the m-directors which give mainly the meta products. The following points will
help to understand both the reactivity i.e., if the reaction will be slower or faster than with
benzene and orientation of the incoming group in a monosubstituted benzene derivative, i.e.,
the position (o, m or p) which the new group will take.
(A) Activation and DeactivationTheory of Orientation

(i) Inductive Effect
The terms activation or deactivation are applied when the reactivity of a monosubstituted
benzene (C6H5—S) in electrophilic substitution reactions is compared with benzene (C6H6)
under the identical conditions. An electron-releasing group i.e., +I effect of the substituent
helps to stabilize the positive charge of the reaction intermediate (the σ complex) produced in
the rate-determining step by furthering the delocalization of the charge (Scheme 8.27). This
will serve to lower the activation energy in the rate-determining step relative to that of benzene.
Thus, the compound (C6H5—S) where S has +I effect will undergo electrophilic substitution
reactions more readily than benzene itself (i.e., faster rate or milder conditions). Such a group
is said to be an activating group. An example is of methyl group in toluene (Scheme 8.27). On
the other hand, an electron-withdrawing group, (– I effect) will exert the opposite effect. It
destabilizes the positive charge of the raction intermediate (the σ complex) in the
rate-determining step by depleting electron density away from the ring, thus intensifying the
positive character of the ring carbons compared with benzene to raise the activation energy of
its rate-determining step, thus rendering the compound C6H5—S less reactive than benzene in
electrophilic substitution reactions. Such a group is called a deactivating group and examples
are of –N+Me3 group and trifluoromethyl (CF3) group (Scheme 8.27).
CH3 CH3 CF3 CF3

+ +
E E
+ +
E H E H
Arenium ion is Arenium ion is
stabilized destabilized
SCHEME 8.27
(ii) Mesomeric Effect

A substituent however, releases electron density to the aromatic ring or depletes electron
density from it via both inductive (I) and mesomeric (M) effects. This is explained by taking
following examples:
Toluene: The CH3 group is activating and +I and +M effects (caused by hyperconjugation)
work together to push electron density into the ring (Scheme 8.28), therefore, toluene is more
susceptible to electrophilic attack than benzene.
H H H H
+ + +
H—C—H H—C H H—C H H—C H
:– –:
–
:
a + I effect + R effect (hyperconjugation)
SCHEME 8.28
Anisole: When a substituent has a lone pair on the atom which is directly attached to
the benzene ring, the lone pair can get delocalized into the ring; the substituent is said to
donate electrons by resonance (mesomeric effect). Substituents e.g., NH2, OH, OR, and Cl
donate electrons by resonance and these also withdraw electrons inductively since the atom
attached to the benzene ring is more electronegative than a hydrogen (Scheme 8.29).
:OCH3 +
:
:OCH3
:
+ OCH + OCH OCH3

3 3
–
–
:
–
:
Electrons are donated to the benzene ring by mesomeric effect +M (resonance)
SCHEME 8.29
Nitrobenzene: When a substituent is attached to the benzene ring via an atom which
is doubly or triply bonded to a more electronegative atom, the π-electrons of the ring can get
delocalized onto the substituent. Thus C O, C N, and NO2 withdraw electrons by resonance.
and these substituents also withdraw electrons inductively since the atom attached to the
benzene ring has a full or partial positive charge and, is thus more electronegative than a
hydrogen (Scheme 8.30).
– – – – – – – –
:O O: :O O: :O O: :O O: :O O:
:
: :
: :
: :
:
: :
: :
: :
: :
: :
+ + + + +
N N N N N
+ +
+
Electrons are withdrawing from the benzene ring by mesomeric effect (–M)
SCHEME 8.30
(B) An Introduction to Relative Reactivity of Substituted Benzenes and Orientation

• Electron-donating substituents (activating substituents) activate the benzene ring to
electrophilic attack to results in the formation of the ortho- and para- disubstituted
benzene derivatives.
• Electron-withdrawing substituents deactivate the ring for attack by electrophiles,
which occurs at the meta position (Scheme 8.31).
Me Me Me NO2 NO2
NO2
HNO3 HNO3
+
H2SO4 H2SO4
NO2
NO2
CH3 is an electron donating substitutent NO2 is an electron withdrawing substitutent
SCHEME 8.31
• All the strongly activating substituents (Scheme 8.32) donate electrons into the ring
by resonance and withdraw from the ring inductively. These however, have been
found experimentally to be strong activators to indicate that electron donation into
the ring by resonance has more significance than inductive electron withdrawl from
the ring (i.e., +M effect dominates over the inductive effect –I ).
:
:OH :NH2 :OR
:
Strongly activating groups of –I and +M type—these are o, p-directing
SCHEME 8.32
• All strongly deactivating groups (Scheme 8.33) strongly withdraw electron density
from the benzene ring both via; inductive (–I) and mesomeric (–M) effects (one may
note that ammonium ions have no mesomeric effect, however, the positive charge on
the nitrogen atom strongly withdraws electrons by inductive effect.
O –
O O
+ + +
O S—OH N C N NR3
Strongly deactivating substituents–meta directing

SCHEME 8.33
• The relative stabilities of the three carbocations formed by the attack of the incoming
electrophile (ortho-substituted carbocation, meta-substituted carbocation and para-
substituted carbocation) help to predict the preferred pathway of a reaction. More
stable the carbocation, the less energy will be needed to generate it and any feature
which affects its stability will influence its ease of formation and thus the outcome of
the reaction.
(C) Examples of Ortho-, Para-Directing Groups

Except for alkyl and phenyl substituents (which are o, p- directing) all of the ortho, para directing
groups have atleast one non-bonding electron pair on the atom directly attached to the benzene
ring (see Scheme 8.32). The resonance effect of the amino group is far more important than its
inductive effect in electrophilic aromatic substitution, to make the amino group electron
releasing. Consider the resonance structures of the arenium ions (carbocations) resulting from
ortho and para attack (Scheme 8.34) on aniline. The structures (I and II, Scheme 8.34) apart
from the same sets of three resonance structures are relatively stable.
In these structures the nonbonding pairs of electrons on nitrogen form an extra bond
with the ring carbon. This extra bond and the fact that every atom in each of these structures
has a complete outer octet of electrons renders these structures the most stable of all of the
contributors. Because these structures are highly stable thus these make a large and stabilizing
contribution of the hybrid. However, no such structure can be drawn following meta attack
and thus the cation derived from this mode of attack is not additionally stabilized. This means
that the ortho-and para-substituted arenium ions are for more stable than the arenium ion
that is formed from meta-attack. The consequences of the involvement of the amino group are
to stabilize the arenium ions formed after ortho and para attack which lowers the energy of
+
: NH2 : NH2 : NH2 : NH2 NH2
E E E E
E+ +
H H H H
+ +
Relatively stable
contributor
Ortho attack (I)
Immonium ion structure
: NH2 : NH2 : NH2 : NH2
+ +
E E E
E+ H H + H
Metta attack
+
: NH2 : NH2 : NH2 NH2 : NH2
+ +
E+ E H E H E H E H
Para attack Relatively stable
contributor
(II)
Immonium ion structure
+
Attack of an electrophile E on aniline at the three possible positions (ortho, meta and para)
SCHEME 8.34
activation for their formation (see Scheme 8.4). A point of further significance is that an
additional (fourth) canonical form can be drawn for the arenium ions resulting from ortho and
para attack. This fourth resonance structure confers extra stability on the intermediate and
lowers the energy of the transition state leading to it. This however, is not so when the attack
is meta. Thus just like immonium ion structures (Scheme 8.34), the oxonium ions from anisole
and halonium ion structures from a halobenzene from attack on o and p-positions greatly
stabilize the intermediate involved is each case (Scheme 8.34a).
+ + +X +X
OCH3 OCH3
E E
H H
E H E H
Oxonium ions Halonium ions
SCHEME 8.34a
Acyl derivatives of aniline and phenol are much less reactive with a smaller activating
effect. The unshared pair of electrons on nitrogen or oxygen is readily delocalized within the
substituent and is thus not readily available for π orbital overlap in the electron deficient
transition state as shown for example in the case of an acyl derivative of aniline (Scheme 8.35).
–
:O :O :
:
O O
+
:O—CR
:
:
NH—CR HN—CCH3 HN CCH3
The unshared electron
pair on nitrogen is readily
delocalized within the
substituent
O O
+
:
HNCCH3 HNCCH3
The unshared electron pair on –
:
nitrogen is donated into benzene
etc.
ring by mesomerism, however,
less readily
Acyl derivatives of aniline and phenol are moderately activating groups
SCHEME 8.35
EXERCISE 8.4
Why direct nitration of aniline is not a satisfactory reaction ? How it can be carried
out ?
ANSWER. Aromatic amines are highly susceptible to oxidation and nitric acid is
a strong oxidizing agent. Nitration is therefore, carried out on its acyl derivative
which reacts more slowly and then acyl group is removed by hydrolysis (Scheme
8.36). [Aniline is so reactive towards bromination that 2, 4, 6- tribromoderivative
is formed instantaneously. Acetanilide, however reacts more slowly and the
monobromoderivative (mainly para) is isolated. (Recall that both electrophiles
and oxidizing agents seek electrons)].
NH2 NHCOCH3 NH2
1. CH3COCl/base Acid
2. HNO3/H2SO4 hydrolysis
NO2 NO2
p-nitroacetanilide
SCHEME 8.36
MODERATING THE ACTIVATING POWER OF NH2 AND OH GROUPS

Recall that NH2 and OH are highly activating groups and consequentially it is
difficult to stop electrophilic attack on aniline and benzene at the monosubstitution
stage. Use of protecting groups, acetyl for aniline (as in acetanilide) and methyl
for phenol as in anisole moderates their activating power. Deprotection can be
brought about by hydrolysis.
In Alkylbenzenes and biphenyls the alkyl and aryl groups are somewhat weakly activating
substituents (see Scheme 8.28), and are ortho-,para-directors. Consider the electrophilic
substitution on toluene (Scheme 8.37). The arenium ions (I and II, Scheme 8.37) resulting
from ortho and para attack are tertiary carbocations in which a methyl group is directly attached
to a positively charged carbon of the ring making these still more stable. No such benefit
results from attack at the meta position, which is therefore not a favoured position of attack.
H H H H
H—C—H H—C—H H—C—H H—C—H

E + E E E
+
H H H
+ +
Relatively stable
Ortho attack contributor
(I)
H H H H
+ +
E E E
E+ H H + H
Meta attack
H H H H

+
+ +
E+ E H E H E H
Para attack Relatively stable
contributor
(II)
Electrophilic attack on toluene
SCHEME 8.37
EXERCISE 8.5
How biphenyl is attacked by an electrophile? How this reactivity is effected by the
presence of electron—attracting or electron—releasing substituents on an aromatic
ring.
ANSWER. Biphenyl (a benzene with a phenyl substituent) is activated in the ortho
and para positions and slightly deactivated in the meta-position. The deactivation
in the meta-position is because of –I effect of the sp2 hybridized carbon.
+
H H H H
+ +
E E E E
+
SCHEME 8.38
After the attack of E+ (ortho or para-position, Scheme 8.38 only para attack is
shown), the positive charge on the transition state is delocalized by the phenyl
substitutent. The presence of an electron-attracting substituent slows the reaction
and substitution occurs at the ortho and para positions of the unsubstituted ring.
On the other hand, an electron-releasing substitutent increases the reactivity and
causes reaction to occur in the substituted ring.
The halogens are regarded as weakly deactivating substituents and these direct
an incoming electrophile to the ortho and para positions. If one considers
chlorobenzene, the chlorine atom is highly electronegative which influences
reactively. One finds that for electrophilic substitutions on halobenzenes, conditions
comparable to those for benzene are required. Their electron donating mesomeric
effect on the other hand governs orientation (Scheme 8.39). On electrophilic attack,
chlorine atom stabilizes the arenium ion from ortho and para attack compared to
the one from meta attack (this situation is similar to that seen in Scheme 8.34).
:Cl: + +
:
Cl Cl
H
E
H E
Chlorine atom stabilizes the arenium ion formed on ortho or para
+
attack of the electrophile (E ) relative to that from meta attack
SCHEME 8.39
(D) Examples of Meta-Directing Groups

One observes that in meta-directing groups, the atom directly attached to the ring either carries
a partial positive charge or a full positive charge (see Scheme 8.33), these substituents are
strongly deactivating and meta-directing. If one considers the electrophilic attack on
nitrobenzene e.g., nitration with HNO3/H2SO4 it is more difficult than for benzene in keeping
with the reduced electron density at the ring carbon atoms. Moreover, the reasonance
contributors (I and II, Scheme 8.40) formed after attack of the electrophile (E+) at the ortho
and para positions are the least stable since these have a positive charge on each of the two
adjacent atoms, thus the most stable carbocation is formed when the incoming electrophile is
directed to the meta-position.
–
O O
+
NO2 NO2 N
H H H
E E + E
Ortho
attack + +
(I)
– Least stable
O O
+
N NO2 NO2 NO2
+ +
Meta
+ E+ attack H H H
E E + E
Nitrobenzene
–
O O
+
NO2 N NO2
+
Meta
attack + +
H E H E H E
(II)
Least stable
Electrophilic attack on nitrobenzene
SCHEME 8.40
META DIRECTING GROUPS

The arenium ion formed from ortho and para attack always leads to one
contributing structure which is highly unstable relative to all others by having
positive charges located on adjacent atom (the positive charge is located on the
ring carbon which bears the electron withdrawing group). No such highly unstable
resonance structure is involved from a meta attack, compare with Scheme 8.41.
The meta directing groups cannot undergo Friedel-Crafts reactions, since these
reactions need a Lewis acid catalyst. In the presence of a meta director (deactivating
group) the ring will become too unreactive to undergo Fridel-Craft reactions.
Recall that activating groups are o, p-directors these are:
O O
–
—NR2, —NH2, —OH, —O:
:
: :
: :
: :
: :
—N—CR, —O—CR, —OR R, Ar

Strongly activating Activating Weakly activating
Strongly deactivating groups are m-dir+ectors:
+ +
: :
—NO2, —SO3H, X O, C N, —NR3, —CF3, —SR2 —X : , —CH2X

Strongly deactivating Weakly deactivating (o, p-directors)
OH OH OH OH
O S O O S O O S O O S O
d+
+
+ +
+
E H E H E H E
Benzenesulphonic
Highly unstable
acid
(para-attack is shown)
CF3 CF3 CF3 CF3
H H H
+
+ E E E
+ E
+ +
Trifluoromethyl Highly
benzene unstable
(ortho-attack is shown)
SCHEME 8.41
EXERCISE 8.6
..
Why aniline with its strongly activating substituent (– N H2) does not undergo
Friedel-Crafts reactions while phenol and anisole undergo these reactions?
ANSWER. Due to the formation of a + –
complex between the Lewis acid catalyst H2N: H2N—AlCl3
(AlCl3) and the lone pair of the amino
group (Scheme 8.42). The activating amino AlCl3
group is converted into a highly
deactivating group. Aniline
Activating group
Phenol and anisole however, undergo becomes deactivating.
Friedel-Crafts reactions because oxygen,
being a weaker base than nitrogen, does SCHEME 8.42
not complex with the Lewis acid, and the
expected o, p-orientation is observed.
Other examples of moderately deactivating groups which are meta directing have a
carbonyl group directly attached to the benzene ring (Scheme 8.43).
O O O
C C C
CH3 OCH3 OH
Moderately deactivating substituents

SCHEME 8.43
(E) Activating and Deactivating Substituents and their Synthetic Applications

(i) The Ortho, Para Ratio
One may expect more of the ortho product on electrophilic attack on a benzene ring with an
ortho, para-directing substituent since two ortho positions are open for the incoming nucleophile.
However ortho position is sterically hindered thus one would expect the preferential formation
of para isomer if either the substituent on the ring or the incoming electrophile (E+) is bulky.
(ii) Synthesis of Trisubstituted Benzenes
• When a disubstituted benzene has two different groups, the more powerful activating
group generally determines the outcome of the reaction (Scheme 8.44). The acetamido
group is far more stronger activating group compared to methyl, thus one observes
predominant substitution at a position ortho to the acetamide group.
NHCOCH3 NHCOCH3 NHCOCH3 NHCOCH3

directs here
Br
+ Br2 +
Br
CH3 directs here CH3 CH3 CH3
Major product Minor product
p-methylacetanilide
SCHEME 8.44
• Substitution does not occur between meta substituents since steric hindrance makes
this position between the substituents less accessible (Scheme 8.45).
Both the substituents direct the incoming

substituent to these positions
CH3 CH3 CH3 CH3

O2N NO2
HNO3/H2SO4
+ +
Cl Cl Cl Cl
5-chloro- Trace
2-nitrotoluene
NO2
m-chlorotoluene 3-chloro-
4-nitrotoluene
SCHEME 8.45
EXERCISE 8.7
Which product will dominate on electrophilic substitution of p-chlorotoluene?
ANSWER. None, since both the substituents have almost similar activating effect
(Scheme 8.46).
CH3 directs here

CH3 CH3 CH3
E
+
+ E +
E
Cl directs here
Cl Cl Cl
p-chlorotoluene
SCHEME 8.46
(iii) Synthesis of Meta-Substituted Toluenes e.g., Meta-Bromotoluene

One aims at the synthesis of p-acetamidotoluene. Since acetamido group is more strongly
activating than the methyl group despite the steric hindrance to the entry of nucleophile at its
ortho position bromination predominantly occurs meta to methyl. Removal of the acetamido
group gives the desired product (Scheme 8.47).
CH3 CH3 CH3 CH3
HNO3 [H] Acetylation

H2SO4
NO2 NH2 NHCOCH3
Br2
CH3 CH3
1. Hydrolysis
2. Deamination
Br Br
NHCOCH3
SCHEME 8.47
(iv) Synthesis of o-disubstituted Benzenes, the Role of Sulphonic Acid Group as a

Blocking Group (Reversible Sulphonation as a Blocking Procedure)
Recall that nitration of aniline is carried out by first protecting (converting) the NH2 group to
NHCOCH3 in order to moderate the high activating power of NH2 group. One could thus prepare
p-nitroaniline (see Scheme 8.36) in high yield, the acetamido group is purely a para director in
many electrophilic substitution reactions). Sulphonic acid is used in many synthetic sequences
as a blocking group which can be removed by heating in aqueous acid. Thus o-nitroaniline can
be made (Scheme 8.48) in high yield.
O O O
NH2 HNCCH3 HNCCH3 HNCCH3 NH2

O
NO2 NO2
+
CH3CCl H2SO4 HNO3 1. H /H2O
–
Pyridine SO3 2. OH/H2O
Blocking group SO3H SO3H
SCHEME 8.48
8.3 ELECTROPHILIC SUBSTITUTION IN NAPHTHALENE AND LARGER

POLYCYCLIC AROMATIC HYDROCARBONS
Naphthalene is a fused bicyclic aromatic hydrocarbon (stabilization energy = 71 kcal/mole).
Electrophilic substitution reactions on naphthalene and its derivatives occur at the α than β
position due to the relative stability of the respective intermediates (Scheme 8.48a). The
intermediate after the attack at α-position is stabilized by two resonance forms without
disrupting the aromatic sextet in the other ring. Only one structure can be drawn for this
intermediate after the attack at β-position without disrupting the aromatic sextet in the
other ring.
E H E H
+ E
+ + +
E E
More stable + Less stable

25 kcal/mol of resonance energy lost 36 kcal/mol of resonance energy lost
[a-substitution (1-substitution)] [b-substitution (2-substitution)]
Steric interaction
Less interaction
H SO3H H
SO3H
H
Naphthalene-1-sulphonic acid
Naphthalene-2-sulphonic acid
SCHEME 8.48a
Under certain conditions substitution at the β-position predominates, this is so when

the reaction is thermodynamically controlled, as in sulphonation at high temperature. In the
α-derivatives, there is steric repulsion between the substituent and the perihydrogen atom as
shown (Scheme 8.48a) and it is thermodynamically the less stable. Another situation is when
the reaction is kinetically controlled but the reagent is particularly bulky. The reaction then
occurs at the α-position and is markedly hindered sterically by the peri-hydrogen. Naphthalene
and many other polycyclic aromatic hydrocarbons are more reactive than benzene in electrophilic
aromatic substitution. The activation energy for the formation of a complex in these cases is
low than for benzene since more of the initial resonance stabilization is retained in the
intermediated that have a fused benzene ring.
In naphthalene an activating group usually directs the incoming electrophile to the
same ring and a deactivating group directs it away to the other ring preferentially at C-5 and
C-8 (Scheme 8.48). Thus 1-naphthol (I, Scheme 8.48b) undergoes electrophilic substitution at
C-2 and C-4 while 1-nitronaphthalene directs the incoming nucleophile e.g., nitronium ion to
C-5 and C-8 positions.
OH OH OH NO2
8
NO2
HNO3
+
H2SO4
5
(I) NO2 (II)
SCHEME 8.48b
The reactivies of larger polycyclic aromatic hydrocarbons are similar to those of

naphthalene. Thus e.g., the site of preferred electrophilic attack on phenanthrene is C-9 or
C-10 since the major resonance contributor to the cation formed after electrophilic attack has
two intact delocalized benzene rings (Scheme 8.48c).
+ +
E E E etc.
9
10 + H H
Major contributor
SCHEME 8.48c
8.4 ATTACK OF THE ELECTROPHILE AT A CARBON ALREADY BEARING A

SUBSTITUENT (lpso POSITION)lpso SUBSTITUTION
One has seen that during electrophilic aromatic substitution an incoming electrophile has
only three choices in attacking a monosubstituted benzene: at the o, m or p positions. The
attack of the electrophile at the carbon bearing the substituent is not competitve. Although
this is generally true, however, in some cases, the electrophile may add to a position which is
already substituted (ipso reaction). The carbocation formed after such ipso reaction can react
in one of three ways:
(A) Formation of a Substitution Product by the Loss of a Substituent

Ipso substitution is observed in the protodealkylation of an alkylbenzene, a reaction that reverses
the Friedel-Crafts alkylation. Tertiary alkyl groups are most easily removed (Scheme 8.48d).
The mechanism of this process probably begins with protonation by traces of HCl, followed by
the loss of the 1, 1-dimethylethyl (tert-butyl) cation and its subsequent decomposition to
regenerate the proton and 2-methylpropene (Scheme 8.48d). Thus t-butyl group is used to
protect the most reactive position in a compound to effect reaction elsewhere (see, Scheme
8.17). For a related reaction (see Scheme 6.55).
C(CH3)3 H C(CH3)3 H
+ + + +
H
+ + C(CH3)3 C(CH3)3 –H CH2 C(CH3)2
Ipso attack
Electrophilic Ipso substitution
SCHEME 8.48d
(B) Formation of a Diene

When the substituent cannot depart this way (e.g., a CH3 group) a nucleophile in the system
can attack the carbocation to give a diene (see Scheme 8.7). The carbocation formed after the
ipso attack of the electrophile on a phenol can yield a dienone (Scheme 8.48e).
CH3 H 3C NO2 H 3C NO2
CH3 CH3
+
HNO3/AcOH –H
OH OH O
+
SCHEME 8.48e
(C) Rearrangement after Ipso Attack

The rearrangement of alkylbenzenes to their isomers has its base in Ipso attack. An alkyl
group migrates from one carbon on the ring to another one, a situation so typical of an
intermediate carbocations. Thus o-xylene rearranges to m-xylene (Scheme 8.48f). When the
substituent already present on the ring is not a good cationic leaving group, the ipso addition
product formed initially by the attack of an electrophile may undergo a rearrangement to
provide a better leaving group. The end result of such a process may be the formation of the
normal substitution product (Scheme 8.49), e.g., during the nitration (with nitronium acetate)
of p-xylene.
Silyl group has a strong tendency to direct the incoming electrophile to the position it
occupies i.e., “ipso attack”.
CH3 CH3 CH3 CH3
CH3 H H H
+ + +
+ H CH3 CH3 + H
+
H H H CH3
SCHEME 8.48f
CH3 CH3 CH3

CH3 NO2
NO2 NO2
+ – Ac2O +
+ NO2 AcO + + H + H
CH3 CH3 CH3 CH3

1, 4-dimethylbenzene
(p-Xylene)
SCHEME 8.49
8.5 AROMATIC REARRANGEMENTS

(A) Fries Rearrangement
Phenolic esters can be rearranged by heating with Friedel-Crafts catalysts in a synthetically
useful reaction known as the Fries rearrangement. The rearrangement amounts to
intramolecular Friedel-Crafts acylation.The exact mechanism is still not known, but may follow
the path shown (Scheme 8.50). The complex between the ester and the Lewis acid eliminates
an acylium ion which gets substituted at the ortho and para positions, as in Friedel-Crafts
acylation. As in Friedel-Crafts acylation in this case as well an initial complex is formed between
the substrate and the catalyst, consequently one needs a substrate/catalyst molar ratio of
atleast 1 : 1.
Cl
–
COCH3 Cl2Al COCH3 Cl2Al
+
O O O
–
AlCl3 –CH3CO+ , –Cl
CH3CO+ –H+
Cl2Al Cl2Al
OH OH O O
COCH3 COCH3
H2O
+ +
COCH3 COCH3
Fries rearrangement
SCHEME 8.50
(B) Photo-Fries Rearrangement (See Scheme 10.48)

(C) Reimer-Tiemann Reaction (Formylation)
This is a reaction of a phenol with chloroform in basic solution to give an aromatic aldehyde
(Scheme 8.51). Although the yields are poor, the reaction is mechanistically interesting. The
OH OH
CHO
1. CHCl3
+ NaOH
2. H2O
Reimer-Tiemann reaction
– –
CHCl3 + OH :CCl3 :CCl2
Dichlorocarbene
SCHEME 8.51
reaction occurs primarily in an ortho- position unless both are blocked. The electrophile in this
reaction is dichlorocarbene produced by the reaction of chloroform with alkali. The reaction of
phenolate ion with dichlorocarbene affords a dichloromethyl derivative which undergoes a
rapid hydrolysis (Scheme 8.52). That the mechanism presented (Scheme 8.52) is essentially a
– –
:
:
:O: :O:
:
O: OH
H CHCl2 CHO
– H2O
+ :CCl2
:
CCl2
– – OH –
O O O O
CHCl—Cl CHCl –
CHCl CHO
OH
SCHEME 8.52
correct pathway is shown by the isolation of a byproduct from the Reimer-Tiemann reaction on
p-cresol (Scheme 8.53). This can arise by attack of CCl2 para to the OH group, as this position
does not contain a hydrogen, a normal proton loss cannot occur and consequently the reaction
ends when the CCl2 moiety acquires a proton. p-Cresol represent a phenol with blocked
p-position.
OH OH O
–
CHO
OH
+
CHCl3
CH3 CH3 CH3 CHCl2

p-cresol 2-hydroxy-5-methyl- (5%)
benzaldehyde 4-methyl-4-dichloromethyl-
cyclohex-2, 5-dienone
SCHEME 8.53
8.6 SOME NAME REACTIONS

(A) Gattermann-Koch Reaction (Formylation)
Formyl chloride HCOCl is unstable and decomposes to HCl and CO. Thus one cannot carry out
Friedel-Crafts formylation of benzene. The formyl group (CHO) can be introduced into the
benzene ring by treatment with CO under pressure in the presence of HCl and a lewis acid
catalyst. It has been recently found that the electrophilic species is the formyl cation formed
without the mediation of formyl chloride (Scheme 8.53a).
– + + + +
:
:C O: + H H—C O: H—C O:
formyl cation
H CHO
CHO
+ –
[HC O][AlCl4] –
+ AlCl4 + HCl + AlCl3
SCHEME 8.53a
Formylation fails with aromatic compounds of lower nuclear reactivity than the
halobenzenes, so nitrobenzene is used as solvent. It is also unsuccessful with amines, phenols,
and phenol ethers because of the formation of complexes with the Lewis acid.
(B) Gattermann Aldehyde Synthesis (Formylation)

This is an alternative to Gattermann-Koch reaction in which carbon monoxide is replaced by
+
HCN. The ionic intermediate C H NH, analogous to formyl cation is thought to be the
electrophile (Scheme 8.53b). The reaction gives poor yields with benzene and halobenzenes
and gives reasonable yields with aryl ethers and phenols.
AlCl3 + +
HCl + HCN HN CHCl [HC NH HC NH]
HC NH CHO
AlCl3 –
OH
+ HN CHCl HCl +
SCHEME 8.53b
(C) Vilsmeier Reaction (Formylation)

Activated aromatic compounds e.g., N, N-dimethylaniline can be formylated by using a mixture
of dimethyl formamide HCON(CH3)2 and phosphorus oxychloride POCl3. The electrophilic
+
species is chloroiminium ion (CH3)2 N CHCl (Scheme 8.53c). The hydrolysis of imine formed
as an intermediate completes the synthesis.
H
O
+ –
:
(CH3)2N O Cl3P O (CH3)2N CH PCl2—O
Dimethylformamide Cl
O
–
– Cl2P—O
+ +
(CH3)2N—CHCl (CH3)2N CHCl
Electrophilic species
N(CH3)2
H Cl +
Cl
–H
(CH3)2N— + —CH (CH3)2N— —CH
Cl
N(CH3)2 N(CH3)2
:
+ –
H N(CH3)2 –Cl
N(CH3)2
H2O +
(CH3)2N— —CH N(CH3)2
Imine
CHO
Mechanism of Vilsmeier reaction
SCHEME 8.53c
8.7 ELECTROPHILIC SUBSTITUTION ON HETEROAROMATIC COMPOUNDS

Several system like furan, pyrrole, thiophene and other heterocyclic compounds having the
oxygen, nitrogen or sulphur atom in a structure in which it contributes two π-electrons belong
to the π excessive group. This is shown by their resonance structure (see Scheme 2.40), and
this donation of lone electron pair on heteroatom to the diene unit makes the carbon atoms in
these systems electron rich and therefore, more susceptible to electrophilic aromatic substitution
than those in benzene. The reactivity order is pyrrole > furan > thiophene (Scheme 8.54) and
this reflects the order N > O > S for electron donating capacity.
> >
N O S
H
Pyrrole Furan Thiophene
Electrophilic aromatic substitution
SCHEME 8.54
The order N > O is expected on the basis of electronegativity, while the order O > S
points to the better overlap of the oxygen 2p orbital when compared to the sulphur 3p orbital,
with the carbon 2p orbitals of the ring. During electrophilic substitution in these simple five
membered heterocyclic rings (Scheme 8.54) position selectivity is usually 2 > 3. One accounts
for this regioselectivity on the basis that the controlling step is the attachment of the electrophilic
regent (E+) to the aromatic ring in order to give the most stable intermediate carbocation. This
approach explains the position selectivity (2 > 3) in these compounds and is explained by taking
the example of pyrrole (Scheme 8.55).
H H H H H H H E H E
4 3
+ H H
5 2 + +
H H + H +
:
:
H N1 H N H N H N H N
H E H E H E H H H H
Electrophile at C-2—Formation of a more stable carbocation Electrophile at C-3
SCHEME 8.55
Both modes (attack at either C-2 or at C-3) benefit from the presence of the resonance
contributing heteroatom, but attack at C-2 gives an intermediate with an additional resonance
structure, i.e., now the positive charge is delocalized over three atoms. Thus indicating this
position to be the preferred center of substitution. As already explained, the carbon atoms in
these five membered heterocycles are electron rich and therefore, undergo nitration,
halogenation, sulphonation and Friedel-Craft acylation and are more reactive than benzene.
These heterocycles e.g., resemble the most reactive benzene derivatives like amines and phenols
in undergoing reactions like nitrosation, Riemer-Tiemann reaction and coupling with diazonium
salts. The reaction (I, Scheme 8.56) is an example of the Friedel-Crafts acylation. Furan and
pyrrole are polymerized by acidic nitrating systems, and 2-nitro-derivatives are obtained by
nitration by using acetyl nitrate CH3COONO2 formed by mixing acetic anhydride with nitric
acid.
O O
NO2
(CH3—C—O—N+
(CH3CO)2O –
CH3 O
BF3, CH3COOH +
: :
: :
O O C 5°C NO2
:
N N N
Furan O H H H
Pyrrole (Major) (Minor)
SCHEME 8.56
EXERCISE 8.8
Predict the poducts of Reimer-Tiemann reaction from pyrrole.
ANSWER. Pyrrole is close to phenol in its reactivity with electrophiles. The reaction
proceeds through pyrrolate anion and introduces CHO group at C-2 to yield pyrrole
2-aldehyde (Scheme 8.56a) 3-chloropyridine is also formed.
H2O
H
CHCl2 CHO
N N
: CCl2 H H
+
CCl2
: :
N N N Cl
H – Cl
C –Cl
–
– Cl
N N
SCHEME 8.56a
A revealing trend in reactivities of the three heterocyclic compounds is found during

their reaction with maleic anhydride. Pyrrole is significantly reactive toward electrophiles to
take part as a nucleophile e.g., in a Michael addition (see Scheme 6.32) (Scheme 8.57). Furan
is less reactive toward electrophiles compared to pyrrole, which instead undergoes the
Diels-Alder reaction (Scheme 8.57). Here it differs from benzene since less aromatic stabilization
energy is lost on 1, 4-addition. Thiophene is not only less reactive to electrophiles but is less
reactive as a conjugated diene as well, thus it does not react in a Diels-Alder reaction under
normal conditions.
O H O
+
Michael N H2O
O H O
addition CO2H
:
N N
H O –
O CO2H
H
Pyrrole Maleic anhydride
O H O
O + O O O
Furan O H O
SCHEME 8.57
Compounds like pyridine incorporate the –N CH– unit and are π-deficient and are
deactivated to electrophilic attack. Pyridine has an sp2 -hybridized nitrogen atom. In contrast
to pyrrole, there is only one electron in the p-orbital that completes the aromatic π-electron
arrangement of the aromatic ring, as is the case with phenyl anion, the lone electron pair is
located in one of sp2-hybrid atomic orbitals in the molecular plane (see Scheme 2.39b). Thus in
pyridine the heteroatom does not donate excess electron density to the rest of the molecule.
Moreover, in pyridine the –N CH– unit is basic because the electron pair on the nitrogen
does not from a part to the aromatic π system, consequently, nitrogen gets protonated or
complexed with a Lewis acid under many of the conditions which are typical of electrophilic
substitution reactions. This is another factor for the low reactivity of pyridine derivatives
towards electrophilic substitution.
For pyridine, the reactivity towards electrophilic substitution is C-3 > C-4, C-2 and it is
found that substitution (which needs vigorous conditions, like that in a highly deactivated
benzene derivative) occurs mainly at the 3- or β- position. The ring nitrogen acts as a very
strong destabilizing “internal” electron withdrawing substituent in the intermediates formed
by attack at 2- and 4-positions (Scheme 8.58, attack only at C-2 is considered here, attack at C-
4 position is similar to that at C-2 position just as ortho attack resembles para attack in the
benzene series). The nitrogen also deactivates the C-3 position, but less than the 2- and
4-positions. When one considers the intermediates formed by electrophilic attack at C-2 or C-4
and compares these with formed by attack at C-3 (β-position) it is found that in the former case
on structure (shown in box) is especially unstable because in it the electronegative nitrogen
atom has only a sextet of electrons, thus substitution takes place predominantly at the C-3
position.
H H H
H 4+ E H E H E
5 3 H H H Electrophile at C-3
+ + (preferred)
6 N 2 N N
H H H H H H
:
:
1
H H H
H H H H H + H
+
H H H Electrophile at C-2
H N+ H N H N
E E E
:
Unstable
SCHEME 8.58
8.8 DIAZONIUM COUPLING

Diazonium ions are only weakly electrophilic and react particularly with only those aromatic
reactants which are powerfully activated towards electrophiles e.g., amines, phenols and
heterocyclic systems such as pyrrole. The mechanism of electrophilic aromatic substitution
using an arene diazonium ion is similar to electrophilic aromatic substitution with an
electrophile (Scheme 8.59).
H +
+ + –H N
:
(CH3)2N— N N—Ar (CH3)2 N (CH3)2N

N—Ar
N N
Ar
SCHEME 8.59
Azo benzenes are coloured compounds and are used commercially as dyes. Diazonium
compounds are synthetically useful and may react to form an aryl cation by the loss of nitrogen
in an SN1 reaction, or the loss of nitrogen may generate a radical via one electron reduction
(Scheme 8.60).
+ –N2 + e– .
Ar—N N Ar+ Ar—N N Ar + N2
One electron reduction
SCHEME 8.60
The utility of these is several synthetic reactions e.g., Gomberg reaction, Sandmeyer
reaction etc. (see Chapter 16 on the free readicals)
PROBLEMS
8.1. Two procedures are available for the synthesis of 2-phenylethanol. Point out the route
one would select and why?
Br MgBr CH2CH2OH
O
Br2 Mg 1.
(I)
FeBr3 Et2O 2. H+
2-phenylethanol
Br
CH2CH3 CHCH3 CH CH2 CH2CH2OH
CH3CH2Br NBS, D Base 1. BH3

– (II)
AlCl3 peroxide 2. H2O2/OH
8.2. Direct nitration of t-butylbenzene to introduce a NO2 group at the ortho position gives
poor yields of the o-disubstituted product and the NO2 group is introduced mainly at the
p-position. How one can solve this problem?
8.3. Explain the result of nitration in the following alkylbenzenes:
CH3
CH3 CH2—CH3 CH3—CH—CH3 CH3—CH—CH3
Toluene Ethylbenzene Isopropylbenzene tert-Butylbenzene
1.57 0.93 0.48 0.22

The ortho/para ratios are for nitration
8.4. Which of the following products formed by the nitration of p-cymene with nitronium
acetate can be assigned due to Ipso substitution?
CH3 CH3 CH3 CH3

NO2
+ + + CH2 CHCH3
NO2
CH(CH3)2 NO2 CH(CH3)2 CH(CH3)2
1-Isopropyl-4-
methylbenzene (I) (II) (III) (IV)
(p-Cymene)
8.5. The 2-3 benzo derivative of pyrrole i.e., indole undergoes electrophilic substitution mainly
at the 3-position. Explain.
8.6. Toluene on Friedel-Crafts acylation yields mainly the para acyl derivative. How can you
obtain ortho derivative in high yield ?
8.7. The following phenol gives a dienone on nitration (HNO3–AcOH). Explain.
CH3
CH3
OH
8.8. Nitration of pyridine mainly occurs at C3 (see Scheme 8.58). How one can synthesize
4-nitroderivative?
8.9. Considering Scheme 8.56a, depict a synthesis of quinoline from indole.
8.10. N-alkyl-derivatives of aniline and O-alkyl derivatives of phenol have comparable
reactivity with aniline and phenol, however, their acyl derivatives are much less reactive
in electrophilic substitution. Explain.
8.11. For the synthesis of m-nitroacetophenone from benzene show the order in which the
substituents are to be placed in the benzene ring.

8.1. One selects route (I) since the number of synthetic steps are less. Procedure (II) requires
excess amount of the reactant (benzene) to prevent polyalkylation, free radical
bromination (NBS, peroxide, ∆, see Scheme16.8) is likely to yield undesired side products.
8.2. By first blocking the p-position by carrying out sulphonation. Since both the electrophile
(SO3) and the substituent (t-butyl group) are sterically bulky, sulphonation occurs almost
exclusively at para position. Now nitration can only occur in the ortho position to the
t-butyl group and then the blocking group is removed.
C(CH3)3 C(CH3)3 C(CH3)3 C(CH3)3

NO2 NO2
SO3 HNO3/ +
H
H2SO4 H2SO4 H2O
SO3H SO3H
8.3. Among several factors, reaction temperature and steric hindrance, play a role in dictating
the ortho/para ratio. The size of the substituent already present on the ring effects
product distribution. Larger substituents “shields” to some extent the ortho position
from attack by an electrophile, and when this occurs, more para substitution takes place.
8.4. The compounds (I and IV).
8.5. Indole is activated and reacts in the hetero ring. The stabilizing influence of the hetero
atom on the transition state is more effective when the appropriate resonance structure
is benzenoid compared to when the benzenoid system is disrupted.
H E
H
Benzenoid system
+ + + E is disrupted
N N N
H H H
Indole (3-substitution) (2-substitution)
8.6. The para position in toluene is first protected by t-butylation.The acylation in then done
on the t-butyl derivative and the t-butyl group is subsequently removed (see Schemes 8.17
and 8.47).
8.7. The electrophile adds to the ipso position and the dienone is formed by the loss of the
hydoxylic proton.
CH3 CH3 NO2 CH3 NO2

CH3 CH3 CH3
HNO3 +
–H
CH3CO2H
+
OH OH O
8.8. This can be achieved by nitrating pyridine N-oxide. The mesomeric electron-release
from the oxide oxygen atom stabilizes the transition state for 4-substitution, as seen in
the contribution of the resonance structure under box. (Here as expected 2-nitro-
derivative is also formed but in small quantity.)
H NO2 H NO2 H NO2 NO2 NO2
+ + + +
NO2 –H PCl3
+ + + + +
N N N N N N
– – – –
O O O O O
Relatively stable
8.9. It can be achieved by adding methyl-lithium to indole in methylene dichloride solution,

ring expansion occurs via the addition of chloromethylene.
CH2Li H H2O
:
+ CHCl C
CH2Cl2
Cl
N N N
H
Indole Li Quinoline
8.10. In the acyl derivative the unshared electron pair on nitrogen or oxygen is already
delocalized within the substituent itself.
H H+ +
N R N R O R O R
C6H5 C 6H 5 C6H5 C6H5
– –
O O O O
(I) (II)
8.11. Both substituents of meta-nitroacetophenone are deactivating (meta directors). However,

the Friedel-Crafts acylation reaction must be carried out first because the benzene ring
of nitrobenzene would become too deactivated to undergo a Friedel-Crafts reaction.
O O
O C C
1. AlCl3 CH3 HNO3 CH3
+ CH3CCl
2. H2O H2SO4
NO2
m-nitroacetophenone
CHAPTER 9 H
H
Aromatic Nucleophilic H
Substitution H
In electrophilic aromatic substitution, a strong electrophiles replaces a proton on the aromatic

ring. In nucleophilic aromatic substitution, a strong nucleophile replaces a leaving group e.g.,
a halide (Scheme 9.1). Several mechanisms for aromatic nucleophilic substitution are known
and some of these are discussed. A nucleophile can be introduced into the ring provided it is
sufficiently π-electron deficient due to the presence of an electron withdrawing group, e.g.,
nitro (NO2). The more effective leaving groups are the halogens. The nucleophile attacks the
carbon atom to which the leaving group (a halogen atom) is attached (ipso attack). In the
product the nucleophile is on the position of the original substituent. The aryl halides themselves
undergo nucleophilic substitution with great difficulty unless strong electron-withdrawing
groups are present in the ortho or para position to the halogen atom. It is only then that the
mesomeric withdrawal of electrons is possible (Scheme 9.1) to make the cyclohexadienyl anion
intermediate stable.
Cl – Cl OH Cl OH Cl OH Cl OH OH
OH
Slow :– –: Fast
–
X
–
:
NO2 NO2 N N NO2 NO2

– + – + –
O O O O
p-chloronitro- (Product)
benzene (Resonance stabilization)
(reactant) Electrons are delocalized on to the NO2 group
ipso addition by
the nucleophile
SCHEME 9.1
9.1 THE SNAr MECHANISMTHE ADDITIONELIMINATION MECHANISMTHE

GENERAL NUCLEOPHILIC AROMATIC Ipso SUBSTITUTION
Reaction of p-chloronitrobenzene with nucleophiles e.g., hydroxide ion, replaces the halogen
with hydroxide ion (Scheme 9.1). This reaction is called nucleophilic aromatic substitution and
the key to its success is the presence of at least one strongly electron withdrawing substituent,
preferably more, on the benzene ring placed ortho or para to the leaving group. The presence
of these substituents decreases the electron density in the benzene ring, making it more
366
Aromatic Nucleophilic Substitution 367
favourable for nucleophilic attack, and, these further stabilize the intermediate cyclohexadienyl
anion by resonance. Unlike an SN2 reaction of haloalkanes, substitution in these reactions
takes place by a two-step mechanism, an addition-elimination sequence. This is the most
important two step mechanism for nucleophilic aromatic substitution where the first step is
usually (however, not always) the rate determining. A general representation of SNAr
mechanism is shown (Scheme 9.1).
In the first slow step, ipso addition by the nucleophile gives an anion with a highly
delocalized charge. The important feature of this intermediate is the ability of the negative
charge to be delocalized into the electron-withdrawing groups.
In the second step, the leaving group is eliminated to regenerate the aromatic ring.The
reactivity of haloarenes in nucleophilic substitutions increases with the number of electron-
withdrawing groups on the ring, particularly if they are in the ortho and para positions.
• The reaction becomes facile when two or more nitro groups are present in the ortho
–
and para positions as indicated by rate data (reaction with O CH3/CH3OH, 50°C).
Cl Cl Cl Cl
NO2 O2N NO2
NO2 NO2 NO2

Chlorobenzene 1-chloro- 1-chloro- 2-chloro-
4-nitrobenzene 2, 4-dinitrobenzene 1, 3, 5-trinitrobenzene
Increasing rate of aromatic nucleophilic substitution
SCHEME 9.2
• Enough reactivity is generated in aryl halides when two nitro groups are present in
favourable positions to delocalize the charge of the attacking nucleophile.
Moreover, aryl halides which have ortho- or para-nitro groups become sufficiently
reactive to display nucleophilic substitution even with neutral nucleophiles like NH3.
Thus 1-chloro-2, 4-dinitrobenzene (Scheme 9.2) on reaction with NH3 gives 2,
4-dinitroaniline.
• The presence of electron-withdrawing groups is essential at the ortho and para
positions to the site of nucleophilic attack, only then the charge of the nucleophile
(electrons) can be delocalized (Scheme 9.3).
F
– O
Nu : F
N –
–
O
+ Nu :
+
N
–
O O
SCHEME 9.3
• 2, 4, 6-Trinitroanisole does not bear a halide leaving group thus its reaction
(Scheme 9.4) with sodium ethoxide gives a Meisenheimer complex which corresponds
to the product obtained by the nucleophilic addition stage of the SNAr mechanism.
This shows that nucleophilic attack on an aryl halide initially gives a resonance
stabilized carbanion intermediate known as Meisenheimer complex by the initial ipso
addition by the nucleophile’.
NO2 NO2
O O OCH3
+ – +
N— —OCH3 + OCH2CH3 N
O O OCH2CH3
NO2 + NO2
Na
2, 4, 6-Trinitroanisole Meisenheimer complex
SCHEME 9.4
• In case this mechanism is similar to either the SN1 or SN2 mechanisms, the Ar—X
bond should break in the rate-determining step. In the SNAr mechanism however,
the bond is not broken until after the rate-determining step. As expected a change in
leaving group should not effect the rate of the reaction and this has been found to be
the case. However, the rates cannot be expected to be identical, since the nature of
leaving group X effects the rate at which nucleophile (Nu–) attacks. When the
electronegativity of the leaving group is more, there would be a decrease in the electron
density at the site of attack leading to a faster attack by the nucleophile. The fact that
from among halogens, fluoro is the best leaving group in several aromatic nucleophilic
substitutions shows this mechanism to be different from the SN1 and SN2 reactions,
where fluoro is the poorest of the leaving group from among the halogens.
The SNAr mechanism differs from the SN1 or SN2 mechanisms in that fluoride ion
is a good leaving group in the SNAr substitution but is not a good leaving group in
the SN1 and SN2 aliphatic substitution reactions. Aryl fluorides are actually better
substrates than the corresponding aryl chlorides for the SNAr reaction since the
highly electronegative fluorine atom makes its attached carbon atom more reactive
towards a nucleophile. The presence of a nitro group is still required and it should
be present in the ortho or para position to the leaving group. Moreover, like vinyl
halides, aryl halides cannot adopt the geometry necessary for a backside
displacement since the ring shields the backside of the carbon-halogen bond
(Scheme 9.4a).
—F no reaction
–
Nu:
SCHEME 9.4a
EXERCISE 9.1
A fast reaction is observed with sodium methoxide with ortho and para isomer of
fluoronitrobenzene as compared with m-fluoronitrobenzene. Explain.
ANSWER. The mesomeric withdrawal of electrons is not possible from the anionic
intermediate (Scheme 9.5). Direct conjugation of the negatively charged carbon
with the nitro group is not possible in the cyclohexadienyl anion intermediate.
F – F OCH3 F OCH3 F OCH3

OCH3 H H H H H – H
–
:
:
– – –
O: O: O:
: :
: :
: :
–
NO2 H N+ H N+ H N+
:
H H H
:O :O :O
:
:
SCHEME 9.5
The most common type of reactants in nucleophilic aromatic substitutions are those
which have o- or p- NO2 substituents. However, highly fluorinated hydrocarbons fit the
requirements for such a reaction and hexaflurobenzene undergoes substitution of one of its
fluorines on reaction with a nucleophile (NaOR, Scheme 9.6).
F OR
F F –
F F
OR
F F F F
F F
SCHEME 9.6
9.2 THE SN1 MECHANISM IN NUCLEOPHILIC AROMATIC SUBSTITUTIONTHE

ARYL CATION MECHANISMDIAZONIUM SALTS
When aryl diazonium salts are hydrolyzed in water these give the corresponding phenols. The
net result of the reaction is substitution of the nucleophile (water) for the diazonium group
(Scheme 9.7). There is sufficient evidence that this reaction proceeds through an aryl cation
(I, Scheme 9.7). In the case of aryl halides and sulphonates a unimolecular mechanism has
never been established with certainty. However, this mechanism is significant only in the case
of diazonium salts, the driving force for formation of this reactive cation is departure of the
good leaving group, nitrogen. The main evidences in support of aryl cation is the following:
• The rate of decomposition of a diazonium salt follows the first order kinetics and is
independent of the concentration of nucleophile.
• On addition of halides salts in high concentration, the product formed is an aryl halide,
however, the rate is independent of the concentration of the added salts.
+ –
NH2 N2 HSO4 OH
NaNO2 H 2O
H2SO4 D
NO2 NO2 NO2
m-Nitroaniline m-Nitrophenol
90%
+
N N: Nu
+ +
+ N2 – :Nu
(I)
SCHEME 9.7
• The isomerization (Scheme 9.8) of isotopically labelled p-toluene-diazonium 15N

fluoroborate was observed during hydrolysis. This could arise if the nitrogen breaks
aways from the ring and then returns.
+
+ – H3O + –
p-MeC6H4— N N BF4 p-MeC6H4— N N BF4
SCHEME 9.8
9.3 NUCLEOPHILIC AROMATIC SUBSTITUTION BY ELIMINATIONADDITION

THE BENZYNE MECHANISM
Haloarenes do not undergo simple SN2 or SN1 reactions. However, at high temperature and
pressure nucleophilic substitution can be achieved. Thus with hot sodium hydroxide followed
by neutralizing work-up, chlorobenzene gives phenol. Similarly chlorobenzene reacts with
sodium amide (a very strong base). One does not require high temperature in this case. It
occurs in liquid ammonia at – 33°C (Scheme 9.9). Thus unlike the addition-elimination
mechanism for nucleophilic aromatic substitution (Scheme. 9.1) which depends on strong electron-
– +
Cl O Na OH
+
2 NaOH, 350°C H
+ NaCl
H2O
Chlorobenzene Sodium phenoxide Phenol
Cl NH2
– NH3, –33°C
+ Na+ NH2 + NaCl
Chlorobenzene Aniline
SCHEME 9.9
withdrawing substituents on the aromatic ring, under extreme conditions unactivated

halobenzenes react with strong bases.
Direct substitution mechanisms are not operative on these compounds. Significantly
the incoming nucleophile appears only at the ipso or at the ortho position relative to the leaving
group. Thus, p-chlorotoluene reacts with sodium hydroxide to give a 50:50 mixture of meta and
para products (Scheme 9.10). If at all the addition-elimination SNAr mechanism was operative
here, one would expect the formation of only the para product.
To show that the incoming nucleophile does not always end up at the position vacated
by the leaving group (it appear either at ipso position or at the ortho-position relative to the
Cl OH
OH
1. NaOH, H2O, 350°C
2. H+
CH3 CH3 CH3

Chlorotoluene p-cresol (50%)
(50%)
SCHEME 9.10
leaving group), the reaction of 1–14C–chlorobenzene with sodium amide gave equal amounts of
aniline labelled in the 1 position and in the 2-position (Scheme 9.11). This and other observations
can be accounted for by an initial base induced elimination of HX from the benzene ring, a
process reminiscent of the dehydrohalogenation of alkenyl halides to give alkynes. In the present
case, step-by-step elimination through a phenyl anion intermediate gives a highly strained
and reactive species called benzyne, or 1, 2-dehydrobenzene (Scheme 9.12).
Cl NH2
NH2
– NH3 (liq)
+ NH2 +
Chlorobenzene Approximately equal amounts of

(labelled) the two products are formed
SCHEME 9.11
Cl Cl
H
– :– –
:NH2
:
+ + NH3 + Cl
Phenyl anion Benzyne

Formation of benzene intermediate
SCHEME 9.12
The benzyne intermediate is symmetrical and can be attacked by e.g., NH–2 at either of
two positions. This formation of the intermediate benzyne, thus explains why half of the aniline
produced from the radioactive chlorobenzene was labelled at the 2 position (Scheme 9.13).
:
NH2 NH2
:
–
:
:NH2
:
H—NH2
–
: :
—NH2
Benzyne
:
NH2 NH2
–
:
:NH2 :–
:
H—NH2
: :
—NH2
Benzyne
SCHEME 9.13
In some cases, the aromatic nucleophilic substitution occurs at an adjacent position and
is called cine substitution. An important feature of benzyne mechanism is that, it can be attacked
at two positions. The favoured position for nucleophilic attack is the one which leads to the
more stable carbanion intermediate. Thus e.g., in the case of –I groups, the more stable carbanion
is the one in which the negative charge is closer to the electron-withdrawing substituent.The
ortho-derivative (I, Scheme 9.14), on treatment with sodium amide gives m-(tri-fluoromethyl)
aniline (III) as the exclusive product. This is explained on the basis of intermediate formation
of the benzyne (II) which adds an amide ion in the way so as to form a more stable of the two
carbanions (Scheme 9.14). Thus, both steric and electronic factors are operative. Based on
electronic factors an anion (IV, Scheme 9.14) is more stable since CF3 group is inductively
electron-withdrawing. On steric grounds as well it is more favourable for the amide ion to
attack away from CF3 group.
CF3 CF3 CF3
NaNH2
NH3
(–NaCl) NH2
(I) (II) (III)
Benzyne m-(Trifluoromethyl) aniline
Clash
CF3
:
NH2 Less stable carbanion moreover sterically,

attack close to CF3 less favourable
CF3 :–
–
+ NH2
CF3 CF3
:– :NH3 –
:NH2
:
+
NH2 NH2
(IV)
More stable carbanion (negative charge is closer

to the electron-withdrawing trifluoromethyl group)
SCHEME 9.14
In some cases unactivated halides undergo nucleophilic substitution in

a chain reaction involving anion radicals, where the initiation step is
the electron transfer. This is SRN1 process (see Scheme 16.30).
9.4 BENZYNEA STRAINED CYCLOALKYNE

Benzyne is a highly reactive intermediate (an aryne intermediate). The formation of benzyne
−
type of intermediate from a simple haloarene is favoured when the amide ion (N H 2 ) is used as
a base. Due to its strong basic nature it successfully abstracts hydrogens from the aromatic
ring as protons with the formation of ammonia. The halide ion X– departs to give benzyne. One
must have a hydrogen ortho to the halogen for benzyne formation and its formation is favoured
with aryl halides which have electron-donating substituents. On the other hand, the presence
of electron-withdrawing substituents on the ring causes the bimolecular nucleophilic aromatic
substitution reaction to be favoured. The reason for the high reactivity of benzyne is the normal
requirement for alkynes to adopt a linear rather than a bent structure. Due to the cyclic
structure, benzyne cannot meet that requirement. The molecule has only a brief life and has
never been isolated and can be easily trapped by any nucleophile present. Thus, e.g., ammonia
solvent adds to give the product benzenamine (aniline). As the two ends of the triple bond are
equally reactive, nucleophilic addition may be at either carbon to explain the product mixtures
observed from labelled chlorobenzene. The extra bond in benzene is a result of the overlap of
sp2 orbitals on adjacent carbons of the ring (Scheme 9.15). The aromatic framework of six
π-electrons is arranged perpendicular to the two reactive and poorly overlapping additional
hybrid orbitals which make up the distorted triple bond. There is a good deal of deformation in
the molecular structure of benzyne from the regular hexagonal symmetry due to bond alteration
imposed by the presence of triple bond (44 kcal/mole). Spectral data shows the contribution by
a cumulated triene resonance structure (see Scheme 4.50).
R
R H
C
Good C Poor H
overlap overlap
C
C
R R H
Overlapping of p orbitals Bent triple bond H

in a normal triple bond Benzyne with a
distorted triple bond
SCHEME 9.15
Benzyne has been observed spectroscopically under special conditions. One successful
method is the irradiation of phthaloyl peroxide (see, Scheme 10.25) which gives species with
IR and UV spectra typical of benzyne structure (formed by the elimination of two equivalents
of CO2). There are other methods to produce benzyne in addition to base catalysed elimination
of hydrogen halide from a halobenzene. One of the convenient methods is the diazotization of
o-aminobenzoic acids (Scheme 9.16). The benzyne formed in this method in the presence of
other compounds e.g., methanol reacts with these quickly.
NH2 N2+ OCH3

+ CH3OH/D CH3OH
H /THF
+ C5H11O—NO O –CO /–N
diazotization 2 2
CO2H C
Benzyne Anisole
Anthranilic acid (I) :O : –
:
SCHEME 9.16
In the absence of any compound the zwitterion (I, Scheme 9.16) decomposes in an
entropically favourable reaction to give CO2, N2 along with benzyne which has been detected
mass spectrometrically. The peak at m/z 76 points to the presence of benzyne while the one at
m/z 152 shows its dimerization to the dimer (Scheme 9.16a). Recall that the life time of a
particle in a mass spectrometer is around 20 ns (nonasecond = 10–9 second) and during this
period atleast benzyne can exist free in the gas phase.
Benzyne (m/z 76) Dimer of benzyne

(m/z 152)
SCHEME 9.16a
One can prepare bis-Grignard reagents from aryl dihalides when the halogens are remote.
However, when halogen atoms are present ortho to each other elimination occurs to give benzyne
intermediates (Scheme 9.17). Benzyne is capable of dimerization to biphenylene when either a
nucleophile or a reactive unsaturated compound is absent. One can trap benzyne by means of
the Diels-Alder reaction, when benzyne is formed in the presence of a diene, the benzyne
reacts as the dienophile. A diene often used for this purpose is anthracene, which provides the
structurally interesting molecule triptycene (Scheme 9.18). Furans also react with benzyne to
give Diels-Alder addition products (see Scheme 10.26).
Mg, THF
Br
Biphenylene,
a stable dimer
of benzyne
F
Li, pentane Benzyne
SCHEME 9.17
Benzyne Anthracene Triptycene

(dienophile) (diene)
SCHEME 9.18
EXERCISE 9.2
Write the products from the reactions of (I and II, Scheme 9.18a)
CH3 OH
NaNH2 NaNH2
NH3(l) NH3(l)
Br (I) Br (II)
SCHEME 9.18a
ANSWER. These are given (Scheme 9.18b).

R R R R
NaNH2
(I) NH3 (l)
+
NH2
–
Br NH2 NH2
Approximately
–
The NH2 ion can attack both the carbons equal amounts
equally well since R group is away to exert
any steric effect
– – –
OH O O O
NaNH2 NaNH2
(II)
NH3 (l) NH3 (l)
– NH2
:
NH2 –
(A)
Br Br NH3 (l)
–
OH O
meta-product formation is
+
exclusive, since only then the H
two anionic centers in (A) are
as far apart as possible
NH2 NH2
H H
Exclusive
SCHEME 9.18b
9.5 NUCLEOPHILIC SUBSTITUTION OF PYRIDINETHE CHICHIBABIN

REACTION
Pyridine is less reactive than benzene towards electrophilic substitution (pyridine ring is electron
poor) and this is due to the greater electronegativity of its ring nitrogen. Nitrogen in pyridine
is less able to accommodate the electron deficiency in the transition state of the rate determining
step in electrophilic aromatic substitution. Because the pyridine ring is relatively electron
deficient, it undergoes nucleophilic substitution much more readily than benzene. A particularly
useful and both unusual and remarkable example is the synthesis of aminopyridines by the
reaction of a pyridine with an alkali metal amide (Chichibabin reaction). The reaction is initiated
by attack by the nucleophile at C-2 or C-6. This is because the negative charge on the adduct
formed by the addition of the nucleophile is stabilized by delocalization onto the electronegative
nitrogen atom (Scheme 9.19). The second step is the loss of a hydride ion. Pyridine undergoes
–
– 100°C –H
Na+ NH NH2
:
2 toluene
: :
N –N H N NH2
Na+
:
2-aminopyridine
Chichibabin reaction
Stable structure since

– : :–
negative charge is on
: :
nitrogen N NH2 N NH2 N NH2

– H H H
:
:
SCHEME 9.19
similar nucleophilic substitution reactions with e.g., organolithium compounds and potassium
hydroxide (Scheme 9.20).
KOH, O2
+ LiH
110°C, 320°C
N toluene N Ph N N OH N O
Ph 2-phenylpyridine H
Li 2-pyridinol 2-pyridone
Chichibabin-like reactions
SCHEME 9.20
9.6 NUCLEOPHILIC SUBSTITUTION TO ARENECHROMIUM CARBONYL

COMPLEXES
Ferrocene behaves as an electron-rich aromatic system and undergoes many electrophilic
substitutions (Scheme 2.41). The most important π-complexes of aromatic compounds are the
chromium complexes obtained by heating benzene or other aromatics with Cr(CO) 6
(Scheme 9.21). The Cr(CO)3 unit in these compounds is strongly electron-withdrawing and
activates the ring towards nucleophilic attack. Thus 1, 3-dithianyl anion reacts with the complex
to form a carbon-carbon bond. The reaction of the nucleophile occurs on the aromatic ring
away from the face with metal atom. The anion intermediate is stabilized by the transition
metal atom which can accommodate extra electrons. Such an aryl-metal complex however,
S H
+
1. : – Li S
Cr(CO)6 S
2. I2 (excess)
H S
Cr(CO)3
S S
H S Five electrons are
–: in the ring H Removed by the
oxidizing agent I2
S H
—H
+– One electron goes to Cr

Cr Li Cr
CO CO which still has 18 electrons
OC OC around it
CO CO
-(benzene)chromium Metal-stabilized anion
tricarbonyl
I2
H S
3+ –
HI + 3CO + Cr + 3I +
S
Oxidized Reduced
state of state of
chromium iodine
SCHEME 9.21
does not react with all carbon nucleophiles, it does not react with stabilized enolates e.g., from
diethyl malonate or with Grignard reagents or organocuparates. This aryl metal complex,
however reacts well with ions stabilized by nitriles, and with anions of carbon acids with pKa
values greater than 20.
Complexes of aryl halides undergo nucleophilic substitution of the halogens just like
halides with nitro groups (see Scheme 9.1). Thus chromium complex of fluorobenzene reacts
via nucleophilic substitution by the enolate anion of diethyl malonate to yield diethyl
phenylmalonate. This compound is an intermediate in the synthesis of barbiturates which
cannot be prepared directly from diethyl malonate in any other way (Scheme 9.22).
O
O
+–
1. Na :CH(COCH2CH3)2
—F —CH(COCH2CH3)2
2. I2
Cr(CO)3
p-(fluorobenzene)- Diethyl phenylmalonate
chromium tricarbonyl 95%
SCHEME 9.22
Also see sec. 7.2
PROBLEMS
9.1. The reaction of o-bromoanisole gives only meta-aminoanisole on reaction with potassium
amide in liquid ammonia. Explain this regioselectivity.
Br
OCH3 –
H 2N OCH3
NH2
9.2. Nucleophilic aromatic substitution has been used for the identification of amino acids
by Sanger (Nobel Prize 1958) using 2, 4-difluoronitrobenzene (2, 4-DNFB). Explain.
9.3. Show the nucleophilic attack at position 4 in pyridine?
9.4. A pyridinium ion e.g., N-alkylpyridinium ion undergoes hydride addition with lithium
aluminium hydride. Predict the nature of product. Explain if this type of reaction has
biological significance.

9.1. The reaction proceeds through the intermediate formation of benzyne. The amide addition
will occur only at the carbon that will lead to the more stable carbanion where the
negative charge will be closer to the –I effect of methoxy oxygen.
Br
–
:
: :
: :
: :
H 2N
:
OCH3 – OCH3 – OCH3

:NH2 :NH2
:
–
–NH3, –Br
9.2. It is an addition elimination reaction. The amino group of the amino acid adds to the
benzene ring to the position where fluorine is attached. Elimination of fluorine gives a
derivatized amino acid which is highly coloured and identified by usual methods.
R H COOH
H
O2N— —F + C O2N— —N—C—H
H 2N COOH R
NO2 NO2
2, 4-DNFB An amino acid 2, 4-DNB derivative of amino acid
9.3.
–
Nu: H Nu H Nu H Nu H Nu H Nu
–: :– –
– –H
N N : :
N N N N
–
:
:
9.4. The nucleophilic attack by the hydride ion as expected occurs at position 2 and 4 and the
product has a dihydropyridine skeleton. This reaction is the basis of the NADH—NAD+
oxidation-reduction process.
H H
+ LiAlH4 H
+
N – H N N
X
R R R
N-alkylpyridinium A 1, 2-dihydropyridine A 1, 4-dihydropyridine
halide
O O
– H H
:
H C—NH2 C—NH2
:
N+ N
R R
NAD + NADH
CHAPTER 10 S1
Photochemistry S0
The reactions which take place when molecules absorb ultraviolet or visible radiation are called
photochemical reactions.
10.1 ABSORPTION OF ELECTROMAGNETIC RADIATIONQUANTUM YIELD

In photochemistry light quanta are absorbed by individual molecules with the proper
chromophore. The energy associated with ultraviolet and visible light is sufficient to excite
electrons in molecules (photoexcitation). A molecule as a result is excited from its ground to
electronically excited state. In several cases the energies imparted to molecules by photo-
excitation are similar to covalent bond energies which can initiate chemical reactions. Covalent
carbon-carbon bonds have energies around 100 kcal/mole. The absorption at 200 nm and 300 nm
is equivalent to 143.0 and 95.0 kcal/mol respectively. Thus the typical upper limit of energy
available for photochemical processes is near 143 kcal/mol (598 kJ/mol). This corresponds to a
lower wavelength limit of about 200 nm for effective transmission of light through air. Below
200 nm strong absorption by oxygen in the air needs the use of vacuum ultraviolet apparatus
if higher energies (shorter wavelengths) are to be employed. With soft glass as the reaction
vessel, most of the UV-radiation below 360 nm is absorbed by the glass, consequently the
practical energy maximum is near 80 kcal/mol (335 kJ/mol). Pyrex glass is a better light
transmitter, while quartz is the most transparent of the common materials employed in the
study of photochemical reactions.
The efficiency of a photochemical reaction is usually expressed in terms of quantum
yield Φ which is the relation between the number of the molecules that undergo a particular
photochemical reaction and the number of photons absorbed.
Number of molecules undergoing a particular process
Φ=
Number of photons absorbed
In summary, the radiations in the infrared region of the spectrum correspond to 1–10
kcal/mole of energy which produces only vibrationally or rotationally excited molecules. The
light in the visible and ultraviolet region however, has sufficient energy to cover the range of
chemical bond energies and can induce chemical changes by exciting molecules to higher
electronic states. The energy of visible light varies from 38 kcal/mole (750 nm) to 71 kcal/mole
(400 nm), whereas ultraviolet light is still more effective as it provides energy up to 143 kcal/mole
(200 nm).
380
Photochemistry 381
10.2 EXCITED STATES

• In most stable compounds the electrons are paired and their spins (represented as
+ 1/2 or – 1/2) cancel each other.
• When the electron spins in a molecule cancel, regardless of whether the electrons are
all paired in orbitals, the molecule is then said to be in the singlet state (S). Thus a
molecule with all electrons paired is said to be in a singlet state (S).
• When the electrons are paired in their lowest energy orbitals, the molecule is in the
ground state (S0), and the molecule is said to be in the lowest energy singlet state
(S0).
• The energy associated with ultraviolet and visible light is sufficient to excite electrons
in molecules. An electron is promoted from the ground state orbital to an excited
state orbital, a process termed photoexcitation.
• Initially, almost all molecules are in the lowest vibrational level of the ground state,
S0. When a ground state singlet absorbs a photon of sufficient energy, it is converted
to an excited singlet state. The photoexcitation process is very rapid (10–15 second), it
is even faster than a molecular vibration. This excited state in which there is no spin
inversion in called excited singlet state S1, S2 or higher which depends on the energy
of the excited state.
• When two electrons occupy different orbitals, according to Hunds rule, the lowest
energy state will be that where these two electrons have parallel spins and are
unpaired. A triplet state (T1, T2 etc.) of a molecule is that in which two electrons are
unpaired. This may be represented by considering a diatomic molecule in which the
configurations in its ground and lowest excited states are presented (Scheme 10.1).
Thus a triplet (T) represents an excited state where the spin states of electrons in a
molecule do not cancel as the spin state of one electron in the molecule is changed.
Antibonding
Bonding
Ground state Excited singlet (S1) Excited triplet (T1)

singlet (S0) electrons with electrons with the
opposite spin same spin
SCHEME 10.1
• In organic photochemistry the transitions n π* and π π* are of significance.

The n π* transition is the lowest energy transition e.g., in the case of most
ketones and consequently the S0 S1 transition. The lower energy n π*
transition occurs at longer wavelengths compared to the π π* transition. The
π
€ π* transition is the S0 S2 transition.
10.3 THE FATE OF THE MOLECULE IN S1 AND T1 STATES (JABLONSKI DIAGRAM)

The S1 state of a molecule (lowest vibrational level) has a longer lifetime, about 10–8 to 10–7 sec.
and its energy is rapidly dissipated through molecular collisions and one of the following
processes takes place (explained by Jablonski diagram).
• An excited molecule with electrons in S1 state can return to ground state S0 by emitting
radiation (hν), a process called fluorescence (Scheme 10.2).
The fluorescent light has longer wavelength than the light needed for the original
excitation.
• Immediately after promotion (~ 10–11 sec.), the molecule returns to the lowest excited
singlet state S1 by giving up it energy as heat. This process is called internal conversion
(Scheme 10.2).
S2
Internal conversion
~ 10–11 sec.
Intersystem crossing
S1
Excited triplet (T1)

h
Fluorescence
Phosphorescence
The ground state S0

Jablonski diagram—photochemical reactions
SCHEME 10.2
• S1 can undergo intersystem crossing involving a spin inversion to the triplet state T1.
A triplet state is reached when one of the unpaired electrons in the excited molecule
undergoes an inversion of its spin and gives rise to a lower-energy state described as
a triplet, T1.
• The S1 and T1 are the major reactive states in photochemical reactions since
nondissociative chemical reactions are more probable in long lived excited states.
The triplet state T1 has even a longer lifetime compared to S1.
• The triplet state may return to the ground state with a further spin inversion, either
by emitting radiation (phosphorescence) or by giving up energy as heat. It may also
Photochemistry 383
take part in a chemical reaction. It may transfer its energy to another molecule which
is thereby raised to the triplet state. The triplet state is paramagnetic since it has two
parallel unpaired electrons, while the single state is diamagnetic. Thus the
photochemical reactions involving triplet states can be quenched by paramagnetic
salts and by free radical scavengers like oxygen.
• Phosphorescence is the light emission from the triplet state as it returns to the ground
state. Phosphorescence and internal conversion of T1 to S0 are spin forbidden processes.
An intermolecular reaction is particularly favoured due to the longer life of T1 state
compared to S1 state.
10.4 ENERGY TRANSFER

Excitation energy of an electronically excited molecule can be transferred to the ground state
of another molecule. The method provides alternative means to generate electronically excited
molecules. The method is normally employed to produce triplet excited states.
10.5 ENERGY TRANSFER AND PHOTOSENSITIZATION

A molecule in an excited state (S1 or T1) may transfer its excess energy all at a time to a
different compound in the environment. This process is termed photosensitization. Thus, the
excited molecule is converted to S0 while the acceptor molecule becomes excited. A triplet
excited state generates another triplet and a singlet generates a singlet.
Photosensitization is very important aspect of photochemistry. It is an alternative process
for creating excited states which are otherwise difficult to attain by direct irradiation. Thus a
photochemical reaction can carried out on a molecule which cannot be brought into the desired
excited state by direct absorption of light by the use of a photosensitizer. An example is of
simple (unconjugated) alkenes which absorb only in the far UV region which is difficult to
reach experimentally. The photochemistry of such compounds, is thus studied with the help of
photosensitization.
The role of a sensitizer is to transfer the excitation energy from an electronically excited
molecule (the sensitizer itself) to the ground state of another molecule to give a triplet excited
state. Singlet excitation energy can be transferred, however, the lifetimes of singlet excited
states are very short (10–8 sec.) compare to triplet excited states (> 10–6 sec.). The triplet energy
transfer requires that the triplet energy of the donor be higher compared to the acceptor molecule
by 3 kcal/mol.
A common triplet sensitizer is benzophenone (Scheme 10.3), with a triplet energy level
of 69 kcal/mol (289 kJ/mol). The triplet energy of naphthalene (61 kcal/mol i.e., 255 kJ/mol) is
lower than that of this sensitizer. Naphthalene does not absorb appreciably at 345 nm. When
however, a mixture of benzophenone and naphthalene in ethanol-ether is irradiated at 345 nm
(at low temperature) one observes the phosphorescence of naphthalene. Thus the requisite
triplet excitation must come from excited triplet of the sensitizer benzophenone. In conclusion,
since naphthalene is photosensitized by triplet benzophenone. The triplet energy of naphthalene
must be lower than that of benzophenone which indeed is so.
hv
(C6H5)2C O (C6H5)2 O 1 (C6H5)2C O 3
Excited triplet of
benzophenone
Energy transfer
Naphthalene
3
h + (C6H5)2C O +
Phosphorescence
SCHEME 10.3
10.6 FORBIDDEN TRANSITIONSINTERSYSTEM CROSSING

• Intersystem crossing S1 T1 is although energetically gainful but it is formally a
spin forbidden process. The average energy of the lowest-energy triplet excited state
T1 is normally greater than S0, however less than that of S1 (Scheme 10.3a).
• If the singlet state is sufficiently long lived as is so in aromatic and carbonyl systems,
the S1 T1 change called intersystem crossing occurs with almost 100% efficiency.
• The efficiency in intersystem crossing depends, among other factors on the energy
gap between S1 and T1 (the S1 – T1 energy gap). When this energy difference is small,
the intersystem crossing is efficient. Generally intersystem crossing efficiencies for
ketones is maximum. A typical example is of benzophenone for which intersystem
crossing has 100% efficiency since the energy gap is small (5 kcal/mol, Scheme 10.3a).
Aromatic compounds have intermediate to high, while olefins have low intersystem
crossing efficiencies. Thus when the energy gap is large, intersystem crossing efficiency
may be low or zero and spin forbiddenness becomes important.
C6H5CC6H5 S1
Energy
107–124 kcal/mol
gap
5 kcal/mol
S1
T1 T1
60 kcal/
74 kcal/mol A
69 kcal/mol
mol
S0 S0
Intersystem crossing in Intersystem crossing efficiency
benzophenone is almost zero
A represents 100% efficiency S1 T1 intersystem

crossing for a sensitized reaction
SCHEME 10.3a
Photochemistry 385
For other examples of sensitization in photochemistry (see Schemes 10.39a and 10.39b).
A Summary of Photochemical Processes

hv Fluorescence
• S0 S1 S0
Excitation or internal
conversion
Phosphorescence or
intersystem crossing
S0
Chemical
reaction
Chemical reaction
Intersystem crossing
T1
Fragmentation
S1 Two species
Fragmentation
Two species
+ Molecule
S0 + Molecule (T1)
+ Molecule
S0 + Molecule (S1)
SCHEME 10.3b
• S1 and T1 are main reactive states in photochemical reactions.

• Chemical reactions are favoured by the longer lifetime of T1 state relative to S1.
• S1 on intersystem crossing goes to the triplet state T1. In the triplet state the
spin of one electron has been changed so that now the molecule has two electrons
which cannot pair.
• Intersystem crossing (S1 T1 ) in many compounds is an improbable process
which involves switching of an electronic spin, thus triplet states assume no
importance in the photochemistry of such compounds. In most other compounds
e.g., π π* states of polycyclic aromatic hydrocarbons and n π* of
several ketones, the process of intersystem crossing occurs with high efficiency.
• The efficiency of intersystem crossing depends largely on the difference in energy
between singlet and triplet excited states (i.e., S1 – T1 energy gap). Excited
benzophenone provides an example which converts completely from S1 to T1.
• Triplet state is long-lived with lifetime greater than 10–5 sec., since the conversion
to S0 would require a switching an electronic spin. The energy difference between
S1 and T1 is far less than between T1 and S0 so the latter intersystem crossing is
far less probable.
10.7 PHOTOCHEMICAL REACTIONS

(A) Photoreduction (Hydrogen Atom Abstraction)
Many aromatic ketones react by hydrogen atom abstraction from solvent or some other hydrogen
donor to give diols as the stable products formed by the coupling of the resulting α-hydroxybenzyl
radicals (Scheme 10.3c). This is the common reaction of a photoexcited carbonyl group and the
details are in (Scheme 10.4).
R R
h HX .
ArCR ArCR . ArCR ArC—CAr
–X
O O OH OH OH
SCHEME 10.3c
An aryl ketone e.g., benzophenone on irradiation in the presence of a hydrogen donor

like a secondary alcohol, brings about a reductive coupling reaction. The initial excited singlet
state (S1) goes to a triplet state (T1). The triplet contains two unpaired electrons and thus is a
diradical. This radical can abstract a hydrogen atom from some other molecule in solution. In
the photoreduction, the diradical abstracts a hydrogen atom from the secondary alcohol and
forms two benzhydryl radicals that can dimerize to benzopinacol.
In this reaction the quantam yield for disappearance of benzophenone is 2.0. This is so
since, the radical after hydrogen atom abstraction from 2-propanol transfers a hydrogen atom
to benzophenone. Thus two molecules of benzophenone are reduced by absorption of only one
photon of light.
. .
O O O
h Intersystem
C6H5CC6H5 C6H5CC6H5 crossing . 6H 5
C6H5CC Step 1 (Formation of T1)
Benzophenone S1: electrons paired T1: a diradical
.
O H . O—H
–(CH3)2COH
C6H5CC
. 6H5 + (CH3)2COH C6H5CC
. 6H 5 Step 2 (Hydrogen abstraction)
A hydrogen donor
(an alcohol)
.
(C6H5)2C O + (CH3)2COH (C6H5)2COH + (CH3)2C O
The radical from the secondary alcohol (2-propanol) transfers a hydrogen
atom to ground state benzophenone in a non-photochemical reaction.
OH OH OH
2C6H5CC
. 6H5 (C6H5)2C—C(C6H5)2 Step 3 (Dimerization)
Diphenylhydroxy- Benzopinacol
methyl radical
SCHEME 10.4
PROBLEM 10.1
The photoreduction of benzophenone is carried out in the presence of toluene. The
benzyl radical formed after the triplet excited state of benzophenone abstracts a
hydrogen atom from toluene dimerizes to bibenzyl. In the same reaction in the
Photochemistry 387
presence of 2-propanol the intermediate free radical 2-hydroxy-2-propyl radical

instead gives up a hydrogen atom to benzophenone. Explain and give the mechanism
and other products formed if any.
ANSWER. The benzyl radical is resonance stabilized (Scheme 10.5).
h 1 3
(C6H5)2C O (C6H5)2C O (C6H5)2C O
(S1) (T1)
3 . .
(C6H5)2C O + C6H5CH3 (C6H5)2C—OH + C6H5CH2
Benzophenone ketyl Benzyl free
radical
OH OH
.
2(C6H5)2C—OH (C6H5)2C C(C6H5)2
Benzopinacol
.
2C6H5CH2 C6H5CH2CH2C6H5
Bibenzyl
OH
. .
(C6H5)2C—OH + C6H5CH2 (C6H5)2CCH2C6H5
Benzyldiphenyl carbinol
SCHEME 10.5
In the case of reduction of benzophenone, pinacol could also be formed via the dimerization
of the hydroxyisopropyl radicals, however, pinacol is not formed. This shows that the lifetime
of the hydroxyisopropyl radical is too short for it to combine with another radical to form the
dimer, it however, transfers its hydroxylic proton too rapidly (see box, Scheme 10.4) and is
converted to acetone. The diphenylhydroxy methyl radical has a relative long lifetime due to
resonance stabilization, and is sufficiently stable not to attack Me2CHOH.
Photoreduction may be described as light initiated reduction of different type of

functional groups in the presence of an electron donor.
(B) Photoenolization
Benzophenone derivatives which have an ortho alkyl substituent do not display photoreduction.
These derivatives however, display a different photoreaction in which the intramolecular
hydrogen abstraction occurs from the benzylic position. This yields an enol which gives the
more stable starting benzophenone without any photoreduction. This photoenolization can be
detected when photolysis is carried out in deuterated solvents (Scheme 10.6). Photoenolization
CH2—R CH—R CH—R

H
C—Ph C O C—O—H
O Ph Ph
(I) (Triplet) Enol
photoenolization
ROD
D
CH—R CH—R
C—Ph C—O—D
O Ph
(Ia)
SCHEME 10.6
can as well be detected when an enol is trapped as its Diels-Alder adduct (Scheme 10.7).
R HO R R
CO2R CO2R
OH –H2O
+ RCO2—C C—CO2R
CO2R CO2R
SCHEME 10.7
(C) Photooxidation (Formation of Peroxy Compounds)

Molecular oxygen is a triplet in its ground state (T0) and it does not add to cyclic dienes. It is
promoted to an excited state, known as singlet oxygen with all electrons paired. An interesting
cycloaddition reaction takes place on irradiation of some dienes and polyenes with oxygen in
the presence of a triplet sensitizer such as the dye methylene blue (Scheme 10.8). The sensitizer
in its triplet state transfers its energy to the triplet oxygen molecule i.e., the ground state of
oxygen to give singlet oxygen (i.e., an excited oxygen molecule). The sensitizer subsequently
returns to its ground state (S0). Singlet oxygen behaves as a dienophile and adds to the diene
to give an endoperoxide by a typical Diels-Alder reaction (Scheme 10.8).
The synthetic utility of this reaction is based in the reduction of peroxides to diols (Scheme
10.8). Olefins with an allylic hydrogen atom give hydroperoxides (Scheme 10.9) which can be
subsequently reduced to allylic alcohols. When an olefin does not have an allylic hydrogen, it
then gives dioxetans (Scheme 10.9) which on heating afford carbonyl compounds.
Photochemistry 389
Sens Sens 1
h O2 O
3 1 O
Sens + O2 Sens + O2 singlet oxygen
O2/h O
sensitizer O
O H OH
O
:
:
O [H]
+ O
O
O
:
:
Singlet H OH
1
oxygen ( O2)
SCHEME 10.8
In summary the peroxy compounds are formed when one irradiates the substrate in the
presence of oxygen and a sensitizer. The sensitizer is excited to the triplet state which then
1 1 1
R R R
h O O
O2 (T0) O2 (S1) + R R
sens. O O
R H R H R R H
Hydroperoxide
Olefin with an
allylic hydrogen
O2 heat
R2C CR2 R2C—CR2 2R2CO
sens
h O—O
Olefin with no
allylic hydrogen Dioxetan
SCHEME 10.9
activates the oxygen molecule which then reacts with a variety of unsaturated hydrocarbons
(Schemes 10.8 and 10.9). The triplet sensitizer can as well abstract a hydrogen atom from the
substrate to generate a radical (Scheme 10.10) which then reacts with oxygen. Thus a secondary
alcohol can be oxidized to a hydroxy-hydroperoxide by using benzophenone as the sensitizer.
The triplet benzophenone generates a carbon radical by reacting with alcohol (Scheme 10.10).
This adds oxygen and a chain reaction is propagated. The hydroxy hydroperoxides tend to
eliminate hydrogen peroxide to give carbonyl compounds.
. . . .
Ph2C—O + R2CH—OH Ph2C—OH + R2C—OH
Triplet
benzophenone
.
O—O
.
R2C—OH + O2 R2C—OH
O—O. O—OH
.
R2C—OH + R2CH—OH R2C—OH + R2C—OH
Hydroxy-
hydroperoxide
.
O—O
.
R2C—OH + O2 R2C—OH
Propagating steps
OH
R2C R2CO + H2O2
O—O—H
SCHEME 10.10
(D) Cis-trans Isomerization (Photoisomerization)

Alkenes display a characteristic photochemical interconversion of cis and trans isomers (Scheme
10.11). Generally, the trans isomer is thermodynamically more stable and photolysis gives a
mixture which however is richer in the cis isomer. Irradiation, is therefore, a useful method of
converting a trans alkene to its cis isomer. The reaction is promoted by direct irradiation of the
substrate and also by photosensitized energy transfer. In several alkenes the E isomer absorbs
energy more effectively (it has a larger molar absorptivity ε) and at a slightly different
wavelength compared to the Z isomer. It is sometimes possible to convert an E isomer to its
thermodynamically less stable Z from—a technique called optical pumping (Scheme 10.11).
The isomerization takes place, since the excited states (both S1 and T1) of many olefins have a
perpendicular rather than a planar geometry (Scheme 10.12).
H H H
C C C C
H h
trans-stilbene cis-stilbene
max = 295 nm max = 280 nm
= 27,000 = 13,500
Photosensitized cis-trans isomerization

SCHEME 10.11
Photochemistry 391
R
H R hn H H H
R H R R R
H
trans isomer twisted S1 or T1 cis isomer
SCHEME 10.12
The isomerization occurs because the π bond which normally prevents it, is lost in passage
to the excited state, in which the two sets of substituents now occupy mutually perpendicular
planes (Scheme 10.12). Thus, cis-trans isomerism disappears on excitation. When the excited
molecule drops back to the S0 state either isomer can be formed. In case a wavelength of light
is selected at which the trans isomer absorbs while the cis-isomer doesnot than the trans
isomer can be converted completely to the cis.
The photochemical isomerization of vitamin A aldehyde (11 Z-retinal to 11 E-retinal) on
absorption of light is the primary event in vision processes (Scheme 10.12a). The natural form
cis H cis
11
H
9 12 11
10 12
13
–H2O
+ H2N—opsin Rhodopsin
+
11-cis-retinal CHO CH NH—opsin
(hn)
H2O
H
CHO
+ H2N—opsin
trans H
All-trans-retinal
SCHEME 10.12a
of vitamin A aldehyde is all -trans. A protein opsin in the retina of human eye has a pocket
where only 11 Z-retinal fits and is bonded with it via an imine linkage. The complex molecule
which is formed is called rhodopsin which absorbs light energy in the visible region of the
spectrum. On absorption of light 11 Z-retinal is isomerized to the all trans-from 11 E retinal.
In this form the fit into the opsins pocket is disturbed and dissociation to 11 E-retinal and
opsin takes place, neither of which absorbs light in the visible region of the spectrum 11 E-retinal
is reconverted into the cis- form now by an enzyme and the visual cycle begins again.
Photoexcited cyclic olefins add hydroxylic solvents provided the size is appropriate to
accommodate a trans double bond. These additions involve the formation of E isomer of the
alkene as the key intermediate which may be strained as e.g., in the case of cyclohexene.
CH2 H
CH2 C H
OCH3
hn CH3OH +
H
C CH2 H H
H CH2
Trans-cyclohexene highly strained to exist at room temperature
SCHEME 10.12b
The trans-cycloalkenes can be protonated very easily since strain is relieved on protonation.
Norbornene does not display this addition of methanol, since the trans isomer of norbornene
would be highly strained if formed. This is again the case with cyclopentene. It may be mentioned
that rings of cycloalkenes containing five carbon atoms or fewer exist only in the cis form. The
introduction of a trans double bond into these rings would introduce large strain. Trans-
cyclohexene can be formed as a very reactive short lived intermediate in some reactions.
Trans-cycloheptene has a very short lifetime and has not been isolated, trans-cyclooctene has
however, been isolated and is stable at room temperature. In this case the ring is large enough
to accommodate the geometry required by a trans double bond, and thus these add methanol.
Cycloheptenone and larger rings also undergo a similar photoisomerization (see

Scheme 10.36a).
Cyclohexene, cycloheptene and cyclooctene on photoexcitation all give products
derived from ring contraction and carbene insertion products (Scheme 10.12c).
:CH
hn
:CH
hn
+
SCHEME 10.12c
(E) Photoisomerization Followed by Oxidative Coupling

Many olefinic compounds undergo geometrical isomerization which is their typical
photoreduction. The reaction occurs under direct irradiation of the reactant as well as by
photosensitized energy transfer.
On irradiation cis- or trans-stilbene gives only an equilibrium mixture of the two
(Scheme 10.11). In the presence of oxygen, however, cis-stilbene photocyclizes reversibly to
give a small proportion of dihydrophenanthrene which is oxidized to phenanthrene irreversibly
with oxygen (Scheme 10.13).
Photochemistry 393
hn
hn
H
O2
H
SCHEME 10.13
(F) Photolysis (Photochemical Fragmentation)

(i) Photolysis of carbonyl compounds
It was seen during photochemical reductions (Sec. 10.7, A) that the excited states of the carbonyl
groups of many aldehydes and ketones are very efficient hydrogen abstractors from solvent or
some other hydrogen donor (see Scheme 10.3c).
The prominant photochemical reaction displayed by ketones in the gas phase is the
fission of the carbon-carbon bond adjacent to the carbonyl group and is called α-cleavage (Scheme
10.13a).
H—X . .
R2C—OH + X
H-abstraction
O O
hn
R—C—R R—C—R

-cleavage . .
vapor phase RC O + R
Norrish type I cleavage
SCHEME 10.13a
Norrish Type I Process

A molecule on irradiation usually leads to homolytic bond cleavage to generate
free radical intermediates. The cleavage at the carbon-carbon bond α- to the
carbonyl group is often termed Norrish Type I cleavage.
The Norrish type I process dominates in the vapor phase than in solution, however,
under solution conditions the two radicals generally recombine within the solvent
cage where these are generated. This process becomes significant when the relatively
stable carbocation (tertiary or benzylic type) is formed.
(a) Norrish type I reaction of carbonyl compounds

The process ‘Norrish type I’ cleavage (α-cleavage) originates from the carbonyl n, π* state and
involves the homolytic cleavage of one of the carbonyl alkyl groups (i.e., photochemical cleavage
at the carbon-carbon bond α to the carbonyl group) as the primary photochemical reaction

n
. .
. . . .
. C .
O C—O . C .
O —C O + R
. R
R .
The carbonyl n, state R
(excited state)
Norrish type I cleavage
SCHEME 10.14
(Scheme 10.14). This is followed by decarbonylation and subsequent reactions of alkyl free
radicals (Scheme 10.15).
O O
hn . .R
R—C—R R—C + Primary process

-cleavage
An acyl An alkyl
radical radical
O
. .
R—C R + CO
Secondary processes
.
R + R. R—R
SCHEME 10.15
The nature of the products depends on the structure of the radicals. This is shown by
Norrish type I reaction on irradiation of gaseous acetone at 313 nm (Scheme 10.15a).
O O O
hn
CH3CCH3 CH3CCH3 CH3C. + .CH3 Norrish type I fragmentation
Acetone Ethanoyl radical Methyl radical
O O O
2CH3C. CH3C—CCH3
2.CH3 CH3CH3
O Subsequent free-radical reactions
CH3C. . CH + CO
3
CH3C. + . CH3 CH2 C O + CH4
SCHEME 10.15a
Photochemistry 395
With unsymmetrical ketones, the α-cleavage occurs so as to give the more stable of the
two possible free radicals. This is followed by reactions like disproportionation or intermolecular
hydrogen atom abstraction by the acyl radical (Scheme 10.15b).
O O
hn .
(CH3)3CCCH3 (CH3)3C + CH3—C. (CH3)3CH + (CH3)2C CH2 + CH3CHO
SCHEME 10.15b
Smaller ring ketones e.g., cyclohexanone on α-cleavage (Norrish type I process) yield a
diradical and subsequent intramolecular hydrogen abstraction gives an aldehyde
(Scheme 10.16), while loss of CO gives cyclopentane.
O O O O
. . .
hn CH2 H
H

-cleavage .
CH2
Cyclohexanone Ring opened
aldehyde
O
. . .
. CH2 CH2
CH2 –CO
Cyclopentane
SCHEME 10.16
The Norrish type I cleavage (Ronald Norrish shared the Nobel Prize in Chemistry in
1967) is useful for ring cleavage of cyclic ketones.
EXERCISE 10.2
Predict the products from the compounds (Scheme 10.17) on photochemical
reactions via α-cleavage.
O
Ph
CH3
CH3 O O
(I) (II) (III) Ph
SCHEME 10.17
ANSWER. (I) It cleaves to give the most stable tertiary radical rather than primary
radical (Scheme 10.18), intramolecular hydrogen transfer reactions then gives
different products.
O
O O O
CH2
CH3 . . CH3
H
C
H CH3
C C—CH3 + C
CH3 CH3 CH3
SCHEME 10.18
In (II) and (III), decarbonylation is the major reaction pathway (Scheme 10.19).
Ph
+ CO ,
Ph
SCHEME 10.19
EXERCISE 10.3
Often a ketene is observed as one of the products during α-cleavage (Norrish Type
1 process) of small ring compounds. How this is formed ?
ANSWER. Via disproportionation (Scheme 10.19a).
O
O O C
. .
HC CH3
hn H CH2
SCHEME 10.19a
(b) Norrish type II, cleavage
Norrish Type II Process

In this photolysis reaction, the carbonyl n, π* state is involved leading to
photoelimination which proceeds through a six centered fragmentation initiated
by γ-hydrogen abstraction in the primary photochemical step. Secondary reaction
of the diradical leads to cleavage to yield an alkene and a new ketone.
This reaction (a photoelimination) is observed in ketones in which a hydrogen atom

attached to the γ-carbon atom is available. The photoexcited carbonyl group (n, π* state) abstracts
the γ-hydrogen via a six-membered cyclic pathway (Scheme 10.19b) to give a diradical which
leads to fission between Cα and Cβ (referred to as Norrish type II, photoelimination) to an
alkene and an enol which tautomerizes to the carbonyl compound (a new ketone). A similar
Photochemistry 397
reaction occurs in the mass spectral fragmentation of carbonyl compounds where it is identified
as the Mc Lafferty cleavage. In addition to the fragmentation process between α- and β-carbon
atoms (Scheme 10.19b), the Norrish type II process is also followed by ring closure
(Scheme 10.20).
H
O O CH—CH3 OH
hn .
CH3CCH2CH2CH2CH3

CH3C CH2 .
CH3C—CH 2—CH2—CHCH3 CH2 CHCH3

CH2 A diradical
OH O
Carbonyl n, state
+ CH3C CH2 CH3CCH3
H
. H CH3
O
.
CH3
Norrish type II cleavage
SCHEME 10.19b
which involves the formation of a cyclobutanol by ring closure of the diradical.
Fragmentation
CH2 CH—CH3
. between C
and C
OH CHCH3 +
CH3COCH3
C. CH2 OR
CH3 CH2 OH
A diradical
H 3C CH3
Ring closure
SCHEME 10.20
In larger ring compounds a Norrish type process is observed to give ring closure as
shown in the case of cyclodecanone. This gives a bicyclic compound in which both rings are
six-membered (Scheme 10.20a).
:OH
:
OH OH
.
.
:O
hn H :O . H +
.
:
:
H H H
Major Minor
SCHEME 10.20a
EXERCISE 10.4
Predict the product from the compound (Scheme 10.20b) Ph Ph
involving intramolecular hydrogen abstraction by the excited O
carbonyl group followed by ring formation.
ANSWER. The reaction can be considered as Norrish type II
process (Scheme 10.20c).
SCHEME 10.20b
Ph
Ph Ph H .
Ph . . C—OH. OH
C O C—O CH—Ph CHPh Ph Ph
hn
Intramolecular
hydrogen atom
abstraction
SCHEME 10.20c
+ −
(ii) Photolysis of compounds containing the N N group
On irradiation, diazomethane gives the simplest carbene i.e., methylene (Scheme 10.21).
This reactive intermediate can exist in either a singlet or triplet state. In singlet methylene
.
– + + – hn Collisional
N: N: : CH2 + N2 : CH2
1
.CH2 3
:
CH2—N CH2 N deactivation

Diazomethane Methylene
SCHEME 10.21
the nonbonding electron spins are paired and this is usually formed first in the photolysis
reaction. Its triplet state has however, lower energy of the two electron configurations and the
electrons are not spin paired.
When diazomethane is irradiated it generates carbene in the singlet state. The
deactivation of singlet to triplet state (the triplet state of methylene has the lower energy of
the two electron configurations) occurs on collision with other molecules if these are present in
the reaction medium. Carbene in triplet state can be generated via photolysis in the presence
of a triplet sensitizer.
Diazomethane on photolysis in the presence cis-2-butene is largely stereospecific
concerted syn addition to the double bond to give cis-1, 2-dimethylcyclopropane. While this
stereospecificity decreases when an inert gas or a liquid is introduced in the medium (Scheme
10.21a) and both cis- and trans-cyclopropanes are formed. In the latter case the insertion of
carbene is not concerted but is a stepwise addition. Where the initial adduct, a triplet has
sufficient time to allow rotation about the central C—C bond (more details are in Schemes 11.13a
and 11.13b).
Photochemistry 399
CH3 CH3 CH3 CH3 Exclusive formation

:CH2 1 H H H H of cis-1, 2-dimethyl-
C C cyclopropane.
H H CH2
Concerted addition
C C
CH3 CH3 . H H
.CH 3 CH3 CH3 CH3 H
C—C. C—C .
2
. CH2 H . CH2 CH3

Rotation around
C—C bond
H H H
CH3 CH3 CH3
C—C . C—C .
. CH2 H . CH2 CH3
Spin inversion
CH3 CH3 CH3 H Mixture of cis as

H H + H CH3 well as trans
cyclopropanes.
Ring closure
SCHEME 10.21a
Carbenes are so reactive that they add to the “double bonds” of aromatic rings. The
products of initial addition are generally not stable and rearrange to give ring expansion. Thus
irradiation of diazomethane in benzene leads to addition of methylene across C C, followed
by a spontaneous Cope rearrangement (Scheme 10.22).
:CH2 Cope
Cycloheptatriene
SCHEME 10.22
The α-diazoketones on photolysis give carbenes which undergo a fast rearrangement to

a ketene (Scheme 10.23) which can be subsequently trapped by an olefin and the techniques
form a useful method for the synthesis of four membered rings (Scheme 10.23). The method
forms a good technique for ring contraction starting from cyclic. α-diazoketones (Scheme 10.24).
Ph O
PhCO—C—Ph Ph
hn PhCH CH2
:
– + CO—C—Ph Ph2C C O + N2
N N
Ph Ph
SCHEME 10.23
O O
hn CH3OH
C O —COOCH3
CH3OH
:
N2
SCHEME 10.24
(iii) Photolysis to produce reactive intermediates

Photolysis to generate some highly reactive intermediates under the condition where these
are stable has been successfully carried out on suitable substrates. The process for benzyne
formation involves a photochemical elimination of carbon dioxide (Scheme 10.25) from 1, 2-
benzenedioyl (phthaloyl) peroxide. It may be mentioned that benzyne intermediate can be
O
O
hv
O hv + CO2
+ 2CO2 O 77 K
O 77 K
1, 3-Cyclobutadiene
O Benzyne
(or dehydrobenzene)
1, 2-Benzenedioyl
(phthaloyl) peroxide
SCHEME 10.25
trapped as its Diels-Alder adduct with furan (Scheme 10.26) and as other compounds, (see
Schemes, 4.50, 9.17 and 9.18).
+ O O
Benzyne intermediate Furan A Diels-Alder adduct
SCHEME 10.26
(G) Photoaddition
Most of the typical photoadditions involve the formation of a 1 : 1 adduct via reaction of an
excited state of one molecule (generally e.g., a carbonyl compound, aromatic compound or
another molecule of the same olefin) with the ground state of another (generally an olefin)
with the formation of a ring compound.
(a) Photoaddition of olefins to carbonyl compounds—Paterno-Büchi reaction
Paterno-Büchi reaction normally involves the reaction (photoaddition) of the triplet state of
the carbonyl compound with the ground state of an alkene (Scheme 10.27) to give an oxetane.
The regiochemistry of the reaction is based on the preferential formation of the most stable
CH2—O
hn (CH3)2C CH2
(C6H5)2C O [C6H5C O] H3C C6H5
CH3 C6H5
(Major)
oxetane
SCHEME 10.27
Photochemistry 401
. O———CH2
O CH2
. CH3
. C C .C
C6H5 C 6H 5 CH3 CH3 C6H5 C 6H 5 CH3
Triplet
More stable diradical
2-oxa-1, 4-diradical
SCHEME 10.28
2-oxa-1, 4-diradical intermediate as explained from the reaction between benzophenone and
trimethyl ethylene as another example (Scheme 10.28). The ring formation to generate an
oxetane occurs in two stages. The excited carbonyl compound as its triplet adds via its oxygen
atom to the alkene, as the tertiary radical is more stable. Thus the mode of addition from
(I, Scheme 10.29) is preferred.
O O. O.
. spin
.
hn
Ph—C—Ph Ph—C—Ph Ph—C—Ph
inversion
Singlet Triplet
O CHCH3 spin O CHCH3

inversion
(C6H5)2C. C(CH
. 3) 2 (C6H5)2C C(CH3)2
Major product
.
O More stable 3°
. biradical
Ph—C—Ph + CH3CH C(CH3)2 (I)
Triplet
O C(CH3)2 spin O C(CH3)2
inversion
(C6H5)2C. CHCH
. 3 (C6H5)2C CHCH3
Minor product
Less stable 2°
biradical
SCHEME 10.29
As discussed above the reaction is regioselective, however, it is not necessarily

stereospecific since cis- as well as trans-2-butene give the same mixture of products of cis- and
trans-oxetanes when reacted with benzophenone (Scheme 10.29a). This shows that the
intermediate diradical intermediate is long lived to make the rotation around single bonds
possible before the final spin-inversion and subsequent cyclization.
H3C CH3
C C
Ph Ph
H cis H
hn
Ph O Ph O
Ph2C O + or +
H3C H
C C H 3C CH3 H3C CH3
H CH3 Major Minor
trans
SCHEME 10.29a
Stereospecificity of Paterno-Büchi Reaction

Evidence has been provided to show that Paterno reaction though regioselective but
is not stereospecific. Recent work with cis- and trans-isomers of cyclooctene has shown
that at low temperature this photochemical [2 + 2] cycloaddition becomes almost
stereospecific (Scheme 10.29b).
W. Adam, V.R. Stegmann and S. Weinkotz, J. Am. Chem. Soc., 123, 2452 2001;
W. Adam and V.R. Stegmann, J. Am. Chem. Soc., 124, 3600 (2002).
In this case it is suggested that the intermediate 1, 4-diradical undergoes final spin
inversion faster and there is not enough time for rotation to occur about single bonds.
H H
O O
+ Ph2C O . Ph
CPh
. 2
H H Ph
98 : 2 cis
.
CPh2 H
O
H O
+ Ph2C O H . Ph
H Ph
96 : 4 trans
SCHEME 10.29b
EXERCISE 10.5
Write the structure of the product from each of the photochemical cycloaddition
reactions (Scheme 10.29c).
hn hn
PhCH O +
H
(I) O Ph
(II)
SCHEME 10.29c
ANSWER. These are given (Scheme 10.29d).
O
Ph
H
H Ph
O
From (I) From (II)
SCHEME 10.29d
Photochemistry 403
An essential condition for the success of Paterno-Büchi reaction is that the triplet energy
of the alkene is comparable or higher than the carbonyl compound. If this is not so then the
energy transfer from the excited carbonyl group to the ground state alkene will take place and
the carbonyl compound will return to its ground state leading to triplet state olefin. In case
this happens, one will not get an oxetane, but dimerization of the olefin. Since the energy of
the triplet from benzophenone is less than that from norbornene, an oxetane is obtained by the
expected Paterno-Büchi reaction (Scheme 10.30) on irradiation of benzophenone in the presence
of norbornene. Since the energy of the triplet from acetophenone is more as compared with
norbornene, the irradiation of acetophenone in the presence of norbornene gives norbornene
dimerization.
O
C6H5C—CH3 Ph2CO O
Norbornene
hn hn
dimers Ph
Norbornene Ph
Photoaddition
SCHEME 10.30
(b) Photoaddition of alkenes, alkynes and amines to aromatic compounds

Interesting products of cycloaddition are formed when both olefins and acetylenes undergo
photochemical addition to benzene. These [2 + 2] cycloadditions are common photochemical
reactions, and do not normally take place thermally. Similarly, the important [4 + 2] thermal
Diels-Alder cycloadditions usually do not occur on irradiation. These types of contrasting reaction
pathways contributed to the development of the theories of pericyclic reactions. The
photochemical 1, 2-addition to the benzene ring (initiated by the n → π* excitation of the
maleic anhydride, Scheme 10.31) immediately undergoes a 1, 4-addition of Diels-Alder type to
the 1, 3-diene. An extremely strained cyclobutene ring formed (Scheme 10.32) opens up by a
spontaneous electrocyclic reaction.
O O O O
1, 4-addition of
hn Diels-Alder type
+ O O O O
C6H6 O
O 1, 3-Diene
O O O O
O
SCHEME 10.31
CO2Me
CO2CH3 CO2CH3
C hn
+
C
CO2CH3 CO2CH3
CO2Me
The very strained
cyclobutene
SCHEME 10.32
1, 3- and 1, 4-Addition to benzene ring are known reactions. Irradiation of solutions of

alkenes in benzene (or substituted) benzenes gives primarily 1 : 1 adducts where the alkene
bridges meta positions of the aromatic ring. Thus, the key step in the 1, 3-addition of olefins
with benzene is the formation of the intermediate prefulvene (Scheme 10.33) which is formed
from a high vibrational level of the first excited singlet of benzene. When butadiene adds to
benzene, the part of the product structure derived from butadiene has trans geometry (Scheme
10.33). During the 1, 4-addition of a primary or a secondary amine to benzene (via irradiation),
the T1 state of benzene is involved (Scheme 10.34).
CH3 H
. C C
CH3
hn H CH3
.
CH3
Prefulvene
1, 3-Addition
hn H
+
Butadiene
H
SCHEME 10.33
1. hn H NEt2
.
2. Intersystem
crossing Et2NH
.
The T1 state
H H
of benzene
1, 4-Addition to benzene
SCHEME 10.34
(H) Photochemistry of =,>-Unsaturated Ketones

When the carbonyl group is conjugated with a carbon-carbon double bond to give an α, β-
unsaturated ketone, the energy of the highest π orbital is raised and the energy of the π∗ orbital
is lowered. The energy gap between π and π∗ states becomes lesser, and less energy (light of
longer wavelength) is needed for the π → π∗ transition in which the entire C C—C O group
is involved. There is no change in the energy level of the n orbital, however the lowering of the
level of π∗ orbital shifts the n → π∗ transition to a longer wavelength. Generally an α,
β-unsaturated ketone shows two absorption maxima at 220 nm (π → π∗) and at 310 nm (n → π∗).
The irradiation of an α, β-unsaturated ketone can induce either of these transitions, and the
excited state, normally has more π, π∗ than n, π∗ triplet character but an n, π∗ excitation, may
be involved initially.
Among the typical reactions initiated by the π, π∗ states of α, β-unsaturated ketones are
(i) photocyclodimerization and (ii) olefin addition across the double bond to yield cyclobutane
derivatives.
Photochemistry 405
(a) Photocyclodimerization
Both cyclopentenone and cyclohexenone dimerize to give four membered ring compounds
(Scheme 10.35).
O O O O
hn +
2 CH2Cl2
O
O O O O
H H H H
hn
2 +
H H H H
O
SCHEME 10.35
(b) Olefin addition

The triplet state of an α, β-unsaturated carbonyl compound is a delocalized system and can be
represented as a hybrid (Scheme 10.36). Consequently, addition to an olefin can occur both at
C C as well as at C O. However, the former path is normally favoured (Scheme 10.36).
. . . . . .
C C—C—O C—C C—O C—C—C O
t
O O
+ or . .
O O
SCHEME 10.36
(c) Cycloheptenone and larger rings

When the enone system is part of the seven or eight membered ring then photoisomerization
takes place rather than dimer formation. Cycloheptenone and larger rings, undergo
photoisomerization to the trans-cycloalkenones. In seven- and eight-membered rings, the trans
double bonds are highly strained and in nucleophilic solvents addition takes place
(Scheme 10.36a).
O O O O
H
H
hn CH3OH hn
O
H OCH3
H
SCHEME 10.36a
(d) 4, 4-Dialkylcyclohexenones
4, 4-Dialkylcyclohexenones display a photochemical rearrangement which involves the formal
shift of the C-4—C-5 bond to C-3 with the formation of a new C-2, C-4 bond (Scheme 10.36b).
O O
2 2
5 3 5 3
4 4
R R R R
SCHEME 10.36b
(e) Cyclohexadienones
These reactants undergo deep seated rearrangements through a triplet excited state
(Scheme 10.36 c).
O O O O
Ph
hn
(direct or
sensitized) Ph
Ph
Ph Ph Ph Ph Ph
SCHEME 10.36c
(I) Photochemistry of Alkenes, Dienes and Aromatic Compounds

(a) Cis-trans isomerization (see Schemes 10.11 and 10.12)
(b) Photodimerization
This process is common with olefins and aromatic compounds, whereby the photoaddition, the
formation of a 1 : 1 adduct (photodimerization) by the reaction of an excited state (singlet or
triplet) of one molecule of a reactant with another molecule of the same reactant in its ground
states gives dimeric products. Non-conjugated olefins absorb only in the difficulty accessible
region around 200 nm and below. Thus their unsensitized photodimerizations are not common,
however these are concerted reactions and occur through the excited singlet, S1.
The photochemical [2 + 2] cycloaddition is symmetry allowed process (Scheme 10.37).
The Diels-Alder reaction is however, an example of a Thermal cycloaddition reaction. 2-Butene
adds to itself to give a four membered ring when it is irradiated with UV radiation at a
wavelength of 214 nm. The product retains the stereochemistry of the starting alkene. The
major photochemical reaction (Scheme 10.37) is the stereochemical isomerization of alkenes;
the 1-butene isomer is formed by the isomerization of the position of double bond and these
reactions are not concerted reactions.
Photochemistry 407
Olefin photodimerization is easy, through the triplet state, which is generated with a
photosensitizer. Acetophenone with λmax 270 nm undergoes intersystem crossing from its S1
state to T1 efficiently. In the presence of an olefin a singlet sensitizer and a triplet olefin are
formed. The olefin in its triplet state then adds through one carbon atom to a carbon atom of a
second molecule of olefin and subsequently after a spin-inversion ring formation is completed.
+ + +
214 nm
liquid phase
(Z)-2-Butene (E)-2-Butene 1-Butene
(cis-2-butene) (trans-2-butene) Methyl groups retain
Major product the cis orientation
in each alkene unit
SCHEME 10.37
Conjugated dienes do not display photodimerization through the excited singlet but
instead undergo photocyclization. Photodimerization of conjugated dienes can be brought about
via triplet sensitization as in the case of cyclopentadiene with benzophenone (Scheme 10.38).
It may be mentioned that thermal dimerization of cyclopentadiene, gives only endo-
dicyclopentadiene (Scheme 17.45), unlike in the present case where both endo- as well as
exo-dicyclopentadiene is formed.
Ph2C O
2 + +
330 nm
[2 + 2] addition
4 2 product
[ + ] addition
The dimerization of cyclopentadiene
SCHEME 10.38
Anthracene dimerizes (Scheme 10.39) via its excited singlet (π, π*) state. Conjugated
dienes display a variety of photoreactions depending on if the excitation is direct or
photosensitized. When the photochemical dimerization of butadiene is carried out in ether
solution in the absence of a photosensitizer two products are formed by intramolecular
cyclization (Scheme 10.39a). These arise from the excited singlet state, intersystem crossing
efficiency in 1, 3-butadiene is almost zero and as a consequence the triplet derived products
are not observed.
h
2
10
Anthracene
SCHEME 10.39
1
hn
+
Butadiene Cyclobutene Bicyclo [1, 1, 0] butane
SCHEME 10.39a
However, when the photolysis is carried out in the presence of a sensitizer e.g., triplet
excited benzophenone, only dimers are formed involving triplet-excited 1, 3-butadiene formed
by energy transfer from triplet excited benzophenone (Scheme 10.39b). The following points
may be noted:
• On irradiation a mixture of butadiene and benzophenone at 366 nm (78.1 kcal/mol)
light is only absorbed by benzophenone.
• Benzophenone has a small energy gap (S1 → T1), therefore, intersystem crossing
(S1 → T1) has 100% efficiency.
• The triplet energy of benzophenone (69 kcal/mol) is more than adequate for diffusion
controlled energy transfer to butadiene since triplet energy of butadiene is about 60
kcal/mol.
• S0 → S1 energy gap for benzophenone is lower than that of butadiene, therefore transfer
of singlet energy from excited singlet benzophenone to butadiene does not occur (see
Scheme 10.3a).
3
O
3
H
C6H5 C6H5
H H
+ H +
cis-1, 2-divinyl- trans-1, 2-divinyl- 3-vinylcyclohexene

cyclobutane cyclobutane
SCHEME 10.39b
The geometry of the reacting species i.e., orientations reflect in determining the course
of the reaction in terms of the formation of cyclobutane or cyclohexene derivatives (Scheme
10.39c).
s-cis s-trans
1, 3-Butadiene
SCHEME 10.39c
Photochemistry 409
(c) Intramolecular photocyclization of 1, 4-dienes

A 1, 4-diene system in which the two π components are separated by an sp3 carbon displays a
photochemical rearrangement known as di-π-Methane Rearrangement (Scheme 10.39d) to give
a vinylcyclopropane derivative. In this rearrangement either a singlet or a triplet excited state
is involved and may proceed via a diradical formed via bonding between C-2 and C-4. When in
a substrate the central sp3 carbon is unsubstituted, the rearrangement becomes unfavourable
as the second step, would lead to the formation of a unfavourable primary radical.
R R
hn
R R .
RCH R
hn .
. . CH2
CH2 CH2
Di-p-methane rearrangement
SCHEME 10.39d
An analogous rearrangement occurs with β, γ-unsaturated aldehydes and ketones

(Scheme 10.39e) and the rearrangement is then called oxa-di-π-methane rearrangement and
gives cyclopropyl ketones.
CH2 .CH2
R
RCCH2CH CHR RC—CH—CHR
. RCCHCHR
. C R
O .O O O
SCHEME 10.39e
EXERCISE 10.6
Write the structure of the product from a
photochemical intramolecular cyclization O hn
(Scheme 10.39 f). sensitizer
SCHEME 10.39f
ANSWER. It is a system containing a β, γ-unsaturated moiety, and will undergo
oxa-di-π-methane rearrangement (Scheme 10.39g)
H
.
O hn O
sensitizer
O
. H
SCHEME 10.39g
Several dienes and polyenes can be photochemically converted into cyclic isomers. The
hn
205 nm
Norbornadiene Quadricyclane
formed in low yield
SCHEME 10.40
direct irradiation of norbornadiene (205 nm) gives quadricyclane slowly in low yield (Scheme
10.40). However, the reaction becomes highly efficient by triplet energy transfer by using a
triplet sensitizer. Norbornadiene is transparent to light of 313 nm wavelength.
The triplet excited norbornadine thus produced (by energy transfer from triplet excited
acetophenone) gives quadricyclane (Scheme 10.41).
COCH3
spin
hn, 313 nm . inversion
.
. .
Quadricyclane
SCHEME 10.41
(d) Conjugated dienes

One has seen the formation of four membered rings during photocyclodimerization (see
Scheme 10.35). Other examples include the formation of four membered rings from dienes
(Scheme 10.42).
hn
1, 3-cycloheptadiene Bicyclo [3, 2, 0] hept-6-ene
SCHEME 10.42
The different stereochemical outcome of thermal and photochemical reactions is

often exploited when reactions are reversible, to bring about isomerization
between stereoisomers. The thermal conrotatory ring opening of trans-3, 4-
dimethylcyclobutene (I, Scheme 10.42a) to trans, trans-hexa-2, 4-diene (II) is an
efficient reaction (the relief of the ring strain). The photochemical ring closure is
also very effective: the conjugated diene absorbs light at longer wavelengths than
the mono-ene product cis-3, 4- dimethylcyclobutene (III) which is photochemically
inert to normal UV radiation. The photon of light provides lot of energy to make
the endothermic reaction proceed. By this sequence of reactions, geometric isomers
can be interconverted.
Photochemistry 411
heat hn
conrotatory disrotatory
I II III
SCHEME 10.42a
Thus in the case of conjugated dienes when the excited singlet state is involved, the
reaction is concerted, electrocyclic type and stereospecific. Orbital symmetry
principles (see Chapter 17) are employed to rationalize their outcome.
(e) Cage compounds

Several interesting cage compounds can be made from appropriate reactants on irradiation
(Scheme 10.42b).
hn
Dicyclopentadiene A cage-like compound
SCHEME 10.42b
(f) Photoisomerization of benzenoid compounds

Benzene on irradiation with light of 254 nm gives both fulvene and benzvalene (Scheme 10.43),
via prefulvene which are all non-aromatic. Several strained systems like that in Dewar benzene
and a prismane have been reached by the irradiation of substituted benzenes (Scheme 10.44).
.
hn . . . . +
.
Prefulvene Benzvalene Fulvene
SCHEME 10.43
All these photoproducts are valence isomers of the normal benzenoid structure. These products
(Scheme 10.44) are reached from the excited state, however a precise mechanism is not known.
Probably the skeletons of Dewar benzene and a prismane arise from the bent triplet state
(Scheme 10.45) drawn by ignoring the substituents, for simplicity.
The photochemistry of 1, 3, 5-tri-t-butylbenzene and 1, 2, 4-tri-t-butylbenzene is rather
complex and the photostationary state is established which involves carbon frameworks of a
benzvalene, a prismane and a Dewar benzene (Scheme 10.44).
t-Bu t-Bu t-Bu t-Bu t-Bu

t-Bu t-Bu t-Bu
t-Bu t-Bu t-Bu t-Bu

t-Bu
t-Bu t-Bu A Dewar A prismane
Benzvalene
benzene
SCHEME 10.44
.
.
SCHEME 10.45
All these strained systems i.e., Dewar benzene, prismane, benzvalene (as well as
their derivatives) are thermally labile and ultimately end up in benzenoid
compounds. These strained species are thought to be intermediates in
photochemical isomerization reactions of alkyl benzenes to other alkyl benzenes.
Thus o-xylene on irradiation ends up in mixtures containing m- and p- isomers
(Scheme 10.46).
CH3 CH3
CH3
CH3 CH3
CH3
hn
CH3
CH3
o-xylene CH3
CH3
meta- and para-isomers
SCHEME 10.46
( J) Photorearrangements
Several photorearrangements (photocyclizations) leading to intramolecular photocyclized
products, structural isomers or valence bond isomers have already been discussed, leading to
the synthesis of highly stained compounds. Under this section some typical
photorearrangements are discussed.
(a) Rearrangement of acyclic α, β-unsaturated ketones—conversion of conjugated
substrate to unconjugated product
Acyclic α, β-unsaturated ketones with a γ-hydrogen undergo a double bond migration on
irradiation (Scheme 10.47). This process is observed if energy of light is not that high as to
bring about dissociation. The γ-hydrogen abstraction and its transfer to the oxygen atom occurs
Photochemistry 413
via a six-membered cyclic transition state (Scheme 10.47). The substrate changes from
conjugated to non-conjugated system without any equilibrium (as is the case with cis-trans
isomerisation). The reason for this is that irradiation is carried out at a wavelength absorbed
by the conjugated substrate and since this is longer than that absorbed by the non-conjugated
product, the latter remains unaffected after it is formed. Isomerization therefore, yields a less
stable isomer and this isomerization is another example of optical pumping.
H H
O hn O OH O
SCHEME 10.47
(b) Photo-Fries reaction

Phenol esters in solution on photolysis give a mixture of o- and p- acylphenols (Scheme 10.48).
In the gas phase, where solvent cage effects are not operative many other products are formed.
O O
O
hn
CH3C CH3C
CH3C. .
O O O
Excited state Solvent cage
O
O O
O. CCH
. 3 O OH
CCH3 CCH3
Solvent cage
O. O OH
. CCH3 CCH3
CCH3
O O
O
Solvent cage
Photo-Fries rearrangement
SCHEME 10.48
In Fries rearrangement (Scheme 8.50), however, such products are formed in the presence of a
catalyst. Photo-Fries reaction does not need a catalyst and is normally an intramolecular free
radical process. Significantly, the phenol (ArOH) is always a side product which arises from
some ArO• which leaks from the solvent cage and can abstract a hydrogen atom from a
neighbouring molecule.
(c) Photorearrangement of 2, 5-cyclo hexadienones
The excited singlet produced from (I, Scheme 10.49) by an n → π∗ transition in the excited
singlet on intersystem crossing gives triplet state (III, Scheme 10.50). Reorganization of bond,
as shown in (IV, via free radicals) gives another triplet state molecule (V, Scheme 10.49) which
contains a three membered ring. The relaxation yields a singlet state and a ground state
zwitterion (VI). This carbocation then undergoes rearrangements which are typical of such an
ion to give the observed product (VII).
1 . . 3
.O: : O:
:
O: :O :
hn Intersystem
crossing .
Ph Ph Ph Ph Ph Ph Ph Ph
(S1, n ) (III) (IV)
(I) (II) Rearrangement
– . 3
: O: : O:
:
+ .
Rearrangement Relaxation
Ph
Ph Ph Ph Ph Ph
(VII) (VI) (V)
SCHEME 10.49
The cyclohexadienone system in (I, Scheme 10.49) absorbs around 300 nm (n → π∗) and
240 nm (π → π*) and the rearrangements are observed by irradiation at either wavelength.
Thus, one may assume that a lower energy transition (n → π∗) is involved initially. Moreover,
energy transfer is found to occur when (I, Scheme 10.49) is irradiated with triplet energy
sensitizers e.g., acetophenone. These data therefore, reasonably suggest that the
photorearrangement of 2, 5-cyclohexadienones occurs via an n → π∗ triplet state.
(K) Photochemical Aromatic Substitution

Compared to the ground state, the distribution of charge in an excited species can be entirely,
different. Several examples are available where one can control the positional selectivity in
nucleophilic aromatic substitutions by working under photochemical conditions. Thus, the
reaction of 3, 4-dimethoxynitrobenzene on heating with OH– ion leads to the replacement of
4-methoxy group, while at room temperature under UV irradiation, instead the 3-methoxy
substituent is substituted (Scheme 10.50). On heating, the nitro group through its –M effect
makes the ortho and para positions positive compared with the meta position. Under irradiation,
however, the ortho and meta positions are rendered positive compared to the para position.
Photochemistry 415
OCH3
OCH3
NO2
3, 4-Dimethoxynitrobenzene
– –
OH OH
hn heat
OCH3 OH
OH OCH3
– –
+ CH3O + CH3O
NO2 NO2
SCHEME 10.50
PROBLEMS
10.1 Plan a synthesis of the following compound:
O
10.2 Write the structures and mechanism of formation of products from the irradiation of
cyclopentanone.
10.3 Write the structure of the products from the photochemical reactions of the following
compounds:
O O
CH3 O
Ph Ph
CH3 C6H5CH2CCH2C6H5
Ph Ph
(I) (II) (III) (IV)
10.4 Considering the photocyclization of norbornadiene to quadricyclene (Scheme 10.40), write

the structure of the product of irradiation of cholesta-3, 5-diene.
R
10.5 Write the structure of the product (with the name of reaction) formed from the irradiation
of the following compound:
O Ph
10.6 Rationalize the following reaction:
O HO
hn
C 6H 5
C6H5
(I) (II)
10.7 Cyclopentadiene adds readily to p-benzoquinone in a [4 + 2] manner on heating. What

product will be formed on the irradiation of product (I) of this reaction?
O
heat O
+
O O
(I)
10.8 Considering the reaction sequence (Scheme 10.42), plan a synthesis of cubane.
Cubane
10.9 A diazo compound on irradiation in heptane at –78°C gives rise to a saturated hydrocarbon
C4H6. This displays three signals in 1HNMR and two signals in 13C NMR spectra in the
aliphatic region. Suggest a structure to this compound.
+ –
:
CH2 CHCH2CH N N:
10.10 1, 4-Cineole and ascaridole are the naturally occurring oxide and peroxide respectively.
There are three isomeric terpinenes which out of these is a suitable isomer for
photochemical conversion into either 1, 4-cineole or ascaridole?
O
O
O
1, 4-cineole Ascaridole
-terpinene -terpinene -terpinene
Photochemistry 417
10.11 The sesquiterpenoids caryophyllene and its geometrical isomer occur naturally in the
oil of cloves. Plan a synthesis of a suitable starting material containing a four-membered
ring.
H H
H H
H H
Caryophyllene Isocaryophyllene
10.12 Write equations for the outcome of Paterno-Büchi reaction of ArCHO with furan and
dihydrofuran.

10.1 The cyclobutane ring can be constructed via photochemical cycloaddition of the alkene
using acetophenone sensitizer.
+
O
10.2 The path followed is the n, π* excitation of the carbonyl group, α-fission, a hydrogen
atom transfer from the γ-position to the carbonyl group (formation of aldehyde) or the
formation of cyclobutane via the loss CO and cyclization of the diradical.
O
H
An unsaturated aldehyde
-hydrogen abstraction
.
hn
O . O CO +
. .
Cyclopentanone Fission of the C—CO bond
the Norrish type I process
10.3 The initial α-cleavage product gets decarbonylated fast if the radical is stabilized (as in
the case of II). The compound (II) thus reacts via the diradical to give either the cyclized
product or the fragmentation product. In the case of (III) which is a β, γ-unsaturated
cyclic ketone, the α-cleavage gives a resonance stabilized allyl radical on one side. The
diradical recombines to give another isomerized ketone.
O O Ph
Ph
Ph Ph . Ph .
Ph Ph
hn –CO .
. (Ph)2C CH2
Ph
Ph Ph
-cleavage
Ph Ph
Ph Ph
From I From II
Ph Ph
via cyclization
O O O
CH3 CH3
.
CH3 CH3 CH3 C6H5CH2—CH2C6H5
hn
.
From (IV)
CH3
From (III)
10.4
R
10.5 It is Paterno-Büchi reaction which leads to the formation of a tetracycloxetane.
H
O Ph
10.6 The photochemical conversion of (I to II) involves the coupling rather than the
fragmentation of the Norrish Type II biradical to the cyclobutanol.
H H
O .O O . HO
hn
. .
C 6H5 C 6H 5 C 6H 5
C6H5
n,
Excited state
10.7 The compound will undergo ring closure to give a cage compound.
O
O
Photochemistry 419
10.8 The potential cage structure of cubane is reached by the dimerization of

2-bromocyclopentadienone which occurs spontaneously. The irradiation step was best
performed on a ketal derivative of the dimer from which the keto group was subsequently
regenerated by hydrolysis. The successive base induced ring contractions are reactions
of Favorskii type. The cubanedicarboxylic acid has been converted into cubane itself by
heating the t-butyl perester (from the acid chloride with t-butyl-hydroperoxide) in cumene;
homolysis of the peroxide bond is followed by decarboxylation and uptake of a hydrogen
atom from the solvent.
O
O
Br
Br
O – CO2H
hn OH
2 O Br
Br HO2C
Br
O
heat . .
RCO2H RCO—O—O—C(CH3)3 RCO—O + OC(CH3)3
. –CO2 PhCHMe2 .
RCO2 R. RH + PhCMe2
10.9
H
H H
H H
H
10.10 Formation of cyclic peroxides by conjugated dienes is a general reaction, and although
ultraviolet light often initiates the reaction, better results are achieved by carrying out
the irradiation of α-terpinene in the presence of sensitizers, e.g., chlorophyll, dyes, etc.
10.11
hn
+
O O
cis + trans
10.12 The regioselectivity of the reaction can be explained by invoking the formation of the
most stable intermediate-2-oxa-1, 4-diradical. For this reason one finds the reversal of
orientation during the photochemical addition of ArCHO to furan and dihydrofuran.
A.G. Criesbeck and S. Stadtmuller, Chem. Ber. 123, 357 (1990).

Ar
.
O
. O
O O Ar O
Preferred diradical
ArCH O
O Ar
. O
.
O O Ar
O Preferred diradical
CHAPTER 11 Br+
Addition to Carbon-Carbon and Br–
Carbon-Hetero Multiple Bonds
In this chapter the broad mechanistic and stereochemical aspects of addition reactions involving
electrophiles, nucleophiles and free radicals to a multiple bond are described. The other specific
topics and reactions are described elsewhere as indicated:
• HYDROGENATION
• HYDROBORATION
• MICHAEL REACTION
• SHARPLESS ASYMMETRIC EPOXIDATION
• METAL HYDRIDE REDUCTIONS
• ADDITION OF ORGANOMETALLIC REAGENTS TO CARBONYL
COMPOUNDS
• WITTIG REACTION
• CONDENSATION REACTIONS INVOLVING ENOLATES
• HYDROLYSIS OF ESTERS, AMIDES AND AMMONOLYSIS OF ESTERS
11.1 ADDITION OF ELECTROPHILES TO A MULTIPLE BOND

(A) Introduction
+
A proton and other electrophiles e.g., Br readily add to one end of a C C or C C bond, and
to the more electronegative atom in C N, C N or C O bonds. During addition to a C C or
C C bond, the addition involves the formation of the most stabilized cation. Alkyl groups
stabilize a carbocation by inductive and hyperconjugative effects; unsaturated and aromatic
groups stabilize a cation by delocalization of the positive charge onto remote atoms. Propene
reacts with HBr in the first step to give the secondary prop-2-yl cation, rather than the less
stable primary prop-l-yl cation (Scheme 11.1).
Br
+ –
Br
CH3—CH—CH3 CH3—CH—CH3
H—Br
CH3—CH CH2
+
Propene CH3—CH2—CH2
SCHEME 11.1
421
The addition of HCl to 3, 3, 3-trifluoropropene occurs in the opposite direction, the proton
adds to the central carbon instead of the terminal carbon as seen in the case of propene. In this
case, the secondary carbocation would be destabilized by the electron withdrawing CF3 group
(Scheme 11.1a).
+ –
Cl
CF3—CH2—CH2 CF3—CH2—CH2—Cl
H—Cl
CF3—CH CH2
+
CF3—CH—CH3
SCHEME 11.1a
EXERCISE 11.1
Why unlike the hydration of a mono-alkyl-substituted ethene, the hydration of
alkoxysubstituted alkene (a vinyl ether) with aqueous acid occurs under much
milder conditions and with complete regioselectivity ?
ANSWER. The substituents which stabilize the intermediate carbocation by an
electron donating resonance interaction will not only largely accelerate the reaction
but also control the regioselectivity (Scheme 11.1b).
H3O + +
RO—CH CH2 RO—CH—CH3 RO CH—CH3
RO—CH CH2 + HCl RO—CHCl—CH3
SCHEME 11.1b
A vinyl ether reacts rapidly with hydrogen chloride, however in the presence of
water i.e., reaction with hydrochloric acid, the intermediate carbocation reacts
with water to give a hemiacetal (see, Scheme 14.37).
EXERCISE 11.2
Why ethylene reacts with HCl faster than vinyl chloride ?
ANSWER. Consider the carbocations involved during the addition of HCl
(Scheme 11.1c). The cation (III) is less stable than (I, –I effect of chlorine). The
cation (II) has the halogen nearer the positive charge so considering –I effect of
chlorine, this cation is more strongly destabilized and this factor overweighs the
+
+ M effect of chlorine (CH3— CH —Cl CH3—CH Cl+). Thus the ease of
+ +
formation of the ions (I-III) decreases in the order CH3— CH 2 > CH3— CHCl >
Addition to Carbon-Carbon and Carbon-Hetero Multiple Bonds 423
+ +
H
CH2 CH2 CH3—CH2
(I)
+
CH3—CHCl
+ (II)
H
CH2 CHCl or
+
CH2—CH2Cl
(III)
SCHEME 11.1c
+
CH 2 —CH2Cl. Thus vinyl chloride reacts at a slower rate than ethylene but orients
in the same way as propylene.
The carbonyl group gets protonated to give a delocalized cation. This reversible reaction
is the first step of several acid catalysed reactions on carbonyl compounds (Scheme 11.1d).
R H R R
–H2O +
C O H—O+ C—O C O+
R H R H R H
SCHEME 11.1d
(B) Addition of Halogens

Chlorinations and brominations of alkenes are electrophilic additions and involve a discrete
positively charged intermediate which may be a bridged cyclic halonium ion (e.g., bromonium
ion I, Scheme 11.2) or a carbocation. This positively charged intermediate is formed after the
+
addition of Br to the alkene (see, also Scheme 4.23).
:
:Br :
: Br : +
:
:Br : :Br: :Br:

:
R H + + –
R2C—CHR R2C—CHR R2C—CHR + Br
R R
(I) (II) (III)
SCHEME 11.2
The bridged bromonium ion is best represented by the hybrid (Scheme 11.2) where a
tertiary carbocation (II) is a far more important contributor to the hybrid than the secondary
carbocation (III, Scheme 11.2). Consequently the carbon with an alkyl substituent(s) will be
more electrophilic. The regioselectivity is explained on this stability feature and the addition
of bromine to propylene in water (water competes with bromide ion as the nucleophile) gives in
addition to dibromo compound, 1-bromo-2-hydroxypropane as the major product than 2-bromo-
1-hydroxypropane (Scheme 11.2a). Thus regioselectivity of addition of BrOH to an
unsymmetrical olefin is explained on the charge distribution within the delocalized reactive
intermediate (bromonium ion) (See, Scheme 11.2). In fact the three membered ring of the
halonium ion is symmetrical provided the original double bond is symmetrical. Greater
stabilization of the 2° carbocation makes the bridged bromonium ion infact an unsymmetrical
species (I, Scheme 11.2a).
+
Br Br Br
Br2 +
–H
CH3CH CH2 CH3—CH—CH2 CH3—CH—CH2 CH3—CH—CH2
H 2O
OH (I)
H 2O :
:
Major product
SCHEME 11.2a
The formation of a bromonium ion intermediate ensures the formation of anti product.
The bridging will prevent free rotation around the C—C bond which will ensure the formation
of a mixture of diastereomers. Note that the opening of the cyclic bromonium ion is an SN2
reaction in which the incoming nucleophile attacks on the opposite side of the leaving group.
Moreover, when bridging is strong, the anti product is formed as a major or exclusive product.
The anti-addition of bromine is observed for alkenes which do not have substituent
groups that would stabilize a carbocation intermediate (Scheme 11.2). Thus, addition of bromine
to cis- and trans-2-butene is stereospecific (Scheme 11.3). The first step is the formation of a
Br
H
CH3
+ H
H Br (a) CH3
Br—Br CH3
H Br
CH3
+
H H (b)
H CH3
CH3 CH3
(a) (b) Br
cis-2-butene Br – Br
– H CH3
On bromonium ion attacks (a) and (b) are equally likely, Br
attacks the bottom face (SN2 reactivity). The bromonium ion enantiomers
rac-2, 3-Dibromobutane
has a mirror plane thus the two central carbons are
enantiotopic Br
H
CH3
+ CH3
H Br (a) H
Br—Br CH3
H Br
CH3
(b)
CH3 CH3
H H H CH3
(a)
trans-2-butene Br – (b) Br
Br
This intermediate bromonium ion has a C2 axis, CH3 H
thus the two central carbons are homotopic
meso-2, 3-Dibromobutane
SCHEME 11.3
positively charged bridged bromonium ion and in the second step the nucleophile, Br– adds to
the face away from the bridging group to give the overall anti addition.
When the alkene has phenyl group on the double bond, the selectivity becomes less and
both anti and syn adducts are formed. This is so, because now the positive charge in the
intermediate is delocalized on the aromatic ring (Scheme 11.3a). The presence of a phenyl
group, therefore, provides sufficient stabilization to allow carbocation formation (Scheme 11.2).
This situation reduces the strength of bromine bridging and allows rotation to occur as shown
(Scheme 11.3a). The freely rotating open carbocation would give both syn as well as anti addition
+ Br +
Br Br
H H H H
Br2
CH3 CH3 CH3 syn and anti
Ph CH3 addition products
+ Ph
H H
Ph
Ph H
A freely rotating open carbocation
SCHEME 11.3a
products. Thus syn and anti addition is observed with both Z-1-phenylpropene (Scheme 11.3a)
as well as with E-1-phenylpropene
ADDITION OF HALOGENS TO ALKENES

A weakly bridged bromonium ion can lead to the loss of stereospecificity during
halogen addtion. The unconjugated alkenes involved in strong bridging leading
to predominant anti-stereospecificity. The presence of a phenyl group on the double
bond generates a cationic character at the benzylic site leading to the formation of
more syn addition. Chlorine has a smaller size and lesser polarizability than
bromine, consequently chloronium ion is far less bridged. Thus overall bromination
gives more pronounced anti addition than chlorination.
Cyclohexene and its derivatives add chlorine and bromine to yield trans diaxial product
since only axial positions on adjacent carbons in a cyclohexane are anti and coplanar. The
initial trans diaxial product undergoes a conformational change and is in equilibrium with the
more stable trans diequatorial conformation (Scheme 11.3b). When a t-butyl group is introduced
on the cyclohexene ring, then the molecule exists almost exclusively in a conformation in which
the t-butyl group is equatorial. Thus when 4t-butylcyclohexene is brominated, the product
has t-butyl group equatorial with bromine atoms in the axial positions in the favoured product.
Br Br
Br2 Br Br2
Br
Br trans-diequatorial Br
trans-diaxial more stable 4-t-butylcyclohexene 1, 2-dibromo-
4-t-butylcyclohexane
SCHEME 11.3b
In several situations bromonium ions have been observed. Under superacid conditions
1-bromo-2-fluoropropane (Scheme 11.4) gives a cation, which infact is a bromonium ion related
to propene as shown by NMR spectroscopy. The highly hindered alkene adamantyli-
deneadamantane gives a bromonium ion (Scheme 11.5). An X-ray crystal structure
determination on its derivative has shown the cyclic nature of the bromonium ion. In this case
the bromonium ion is not attacked by Br–, the attack is completely prevented by the steric
hindrance offered to the backside approach of the bromide ion by the extremely bulky cage like
structure.
SbF5 –
CH3CHCH2Br CH3CH—CH2 + SbF6
SO2 – 60°C
F Br +
SCHEME 11.4
: :
: :
: Br—Br :
Br+
Br–
SCHEME 11.5
Whether the intermediate is a halonium ion or an open carbocation the mechanism is

termed AdE2 i.e., electrophilic addition, bimolecular.
One may recall that allylic bromination (instead of addition) of an alkene is the reaction
on treatment with NBS in CCl4 in the presence of peroxides or light (see, Scheme 2.19, Problem
2.3). In summary, in a non-polar solvent and a very low concentration of bromine, the reaction
is not addition of bromine but it reacts to substitute an allylic hydrogen atom. NBS provides a
very low concentration of bromine by reacting with HBr. To understand the reason for allylic
substitution at high temperature over addition a consideration of entropy changes is important.
Addition of bromine combines two molecules into one, thus the reaction has a substantial
negative entropy change (Sec. 4.4). However, at low temperature the T∆S° term in ∆G° = ∆H°
– T∆S° is now not large to offset the favourable ∆H° term, at higher temperatures, the T∆S°
term gains more significance, consequently ∆G° becomes more positive and the equilibrium
becomes more unfavourable. (In the addition of bromine, the bromonium ion formation is a
reversible step).
Bridged ions
The term bridged ions is infact synonymous with nonclassical cations. A
nonclassical carbocation involves three-center two electron bonding, a bromonium
however, does not involve this. The term bridged ion as used here for a bromonium
ion is thus ambiguous.
EXERCISE 11.3
Why acenaphthylene (Scheme 11.5a) on reaction with bromine
gives the expected trans dibromide (anti addition) alongwith a
large amount of cis dibromide (syn addition).
ANSWER. Due to the formation of a resonance stabilized open
carbocation. SN2 reaction on cyclic bromonium ion will give Acenaphthylene
only the trans product, while the open cation will give both cis
and trans products (Scheme 11.5b) SCHEME 11.5a
+
Bromonium ion Br Br Br Br Br Br
Open cation, well
+ stabilized by
resonance
cis dibromide trans dibromide
SCHEME 11.5b
(C) Addition of Hydrogen Halides to Alkenes

The first aspect of mechanism of addition of hydrogen halides to alkenes is the observed
regioselectivity controlled by Markovnikov rule i.e., the relative ability of the carbon atoms to
accept positive charge. The regioselectivity of addition of HBr can be complicated when a free
radical chain addition occurs (formation of anti-Markovnikov addition product) in competition
with the ionic addition (see, Scheme 16.13).
The addition of hydrogen halides to alkenes yields mostly anti product. An unsymmetrical
alkene will follow the Markovnikov rule during addition of hydrogen halides, since the
partial positive charge, which develops will reside largely at the carbon which is most able to
Ph
Ph H Ph
H3O+ Br– or
+
+
Me
Me Me
H
(I) (II)
– –
Br Br
H Ph
Me H
Ph Br
H Me Ph H
Br Me
Ph Br Br Me
(III) (IV)
Observed product
Regioselectivity in the addition of HBr to 2-methyl-1-phenylcyclohexene using
SCHEME 11.6
accommodate it, i.e., the more substituted of the unsaturated carbons. Consider the addition of
HX (e.g. HBr) to an unsymmetrical alkene 2-methyl-1-phenyl-cyclohexene (Scheme 11.6).
Considering the normal anti addition, the regioselectivity can be determined by the following
argument. If the protonation occurs from above the plane of cyclohexene derivative, attack at
C1 gives (I), while at C2 give II. The carbocation (II, Scheme 11.6) is far more stable, since in
its case extensive π-delocalization of the positive charge is available. The carbocation II is
captured by bromide from the face opposite to the one holding the proton to give (IV) the
product of normal anti addition. While the other route to give III is not followed.
Hydrogen halides and other acids do not form bridged ions with alkenes. The contribution
of a structure of the type (I, Scheme 11.7) i.e., a complex may be there on the mechanistic
pathway, which may be attacked from backside to give an anti product (II, Scheme 11.7).
Many additions of HBr and HCl to alkenes follow a third order rate expression and the
stereochemistry of addition to unconjugated alkenes is largely anti. These observations of rate
expression and stereochemistry point to the formation of a complex (I, Scheme 11.7) the anti
product being formed by the backside attack on the complex, i.e., the transition state involves
proton transfer to the alkene from one hydrogen halide molecule and capture of the halide ion
from the second (Scheme 11.7).
H—X H
H—X H+ + –
C C H + C C +X
C C + H—X C C or C C
H—X X
Backside attack on the complex
to give anti product
(I) (II)
SCHEME 11.7
When the double bond is conjugated with an aryl group the syn adduct predominates.
As in the case of bridging, the stabilization of the carbocation intermediate by the aryl group
reduces the effectiveness of the complex formation and an ion pair may be the key intermediate
(Scheme 11.8). When the ion-pair (formed by the initial alkene protonation), collapses to the
product faster than the rotation, the result would be syn addition because the proton and the
halide ion initially remain on the same side of the molecule.
–
X—H X H
H H H + X H
H
C C C C H H
Ph R Ph R Ph R
An ion-pair syn adduct
SCHEME 11.8
An example where both syn and anti addition of DBr is observed is of acenaphthylene
(Scheme 11.8a).
D Br
H H
DBr
CH2Cl2 Predominant
syn addition
Acenaphthylene
SCHEME 11.8a
Other examples of electrophilic addition reactions to alkenes include,

epoxidation (A, Sec. 13.4), bis-hydroxylation (D, Sec. 13.4) and
hydroboration-oxidation (Sec. 7.6)
(C) Electrophilic Addition to Alkynes

The mechanism for electrophilic addition to alkynes appears similar to those for alkenes. The
first step of the reaction of HBr to terminal alkyne generates formally a vinyl carbocation.
Markovnikov regiochemistry is observed for this reaction. The more stable 2° vinylic carbocation
is formed in preference to a less stable 1° vinylic carbocation (Scheme 11.9). The alkenyl bromide
then reacts with the second equivalent of HBr, and the product again with Markovnikov
regiochemistry is the geminal dibromide, which has both bromine atoms attached to the same
carbon atom.
The vinyl carbocation formed as the first intermediate is not equally stable as a secondary
or tertiary carbocation. Thus, the free energy of activation is higher for addition to a triple
bond than that for a double bond. Consequently the reaction of a second equivalent of the
reagent with an alkyne is usually more facile than reaction of the first equivalent. One may
add only one equiv. of a reagent to a triple bond with controlled experimental conditions.
H H Br H
H—Br + + Br–
H3C—C C—H H3C—C C H3C—C C C C
Step 1 H H Step 2 CH3 H
Vinyl carbocation (linear)
a 2° vinylic carbocation
H Less stable primary carbocation

+
CH3C—CH2
: :
H—Br: :Br: More stable secondary carbocation

(resonance stabilized)
:
CH3C CH2
:
:Br: H H :Br:
:Br –:
: :
:
+
CH3C—CH2 CH3C—CH2 CH3CCH3
:Br: +Br: :Br:
:
SCHEME 11.9
Compared to regioselectivity, stereoselectivity is much lower than seen for alkenes and
in less polar solvents there is some preference for syn addition (Scheme 11.9a).
C6H5 D C6H5 H
AcOH
C6H5—C C—D + HCl C C + C C
Cl H Cl D
60 % 40 %
SCHEME 11.9a
EXERCISE 11.4
During addition of bromine to acetylenedicarboxylic acid, the reaction is easily

stopped after the addition of the first mole of Br2. Explain.
ANSWER. Addition of one mole of Br2 to an alkyne gives a dibromoalkene via the
bridged bromonium ion. The reaction is stereoselective leading to anti addition.
After the addition of first mole of bromine to acetylene-dicarboxylic acid, the initial
product (Scheme 11.9b) has four deactivating groups
+
: :
HOOC Br Br
Br2
HOOC—C C—COOH C C C C
Br COOH
SCHEME 11.9b
(D) Some Other Aspects of Electrophilic Addition Reactions to Alkenes and Alkynes
• The intermediate carbocation may not react with the nucleophile to complete the
addition, but may lose a proton. This situation arises when there is steric hindrance
(see, Scheme 1.35).
• The enols also lose a proton (see, problem 11.2).
• Though aromatic carbon-carbon double bonds react with electrophiles by substitution,
however, addition may compete with substitution as in e.g., anthracene (see,
Scheme 2.41c).
• Like alkenes, alkynes react with carbene to form cyclopropenes or bicyclobutanes
depending on the amount of carbene present (Scheme 11.9c).
CH2 CH2
: CH2
CH3—C CH + : CH2 CH3C CH CH3C—CH
CH2
SCHEME 11.9c
• The initially formed carbocation can undergo molecular rearrangement, particularly

when after rearrangement a more stable carbocation is formed. This is seen e.g.,
during the addition of HBr to 3, 3-dimethyl-1-butene (Scheme 11.9d).
H Br CH3
–
Br
H2C—CH—C—CH3
CH3 H CH3
+
CH3
H – +
CH2 CHC—Me Br + H2C—CH—C—CH3 Markovnikov addition
3-bromo-2, 2-dimethylbutane
CH3 CH3 : Me
3, 3-dimethyl-1-butene shift
CH3 CH3
+ –
Br
CH3CH—C—CH3 CH3—CH—C—CH3
H 3C H 3C Br
More stable 3° cation 2-bromo-2, 3-dimethylbutane
SCHEME 11.9d
(E) Electrophilic Additions Involving Metal Ions (MercurationReduction)

Metal cations promote addition by electrophilic attack on alkenes in a reaction e.g.,
oxymercuration which involves the addition of OH from water and HgOAc group from a solution
of mercuric acetate Hg(OAc)2 in water/THF. The reaction gains its importance due to the ease
with which the mercury substituent is removed with sodium borohydride. Oxymercuration—
demercuration yields the same product as obtained by hydration. The reaction is generally
stereospecific (anti) and regioselective. Thus in a conformationally biased cyclic alkenes e.g.,
4-t-butylcyclohexene, the reaction yield exclusively the product of anti-addition and reflects on
the intermediate formation of a cyclic mercurinium ion intermediate (Scheme 11.10) to give
anti-diaxial addition.
OH OH
CH3
Hg(OAc)2 CH3 NaBH4 CH3
HgOAc H
SCHEME 11.10
The mechanism of the reaction may be studied by considering the following points:
• This is a two step process and in the first step, the electrophilic attack by Hg(OAc)+ at
the less substituted carbon of the double bond gives a cyclic (bridged) mercurinium
ion intermediate. As in the case of bromonium ion the cationic intermediate may be
bridged (mercurinium ion) or open which is dictated by the structure of the olefin
(Scheme 11.10a).
• The addition is completed by the attack of a nucleophile with the highly substituted
carbon atom which is more positive.
• After the first step of addition the mercury is replaced by hydrogen by the use of a
reducing agent.
H2O + –
Hg(OAc)2 Hg(OAc)2 AcO
H2O:
:
+
Hg(OAc) + NaBH4
–H
HgOAc H2O
HgOAc
H H OH H OH
Oxymercuration reduction
SCHEME 11.10a
• The two step procedure thus generally involves the formation of a mercurinium ion
intermediate and avoids the formation of an open carbocation. Therefore,
rearrangements are not observed as is the case during acid catalysed hydration
(Scheme 11.10b).
H2O H Rearrangement H2O HO

+
H2SO4 +
H H H H H
2° carbocation 3° carbocation 3° alcohol
Acid-catalysed hydration
SCHEME 11.10b
11.2 NUCLEOPHILIC ADDITIONS TO ALKENES AND ALKYNES

Nucleophiles do not attack alkenes, however, if the carbon-carbon double bond is conjugated to
a group of –M type, they readily attack the alkene. Examples of this are seen during Michael
additions and epoxidation of α, β-unsaturated aldehydes and ketones with alkaline hydrogen
peroxide.
Powerful nucleophiles e.g., an alkoxide ion (in an alcoholic solution) react with alkynes
(Scheme 11.11). A terminal alkyne on base catalysed nucleophilic addition of ethanol gives a
substituted vinyl ethyl ether (Scheme 11.11). A simple alkene however, does not undergo
nucleophilic addition of an alkoxide. In this case as well the regioselectivity as observed in
alkenes is followed i.e., the nucleophile adds to that carbon which gives more stable of the
possible carbanion intermediates.
R R
– EtOH – EtOH –
R—C C—H + EtO C C—H C CH2 + EtO
EtO EtO
A synthetic intermediate
R + R
H3O
C CH2 EtOH + C—CH3
EtO O
SCHEME 11.11
However, with less powerful nucleophiles like water a catalyst like mercury (II) ion is
needed. This ion complexes and consequently draws electrons from the triple bond. Thus water
adds to an alkyne in the presence of mercury (II) sulphate and dilute sulphuric acid to initially
give an enol which tautomerizes to a ketone (Scheme 11.12).
2+ Hg+
Hg + H 3C Hg+ H3C Hg+
C C +
–H
H3C—C C—H H C C C C
H 3C H +
O: H : O: H
:O—H
:
H H
H
A bridged mercurinium
ion intermediate is
attacked by H2O
+
:OH :OH
:
:
H—OH2 + OH
:
+ : OH2
:
R—C CH R—C—CH2 R—C—CH2
+
+ + +
Hg Hg Hg
Protonation occurs at the Resonance-stabilized carbocation
carbon bearing mercury
:O
:
OH OH
2+
–Hg
R—C—CH2 R—C CH2 R—C —CH3
+
enol
Hg+
Dissociation of mercury from
the carbocation liberates the
catalyst and the enol
SCHEME 11.12
11.3 ADDITION OF CARBENES

Carbenes add to alkenes to give cyclopropane derivatives. Singlet methylene e.g., reacts with
an alkene is stereospecifically, the addition occurs in one step (concerted addition) and the
stereochemistry of the alkene is preserved in the product (Scheme 11.13). The electrons in the
R R R R R R
C C C C
H H
H H H H
1 CH2
CH2 cis-Dialkylcyclopropane
cis-alkene
+ singlet methylene
SCHEME 11.13
triplet methylene are not paired and consequently it reacts with an alkene in a stepwise process
(Scheme 11.13a). The initial reaction is the formation of a biradical and this has sufficient
lifetime to allow rotation. The addition is therefore, non stereospecific.
R R R R H R
C. .C C. C C. C
(Bond rotation)
H H H .CH H R .CH H
2 2
.
. CH 3
2
cis-alkene 1. Spin inversion 1. Spin inversion
+ 2. Ring closure 2. Ring closure
triplet methylene
R R H R
+
H H R H
cis-cyclopropane trans-cyclopropane
SCHEME 11.13a
Carbene addition to a double bond is complicated due to too many side products. The
Simmons-Smith procedure is superior and leads to same results. The reaction involves reaction
of a double bond compound with diiodomethane (CH2I2) and a Zn-Cu couple, the attacking
species is an organozinc intermediate (ICH2ZnI), a carbene like species called a carbenoid
(Scheme 11.13b).
C C ZnI C
+ ICH2ZnI CH2 CH2 + ZnI2
C A carbenoid C I C
Zinc iodide
The Simmons–Smith synthesis
SCHEME 11.13b
11.4 NUCLEOPHILIC ADDITIONS TO CARBONYL COMPOUNDS (ALDEHYDES

AND KETONES)
Aldehydes and ketones display nucleophilic addition reactions when the nucleophile is either
–
a hydride ion or a carbon nucleophile e.g., CN . In their case since the carbonyl group is attached
– –
to a group which is too strong a base to be eliminated (H or R ), thus substitution does not
occur (Scheme 11.14). When the nucleophile that adds to the aldehyde or ketone is one in
which Nu is not electronegative (Nu is an H or a C nucleophile), the tetrahedral addition
product will be stable. The alkoxide ion will be protonated to yield the final product.
–
O Nu = C or H O 3 OH
2 sp +
sp – HB
C + Nu: R—C—R¢ R—C—R¢
:B Stable product of
R R¢
Nu Nu nucleophilic addition
Example
–
O O OH
– H—C N –
C + :CN CH3CC N CH3CC N + CN
CH3 CH3
CH3 CH3
Acetone Acetone cyanohydrin
SCHEME 11.14
In case however, the nucleophile Nu that adds to the aldehyde as ketone is a nitrogen or
an oxygen nucleophile, than the tetrahedral intermediate is not stable and from it water will
be eliminated and then the process is termed nucleophilic addition-elimination reaction. The
example is of the formation of an imine and an enamine when a primary or a secondary amine
adds respectively as a nucleophile to the carbonyl group of an aldehyde or a ketone
(Scheme 11.15). Note that when the nucleophile is a secondary amine, the proton loss is from
α-carbon rather than nitrogen in the last step.
– +
:O: :OH :OH2
:
+
:
CH3—NH2 H
O
NH2CH3 NHCH3 NHCH3
+
:
Neutral tetrahedral
intermediate a
carbinolamine —H2O
The mechanism of imine formation involves the (unstable)
addition of nucleophilic amine to the carbonyl
carbon, followed by the loss of a proton from the +
nitrogen and gain of a proton by oxygen. This is NCH3 +
NCH3
–H
followed by protonation of OH group and its loss as
H2O in an elimination reaction An imine H
Proton loss
Mechanism of imine formation
:OH :OH2 CH3 CH3

:
+
H –H2O +
:
N N
:N—CH3
:
N—CH3 CH3 CH3

CH3 H 3C H An enamine
Tetrahedral intermediate This intermediate cannot
(neutral) a carbinolamine lose a proton from N, so a
from reaction with a loss of a proton from an
secondary amine a-carbon takes place
(unstable)
Mechanism of enamine formation
SCHEME 11.15
11.5 NUCLEOPHILIC ADDITIONS TO THE CARBONYL CARBON OF A

CARBOXYLIC ACID DERIVATIVE
These derivatives form a tetrahedral intermediate, since both Y and Nu are electronegative
– –
atoms. This intermediate is unstable (Scheme 11.16) the relative basicities of Nu and Y
determine as to which will be lost from the tetrahedral intermediate.The weaker base is lost
easily (weaker the base, the better it is as a leaving group). Because a weak base does not share
its electrons that well as a strong base. Thus, a weaker base forms a weaker bond which is to
– – –
break. If Nu is a much weaker base than Y then Nu will be expelled and thus no new
– –
product will be obtained. When on the other hand Y is a much weaker base compared to Nu
–
then Y will be expelled leading to the formation of a new product, this mechanism is called
nucleophilic acyl substitution reaction. The mechanism of hydroxide ion promoted hydrolysis
of an ester (see Scheme 6.61) is an example.
:O :
– : :
:
O O
:
:
3
sp 2
k1 sp k2 sp2
– –
C + Z: R—C—Y C + Y:
k–1 k–2
R Y R Z
Z
A carboxylic acid A tetrahedral Product
derivative intermediate
SCHEME 11.16
11.6 RADICAL ADDITIONS TO ALKENES
For a detailed discussion see Chapter 16.
11.7 NUCLEOPHILIC ATTACK ON CARBON-NITROGEN TRIPLE BOND

–
The nitriles are attacked by powerful nucleophiles e.g., OH ion in water (Scheme 11.17) while
acid is needed for attack by weaker nucleophiles like water and alcohols. Nitriles are treated
as carboxylic acid derivatives since their hyrdrolysis yields carboxylic acids.
Alkaline hydrolysis occurs by nucleophilic attack on the partially positive carbon of the
nitrile group.
–
: :
: :
– Heat – H—OH H—OH 1. OH

N: + :OH N:
:
:
: :
RC RC – RC NH RC—NH2 RCOOH
–OH –H2O 2. H +
:OH :O—H :O
:
Intermediate
amide
SCHEME 11.17
During acid hydrolysis the weakly basic nitrogen is protonated and then a weaker
nucleophile e.g., water attacks the electropositive carbon atom (Scheme 11.18).
+ +
H + + H2O –H
RC N: RC NH RC NH RC NH RC NH
:
HOH :OH
:
+
+
H
OH
+ + +
+ H2O, H –H
NH4 + RC RC—NH2 RC NH2
:
O O: H—O :
:
Intermediate
amide
SCHEME 11.18
PROBLEMS
11.1 How ICl will add to Me2C CH2?
11.2 Write the mechanism for the formation of a ketone on addition of bromine to the enol (I),
and the addition of HCl to (II).
OH
CH3—C CH—CO2Et O2N—CH CH2

(I) (II)
11.3 Cyclohexene adds bromine to yield only a trans-1, 2-dibromo product (see, Scheme 4.23).
Dihydropyran on a similar addition however, gives both cis and trans isomers. Explain.
11.4 Why alkynes are less reactive compared to alkenes toward addition of bromine?
ANSWER TO THE PROBLEMS

11.1 As chlorine is more electronegative than iodine, ICl contains the electrophilic iodine.
Thus according to Markovnikov rule the product is 2-chloro-1-iodo-2 methylpropane
(Me2CCl CH2I).
11.2 Electrophilic addition to enols takes this course i.e., the loss of a proton after the addition
of an electrophilic reagent.
OH
(i) CH3—C CH—COOEt
–
Br2 –Br
OH + OH O
+
–H
CH3—C—CH—CO2Et CH3—C—CH—CO2Et CH3—C—CH—CO2Et
+
Br Br Br
–
+ Cl
(ii) O2N—CH CH2 + HCl O2N—CH2—CH2 O2N—CH2—CH2Cl
11.3 The initially formed product of electrophilic addition is a resonance stabilized carbocation
and not a bromonium ion.
H H H H
H
Br Br – Br Br
Br
Br—Br +
H Br
O + H
: :
: :
: :
O H O H O O
+ Br H
11.4 Alkynes undergo the same type of reactions as alkenes, however, since alkynes contain
two π bonds, they undergo addtion with two moles of the reagent. The bromonium ion
from an alkyne has a double bond, thus it is more strained and less stable than that
from an alkene. Moreover, the carbon atoms in I have more s character than II, making
I less stable than II.
CHAPTER 12 B H
C C
Elimination Reactions L
Elimination is one of the major classes of reactions displayed by organic compounds. Elimination
reactions involve the loss of two groups or atoms from a molecule. Elimination reactions are
classified under two general headings, β-eliminations [(1, 2 eliminations) are the most common
elimination reactions] in which groups on adjacent atoms are eliminated with the formation of
an unsaturated bond (Scheme 12.1). The β-eliminations include acid catalysed dehydration of
alcohols, solvolytic and base induced elimination reactions from sulphonates, alkyl halides,
and the Hofmann eliminations from quaternary ammonium salts (see, Scheme 15.29).
– – X = e.g., OH, OCOR,

OH – –Cl
CHCl3 CCl3 : CCl2 —C—C— —C C— + HX halogen, OSO2Ar,
–H+ + +
Carbene NR3, SR2.
H X b-elimination
a-elimination
SCHEME 12.1
The second mode of elimination involves two groups departing from the same atom.
These 1,1- or α-eliminations are used for generating the reactive intermediates called carbenes
(for further details see, Scheme, 4.44).
β-elimination reactions can occur by a variety of mechanisms and three mechanistic
pathways are normally distinct routes (Scheme 12.2). Of these E2 and E1 (see, Schemes 4.3
and 4.6) are the most common. These two processes are closely related to the SN2 and SN1
mechanisms of substitution. A third mechanism is designated as E1cB (elimination,
unimolecular of the conjugate base) which is less common. The E1cB mechanism involves a
carbanion intermediate and the substrate must contain substituents which stabilize it. The
substrate undergoing E1cB elimination has a leaving group which is β placed to a carbanion
stabilizing group e.g., C O, NO2, cyano etc. A good example is of Knoevenagel reaction (see,
Scheme 6.29). Another example is in (Scheme 12.2a). One may note that if a substrate
–
undergoing elimination has a poor leaving group (e.g., OH ), the transition state of otherwise
E2 elimination gains E1cB character.
438
Elimination Reactions 439
–
B: B
H H
H H
R—C—C—R R R RCH CHR
H L
H L
Transition state
(L = leaving group)
(E2—mechanism concerted)
H H H H
+
R—C—C—R R—C—C RCH CHR
L
H L H
Carbocation
intermediate
–
E1—mechanism
B:
H H H
–
:
R—C—C—R C—C—R RCH CHR
H L L
Carbanion
intermediate
E1cb—mechanism
SCHEME 12.2
–
Consider the example of elimination of (OH ) as water from a β-nitroalcohol after it is
–
deprotonated with base. The resulting carbanion is stabilized by resonance from which OH
group eliminates in the second slower step (Scheme 12.2a).
:B
H
– –
R R –OH
:
RCH CHNO2
NO2 NO2
+
OH OH
CH3OH
Carbanion stabilized +
B NaOCH3 by nitro group
NaOH
SCHEME 12.2a
12.1 THE BIMOLECULAR MECHANISM FOR ELIMINATIONE2 PROCESS
(A) E2 Mechanism
In this process both substrate and the base participate in the single step in the bimolecular
transition state from which the removal of a proton β to the leaving group is concerted with the
leaving group (Scheme 12.2).
The structure of the organic compound undergoing elimination and the strength of the
base used for the E2 elimination reflects on the extent of these three bond changes at the
transition state. One may thus study the transition state for E2 reaction as a hybrid of structures
(I-IV, Scheme 12.3). These structures gain individual importance which are based on several
factors:
• Structure (III, Scheme 12.3) would gain importance when L– is the poor leaving group,
or if the negatively charged carbon is adjacent to group with – I effect.
+ +
B B
B: B:
H H H H
– +
C—C C C C—C C—C
– –
L L L L
(I) (II) (III) (IV)
(B = base, L = leaving group)
The spectrum of E2 transition states (variable transition
state theory of elimination reactions)
SCHEME 12.3
• Structure (IV) gains importance, when on the other hand, L– is a good leaving group,
while B: is a weak base.
• The structure (II, Scheme 12.3) i.e., the alkene like character of the transition state
becomes significant when L– is a good leaving group and B: is a strong base.
• The transition state (III) will have considerable carbanion character when the leaving
group is poor e.g., NMe3 in Hofmann elimination.
(B) Direction of Elimination in E2 Reactions

A study of the spectrum of E2-transition states (Scheme 12.3) helps to explain the orientation
of the double bond. With several substrates the elimination can take place in more than one
way. Generally the more substituted alkene is formed as the major product (Scheme 12.4).
OCH3
CH3CH CHCH3 CH3CH CHCH3

2-butene
Br
(Major 80%)
More stable
CH3CHCH2CH3 – transition state
CH3O
Br CH3OH
2-bromobutane OCH3
CH2 CHCH2CH3 CH2 CHCH2CH3

1-butene
Br (minor 20%)
Less stable
transition state
SCHEME 12.4
This generalization is known as the Saytzeff rule. When 2-bromobutane reacts with a base,
one expects two elimination products (Scheme 12.4), since in the transition state both the
C—H as well as C—Br bonds are breaking. The transition state has alkene like structure and
the factors which stabilize an alkene (the larger number of alkyl substituents bonded to the
sp2 carbons) also stabilize the transition state. Thus 2-butene is formed as the major product.
The relative reactivities of alkyl halides in an E2 elimination follows the order:
tertiary alkyl halide > secondary alkyl halides > primary alkyl halides
This is due to the predominant formation of a more substituted alkene (Scheme 12.4a).
R
RCH2CR RCH2CHR RCH2CH2Br
Br Br
E2 Base E2 Base E2 Base
RCH CR RCH CHR RCH CH2
Increase in the order of reactivity
SCHEME 12.4a
Exceptions to Saytzeff rule are observed from base induced eliminations from quaternary
ammonium salts and from sulphonium salts which give predominantly the less substituted
alkene (Hofmann rule, Scheme 12.5).
CH3CH(CH2)2CH3 –
OH
CH2 CH(CH2)2CH3 + CH3CH CHCH2CH3
N(CH3)3
+ Major Minor
CH3CH2CHCH3 –
OC2H5
CH3CH2CH CH2 + CH3CH CHCH3
S(CH3)2
+ Major Minor
Hofmann rule Saytzeff rule

SCHEME 12.5
One can understand this difference between the eliminations from an alkyl bromide
(see Scheme 12.4, Saytzeff rule) and from a quaternary ammonium ion (Scheme 12.5, Hofmann
rule) on the basis of the poor leaving group tendency of amine compared with Br– (Scheme 12.5a).
–
OH
H
–
OH
CH2—CH—CH2—CH3 CH2 CHCH2CH3 + (CH3)3N: + H2O
150 °C
Major alkene
N(CH3)3 (Hofmann product)
+ Poor leaving group
SCHEME 12.5a
Thus in the E2 elimination of a quaternary ammonium ion, the C—H bond is almost fully
broken in the transition state and consequently the structures (I or II, Scheme 12.6) may be
considered as important contributors to the transition state i.e., the transition state is
“carbanion-like”, but between (I and II), structure (I, Scheme 12.6) is much more significant
: :
: :
+ + HO H HO H
HB HB
– –
:
CH2CHCH2CH3 :
CH3CHCHCH3 —C—C— —C C—
N(CH3)3 N(CH3)3 N(CH3)3 Br

+ + +
(I) (II) Carbanion-like transition Alkene-like transition
state leads to state leads to
Hofmann product Saytzeff product
SCHEME 12.6
since an alkyl group destabilizes an adjacent negative charge, therefore, the less substituted
alkene predominates. In the case of an alkyl bromide the transition state, will be more alkene
like. Further, it is seen that with an alkyl bromide itself, the Hofmann orientation predominates
in case the proton removed the Saytzeff orientation is in an sterically hindered environment.
In such a case the use of sterically hindered base may lead to Hofmann orientation (Scheme 12.7).
Greater crowding at the H 2

internal (2°) hydrogen atoms The more exposed (1°)
H 1 CH2 hydrogen atoms
CH3CH—C—Br
CH3
2-Bromo-2-methylbutane
1 2
CH3 CH2
CH3CH C CH3CH2C
CH3 CH3
2-Methyl-2-butene 2-Methyl-1-butene
Base % %
–
EtO 70 30
–
Me3CO 28 72
–
Et3CO 12 88
Saytzeff Hofmann
SCHEME 12.7
A consideration of the transition state as the hybrid of structures (Scheme 12.3) helps in
explaining the orientation observed in the four 2-halohexanes (Scheme 12.8). With X F; the
orientation is largely Hofmann while with X I, the orientation is predominantly Saytzeff.
Two factors may be considered, firstly the bond strengths lie in the order C—I < C—Br < C—Cl
< C—F, and secondly the electron withdrawing effect of X follows the order F > Cl > Br > I.
CH3CH2CH2CH2CHCH3
X
E2
2-hexene + 1-hexene
X=I 81% 19%
Br 72 28
Cl 67 33
F 30 70
Saytzeff Hofmann
SCHEME 12.8
Thus iodide is the best leaving group of the series and fluoride is the worst. With fluorine
therefore, one has predominant C—H bond breaking with little alkene character but
considerable carbanion character in the trasition state (i.e., it resembles III, Scheme 12.3). In
the fluorine case, the primary hydrogen is preferentially abstracted by base, since it allows the
negative charge to develop on a primary carbon which can best accomodate it to give Hofmann
orientation.
(C) The Rate of E2 Reactions and other Aspects

The reaction rate increases with the increasing strength of the base (I, Scheme 12.9). The rate
also increases with a good leaving group and the leaving group ability parallels the stability of
the anion. Ethers and alcohols do not undergo E2 elimination reaction since alkoxide and
hydroxide ions are relatively high energy species, while a sulphonate (II, Scheme 12.9) displays
this reaction readily, since sulphonate anion is very stable (the conjugate base of a strong acid.)
– – – – –
CH3CO2 < HO < EtO < Me3CO < NH2 (I)
–
B:
H
+ –
—C—C— BH + L + C C (II)
L (Sulphonate L = –OSO2R
SCHEME 12.9
Elimination is facile when the new double bond can come into conjugation with an existing
unsaturated bond. The stabilization energy associated with conjugation in the product formed
is partly developed at the transition state. Thus CH2 CH—CH2—CH2Br eliminates HBr to
give butadiene more readily when compared with 2-bromobutane.
One has seen that normally during E2 elimination, Saytzeff rule predicts the formation
of a more substituted alkene and the exceptions are when the leaving group is poor (see
Scheme 12.5). In this case negative charge will build up on the carbon from which the proton is
lost and therefore, the carbanion stability determines the major alkene product. Moreover, in
several eliminations, the less stable alkene predominates e.g., when the base is bulky and
sterically hindered (see Scheme 12.7). As the last example, it is conjugation which determines
the regiochemistry of E2 reactions. A conjugated alkene is more stable even though it may not
be the most substituted alkene. A conjugated product is more stable than a nonconjugate
product due to resonance. The transition state in such cases has a partial development of
conjugation which provides it enough stabilization. Thus the elimination (Scheme 12.10) gives
the conjugated product as the major alkene though it is not highly substituted.
CH3 CH3 CH3

Base
CH2CHCHCH3 CH CHCHCH3 + CH2CH C—CH3
OTs (Major) (Minor)

Double bond conjugated
with the benzene ring
SCHEME 12.10
EXERCISE 12.1
Write the products of elimination (Scheme 12.11)
Br CH3 CH3
– – –
(CH3)3CO (CH3)3CO + OH
CH3CHCH2CH3 PhCH2CHCHCH3 CH2—CH2—N—CH2CHCH3
t-BuOH t-BuOH
OTs H CH3 H
(I) (II) (III)
SCHEME 12.11
ANSWER. (I) More of 1-butene (CH2 CHCH2CH 3) would be formed than

2-butene (CH3 CH CHCH3) since the base is strong and sterically hindered.
CH3
(II) The major product is conjugated less highly substituted (PhCH CH CH—CH3 ).
(III) In this case the alkyl groups bonded to nitrogen are larger than methyl thus
elimination from these groups is also to be considered. In previous example (see
Scheme 12.5a) the elimination could occur only in the butyl group. In the present
case, β hydrogen could be lost either from ethyl or propyl group, since Hofmann’s
rule predicts the formation of less highly substituted product, ethene would be
formed as the major product (Scheme 12.11a) while propene (CH3—CH CH2)
would be a minor product.
CH3
+ From major
CH2—CH2—N—CH 2—CHCH3 CH2 CH2 + (CH3)2NCH2CH2CH3
pathway
– –
OH H CH3 H OH
Major pathway Minor pathway
SCHEME 12.11a
(D) Stereochemistry of E2-Elimination

In an E2 elimination the carbon sp3 orbital of the C—H σ bond and the carbon sp3 orbital of the
C—L σ bond (L is the leaving group) must begin to overlap to form a π bond. Consequently
these two sigma bonds have to be coplanar and two arrangements are syn-periplanar and anti-
periplanar. In synperiplanar conformation these two bonds are on the same side of C—C
bond while in anti- periplanar conformation these are on opposite sides of the C—C bond
(Scheme 12.12).
Anti coplanar
H B H transition state
B – H
:B
:
Base
C C – C C H C C
B:
Cl
X
Anti elimination
L L
Anti relation between
proton and leaving group
some p-bonding has begun
in the transition state
H L B H L
B Cl H X
:
–
Base B:
C C – C C H
i.e., B : C C
syn coplanar Syn elimination

transition state
Some p-bonding has begun
in the transition state
SCHEME 12.12
The evidence that a partial alkene structure exists at the transition state is shown by
the predominant formation of more of the trans alkene (sterically less congested) when
geometrical isomers are possible in the E2 elimination. Consider E2 elimination from 2-
bromopentane which is regioselective and as expected the Saytzeff product 2-pentene is formed
as the major product (Scheme 12.12a). E2 reaction is also stereoselective since 2-pentene which
can exist as a mixture of stereoisomers, contains more of E stereoisomer than Z isomer. In the
two conformations (I and II, Scheme 12.12a) of 2-bromopentane, conformation (II) is more
stable than (I), since in the former –CH3 is in gauche relationship with H, in (I), however,
–CH3 is gauche placed with respect to the bulkier –CH2CH3,
The E2 eliminations occur very fast if the two eliminated groups are anti to each other
and they as well as the connecting carbon atoms are coplanar. This geometry is termed anti-
periplanar stereochemical arrangement for concerted elimination reactions. Thus the dihedral
angle between the proton and the leaving group in the anti-periplanar conformation is 180°.
In this arrangement i.e., when the hydrogen and the leaving group are at a dihedral angle of
180°, their orbitals are aligned.
Br
E2
CH3CH2CH2CHCH3 CH3CH2CH2CH CH2 + CH3CH2CH CHCH3
2-bromopentane 1-pentene 2-pentene major product
minor product (mixture of E and Z)
CH3—CH2 Br CH3CH2 H
H CH3CH2 H
Br C
H
C
H CH3 H CH3
Br H H CH3
(II)
(E)-2-pentene
CH3CH2CH2CHCH3 major
2-bromopentane Br H CH2CH3
H CH2—CH3
H CH2CH3
Br C
(Can eliminate HBr via
H
C
two conformations) H CH3 H CH3 Clash
H H CH3
(I)
(Z)-2-pentene
minor
SCHEME 12.12a
The other arrangement for the concerted transition state of the E2 raction where the
orbitals of the hydrogen atom and the leaving group are aligned so that they can begin to form
a pi bond in the transition side is syn coplanar (i.e., the departing groups are coplanar on the
same side of the molecule). In the syn-coplanar arrangement the hydrogen and the leaving
group are eclipsed (dihedral angle 0°).
The transition state for the anti-coplanar arrangement (Scheme 12.12) represents a
staggered conformation and the base (nucleophile) is far removed from the leaving group and
generally this transition state is of lower energy. The transition state for the syn-coplanar
elimination is an eclipsed conformation. This is higher in energy due to eclipsing interactions
and due to an interference between the attacking base and the leaving group.
A strong preference is observed for anti elimination in cyclohexyl systems where the
departing groups on the adjacent carbons occupy axial positions (anti- coplanar arrangement).
Br
Br
H H
Reacts very fast in Reacts very slow
E2-elimination
SCHEME 12.12b
(E) Examples of Anti and Syn E2 EliminationsConformation and Chemical Reactivity

1. Reactions in acyclic systems
Consider an alkyl bromide, 2-bromobutane (Scheme 12.13). It has one stereocenter and
therefore, only two stereoisomers exist i.e., the compound has an enantiomeric pair. Elimination
of HBr from either enantiomer gives the same result: the mixture of cis- and trans- isomers of
butene (Scheme 12.13). This is an example of a compound which reacts stereoselectively. The
E2 elimination reaction must involve only those conformations of bromobutane molecule in
which the ligands to be eliminated attain an anti- periplanar arrangement. One can write
three possible staggered conformations of 2-bromobutane (I—III, Scheme 12.13). The

conformations I and II satisfy the coplanarity condition. Thus I gives rise to the cis olefin
while II to its trans isomer.
In conformation (III, Scheme 12.13) anti relationship between the departing ligands H
and Br is not available and therefore, it cannot undergo E2 elimination of HBr. Moreover, it is
found that mainly trans alkene is obtained to prove that elimination from rotamer (II) is more
facile than (I). The reaction from (II) is favoured due to larger stability of transition state from
(II, Scheme 12.13) than a trasition state from (I).
Br Br Br Br Br
H CH3 H CH3 H 3C H H 3C H H H
H CH3 H CH3 H CH3 H CH3 H CH3

H H H H CH3
(I) (II) (III)
Base Base
Transition state Transition state Not suitable rotamer
for E2-elimination
of HBr
H H 3C
CH3 H
H H
CH3 CH3
cis-2-Butene trans-2-Butene
Z-2-Butene (20%) E-2-Butene (80%)
anti-Periplanar arrangement is available between H and Br in both I and II, the staggered
conformations of 2-bromo-butane. Steric interactions between the methyl groups in (I), the
resulting transition state and the product cis-2-butene destabilize each of these compared to
(II). Thus the formation of trans-2-butene (major product) is more favourable.
SCHEME 12.13
Stereospecificity and Stereoselectivity

A stereoselective reaction is one in which a single starting material can give two
or more stereoisomeric products but one of these in greater amounts (or even to the
exclusion of the other). Thus 2-bromobutane undergoes a stereoselective base
induced elimination of hydrogen bromide (Scheme 12.13).
In a stereospecific reaction stereoisomeric starting materials yield products which
are stereoisomers of each other. The dehalogenation of meso and ( ± )-2,
3-dibromobutane is thus a stereospecific reaction.
Recall that Curtin-Hammett principle relates the product distribution to relative energies
of the transition states (see, Scheme 4.18i).
Dehalogenation of vic-dihalides with I– (iodide ion) has an E2-like transition state and
has similar mechanistic requirements e.g., in 2,3-dibromobutane (Scheme 12.14). The molecule
has two stereocenters and therefore, four stereoisomers can exist. The compound has, however,
only three stereoisomers, a (±) pair and a meso form. Elimination of two bromines with iodide
ion from the meso-isomer (I, Scheme 12.14) gives trans-2-butene while the (+) or (–) or the (±)–
pair gave cis-2 butene. This is so, because elimination can occur only via a comformation of the
starting compound in which the two bromine atoms are in an anti-periplanar arrangement,
regardless of the fact if or not this is the most stable conformation. The reaction on (±) isomer
(II, Scheme 12.14) involves a less stable transition state compared to the meso isomer (I). In B
two methyl groups are gauche placed, as a result, the elimination is slower by a factor of about
two for the (±)- than for the meso-isomer.
– Br
H CH3 I H CH3 H CH3 H
Br H 3C
H 3C
H Br Br C C
H 3C H H 3C H H CH3
Br Br
meso-2, 3-dibromobutane meso-2, 3-dibromobutane (A) trans-2-butene
(eclipsed) (staggered)
(I)
CH3 Br
H H CH3
H CH3 H 3C CH3
Br Br
Br or Br C C
CH3 H H CH3 H CH3 H H
(II) Br
(B) cis-2-butene
(±)-2, 3-dibromobutane
SCHEME 12.14
Preparing to understand the outcome of E2

Eliminations—Conformation and Reactivity
• Understand the stereochemistry of the reactant
• Start by drawing the Fischer projection
• Convert the Fischer projection to a staggered conformer
• Consider only the conformers in which the groups to be eliminated are anti
coplanar.
Consider the reactant 1, 2-dibromo-1,2-diphenylethane with two stereocenters. As
the groups on each stereocenter are the same one has a meso stereoisomer. Consider
E2 elimination with base on this stereoisomer (Scheme 12.14a) which gives only
the cis- isomer of the product alkene. One may alternately draw the meso form of
the compound on a wedge and dash structure (Scheme 12.14b) which is easy since
the projection has a plane of symmetry (a consideration of models will help).
Rotation (by only 60°) to bring H and Br anti periplanar to each other followed by
E2 reaction leads to cis- alkene (see, Scheme 12.14b).
Br Br
C6H5 H rotate
H Br H Br –
H Br Br CH3O H C
+ HBr
H Br E2 C C6H5
H C6H5
C6H5 C 6H 5
C6H5 C6H5
C 6H 5
Meso-1, 2-dibromo- Eclipsed Staggered (E)-1-bromo-1, 2-
1, 2-diphenylethane Newman projection Newman projection diphenylethene
Fischer projection
(R, S)
SCHEME 12.14a
Br Br Br H Br
Br
Base
C6H5 + HBr
H H H
C 6H 5 C 6H 5 C 6H 5 H C6H5 C 6H 5
–
meso-1, 2-dibromo-1, 2- B: (E)-1-bromo-1, 2-
diphenylethane (Staggered) diphenylethene
R, S (eclipsed) (cis)
SCHEME 12.14b
Apart from the meso- stereoisomer other two stereoisomers represent a pair of
enantiomers. Either of these enantiomers or the racemic mixture give the same
product trans alkene (Scheme 12.14c). By switching (interchanging) two groups
around one stereocenter on the meso- stereoisomer gives one of the enantiomers
(Scheme 12.14c) while the third stereoisomer would be its mirror image.
C6H5 C 6H5
C 6H5 Br
Br H Br –
H Br H H Rotate CH3O H C
+ HBr
Br H E2 C Br
H Br
C 6H5 C 6 H5
C 6H 5 C6H5
Racemic-1, 2-dibromo-1, 2-diphen- C6H5
ylethane or one enantiomer of (Z)-1-bromo-1, 2-
the racemic mixture diphenylethene (trans)
Br Br Br H C 6H 5
C 6H 5 –
ä
Rotate one CH3O

Br + HBr
C 6 H5 carbon 60° E2
H H H C 6H 5 Br
C 6H 5 H C 6H 5
(A) – (trans)
B:
(R, R)-1, 2-dibromo-1, 2-(eclipsed) (Staggered) (B)
Rotation of the carbon shown by arrow in (A) by 60° brings H and Br anti coplanar. After
rotation H comes in the plane of paper (shown on a continuous line) similarly Br rotates from
the plane of paper towards ones eyes to be put on a thick wedge. The orientation of C6H5
remains same i.e., away from ones eyes as seen in (B).
SCHEME 12.14c
This carbon shall have to be

rotated 180° to bring departing
bromine atoms anti coplanar
C6H5
Br Br Br C6H5
H
H H H C6H5
C 6H 5 C 6H 5 C 6H5 Br
trans
–
meso-R, S-1, 2-dibromo- I
1, 2-diphenylethane (eclipsed) (meso-staggered)
Br Br Br H
C6H5
H C6H5 H Br C6H5 C 6H 5
C6H5 H C6H5
– cis
(R, R) I
(eclipsed) (R, R) (staggered)
SCHEME 12.14d
Now consider, the elimination of Br2 with an iodide ion instead of HBr from the
molecule of 1, 2-dibromo-1, 2-diphenylethane (Scheme 12.14d). Considering the
meso stereoisomer written as eclipsed conformation has to be properly staggered
(180° rotation of one carbon with respect to other) to bring two bromine atoms anti
coplanar. Unlike the previous elimination of HBr (see, Scheme 12.14b) elimination
of bromine now gives trans alkene. Similarly either of the pure enantiomers alone
or the racemic mixture gives the cis alkene.
2. Reactions in cyclohexane systems

Generally all cyclohexanes are most stable in their chair conformations with all the carbon-
carbon bonds staggered. In a chair cyclohexane any two adjacent axial bonds (trans- diaxial)
are in an anti- periplanar conformation. A chair cyclohexane molecule can flip to bring about
an anti-coplanar relationship between the departing groups for the success of an E2 reaction.
When HBr eliminates from bromocyclohexane to give cyclohexene, the initial more stable
conformation, in which the bromine atom is equatorial undergoes a chair-chair interconversion
(Scheme 12.15). This process inverts the axial and equatorial relationships. This flip can now
bring the leaving group in the desired axial position to have an anti-coplanar relationship with
an axial hydrogen on the adjacent carbon.
Br
NaOH
axial
Br Br
HO
– H Equatorial –
OH
E2
H E2
Br H
H
H H axial H
(More stable) (Less stable)
Only this conformation with
both departing groups trans and
coplanar undergoes E2 reaction
SCHEME 12.15
Another example to show that the E2 elimination in a six membered ring proceeds best
when the adjacent trans groups can adopt an anti-periplanar conformation (1,2-diaxial) even
if this is a higher energy conformation is of menthyl chloride. Menthyl chloride can have two
conformations (I and II, Scheme 12.16). In (I, all the three substituents equatorial) the chlorine
is equatorial and as such antiperiplanarity with an adjacent hydrogen cannot be achieved.
For the E2 elimination to occur menthyl chloride undergoes a ring flip to give a high energy
and therefore, unfavourable conformation (II, Scheme 12.16) which has an axial hydrogen on
one side. The reaction occurs through an unfavourable conformation. Consequently the
elimination of HCl is very slow. In neomenthyl chloride (Scheme 12.17) the chlorine is axial
(methyl and isopropyl being equatorial) and axial hydrogens for E2 elimination are available
on neighbouring carbons on both sides. Thus a facile elimination occurs to give two olefins. The
olefin (I, Scheme 12.17) being the Saytzeff product predominates.
3. Eliminations in bridged compounds—Syn Elimination
In most of these systems syn-eliminations are more common. In these compounds, anti-
elimination is disfavoured both by conformational and steric reasons. Deuterated norbornyl
CH3 Cl
E2 –
CH3 CH(CH3)2 EtO
2 Cl
1 3
More stable H CH(CH3)2 100%
(I) Less stable
(II) (2-menthene)
Menthyl chloride
SCHEME 12.16
H H
–
CH3 CH(CH3)2 OEt/E2
+
Cl (I)
More stable
3-menthene 2-menthene
Neomenthyl chloride (major) (minor)
SCHEME 12.17
bromide (A, Scheme 12.18) on E2 elimination gave almost exclusive product containing no
deuterium. Firstly the rigid ring system prohibits attainment of an anti- elimination process
i.e., the leaving exo Br group cannot achieve a dihedral angle of 180° with endo hydrogen (the
angle being only 120°). Thus the leaving groups (D and Br) prefer syn elimination (via a planar
transition state) with a dihedral angle of about 0° to anti-elimination.
Br Dihedral
E2
angle of H + H
D about 0°
H H D
94%
H via syn-elimination (II)
endo-hydrogen (I)
(A)
SCHEME 12.18
12.2 THE UNIMOLECULAR MECHANISM FOR ELIMINATIONE1 PROCESS
Some Guidelines for E1 and E2 Reactions

• E1 reaction is favoured by a protic polar solvent and when no good base or
nucleophile is present.
• During E1 reactions since a carbocation is formed, the carbon skeleton can
rearrange before the loss of a proton.
• High concentration of a strong base in the presence of an aprotic polar solvent

will favour an E2 reaction
• Primary substrates (R–CH2–L) with low steric hindrance generally undergo
SN2 reaction with any nucleophile. These can be forced to display E2 elimination
by using a hindered strong base like potassium t-butoxide. Primary allylic or
benzylic substrates may display E1 reactivity (or SN1 substitution).
• When the substrate is secondary, a weak basic nucleophile e.g., CH3COO–, CN–
will bring about SN2 substitution, however, E2 elimination will be predominant
with a strong base e.g., OH –, OR – etc. E1 elimination (along with S N1
substitution) will be observed with a polar solvent in the absence of a good
nucleophile or base. An example is the use of an alcohol both as a solvent and a
nucleophile.
• Tertiary substrates R 3CL give high yields of elimination product by E2
mechanism using a strong base.
• An E2 reaction is regioselective, the more stable of the alkenes being formed as
the major product. When the leaving group is poor or the base is sterically
hindered then the less stable alkene may be the major product. An E2 reaction
also displays stereoselectivity both E and Z products are formed from suitable
reactants. The product alkene with bulky groups on the opposite side of the
double bond being more stable will be formed in greater proportion.
• An E1 reaction is also stereoselective. The major alkene is the one with bulkiest
groups on opposite side of the double bond.
(A) E1 Mechanism
This elimination takes place (without the participation of a base) in two
steps, unimolecular ionization, being rate determining (see Scheme 4.6
and 12.2)
(B) Direction of Elimination

The E1 eliminations from the intermediate carbocation (see Scheme 12.2) give rise to the more
substituted alkene as the principal product (Saytzeff rule, Scheme 12.19). 2-Bromo-2-
methylbutane on reaction with water in ethanol gives substitution as the major product when
both water and ethanol can act as nucleophiles to give an alcohol or an ether (Scheme 12.19).
The major alkene formed is more highly substituted.
CH3 CH3 CH2

CH3
CH3CH2OH
CH3CH2CBr CH3CH2COR + CH3CH C + C
H2O
CH3 CH3 CH3 CH3CH2 CH3
(R = H or CH2CH3) (Major) 6%
(60%) 34%
SCHEME 12.19
As a last point recall that weak bases are good leaving groups, thus from among alkyl
halides with the same alkyl groups the alkyl fluorides display least reactivity in E1 elimination
reactions (Scheme 12.20).
RF < RCl < RBr < RI
Increasing reactivity in an E1 reaction
SCHEME 12.20
(C) E1 Elimination from Cyclic Compounds

Since a carbocation is formed in the first step of the E1 reaction, (unlike a E2 reaction) the
relative stereochemistry of the leaving groups (anti coplanarity) is not important. When menthyl
chloride (see Scheme 12.16) undergoes E2 reaction only one alkene is formed in 100% yield
due to the need for the departed groups to attain diaxial positions. When menthyl chloride is
subjected to E1 reaction conditions two alkenes are formed, the major product is in accord with
Saytzeff rule (Scheme 12.21).
CH(CH3)2 CH(CH3)2
H 3C H 3C E1
Cl +
+
CH3OH/H2O
Carbocation 3-menthene 2-menthene
(major) (minor)
SCHEME 12.21
EXERCISE 12.2
Predict the product from the E1 elimination of compound
(Scheme 12.22). H
ANSWER. The reaction conditions of E1 elimination CH3

(CH3CH2OH/H2O) generate a carbocation. A carbocation H
Cl
rearrangement may involve the formation of a more stable CH3
carbocation and the major/exclusive product may be derived
from this (Scheme 12.23). SCHEME 12.22
H H H H
H H CH3
CH3 CH CH OH/E1 CH3 1, 2-H shift CH3
3 2
H –
–Cl
+ H +
Cl H CH3
CH3 CH3 CH3
2° carbocation 3° carbocation
SCHEME 12.23
EXERCISE 12.3
Recall the normal E2 anti pathway followed during the elimination of a bromine
molecule from a 1, 2-bromide with iodide ion. The meso-1,2-dibromo-1,2-
diphenylethane gives the trans alkene (see, Scheme 12.14d).
Why compound (Scheme 12.24) instead eliminates bromine to give a cis alkene.
Br Br
H H
D D
SCHEME 12.24
ANSWER. In this case now bromine is attached to a primary carbon. One may
explain the outcome by first invoking an SN2 reaction followed by E2 elimination
(Scheme 12.25).
Br Br Br H
SN 2 D
E2
H H H D D
D D D I
–
I – cis
I
meso
SCHEME 12.25
(D) Curtin-Hammett Principle

The Curtin-Hammett principle applies to a conformationally heterogenous reactant where the
products must be non-equilibrating. (IUPAC Commission, Gold 1983). The Curtin-Hammett
principle implies that in a chemical reaction which give one product from one conformer and a
different product from another conformer (provided the products do not interconvert while the
two conformers are rapidly interconverting relative to the rate of product formation). The
product composition is not determined by the relative populations of the ground state conformers
but largely depends on the relative energies of the corresponding transition states involved
(Scheme 12.26).
Br Br
H H CH3 H 3C H H 3C
CH3 H
H H
CH3 H CH3 H CH3 CH3
cis-2-butene H H trans-2-butene
20% 80%
(I) (II)
Curtin-Hammett principle relates the product distribution to relative energies of the transition states from
e.g., the conformers of 1-bromobutane (conformationally heterogeneous starting material) rather than the
relative populations of the conformers [the products must be non-equilibrating and the conformers are
rapidly interconvertable relative to the rate of product formation].
SCHEME 12.26
12.3 PYROLYTIC SYN ELIMINATIONEiELIMINATION INTERNAL

These thermal eliminations occur within a small family of compounds, like acetate esters,
methyl xanthate esters and tertiary amine oxides with the formation of olefins and eliminating
acetic acid, COS and CH3SH and dimethylhydroxyl amine respectively (and are the reverse of
ene-reaction, see, Scheme 17.97). These eliminations have a common mechanistic feature: a
concerted reaction via a cyclic transition state within which an intramolecular proton transfer
is accompanied by elimination to form a new carbon carbon double bond. The cyclic transition
states dictate the syn eliminatation i.e., the hydrogen atom and the leaving group depart from
the same side of the incipient double bond (Scheme 12.27). These eliminations do not involve
acidic or basic catalysts. There is a wide variation in temperatures at which these eliminations
proceed. The pyrolysis of carboxylic esters and xanthates provide a useful alternative for
dehydration of alcohols without rearrangement.
R
H O R
D
H O O +
O
R¢ H
R¢
Pyrolytic syn elimination
SCHEME 12.27
(A) Stereochemistry of Thermal Eliminations

As already said these eliminations occur with syn stereochemistry and the reactions therefore,
on the whole are often referred to as thermal syn eliminations. On pyrolysis, erythro and threo
isomers of 1-acetoxy-2-deutero-1,2-diphenylethane gave in each case trans- stilbene (Scheme
12.28). The syn elimination is proved by retention of deuterium in the product from erythro
isomer (A, Scheme 12.25) and its loss from the threo isomer B. For this syn process either the
hydrogen or the deuterium could be syn placed to the acetoxy group. However, in the preferred
conformations have the phenyl groups as far apart as possible. The molecule has two
stereocenters and therefore, four stereoisomers are possible i.e., a pair of enantiomers in each
erythro and threo isomer. In eclipsed conformations (I and II, Scheme 12.28) Ph/Ph θ = 0°. The
elimination, thus takes place from conformations with Ph/Ph far removed. In the transition
state from A, a H is syn placed with the acetoxy group. In B now it is D which is syn placed with it.
Ph D
D H Ph
H
D—C—H H Ph Ph H
AcO C C
Ph O
AcO—C—H H Ph D
O C
Ph (I)
Ph CH3
Rotate to keep Ph groups
(A) as far apart as possible
Erythro isomer this brings OAc and H syn
Ph H
H D Ph
H
H—C—D H Ph Ph D
AcO C C
Ph O
AcO—C—H H Ph H
O C
Ph (II)
Ph CH3
(B)
Threo isomer
Pyrolysis of 1-acetoxy-2-deutero-1, 2-diphenylethane
SCHEME 12.28
(B) Product Composition

When a conjugating group is present in the β position, the elimination takes place in that
direction to yield the conjugated olefin. In the absence of such a situation, the composition of
the product is mainly determined by the number of hydrogen atoms available on each of the
β-carbons. Thus 2-butyl acetate on pyrolysis affords a mixture containing 57% 1-butene and
43% 2-butene (Scheme 12.29).
CH3CH2CH CH3
+ OAc
CH3 H H Less hindered
C C H CH3 synperiplanar
relationship
H CH3
CH3CH2CHCH3 CH3 H
D
OAc (CH3/CH3 q = 120°)
+
2-Butyl acetate
OAc
CH3 CH3 H More hindered
C C H CH3 synperiplanar
relationship
H H
H CH3
(CH3/CH3 q = 0°)
SCHEME 12.29
This product formation closely agrees with the 3:2 ratio of β-hydrogens. Moreover, of
the 2-butenes, the E-isomer is formed as the major component. This may be due to less steric
crowding between the two bulky methyl substituents in the transition state which leads to the
E-alkene (Scheme 12.29).
(C) Thermal Elimination Reactions in Cyclohexanes

In cyclohexane systems if a leaving group is axial then for the cis relationship a β-placed
equatorial hydrogen on the ring should be available for syn elimination. This is explained by
H H
S D
O + 2-Menthene
2
1 3 C
H 3-menthene (Minor)
SCH3 (major)
Menthol (xanthate ester)
D
H + 3-Menthene
H
O 2-menthene (Minor)
(major)
S C
SCH3
Neomenthol (xanthate ester)
SCHEME 12.30
considering the methyl xanthate esters from menthol and neomenthol (Scheme 12.30). Recall
that during E2 reaction the system of menthol and neomenthol (trans coplanarity condition)
give opposite results.
The Cope reaction involves the pyrolysis of amine oxides (Scheme 12.31) having a
hydrogen atom β to the amine group. The syn elimination affords an alkene and
dialkylhydroxylamine.
–
H O
OH
+
N(CH3)2 D
+ N(CH3)2
SCHEME 12.31
(D) Elimination from Selenoxides

Selenoxides are more reactive than amine oxides toward β elimination and many undergo
thermal syn elimination to form alkenes under milder conditions (room temperature). The
selenoxides can be easily made from the corresponding selenides by oxidation with hydrogen
peroxide. A selenides is formed e.g., by the nucleophilic substitution on a tosylate by selenol
(Scheme 12.32). The orientation is satistical i.e., depending on the number of β-hydrogens
available on each side and Hofmann product predominates.
H H C6H5Se H
CH3
NaOEt/EtOH
C—C + C6H5SeH C—C
CH3 H CH3
TsO Selenol
C6H5 CH3 C6H5
A selenide
–
:O:
:
C6H5Se H H CH3 CH3

H2O2 +
C—C C C + CH2 CHCHC6H5
H CH3
CH3 C 6H 5 CH3 C6H5 (30–40%)
A selenoxide (15%)
SCHEME 12.32
Selenoxide eliminations find many synthetic uses and an example is the formation of
α, β-unsaturated ketones. Lithium enolates from ketones (made by employing LDA) react with
benzene selenide bromide (C6H5SeBr) to give selenides in which C6H5Se-group is attached in
the α-position. Treatment of the selenide with H2O2 (room temperature) gives α, β-unsaturated
ketone (Scheme 12.33).
O + –
Li O O
CH3 SN 2 CH3
CH3 C6H5Se—Br –
C 6H 5 –Br CH
H H C 6H 5 C6H5
H
SeC6H5
– +
(i-C3H7)2N Li a selenide
(LDA) H2O2/20°C
O
O H2
C C
C –C6H5SeOH
C6H5 CH H
C6H5 CH CH2
+ Se
–
: :
C6H5 O:
a selenoxide
SCHEME 12.33
PROBLEMS
12.1 Why in syn thermal eliminations no skeletal rearrangements are observed?
12.2 What products are expected on E2 elimination and in what yield from the following
ammonium and sulphonium substrates?
Me
b b +
+
Me—N—CH2CH2CH3 MeCH2CHSMe2
CH2CH3 CH3
b b
(I) (II)
12.3 Which of the threo- or erythro- 1,2-diphenyl-propylamine will react faster under E2-
elimination reaction conditions (sodium ethoxide and ethanol)?
C 6H 5 C 6H 5
H—C—N(CH3)3 H—C—N(CH3)3
+ +
H3C—C—H H—C—CH3
C 6H 5 C 6H 5
(threo) (erythro)
12.4 On pyrolysis of the following ester gave in addition to acetic acid, the mixture of olefins
I and II in a nearly statistical ratio of 3:2. Explain.
H3COOCH(CH3)CH2CH3 H 2C CHCH2CH3 CH3CH CHCH3

(I) (II)
12.5 In several situations the E2 elimination gives a complex mixture of regio- and
stereoisomers of alkenes. Explain giving a suitable example.
12.6 Sodium alkynides acting as nucleophiles, displace a halide ion from primary alkyl halides
(alkylation of alkynide ion). With secondary or tertiary halides, the alkyne from which
sodium alkynide was orginally derived is isolated. Explain.
12.7 Predict the outcome of the following reactions:
CH3 Cl Cl
CH3OH EtOH EtOH
C——CHCH3 CH3CCH3 CH3CCH3 –OEt
CH3CH2OH
CH3 Br CH3 CH3
(I) (II) (III)
12.8 Select one product from each of the following reactions giving arguments.
H
D
CH3 CH3CH2OK
Br CH3 CH3 CH3
CH3CH2OH
H
H
(I) D (II) H (III) D (IV)
Br
CH2 CH3 CH3
CH3 NaOCH3
CH3OH
(V) (VI) (VII) (VIII)

12.1 Since no intermediates that are prone to such rearrangements are involved.
12.2 The elimination will largely involve that β position, the loss of a proton from which will
end up with a stabler carbanion (involvement) of a carbanion like transition state).
(I) CH2 CH2 + MeCH CH2 (II) MeCH2CH CH2 + MeCH CHMe
(Major product) (Minor product) (Major product) (Minor product)
12.3 These isomers will undergo stereospecific elimination. Due to the rigid requirements of
the transition state (trans-coplanarity) the erythro-isomer will react slowly since the
desired conformation has crowding of the two phenyl groups.
H
H C6H5 CH3 C6H5
threo C C
C 6H5 CH3 C6H5 H
+ N(CH3)3
H
H C6H5 C 6H 5 C6H5
erythro C C
CH3 C6H5 CH3 H
+ N(CH3)3
12.4 There are two β-positions from which H can be lost. Product (I) is obtainable by the loss
of 3 β-hydrogens while II by the loss of only two β-hydrogens.
CH3 O CH3 O
C CHEt C CHMe
(I) (II)
O C O C
H H H CH3
H H
12.5 It is due to several possible E2 elimination routes e.g., in 3 chlorohexane.
Me
H H Me H H H H H Et H H H
Me
+ +
H H
Me Pr H Pr Me Cl Cl H Et Et Et
Me
3-chlorohexane
12.6 The alkynide ion, acting as a nucleophile displaces a halide from the primary alkyl
halide in an SN2 reaction to give a substituted alkyne. With secondary and tertiary
halides, the alkynide ion acting as a base (rather than a nucleophile) brings about an
E2 elimination.
– + liq. NH3
HC C: Na + CH3—Br H—C C—CH3 + NaBr
SN 2
Propyne
: X:
:
E2
—C——C— –
C C + R—C C—H
—X
H
–
RC C:
acts as a base
12.7 It is an E1 reaction, the initially formed secondary carbocation from (I) undergoes a 1,
2-methyl shift to give a more stable tertiary benzylic cation and the final product after
the loss of a proton. The substrate II is tertiary and strong base is absent. The reaction
will give mainly substitution, with some elimination. The reactant III is a tertiary halide,
strong base gives elimination by E2 pathway in a high yield.
CH3 1, 2-methyl CH3 CH3

+ shift +
+ –H
C—CHCH3 C—CHCH3 C CCH3
CH3 CH3 CH3

2° Carbocation More stable
3° benzylic cation
OCH2CH3 CH2
CH2
CH3CCH3 + CH3CCH3
CH3CCH3
CH3
98%
80% 20% Product from (III)
Product from (II)
12.8 Generally E2 eliminations require a conformation in which the β-hydrogen atom and
the leaving group are anti. In a cyclohexane ring of (I) the hydrogen and the leaving
group have to be diaxial. To place the bromine in axial orientation ring flips and anti
elimination from it will give (IV) as the only alkene that can be formed. The products
(II and III) could arise via a syn elimination which is not the case.
H
D Br
CH3
Br D H
H H
H H CH3
The substrate (V) has got three types of β-hydrogens. The compounds (VII and VIII) are
trisubstituted, while (VI) is the least stable. The compound (VIII) is the alkene formed
since the new double bond is in conjugation with the aromatic ring.
13
:
B
H O
CHAPTER —C—O—Cr—OH
Oxidation Methods
An oxidation reaction is defined as addition of oxygen to an organic compound, removal of

hydrogen or removal of one electron as e.g., in the conversion of phenoxide anion to phenoxy
redical (see Schemes 14.2 and 14.3).
13.1 OXIDATION OF ALCOHOLS TO ALDEHYDES, KETONES OR CARBOXYLIC

ACIDS
(A) Chromium (VI) Oxide/Chromium Trioxide (CrO3)

From among a variety of transition metal oxidants, the Cr (VI)— derived reagents are highly
useful. The oxidation state of Cr in these reagents is (VI), and these are powerful oxidizing
species. The CrO3 based oxidants convert an alcohol to the corresponding ketone or aldehyde
(oxidation of a primary alcohol proceeds through the aldehyde to carboxylic acid) and the
general mechanism is given (Scheme 13.1). The most commonly used reagent is chromic acid
H2CrO4, which is usually prepared by adding chromium VI oxide (CrO3) or sodium dichromate
(Na2Cr2O7) to sulphuric acid. When the oxidations are carried out in aqueous acetone the
process is termed Jones oxidation (or oxidation by the Jones reagent, CrO3—H2SO4—H2O.
The mechanism involves the formation of a chromate (VI) ester and a subsequent
fragmentation (an E2 elimination reaction) to form a ketone (by the loss of H+ and HCrO3–).
Base B:
H H O –
O
+
R—C—OH + CrO3 R—C—O—Cr—OH R—C O + BH + O Cr
R R O R OH
A chromate (VI) ester
A secondary alcohol A ketone
SCHEME 13.1
A marked isotope effect (~ 6) was observed with propan-2-ol. Thus when chromic acid is
used in the oxidation of CH3CDOHCH 3 and isopropanol, CH3CHOHCH3, the deuterated
compound reacted about six times slower, so that kH/kD is ~ 6 to prove that the rate determining
step involves the cleavage of a C—H bond.
462
Oxidation Methods 463
EXERCISE 13.1
A useful laboratory test for aldehydes is the silver mirror test when silver (I) oxide
(Ag2O) brings about the oxidation of an aldehyde to a carboxylic acid. Give a
mechanism of the reaction.
ANSWER. This is in Scheme 13.1a and the mechanism involves the nucleophilic
addition of silver oxide to the carbonyl group of the aldehyde.
– –
O O
O +
+ Ag
R—C Ag R—C—O—Ag R—C O + Ag—Ag
–
H O—Ag H
SCHEME 13.1a
A very useful Cr (VI) reagent is pyridinium chlorochromate (abbreviated PCC), which
is prepared by dissolving CrO3 in hydrochloric acid and by subsequent treatment of the solution
with pyridine (Scheme 13.2). When PCC is dissolved in DMF or is used as a suspension in
CH2Cl2, it oxidizes the secondary alcohols to ketones and allylic primary alcohols to the
corresponding aldehydes. Saturated primary alcohols are oxidized to an aldehyde or the
carboxylic acid depending on the conditions.
Collins reagent is obtained by adding chromium (VI) oxide to pyridine and is chromium
(VI) oxide-pyridine complex, (CrO3–2 pyridine) which is used for the oxidation of alcohols
+
containing acid-sensitive functional groups. Pyridinium dichromate (C 5H 5 N H 2) Cr2O 7
abbreviated (PDC) is obatined by the reaction of chromium trioxide with pyridine in water.
All these reagents are readily soluble in organic solvents and PCC and PDC are conveniently
available as stable solids. Irrespective of which one is used these perform the same function.
Other complexes e.g., chromium (VI) oxide dimethylpyrazole complex provide an added
advantage as the internal base is available for the decomposition of the intermediate chromate
(VI) ester (see, Scheme 13.1). Examples of oxidation with these reagents are in (Scheme 13.2a).
CH3
+ –
CrO3 + HCl + N N—H CrO3 Cl
CrO3
N
H 3C
Pyridinium chlorochromate N
(PCC) H
(A)
SCHEME 13.2
PCC
C6H5CH CH—CH2OH C6H5CH CH—CHO
80%
OH O
PDC
CH2 CHCH2—CH—CH3 CH2 CHCH2—C—CH3
SCHEME 13.2a
(B) Use of Dimethyl Sulphoxide (DMSO)

Dimethylsulphoxide in combination with an electrophilic molecules like dicyclo-
hexylcarbodiimide, acetic anhydride, oxalyl chloride and sulphur trioxide brings about the
oxidation of alcohols.
• DMSO on reaction with an electrophile gives a species which is activated and thus
an alcohol adds to the sulphur atom and the adduct thus formed has a good leaving
group as well.
• The alcohol is converted into its halide or tosylate and then reacted with DMSO. In
either case there is an intermediate formation of an alkoxysulphonium ion from which
carbonyl compound is formed by base catalysed elimination.
(i) By the use of DCC
In this method (Scheme 13.3) DMSO is activated by using DCC and an acid is used to catalyse
the first step to give an intermediate (A, Scheme 13.3) which is attacked by alcohol. This
oxidation can be specifically used for the oxidation of primary alcohols to aldehydes.
DCC O
R H
+
H –RNHCNHR
N C N NHC N +
R O—S(CH3)2
O + +
– + S(CH3)2 –H
O—S(CH3)2 (A)
DMSO R R
: :
R—C—OH C O + (CH3)2S
R
H
Ketone
Alcohol reactant
SCHEME 13.3
Further uses of DCC-Formation of Amide Bond in Peptide Synthesis

(formation of aliphatic carbon-nitrogen bonds)
Carboxylic acids react with amines only under very vigorous condition. It is thus
necessary to convert the acid into a derivative which is more reactive towards the
nucleophiles. The requirement is that the group X in the derivative RCOX should
be a good leaving group. Conversion to an acyl chloride is a common way to
accomplish this for normal organic reactions. However, acyl chlorides are quite
reactive and do not give high enough yields in peptide synthesis due to side
reactions, thus milder methods for the amide bond formation are to be employed.
The most common method to form an amide bond in peptide synthesis makes use
of DCC as the coupling reagent.
The two C N bonds in DCC (Scheme 13.3a) make the central carbon electrophilic
and highly reactive towards nucleophiles. The carboxylic acid (nucleophile) first reacts
with DCC to form an intermediate that resembles an anhydride but with a carbon-
nitrogen double bond in place of one of the carbonyl groups (—CO—O—C N—R).
The amino group then reacts with the intermediate (I, Scheme 13.3a) to give a
tetrahedral intermediate (II). The C—O bond of the tetrahedral intermediate breaks
easily as these bonding electrons are delocalized to form dicyclohexyl urea—a stable
diamide. One may recall that weaker (more stable) the base, the better is the
tendency for it to act as a leaving group.
O O
:
:
NH
: :
RCOH + N C N RC—O—C
N
:
Dicyclohexylcarbodiimide R¢NH2
(DCC) (I)
–
:O:
:
O NH NH
:
: :
RCNHR¢ + O C R—C—O—C
:
An amide
NH +
R¢N—H N
(II)
Dicyclohexylurea H
(a stable diamide)
SCHEME 13.3a
(ii) Swern oxidation—use of DMSO and oxalyl chloride

Swern oxidation (Scheme 13.4) DMSO is activated towards the addition step by oxalyl chloride.
The resulting alkyloxy-sulphonium salt (A, Scheme 13.4) on treatment with a base (usually
triethylamine) gives the corresponding carbonyl compound in high yields under mild conditions.
Thus a primary alcohol gives an aldehyde and a secondary alcohol gives a ketone.
O O
+
Me2S O Cl Me2S +
Cl –CO
DMSO Cl O Me2S—Cl
–CO2
O –
– O Cl
Oxalyl chloride Cl
Dimethylchloro-
sulphonium ion
Activation of DMSO—formation of oxidizing agent
H B: H (H)R
+ +
(H)R—C—OH + Me2S—Cl (H)R—C—O—SMe2 C O + Me2S
– – R
R Cl R Cl
Aldehyde or
Alcohol Oxidizing (A) ketone
primary or secondary agent
Oxidation of an alcohol with dimethylchlorosulphonium ion–Swern oxidation
SCHEME 13.4
(iii) Use of substrates with good leaving groups

Substrates with good leaving groups e.g., the alcohols toluene–p–sulphonates usually derived
from an alcohol and the sulphonyl chloride give the corresponding aldehydes or ketones on
treatment with DMSO (Scheme 13.5). The presence of a base facilitates the reaction by removing
the proton. Reaction occurs via an initial SN2-displacement followed by base catalysed
elimination on the resulting sulphonium salt (Scheme 13.5).
TsCl
R—CH2OH RCH2OTs RCHO
CH3SCH3
Tosylate
O
H
SN2 + –(CH3)2S
RCH2—OTs RCH—O—S(CH3)2 R CHO
+ –
(CH3)2S—O
SCHEME 13.5
Specific Oxidation of Primary Alcohols to Aldehydes

Methods are available e.g., use of DMSO to specifically oxidize primary alcohols
to aldehydes by arresting over-oxidation to carboxylic acids. A variety of amine
oxides e.g., pyridine N-oxide react in a way similar to DMSO and are useful
reagents to oxidize primary alcohols to aldehydes (Scheme 13.6). In this reaction
pathway, nothing is in the reaction sequence which can oxidize the initially formed
aldehyde to an acid.
+ –
NO
H
TsCl SN2 +
Br CH2OH Br CH2—OTs Br C—O—N
Br CHO + N
SCHEME 13.6
Periodinane Oxidation (Use of Dess-Martin Reagent) DMP

This is a very mild oxidation via which a primary alcohol can be converted into
an aldehyde. The reagent periodinane is made from 2-iodoxybenzoic acid and
acetic anhydride (Scheme 13.6a). An alcohol reacts with it to displace an acetate
moiety and the intermediate formed undergoes a fragmentation as in Swern
oxidation.
B: H
R—C—O
OAc OAc OAc OAc
+ OAc H +
I H I I
OAc
O + R—C—OH O O + R—C O
H H
O O O
Dess-Martin Periodinane
(DMP)
SCHEME 13.6a
One may recall that DMP has a high valent iodine atom bonded to several oxygen
atoms.
(C) Oppenauer Method

The developments in CrO3-pyridine and DMSO based methods for oxidation have pushed
several classical methods into background. One such method which is interesting
mechanistically, is Oppenauer oxidation, this is the reverse of the Meerwein– Pondorff – Verley
reduction. The technique involves heating the alcohol to be oxidized with an aluminium alkoxide
in the presence of a carbonyl compound usually acetone in large excess. The carbonyl compound
acts as the hydrogen acceptor within a cyclic complex (Scheme 13.7).
t t
3R2CHOH + Al(OBu )3 (R2CHO)3Al + 3 Bu OH
Alcohol
O
(R2CHO)3Al + CH3COCH3 R 2C Al(OCHR2)2 R 2C O + (CH3)2CH—O—Al(OCHR2)2
Ketone
H O
(CH3)2C
Acetone
SCHEME 13.7
(D) Oxidation with Oxoammonium Ions (A recent method N. Merbouh, J.M. Bobbitt and C. Brueckner,
Org. Prep. Proced. Int. 36, 3 (2004).
This oxidation method uses an oxoammonium ion, generally derived from the stable
nitroxide—tetramethylpiperidine nitroxide (A, Scheme 13.8) abbreviated TEMPO. It is
regenerated in a catalytic cycle by the use of hypochlorite ion as the stoichiometric oxidant.
During oxidation an alcohol forms an intermediate adduct with the oxoammonium ion.
CH3 CH3 CH3
CH3 CH3 CH3 O
+ + OH
N O + R2CHOH N NOH + CR2
O—CR2
CH3 CH3 CH3
CH3 CH3 H CH3
(A)
SCHEME 13.8
This oxidation system has been selectively used to oxidize primary alcohols in the
presence of secondary hydroxyl groups (Scheme 13.9). The reagent has been further reported
to form carboxylic acids from primary alcohols by using sodium chlorite as a cooxidant.
HOCH2 HO2C
O OCH3 O OCH3
TEMPO
OAc OAc
NaOCl
HO HO
OCH2Ph OCH2Ph
SCHEME 13.9
(E) Oxidation of Allylic AlcoholsActive Manganese Dioxide and Quinones

Manganese dioxide specifically oxidizes allylic and benzylic hydroxyl groups to give α, β-
unsaturated carbonyl compounds. The reagent does not attack carbon-carbon double and triple
bonds and saturated hydroxyl groups (eq. I, Scheme 13.10).
Several high potential quinones for example, chloranil are capable of oxidizing allylic,
benzylic and propargylic alcohols. Mechanistically, the reaction proceeds via the formation of
resonance stabilized carbocations which are generated by hydride loss from the reactant (eq.
II, Scheme 13.10).
CH2OH CHO
MnO2
MnO2 C6H5CH CH—CH2OH C6H5CH CH—CHO (I)
Cl Cl
+
—C C—C—H O O —C C—C+ —C—C C (II)
OH OH OH
Cl Cl
Allylic alcohol Chloranil
Cl Cl
HO OH + —C C—C O
a, b-unsaturated
Cl Cl ketone
SCHEME 13.10
(F) Benzylic AlcoholsSommelet Reaction

In this method a halide from benzyl alcohol is reacted with hexamethylenetetramine and the
salt thus obtained (Scheme 13.11) is subjected to hydrolysis in the presence of more
hexamethylenetetramine. (Recall Oppenauer oxidation, in this case as well, the equilibrium
is diplaced with the excess of amine.) The mechanism involves the tranfer of a hybride–ion
from benzylamine to methyleneimine.
–
N Benzylic halide X N
ArCH2X +
H /H2O
+ ArCH2NH2 + CH2O + NH3
N N ArCH2N N
N N
Hexamethylene- Quaternary +
tetramine benzyl salt CH2 NH2
:
ArCH—NH2
–CH3NH2 + H2O
ArCH NH2 ArCHO
H –NH3
+ Imine
CH2 NH2
Sommelet reaction
SCHEME 13.11
13.2 ALLYLIC OXIDATION OF ALKENES

Allylic oxidation of alkenes can be brought about with selenium dioxide to give carbonyl
compounds, allylic alcohols, or esters depending on conditions. This oxidation is thought to be
an ene reaction and subsequent [2, 3] sigmatropic rearrangement. The hydrolysis of the Se(II)
ester finally leads to an allylic alcohol (Scheme 13.12). The sigmatropic rearrangemant brings
the double bond in the original position (A, Scheme 13.12). The alcohols formed originally are
further oxidized to the carbonyl compound.
O OH
SeO2 Se
Se
O
H OH H O OSeOH
(A)
Hydrolysis
+ Se(OH)2
H O OH
SCHEME 13.12
Allylic alcohols are the initial products of oxidation and these are further oxidized to
carbonyl groups with selenium dioxide. Essentially it is the carbonyl compound that is isolated.
If one wants to end up with an alcohol, the oxidation is carried out in acetic acid as the solvent
and then acetate esters and formed. The oxidation is carried out with catalytic amount of
selenium dioxide and t-butyl hydroperoxide (TBHP) which reoxidizes the used catalyst.
In summary, the allylic oxidation of alkenes follows the following steps :
• The initial reaction is the formation of allylic selenic acid (A, Scheme 13.12)
• Allylic rearrangement on (A) gives an unstable compound which rapidly gives an
allylic alcohol
• The oxidation continues to yield an aldehyde or ketone.
A useful alternative technique which is equivalent to allylic oxidation of alkenes, but

now with a shift in the position of the double bond involves the intermediates formation of a
β-hydroxy-selenide. The hydroxyselenide is obtained by the addition of phenyl selenenic acid
to an alkene (Scheme 13.13). The hydroxyselenide is oxidised with t-butylhydroperoxide (TBHP)
to unstable selenoxide which immediately eliminates phenylselenenic acid (PhSeOH) to give
the E-allylic alcohol. With trisubstituted alkenes (I, Scheme 13.13) the addition of phenyl
selenenic acid is highly regioselective, the hydroxyl group gets attached at the more substituted
end of the carbon-carbon double bond. Thus this addition follows Markovnikoff’s rule where
“Ph Se+”, behaves as the electrophile. The elimination always specifically proceeds away from
the oxygen functionality to give the allylic alcohol. Eliminations from selenoxides are discussed
(see, Schemes 12.32 and 12.33).
OH 1 OH
R H
t-C4H9OOH H
1 2 PhSeOH 1 2 2
R R R R R
(TBHP) +
SeC6H5 H SeC6H5
–
O
R R –PhSeOH
OH
OH
1 2
R R
(I)
(E)-allylic alcohol
SCHEME 13.13
13.3 OXIDATION OF SATURATED CH GROUPS

(A) Selenium Dioxide Oxidation
Methylene groups adjacent to cabonyl (–CH2–CO–) can be oxidized with selenium dioxide to
give α-dicarbonyl compounds (Scheme13.14). In the case of unsymmetrical ketones, oxidation
generally occurs at that CH2 group which is easily enolized.
SeO2
R—C—CH2—R R—C—C—R
O O O
Methylene group adjacent to C==O
SCHEME 13.14
This conversion uses selenium dioxide in the presence of a base. The mechanism involves
the attack by the enolate on the selenium atom to yield the selenate ester of the enol (I,
Scheme 13.15). The selenate ester rearranges to regenerate the carbonyl group with the transfer
of the oxygen atom to the α-carbon. The removal of the remaining α-hydrogen atom with base
initiates the fragmentation shown (II, Scheme 13.15) to yield the α-diketone.
O
Base CH O
—C—CH2— —C CH— Se
C Se
–
O O– O O O
(I)
O O—Se—OH
–
+ Se + OH base: H—C
O C
O
(II)
SCHEME 13.15
Another proposal suggests the intermediate formation of a β-ketoselenic acid (Scheme

13.16). An example of its application is the conversion of acetophenone to phenylglyoxal.
OH O O O
SeO2 –H2O H2O
RC CHR¢ RC—CHR¢ RC—CR¢ RC—CR
–H2SeO
Se Se O
OH
O O
b-ketoselenic acid
O O
C C H
CH3 SeO2 C
O
Acetophenone Phenylglyoxal
SCHEME 13.16
(B) Monohalogenation and Subsequent Reaction with DMSO

It is substitution-elimination reaction (Scheme 13.17) similar to the one observed during
oxidation of e.g., secondary alcohols to ketones with chromium (VI) oxidants.
+
S(CH3)2
O
Br2 DMSO –
R¢COCH2R R¢COCHBrR R¢COC—H Br R¢COCOR
R
SCHEME 13.17
It is also possible to selectively oxidize an unactivated C—H group in the molecule

which has alternative centers. An example is the Barton reaction (see, Scheme 16.31) where
an intramolecular free radical abstraction reactions occur specifically through six membered
cyclic transition states and it is possible to oxidize selectively δ C—H bonds.
One can also introduce a C C bond in a substrate, e.g., a steroid with high regioselectivity
via specific dehydrogenation. Thus in 3 α-cholestanol (Scheme 13.18) a double bond at a specific
position is introduced remote from any functional group. One starts with irradiation of an
ester of 3 α-cholestanol of suitable geometry so that the ketones triplet (in the benzophenone
portion) is now within bonding distance only with the hydrogen atom at C-14. The abstraction
of this hydrogen followed by another internal abstraction affords the unsaturated ester from
which the alcohol is generated by hydrolysis. In case the nature (size) of the esterifying acid is
changed, other regioselective dehydrogenations can be carried out.
R R
CH3 CH3
CH3 CH3
(1) Esterification
(2) hn
HO HO
3a-cholestanol 5a-cholest-14-en-3a-ol
CH3 CH3
CH3 R CH3 R
2
1
14
.
3
hn
.
O Abstraction of H O
C O C
CH2 CH2 .
O C—Ph O C—Ph
OH
.
H abstraction
CH3
CH3 R
O
C
CH2
O CH—Ph
OH
SCHEME 13.18
Alicyclic compounds (the reduction products of aromatic systems i.e., hydroaromatic

compounds) can be dehydrogenated to their corresponding aromatic systems in several ways.
This can be done by heating the compounds with those catalysts which are used for their
hydrogenation or by using selenium (Scheme 13.19). Quinones which are easily reduced to the
corresponding hydroquinones can also be used for aromatizations. Chloranil (2, 3, 5, 6-
tetrachloro-1, 4-benzoquinone) and DDQ (2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone) are
often used. The mechanism with quinones involves a transfer of hydride from the substrate to
CH2
Pd
+ 2 H2 CH2 Pd
heat –H2
N N
SCHEME 13.19
the quinone oxygen and subsequent loss of a proton (Scheme 13.20). Loss of a hydride ion from
the reactant gives a carbocation which can only be formed readily provided it is stabilized e.g.,
in case it is allylic or benzylic.
H O H H
H X Y +
X Y
+
O OH
+ X Y
Chloranil X = Y = Cl –H
DDQ X = Cl, Y = CN +
X Y
OH
SCHEME 13.20
EXERCISE 13.2
Predict the reagents to bring about each of the oxidations (Scheme 13.20a).
O O
O B
A
O CHO O COOH
O O
SCHEME 13.20a
ANSWER. A, SeO2 ; B, Ag2O ; C, DDQ.
Oxidation of side chains on aromatic rings is a useful reaction. Benzylic site is activated
to oxidation since the intermediate radical or carbocation intermediates are stabilized by
resonance. Moreover, since the aromatic ring is resistant to attack by Cr (VI) and Mn (VII)
reagents, these reagents are used widely for these oxidations (Scheme 13.21).
CH3 CO2H CH3 CO2H

CH3 CO2H
KMnO4 (K2Cr2O7)
in aqueous base H2SO4
NO2 NO2
m-Nitrotoluene m-Nitrobenzoic acid o-Xylene Phthalic acid
SCHEME 13.21
13.4 ADDITION OF OXYGEN AT CARBON-CARBON DOUBLE BONDS
(A) Epoxidation
Peroxycarboxylic acids e.g., perbenzoic acid (PBA) or m-chloroperoxybenzoic acid (MCPBA)
are used to convert alkenes to epoxides. The ionic intermediates (e.g., carbocations) are not on
the reaction pathway which excludes the formation of one bond at a time. In that case, however,
a rotation about the C-C single bond will convert e.g., a cis-alkene to a mixture of both cis-and
trans- epoxides. Epoxidation is thus a stereospecific syn-addition e.g., cis-2-butene gives only
the cis-product (Scheme 13.22). It is a concerted process (no intermediates) where the two
bonds are formed at the same time and thus, the stereochemical relationships of the groups in
the starting alkene (see, Scheme 13.22) e.g., cis-2-butene does not change and it gives only the
cis product (Scheme 13.22). The oxidation thus follows a concerted pathway (Scheme 13.22).
The peroxy acid acts as an electrophile since the rate of epoxidation is increased by alkyl
groups and other electron donating substituents on the alkene (electron rich alkenes). Electron
poor alkenes e.g., α, β-unsaturated aldehydes and ketones can be epoxidized only by alkaline
solutions of hydrogen peroxide involving nucleophilic addition of HO −2 which is facilitated by
the C O group (see, Michael addition).
R O OH
H H O O
Peroxyacid
C C C C O O H2C—CH—R
H H
H 3C CH3 H 3C O H Epoxide
CH3
cis-2-butene Only cis-epoxide
is formed H 2C CH—R
SCHEME 13.22
–
– –OH
C—O:
: :
—C C—C O —C—C —C—C—C O
–
H—O—O:
: :
: :
H—O—O O
SCHEME 13.23
Stereochemically the addition of oxygen occurs preferentially from the less hindered
side of the molecule, norbornene gives almost exclusively the exo-product (Scheme 13.24). In
such molecules where the alternative modes of approach are not largely different, mixture of
products are formed; the unhindered exocyclic double bond in 4-t-butyl-methylene-cyclohexane
yields both stereoisomeric epoxides (Scheme 13.24).
PBA
O
Norbornene H
H
exo-epoxide
96%
O CH2
CH2 O
MCPBA +
(CH3)3C (CH3)3C
SCHEME 13.24
As expected, 2-cyclohexenyl acetate yields the trans-epoxide from an attack by the peracid
on the less hindered side of the double bond (Scheme 13.25). However, with the free alcohol (I,
Scheme 13.25) i.e., with the OH group in the allylic position, the epoxidation is on the more
hindered face. It is suggested that hydrogen bonding between the hydroxyl group and the
peracid stabilizes the transition state for cis-epoxidation.
Ar
O O
OAc OAc OH O H OH
H
O
MCPBA MCPBA
O O
H
OH group occupies
pseudoequatorial position
SCHEME 13.25
Sharpless epoxidation reaction is a highly useful stereoselective reaction for carrying

out asymmetric epoxidation of allylic alcohols. Oxidation of allylic alcohols with t-butyl
hydroperoxide in the presence of either (+) – or (–) – diethyl tartrate (DET) and titanium
tetraisopropoxide affords the corresponding enantiomer in high optical yield. Thus oxygen is
delivered from the bottom face in the presence of (+)–tartrate or from the top face in the
presence of (–)–tartrate (Scheme 13.25a).
Delivery of oxygen
with D(–) DET
R O CH2OH
R
CH2OH R R
R R CH2OH
R
Delivery of oxygen
R O R
with L(+) DET
SCHEME 13.25a
(B) Epoxidation with Dioxirane and its Derivatives

[D.Yang, Acc. Chem. Res., 37, 497 (2004)]
Dimethyldioxirane, DMDO can be obtained from acetone and hydrogen persulphate ion HSO 5−
(Scheme 13.25b). DMDO and other dioxiranes derived from other ketones can bring about the
epoxidation of double bonds and often react with less reactive compounds (A, Scheme 13.25b).
O O
– O
HSO5 DMDO
(CH3)2C O (CH3)2C O
O
Dimethyldioxirane (A)
(DMDO)
SCHEME 13.25b
Chiral dioxiranes derived from fructose derivatives (Scheme 13.25c) display good
enantioselectivity with several alkenes (Scheme 13.25d).
O O O
O O O
O O O
HSO5– O
O O H2O, CH3CN O O O
O
O O O
D-FR Derived dioxirane L-FR

(from D-fructose) (from L-sorbose)
SCHEME 13.25c
– H
D-FR, HSO5 O
H2O, CH3CN
R
R
H
– H
L-FR, HSO5 O
H2O, CH3CN
R
R
H
SCHEME 13.25d
(C) Transformations of EpoxidesUse in Synthesis

Epoxides are highly reactive and useful synthetic intermediates, since these react with a variety
of nucleophiles with opening of the epoxide ring, which relieves the strain of the three membered
ring.
Epoxidation of an alkene followed by the acid-catalysed hydrolysis gives a method for
anti-hydroxylation with the general mechanism (eq. I, Scheme 13.26). This is well compared
with syn-hydroxylation carried out with an alkene with osmium tetroxide.
Acid catalysed hydrolysis of 1, 2-epoxy-cyclopentane proceeds by water attacking as the
nucleophile on the protonated epoxide from the side opposite the epoxide group. The carbon
atom being attacked (shown by an arrow) undergoes an inversion of configuration (the attack
similarly could occur at the other carbon as well on the symmetrical system and will give the
enantiomeric form of trans- 1, 2-cyclopentanediol (eq. II, Scheme 13.26).
H H
:O—H :O—H
+
:OH
:
:
+
H2C—CH2 + H+ H2C—CH2 H2C—CH2 H2C—CH2 + H (I)
:O: :O :O: HO:
+
:
H H
H OH
OH
ArCO3H
O H (II)
H
H OH
OH
trans-1, 2-cyclopentanediol
OH
Cyclopentene OH
OH
OsO4
H
OH
H
cis-1, 2-cyclopentanediol
SCHEME 13.26
The reactions of epoxides leading to cleavage of one carbon-oxygen bond in a nucleophilic

substitution reaction that follows generally the SN2 pathway. Under neutral or basic conditions,
as expected of SN2 mechanism the nucleophile attacks the less sterically congested carbon
(Scheme 13.27).
–
:O:
:
:O:
:
(SN2) OH
CH3OH H—OCH3
H3CC—CHCH3 H3CC CHCH3 H3CC CHCH3
CH3 – CH3 OCH3 CH3 OCH3

: :
:OCH3
Opening of an epoxide (basic solution)
H H H
+ OCH CH3 OH
O 3 O
+
–H
CH3C—CHCH3 CH3—C CHOH H3CC CHCH3 CH3C—CHCH3
: :
CH3OH
CH3 CH3 CH3 OCH3 H 3C
(A) (B)
Developing tertiary carbocation Developing secondary carbocation
Opening of an epoxide (acid solution)
SCHEME 13.27
In the acid solution, the protonation of the epoxide weakens the C—O bonds. If the
C—O bonds are largely intact at the transition state the nucleophile will attack the less
substituted carbon (steric requirements of SN2 reaction). However, if the C—O rupture is
significant when the transition state is reached, the attack by the nucleophile is on the more
substituted carbon (Scheme 13.27). This change, in regioselectivity is due to the ability of the
more substituted carbon to stabilize the developing positive charge so that nucleophile attacks
this carbon. One may note that the protonated epoxide opens preferentially so as to generate
the partial positive charge on the more substituted carbon. Thus the other opening pathway
(B, Scheme 13.27) is far less favourable since a tertiary carbocation (A) is more stable than a
secondary carbocation. Although this is typically true of SN1 reactions, however, the nucleophile
approaches the protonated epoxide from the side opposite the leaving oxygen (SN2 characters).
One would call such a reaction which is partially SN1 and partially SN2. Thus working with a
chiral epoxide (Scheme 13.27) the ring opening under two conditions will give optically active
products which will be constitutional isomers.
In cyclohexanes the ring opening gives the axial alcohol (Scheme 13.27a).
–
H3Al–H
H
O –
O
SCHEME 13.27a
Epoxides undergo a rearrangement on treatment with strongly basic reagents to give

allylic alcohols. A proton abstraction takes place from a carbon adjacent to the epoxide ring
and the proton which is cis to the epoxide is selectively removed i.e., the reaction involves a
concerted syn elimination (Scheme 13.27b).
O
D HO H
Li N(C2H5)2
H
SCHEME 13.27b
Lithium aluminium hydride acts as a nucleophilic reagent in the reduction of epoxides

to give saturated alcohols. The hydride is added to the less substituted carbon atom of the
epoxide ring (Scheme 13.28).
OH
LiAlH4
CH—CH2
O
H
CH—CH2
OH
Styrene oxide CH—CH2—CH CH2
(CH2 CH)2Cu Li
SCHEME 13.28
The reaction of epoxides with lithium diorganocopper (Gilman) reagents also brings
about regioselective ring opening at the less substituted carbon which is also in agreement
with SN2 reactivity.
EXERCISE 13.3
Depict the reaction of trans-2-butene with meta-chloroperbenzoic acid followed by
the reaction of the product with CH3OH/H2SO4.
ANSWER. It is a stereospecific epoxidation leading to only the trans epoxide. The
ring opening in acid solution is an SN2 reaction occurring with inversion of
configuration (Scheme 13.28a).
CH3
CH3 CH3 R
R
MCPBA + H H OH
H H H3CO
CH3OH
H 3C R O S
H 3C H CH3
SCHEME 13.28a
EXERCISE 13.4
Predict the reaction of optically active (S)-1, 2-epoxybutane with HCl which gives
two products. Explain the stereoisomerism/constitutional isomerism of the reaction.
ANSWER. It is an “SN2 like SN1” reaction (Scheme 13.28b). The protonated epoxide
exists in equilibrium with a structure (III, Scheme 13.28b) which places the positive
charge on the carbon that can best stabilize it (position b). The structure (III) is
infact a bridged carbocation which is blocked on one face by the oxygen, therefore,
the nucleophile attacks it from the opposite side. The nucleophile Cl– can attack
either at the less substituted carbon atom (less hindered) or the carbon atom with
a positive charge, but in both cases from the face opposite to oxygen. The products
are optically active constitutional isomers.
O O+ CH3CH2 OH
S HCl + a
C C C C C C
CH3CH2 H CH3CH2 H b H
H H H H H H
– –
Cl Cl
(I) (II) (III)
H CH3CH2
HO OH
S H H R
C C C C
CH3CH2 H
Cl Cl H
H
Optically active Constitutional isomers
SCHEME 13.28b
Epoxides undergo acid catalysed rearrangement to carbonyl compounds. Lewis acids

e.g., boron trifluoride etherate, mineral acids acids or magnesium bromide are often used as
catalysts (Scheme 13.29).
H
+ – –BF3
R—CH—CH2 R—CH CH R—CH2—CH O—BF3 R—CH2—CHO
BF3
O O+
–
BF3
O
MgBr2 + MgBr
O O—MgBr —CHO
+
SCHEME 13.29
Reaction with dimethyl sulphoxide yields an α-ketol (Scheme 13.30).
– +
O—S(CH3)2 O—S(CH3)2
+
R—CH—CH—R¢ R—CH—C—H R—CH—CO—R¢ + S(CH3)2
–
O O R¢ OH
SCHEME 13.30
Alkenes are epoxidized with retention of configuration (see Scheme 13.22). Methods are
available for the inversion of configuration of alkenes and in one process involves epoxidation
deoxygenation. The nucleophilic attack by a phosphorus reagents e.g., triphenylphosphine at
the oxirane carbon leads to inversion of configuration and gives a charge-separated intermediate
(a betaine). This undergoes syn elimination via a four center cyclic transition state which
requires a 180° rotation around the C—C bond to establish the appropriate geometry. The
stereochemical outcome of such a reaction is to put the R groups attached to the oxirane
carbons in a different stereochemical relationship in the oxirane and alkene (Scheme 13.31).
–
R R O O R
PBA Inversion H
C C C—C R C—C
R R
H H H H H Ph P+
3
cis-alkene
:
Ph3P
Nucleophilic substitution 180° rotation
with triphenylphosphine around C—C bond
– +
O PPh3
R H
Ph3PO + C C R C—C H
H R H R
trans-alkene A four-center elimination
SCHEME 13.31
(D) Diol Formation

Two reagents oxidize an alkene to a 1, 2-diol: osmium tetroxide OsO 4 and potassium
permanganate KMnO4. Both osmium and manganese are in a highly positive oxidation state
and therefore, both attract electrons. Both MnO4− and OsO4 form cyclic intermediates on
reaction with an alkene. Both add syn to the π bond of an alkene and as a result both the
oxygens are added to the same side of the double bond to give only a cis-diol after the hydrolysis
of the intermediate cyclic ester and thus, the reaction is stereospecific (syn-addition,
Scheme 13.32).
H – H
– O O OH
O O
H2O
Mn Mn – + MnO2
OH
O O O O OH
Cyclopentene H H
A cyclic manganate cis-1, 2-cyclopentanediol
intermediate
OH
O O H H H
H2O2
Os H H + Os
O O O OH H
Cyclohexene O—Os O OH OH
cis-1, 2-cyclohexanediol
O
A cyclic osmate
intermediate
SCHEME 13.32
The attack of the reagent can either be from top or bottom face which gives both
enantiomers (as a racemic mixture). When there is a choice the reagents predominantly attacks
from the less hindered side of the double bond (Scheme 13.32a).
KMnO4 OH
–
OH/H2O
OH
exo-1, 2-diol
SCHEME 13.32a
The permanganate ion is a more powerful oxidizing agent than osmium tetraoxide and
yields of glycols are generally low due to overoxidation. KMnO4 is used in acid solution to
cleave a double bond of an alkene (Scheme 13.32b).
KMnO4 HOOC
H3O+
COOH
SCHEME 13.32b
Alkenes are oxidized to 1, 2-diols with a basic solution of KMnO4 which are then cleaved
with HIO4 to form carbonyl compounds. Under acidic conditions or if the basic solution of
KMnO4 is heated, the reaction does not stop at the diol and the alkene is cleaved. A solution of
KMnO4 in benzene containing [18]-crown 6 (pink benzene, see Scheme 1.20) cleaves the alkenes
to gives the products in high yield (Scheme 13.32c).
O
CH3C
KMnO4
[18]-crown-6
CH2COOH
a-pinene Pinonic acid 90%
SCHEME 13.32c
EXERCISE 13.5
How maleic and fumaric acid can be converted into meso-tartaric acid and fumaric
acid into its enantiomeric pair by using two different methods.
ANSWER. Maleic acid (cis-isomer) adds KMnO4 by syn addition and the original
configuration of the reactant is retained in the product to give meso-tartaric acid.
Meso-tartaric acid can also be obtained from fumaric acid (the trans-isomer) by
epoxidation and then opening the epoxide with aqueous solution of hydroxide.
Since this reaction involves one inversion of configuration fumaric acid also gives
meso-tartaric acid (Scheme 13.32d).
COOH
HOOC COOH
KMnO4 H OH
C C –
OH /H2O H OH
H H COOH
Maleic acid (2R, 3S)-tartaric acid (meso)
COOH
HOOC H
(1) RCOOOH H OH
C C –
(2) OH /H2O H OH
H COOH COOH
Fumaric acid 2R, 3S-tartaric acid (meso)
COOH COOH
HOOC COOH
(1) RCOOOH H OH HO H
C C – +
(2) OH /H2O HO H H OH
H H COOH COOH
Maleic acid 2R, 3R 2S, 3S
Enantiomeric pair tartaric acid
COOH COOH
HOOC H
KMnO4 H OH HO H Same enantiomeric
C C – +
OH /H2O HO H H OH pair of tartaric acid
H COOH COOH COOH
Fumaric acid
SCHEME 13.32d
Woodward and Prevost method involves the reaction of an olefin with iodine and silver
acetate. Under dry condition (absence of water) this method leads to a trans-1, 2-diacetate
(Scheme 13.33) from which the trans- diol is obtained by hydrolysis. Woodward reaction is
carried out in the presence of water to yield the monoester of the cis- diol, and the final hydrolysis
gives the cis- diol (Scheme 13.33). The olefin is reacted with iodine in the presence of silver
acetate. Iodine reacts with the double bond to give an iodonium ion which undergoes
displacement by acetate in the SN2 type reaction, giving a trans-iodo-acetate. Anchimeric
assistance by the acetate group, together with the powerful bonding capacity of silver ion for
iodide, gives a cyclic acetoxonium ion (I, Scheme 13.38) which gives a trans-1, 2-diacetate. The
acetoxonium ion, under wet conditions traps water and reacts to yield a cis-hydroxyacetate.
CH3 CH3
–
OAc
O C C+
–AgI O O O
C C C C
I+ C C— C C—
–
I—I Ag+/OAc
I (I)
Ag+
H 3C
C
+
OH OAc O O
Hydrolysis
C C— C C— C C—
OH OAc –
OAc
trans-diol
Prevost reaction (dry)
(Iodine silver-acetate)
CH3 CH3 H2O CH3

O OH
:
C C C+
OH OH O OH O O O O
Hydrolysis Woodward
—C C— —C C— —C C— —C C—
reaction
(H2O)
(I)
cis-diol
Woodward reaction (wet)
(Iodine silver-acetate)
SCHEME 13.33
The reaction (Prevost) is depicted (Scheme 13.34) to show the stereochemical

consequences of the reaction more clearly with the chair conformation of cyclohexane system.
Thus in summary, both Woodward and Prevost reactions a 1, 2-glycol is formed from an
olefin by reacting it with iodine and silver acetate. In the presence of an aprotic solvent (Prevost-
method) trans-1,2-glycols are formed. In the presence of water (Woodward-method) the product
is a cis-diol.
O CH3 CH3
O– O O
H
I2
+I I H
+ –
Ag /OCOCH3 O H
–AgI COCH3 I
H Ag+
–AgI
Ph
H
OH O +
–
OH O
OAc
OH AcO H
trans-diol H O– H
CH3—C
Prevost reaction O
SCHEME 13.34
13.5 OZONOLYSIS
Ozonolysis provides a method for the fission of carbon-carbon double bonds. The process involves
two key intermediates, an initial ozonide (1, 2, 3-trioxolane) and the ozonide (1, 2, 4-trioxolane).
The first step of the mechanism involves a cycloaddition to give the initial ozonide, subsequent
fragmentation and recombination yields the isomeric product, ozonide. The first step is a 1,
3-dipolar cycloaddition reaction (Scheme 13.35), ozone being highly electrophilic 1, 3-dipole
(resonance structures, Scheme 13.35).
+
O O
– +O –
O O O
Ozone
1 3 2 3
R R R R 3
1 4 R
R R 1 1 O 3
R O R R Aldehydes
4
2 4
+ R Zn
R R O O – 4 + and/or
2 2 H , H2O
– O—O R ketone
O O+ O
R R
O O
O Molozonide Ozonide
(initial ozonide)
OOH
1 2+ – CH3OH 1 2
R R C—O—O RRC
OCH3
Methoxyhydroperoxide
SCHEME 13.35
Methanol (the nucleophilic solvent) when cooled to – 20°C is not attacked by ozone and
is used in many cases as the ozonisation solvent. In these cases the main product of addition of
ozone to the alkene is not the usual ozonide but, is the methoxyhydroperoxide. Direct solvolysis
of ozonides gives ketones and/or acids, depending on the structure of the alkene (Scheme
13.36).
CH2 O
H H
Ozonolysis
C C + C
Ph H Ph H
O
SCHEME 13.36
Ozonolysis of α, β-unsaturated carbonyl compounds e.g., ketones and acids give abnormal
products of ozonolysis with fewer than the expected number of carbon atoms. With α,
β-unsaturated compounds the loss of a carbon involves the formation of a hydrated form of the
ozonide (Scheme 13.37).
1 1 1
R R R R R
O
O3 –
R—CO—C C HO—C—C C HO—C + C—O + O C
H2O
H—O O O O O
SCHEME 13.37
13.6 CLEAVAGE OF GLYCOLS AND RELATED COMPOUNDS

Carbon-carbon double bonds are cleaved via the glycols (1, 2-diols) by reaction with lead tetra-
acetate. The fragmentation is believed to occur within a cyclic adduct of the glycol and the
oxidant (Scheme 13.38).
OAc
R OH R O—Pb(OAc)2 R R
O O
:
Pb(OAc)3 – –
–OAc –OAc
Pb(OAc)2 +
–H+ –H+ R
OAc O
:
R OH R OH R O
+
Pb(OAc)2
SCHEME 13.38
Glycol cleavage with periodic acid (HIO4) involves a similar cyclic intermediate (Scheme
13.38a). The reaction, therefore, seems to have stereochemical requirements and to form a
cyclic intermediate, the two hydroxyl groups of a cyclic diol should be positioned appropriately
to form this intermediate. In the case of a 1, 2-cyclohexane diol the two OH groups can be both
OH
O I O OH OH
O O
O
I O I O
HO OH O O O O
HIO4
H—C—C—H H—C—C—H C—H H—C
H H H H H H
Ester of periodic acid
SCHEME 13.38a
equatorial, both axial or one axial and one equatorial. In one of these situations when the two
hydroxyl groups occupy axial positions, these are too far away from each other to form the
cyclic intermediate and such a conformer will not react with HIO4. Thus between (I and II,
Scheme 13.39) with t-butyl group in equatorial position, (II) does not react with HIO4.
OH
OH
(CH3)3C OH
(CH3)3C OH
(I)
OH
OH
(CH3)3C
(H3C)3C OH
(II) OH
SCHEME 13.39
Oxidative Cleavage of 1, 2-glycols

Some glycols which however, cannot form a cyclic intermediate have been found
to undergo cleavage. To explain this an acyclic pathway may be followed (Scheme
13.40).
OH OH O
Pb(OAc)4
OH OH O
OAc
C—O—Pb—OAc
—C + C—
H—O—C OAc
O O
SCHEME 13.40
Several other combinations of adjacent functional groups are also cleaved with these
−
reagents (Scheme 13.41). The cleavage of diketones with IO 4 involves a reactive cyclic
intermediate formed via the nucleophilic attack on the diketone (Scheme 13.42). Compounds
with carboxyl groups on adjacent carbons (succinic acid derivatives) can be bisdecarboxylated
with lead tetra-acetate (Scheme 13.43) to give alkenes.
HIO4
—C—C— —CO + OC— + NH3 + HIO3
H2N OH
HIO4
—C—CO—R —CO + RCO2H + HIO3
OH
HIO4
RCO—COR¢ RCO2H + R¢CO2H + HIO3
H2O
SCHEME 13.41
OH OH
CH3 O 2– O
– CH3—C
IO4 CH3—C—OIO4 H2O – –
– IO4H 2CH3CO2H + IO3
OH CH3—C
CH3 C O
O
CH3 O
OH
SCHEME 13.42
OAc
—C—CO2H –HOAc
—C—CO—O—Pb—OAc —C
+ Pb(OAc)4 + Pb(OAc)2 + 2CO2
—C—CO2H OAc —C
—C—CO—O
H
SCHEME 13.43
13.7 OXIDATION OF ALKENES TO ALDEHYDES AND KETONES CATALYSED WITH

PALLADIUM AND OXIDATION OF ALKYLBORANES
Oxidation of mono-substituted and 1, 2-disubstituted olefins can be carried out to give aldehydes
and ketones with palladium chloride and similar salts of noble metals (Scheme 13.44). The
oxidation of ethylene to accetaldehyde with this reaction is an industrial process (the Wacker
process). The palladium chloride is reduced to the metal, however the reaction is made catalytic
with a co-oxidant (CuCl2), whereby the palladium Pd(0) is re-oxidized to Pd(II). The mechanism
of the reaction (Scheme 13.45) involves π-comlexes from Pd(II) and an alkene and these
complexes are activated to nucleophiles. The mechanism of reaction for ethylene and water as
the nucleophile is presented (Scheme 13.45).
H
PdCl2
C C— —C—C—
H2O
H O
SCHEME 13.44
Cl H Cl
H2O CH2 H2O CH2
CH2 CH2 + PdCl2 Pd—Cl O Pd—Cl
CH2 CH2
H 2O H H2O
A p complex
–
H—O HO
HO Cl
C CH3 C CH2
H +
H CH2—CH2—Pd—Cl + H
PdCl2 H—PdCl2
H 2O
H 2O H2O A s complex
In the key step of mechanism

O there is a transfer of a hydride
ion from one carbon of
H—C—CH3 + PdCl2 + H2O ethylene to the other via Pd.
SCHEME 13.45
Ethylene reacts with Pd(II) to afford a π complex (Scheme 13.45) which is attacked by
nucleophile (water) to give a σ complex.
The following steps may be involved (also see Scheme 7.2)
1. Trans hydroxypalladation of ethylene to an unstable complex.
2. β-Elimination within the complex, with transfer of hydride ion from one carbon of
ethylene to the other via palladium (see, Scheme 7.1).
3. When the oxidation is conducted in deuterium oxide, acetaldehyde formed does not
contain deuterium, to show that all the four hydrogens of the acetaldehyde come
from the original ethylene and none from the solvent. This explains the hydride
migration step of the mechanism (Scheme 13.45).
With monosubstituted alkenes bonding to palladium is through the unsubstituted carbon
atom therefore, the reaction of a terminal alkene with water gives a methyl ketone
(Scheme 13.46). 1, 2-Disubstituted alkenes (internal alkenes) are oxidized only slowly compared
to terminal bonds and this enables the reaction to become selective.
Oxidation with PCC of an alkylborane formed by the hydroboration of a terminal alkene
with Sia2BH provides a useful alternative route to an aldehyde (Scheme 13.47). Disiamyl
borane is highly regioselective, a very small amount of the alkyl methyl ketone (< 1%) is formed.
Moreover, with a non-conjugated diene, with a terminal and non-terminal carbon-carbon double
bonds, the terminal bonding system reacts preferentially to give at the end an unsaturated
aldehyde as in the case of limonene.
R CH3
PdCl2/H2O
R C
CuCl2/O2
O
O
PdCl2/H2O
CH3OCO CuCl2/O2 CH3OCO
SCHEME 13.46
Oxidation H
Sia2BH PCC
R CH2 R R
BSia2 O
A terminal alkene Alkylborane
BSia2 O
Limonene H
p-menth-1-en-9-al
SCHEME 13.47
13.8 OXIDATION OF KETONES

1. Cyclohexanone gives adipic acid (Scheme 13.48) and is an important industrial process.
Several reagents can be used for the purpose, chromic acid or alkaline potassium
O
COOH
CrO3 COOH
Cyclohexanone Adipic acid
OH
+
—C C— + O Cr—OH —C—C—
:
OH O HO O—Cr—(OH)2
O–
+
–H
Hydrol.
—CO2H + HO2C— —C—C— —C—C—
–
O OH O OCrO3H2
SCHEME 13.48
permanganate. These strong oxidizing agents give carboxylic acids, reaction occurring
through the enol (acid solution) or the enolate anion (basic solution). The process for
alkaline potassium permanganate is also given (Scheme 13.49).
– –
O O O O O O
– –
OH MnO4
—C—CH2— —C CH— —C CH— —C —CH— —C —C— —CO2H
+
OH OH OH
HOOC—
SCHEME 13.49
2. Methyl ketone are oxidized by chlorine, bromine or iodine in alkaline solution to yield
acids and the corresponding haloform. The process is a base catalysed halogenation
followed by elimination of the conjugate base of the haloform (Scheme 13.50). The process
provides a useful route to aromatic acids, a methyl ketone which may be prepared by Friedel
Crafts reaction, is oxidized with iodine in sodium hydroxide solution (Scheme 13.50).
–
O
–
3Br2 HO
R—CO—CH3 R—CO—CBr3 R—C—CBr3
NaOH
OH
– –
HCBr3 + RCO2 CBr3 + RCO2H
COCH3 CO2H
I2
–
OH
SCHEME 13.50
3. Ketones on treatment with peracids like perbenzoic acid or peracetic acid in the presence
of acid catalyst give related esters by insertion of oxygen. The mechanism of this reaction
(Baeyer-Villiger reaction) involves a rearrangement to electron deficient oxygen and is
related to the pinacol rearrangement. Nucleophilic attack of the peracid on the carbonyl
group gives an intermediate which rearranges with the loss of the anion of an acid
(Scheme 13.51).
+
O O—H OH :O—H
+ –
H 1 2 –ArCOO 2 2 1
C C R — C—R + C—R
+
R COOR
–H (Ester)
R1 R2 R1 R2 O O
Ketone
O O R
1
– C
Ar C—O—O
(A peracid) O Ar
Concerted step
The Baeyer-Villiger reaction

SCHEME 13.51
In an unsymmetrical ketone, that group migrates which is more nucleophilic of the two
better able to supply electrons. Thus among alkyl groups the ease of migration is tertiary >
secondary > primary > methyl (Scheme 13.52). Aryl groups migrate in preference to primary
alkyl groups. The intramolecular concerted nature of the reaction has been proved, since the
chiral migrating groups retain their configuration in the rearranged product. Tertiary
hydrocarbons form hydroperoxides readily by autoxidation. Cumene can be prepared by Friedel
Crafts alkylation of benzene with propylene and it gives cumene hydroperoxide readily. Cumene
hydroperoxide undergoes an acid catalysed rearrangement (Scheme 13.53), like Baeyer-Villiger
reaction to give a hemiacetal which is hydrolyzed under acid conditions (see Scheme 14.37).
O
H3C
O O C O O—C—CH3
ArCO2OH
C6H5—C—CH2CH3 C6H5O—C—CH2CH3 ArCO2OH
SCHEME 13.52
Ph Ph
+
H + –H2O +
(CH3)2C—O—OH H3C—C—O—OH2 CH3—C O—Ph
:
Cumene hydroperoxide
CH3 CH3
+
H2O H
+
H
(CH3)2C O + PhOH (CH3)2C—OPh
Acetone Phenol
OH
(A hemiacetal)
SCHEME 13.53
Aromatic aldehydes and ketones are converted to phenols and quinones on treatment
with alkaline H2O2, provided there is an OH or NH2 group in the o– or p–position (Scheme 13.54).
This is Dakin reaction which proceeds by a mechanism similar to that of Baeyer-Villiger reaction.
–
OH OH O OH
CHO –
OH O
HO2 –
O –OH CHO
–
OH –HCOO–
OH OH
–
OH O
+
H
Catechol
Dakin reaction
SCHEME 13.54
EXERCISE 13.6
What product one expects from the Baeyer-Villiger oxidation
of the ketone (Scheme 13.55). Give a mechanism. O
ANSWER. The Baeyer-Villiger oxidation of ketones gives
esters and therefore, cyclic ketones give lactones (cyclic esters).
Considering the migratory aptitudes t-alkyl > s-alkyl > aryl >
n-alkyl > methyl, the more highly substituted group (as
SCHEME 13.55
expected) migrates i.e., oxygen is inserted toward the more
highly substituted carbon (Scheme 13.56).
O C O
H—O O
O Ar
ArCO2OH –ArCOOH O
H+
Lactone
SCHEME 13.56
13.9 OXIDATION OF α-KETOLS

These systems are oxidized easily by using one electron oxidants in basic solution to give
α-dicarbonyl compounds. On mechanistic grounds, the carbanion formed on reaction with base
can donate one electron to the oxidant to yield a delocalized radical (Scheme 13.57) subsequent
loss of a second electron completes the oxidation. Thus benzoin can be oxidized to give benzil
in 90% yield.
Base – –e –e
:
—CH—C— —C—C— —C C— —C C— —C C— —CO—CO—
OH O –
O O –
O O – .O O – –
O O.
CuSO4
C6H5CHOHCOC6H5 C6H5—C—C—C6H5
pyridine
O O
Benzoin Benzil
SCHEME 13.57
13.10 OXIDATIVE DECARBOXYLATION OF ACIDS

Carboxylic acids can be decarboxylated with lead tetraacetate and if a β-hydrogen is present,
the alkene is formed by the elimination of H and COOH. High yields of alkenes are formed on
heating carboxylic acids with lead tetraacetate in the presence of a catalytic amount of copper
(II) salt (Scheme 13.58).
Cu(OAc)2—Pb(OAc)4
—CH—C—CO2H —C C— + (AcO)2Pb + 2 HOAc
—CO2
SCHEME 13.58
The mechanism is of free radical type and occurs via the homolysis of the lead carboxylate
followed by a free radical chain mechanism (Scheme 13.59). The effect of Cu2+ ions is to oxidize
the radicals to alkenes.
RCH2CH2CO—O—Pb(OAc)3 RCH2CH2CO—O. + . Pb(OAc)3

–CO2 .
RCH2CH2CO—O . RCH2CH2
RCH2CH2. + Cu
2+ + +
RCH CH2 + H + Cu
SCHEME 13.59
13.11 AROMATIC RINGS OF PHENOLSCOUPLING

The aromatic rings of phenols are highly prone to oxidation by one electron oxidants, since the
removal of a hydrogen atom gives a delocalized aryloxy radical (Scheme 13.60). The phenoxy
radical displays several reactions depending on its structure. One important mode is by coupling
i.e., dimerization (Scheme 13.60) which is predominantly of the C—C type (o–o, p–p, or o–p).
H
:O: .O O O O
. .
3+ 2+ +
+ Fe Fe + H +
[O]
.
Oxidation
H H
O O O O O O
. . Enolization
H H
Ortho-ortho Coupling
O O OH
. . O O — —OH
H H
Ortho-para Coupling
O . . O O O HO— — —OH
H H
Para-para Coupling
SCHEME 13.60
The ortho and para dihydric alcohols can be oxidized to yield the corresponding quinones
by the use of one electron oxidants like Fe3+ (Scheme 13.61).
.
OH O O– O O– O
3+ 3+
[O] – Fe Fe
+ 2H+ + 2e
[H]
– –
OH O O O O. O
Hydroquinone 1, 4-Benzoquinone
(quinone)
SCHEME 13.61
Substituted quinones and hydroquinones form an important part of the electron transport
system in biological organisms. These compounds are involved in the cellular interconversions
of Fe3+ to Fe2+ reactions which are essential for the utilization of oxygen gas.
13.12 OXIDATION OF AMINES

Dioxirane prepared by the reaction of acetone with persulphate ion (see Scheme 13.25b) is a
highly useful reagent for the oxidation of amines. Primary amines give nitro compounds while
secondary amines give the corresponding hydroxylamine (Scheme 13.62).Tertiary amines on
reaction with a peracid or H2O2 give an N-oxide.
CH3 CH3
O O
C C
COOH O COOH O
CH3 CH3
NH2 NO2
H 2N O2N
90% 90%
Oxidation of primary amines with dioxirane

CH3
O H2O2
C R R
H O
OH
RCO3H or + –
R¢—N: R¢—N—O :
: :
CH3 N N+
R N R R N R H2O2
95% R² R² O–
Pyridine N-oxide
A secondary amine
Tertiary amine
SCHEME 13.62
13.13 PHOTOOXIDATION OF ALKENES

This is discussed (chapter 10) and offers another method to give allylic hydroperoxides which
can be reduced to allylic alcohols. Singlet oxygen is the excited state of molecular oxygen, the
ground state of molecular oxygen is a triplet with unpaired electrons (Scheme 13.63). Singlet
oxygen (a dienophile) reacts e.g., with a 1, 3-diene to form a peroxide via cycloaddition–Diels-
Alder reaction. These peroxides can be reduced to diols (see Scheme 10.8).
. . hn
O
:O O: :O O: O
Photo-
:
:
:
:
Triplet Singlet O
sensitizer O
oxygen oxygen Dienophile
Diene
SCHEME 13.63
PROBLEMS
13.1 Write the structure of the product of monoepoxidation with a peroxy acid from the
following compounds:
H CH3
CH3 C C
H
CH3
(I) (II) (III)
13.2 Why trifluoroperacetic acid is an effective reagent compared to peracetic acid for
epoxidation of alkenes?
13.3 Write the stereostructure of the product of epoxidation from the following olefin.
CH3
H
13.4 Which of the 1, 2-diols is expected to react faster with lead tetraacetate?
OH OH
OH OH
(I) (II)
13.5 How peracids react with carbon–carbon double bond and carbon–oxygen double bond?
Give the mechanism of each pathway.
13.6 Write the stereostructures of the epoxide ring opening.
H O
–
OH LiAlH4
O (I) (II)
13.7 How can hexanedial (adipaldehyde) be prepared starting from cyclohexene?

13.8 Write the mechanism of ozonolysis of an α, β-unsaturated carboxylic acid which proceeds
by the loss of CO2.
13.9 For the success of Dakin reaction (see Scheme 13.54) there must be an OH or NH2 in
the ortho or para-position of the aromatic aldehyde or ketone. Explain.
13.10 Why in rigid ring systems, axial alcohols are oxidized (CrO3) faster than equatorial
ones?
OH H
CH3 CH3
H OH
CH3—C CH3—C
CH3 CH3
Relative rates: 3.2 1
13.11 How can (II) be obtained from (I)? What product is expected from the ozonolysis of (II),
using dimethyl sulphide for reductive cleavage?
OMe OMe
(I) (II)
13.12 Predict the products from each of the unsymmetrical ketones on Baeyer-Villiger reaction.
Me3C—CO—CH3 Ph—CO—CH3
(I) (II)
13.13 α-Hydroxycarboxylic acids undergo an easy oxidative decarboxylation with lead
tetraacetate to give ketone. Suggest a mechanism.
13.14 Which of the following 1, 2-glycols is expected to react faster with HIO4 to bring out the
oxidative cleavage.
OH H
H OH
OH OH
H H
(I) (II)

13.1 Epoxidation of an alkene with a peroxy acid takes place by electrophilic attack of the
peroxy acid on the double bond. In this case the reaction will, therefore, preferentially
occur on the electron rich double bond.
Mirror
CH3
O O
O O H CH3 H 3C H
CH3 C6H5 H H C6H5

(I) (II) (III)
In the case of (III) two stereogenic carbons are created and since epoxidation is a syn
addition, only two of the four possible stereoisomers are formed.
13.2 The rate of epoxidation is expected to increase with electron withdrawing groups in the
peroxy acid.
13.3 The reagent will approach predominantly from the less hindered side of the substrate
i.e., α-side in this case.
O CH3
H
13.4 Compound (II) will cleave faster since the preferential mechanism involving a cyclic
adduct can be easily reached.
OAc
OAc
O—Pb—OAc
AcO—Pb—O
OAc
OH OH
Pb(OAc)4 O Pb(OAc)4
O
OH OH
(II) (I) H
13.6 Like the action of aqueous acid on epoxides, base also gives a 1, 2-diol. The product
again has the anti-stereochemistry as a result of the stereo-specificity of
SN2-displacements. The ring-opening of epoxides from rigid cyclohexenes as in the present
case yields trans-diaxial products.
Inversion of OH
OH
configuration
H
H
Retention of
configuration OH
(I) (II)
13.7 By its ozonolysis and a careful reductive cleavage of the ozonide.
O3 O Pd/H2 CHO
O
O CHO
(Adipaldehyde)
13.8
R O R
O3 HO R
C C C C O + C + CO2
CO2H O O C—O—H
O
O
13.9 The hydroxide ion is not a good leaving group. The function of the aromatic substituent
may be to provide powerful anchimeric assistance to bring about heterolysis of the o–o
bond.
13.10 Since the rate determining step in this reaction involves the breaking of the C–H bond
the more exposed equatorial C–H in reacts faster than axial C–H in rigid ring systems
so that axial alcohols react faster than equatorial ones.
13.11 p-Methoxytolune (I) can be converted into diene (II) by Birch reduction. The presence of
methoxyl group activates the double bond to which it is attached for the attack by
electrophilic reagents.
OMe
:
OMe MeO O MeO SMe2

O O
O CO
+ –
O—O—O O O CHO
–Me2SO
Molozonide Ozonide
13.12 That group migrates which is better in supplying electrons.
Me3C—O—CO—CH3 Ph—O—CO—CH3
t-butyl acetate Phenyl acetate
(I) (II)
13.13
O—H
R 2C R 2C O + CO2 + Pb(OAc)2 + CH3CO2H
C—O—Pb(OAc)3
O
a-hydroxycarboxylic acid
(undergoes oxidative decarboxylation)
13.14 The cyclic intermediate formation during oxidative cleavage with HIO4 is easy when
the two OH groups are on the same side of the molecule. Thus (II) will be cleaved faster
than (I).
CHAPTER 14 CH3
C
O
H
Ph
P
Ph
Rh
Cl
CH3 O P Cl
H
Reduction Methods
Ph
Ph
An increase in hydrogen content or a decrease in oxygen content of an organic compound is

usually described as its reduction (Scheme 14.1). The opposite of reduction is oxidation i.e., it
is either increasing the oxygen content or decreasing the hydrogen content of an organic molecule
(Scheme 14.2). Generally, the oxidation of an organic molecule is defined as a reaction which
leads to an increase in it of any element which is more electronegative than carbon (Scheme
14.3). The replacement of hydrogen atoms in a compound by chlorine atoms is an oxidation
reaction.
When an organic compound is reduced the “reducing agent” is oxidized, whereas when
an organic compound is oxidized the “oxidizing agent” is reduced.
O
[H]
R—C—H RCH2OH Hydrogen content increases
Aldehyde Reduction Alcohol
O O
[H]
R—C—OH R—C—H Oxygen content decreases
Carboxylic Reduction Aldehyde
acid
[H]
RCH2OH RCH3 Oxygen content decreases
Reduction
SCHEME 14.1
Lowest oxidation state Highest oxidation state

O O
[O] [O] [O]
RCH3 RCH2OH RCH RCOH
[H] [H] [H]
SCHEME 14.2
[O] [O] [O]

Ar—CH3 Ar—CH2Cl Ar—CHCl2 Ar—CCl3
[H] [H] [H]
Oxidation
SCHEME 14.3
500
Reduction Methods 501
Most of the oxidizing and reducing agents are generally inorganic compounds. The
reductions are generally carried out either by catalytic hydrogenation or chemically. Three
main pathways for reduction may be considered:
1. The catalysed addition of molecular hydrogen (Scheme 14.4, eq. I). Hydrogenolysis
process involves, the addition of hydrogen followed by bond rupture (Scheme 14.4, eq. II).
Ni Catalyst
CH3CH CH2 + H2 CH3CH2CH3 (I) ArCH2—NMe2 + H2 ArCH3 + HNMe2 (II)
Propene Propane
(Propylene)
Hydrogenation Hydrogenolysis
SCHEME 14.4
2. By the transference of hydride ion e.g., in the reduction of a carbonyl group by lithium
aluminium hydride (Scheme 14.5).
LiAlH4
C—CH3 CH—CH3
O OH
Acetophenone a-Phenylethyl alcohol
The transference of hydride ion
SCHEME 14.5
3. By the addition of electrons, followed by coupling, as in the reduction of ketones to

pinacols (Scheme 14.6).
–
e . – R2C—O 2H
+ R2C—OH
R2C O R2C—O
–
Addition of R2C—O R2C—OH
electrons Coupling Pinacol
SCHEME 14.6
14.1 CATALYTIC REDUCTION-REDUCTION WITH DIIMIDE AND

HYDROBORATION
(A) Heterogeneous Catalytic Hydrogenation
(i) The role of catalyst
Alkanes, which are strained can be reduced catalytically by rupturing C—C bonds. The C—C
cleavage relieves the strain (Scheme 14.7). Normally almost all olefins can be reduced by
treatment with hydrogen in the presence of a catalyst. The process of hydrogenation is thought
to proceed via a mechanism involving the adsorption of hydrogen molecules on the surface of
Strained cyclic CH2 CH2 [H]

compound CH3CH2CH3
Reduction
CH2
SCHEME 14.7
the catalyst to form metal hydrogen bonds. The surface bearing adsorbed hydrogen causes
adsorption of the alkene as well and a subsequent stepwise transfer of hydrogen atom occurs.
This process yields an alkane before the organic molecule leaves the catalyst surface. As a
result, both hydrogen atoms usually add from the same side of the molecule, a process termed
syn addition (Scheme 14.8).
1 2 3
—C C—C— 1 2 3
—C C—C—
H
H—H + H H H
Alkene
Platinum metal
(catalyst surface)
(I)
Hydrogen and alkene complexed
to catalyst surface
(a p complex)
1 3 1 3 1 3
—C 2 C— —C 2
C— —C 2 C—
C C C
H H H H H
H H H
H
syn addition
(III) (II)
Half hydrogenated form
(a s bond formation)
1 2 3
—C—C C—
Free catalyst H
The initially formed p complex between the alkene and catalyst +
adds a hydrogen atom with the formation of a carbon-metal s bond H H
as in (III). This then adds another hydrogen to give an alkane. The
double bond isomerization may result from an equilibria between p
Isomerization of double bond
bonded species (I and II) and half hydrogenated form (III).
(IV)
SCHEME 14.8
Thus as expected Z-1, 2-dimethylcyclohexene gives a meso product on catalytic

hydrogenation and a racemic mixture results from (I, Scheme 14.8a).
H
CH3 CH3
H2
PtO2—H2O
CH3 Acetic acid CH3
H
meso
O O O
H2
+
Pd/c (10%) H H
EtOH
(I)
Racemic mixture
SCHEME 14.8a
The hydrogenation is thought to involve an equilibria between (II and IV, Scheme 14.8),
and (III) which is the half hydrogenated form. The half hydrogenated form then either picks
up the second hydrogen atom to afford the hydrogenated product or it can give back the starting
alkene, or it can afford an isomeric alkene (IV). The formation of isomeric alkene can explain
the anti addition of hydrogen which is often the mode of addition particularly with Pd as the
catalyst (see Scheme 14.12).
(ii) Evidence for syn addition
Stereochemically, the hydrogenation of an olefin generally occurs in a syn- fashion (Scheme
14.8). Thus, when one considers the hydrogenation of the E-stilbene derivative (I, Scheme
14.9), the syn addition gives the (±)-dihydro-derivative while the syn-addition to the Z isomer
(II) gives the meso isomer.
syn addition from top
CH3 H 3C C 6H5 H
C6H5 H2/Pd
C6H5 C6H5 CH3 + H CH3 C6H5
H
CH3 C 6H5 CH3
(I) H
The E-stilbene
derivative syn addition from bottom
Racemic mixture
syn addition from top
C6H5 C6H5 CH3 H

C6H5 H2/Pd
CH3 C6H5 CH3 H CH3
H C6H5
CH3 C6H5 CH3
(II) H
The Z-stilbene
derivative syn addition from bottom
meso compound
A syn stereospecificity:
Both hydrogen atoms add from the same side of the molecule
SCHEME 14.9
(iii) Syn addition from less hindered side

Generally the hydrogenation occurs by syn addition of hydrogen and from the less hindered
side of the unsaturated center. This is seen in the case of cholesterol (Scheme 14.10), which on
hydrogenation gives mainly, trans- ring-fusion (5α), since the angular methyl group hinders
the fit of the catalyst on the β-face. In cholesterol the 3-OH group is equatorial, however if in
such a system a 3-substituent is axial (A, Scheme 14.10) the fit to the catalyst is hindered on
both sides and hydrogenation then gives a mixture of cis and trans decalin systems in almost
equal amounts.
CH3 H 3C
CH3
H
HO
H
HO (A)
H H OH
H added from less
hindered side
Fit of cholesterol on its less hindered

-side on the surface of catalyst
SCHEME 14.10
(iv) The facial stereoselectivity of hydrogenation

In some instances, the affinity of a particular substituent group for the catalyst surface may
force addition of hydrogen from the same side of the molecule occupied by the substituent
irrespective of steric effects. The hydroxy methylene group (– CH2OH) is in particular effective
in this regard. Thus, in the hydrogenation of the tetrahydrofluorene derivative (Scheme 14.11)
there is excess of syn addition of hydrogen. However, the syn-addition is reduced to only 10%
when this group is replaced by – CONH2 in the same system (Scheme 14.11). The syn directive
effect indicates that the hydroxyl group interacts with the catalyst surface. Thus the alcohol
yields a predominant product with cis ring juncture, the same system with –CONH2 group
gives as expected a major product with trans-stereochemistry. (Scheme 14.11).
O H O H O
O H2, Pd/C O O
+
EtOH
CH3O R CH3O R CH3O R
R = CH2OH 90% 10%
R = CONH2 10% 90%
SCHEME 14.11
(v) Stereoselectivity for unhindered alkenes—the nature of a catalyst

Generally hydrogen adds to an alkene in a syn fashion, anti-addition is often observed
particularly with palladium catalyst. Thus 1, 2-dimethylcyclohexene (Scheme 14.12) gives
different mixtures of cis- and trans- 1, 2-dimethylcyclohexene depending on catalyst. This
anti- addition has been explained as a result of the migration of the methyl substituted double
bond (Scheme 4.13).
H
CH3
H2/Pt
CH3
H
CH3 cis-1, 2-dimethylcyclohexene
(82%)
(product of syn addition)
CH3
Z-1, 2-dimethylcyclohexene H H
cis- CH3 CH3
+
H2/Pd
CH3 H
H CH3
27% trans-1, 2-dimethylcyclohexene
73%
product of anti addition
SCHEME 14.12
CH3 CH3
Pd H2
Products
CH3 Pd
CH3
H
Hydrogenates more slowly Hydrogenates more quickly
SCHEME 14.13
The hydrogenation of a carbon-carbon double bond can also be carried out by the supply
of hydrogen by a donor e.g., cyclohexene or hydrazine (Scheme 14.14). The driving force in the
case of cyclohexene is due to the gain in aromatic stabilization energy on the formation of
benzene while with hydrazine, the strongly bonded N2 molecule is formed. The advantage of
this method is that no special apparatus is needed.
Pd
2 C C + 2 CH—CH +
100°C
SCHEME 14.14
(B) Homogeneous Catalytic Hydrogenation Using Wilkinsons Catalyst

Heterogeneous catalytic hydrogenation suffers from several disadvantages and these are:
1. No selectivity is observed when more than one unsaturated center is present.
2. Double bond migration occurs.
3. Several groups suffer an easy hydrogenolysis (see Scheme 14.18).
4. One may not be able to predict, the stereochemical outcome, despite a number of
rules, since heterogeneous catalytic hydrogenation depends on chemisorption and
not on reaction between molecules.
Some of these difficulties have been solved by homogeneous

catalytic hydrogenation in which the metal is replaced by a soluble PPh3
complex of rhodium or ruthenium and by carrying out the reduction in Ph3P—Rh—Cl
homogeneous solution. Several soluble catalysts have been used and
PPh3
the more effective are the ones derived from rhodium and ruthenium Wilkinson’s catalyst
(Scheme 14.15). The rhodium complex used is (Ph3P)3RhCl (called
Wilkinson’s catalyst, see, Sec. 7.1E), is prepared by heating rhodium SCHEME 14.15
chloride RhCl3, 3H2O with excess of triphenylphosphine in boiling
ethanol and with this catalyst, hydrogenation occurs in a single phase — in solution.
The Wilkinson’s catalyst is thought to act by exchanging one phosphine ligand for a
solvent molecule (S) to afford a complex which can then bind two hydrogen atoms on the metal
(Scheme 14.16). Displacement of the solvent molecule by the alkene is followed by step-wise
stereospecific syn-transfer of the two hydrogen atoms, and the saturated molecule then leaves
the metal center.
Ph3P H
PPh3 P S
S H2
Ph3P—Rh—PPh3 P—Rh—S Rh
Cl Cl Ph3P
Wilkinson’s catalyst S = Solvent Cl H
(Ph3P)3RhCl The solvated species The dihydrido complex
RCH CHR
RC
Ph3P H
H
CH
(PhP)2Rh(S)Cl + RCH2CH2R Rh
R
syn addition
Ph3P
of hydrogen Cl H
The dihydrido complex
Mechanism of hydrogenation with Wilkinson’s catalyst
SCHEME 14.16
The Wilkinson’s catalyst has its merit that whereas olefins and acetylenes are reduced,
other common groups like C O, C N and NO2 are not attacked and selective reductions can
be carried out (Scheme 14.17). Moreover, mono- and disubstituted double bonds are reduced
more rapidly compared to more substituted types i.e., tri- and tetra- substituted double bonds.
OH OH
H2/(Ph3P)3RhCl H2/(Ph3P)3RhCl
C6H5CH CHNO2 C6H5CH2CH2NO2
-nitrostyrene Phenylnitroethane
SCHEME 14.17
Hydrogenolysis implies a process of cleavage of a carbon-heteroatom bond by catalytic

hydrogenation. Aliphatic alcohols e.g., are inert toward catalytic hydrogenation, but benzylic
alcohols are reduced to the corresponding hydrocarbons (Scheme 14.18). This type of a reaction
where reduction is used to cleave a single bond e.g., C—OH in the case of a benzylic alcohol is
called hydrogenolysis.
Thus hydrogenolysis is the cleavage of a C—X single bond during addition of hydrogen
and represents one of several reactions hydrogen brings about over metal catalysts.
O O
CHCl2 CH3
H2/Pd H2/Pd
C6H5CH2—OH C6H5CH3 CH3 CH3
Hydrogenolysis
SCHEME 14.18
An advantage of working with homogeneous catalytic hydrogenation is that

hydrogenolysis does not take place. Thus with Wilkinson’s catalyst, e.g., benzyl cinnamate
affords cleanly the dihydro–derivative while, hydrogenation using a metal catalyst results (in
addition to hydrogenation) in cleavage of the O-benzyl bond (Scheme 14.19).
H2/(Ph3P)3RhCl
PhCH2CH2CO2CH2Ph
Normal hydrogenation product
PhCH CHCO2CH2Ph
Benzyl cinnamate
PhCH2CH2CO2H + PhCH3
H2/metal catalyst
Hydrogenolysis
Hydrogenolysis is the cleavage of C—X single bond
with hydrogen over metal catalyst
SCHEME 14.19
Rhodium has a strong affinity for carbon monoxide, the Wilkinson’s catalyst thus brings
about decarbonylation of an aldehyde group. Olefins therefore, with aldehyde groups are
degraded (e.g., cinnamaldehyde gives styrene, Scheme 7.1d).
The hydrogenation of an achiral substrate with optically inactive Wilkinson catalyst
will always produce a racemic modification. Thus an alkene with enantiotopic faces on
hydrogenation with Wilkinson’s catalyst gives racemic product since there is equal probability
for hydrogen to add to the either face. However, when the Wilkinson’s catalyst is made chiral
(optically active) by attaching optically active ligands, then the hydrogenation occurs in a
chiral medium and can give optically active products. A large number optically active ligands
have been developed where the chirality is due to either stereogenic carbon or stereogenic
phosphorus.
It may be mentioned that catalytic hydrogenation is the second important class of
reduction methods after hydride reductions.
DIOP is a complex of rhodium with a chiral ligand which has been used to synthesize
biologically active (–) form of dopa. As the catalyst is chiral, the transition states which would
lead to two enantiomers are diastereotopic, and have different energies, the transition state
which leads to the one of the enantiomers is of lower energy and is favoured (Scheme 14.19a).
Ph
H Ph
CH3 O P Cl
Rhodium (DIOP)Cl2—a chiral catalyst Rh
C
for enantioselective reduction
CH3 O P Cl
H Ph
Ph
HO
H2
HO CH2
H Rhodium (DIOP) Cl2
HO C
H C
HO COOH
C
H2N COOH H 2N
(S)-(–)-dopa
(biologically active)
SCHEME 14.19a
(C) Other Catalysts and Specially Conditioned Catalysts

A catalyst which brings about hydrogenation of an alkyne to an alkene is the nickel boride
catalyst (P-2 catalyst). This catalyst can be prepared by the reduction of nickel acetate with
sodium borohydride (Scheme 14.20). Hydrogenation of alkynes with P-2 catalyst leads to syn-
addition of hydrogen and gives an alkene with (Z) or cis configuration (Scheme 14.20).
O P-2 catalyst CH3CH2 CH2CH3

NaBH4 H2
Ni OCCH3 Ni2B CH3CH2C CCH2CH3 C C
2 C2H5OH or
(P-2) 3-Hexyne Lindlar’s catalyst H H
H2 (Z)-3-Hexene
(Z) or cis configuration
(syn addition of hydrogen)
SCHEME 14.20
Specially modified catalysts lead to partial hydrogenation of alkynes to (Z) alkenes.

Metallic palladium on calcium carbonate after it has been partially deactivated with lead
acetate and quinoline is called Lindlar’s catalyst. Reductions of alkynes with these type of
catalysts proceed with high stereoselectivity. Normally the reduced product is composed largely
of the thermodynamically less stable (Z)-alkene (Scheme 14.20).
In Rosenmunds reduction of acid chlorides to aldehydes (Scheme 14.21) with hydrogen
on a palladium catalyst, barium sulphate it is often helpful to poison the catalyst.
RCOCl + H2 RCHO + HCl

Rosenmunds reduction
SCHEME 14.21
A variety of functional groups are prone to catalytic hydrogenation and acid chlorides
are the most reactive and the arenes are the least reactive. Since C C is weaker than C O,
catalytic hydrogenation can be used to carry out selective reduction of C C in the presence of
a carbonyl group. Other groups which are reduced during catalytic hydrogenation are in
(Scheme 14.21a).
Ar—NO2 Ar—NH2 R—C N [R—CH NH] R—CH2—NH2
SCHEME 14.21a
(D) Reduction of Double Bonds via Hydroboration of Alkenes Followed by Reaction with Organic
Acids
Alkanes from Alkenes Via Hydroboration

The organoboranes made from alkenes on reaction with organic acids give alkanes.
Details are in Schemes 7.54a and 7.54b.
(E) Hydrogen Transfer from Diimide

Diimide (HN NH, obtained by the copper (II)–catalysed oxidation of hydrazine) is unstable
and decomposes to nitrogen and hydrogen (in the absence of additive). When diimide is liberated
in the presence of an alkene a rapid syn- stereospecific reduction occurs (Scheme 14.22).
2+ H
Cu /O2
:
:
:
H2N—NH2 N N N N
:
H
H H
anti form
Diimide syn form
N N H H
H H N N +
Nitrogen Alkane
C C
SCHEME 14.22
Although both the syn and anti forms of diimide are produced by the oxidation of
hydrazine, only the syn form reduces the double bonds by a cyclic mechanism. The addition is
therefore, stereospecifically syn (Scheme 14.22). More strained double bond reacts selectively
in the presence of a cis double bond (Scheme 14.23).
NH2NH2 NH2NH2
2+ 2+
Cu /O2 Cu /O2
SCHEME 14.23
Diimide is a highly selective reagent which generally reduces readily the symmetrical
bonds like C C, C C, N N, and carbonyl containing groups, nitro groups and sulphoxides
are not reduced (Scheme 14.24). Significantly the otherwise highly reducible disulphide bond
remains unaffected with diimide.
O O
NH2NH2 NH2NH2
O 2+
O (CH2 CHCH2S)2 (CH3CH2CH2S)2
Cu /O2
O O
SCHEME 14.24
14.2 REDUCTION BY DISSOLVING METALSMETAL AND AMMONIA

(i) Reduction of a double bond conjugated with a carbonyl group
Conjugate reduction of α, β-unsaturated ketones is carried out by adding electrons from a
metal e.g., lithium dissolved in liquid ammonia (a dissolving metal reduction). An alcohol is
often added to the reduction medium to provide protons (Scheme 14.25). The stereochemical
outcome of the reduction is established by the proton transfer to the β-carbon. When one
stereocenter is created a racemic mixture is formed (I, Scheme 14.26). With a chiral enone
system of ∆1,9-2-octalone, the product has a trans- ring junction.
– – –
:O: :O: :O:
:
:
:O:
e– . e– – HOR –
:
+ OR
Li/NH3
R R R R R R R R
(A)
, -unsaturated
ketone
–
:O:
:
:O:
HOR –
+ OR
R R R R
Saturated ketone
SCHEME 14.25
O O O
Li/NH3 Li/NH3
+
EtOH EtOH
O O
(I) Racemic (II) H
SCHEME 14.26
(ii) Utility in carbon-carbon bond formation

If during reduction of an α, β- unsaturated ketone, only one equivalent of the proton donor
(ROH) is used the enolate (A, Scheme 14.25) remains available for a suitable subsequent
reaction. Thus if the enolate (I, Scheme 14.27) is not protonated it can be employed in alkylation
reactions.
– +
O O Li O
Br
Li/NH3
1 equiv H2O
(I)
H H
1. Li/NH3
2. C4H9I
O O
H
C4H9
SCHEME 14.27
Generating a Specific Enolate of a Ketone
The dissolving metal reduction of an enone is method of high merit to generate a

specific enolate of a ketone regioselectively. Use of LDA with a ketone (Scheme
14.28) will however, give a mixture of enolate ions.
– + – +
O O Li O Li
LDA, THF
+
SCHEME 14.28
Thus the following points regarding reduction of α,β-unsaturated ketones in liquid

ammonia may be noted:
• Li/NH3 in the presence of excess protons from a source like t-butyl alcohol will reduce
the C C bond of enones to give saturated ketones.
• Li/NH3 without an added proton source/or with 1 equivalent of proton source will
give an enolate ion which can undergo alkylation in the α-position of the ketone.
(iii) Reduction of alkynes with metal and liquid ammonia
Electrons are transferred to acetylenes more readily than to alkenes because of greater reactivity
of acetylenes towards nucleophiles. The reagents of choice are sodium or lithium in liquid
ammonia. The reaction stops at the alkene stage and internal alkynes are converted into
trans alkenes using lithium in liquid ammonia (Scheme 14.29). A cis alkene can however, be
made by the catalytic hydrogenation on a deactivated Lindlar catalyst. With a metal catalyst
only syn addition occurs (Scheme 14.29).
H C 2H 5
Li/NH3(l)
C C anti-reduction
C2H5 H
trans-3-hexene
C2H5C CC2H5 Major product
3-hexyne C2H5 C2H5
H2
C C syn-reduction
Lindlar
catalyst H H
cis-3-hexene
98-99% pure
SCHEME 14.29
The mechanism of the reaction with Li/NH3 is thought to involve successive electron
transfer and protonation steps (Scheme 14.30).
. R R
Na . .
R—C C—R C C– C C
H—NH2
R R H
:
Alkene radical anion A vinylic radical

–
+ Na+ + NH2
One electron transfer and protonation
R . R H R
:
. Na – H—NH2
C C C C C C
R H R H R H
A vinylic anion A trans alkene
–
+ NH2
Second, one electron transfer and protonation
SCHEME 14.30

• The transfer of the s orbital electron from sodium or lithium is an easy process. Sodium
and lithium have a strong tendency for losing the single electron of their outer-shell
s orbital.
• The radical anion formed after the first electron transfer (Scheme 14.30) is a very
strong base and can therefore, remove a proton from NH3.
• The vinylic anion can adopt either the cis or trans configuration, however, the
equilibrium favours the more stable trans configuration with bulky groups as far
apart as possible (Scheme 14.31).
H R H
:
C C– C C–
R R R
:
(More stable)
trans vinylic cation
SCHEME 14.31
Thus in summary an alkyne can be reduced to a cis-alkene by employing a poisoned

catalyst. Treatment of an alkyne with Na/NH3 brings about reduction to give a trans-alkene.
Na/NH3 reduction proceeds involving a series of electron and proton-transfer steps.
EXERCISE 14.1
Write the outcome from the reactions (Scheme 14.32).
O
CH3
Li 1. Li/NH3
CH3C CHCH2C CH3
NH3 (1 equi ROH)
2. CH3I
(I) (II)
SCHEME 14.32
ANSWERS. (I) A carbon-carbon double bond is inert towards lithium in liquid

ammonia and is not reduced. Alkyne is reduced to a trans alkene the product
formed is (III, Scheme 14.33).
(II) The conditions of the reaction will give a specific enolate ion which subsequently
undergoes alkylation with CH3I. These reactions normally form the trans isomer
as the predominant product provided the alkyl substituents are on adjacent carbons,
thus the product formed is (IV).
O
H CH3 CH3
CH3 C C
CH3C CHCH2 H
(III) (IV)
SCHEME 14.33
EXERCISE 14.2
Convert 1-butyne (I, Scheme 14.33a) in to the cis-epoxide (II). How the same epoxide
with trans- geometry (III) could be prepared?
O O
H H H CH2CH3
CH CCH2CH3
H 3C CH2CH3 H3C H
(I) (II) (III)
SCHEME 14.33a
ANSWER. This is given in Scheme 14.33b.
H O
H H H
H2/Lindlar PBA
C C C C
Catalyst
H 3C CH2CH3 H3C CH2CH3
–
1. NH2
CH CCH2CH3 CH3C CCH2CH3
2. CH3I
O
H CH2CH3 H CH2CH3
Na PBA
C C C C
NH3
H 3C H H 3C H
SCHEME 14.33b
(iv) Reduction of aromatic rings—two successive electron transfer/protonation steps

Partial reduction of aromatic rings is carried out by dissolving metal systems and the reaction
is called Birch reduction. The reduction medium usually consists of lithium or sodium in liquid
ammonia and an alcohol is usually added to serve as a proton source. The mechanism of Birch
reduction begins with the addition of the electron to form a radical ion (Scheme 14.34).
Protonation of the radical ion gives a neutral radical. Addition of another electron gives a
carbanion, which is protonated to yield 1, 4-cyclohexadiene. The isolated double bonds in the
dihydro product are much less easily reduced than the aromatic ring and thus reduction stops
at the dihydro stage.
+
NH3 + Na (NH3) ...e(NH3) (deep blue solution) + Na
:
H – H—O—R H H H H H H
: :
:
H—O—R
Alcohol +e –
+ e + OR
. . –
:
H H H H H
Benzene Radical anion Radical Carbanion 1,4-cyclohexadiene
(90%)
Birch reduction
A two-electron reduction of aromatic rings using a
solution of alkali metal in liquid ammonia
SCHEME 14.34
The two carbon atoms which are reduced to give the dihydro product pass through the
carbanionic intermediates (see Scheme 14.34). The electron withdrawing substituents (COOH)
stabilize them while electron donating substituents (OCH3) destabilize them. Reduction thus
takes place on carbon atoms attached with electron withdrawing substituents and not on
carbon atoms on which electron releasing substituents are present (Scheme 14.35).
OCH3 OCH3 OCH3 COOH COOH COOH

H .
:
Li/NH3 Li/NH3 –
EtOH :– EtOH
.
H H
SCHEME 14.35
The reduction of methoxybenzenes is used in the synthesis of cyclohexenones via

hydrolysis of the intermediate enol ethers (Scheme 14.36) vinyl ethers react with aqueous
acids e.g., with aqueous hydrochloric acid to give an intermediate carbocation, which reacts
with water to give a hemiacetal which is hydrolyzed (Scheme 14.37).
OCH3 CH3O O O
+
Li/NH3 H3O
EtOH
2-cyclohexenone
SCHEME 14.36
+
H + +
CH3O—CH CH2 CH3O—CH—CH3 CH3O CH—CH3
Vinyl ether
H
+
CH3O + CH3O + CH3O +
H2O –H H –H
CH—CH3 CH—CH3 CH—CH3 CH3CHO + CH3OH
+
H2O HO O
A hemi-acetal H
SCHEME 14.37
Recall that unlike catalytic hydrogenation of benzene which is a difficult process, sodium
in liquid ammonia and a little alcohol brings about its reduction. However, there is an important
difference, during Birch reduction the ring is not totally reduced and the reaction steps at the
diene stage.
14.3 ADDITION OF HYDROGEN AND REDUCTIVE COUPLING OF CARBONYL

COMPOUNDSDISSOLVING METAL REDUCTIONS
One has already studied the role of a metal as the reducing agent where the metal (Na or Li)
provides one or more electrons to the organic reactant. A ketone forms a ketyl radical after the
transfer of a single-electron by a metal to it. The radical may be protonated to give alcohols or
may get dimerized to a pinacol by the dimerization of anion radicals in the absence of a proton-
donor (Scheme 14.38).
Na/ether . H3O
+
C6H5CC6H5 C6H5CC6H5 (C6H5)2C—C(C6H5)2 (C6H5)2C—C(C6H5)2
O :O:– –
O O– HO OH
:
Benzophenone A ketyl radical A pinacol
CH3CH2OH –
:
C6H5CHC6H5 C6H5C C6H5
:O. Radical :O.

:
:
Na
+ C6H5CHC6H5
H3O
C6H5CHC6H5
OH
–
:O : Benzhydrol
:
SCHEME 14.38
Acetone on reduction with dissolving metals in the absence of proton donors gives pinacol
(Scheme 14.39). The common reagents are magnesium, and magnesium amalgams. Currently
use of titanium tetrachloride along with magnesium amalgam gives improved yields.
–
Mg/Hg .– . – (CH3)2C—O H 2O (CH3)2C—OH
(CH3)2C O (CH3)2C—O (CH3)2C—O
–
(CH3)2C—O (CH3)2C—OH
SCHEME 14.39
14.4 REDUCTIVE REMOVAL OF FUNCTIONAL GROUPS AND REDUCTIVE

FISSIONHYDROGENOLYSIS
Role of a variety of reagents for this purpose under different experimental conditions are
known. Here a few typical examples are discussed.
(A) Zinc as the Metal

Compared to alkali metals, metallic zinc is a milder reducing agent which can selectively
remove many oxygen functional groups from α-substituted ketones. The reaction is thought to
be a two electron reduction followed by the loss of the substituent as an anion. This reaction is
thought to be a concerted process, since the isolated functional groups do not react. The reaction is
shown with a cyclohexanone derivative (Scheme 14.40) which proceeds with zinc and acetic acid.
–
O O O
AcO
Zn: CH3COOH
SCHEME 14.40
Zinc as electron-transfer agent reacts with 1, 2-dihalides in a different manner; both

halogen atoms are eliminated and an olefinic bond is introduced (Scheme 14.41). Allene may
be obtained in 80% yield by the treatment of 2, 3-dichloropropylene with zinc in aqueous
ethanol.
Zn: Br
Zn
CH2 C—CH2 CH2 C CH2
—C—C— C C + ZnBr2 – ZnCl2
Allene
Cl Cl
Br
SCHEME 14.41
(B) Conversion of Alcohols into Their Parent Hydrocarbons

This can be achieved by the reductive elimination of the tosylate group from an alcohol tosylate
with lithium aluminium hydride (Scheme 14.42) and is an SN2 type of reaction.
– +
AlH3/Li
TsCl H
–
RCH2—OH RCH2—OTs RCH3 + OTs
Alcohol Tosylate derivative
SCHEME 14.42
Lithium aluminium hydride and sodium borohydride also reduce primary and secondary
alkyl halides to hydrocarbons (Scheme 14.42a) via a similar SN2 process, however other
functional groups may, also be reduced. Sodium cyanoborohydride is a weaker and more
selective reagent (see, Scheme 14.85).
LiAlH4 LiAlH4
—CH2Br —CH3 CHBr CH2
SCHEME 14.42a
(C) Conversion of Primary Amines to Their Parent Hydrocarbons

Primary amines can be reduced to their corresponding hydrocarbons on reacting their derived
toluene-p-sulphonamide with a large excess of hydroxylamine-O-sulphonic acid in alkaline
ethanol. Use is made of the strong leaving group potential of sulphates and sulphinates and
the instability of the –N NH grouping (Scheme 14.43).
TsCl NH2OSO2OH
RCH2—NH2 RCH2—NH—Ts
–HCl –H2SO4
–
NH2 NH
– –
OH –Ts –N2
RCH2—N—Ts RCH2—N—Ts [RCH2—N NH] RCH3
SCHEME 14.43
(D) Synthesis of PeptidesAmino and Carboxyl Group Protection and Removal of Protecting
Groups via Hydrogenolysis
• In order to obtain a correct sequence in peptide synthesis the N–terminal end of one
of the amino acids (or peptides) is protected, the C–terminal end of the second amino
acid (or peptide) is also protected.
• In case this is not done a random peptide bond formation takes place e.g., a reaction
of phenylalanine with glycine would result in the formation of four dipeptides as
products (Scheme 14.43a).
+ – + –
H3N—CH—COO + H3NCH2CO2 Phe-Gly + Phe-Phe + Gly-Phe + Gly-Gly
CH2C6H5 Glycine
Phenylalanine
SCHEME 14.43a
• In order to form Phe-Gly, the N-protected phenylalanine has to be reacted with

C–protected glycine followed by the removal of protecting groups (Scheme 14.43b). The
O O O O
Couple
P —NHCHCOH + H2NCH2C— P P —NHCHC—NHCH2C— P
CH2C6H5 CH2C6H5
N-protected C-protected Protected Phe-Gly
Deprotect
O O
+ –
H3NCHC—NHCH2CO
CH2C6H5
Phe-Gly
SCHEME 14.43b
amino group is protected by acylation with benzyloxycarbonyl group. This group is

introduced on acylation of an amino acid with benzyloxycarbonyl chloride (Scheme
14.43c). The benzyloxycarbonyl protecting group is removed easily by hydrogenolysis
in the presence of Pd or by reduction with Na/NH3.
Recall that hydrogenolysis is the cleavage of a C—X bond with hydrogen over metal
catalyst (See, Scheme 14.19). Hydrogenolysis represents one of the several reactions
which hydrogen brings about over metal catalysts.
O O O
+ – 1. NaOH, H2O
—CH2OCCl + H3NCHCO +
—CH2OC NHCHCO2H
2. H
CH2C6H5 CH2C6H5
P
Benzyloxycarbonyl Phenylalanine N-Benzyloxycarbonylphenylalanine
chloride
H2/Pd
O H
– CO2
H2N—CH—COOH HO—C—N—CH—COOH + —CH3
CH2C6H5 CH2C6H5
Toluene
Phenylalanine Carbamic acid
SCHEME 14.43c
• Carboxyl groups of amino acids are generally protected as esters and benzyl esters
have a choice since these can also be removed by hydrogenolysis (Scheme 14.43d)
O O
+ H2, Pd + –
H3N—CH—C—OCH2 H3N—CH—C—O + CH3—
CH2—C6H5 CH2—C6H5
Phenylalanine benzyl ester Phenylalanine Toluene
SCHEME 14.43d
Hydrogenolysis
When the benzylic group is attached to OH, OR, OCOR, NR2, SR or a halogen,
then it is sensitive to catalytic reduction, electron transfer agents and nucleophilic
reducing agents. From the protected thiol groups the benzyl residue is removed by
electron transfer reduction (Scheme 14.43e). Here hydrogenolysis with Pd is not
carried out since sulphur will poison the catalyst.
NH2 NH2
Na/NH3
C6H5CH2 S CH2CH2—CH C6H5CH3 + HSCH2CH2CH
COOH COOH
Cysteine
SCHEME 14.43e
14.5 REDUCTIVE DEOXYGENATION OF CARBONYL GROUPS

The reductive removal of carbonyl groups from organic molecules can be carried out by several
methods and these lead to complete reduction to methylene groups or conversion to alkenes.
The choice of a method depends on the sensitivity of the substrate under reducing conditions.
(A) Clemmensen Method

Amalgamated zinc and hydrochloric acid is a classical reagent combination for conversion of
carbonyl groups to methylene groups. The mechanism is not known in detail and probably
takes the course shown (Scheme 14.44). The mechanism may involve carbon-zinc bonds at the
metal surface. Transfer of electrons from the metal surface to the carbonyl carbon atom has
been suggested. The concentrated acid is probably needed to bring about the initial protonation;
amalgamation of the zinc raises its hydrogen-overvoltage so that molecular hydrogen is not
generated. Thus it survives as a reducing agent in the acid solution and is not used up in
reaction with the acid to give molecular hydrogen. Only halogen acids are effective, probably
because by complexing the initial –Zn+ species, they provide a medium for the reduction of
this species by a second atom of zinc.
+ +
O OH OH OH2
+ +
H H
C C C C
R Zn C6H5 R C6H5 R C6H5 R
C6H5
+ +
:
:
A ketone Zn Zn Zn Zn Zn Zn Zn Zn Zn
2+
– Zn
– H2O
+
2H
C6H5CH2R C6H5—C—R
2+
– Zn
+
:
:
Zn Zn Zn
Clemmensen reduction
SCHEME 14.44
(B) The Wolff-Kishner Reduction

The reaction involves the reduction of carbonyl group to a methylene by base catalysed
decomposition of the hydrazone of the carbonyl compound. Alkyldiimides are believed to be
formed which collapse with loss of nitrogen (Scheme 14.45). The loss of the especially stable
molecule of nitrogen provides the driving force for the reaction.
R
NH2—NH2 – –
OH H2O
:
R 2C O R2C N—NH2 R2C N—NH –

R—C—N N—H
– H2O – OH
Formation of H
A ketone
a hydrazone –N2
R2CH2
–
H2O/–OH
Wolff-Kishner reduction
SCHEME 14.45
A modification employs potassium t-butoxide as the base and dimethyl sulphoxide as

solvent. Alkoxide bases are very much more powerful in this solvent than in water or hydroxylic
solvents and reduction occurs at room temperature.
(C) Tosylhydrazone Method

A carbonyl compound reacts with toluene-p-sulphonylhydrazine to give its corresponding
tosylhydrazone (Scheme 14.46). The reduction of tosylhydrazones with sodium borohydride
converts the carbonyl group to a methylene group. The mechanism (Scheme 14.47) probably
involves the formation of a diimide as in the case of Wolff-Kishner reduction.
TS
–H2O NaBH4 + –
R2CO + H2N—NH—SO2Ar R 2C N—NH—SO2Ar R2CH2 + N2 + Na O2SAr
Toluene- Tosylhydrazone
p-sulphonylhydrazine
SCHEME 14.46
–
H3B—H
– ArSO2–
R2C N—NH—SO2Ar [R2CH—N NH] R2CH2 + N2
Tosylhydrazone
SCHEME 14.47
The conversion of ketone p-toluenesulphonyl hydrazones to alkenes occurs on treatment

with a strong base e.g., an alkyl lithium called Shapiro reaction (Scheme 14.48). This reaction
proceeds via the anion of a vinyldiimide which subsequently decomposes to a vinyl lithium
reagent. This intermediate on contact with a proton source gives the alkene (Scheme
14.48).While dealing with unsymmetrical acyclic ketones, one has to consider both
regiochemistry and stereochemical aspects. Thus, 2-octanone gives exclusively 1-octene (Scheme
14.49) and the observed regiospecificity is dictated by the stereochemistry of the C N bond of
the starting hydrazone. There is preference for the removal of a proton which is syn to the
arenesulphonyl group since the arrangement allows chelation with the lithium ion
(Scheme 14.49).
+ – – +
NNHTs Li NNTs N N Li Li
2 RLi –LiTs – N2 H2O
RCCH2R¢ RCCHR¢ RC CHR¢ RC CHR¢ RCH CHR¢
Ketone Li
p-toluenesulphonylhydrazone
The Shapiro reaction
SCHEME 14.48
– –
TsN TsN
TsNHN N Li N
CH3C(CH2)5CH3 CH2 CH(CH2)5CH3 CH3CCH2R CH2CCH2R CH2 CHCH2R

p-toluenesulphonylhydrazone 1-octene
(2-octanone)
SCHEME 14.49
(D) Desulphurization of Thioketals (Mozingo Reaction)

A carbonyl group of a ketone can be converted into a methylene group by desulphurization of
its thioketal. The carbonyl compound an aldehyde or ketone is reacted with ethylene dithiol in
the presence of a Lewis acid to its thioacetal or ketal. Reaction with excess Raney nickel
causes hydrogenolysis of both C—S bonds (Scheme 14.50). Freshly prepared Raney nickel has
enough hydrogen to reduce the thioacetal or thioketal without added hydrogen.
Me Me Me
HS SH
Ni
BF3 S H2
O
S
Desulphurization (A hydrogenolysis)
SCHEME 14.50
Recall that C—O bonds are strong while C—S bonds are very weak and one can remove
a keto group of an aldehyde or ketone via its conversion into a thioacetal or thioketal which is
hydrogenolized over Raney nickel. This reaction is sometimes called Mozingo reaction.
Reduction of aldehydes and ketones to hydrocarbons

The Mozingo reaction offers a useful alternative for the reduction of carbonyl
compounds which are sensitive to acids and bases under Clemmensen and Wolff-
Kishner reduction conditions respectively.
Acetals and ketals are used as protecting groups

One can reduce an ester in the presence of a ketone when both are present in the
same compound by first protecting the ketone group to a function which would be
stable to the reducing agent (Scheme 14.50a). The ketone group is protected as a
ketal and after the reduction of the ester the protecting group is removed to
regenerate the ketone.
+
O O HO OH, H LiAlH4
+
H /H2O
O
O O O O O
OEt – H2 O OH
(I)
OEt OH
SCHEME 14.50a
14.6 REDUCTION BY HYDRIDE TRANSFER REAGENTS
(A) Lithium Aluminium Hydride and Sodium BorohydrideReduction of Aldehydes and Ketones to
Alcohols
Carbonyl componds are reduced with reagents which transfer a hydride from boron or
aluminium. A variety of reagents of this type are available to achieve a considerable degree of
chemoselectivity and stereochemical control. Sodium borohydride and lithium aluminium
hydride are the most widely used of these reagents. Sodium borohydride is a mild reducing
agent which reacts rapidly with aldehydes and ketones but only slowly with esters. Lithium
aluminium hydride is a more powerful hydride-donor reagent (Scheme 14.51). It reduces esters,
acids, nitriles, and amides, as well as aldehydes and ketones. Neither sodium borohydride nor
lithium aluminium hydride react with isolated carbon-carbon double bonds.
Not reduced by NaBH4 Easily reduced by NaBH4
O O O O O
R—C—OH < R—C—NR2 < R—C—OR < R—C—R < R—C—H
Carboxylic acid Amide Ester Ketone Aldehyde
ease of reduction, all reduced by LiAlH4
SCHEME 14.51
Sodium borohydride is easy to handle than lithium aluminium hydride and is also far
more selective. Thus NaBH4 will reduce the nitroketone only at the carbonyl group while
LiAlH4 will reduce at the nitro group as well (Scheme 14.52). NaBH4 dissolves in water while
LiAlH4 reacts with water violently and catches fire. Reductions with LiAlH4 are thus carried
out in anhydrous solvents (ether or THF). This is due to the fact that lithium is a stronger
Lewis acid compared with sodium and also AlH4– is far more reactive hydride donor than BH4–.
O OH
NaBH4
H3C NO2 H3C NO2
SCHEME 14.52
The most commonly used reagent for the reduction of aldehydes and ketones is sodium
borohydride (Na+ –BH4). Since a BH4– ion contains four hydrides, it is capable of reducing four
molecules of aldehyde or ketone (Scheme 14.53). The mechanism with both NaBH4 and LiAlH4
involves the activation of the carbonyl group with the metal cation and a subsequent hydride
transfer (Scheme 14.53). As all the four hydrides are transferred, several distinct reducing
agents may be involved during reduction with these reagents. For example during reduction
with NaBH4 in ethanol an alkoxyborohydride anion EtOB H 3− formed after the first hydride
transfer, may reduce three more molecules of carbonyl compound and transfer all of its three
+
Na
NaBH4
EtOH
R O R2CHOH
O
– Alcohol
H3B—H +
C R Li
R R R O
Ketone LiAlH4 R2CHOH
–
THF H3Al—H Alcohol
R
SCHEME 14.53
hydrogen atoms stepwise. The mechanism with LiAlH4 is same (see, Scheme 14.53). As LiAlH4
catches fire when in contact with water, the reduction with it are carried out in aprotic solvents
e.g., THF. At the end of reaction the product is isolated by the hydrolysis of the aluminium
alkoxide. The reduction of the four molecules of a carbonyl compound with LiAlH4 is depicted
(Scheme 14.54).
–
O O
– – R2C O –
R 2C H—AlH3 R2CH + AlH3 R2CH—O—AlH3 (R2CHO)2AlH2
R2C O
+
H – RR¢C O –
4R2CHOH (R2CHO)4Al (R2CHO)3AlH
SCHEME 14.54
(B) Role of Lithium Aluminium Hydride Reduction of Esters to Alcohols

Often LiAlH4 is the reagent of choice for the reduction of esters to alcohols (Scheme 14.55).
This reduction involves the collapse of tetrahedral intermediate (A, Scheme 14.55) after the
first hydride transfer which involves an elimination step. The aldehyde gets reduced to an
alcohol by a second reduction.
+
Li Li
O O
C C RCHO
R OR R OR aldehyde
H
Ester
– Tetrahedral
H3Al—H intermediate
(A)
Initial reduction of an ester to an aldehyde

+ –
Li Li AlH3
O O AlH3 O
+
C H
C C RCH2OH
R H R H R H
H H
–
H3Al—H
Reduction of the aldehyde to an alcohol
SCHEME 14.55
(C) Role of Lithium BorohydrideReduction of Esters to Alcohols

A milder alternative to lithium aluminium hydride is lithium borohydride which reduces esters
and not acids or amides (Scheme 14.56). Sodium borohydride reduces esters but very slowly if
at all. Thus the chemoselectivity of hydride donors is reflected in the nature of metal cation
and the ligands present. LiBH4 has enhanced activity over sodium borohydride which is due
to greater Lewis acid strength of Li+ over Na+. LiBH4 also reduces lactones in a facile manner.
CH3 LiBH4 CH3

HOOC COOCH3 HOOC CH2
EtOH
OH
LiBH4
RCH(CH2)2CH2OH
R O O
OH
A lactone
SCHEME 14.56
(D) Lithium Aluminium Hydride Reduces Amides to Amines

The mechanism of reduction of amides to amines with LiAlH4 is similar to that of reduction of
esters to alcohols. However, the initially formed tetrahedral complex collapses to give an
iminium ion and does not eliminate NR 2− since nitrogen is a poorer leaving group than oxygen
(Scheme 14.57).
+ –
Li Li AlH3 +
O O AlH3 O NR2
–
–OAlH3
C C C C
:
R NR2 R NR2 R NR2 R H

H H Iminium ion
–
H3Al—H Tetrahedral intermediate
+
NR2 NR2
C C
R H H
R H
– Amine
H3Al—H
Reduction of amides to amines with LiAlH4
SCHEME 14.57
Diborane Reduces Amides to Amines

Neutral borane BH3 can also transfer its hydrogen as a hydride. Borane, however,
is an electrophilic species which has a strong tendency to accept an electron pair
in its vacant p orbital, BH3 is therefore, expected to reduce electron rich carbonyl
groups. Sodium borohydride (NaBH4) is, however, nucleophilic and reacts by
addition of a hydride ion to the more positive end of the polarized bond. Thus
although NaBH4 quickly reduces an acyl halide to a primary alcohol, borane does
not react with an acyl halides, the carbonyl group of an acyl chloride is electron
poor due to the electron—withdrawing effect of halogen (Scheme 14.58). Similarly,
the reaction of borane with esters is also sluggish.
BH3
O
C
R Cl
An acyl chloride RCH2OH
(carbonyl group is relatively NaBH4
A primary
electron poor) alcohol
SCHEME 14.58
Reduction of carbonyl groups with borane occurs via addition of electron deficient
borane to the oxygen atom followed by irreversible transfer of a hydride ion from
boron to carbon (Scheme 14.59).
+ –
O O BH2 O—BH2
C + BH3 C H C
H
SCHEME 14.59
Amides require vigorous conditions for reduction with LiAlH4 to amines so that
chemoselectivity may be lost. Diborane offers a useful alternative for this reduction
and involves the electrophilicity of borane (Scheme 14.60). The process involves a
complex formation between carbonyl group (Lewis base) and the empty p orbital
of borane (Lewis acid). A transfer of hydride from anionic boron to electrophilic
carbon gives a tetrahedral intermediate which collapses to an iminium ion. The
iminium ion is again reduced by BH3.
H
–
H—B BH2 BH2
H O O H
O H R H RCH2
C +
C C H—B
:
C R NR2 R NR2 NR2

H
:
R NR2 H + NR2
Amide Tetrahedral Iminium ion Amine
intermediate
SCHEME 14.60
Borane—a Reagent of Choice for the Reduction of Acids to Alcohols

Borane is a choice reagent for the reduction of carboxylic acids to primary alcohols.
Moreover, it is highly stereoselective and reduces carboxylic acids to primary
alcohols without affecting other unsaturated groups e.g., nitro and cyano groups
and even other reducible groups like esters are left unchanged. The reduction of a
carboxylic acid proceeds through the formation of the triacyloxyborane intermediate
by the protonolysis of the B—H bonds (Scheme 14.61) and the carbonyl groups are
subsequently reduced by further reaction with borane.
O
BH3
3 RCOOH (RCOO)3B C B
–3H2
R O
3
:
OH2
–
BH2 BH
+
O O H H H
H H2O
C C C B RCH2OH
R O R O R O OH
H H
B B
SCHEME 14.61
EXERCISE 14.3
Comment on the reaction outcome (Scheme 14.62)
H Me H Me
BH3 +
H
S
H Me CO2Et O O
OH
Enantiomers
CO2Et CO2H
H Me H Me
One pure
enantiomer +
H
R
LiBH4
CO2H O O
HO
SCHEME 14.62
ANSWER. Borane and lithium borohydride have opposite relative reactivities.
One can either reduce the ester group or carboxylic acid by reaction with either of
the reagents. The same chiral substrate can therefore, be converted into either R or
S lactone.
(E) Further Uses of Lithium Aluminium Hydride and Sodium Borohydride

• Reduction of carboxylic acid with LiAlH4
Recall that carboxylic acid derivatives are converted into alcohols or amines by the
addition of hydride ion to the carbonyl group during reduction with LiAlH4. The
tetrahedral intermediate thus formed then collapses to give the product after the
elimination of the better leaving group (see, Schemes 14.55 and 14.57).
Carboxylic acids are reduced with LiAlH4 to the corresponding alcohols with a different
mechanism than involved in the reduction of carboxylic acid derivatives since a leaving
group is not present (Scheme 14.63). The aluminium atom rather than the lithium
ion bonds with the second oxygen atom. This gives a good leaving group H2Al—O–
which is the conjugate base of H2Al—OH which is a strong acid. (Recall that alone
AlH3 like BH3 can transfer a hydride ion and is also an electrophilic species due to a
vacant p orbital and is a Lewis acid).
AlH2
AlH2
H
O O O
– + –
H—AlH3Li – + – + –H2Al—O LiAlH4
R—C—O—H –H2, –AlH3
R—C—OLi R—C—OLi R—C O RCH2OH
H H
SCHEME 14.63
• Reduction of nitriles with LiAlH4

Nitriles on reduction with LiAlH4 give a primary amine via the formation of the
imine salt (Scheme 14.64). When the reduction is carried out with an hindered hydride
the reaction stops at the imine stage and hydrolysis gives an aldehyde.
–
H—AlH3
–
AlH3
– LiAlH4 H2O
R—C N R—CH N—AlH3 R—CH2—N R—CH2—NH2
–
AlH3
SCHEME 14.64
• Reduction of α, β-unsaturated aldehydes and ketones

Both NaBH4 and LiAlH4 react preferentially with the carbonyl group of an α, β-
unsaturated aldehyde or ketone, however the reduction of both π bonds is common
(Scheme 14.65). When 1, 2-addition is desired, the reduction is carried out in the
presence of a lewis acid cerium chloride. The cerium ion seems to activate the carbonyl
group (I, Scheme 14.65) toward nucleophilic attack and directs hydride reduction by
complexing with the carbonyl group.
H
O OH OH O OH H
–
B—H
NaBH4 NaBH4
+ H
CeCl3 Ce(III)
(> 99%) C O
Direct addition Conjugate addition
51% 49%
SCHEME 14.65
Reduction of Alkene Portion of an α, β-Unsaturated Compound

Recall that C C is weaker than C O. Catalytic hydrogenation reduces the C C
double bonds and leaves the carbonyl group of an α,β-unsaturated ketone unaffected
(Scheme 14.66).
O O
H2
Pd/C
HO HO
SCHEME 14.66
14.7 STEREOSELECTIVITY OF REDUCTION WITH SMALL HYDRIDE DONORS

In rigid cyclic ring ketones, the stereochemistry of hydride reductions appears to be determined
normally by the relative importance of competing influences:
1. Stability of the final product.
2. Steric hindrance to the approach of the reagent (steric approach control).
The two faces of the carbonyl group of camphor (i.e., exo and endo) have different
accessibility to nucleophilic reagents. The approach of the reagent to the bottom (endo) face is
hindered due to the U-shaped cavity of the molecule, but the top (exo) face is strongly hindered
by the overhanging C-7 methyl group. Thus reduction with LiAlH4 (or with bulky hydrides
−
and Grignards reagents) occurs exclusively by approach of the AlH 4 from the endo side
(Scheme 14.67). In the case of norcamphor, however, the exo side now becomes free of hindrance
but the hindrance to approach from the endo side still remains. Thus, hydride reduction occurs
by attack of the AlH 4− now from the exo side (Scheme 14.68).
H 3C CH3 H 3C CH3 + H3C CH3 H3C CH3

7 Li
H
exo-
4 –
5
3 H—Al—H
1 2 O OH
H +
6 H 3C O H3C O H3C Li H 3C
H H
endo-
AlH3 endo
Camphor
Transition state
SCHEME 14.67
H
–
H—Al—H
H exo
O H
Norcamphor
OH
SCHEME 14.68
The stereochemical outcome of the reduction of cyclohexanes e.g., with lithium aluminium
hydride is difficult to predict. With comparatively unhindered ketones, the more stable
equatorial alcohol generally predominates. According to Felkin’s model, in cyclohexanones
the outcome of reduction (and addition of other nucleophiles) is a balance of both steric and
torsional strain. Formation of an equatorial alcohol (e.g., by an axial attack of hydride) requires
a staggered transition state (I, Scheme 14.69) which could suffer from steric strain between
the nucleophile and the β-axial substituents (substituents at C-3). Thus with less bulky
nucleophile e.g., AlH −4 and with no axial substituent at C-3 i.e., with only a tiny hydrogen at
C-3, the energy of I is lower and an equatorial alcohol predominates. In case the nucleophile is
sterically demanding (see Scheme 14.72) and/or a bulky axial substituent is present at C-3
(Scheme 14.70) the energy of transition state (I, Scheme 14.69) increases and then an axial
alcohol formation predominates (Scheme 14.70). Formation of an axial alcohol i.e., attack by
nucleophile e.g., a hydride at equatorial position requires a partially eclipsed transition state
(II, Scheme 14.69) with torsional strain between the nucleophile and the axial α-hydrogen
substituents.
Rb Nu
Rb Nu
Ha Ha
Axial OH
attack
O
Ha
Rb Ha
Ha O
(I)
Ha Rb O
Rb OH
Equatorial Ha Ha
attack Nu
Ha
Ha Nu
(II)
SCHEME 14.69
H CH3 CH3 OH
O O
LiAlH4 OH LiAlH4 H
SCHEME 14.70
14.8 STEREOSELECTIVITY OF REDUCTION WITH HINDERED HYDRIDE

DONORS-SELECTRIDE
The stereochemistry of reduction of ketones by bulky hydride donors have been studied. The
steric approach control becomes significant when the hydride reagent becomes more highly
substituted and thus hindered. The alkyl substituted borohydrides have particularly high
selectivity for the least hindered direction of approach.
The reagent lithium tri-sec-butylborohydride trade name as ‘Selectride (Scheme 14.71)
is the reagent of choice for the reduction of cyclic and bicyclic ketones in a highly stereoselective
manner, giving the less stable isomer. This is in contrast to the usual reagents e.g., lithium
aluminium hydride and sodium borohydride. Thus 4-t-butylcyclohexanone (Scheme 14.61)
which gives equatorial alcohol on reduction with NaBH4 (80%) or LiAlH4 (92%) as the major
product, with lithium tri-sec-butyl-borohydride selectride give the axial alcohol as the major
product. In summary the introduction of bulky alkyl groups into the borohydride anion
dramatically alters the direction of attack on a cyclic ketone, and cyclohexanones are attacked
predominantly from the equatorial side to afford the axial alcohol.
– +
Li
L-Selectride LiHB[CH(Me)CH2Me]3 B
H
H
O
LiAlH4 OH
(CH3)3C or (CH3)3C
NaBH4
(Major product)
OH
O
LiBH(sec-Bu)3 H
(CH3)3C (Selectride) (CH3)3C
(Major product)
SCHEME 14.71
Consider the delivery of the hydride ion via the axial approach i.e., the top face of the
cyclohexanone derivative. This axial approach of the bulky reagent is severely restricted by
interaction between the large groups —CH(CH3)CH2CH3 on the boron and the vertical axial
H atoms on the chair conformation (Scheme 14.72).
Thus the ketone (Scheme 14.72) during reduction with a bulky reducing agent is under
kinetic control and the selectride is facially selective. The major product being formed by the
delivery of the hydride via equatorial face which involves a stable and less crowded transition
state as compared to the one involved via axial approach by the bulky reducing agent.
CH3
CH3CH2 CH CH2CH3
CH3 CH
B CH3
HC
+
Clash H C—CH H O Li Added
3 2 nucleophile
HH H
H H
OH
Very crowded; H
transition state (high energy) minor product
HH H OH
O Li + H Added
H nucleophile
CH3 (Major product)

CH H
B CH2—CH3
CH3—CH2 CH2—CH3
CH
R R = —CH
CH3 CH3
Less crowded;
transition state (lower energy)
SCHEME 14.72
Another hindered reagent is diisobutylaluminium hydride –DIBAL (or DIBAL—H) which

is used as the hydride donor at low temperature. Using DIBAL, the reduction of an ester can
be stopped after one equivalent of hydride ion has been added (Scheme 14.73). This however,
is not the case with LiAlH4 and the aldehyde formed in the first reduction is reduced further
to an alcohol (see, Scheme 14.55) DIBAL is also a good reagent for reducing nitriles to aldehydes
(Scheme 14.74).
H Al(iBu)2
O O O
Al +
DIBAL H3O
C R OR¢ C
–70°C
R OR¢ H R H
DIBAL Ester Aldehyde
SCHEME 14.73
H O
+
DIBAL H3O
R—C N C N C
–70°C
A nitrile R Al(iBu)2 R H
An aldehyde
SCHEME 14.74
Use of DIBAL
Diisobutylaluminium hydride DIBAL is a reagent of choice for the preparation of
aldehydes (see, Schemes 14.73 and 14.74) by working at low temperatures. At
room/ordinary temperatures ketones, esters (Scheme 14.74a) and epoxides are
reduced to alchols while nitriles give amines. At ordinary temperatures this reagent
brings about the conversion of α, β-unsaturated compounds to allylic alcohols
(Scheme 14.74b).
DIBAL
O C6H5CHO
–70°C
C6H5C—OC2H5
C6H5CH2OH
DIBAL
No cooling
SCHEME 14.74a
O OH
DIBAL
O OH
SCHEME 14.74b
When some of the hydrogens of LiAlH4 are replaced by OR groups, the original reactivity
of the metal hydride is significantly reduced. One such reagent is lithium tri-tert-
butoxyaluminium hydride which reduces an acyl halide only up to the aldehyde stage whereas
with LiAlH4 the product is an alcohol (Scheme 14.75).
O O
1. LiAl[OC(CH3)3]3H/–70°C
C C
2. H2O
R Cl R H
Acyl chloride Aldehyde
SCHEME 14.75
14.9 CHIRAL BORANESENANTIOSELECTIVE REDUCTION OF CARBONYL

COMPOUNDS
A chiral, optically active reducing agent, e.g., Ipc. BBN (alpine-borane, Scheme 14.76 brings
about asymmetric reduction of unsymmetrical (prochiral ketones R—CO—R′ R ≠ R′) to optically
active secondary alcohols with a very high degree of enantioselectivity even when the ketone
itself is achiral. The chiral reagent is prepared from 9-BBN and α-pinene. It is suggested that
hydride is transferred by the adduct (Ipc. BBN) by adopting a boat shaped six-membered
cyclic transition state (Scheme 14.76).
H
B H H
B BCl
2
+
9-BBN (+) a-pinene (Ipc. BBN) (Ipc)2 BCl

(R-Alpine borane)
H O
B C6H5
C6H5CCH3 B +
H
O + HO
H 3C H H3C CH3
C 6H 5 H
C
Ipc. BBN CH3 CH3 (Major)
H 3C CH3
(Alpine borane) CH3 Enantiomer
(S)
A boat shaped transition state
SCHEME 14.76
The larger group on the ketone (phenyl group in this

case) directs away from the terpenoid moiety so that steric B
hindrance is kept at minimum thus this arrangement leads
O
to the major enantiomer. The other alternative arrangement H3C H
CH3
(Scheme 14.77) would give the minor enantiomer of the CH3
C
product. CH3
C6H5
Both the enantiomers of α-pinene can be made to react
with 9-BBN and thus the S enantiomer of the secondary SCHEME 14.77
alcohol (Scheme 14.76) can also be synthesized.
Diisopinocampheylchloroborane (Ipc)2 BCl (Scheme 14.76) is another reagent of choice
which brings about an enantioselective reduction of a wide variety of ketones.
14.10 MEERWEIN-PONNDORF REDUCTIONTHE HYDRIDE TRANSFER

REACTION
The reduction of carbonyl compounds to alcohols with aluminium isopropoxide has long been
known and is called Meerwein-Ponndorf-Verley reduction. The reduction is done by heating
the components together in solution in isopropanol. An equilibrium is set up and the product
is obtained by using an excess of the reagent or by distilling off the acetone as it is formed. The
reaction involves a transfer of hydride ion from the isopropoxide to the carbonyl compound
through a six-membered cyclic transition state (Scheme 14.78).
Thus in summary Meerwein-Ponndorf-Verley reduction is carried out by aluminium
isopropoxide when the carbonyl group of an aldehyde or a ketone gives a primary or a secondary
alcohol respectively. In this reduction, the hydride ion is donated by carbon unlike a metal
hydride. The reverse reaction, oxidation of a primary or a secondary alcohol to the carbonyl
function in the presence of an aluminium alkoxide is the Oppenauer oxidation.
R2C O + Al[OCH(CH3)2]3 R2C O

Ketone H Al[OCH(CH3)2]2
Instead of using a complex (reactant)
metal hydride as a source of (CH3)2C—O
hydride ion, the hydride ion
may be donated by a carbon -(CH3)2C O
atom in Meerwein—Ponndorf (Acetone)
Verley reduction.
(CH3)2CHOH
R2CHOH + Al[OCH(CH3)2]3 R2CHOAl[OCH(CH3)2]2
Alcohol
(product)
SCHEME 14.78
14.11 CANNIZZARO REACTION

Aldehydes without α-CH groups cannot undergo base-catalysed condensation, however, they
react with bases by disproportionation involving the transfer of hydride ion (Scheme 14.79).
–
O Ph
–
HO – –
PhCH O Ph—C—H C O PhCO2H + PhCH2O PhCO2 + PhCH2OH
OH H
SCHEME 14.79
Crossed Cannizzaro reaction between one molecule of such aldehyde and formaldehyde leads
to reduction of the former and the oxidation of the latter, since formaldehyde is more reactive
than other aldehydes towards nucleophiles and rapidly gives a high concentration of the donor
anion (Scheme 14.80). This fact has been used for reductions, thus benzaldehyde is reduced by
formaldehyde in the presence of potash in refluxing methanol to give benzyl alcohol in high
yield.
–
O R
–
OH – –
H 2C O CH—H C O HCO2H + RCH2O HCO2 + RCH2OH
OH H
SCHEME 14.80
14.12 REDUCTION OF ALDEHYDES AND KETONES WITH AN ADJACENT

STEREOCENTER (ASYMMETRIC INDUCTION)
The stereochemistry of reduction of acyclic aldehydes and ketones is a function of the
substitution on the adjacent stereogenic carbon. The formation of the major product can be
predicted on the basis of a conformational model of the transition state (Scheme 14.81, Crams
rule). According to this model, that diastereomer will be formed as the major product which
involves minimal steric interaction of the nucleophile with the groups L and M (S, M and L are
the relative sizes of the substituents). Thus the reagent (e.g., hydride ion H:– during reduction
with lithium aluminium hydride I, Scheme 14.70) approaches the less hindered side of the
carbonyl group when the rotational conformation of the molecule is the one in which the carbonyl
group is flanked by the two least bulky groups on the adjacent stereocenter (Scheme 14.81).
–
Nu :
O Nu
–
M S O S Nu M S
M (I)
–
O R
L L
R R L
(Eclipsed) (Staggered)
(major product)
O CH3 CH3
Me H CH3 MgBr Me H Me H
+ (II)
HO H H OH
Ph
H Ph Ph
erythro (major) threo (minor)
Application of Crams rule
SCHEME 14.81
Erythro and Threo Nomenclature

A compound with two stereocentres and with two substituents in common Cabc —
Cabd are given shorthand nomenclature erythro and threo. When written in
Sawhorse or Newman projection one can recognize these. In erythreo configuration
it is possible to eclipse each of the like substituents and also the unlike substituents
as in (Scheme 14.81). In a threo configuration one can only eclipse at a time either
any two of the like substituents or the unlike substituents.
Crams rule can thus be used to determine the stereochemistry of the major product.
The rule has been now rationalized in the form of Felkin–Anh model. The Newman projection
(in the lowest energy arrangement) is the one with the C—L bond perpendicular to the carbonyl
group (L, M and S represent the largest, medium-sized and smallest substituents on the
stereogenic carbon). The nucleophile is delivered to the carbonyl carbon in a plane perpendicular
to the C O fragment from the side opposite the C—L bond so as to make an obtuse angle with
C O corresponding nearly to the tetrahedral angle of Nu—C—O in the product. Of the two
possible arrangements (I, Scheme 14.81a) is of lower energy due to less steric interference
(between the Nu and the smallest group). The major product is thus (II).
–
H: H L
S M S M S M S M
O H R R O
R – L L
R O – – M S
R O O H –
L L H:
(I) (II)
Arrangement of Major product Arrangement of

lower energy higher energy
Felkin Anh model for diastereoselective synthesis
SCHEME 14.81a
The diastereoselectivity as predicted by Cram’s rule (Felkin Anh modification) during

the nucleophilic addition with Grignards reagents is further increased by the use of σ
organotitanium compounds (see Scheme 7.6a the yield of predicted diastereomer is for greater)
as shown (Scheme 14.81a).
Cram’s rule may not be followed when the conformation of the carbonyl compound in
the transition state does not depend on steric factors. In such examples one of the substituents
on the stereocenter is an alkoxy, hydroxyl or other complexing group. Lithium cations e.g.,
coordinate effectively with oxygen atoms and thus reduction of ketones of the type (I, Scheme
14.81b) with lithium aluminium hydride involves a rigid chelate system of type (II). Thus the
reagent brings about the reduction by first locking the conformation by coordination with both
the methoxy oxygen and the ketone oxygen. A high degree of stereoselectivity is due to the
attack of the chelate from the less hindered side (i.e., away from the phenyl group, in this case
it is the Re face which offers the least resistance to the approach of the reagent) and this may
not be in accordance with Cram’s rule.
+
– Li
H3AlH
+
Li CH3O O
CH3O O CH3O OH
LiAlH4 CH3O O – H
H H H
C 6H 5 p-tolyl H C6H5 p-tolyl
C6H5 H
(I) C6H5 p-tolyl p-tolyl (III)
2-methoxy-2-phenyl- –
H Major product
1-(p-tolyl)ethanone (II)
SCHEME 14.81b
The formation of one product stereoisomer over the other depends

on the difference in size between S and M. In case S and M are very L O S
similar, their interactions with the incoming nucleophile (as well as R) –
would be small and the diastereoselectivity of such molecules will be Nu
poor. In cases when one of the substituents is strongly electronegative Cl R
(e.g., chlorine) the preferred transition state corresponds to conformation
(Scheme 14.81c) due to the tendency of the negatively polarized oxygen SCHEME 14.81c
and chlorine atoms to be as far apart as possible and in these cases
Cram’s rule may not be followed.
14.13 REDUCTION OF EPOXIDES
A detailed study of reaction of epoxides is presented in chapter 13 (Schemes 13.27-

13.28). Here some examples of reduction of epoxides with LiAlH4 and borane are
given.
Epoxides are converted to alcohols by LiAlH4. Since epoxides can be easily prepared from
olefins, the overall reaction provides a method to hydrate an olefin. The reaction proceeds by
SN2 substitution by hydride ion and a new C—H bond is formed. With unsymmetrical epoxides
therefore, the hydride addition occurs at the less hindered carbon of the epoxide (eq. I, Scheme
14.82). Moreover, as expected of nucleophilic SN2 attack of an epoxide by the hydride reagent,
inversion of configuration occurs at the carbon atom which is attacked (eq. II, Scheme 14.82).
Moreover, substituted cyclohexene epoxides are preferentially reduced in such a direction as

to give an axial alcohol (eq. III, Scheme 14.82), i.e., the reaction has the trans stereochemistry
characteristic of SN2 reactions.
Hydride selectively attacks

–
H: the less alkylated carbon
Peroxyacid 1. LiAlH4
RCH CH2 RCH—CH2 RCH—CH3 (I)
2. H3O+
O OH
More highly alkylated alcohol
CH3 CH3
SN2 OH
O (II)
CH3
CH3 H
H
Inversion of configuration
H—Al—H
trans-1, 2-dimethylcyclohexane
H
–
H3A—H CH3 H CH3
(III)
Axial alcohol
O OH
SCHEME 14.82
Epoxides on reduction with borane (in contrast with lithium aluminium hydride) give
rise to less substituted alcohol and the reaction is thus complementary to the reduction with
LiAlH4 (Scheme 14.83). This reduction is catalysed by lithium borohydride.
CH3 OH
BH3
CH3—C—CH—CH3 (CH3)2CHCHOHCH3 + (CH3)2CCH2CH3
LiBH4
O Major product Minor product
SCHEME 14.83
14.14 REDUCTIONS WITH ENZYMESBAKERS YEAST

Reductions can be catalysed by enzymes e.g., a prochiral ketone is reduced to optically active
secondary alcohol. The enzyme is only the chiral catalyst which, however, does not provide the
hydrogen atom for reduction. The hydrogen atoms, instead are provided by the relevant
coenzyme e.g., NADH. One may carry out the reduction using whole cells, like bakers yeast
where both the enzyme and the coenzyme are provided by the organism. Thus ethyl acetoacetate
(Scheme 14.84) is reduced selectively to ethyl (S)-(+)-3-hydroxybutanoate using one of the
reducing enzymes found in Baker’s yeast alcohol dehydrogenase. It is one of the enzymes
which are involved in the metabolism of D-glucose to ethanol. In this reaction enantiomeric
excesses ranging from 70–97% have been achieved particularly when oxygen is excluded during
the fermentation (anaerobic). The best enantioselectivities are obtained provided the ketone
has a β-ester group. However, a dependence on the size of the two groups has been discovered.
Reduction of ethyl acetoacetate (Scheme 14.84) with Baker’s yeast yielded the (S) alcohol but
reduction of ethyl β-ketovalerate instead gave the (R) alcohol.
Baker's HO H Baker's HO H
O O yeast
yeast
CO2Et CO2Et CO2Et CO2Et
Ethyl acetoacetate (S)-alcohol Ethyl b-ketovalerate (R)-alcohol
SCHEME 14.84
14.15 LESS REACTIVE MODIFIED BOROHYDRIDESSODIUM

CYANOBOROHYDRIDE AND SODIUM TRIACETOXYBOROHYDRIDE
Role of several modified and hindered hydride donors has been discussed. These are:
• Lithium tri-sec-butylborohydride (selectride)
FCH CH CH  I –
B H Li+ (see, Schemes 14.71, 14.72)
GG 3

2
JJ
H CH K 3
3
• Diisobutylaluminium hydride (DIBAL) AlH [CH2CH(CH3)2]2 a derivative of alane

(AlCl3), (see Schemes 14.73, 14.74 and 14.74b)
• Lithium tri-tert-butoxyaluminium hydride LiAlH[OC(CH3)3]3 (see Scheme 14.75).
Sodium cyanoborohydride (NaBH3CN) is yet another useful reagent which is weaker
than sodium borohydride, but is more selective. It readily reduces iodides, bromides
and tosylates to the hydrocarbons (just like LiAlH4 see Scheme 14.42a) in neutral
solution in hexamethylphosphoramide (HMPA) as the solvent even in the presence
of carbonyl and other reducible groups like epoxides (Scheme 14.85).
O O
NaBH3CN
C6H5—CH—CH—CH2Br C6H5—CH—CH—CH3
HMPA
NaBH3CN
Br(CH2)4COOC2H5 CH3(CH2)3COOC2H5
SCHEME 14.85
Due to the electron withdrawing effect of the cyano group, the reagent becomes weaker
(less nucleophilic and thus more selective than NaBH4. This reagent is stable at pH 3–4 and
+
in this acid medium a carbonyl group is converted to its protonated form C OH which is
readily reduced to the corresponding alcohol. Thus aldehydes and ketones are reduced in acidic
media and remain unaffected around a neutral pH.
Aldehydes and ketones at pH = 6 are not disturbed by sodium cyanoborohydride,
therefore, amines are made through reduction of an imine derivative (reductive amination
Scheme 14.86).
O NHR²
NaBH3CN
C + R²NH2 C
R R¢ pH6
R H
trans amination R¢
SCHEME 14.86
Recall that C N double bond reacts with nucleophiles in a way similar to a C O

double bond. Moreover, an imine is a better base than its carbonyl precursor so it is readily
protonated near pH 6 and the mechanism of transamination is presented (Scheme 14.87).
+
O pH6 NC2H5 NHC2H5
(–H2O) pH6
C + C2H5NH2 C C
C 6H 5 H C6H5 H C 6H 5 H
Amination
+
NHC2H5 NHC2H5 NHC2H5
–
:
H
C C+ C
NaBH3CN H
C6H5 H C6H5 H C 6H 5
H
SCHEME 14.87
Sodium acetoxyborohydride NaB(OAc)3 H is less reactive than sodium borohydride and

can reduce selectively an aldehyde in the presence of a ketone (Scheme 14.88).
O O
NaB(OAc)3H
CHO CH2OH
SCHEME 14.88
The use of NaBH4 may reduce both the groups. NaB(OAc)3H is generated by dissolving
NaBH4 in acetic acid.
PROBLEMS
14.1 Predict the stereochemistry of the product which would be obtained on hydrogenation
of α-pinene over platinum catalyst.
CH3 CH3
H
CH3
a-Pinene
14.2 When acetone is treated with magnesium in benzene, a strongly exothermic reaction
occurs. This on aqueous work up gives pinacol. What is the mechanism of this reaction?
14.3 Write the structure of the product when the following compound is treated with (Na/
Hg).
+ –
PhCH CHCH2N(CH3)3I
14.4 Sodium in liquid ammonia, containing ammonium acetate reduces amides to aldehydes.
Write the mechanism of the reaction. What end product is expected in the presence of
ethanol?
14.5 Write the outcome of the following reactions:
CH3
CH3
CH2N
NaBH4 H2
CH3
Pd
O N
(I) H (II)
14.6 Write the structure of the major products from following reactions:
O O
LiAlH4 LiAlH4 B2 H 6
O
N
CH3 (I) (II) (III)
14.1 The major product will be the one formed by addition of hydrogen from the more accessible
side of the double bond. Thus in the product the added hydrogen occupies the less
hindered face i.e., trans to the bridge with gem dimethyl group.
CH3 CH3
H
H CH3
H
H
Added hydrogens
14.2 It is the one electron reduction of acetone with magnesium metal. The carbonyl group
accepts an electron to give a radical anion. In the subsequent reaction, two of the
radicals couple to give a dianion which is protonated on aqueous work up.
CH3 Magnesium CH3 CH3
· Mg · – . –
O·
2+
2 C O C C O + Mg
C6H6
CH3 CH3 CH3
Acetone A radical anion, or ketyl
–
(CH3)2C—OH 2H2O (CH3)2C—O
Mg(OH)2 +
–
(CH3)2C—OH (CH3)2C—O
Pinacol
14.3 The compound will undergo a hydrogenolysis reaction i.e., a reductive fission of a benzylic
type system. The activating effect of the benzene ring is transmitted through conjugated
double bonds.
PhCH CHCH3 + N(CH3)3
1-Phenylpropene
14.4 Ammonium acetate is acting as a weak proton donor. In the presence of a stronger
proton-donor e.g., ethanol further reduction will occur to give an alcohol.
+ –
2e – NH4 OAc
R—C—NH2 R—C—NH2 R—CH—NH2 R—CH O
–
O O –O
14.5 The steric effects around the carbonyl group in (I) are not severe, thus the product will
be the more stable equatorial alcohol. In the case of (II) hydrogenolysis occurs.
CH3 CH3
CH3
–
(I) O (II)
O N
H H
–
H3B—H
14.6
OH
OH
(II) (III)
(I)
N
CH3
CHAPTER 15 R
C—N:
:
O
Molecular Rearrangements
When in a reaction on an organic compound, the basic skeleton of the molecule undergoes a
change, one then speaks of the occurrence of a molecular rearrangement. The majority of the
rearrangements involve a migration from an atom (migration origin) to an adjacent one
(migration terminus) and are termed 1, 2 shifts (Scheme 15.1). Most of these rearrangements
are intramolecular processes and may occur in:
1. Electron deficient systems
Migrating group moves with its bonding pair of electrons to the migration terminus which is
electron deficient with an open sextet. This is seen in the formation of a nitrene (electron
deficient nitrogen) during the decomposition of an acyl azide. Once formed the nitrene undergoes
a molecular rearrangement (Scheme 15.1). These rearrangements are also called nucleophilic
or anionotropic rearrangements.
Migrating group
Migration terminus
R R
–
–N2 Rearrangement
C—N:
: :
R—C—N N N C N
+ of a nitrene
:
O O O
Acyl azide Migration origin Open sextet Rearrangement product
(a stable isocyanate)
Nitrene
SCHEME 15.1

The migrating group or atom (M) e.g., M = halogen, RO–, RS–, R2N—, (— C  or H)

migrates from one atom A to an adjacent atom B along with a pair of bonding electrons
(Scheme 15.1a). The essential requirement for the 1, 2-shift involved in this rearrangement is
M
—A—B— —A—B—
Electron deficient atoms
SCHEME 15.1a
543
the formation of the atom B which has only a sextet of electrons. The electron sextet may be
generated in neutral species for examples nitrenes (see, Scheme 15.1) or carbenes and also in
cationic species like carbocations, and in electron deficient oxygen and nitrogen.
2. Electron rich systems
In these rearrangements (which are less common), the migration group migrates without its
electron pair. An example is prototropic rearrangement where the migrating group is hydrogen.
These rearrangements are also termed electrophilic or cationotropic rearrangements. These
rearrangements include reactions which are initiated by the formation of an anion
(Scheme 15.1b) and are usually called anionic rearrangements. Most anionic reactions begin
with the removal of a proton by a strong base and these rearrangements may proceed by ionic
or free radical pathways.
R R
– – + +
:
X—C X—C (X = N, S, O)
R migrates without its bonding pair
SCHEME 15.1b
3. Free radical rearrangements

The least common of the rearrangements are free radical rearrangements where the migrating
group moves with just one electron.
The 1, 2-shifts (rearrangements) via carbocations are much more common than the
similar rearrangements that involve carbanions or free radicals. Only in the transition state
for the carbocation case (I, Scheme 15.2) one has two electrons which both can go into the
bonding orbital, consequently one has a low energy transition state. However, in the free
radical or carbanionic migrations, one has, electrons in excess of two which have to be
accommodated in antibonding orbital of much higher energy. Thus as one would expect, during
1, 2 shifts of free radicals or 1, 2 shifts involving carbanions the migrating group is generally
an aryl or a similar group which can accommodate the extra electrons and therefore, effectively
removes these from the three membered transition state.
M
+
C C
(I)
Antibonding
Bonding
Nucleophilic Free radical Electrophilic
SCHEME 15.2
Molecular Rearrangements 545
15.1 REARRANGEMENTS TO ELECTRON DEFICIENT CARBON

(A) Wagner-Meerwein Rearrangement (Carbon to carbon migration of R, H and Ar)
1. A migration of an alkyl group in neopentyl system
These rearrangements involve the intermediate formation of a carbocation which is an electron
deficient open sextet in which a 1, 2 shift (rearrangement) occurs when such a shift leads to
the formation of a carbocation of greater stability and this is the driving force of the
rearrangement. A further requirement which is often necessary for this rearrangement to
occur is the presence of two or more alkyl groups (high degree of substitution) on the migration
origin. One of the simplest systems within which carbon (as a methyl group with its bonding
pair of electrons) migrates to an electrons deficient carbon atom is the neopentyl system.
Migrations to an electron deficient carbon atom are broadly known as Wagner-Meerwein
rearrangements. As an example consider the solvolysis of neopentyl iodide (H2O, Ag+). In the
absence of Ag+ ion no reaction is observed at all. Neopentyl iodide cannot display SN1 reaction
since the primary carbocation if formed would be highly unstable and SN2 reaction is also not
observed since the substrate is too hindered. In fact on solvolysis a rearranged alcohol
2-methyl-2-butanol is formed (Scheme 15.3 and 15.3a).
AgNO3 –
CH3 CH3 CH3 CH3
:
H2O Nu
+
CH3—C—CH2—I CH3—C—CH2 CH3—C—CH2OH CH3—C—CH2—I
CH3 CH3 CH3 CH3

Neopentyl iodide Neopentyl cation Neopentyl alcohol SN2 too hindered
primary cation
(too unstable to form)
SCHEME 15.3
A shorthand method to depict this Wagner-Meerwein rearrangement is in (Scheme

15.3a). However, recall from (Scheme 15.3) that the presence of a primary carbocation is highly
unsettling and this being highly unstable may not be at all on the reaction pathway.
CH3 CH3 CH3 OH CH3

AgNO3 + + H2O
CH3—C—CH2I CH3—C—CH2 CH3—C—CH2 CH3—C CH2
H2O SN1
CH3 CH3 CH3 CH3
Neopentyl iodide Neopentyl cation Tertiary carbocation 2-methyl-2-butanol
primary carbocation 97%
Wagner-Meerwein rearrangement on a neopentyl system
SCHEME 15.3a
Keeping this in mind a variant of mechanism (Scheme 15.3b) is presented to display as

if methyl group migrates as iodide departs and by doing so the migrating alkyl group allows
the formation of a stable tertiary carbocation. Infact it is suggested that the migration is
concerted with the departure of the leaving group. The migrating group infact is never free
but keeps on attached with the substrate in some way. It has been demonstrated that if the
migrating group is chiral, its configuration is retained in the rearranged product. In summary
it is suggested that the migrating group must bridge the migration origin and terminus. Much
effort has been spent in determining if such bridged ions are transition states or intermediates
and recall this information from chapter 5 on nonclassical carbocations.
+
+
CH3 CH3 CH3 HO CH3
+ + H2O
CH3—C—CH3—I CH3—C¾¾CH2 H3C—C—CH2 CH3—C CH2
CH3 CH3 CH3 CH3

Neopentyl iodide Cyclic transition state Migration of methyl to 2-methyl-2-butanol
migration of methyl carbon affords a stable
to avoid the formation tertiary carbocation
of highly unstable
primary carbocation
More realistic representation of a 1, 2-shift during Wagner-Meerwein rearrangement
SCHEME 15.3b
2. Relief of strain via ring expansion provides a driving force for Wagner-Meerwein
shift-shift of a carbon-carbon bond
α-Pinene with a strained four membered ring on reaction with hydrogen chloride gives a strained
carbocation (I, Scheme 15.3c) in which the ring expands to give a less strained five-membered
Four-membered ring
Cl
HCl
Isobornyl chloride
a-pinene four-membered Five-membered ring
ring in bold face
+
H
+ Cl
–
C—C bond + Cl
migration
a-Pinene (I) Isobornyl chloride
Or
+ –
H Cl
+ Cl
+
a-pinene Isobornyl chloride
four-membered ring
shown in bold face
SCHEME 15.3c
analogue. In this case despite the fact that the rearrangement transforms the initially formed
stable tertiary carbocation to a less stable secondary carbocation, relief of ring strain makes
the rearrangement favourable.
3. The migrating group to be anti-periplanar to the leaving group—a general
stereochemical requirement in rearrangements
Consider the conversion of camphene into isobornyl chloride (Scheme 15.3d). Camphene on
protonation gives a tertiary carbocation followed by its capture by the chloride ion. The initial
product (I, Scheme 15.3e) loses chloride assisted by nicely poised C—C bond which acts as a
neighbouring group to lend anchimeric assistance via backside attack to give (II) which is
then captured by chloride to give isobornyl chloride.
H3C CH3
CH3
HCl
Cl
CH3
H3C
CH2
Camphene Isobornyl chloride
SCHEME 15.3d
CH3 H
+ CH3 CH3
CH3 Cl
CH3 + –
Cl CH3
CH2 CH3 CH3
Camphene A tertiary carbocation (I)
Camphene hydrochloride
H 3C CH3 H 3C CH3
CH3
–
Cl
Cl +
+ H C CH3
H 3C 3
CH3
Isobornyl chloride (II)
SCHEME 15.3e
This is the case of rearrangement since the participating C—C bond ends up bonded to
a different atom.
PROBLEM 15.1
Predict the product of the reaction (Scheme 15.3f) and give the mechanism.
+
H
or
OH
Camphenilol (I) (II)
SCHEME 15.3f
ANSWER. Santene will be formed. Recall that in (III, Scheme 15.3d) the loss
+ +
H Loss of H
H +
OH OH2 Secondary Violation of
+
(III) carbocation Bredt’s rule
Methyl migration
+ +
Loss of H
H
Tertiary carbocation Santene

SCHEME 15.3g
of water cannot be assisted by the C—C bond as in (Scheme 15.3e) since now it is
not in a anti position. Thus unassisted loss of water gives a carbocation on which
a methyl migration gives the product after proton loss.
PROBLEM 15.2
Why the trans decalin system in (I, Scheme 15.3h) undergoes ring contraction on
treatment with acid?
H H
+
H
HO
H H
(I)
SCHEME 15.3h
ANSWER. This is a result of Wagner-Meerwein rearrangement. The equatorial

OH group is antiperiplanar to a C—C ring residue and the loss of H2O from (II) is
assisted by this C—C bond to give a ring contracted carbocation from which loss
of proton gives the product. Recall that this is a molecular rearrangement since
the participating C—C bond has ended up bonded to a different carbon atom. In
(I, Scheme 15.3i) there is no anti-hydrogen available to the hydroxyl group so as to
exclude the possibility of simple dehydration.
H+ +
HO H2O
+
(I) (II) H +
–H
Antiperiplanarity of OH group with ring
C—C bond is shown in bold face
SCHEME 15.3i
4. Aryl groups are prone to migrate and have a far greater migratory aptitude than
alkyl groups or hydrogen
Compared to neopentyl system, in neopentyl iodide (see, Scheme 15.3), the halide
(I, Scheme 15.4) undergoes solvolysis with rearrangement several thousand times faster. The
aryl group provides anchimeric assistance to the loss of halogen and involves the formation of
a phenonium ion.
+
+ +
C CH2 C C C C C C
H 3C H H H
H 3C H 3C H 3C
CH3 Cl
CH3 H CH3 H CH3 H
(I)
H 3C H 3C +
+
C C
H 3C H 3C C C
H 3C H
(Rearranged)
H 3C H
SCHEME 15.4
(B) Pinacol and Semipinacol Rearrangement

Pinacols (1, 2-diols) on treatment with acids display a rearrangement to ketones (pinacolones).
The rearrangement is similar to Wagner-Meerwein shift, but for the fact that here the
rearranged intermediate carbocation, the conjugate acid of the ketone is more stabilized than
the rearranged carbocation formed in the Wagner-Meerwein shift (Scheme 15.5). Thus in pinacol
rearrangement a shift still takes place eventhough the migration terminus may be a tertiary
carbocation.
Ph migrates in preference to Me
Ph Ph Ph Ph Ph Ph
+ –H2O
H
Ph—C—C—Me Ph—C—C—Me Ph—C—C—Me
Step Step + Step
1 2 3
HO OH H2O OH OH
+
Ph Ph Ph
+ +
–H
Ph—C—C—Me Ph—C—C—Me Ph—C—C—Me
Step
4
Ph OH Ph OH Ph O
+
Protonated ketone
Pinacol rearrangement
SCHEME 15.5
A further observation is that with unsymmetrical glycols the product formation depends
mainly by which OH is lost to leave behind the more stable of the two carbocations, and
thereafter by which is the better migrating groups (order of migratory aptitude, is Ar > H > R).
Thus pinacol (Scheme 15.6) reacts as shown i.e., initial formation of a more stable carbocation
(benzylic) and then migration of hydrogen rather than methyl. Another example is the
rearrangement (Scheme 15.7).
Formation of the more stable

benzylic carbocation
1 2 + + +
H –H
PhCH—CHCH3 PhCH—CHCH3 PhCH2—CCH3 PhCH2COCH3
–H2O +
OH OH OH OH
Migration of H rather than CH3
Order of migratory aptitudes is Ar >> H > R
SCHEME 15.6
HO O
HO OH OH + CH3 CH3
+ + +
H –H
C—CH3 C—CH3 Ph Ph
–H2O
Ph Ph
SCHEME 15.7
Deamination of α-amino alcohols is closely related with pinacol rearrangement and is

called semipinacol rearrangement. These rearrangements are typical where a hydroxyl group
provides the electrons to migrate a group and the driving force is provided by the loss of the
leaving group other than water (Scheme 15.8).
H
+
OH NH2 OH N2 O O
HNO2 –N2 + +
–H
(C6H5)2C¾¾CHCH3 (C6H5)2C¾¾CHCH3 C6H5C¾¾CHCH3 C6H5C¾¾CHCH3
C6H5 C6H5
Semipinacol rearrangement
SCHEME 15.8
The rearrangement has been used to bring about both ring contraction as well as ring
expansion (Scheme 15.9).
H
NH2 O OH O O
HNO2 – +
C NH2 HNO2 N2 –H
–N2 –N2
OH H
2-Aminocyclo- Cyclopentane-
hexanol carboxaldehyde
SCHEME 15.9
PROBLEM 15.3
Write the product with mechanism on reaction with HNO2 from each of the four
diastereomers with mechanism (Scheme 15.10).
OH OH
OH OH
NH2
NH2
NH2 NH2
(I) (II) (III) (IV)
SCHEME 15.10
ANSWER. In each case t-butyl group locks the ring in the conformation shown.
The stereochemical requirement requires an antiperiplanar arrangement between
the migrating and leaving group (–N2+). In each of the reactions the OH group
provides the electronic push (Scheme 15.11).
:OH
H
O Oxygen of the OH group
displaces N2 to give
+ an epoxide
N2
(I) Epoxide
H H
OH C—O +
+ + CHO Equatorial –N2 antiperi-
N2
H planar with C—C bond
H H of the ring
Aldehyde
(II)
OH
+
Again equatorial –N2 anti-
H periplanar with the
+ C—C bond of the ring
N2
(III)
H
+ H O +
OH O H and –N2 are antiperi-
H H planar, shift of hydride
gives a cyclohexanone
+
N2 H
(IV)
SCHEME 15.11
(C) Benzil-Benzilic Acid Rearrangement

1, 2-Diketones (α-diketones) on treatment with hydroxide ion undergo a rearrangement to
give α-hydroxy acids e.g., benzil gives benzilic acid (Scheme 15.11a). The arrangement has its
driving force in the removal of the product by ionization of the carboxyl group.
One may note here, that the migrating phenyl (with its bonding pair of electrons) is not
migrating to a carbon with open sextet, but to a carbon from which the π electrons shift from
the carbonyl bond to the oxygen (I, Scheme 15.11a).
C 6H 5 C 6 H5 C6H5 C6H5
–
OH Proton –
C—C—C6H5 HO—C C—C6H5 HO—C C—C6H5 O—C —C—C6H5
shift
O O O
– O O O– O OH
Benzil (I)
Benzilic acid rearrangement
SCHEME 15.11a
(D) Rearrangements Involving Diazomethane

Wolff rearrangement is the loss of nitrogen from a α-diazoketone by the action of silver oxide
or irradiation with light to yield an intermediate carbene. The Arndt-Eistert synthesis is a
method to convert a carboxylic acid to its next higher homolog by the operation of Wolff
rearrangement. The carboxylic acid is converted into its acyl halide which on reaction with
diazomethane gives a diazoketone (I, Scheme 15.12).
Acid chloride
–
O O O H O
+ –HCl +
R—C—Cl R—C—Cl R—C—C—N2 R—C—CH—N2
–
:
– Diazoketone
+ H—C—H H
:
CH2—N N – (I)
Diazomethane N+2 Cl
Formation of a diazoketone
The Wolff rearrangement

O O
– +
+ Ag H2O
:
R—C—CH—N2 R—C—CH R—CH C O RCH2COOH

–N2
(I)
A diazoketone A keto carbene Ketene
Arndt–Eistert synthesis
SCHEME 15.12
When diazomethane adds to an aldehyde or a ketone a product of CH2 insertion is

obtained. Thus cyclohexanone is converted into cycloheptanone (Scheme 15.12a). The
intermediate is similar to the one involved in semipinacol rearrangement (See, Scheme 15.8).
Cyclohexanone
–
O N
O +
N O
– + CH2
CH2—N N
Cycloheptanone
Diazomethane
SCHEME 15.12a
A disadvantage of this reaction is that an epoxide is formed as a by-product and in some

cases it may be the only product (Scheme 15.12b).
–
O O O O
CH2N2 +
R—C—R¢ R—C—CH2—N2 R—C—CH2 + RCH2—C—R¢
R¢ R¢
Epoxide
Formation of an epoxide during reaction of a ketone with diazomethane
SCHEME 15.12b
The mechanism (Scheme 15.12) involves the formation of a carbene (electron deficient
carbon) to which the migrating group brings its electron pair to afford a ketene and finally a
carboxylic acid.
(E) Rearrangement of Alkanes

Saturated hydrocarbons display skeletal rearrangements when treated with a Lewis acid in
the presence of a catalytic quantity of an organic halide (Scheme 15.13). The rearrangement is
of Wagner-Meerwein type and involves the intermediate formation of a carbocation whose
formation is initiated by the organic halide. The carbocation then initiates the rearrangements
by abstracting hydride ion from the alkane (Scheme 15.13).
Significantly in the rearrangement of alkanes the product is derived from the less stable
carbocation. Unlike Wagner-Meerwein rearrangement which is kinetically controlled
(immediate reaction of the rearranged carbocation with nucleophile), the alkane
rearrangements are under thermodynamic control. Practically no nucleophile is present (the
concentration of AlCl4– is negligible), the reactions are thus reversible. As a consequence the
relative proportions of the alkanes formed are under thermodynamic control.
An interesting applications of this method is the conversion of all tricyclic alkanes to
adamantanes. The success of this reaction (Scheme 15.13) is due to high thermodynamic
stability of adamantane. Dimeric cyclopentadiene (which is readily available e.g., via Diels-
Alder reaction on cyclopentadiene) gives adamantane on reaction with AlCl3 around 180°C.
+ –
R—Cl + AlCl3 R + AlCl4
CH3 CH3 CH3

–RH + RH
CH3—CH—CH2—CH3 CH3—CH—CH2 CH3—CH—CH2 CH3—CH—CH3
+
H
R+
H2 . PtO2 AlCl3
180°C
Cyclopentadiene Adamantane
dimer
Rearrangement of alkanes are thermodynamically controlled
SCHEME 15.13
15.2 REARRANGEMENTS TO ELECTRON DEFICIENT NITROGEN

(A) Hofmann Rearrangement
Amides which do not have a substituent on the nitrogen display a molecular rearrangement
(Hofmann rearrangement) on treatment with alkaline aqueous solutions of bromine or chlorine
to give primary amines (Scheme 15.14). In this rearrangement, the carbonyl carbon atom of
the amide is lost and the R group of amide gets attached to the nitrogen of the amine
(Scheme 15.15). The mechanism involves the following steps:
O
H2O
R—C—NH2 + Br2 + 4 NaOH RNH2 + 2 NaBr + Na2CO3 + 2 H2O
An amide
A 1° amine
Hofmann rearrangement
SCHEME 15.14
1. It is a base promoted bromination of an amide, just like the base promoted

halogenation of a ketone.
2. The base abstracts a proton from the nitrogen to give an unstable bromamide anion.
The anion spontaneously rearranges by the migration of R to the electron deficient
nitrogen to give an isocyanate.
3. Lastly the isocyanate undergoes hydrolysis to give an amine.
: : : : : :
O O O
–:
: :
C OH C C
– Br—Br –
:
N:
:
R N—H R R N—Br + Br Step 1 Bromination of N
H H H
Amide + H2O
N-bromamide
: : : :
O O
C C – +
:
: :
:
R
::
R N—Br N—Br – R—N C O Step 2 Extraction of H by

–:
: :
OH (–Br ) –
OH and rearrange-
H Bromamide Isocyanate ment of the anion
N-Bromamide anion (unstable)
+ H2O
O
– –
OH – OH 2–
RN C O RNHC—O RNH2 + CO3
H2O H2O
Amine
Mechanism of Hofmann rearrangement
SCHEME 15.15
An interesting stereochemical observation is, that if the migrating group (R) is chiral
its configuration is retained in the product amine (I, Scheme 15.16). Thus this arrangement is
intramolecular, the migrating group does not become free, but remains attached with the
substrate in some way e.g., via a bridged transition state. Thus if one starts from
(R)-2-methylbutanamide, the end product is (R) sec-butyl amine (Scheme 15.16). The
intramolecular nature of the rearrangement was shown by carrying out the reaction with a
mixture of 3-deuteriobenzamide and 15N-benzamide. Mixed anilines were not formed to indicate
that the migrating group does not separate during the rearrangement (Scheme 15.16a).
Hofmann degradation
O NaOH proceeds with retention
+ Br2 (I) of configuration of the
H2O NH2
C migrating group.
NH2
H H
CH3 CH3 CH3 O CH3

O O
C
CH3CH2 C C CH3CH2 C C CH3CH2 C CH3CH2 C NH2
– N
: :
NH2 N Br
:
H H H H
(R)-2-methylbutanamide Br Bridged (R)-sec-butylamine
transition state
The derived bromo amide anion
SCHEME 15.16
C6H4DCONH2 + C6H5CO NH2 C6H4DNH2 + C6H5 NH2 C6H4D NH2 or C6H5NH2

Not formed
SCHEME 15.16a
(B) Curtius, Schmidt and Lossen Rearrangements

These rearrangements and also Hofmann rearrangement are closely similar in that a carbon
migrates from carbon to nitrogen to give an isocyanate. In these 1, 2-shifts the migrating
group (carbon) is an alkyl or aryl group and the leaving group may be Br (Hofmann
RCOCl + NaN3 RCON3 + NaCl

Acid azide
Sodium azide (acyl azide)
–
O O O
+ – – + +
:
: :
N: N: N:
:
R—C—N N R—C—N—N R—C N—N

:
Formation of an acyl azide
: : : :
O O
NaN3 Heat H2O
:
C C R—N C O R—NH2 + CO2

::
–
(–NaCl) + –N2
: :
Cl : N:
: :
R R N—N
Isocyanate Amine
Acyl chloride Acyl azide
The mechanism of Curtius rearrangement
SCHEME 15.17
rearrangement); N2 (Curtius and Schmidt rearrangements) or RCOO– (Lossen rearrangement).

The Curtius rearrangement involves the pyrolysis of acyl azides (acid azides) to give isocyanates.
Acid azides are prepared from acid chlorides on treatment with sodium azide, and best repre-
sented as a resonance hybrid (Scheme 15.17).
Schmidt reaction involves the treatment of a carboxylic acid with hydrazoic acid
(HN3, hydrogen azide) which yields amines via the isocyanate when catalysed by an acid e.g.,
sulphuric acid (Scheme 15.18). The protonated azide undergoes the rearrangement.
H
+ –
H + HN3 + +
N:
:
R—C—OH R—C R—C R—C—N N
–H2O
O O: O+ O
:
:
Acylium ion
Protonated azide
Formation of protonated azide
H H
+ + – –N2 +
: :
R—C—N N N C N—R Hydrolysis

RNH2 + CO2
O O
Schmidt reaction
SCHEME 15.18
There are many variations of Schmidt reaction and can be applied to ketones to give
amides which is a general procedure (Scheme 15.18a).
+
O OH OH
+
H HN3 + –H2O +
:
:
R—C—R R—C—R R—C—N—N N R—C N—N N
Ketone
R H R
–N2
+
–H H2O +
:
:
:
R—C—NH—R R—C N—R R—C N—R

Tautomerization
O OH2
Amide +
Conversion of ketones to amides via Schmidt reaction

SCHEME 15.18a
The Lossen rearrangement occurs when O-acyl derivatives of hydroxamic acid are heated
with bases (Scheme 15.19). The hydroxamic acids display tautomerism, the keto form is termed
hydroxamic form while the enol form is called hydroximic acid. Hydroxamic acid is prepared
by the action of hydroxylamine on acid chloride (Scheme 15.19).
Thus in summary all the three reactions give an amine as the end product with one less
carbon. Curtius reaction starts with a carboxylic acid through an acyl azide, Schmidt reaction
starts with a carboxylic acid through an azide and Lossen reaction is the dehydration of a
hydroxamic acid.
O OH
R—C—NHOH R—C NOH

The hydroxamic form The hydroximic form
Hydroxamic acids exhibit tautomerism
RCOCl + NH2OH R—C—NHOH + HCl

Hydroxylamine
O
O – H2O
H
: :
R N—O—C—R R—N C O RNH2
Base
R N—O—C—R C
:
C O
O Lossen rearrangement
SCHEME 15.19
(C) The Beckmann Rearrangement

On treatment with acids, oximes rearrange to substituted amides and this reaction is termed
as Beckmann rearrangement (Scheme 15.20). The rearrangement is stereospecific and the
group that normally migrates is the one that is anti placed with respect to the hydroxyl. The
method is often used to determine the configuration of the oxime. Acetophenone oxime gives
only acetanilide (Scheme 15.21). The intermediate formation of nitrilium iron (Scheme 15.20)
has been confirmed by spectral methods. The rearrangement is intramolecular, since if the
migrating group is chiral it retains its configuration in the product.
:
OH2
R R
H+ –H2O H2O
C N C N R¢—C N—R R¢—C N—R R¢—C—NH—R
+ –H +
:
+
R¢ OH R¢ OH2 Nitrilium ion OH O
The Beckmann rearrangement
SCHEME 15.20
The function of the acidic reagents is to convert the hydroxyl group to a better leaving
group. Thus e.g., with H2SO4, this group is converted into OH+2 and with PCl5, it is the phosphate
which is the leaving group (Scheme 15.21).
anti to OH group
1 2
Ph CH3 R R
Beckmann
C rearrangement C
PhNHCOCH3
N Acetanilide N
OH OPCl4
Acetophenone oxime
SCHEME 15.21
The oximes of the cyclic ketones give ring enlargement (Scheme 15.22). Caprolactam
gives a polymer of the nylon group when heated.
OH O
H2SO4 Heat H
N NH N
Cyclohexanone oxime e-Caprolactam O n

(a cyclic amide) Nylon
SCHEME 15.22
15.3 REARRANGEMENTS TO ELECTRON DEFICIENT OXYGEN

(A) Baeyer-Villiger Rearrangement
Baeyer-Villiger oxidation has been discussed (see, Schemes 13.51–13.53) and involves the
insertion of oxygen atom next to the carbonyl group. The migratory aptitudes have been
discussed and it is seen that methyl group has the least tendency to undergo migration and
consequently methyl ketones end up with acetates and retention of stereochemistry if the
migrating group is chiral is the rule (Scheme 15.22a).
H
O O CH3
O C6H5 O CH3
C6H5 C6H5COOOH C6H5 O C6H5
CH3
O O
H CH3 H CH3 H CH3
Chiral migrating group Complete retention
Baeyer-Villiger oxidation of configuration
SCHEME 15.22a
Often unsaturated ketones are not good candidates for Baeyer-Villiger oxidation since
an alkene will get epoxidized. However, if a double bond is not so electron rich as a disubstituted
double bond in (Scheme 15.22b) it will remain unattacked.
This secondary group migrates in preference

to the other which is primary, thus oxygen
gets inserted on this side
BnOCH2 H BnOCH2 H
m-CPBA
O O
O
Bn = C6H5CH2—
SCHEME 15.22b
Recall that during hydroboration as well during the oxidation of an organoborane with
alkaline H2O2 gives alcohols by the migration of carbon from boron to oxygen. The migrating
group retains its configuration (Scheme 15.22c). The stereochemistry of the product is dictated
during the hydroboration step itself and is retained in the product.
H2
–
BH2 B OH O OH
H H H BH2 H
– O
BH3 H 2O
Boron adds to less Retention of configuration

substituted carbon in the chiral migrating group
SCHEME 15.22c
Identical product can be made using a Baeyer-Villiger oxidation by starting with a

substrate with appropriate stereochemistry and keeping in mind that this configuration will
be retained during migration step (Scheme 15.22d).
O
:
O HO
CH3 O O OH
H H H H
O
Peracid O Hydrolysis
Retention of configuration
in the migrating group
SCHEME 15.22d
(B) Dakin Reaction

(See Scheme 13.54)
15.4 REARRANGEMENT TO ELECTRON RICH CARBON

(A) Favorskii Rearrangement
The reaction of α-halo ketones (containing an α-hydrogen on the non halogenated side of the
carbonyl) with alkoxide ions give rearranged esters, a process termed Favorskii rearrangement
(use of hydroxide ions gives the free acid).
The mechanism of Favorskii rearrangement involves a cyclopropanone derivative
(II,Scheme 15.23) which is formed by the “internal SN2” displacement of the halide ion by an
initially formed α-carbanion (I). Base then adds to the cyclopropanone carbonyl and the ring
opening takes place in a way (IV, Scheme 15.23) so as to gives more stable of the carbanions.
Thus in the absence of resonance stabilization, the less substituted alkyl anion is formed
(Scheme 15.24).
a-hydrogen
H
– – –
OCH3 –Cl
:
—C—C—C—Cl —C—C—C—Cl— C C C C
O O C – C
OCH3 –
(I) O OCH3
O
(II) (III)
a-haloketone Cyclopropanone
intermediate
C C C C O
– HOCH3
:
C or C —C—C—C—OCH3 CH—C—COOR
– –
O OCH3 O OCH3
(IV)
More stable of the two possible
carbanions is formed
Mechanism of Favorskii rearrangement
SCHEME 15.23
O OCH3
Br O O CH3
C
– –
OCH3 CH3OH
:
CH3—CH—CCH3 H3CCH—CH2 CH3—CH—COOCH3

H3C More stable
carbanion
SCHEME 15.24
Favorskii reaction involves the formation of cyclopropanones as the intermediates. The

formation of such intermediates has been clearly established e.g., 2, 3-di-tert-butylcyclo-
propanone (Scheme 15.24a) which is somewhat unreactive towards base has been isolated
from the reaction of the corresponding α-chloroketone with potassium hydroxide
(Scheme 15.24a).
O O
KOH
(CH3)3CCH2CCH
Cl (CH3)3C C(CH3)3
SCHEME 15.24a
Alkyl groups destabilize carbanions while aryl groups stabilize them (delocalization of
the negative charge). Both the isomers (I and II, Scheme 15.25) give the same product and this
requires the formation of the same common cyclopropanone intermediate from both the
reactants which opens only in one direction to give the more stable resonance stabilized benzylic
carbanion (Scheme 15.25).
O Cl
– –
Cl OCH3 OCH3 OCH3
O O
(I) (II)
Same product
H Cl H
– –
Cl OCH3 O OCH3
O O
Both isomers give the

same cyclopropanone
–
OCH3
H
–
:
C6H5—C CH2 C6H5C—CH2
–
:
Product C6H5—CHCH2COOCH3 C COOCH3

More stable –
O OCH3 Less stable
benzylic carbanion carbanion
SCHEME 15.25
One can thus bring about a ring contraction by working with cyclic systems (I, Scheme
15.26). Moreover, by working with 2-chlorocyclohexanone in which C-1 and C-2 were equally
labelled with 14C the product contained 50% of the label on the carbonyl carbon and 25% each
on C-1 and C-2 (II, Scheme 15.26). These results are further in keeping with the formation of
symmetrical cyclopropanone derivative.
O
–
OH
COOH (I)
Br
3 2
2 Cl –
4 OCH3
1
COOCH3 (II)
5
1 O
6 –
– O
:
O – O O –
OCH3 OCH3
OCH3
Cl Cl
–
:
CH3OH
CO2CH3 COOCH3
SCHEME 15.26
(B) Wittig Rearrangement

Alkyl benzyl and related ethers rearrange when reacted with a strong base to give alcohols via
a rearrangement called Wittig rearrangement (Scheme 15.27). A radical pair mechanism is
suggested after the base removes the proton from the ether. As part of the evidence for this
mechanism (Scheme 15.27) it is seen that migratory aptitudes in this 1, 2-shift follow the
order of free radical stabilities and not the carbanion stabilities.
+
Li CH3 CH3
CH3 – CH3 +
PhLi H
: +
:
C6H5 O –PhH C6H5 O C 6H 5 O : Li C6H5 OH
–
:
.
R¢ R¢
– .
R¢ – R¢ .
:
.
:
R O – –
R O R O R O
Solvent cage
Wittig rearrangement
SCHEME 15.27
(C) The Neber Rearrangement

Ketoxime tosylates on reaction with base rearrange to give α-amino ketones in a reaction
called Neber rearrangement. The mechanism of the rearrangement (Scheme 15.28) involves
the intermediate formation of an azirine.
Base H2O
RCH2—C—R¢ RCH—C—R¢ R—CH—C—R¢ R—CH—C—R¢
–
:
N—OTs N—OTs N NH2 O

Ketoxime tosylate Azirene intermediate a-Amino ketone
The Neber rearrangement
SCHEME 15.28
(D) Stevens Rearrangement

Quaternary ammonium salts which have β-hydrogen atoms undergo E2 (Hoffmann) elimination
on reaction with base (Scheme 15.29). However, if in a quaternary ammonium salt none of the
alkyl groups have a β-hydrogen, but one has an electron withdrawing group in this position
e.g., a β-carbonyl group then an ylide is formed by the loss of an α-hydrogen with a base. The
ylide rearranges to a tertiary amine and is termed Stevens rearrangement (Scheme 15.30).
The role of the electron withdrawing carbonyl group in this example, is to assist the formation
of the ylide by stabilizing the charge. This charge is neutralized by a 1, 2-shift.
– +
HO H—CR2—CR2—NR3 H2O + CR2 CR2 + R3N
b a
Removal of a b-hydrogen
E2 (Hoffmann) elimination with base

SCHEME 15.29
– –
C6H5 OH C6H5 C6H5
:
+ + +
C 6H 5 N C 6H 5 N C6H5 N
CH3 CH3 O CH3 CH3 O CH3 CH3 O –
A quaternary ammonium salt An ylide
C 6H 5
– CH3
C6H5 C6H5
:
+
C6H5 N N
CH3 CH3 O CH3
O
The Stevens rearrangement
SCHEME 15.30
(E) The Sommelet-Hauser Rearrangement

This rearrangement is typical of benzyl quaternary ammonium salts which on reaction with
alkali metal amides give benzyl tertiary amines (o-methylbenzylamines, Scheme 15.31). Thus
compared to the substrates in the Stevens rearrangement, in Sommelet Hauser rearrangement,
a strongly electron withdrawing group (e.g., a β-carbonyl) is absent. The α-hydrogen is too
weakly acidic for the rearrangement to be induced by hydroxide ion. Stronger base, is thus
required and the rearrangement then follows a different path instead of a 1, 2-shift. The
Sommelet rearrangement is in fact a [2, 3]-sigmatropic rearrangement.
–
CH2
+ – +
:
CH2—N(CH3)3 CH—N(CH3)3 CH2—N(CH3)2

NaNH2 +
liq. NH3
(II)
(A) (I) [2, 3]-sigmatropic shift
CH2N(CH3)2 H CH2N(CH3)2
CH3 CH2
NaNH2
NH3
Sommelet-Hauser rearrangement
SCHEME 15.31
The mechanism involves the loss of a proton from the benzylic position to give the ylide
(I, Scheme 15.31) which is in equilibrium with the second ylide (II). The ylide (II, Scheme
15.31) then undergoes a [2, 3]-sigmatropic rearrangement followed by aromatization to give
the product.
The evidence that indeed it is a [2, 3] migration on the ylide (II, Scheme 15.31) rather
than a [1, 4] shift on the benzylic ylide (I) was provided by working with a substrate
(A, Scheme 15.31) in which benzylic carbon was labelled (14C). As expected of [2, 3] sigmatropic
shift on (II, Scheme 15.31), the label was found on the methyl group of the aromatic ring. In
case this rearrangement instead involved a [1, 4]-shift on the benzylic ylide (I, Scheme 15.31)
the label will not be on the methyl group of the aromatic ring (Scheme 15.32).
+
H3C—N(CH3)2
CH3
–
CH CH2N(CH3)2
(I, Scheme 15.31)
SCHEME 15.32
PROBLEM 15.4
When dibenzyldimethylammonium salt (Scheme 15.32a) CH3
is reacted with a strong base PhLi, both Steven’s and +
Sommelet-Hauser rearrangements were observed. Write C6H5CH2—N—CH2C6H5
the products from each rearrangement. CH3
SCHEME 15.32a
ANSWER. These are in Scheme 15.33.
Ph Ph CH3
–
CH CH—N
CH3 Sommelet-Hauser
+ CH3
N Rearrangement
CH2 CH3 CH3
CH3
+ PhLi
PhCH2—N—CH2Ph
Ph
CH3 – Ph
CH CH3
CH3 Steven’s
+ CH—N
N Rearrangement
CH2 CH3 CH2 CH3
SCHEME 15.33
15.5 AROMATIC REARRANGEMENTS

The rearrangement of alkyl benzenes to their isomers is observed after Ipso attack. The alkyl
migration in these cases are typical of carbocation intermediates. The following aromatic
rearrangements have already been discussed.
A. Fries Rearrangement (see Chapter 8).
B. Photo-Fries Rearrangement (see Chapter 10).
C. Reimer-Tiemann Reaction (see Chapter 8).
D. Benzidine Rearrangement.
In this remarkable rearrangement (Scheme 15.34) an intramolecular migration from
nitrogen to carbon takes place, and hydrazobenzenes give benzidines on treatment with acid.
The 4, 4′-compound is formed by a [5, 5]-sigmatropic rearrangement.
+
H
—NHNH— H2N— —— —NH2
D
Hydrazobenzene 4, 4¢-diaminobiphenyl
benzidine
+
–2 H
+ + 2+ +
H 2N NH2 H 2N NH2 H2N +NH
2
H H H H H H
Transition state
Benzidine rearrangement
SCHEME 15.34
15.6 FREE RADICAL REARRANGEMENTS (See Sec. 16.9)
PROBLEMS
15.1 How the following compound will undergo a pinacol-pinacolone rearrangement?
CH3
CH3
OH OH
(I)
15.2 A ketone reacts with diazomethane to give either the next higher homologue or an
oxirane. Give mechanisms.
15.3 Give the mechanism of the reaction of a ketene with diazomethane to give cyclopropanone.
15.4 Write the structure of the reaction product from succinimide with bromine and aqueous
potassium hydroxide.
15.5 Preparation of β-amino pyridine via electrophilic nitration of pyridine which occurs
chiefly at the β-(or 3-position) gives poor yields. Pyridine resembles a highly deactivated
benzene derivative. How one can plan the synthesis of β-aminopyridine from naturally
occuring nicotinamide.
15.6 Write the products from the reaction of a peracid with cyclohexanone, reaction of
diazomethane with cyclohexanone and reaction of cyclohexanone with HN3/H2SO4.

15.1 The OH group attached to the cyclobutyl group cannot be lost to give a cyclobutyl
carbocation since this would involve an increase in ring strain in going from 90° to 120°.
The formation of the carbocation at the other carbon is followed by the migration of the
ring residue (equivalent to alkyl group).
CH3
CH3 –H
+ CH3
CH3
CH3 CH3
OH OH2 +
+ OH O
15.2 Diazomethane is a resonance hybrid and acts first as a carbon nucleophile.
+ – – +
(CH2 N N CH2—N N)
Diazomethane
A carbon nucleophile carrying
a good leaving group
– O
O O
– + +
:CH2N2 CH2—N2
or Epoxidation
–
O
+
O
CH2—N2
Ring expansion
– O
O +
CH2N2 N N:
15.3 CH2 C O + N2
CH2
Ketene Cyclopropanone
15.4 The product formed will be β-alanine via the half-amide of succinic acid involving
Hoffmann rearrangement.
O O
–
NH2
OH KOH + Br2
NH NH2
CO2– CO2–
O
Succinimide Half-amide of succinic acid b-alanine
15.5 This can be done via Hoffmann rearrangement.

O
NH2
NH2 Br2
–
OH
N N
Nicotinamide b-aminopyridine
15.6 The first two reactions are insertion reactions of oxygen and CH2 group, the nucleophilic
group in a peracid and diazomethane carry a good leaving group. The last reaction is
Schmidt reaction, which with ketones gives amides.
Nucleophilic group
O
O
C—C6H5
: :
HO—O O
O Peracid O O H
N
HN3
O H2SO4
CH2
Diazomethane
– +
CH2—N N
Nucleophilic group
CHAPTER 16 .
Free Radical Reactions

Free radical is any atom or group that possesses one or more unpaired electrons. Elements
such as halogen atoms (Cl•) and alkali metals (Na•) are free radicals, since they have odd
numbers of electrons. Molecular oxygen (O2) exists as a diradical molecule which is its triplet
state (two unpaired electrons, Scheme 16.1) instead of having all of its nonbonded electrons
paired. A species with paired electrons is termed singlet oxygen. Singlet oxygen can be obtained
by the photochemical excitation of O2, generally in the presence of a photosensitizer. It is
singlet oxygen which reacts with unsaturated species by pericyclic mechanisms. One or two
electron reduction of molecular oxygen gives superoxide and peroxide ions which are harmful
to several living organisms and several enzymes eliminate these from a living system.
hn
: O—O: :O O:
: .
: .
photosensitizer
:
:
Molecular oxygen Singlet oxygen
triplet state (a diradical)
e– – e– 2–
: O—O: : O—O:
: :
: .
: .
: .
O2
Superoxide ion Peroxide ion
(a radical anion)
SCHEME 16.1
16.1 STRUCTURE, STABILITY AND GEOMETRY

(i) Structure (see Schemes 4.38 and 4.39)
(ii) Stability and Geometry (see Schemes 4.40–4.42)
Some obvious trends have already been discussed to show that weakest bonds have most
stable radicals. A C—H bond decreases in strength in R—H when R goes from primary to secondary
and then to tertiary. Thus tertiary alkyl radicals are the most stable while methyl radicals are the
least stable (see Table 1.2). Similarly since the benzylic C—H bond and allylic C—H bond are
particularly weak (DH° = 87 kcal/mol), therefore allyl and benzyl radicals are more stable. These
are discussed under section 4.16c. Bond dissociation energies reflect on the stability of free
radicals (see Schemes 1.25, 2.19 and 4.40).
16.2 PREPARATION
Initiation of Radicals
Weak bonds in molecules undergo homolytic cleavage to form free radicals. The
bond homolysis of even weak bonds is endothermic and therefore, energy in the
form of heat (∆) or light (hν) is normally needed to generate free radicals for
initiation step of a free radical chain reaction.
569
(i) Triphenylmethyl Radical—A Stable Radical in Solution

Gomberg (1900) prepared triphenylmethyl radical (Scheme 16.2) by treating triphenylmethyl
chloride with silver metal when a yellow solution developed. The solution was rapidly
decolourized by oxygen and iodine, reagents known to react with carbon free radicals. The
dimeric structure displayed UV (λmax = 313 nm) and 1HNMR spectra (determined in 1970) are
characteristic of a cyclohexadiene structure (Scheme 16.2). The 1HNMR spectrum showed a
typical 1H, singlet at δ 5.0 ppm due to the proton on the cyclohexadiene ring. The other expected
signals are at δ 7.4 ppm (m, 25 protons on the five Ph groups), and a double doublet 5.8 – 6.4
for the four olefinic protons of the cyclohexadiene moiety.
d 5.0 ppm (s, 1H)

H
Ag .
2Ph3CCl 2Ph3C Ph2C
CPh3
Triphenylmethyl Dimer Colourless
radical (yellow)
SCHEME 16.2
The triphenylmethyl radical exists in solution and is stable enough to account for about
2% of the equilibrium mixture. Its stability is due to steric reasons. In fact the phenyl groups
in triphenylmethyl radical are not coplanar but have a propeller shape with phenyl groups
twisted out of the plane by about 30° (Scheme 16.3). The delocalization of the unpaired electron
is thus far less than ideal. The central carbon accommodates most of the radical character, the
steric shielding by the twisted phenyl groups inhibits its reactions. The dimerization is obviously
via its least hindered carbon atoms (Scheme 16.3). Radicals like triphenylmethyl which can
maintain their concentration almost indefinitely (or atleast for a few hours) are called persistent
radicals.
. H
Ph2C
. CPh3
.
Dimer
Triphenylmethyl
radical
SCHEME 16.3
(ii) Other Stable and Persistent Radicals

A good example of another persistent radical is of a nitroxide TEMPO (2, 2, 6, 6-tetramethyl
piperidine N-oxide) a commercial product which can even be sublimed (Scheme 16.3a). Steric
hindrance is one factor which leads to its exceptional stability. Moreover, there is an interaction
between the lone pair orbital on nitrogen and the singly occupied orbital on oxygen which
results in the formation of π bond (Scheme 16.3a). With three electrons available, one has to
Free Radical Reactions 571
1
occupy the π* orbital. As a consequence the N—O bond order is 1 and in case of abstraction
2
or addition reaction of the oxygen atom this strength shall have to be reduced to 1 which is an
unfavourable situation.
. .
O O p*
..
N N N O
p
[I] [Ia] [I] [Ia] [I]
TEMPO
SCHEME 16.3a
(iii) By Thermal Homolysis of Weak Bonds

Homolytic cleavage of sigma bonds can be successful with any compound provided the
temperature is sufficiently high. However, this thermal method is useful with selective weak
σ bonds within a molecule which dissociate at temperatures below about 200°C. Bonds of
peroxy and azo compounds have bond dissociation energies below 40 kcal/mol (170 kJ/mol)
and are therefore, sufficiently weak to be good sources of radicals under typical reaction
conditions (Scheme 16.4). AIBN is another good radical initiator. In this case the carbon radical
which is formed is stabilized by cyano group and due to the strong nitrogen-nitrogen triple bond
of the N2 product. Here unlike the peroxy compound, the C—N bond is not so weak (see Scheme
4.42a). In the thermal decomposition of a peroxide (Scheme 16.4) the reaction involves the
fission of the oxygen-oxygen bond and the initially formed free radical then decarboxylates to
gave the fragmentation products. A fragmentation is thus a process where some initially formed
radical loses a small stable molecule.
O O
O D, 80°C O. .
2 2 + 2CO2
O
O
A peroxide
CN CN CN
D .
CH3—C—N N—C—CH3 2 .C—CH3 In + N2
CH3 CH3 CH3

AIBN
SCHEME 16.4
(iv) By Photochemically Induced Homolytic Bond Cleavage

When a compound is excited by the absorption of a photon of light an electron gets promoted to
an unoccupied orbital. Since this orbital is normally antibonding in character, a bond in the
excited molecule gets weak and subsequently cleaves in a homolytic fashion. The halogens are
readily homolyzed by light to generate radicals which can be useful in chemical reactions
(Scheme 16.5).
O O
hn .
hn . CH3—C—CH3 CH3—C. + CH3
Cl—Cl 2 Cl
SCHEME 16.5
(v) By Abstraction
.
Recall that the H—Br bond is almost as strong as a C—C bond yet Br radicals can be obtained
from H—Br in the presence of alkoxy radicals generated by the homolysis of the weak O—O
bond of a peroxide e.g., dimethylperoxide (CH3O—OCH3, Scheme 16.6). In this generation of
. .
Br from HBr the peroxy radical RO• abstracts a H• from HBr to yield a new radical Br and
gives ROH.
. .
R—O H—Br ROH + Br
SCHEME 16.6
(vi) By Addition Reactions

.
A Br radical for example adds to a double bond to generate a new carbon-centered radical
(Scheme 16.6a).
Br
. .
Br
A carbon centered
A radical preferentially radical
attacks less substituted
end of the double bond
SCHEME 16.6a
(vii) Redox Generation

Free radicals can also be formed from oxidation—reduction (redox) processes. Transfer of
electrons to or from metal atoms and ions is yet another common method to initiate radical
reactions (Scheme 16.6b).
2+ 3+ – .
Fe + H2O2 Fe + OH + HO
SCHEME 16.6b
(viii) Generation of Specific Carbon Centered Radicals within a Molecule

One of the most significant development in organic chemistry of radicals during the past
20 years is the use of tributyltin hydride as a reagent to generate specific carbon centered
radicals in a molecule. Such specific free radical species would undergo a single reaction and
will then undergo termination. The termination step leads to a single product and regeneration
of that radical to continue the chain. Tributyltin radical is one such species obtained by initiation
with AIBN (Scheme 16.6C). Tin forms strong covalent bonds to halogens but very weak bonds
to hydrogen. This feature has been exploited to initiate a radical chain reaction. Thus if the
substrate has a halogen, bromide or iodide (but not fluorine) one can generate a free radical
specifically on that position (Scheme 16.6d).
D/or . .
AIBN In 2 C N
hn
. .
In + Bu3Sn—H Bu3Sn + In H
Tributyltin
hydride
SCHEME 16.6c
.
Bu3Sn .
. Bu3Sn does not abstract hydrogen
Specific radical from the alkyl part, it only abstracts
Br the halide
SCHEME 16.6d
In another alternative method, esters of N—hydroxypyridine-2-thione are used to

generate radicals. The key to radical formation is via decarboxylation of an adduct formed
with tributyltin radical and N—hydroxypyridine-2-thione due to the tendency of tin radicals
to add to carbon-sulphur bonds (Scheme 16.6e). The net result of this sequence is the
decarboxylation and reduction of the original acyloxy group.
D/or .
AIBN hn 2 In
. .
In + Bu3Sn—H InH + Bu3Sn
Tributyltin hydride
. + CO2 + R.
.
Bu3Sn S Bu3Sn—S Bu3—Sn—S
N N N
OCR O—C—R
O O
. .
R + Bu3Sn—H RH + Bu3Sn
SCHEME 16.6e
Lastly mention may be made of alkyl radicals which can be derived from alkyl mercury
halides (Scheme 16.6f ). Alkyl mercury halides are stable compounds, but these on reduction
with NaBH4 give highly unstable alkyl mercury hydrides, which give alkyl radicals.
HgCl2
R MgX R HgX + MgBr2
Grignards An alkyl
reagent mercury halide
NaBH4 20°C .
R HgX R—Hg—H R + Hg + HX
or hn
Highly unstable an alkyl radical
SCHEME 16.6f
16.3 PROPERTIES OF FREE RADICALS

A general review of properties of free radicals is given (see, Scheme 4.42b).
(A) Abstraction
1. Introduction
Free radicals react with saturated organic compounds by abstracting an atom, normally
hydrogen, from carbon. A major factor that determines the selectivity of a free radical towards
C—H bonds of different types is bond dissociation energy. Firstly, the rate of abstraction
increases as the bond dissociation energy decreases (Scheme 16.7), and in general the order is
tertiary C—H > secondary C—H > primary C—H. Recall that weakest bonds have most stable
radicals. In cyclohexene (Scheme 16.7), the bromine atom could abstract a vinylic, an allylic or
the methylene hydrogen, however, since it is only the allylic radical (II, Scheme 16.7) which is
resonance stabilized, it will be formed far more easily than (I or III). Similarly due to low bond
A—B A .+.B Allylic C—H bond is the

0
DH (kcal/mol) weakest DH° = 86 kcal/mol
.
Abstract
CH3CH2 H
Ha Hv
–1
DH°= 98 kcal mol Hm . [I]
Hv .
(CH3)2CH H Br Abstract
–1
DH°= 94.5 kcal mol Ha .
(CH3)3C H [II]
Abstract
.
–1
DH°= 93 kcal mol
Hm
CH2 CHCH2 H [III]
–1
DH°= 86 kcal mol
allylic (weakest) The C—H n bond is the strongest.
Advantage can be taken of the low bond-
CH2 CH H dissociation energy of allylic C—H bond in
–1
DH°= 106 kcal mol free radical halogenation
vinylic (strongest)
SCHEME 16.7
dissociation energy of the benzylic C—H bonds, the benzyl radical is especially stable since
the delocalization spreads out the odd electron into the ring (for details see Scheme 4.40).
Advantage is taken of low bond dissociation energy of allylic (as well as benzylic) carbon-
hydrogen bonds in free radical halogenation, but only under special experimental conditions
to avoid addition to the double bond. Allylic bromination is carried out with N-bromosuccinimide
(Scheme 16.8) in CCl4 in the presence of light.
The reaction is initiated by the formation of small amount of Br• (possibly formed by
the homolytic cleavage of N—Br bond of NBS). NBS provides a constant but very low
concentration of bromine. It does this by rapid reaction with HBr formed in the substitution
reaction. Each molecule of HBr is replaced by one molecule of Br2. With these conditions, in a
non polar solvent and a very low concentration of bromine, it is then involved in the radical
chain bromination of the allylic hydrogen and no significant addition of bromine to double
bond occurs (also see, Scheme 2.19).
O
N—Br Br O
Br
(Br2) O + N—H
If in CCl4/hn (Br2)
Br excess
concentration
kept low O
Succinimide
: Br.
: :
H Br—Br Br
.
.
H—Br + + Br
.
A resonance-stabilized
radical
O O
d– d+ d+ d–
N—Br H—Br N—H + Br—Br
O O
NBS Succinimide
SCHEME 16.8
Allylic substitution of H by Br
Radical allylic bromination is an important method to functionalize an
unfunctionalized center. There are few methods available to an organic chemist
for this purpose and a well known method is Barton reaction (Scheme 16.32).
Allylic bromides can be made to undergo nucleophilic substitutions to generate
other functional groups and in (I, Scheme 16.8a) the regioselectivity is to remove
the less sterically hindered H atom.
Br HO
NBS H2O
CCl4/hn K2CO3
(I)
SCHEME 16.8a
PROBLEM 16.1
What product will be formed from monobromination reactions (Scheme 16.9)
. NBS, CH2Cl2 NBS, CH2Cl2

Br
Ph CH2 CH2 CH3
Br2 hn hn
(I) (II) (III)
SCHEME 16.9
.
ANSWER. (I) C6H5CHBrCH2CH3 via C6H5 C HCH2CH3
(II) Of the several allylic hydrogens the tertiary allylic hydrogen would be abstracted
easily (Scheme 16.9a)
. .
H Br
(Symmetrical)
3°allylic
SCHEME 16.9a
(III) A hydrogen which is both benzylic as well as allylic is the most reactive
(Scheme 16.9b)
Benzylic as well
as allylic
H H H
.
. H
H Br H
Br
+
H
SCHEME 16.9b
The allylic and benzylic C—H bonds are significantly weaker than those in saturated
systems, since the unpaired electron in the resulting radicals is delocalized. Thus compounds
containing these systems not only react readily with free radicals, but also react selectively
(Scheme 16.7) at the benzylic position (or allylic position).
2. Bromine atoms are significantly more selective than chlorine atoms
When chlorine atom abstracts a hydrogen atom e.g., from cyclohexane then only one product
is formed as all the 12 hydrogen are equivalent. A chlorine atom is far less selective than a
bromine atom. In the case of cyclohexene, radical bromination is highly selective and gives the
product of allylic bromination almost exclusively. However, the allylic position in cyclohexene
is only slightly more reactive toward a chlorine atom as compared to other methylene positions
Relative
Relative reactivity = 1.0
reactivity = 0.6
Ha Cl
Hm . Cl
Cl
+
62% 38%
SCHEME 16.10
(Scheme 16.10). Similar is the situation with substitution on saturated compounds. Isobutane
is chlorinated to give comparable quantities of isobutyl chloride and t-butyl chloride while
bromination gives t-butyl bromide almost exclusively (Scheme 16.10a). This selectivity is
explained on the basis of Hammonds postulate (see Scheme. 4.18b).
Cl
Cl
Cl2/hn +
H 60% 40%
Br
Isobutane Br2/hn Br
+
Trace > 99%
SCHEME 16.10a

• Hammonds postulate can be applied well to a multistep reaction.
• An exothermic step has a transition state which looks more like the reactants of that
step.
• The transition state of an endothermic step of a reaction looks more like the products
of that step.
• Consider the rate-limiting step of the radical halogenation of alkanes—the abstraction
of a hydrogen atom by a halogen radical, e.g., during chlorination and bromination of
ethane (Scheme 16.10b).
∆H0 [kcal/mol (kJ/mol)]
CH3CH3 + .Cl → CH3CH2. + HCl 5.0 (21 kJ/mol)
+ 98 103 (exothermic)
CH3CH3 + .Br → CH3CH2. + HBr + 10.0 (41.8 kJ/mol)
+ 98 88 (endothermic)
Very little radical Small degree of

character bond breaking
H H
d. d.
.Cl: CH3H2C . + H—Cl:
: :
: :
CH3—C—H CH3 C H Cl
H H
Structure of transition state
resembles that of reactants
High degree of High degree of

radical character bond breaking
H H
d. d.
.Br : CH3H2C . + H—Br :
: :
: :
CH3—C—H CH3 C H Br
H H
Structure of transition state
resembles that of products
SCHEME 16.10b
• The abstraction of hydrogen by chlorine is exothermic, the transition state will thus
resemble a typical exothermic reaction (Scheme 16.10c) and resembles starting
materials more than the products (the transition state is reached early). Thus with
less radical character on the carbon in the transition state, the stability of the radical
intermediate does not reflect much in the product.
• However, when bromine abstracts hydrogen, it is an endothermic reaction and the
transition state is reached later during the reaction and has a structure which must
be similar to product radical (Scheme 16.10c).
Transition state
Transition state
Products
Energy
Reactants DH
DH
Reactants
Products
Reaction coordinate Reaction coordinate
exothermic reaction endothermic reaction
SCHEME 16.10c
Therefore, the radical stabilities 3° > 2° > 1° are markedly reflected in the transition
state stabilities and regioselectivities in the same order.
3. Neighbouring group assistance in free radical substitution reactions
Photolytic halogenation generally gives a mixture of products although bromine often shows
far better selectivity (see, Scheme 6.10a). However, the bromination of alkyl bromides i.e.,
bromination of carbon chains with a bromine atom displays high regioselectivity. This is
explained by invoking a neighbouring group effect by bromine atom during abstraction
•
(Scheme 16.10d). Normally during abstraction, Br abstracts a hydrogen from R—H to give R•,
.
R¢ Br Br R¢ Br
R¢
R—C—CH2 HBr + R—C—CH2 R—C—CH2
(A)
H Br
. Br—Br
Br
Neighbouring-group assistance in free radical reactions
SCHEME 16.10d
in this case suitably located bromine assists the abstraction process to afford a cyclic
intermediate i.e., a bridged free radical (A, Scheme 16.10d). This cyclic free radical intermediate
is similar to the one invoked in SN2 neighbouring group participation. The involvement of
bridged free radical intermediate is shown by the retention of configuration of the stereogenic
carbon in the substrate.
(B) Addition Reactions of Hydrogen Halides

1. Orientation of addition—A summary
Free radicals add to the common unsaturated groupings to give new radicals. The most
important of the unsaturated groups in free radical synthesis is the C C bond, addition to
which is markedly selective. In particular, addition to the olefins of the type CH2 CHX occurs
almost exclusively at the methylene group, whatever the nature of X (Scheme 16.11). Three
factors seem to control this selectivity. Firstly the steric hindrance between the radical and X
avoids reaction at the substituted carbon atom. Secondly the grouping X stabilizes the radical
(tertiary relative to primary or secondary Scheme 16.11). Moreover, if X is an alkyl group, the
stabilization will result due to hyperconjugation.
2. Chain reactions are involved during addition to multiple bonds
Recall that most useful radical reactions are chain reactions and a radical chain reaction of
the addition of HBr to isobutene is presented (Scheme 16.11). In each step of such a cycle a
radical is consumed while a new radical is generated.
Br
HBr
ROOR hn
Isobutene
INITIATION
D . Free radicals are produced that
RO—OR 2 RO
or hn can start the reaction e.g., via
homolysis of a dialkyl peroxide
. .
R—O H—Br ROH + Br . PROPAGATION
RO abstracts H. from H—Br to yield
a new radical Br
. which can continue
Br the chain. Br then adds to the
. . substrate isobutene to give yet a
Br
new carbon centered radical. The
carbon centered radical abstracts a
substrate hydrogen atom from HBr to yield the
Br Br addition
. product. The regenerated
. . Br can continue the chain by
H—Br + Br
reacting with another molecule of
isobutene
Product
. .
Br Br Br2 TERMINATION
Free radicals are removed from the
Br Br Br system by recombination or other
. . reactions thus interrupting the chain
Br
reaction
SCHEME 16.11
3. Formation of carbon-carbon bonds via addition of some carbon radicals to alkenes

Here (Scheme 16.12), a classic example of addition of a halomethane (chloroform CHCl3 or
bromoform CHBr3) to olefins initiated by benzoylperoxide is presented (the reaction can also
be initiated by photolysis).
D
C6H5COO—OCOC6H5 2 C6H5. + CO2
C6H5. + H—CCl3 . CCl + C H

3 6 6
. CCl + Cl3C .
3
Formation of more
stable radical
Cl3C . + H—CCl3 Cl3C + . CCl3

H
Addition of a haloform to an alkene
SCHEME 16.12
PROBLEM 16.2
Write the product of the reaction (Scheme 16.12a)
Br—CCl3
C6H5CH CH2
hn
SCHEME 16.12a
ANSWER. Under the influence of light . the weakest C—Br bond (rather than
C—Cl bond) undergoes homolysis and C Cl3 radical then adds to the less hindered
(unsubstituted end of the alkene to yield the more stable secondary benzylic radical.
•
The secondary benzylic radical (I, Scheme 16.12b) then abstracts a Br from BrCCl3
to give the observed product.
hn . . .
Br—CCl3 Br + CCl3 CH2 CHC6H5 CCl3—CH2CH C6H5
Weak C—Br bond Addition at CH2 gives

stable secondary
benzylic radical
C—C bond formation
. .
Cl3C—CH2CHC6H5 Br—CCl3 Cl3C—CH2CHBr C6H5 + CCl3
(I)
SCHEME 16.12b
Aldehydes can also add to alkenes to give ketones in a chain reaction (Scheme 16.12c).
Recall that organic free radicals are often formed when other radicals or atoms abstract
hydrogen from C—H bonds of a substrate. However, often this procedure is of less value to
form radicals with specific structures, since in a substrate a hydrogen can be abstracted from
several positions. Free radicals react with aldehydes by a selective attack at a hydrogen bonded
to the carbonyl group to generate acyl radicals. The aldehydic C—H bond is far weaker than
other bonds of CH3 group.
D .
AIBN In + N2
Much weaker
bond than bonds
in the CH3 group
O O
. .
CH3—C—H + In InH + CH3—C
Aldehyde O O
. .
R—CH CH2 + CH3—C R—CH—CCH3
O O O O
.
R—CH CCH3 + CH3—C—H R—CH2—CCH3 + CH3—C.
Addition of an aldehyde to an alkene

SCHEME 16.12c
4. Role of tributyltin hydride Bu3Sn—H to reduce carbon-halogen bonds to carbon-

hydrogen bonds and in carbon-carbon bond formation
Carbon-centered free radicals role of organotin hydride

Recall the carbon-carbon bond formation reaction e.g., during the addition of
actaldehyde to an alkene (see, Scheme 16.12c). In acetaldehyde the aldehydic
C—H bond is far weaker than C—H bonds of CH3 group. Thus the abstracting
radical selectively attacks at the hydrogen bonded to the carbonyl group. In other
cases there may be however, little selectivity between different C—H bonds leading
to mixture of products to be of real synthetic value. Thus, one may look for an
abstracting radical which abstracts an atom other than hydrogen and organotin
radical [trialkyltin radical (Bu)3 Sn•] is one such radical. A trialkyltin radical
readily abstracts bromine or iodine (but not fluorine) from carbon to yield a carbon
center radical (Scheme 16.12d). This radical however, does not abstract a hydrogen
from C—H bond since Sn—H bond is weak.
. .
Bu3Sn + Br—R R + Bu3Sn—Br
SCHEME 16.12d
Tin hydrides have played a highly significant role in organic synthesis involving radical
reactions. Tin forms strong covalent bonds to halogens, but the covalent bond with hydrogen
is very weak. This aspect has been exploited in a radical chain reaction particularly in following
reactions:
• Reduction of haloalkanes to alkanes. During the reduction of an organohalide molecule
with tributyltin hydride an iodine atom is more easily transferred than a bromine
atom or a chlorine atom. When one has a choice, an organoiodide or a bromide can be
selected as the substrate. The substrate reactivity also follows the expected order,
the more stable radical is generated faster in the first propagation step (allyl, benzyl
> 3° > 2° > 1° > vinyl, phenyl).
• Carbon-carbon bond formation
• Intramolecular addition—Formation of five membered rings.
Reduction of haloalkanes to alkanes (Scheme 16.12e) is an excellent synthetic method
for this purpose. The mechanism starts with the homolysis of Bu3SnH with the initiator AIBN.
Use of AIBN is sufficient and a stronger peroxide initiator is not needed since the
Sn—H bond of Bu3Sn—H to be cleaved is very weak and a comparatively less reactive nitrile
stabilized radical generated from AIBN would be sufficient. The RO• radicals from peroxides
are highly reactive and will thus lead to problems by abstracting hydrogens from other positions
as well. The organotin radical preferentially abstracts halogen atoms from the haloalkane
(except fluorine). To generate an alkyl radical, the organotin radical, however, does not abstract
a hydrogen from the C—H bonds of the alkyl halide since the Sn—H bond thus formed would
be very weak. In the next step the alkyl radical preferentially abstracts a hydrogen atom from
the Sn—H bond which is the weakest. Thus in the reaction (Scheme 16.12e) one has generated
a specific radical which abstracts a halogen efficiently and undergoes a single reaction process
and is then terminated. The termination step gives only a single product and the reactive
radical to continue the chain. This reaction can be applied to substrates which have other
. CN
D or .
AIBN + N N +
hn CN
Organotin radical
. .
H—SnBu3 + Bu3Sn
CN CN
Weak bond
Strong bond formed
. .
Bu3Sn Br—R Bu3Sn—Br + R
Alkyl bromide
Useful alkyl radical
. .
R H—SnBu3 RH + SnBu3
A hydrocarbon
Abstraction of a
hydrogen atom
from the weakest
Sn—H bond
Trialkyl tin hydride reagents convert organohalides
to the corresponding hydrocarbons
SCHEME 16.12e
groups e.g., carbonyl which would be readily reduced by reagents like lithium aluminium
hydride.
The method is used for C—C bond formation and the net addition of an alkyl group to a
reactive double bond follows the halogen abstraction by an organotin radical. In this reaction
an organic radical and a hydrogen atom add to the C—C double bond. This is a successful
reaction since the new C—H and Sn—I bonds are far stronger than the previous bonds Sn—H
and C—I which are cleaved.
AIBN .
Initiation Bu3Sn—H Bu3Sn
New C—C bond
Bu3SnI
. R .
.
Propagation Bu3Sn l—R R CN CN
(I)
H
.
R . H—SnBu3 R + Bu3Sn
CN CN
(I)
Role of tributyltin hydride in carbon-carbon bond formation
SCHEME 16.12f
Carbon-carbon bond formation by using radical reactions

The carbon-carbon bond forming reactions (Schemes 16.12b and 16.12f) using
radicals have preparative value since the product radicals (I, Schemes 16.12b
.
and 16.12f) can abstract an atom (Br• in the first case from Br—CCl3 and H from
Bu3Sn—H in the second case) by the cleavage of unusually weaker bonds. The
efficiency of this reaction indeed depends on this step since polymerization can
compete with the atom abstraction step in the chain mechanism (Scheme 16.12g).
Atom A
abstraction R
R¢
R .
R¢ R¢ R¢
.
R CH2 CH (CH2 CH)n CH2 CH R
Addition
to alkene
SCHEME 16.12g
When this method of free radical generation is applied to an unsaturated alkyl halide
e.g., 6-bromo-1-hexene (Scheme 16.12h), the reaction can lead to two pathways. Intramolecular
addition of carbon radical to the C C bond produces a ring or the carbon radical abstracts
a hydrogen atom from tributyltin hydride to give a reduction product (Scheme 16.12h).
.
Br : . SnBu
: :
3
.
. BrSnBu3
Abstraction of a Cyclization of the

bromine atom carbon radical
. H—SnBu3
.
+ SnBu3
Abstraction of a hydrogen Methylcyclopentane
(I)
H . SnBu
3
.
H—SnBu3
Abstraction of a hydrogen 1-hexene
(II)
SCHEME 16.12h
These two pathways i.e., substitution (reduction) and addition compete with each other. The
course of reaction can be changed by changing the concentration of tributyltin hydride. The
substitution reaction is a bimolecular process, thus high concentration of tributyltin hydride
will favour it, while a lower concentration of tributyltin hydride will favour the ring formation.
It is known that the rates of ring-forming free radical cyclizations are 5 > 6 > 7. It was
found that reaction (I, Scheme 16.12h) gives the five-membered ring product exclusively. Thus
the regioselectivity of ring formation is not controlled by thermodynamic considerations, but
rather by kinetic control of the cyclization. It is found that bond formation between the radical
and the alkene stereoelectronically requires an approach angle of about 110° between the free
radical center and the olefinic plane. This is because the free radical addition results via donation
of the unpaired electron on the radical into the π antibonding orbital of the olefin, which
coincidentally makes an angle of about 110° with the olefinic plane (Scheme 6.12i).
.
R 110°
.
. Favoured pathway to give

a cyclopentane ring
SCHEME 16.12i
It is easy to achieve this approach angle during cyclization via attack on that end of the
double bond which is closest to the radical centre (favourable entropy factors) leading to a five
membered ring. For attack on the other olefinic carbon the radical shall have to reach across
the double bond to achieve the proper approach angle. This indeed would be a higher energy
path and is kinetically not favoured, thus six-membered ring formation is not favoured.
One may appreciate that while Diels Alder reaction is one of the methods to form fused
six-membered rings, radical cyclization is superior to synthesize a fused ring system containing
a five membered carbocycle. The power of the method for the synthesis of fused ring system
with a five membered carbocycle is presented (Scheme 16.12j). In this case the reaction is
induced at a bridgehead position where radical reactions are normally difficult since the radical
cannot achieve planar geometry. Thus when the halogen is separated by four carbons from the
double bond, cyclization to give a five membered ring can occur.
(AIBN)
Bu2Sn—H/Light
Br
ROOC
ROOC
SCHEME 16.12j
PROBLEM 16.3
Write the product of the reactions (Scheme 16.12k).
Bu3SnH
CH2 CH—C—R + R¢X I
hn Bu3SnH
O AIBN, D
(I) (II)
Bu3SnH
AIBN, hn CHO Bu3SnH
Br Br AIBN, D
(III) (IV)
SCHEME 16.12k
ANSWER. This is in (Scheme 16.12l)
R¢ H
OH
(I) CH2—CH—C—R ; (II) ; (III) ; (IV)
O O
. .
C Bu3Sn C
[Hint for (IV)]
Br H H
.
OH O
.
Bu3Sn + Bu3SnH
SCHEME 16.12l
5. Peroxide effect (Hydrogen bromide adds to alkenes via a radical pathway and
with apparent anti-Markovnikov regiochemistry
Peroxide effect (Kharasch 1933). The presence of oxygen or peroxides which are formed
when an alkene is exposed to the air, or added peroxides causes the addition of hydrogen
bromide to take place in the direction opposite to that predicted by Markovnikov’s rule (Scheme
16.13). This departure from the rule is termed as the ‘abnormal’ reaction, and was shown to be
due to the ‘peroxide effect’ (Kharasch et al., 1933). Hydrogen chloride, hydrogen iodide and
hydrogen fluoride do not exhibit the abnormal reaction. It has been found that the addition of
hydrogen bromide is ‘abnormally’ effected photochemically as well as by peroxide catalysts.
Markovnikov
orientation
CH3
HBr Br
1-bromo-1-methylcyclohexane
CH3
HBr anti-Markovnikov
1-methylcyclohexene
(Peroxides)
Br
1-bromo-2-methylcyclohexane
SCHEME 16.13
Peroxide is a radical initiator, thus addition of HBr to an alkene involves radicals as

intermediates, the more stable the radical the easier it is to form—the energy barrier is lower
for its formation. Thus the bromine radical adds to that sp2 carbon in the alkene (I, Scheme 16.14)
that is bonded to the most hydrogens to from a stabler (tertiary) of the two possible free radicals
2 RO.
: :
: :
: :
RO—OR
RO. + H—Br : ROH + .Br :

: :
: :
: :
: :
Ch3 CH3
CH2 + .Br :
: :
2Br :
: :
CH3C CH3CCH
. 1
[I]
CH3 CH3
: : CH3CHCH2Br : + .Br:
: :
: :
: :
: :
CH3CCH
. 2Br + H—Br 2
SCHEME 16.14
(tertiary and primary). In the reaction of HBr (absence of peroxides) to an alkene the addition
is ionic, initiated by the addition of H+ to give the most stable carbocation (Markovnikov addition
H H
+ +
CH3CH CH2 + HX CH3CH—CH2 (not CH3CH—CH2)
Electrophilic additions obey the Markovnikov rule
X X
. .
CH3CH CH2 + X CH3CH—CH2 (not CH3CH—CH2 .)
Free radical additions ‘‘disobey’’ the Markovnikov rule
SCHEME 16.15
•
Scheme 16.15). In the presence of peroxides the addition of HBr to an alkene is initiated by Br
to produce the most stable free radical (anti Markovnikov rule, Scheme 16.13). Peroxide has no
effect on the addition of HCl or HI to an alkene, which, however, occurs according to Markovnikov
rule only (heterolytic addition). In a radical reaction, the steps which propagate the chain
reaction compete with the steps which terminate it. Termination steps are always exothermic
since only bond making occurs. Thus, when both propagation steps are exothermic only then
these compete with termination. When one considers the energetics of the two propagating
steps (1 and 2, Scheme 16.16) only for hydrogen bromide these steps are exothermic. For HCl
and HI one of these two steps is on the other hand endothermic.
:Br . + —C—C.
: :
C C Step 1. DH° = – 3 kcal

Exothermic
:Br :
:
—C—C. H—Br: : Br . Step 2. DH° = – 6 kcal

: :
: :
+ —C—C— +
Exothermic
Br Br H
Cl—C—C . + H—Cl Cl—C—C—H + Cl. Step 2. DH° = + 10 kcal

Endothermic
I. + C C I—C—C . Step 1. DH° = + 13 kcal

Endothermic
SCHEME 16.16
16.4 AROMATIC NUCLEOPHILIC SUBSTITUTIONSRN1 SUBSTITUTION

Now several substitution reactions are known which occur by electron transfer processes and
are designated SRN1 reactions (R for radicals). These refer to a nucleophilic substitution via a
radical intermediate which proceeds via a unimolecular decomposition of a radical anion derived
from a substrate. The general mechanistic details may be explained by with an aryl halide as
the substrate.
1. Electron transfer to the substrate gives a radical anion, which then expels the leaving
group.
2. The radical thus obtained reacts with the nucleophile to afford a radical anion which
should be capable of continuing the chain reaction (Scheme 16.17). The similarity of
the first two steps to those in an SN1 reaction, has lead to the designation SRN1
(R for radicals).
Initiation
Electron –
ArI donor
[Arl].
–
[Arl].– Ar . +I
Propagation
–
Ar. + NH2 ArNH2–.
+ Arl.
– –
ArNH2 . + Arl ArNH2
The SRN1 Mechanism
SCHEME 16.17
16.5 HOMOLYTIC AROMATIC SUBSTITUTION

Both alkyl as well aryl radicals substitute in aromatic nuclei by an addition-elimination
sequence. The free radical adds to the aromatic ring to give a reactive cyclohexadienyl
intermediate (I, Scheme 16.18). Alkylation can be carried out on heating the compound with
e.g., diacylperoxide. The yields of the product (II, Scheme 16.18) tend to be low since
alkylbenzenes display enhanced reactivity toward free radicals at the benzylic carbon.
O O O
. .
CH3C—O—O—C—CH3 ¾¾® 2 CH3—C—O ¾¾® 2 CH3 + 2CO2
R
H R H R H R H R
. . .
.
R + . R + RH
.
(I) (II)
SCHEME 16.18
For arylation, diacylperoxides like dibenzoylperoxide are employed. Thus biphenyl can
be made in a high yield from benzene and dibenzoyl peroxide and dimeric products are also
formed (Scheme 16.19).
O O
D . .
C6H5—C—O—O—C—C6H5 ¾¾® 2 C6H5COO ¾¾® 2 C6H5 + 2CO2
H Ph Biphenyl
.
Ph
. H H
Ph Ph
SCHEME 16.19
16.6 SOME NAME REACTIONS

(A) Gomberg Reaction
This reaction involves the synthesis of biaryls by radical reaction. When the acidic solution of
a diazonium salt is made alkaline, the aryl portion of the diazonium salt couples with another
aromatic ring (Scheme 16.20).
+ – NaOH
N2 Cl + NO2 NO2
Gomberg-Bachmann reaction
+ – OH– . .
C6H5N2 Cl C6H5—N N—OH C6H5 + N2 + OH
. .
C6H5 + C6H5NO2 + OH p-C6H5—C6H4NO2 + H2O
a free radical mechanism
SCHEME 16.20
(B) Pschorr Ring Closure

When the Gomberg-Bachmann reaction is carried intramolecularly either by alkaline solution
or with copper powder the procedure is called Pschorr ring closure (Scheme 16.21). Fluorene is
prepared starting with o-aminodiphenylmethane.
CH2 CH2
NaNO2
NH2 H2SO4
+
N2
o-aminodiphenylmethane – Fluorene
HSO4
The Pschorr synthesis
SCHEME 16.21
(C) Hunsdiecker Reaction (Dearboxylative bromination)

This is a free radical substitution reaction, where the reaction of a silver (or mercury) salt of
carboxylic acid with bromine gives a bromo compound and is a method of decreasing the length
of the carbon chain by one unit (loss of carbon dioxide, Scheme 16.22). The reaction involves
the formation of an acyl hypobromite (step 1, Scheme 16.22 which is not a free radical reaction).
The acyl hypobromite then undergoes homolysis (step 2). The acyloxy radical loses carbon
dioxide (step 3) and the resulting radical abstracts bromine from a second molecule of the
hypobromite.
RCO2Ag + Br2 RBr + CO2 + AgBr

The Hunsdiecker reaction
Step 1 RCO2Ag + Br2 R—C—O—Br + AgBr
O Initiation
.
Step 2 RC—O—Br RCOO. + Br
Step 3 RCOO. R. + CO2 Propagation

Step 4 R. + RCOOBr RBr + RCOO.
The mechanism of Hunsdiecker reaction

SCHEME 16.22
A free radical has been generated at bridgehead position via the Hunsdiecker reaction
(Scheme 16.23) to show that a free radical need not be planar.
CO2Ag Br
+ Br2 + AgBr + CO2
87%
SCHEME 16.23
(D) The Ullmann Reaction (Dimerization of aryl radicals)

This reaction is a useful technique for the synthesis of biaryls through the reaction of two
moles of aryl halide in the presence of copper (Scheme 16.24). Thus, o-nitrochlorobenzene on
heating to around 220°C in the presence of copper gives 2-2′-dinitrobiphenyl. The reaction
may involve the formation of free radicals.
O2N
Cu
2 Cl
225°C
NO2 NO2
o-nitrochlorobenzene 2, 2’-dinitrobiphenyl
The Ullmann reaction
SCHEME 16.24
(E) The Kolbe Electrolytic Reaction (Dimerization of alkyl radicals)

This reaction is a free radical substitution. On electrolysis the alkali metal salt of a carboxylic
acid, RCOOH gives the coupled product R—R, via decarboxylation and combination of the
resulting radicals (Scheme 16.25). The alkyl radicals are liberated at the anode. The sodium
liberated at the cathode reacts with the solvent (the electrolysis is done between platinum foil
electrodes, of a solution of the acid in methanol containing enough sodium methoxide to
neutralize about 2% of the acid) to generate more carboxylate anion.
:– . .
C2H5CO2 C2H5CO2 + e C2H5CO2 C2H5. + CO2
Propionate ion Propionate .
discharges at free radical 2C2H5 C4H10
the anode n-butane
Electrolysis of sodium propionate
SCHEME 16.25
(F) The Acyloin Condensation

It is the intermolecular, sodium promoted condensation of two moles of ester or the
intramolecular condensation of a diester to yield an α-hydroxyketone (acyloin, Scheme 16.26).
Na/xylene H 2O
2RCOOR¢ R—C C—R R—CH—C—R
ONaONa OH O
An acyloin
O
CO2Et Na/xylene
CO2Et D H
OH
A cyclic acyloin
SCHEME 16.26
The formation of cyclic acyloins is a useful method to synthesize medium size ring compounds.
The mechanism of the reaction (Scheme 16.27) involves the electron transfer to the carbonyl
group of the ester. The radicals thus formed undergo dimerization and the loss of alkoxide
R OEt R . OEt EtO OEt

Na Dimerization R R –2OEt
O – O Na+ Na+O O
–
Na+
–
– +
O Na OH OH
R R R
R—C—C—R 2Na. R 2H
+
R R
O O Na+O – OH O
A diketone The acyloin
SCHEME 16.27
groups gives a diketone (RCOCOR) intermediate (small amounts of a diketone have been
isolated as side products). Further electron transfer affords the disodium derivative of the
acyloin. In the acyloin reaction ethoxide ion is generated, and therefore, base catalysed ester
condensations can compete (e.g., Dieckmann reaction). Thus the ethoxide ions are trapped by
including chlorotrimethylsilane (eq. I, Scheme 16.28) while carrying out this condensation.
This reagent also reacts with the acyloin dianion (eq. II, Scheme 16.28) to give the bis-silyl
enol ether (A, Scheme 16.28) from which the acyloin is liberated with acid.
– –
(CH3)3 SiCl + EtO (CH3)3Si—OEt + Cl
(I)
–
R O R O—Si(CH3)3 + R OH
2(CH3)3SiCl H3O
– –
R O –2Cl R O—Si(CH3)3 R O
A
(II)
SCHEME 16.28
The first reported catenane (see, Scheme 1.23) was made using acyloin condensation
(Scheme 16.29). This involved the following steps:
1. An acyloin condensation on the diethyl ester of the C34 dicarboxylic acid gave the
cyclic acyloin (I, Scheme 16.29).
2. This was reduced under Clemmensen reduction conditions using DCl instead of HCl
to incorporate deuterium in the reduced product (for detection via spectroscopy) and
the C34 cycloalkane (II) was formed.
3. A repetition of the reaction in the presence of (II, Scheme 16.29) was anticipated to
give (IV), since there was a chance that some molecules of ester will get threaded
through (II, Scheme 16.29) before the cyclization of III, and indeed the catenane IV
was isolated.
CHOH Zn—Hg
C32H64 C34H63D5
DCl
C O
A cyclic acyloin
(I) (II)
CO2Et
O
C34H63D5C32H64 C34H63D5C32H64
OH
CO2Et
(III) (IV)
SCHEME 16.29
(G) The Hofmann-Loffler-Freytag Reaction (Intramolecular free radical reaction)

N-haloamines undergo a photochemical decomposition in acid solution and lead to an
introduction of functionality at a carbon atom remote from the functional group already present.
The following points may be considered.
• The initial product of the reaction is a δ-haloamine.
• The key step during its formation involves the migration of the halogen in a
N-chloroamine (I, scheme 16.30) to the δ-position to give (IV). In this process the
nitrogen cation radical (II, scheme 16.30) abstracts an internal hydrogen atom from
the δ-carbon via a six membered cyclic transition state.
• The abstraction of a chlorine atom from the chloroamine by the alkyl radical (III)
gives (IV, Scheme 16.30). Treatment with a base generates the amino group which
displaces chlorine intramolecularly to a pyrrolidine (V).
(H) The Barton Reaction (Photolysis of nitrites)

This is another non-chain radical reaction which oxidizes a methyl group in the δ-position to
an OH group to a CHO group. The alcohol is first converted to its nitrite ester (I, Scheme
16.31) with nitrosyl chloride, on irradiation the oxyradical (II) abstracts a hydrogen from
δ—CH bond. The alkyl radical (III) thus formed combines with nitric oxide liberated in the
photolysis to give a nitroso compound which tautomerises to the corresponding oxime. This
technique has been used for the synthesis of aldosterone (as its 21-acetate) from corticosterone
acetate. The nitrite ester of the 11 β-hydroxyl group was made by reaction with nitrosyl chloride.
After photolysis the resulting oxime was hydrolysed. Aldosterone exists in part as its hemi-
acetal (Scheme 16.32).
+ d g b a +
H hn
CH3CH2CH2CH2—NCl CH3CH2CH2CH2—NH—Cl .
–Cl
N-chloroamine
R R
(I)
A d C—H group
d .CH
H CH2 2 +
+. + R2NHCl
R—NH CH2 R—NH2 CH2
b g
aCH2 CH2 CH2 CH2
A six-membered cyclic
transition state (III)
(II)
Cl
CH2Cl CH2 CH2
–
+ OH –HCl
:
R—NH2 CH2 R—NH R—N

–H2O
CH2 CH2 CH2 CH2
(IV) (V)
The Hofmann-Löffler-Freytag reaction
SCHEME 16.30
.NO
H H NO H .
CH2 OH CH2 O .
NOCl hn d 2 O
CH CH2 OH
–HCl –NO n b a
An alcohol Nitrite ester Oxy-radical Alkyl radical
(I) (II) (III)
NO NOH O
CH2 OH CH OH C—H OH
Hydrolysis
A nitroso-compound The oxime tautomer

Photolysis of nitrites: the Barton reaction
SCHEME 16.31
CH3
CO N O
H3C
HO R . H R . R
D O CH3 O CH2 HO CH2
H3C C
NOCl hn
C D . C D C D
A B –NO
O
Corticosterone acetate O .
NO
R= C CH3
OH O
OH N N
O
O R R R R
HO CH HO CH HO CH2
Hydrolysis
C D C D C D C D
Hemiacetal Aldosterone
Application of Barton reaction
SCHEME 16.32
16.7 THE COUPLING OF ALKYNES

An oxidative coupling of terminal alkynes gives diynes and the reaction is catalysed by Copper
(II) acetate in pyridine or similar bases.
The loss of an acidic proton of acetylene by the base, and one electron oxidation of the
acetylide anion by copper (II) ion is followed by the dimerization of the resulting acetylide
radicals (Scheme 16.33).
– 2+
C. + Cu
Cu +
:
R—C C—H R—C C R—C

.
2R—C C R—C C—C C—R
SCHEME 16.33
In a different procedure an alkyne is reacted with an aqueous mixture of copper (I)

chloride and ammonium chloride in air. Under these acidic conditions the proton is removed by
complexing between C C bond and (Cu+, copper (I) ion). Some of the copper (I) ions get oxidized
with air to copper (II) ions which in turn oxidizes the acetylide ion to the radical and then get
back to the copper (I) state. A related coupling method consists of treating a monosubstituted
acetylene with a 1-bromoacetylene in the presence of copper (I) ion (Scheme 16.34). The method
is used to synthesize [18] annulene from 1, 5-hexadiyne. The cyclic trimer (Scheme 16.35) is
treated with base to make the system fully conjugated involving prototopic shifts. A partial
hydrogenation of the remaining triple bonds gives [18] annulene.
A monosubstituted
acetylene
A 1-bromoalkyne
+
Cu
R H + Br R¢ R R¢ + HBr
SCHEME 16.34
+ –
Cu -O2 Me3CO
1, 5-hexadiyne
Cyclic trimer
H2-Pd
Pd-CaCO3
[18] Annulene
Fully conjugated
system
SCHEME 16.35
16.8 REACTIONS INVOLVING ELECTRON TRANSFER STEPS

One has already come across a reaction which involves, electron transfer and decarboxylation
of acyloxy radicals in the Kolbe electrolysis (see Scheme 16.25). Many transition metal ions
have two or more relatively stable oxidation states which differ by one electron. Consequently
transition metal ions frequently take part in electron transfer reactions. The strongly catalysed
decomposition of peroxy esters by Cu(I) is due to the oxidation of copper to Cu(II) (Scheme
16.36). Consider the reaction of cyclohexene with t-butyl perbenzoate
O O
–
RCOOR + Cu(I) RCO + RO. + Cu(II)
. –
O2CPh
. Cu(II) + PhCO2
(CH3)3C—O + (CH3)3COH +
t-butoxy radical
an allylic radical the carbocation
SCHEME 16.36
mediated by Cu(I). The t-butoxy radical thus formed (via the reductive cleavage of the peroxy
ester) abstracts a hydrogen from cyclohexene to afford an allylic radical. The oxidation of the
radical is brought about by Cu (II) and the intermediate carbocation formed then reacts with
the benzoate ion. This is therefore, a reaction where both the intermediates a radical and a
carbocation are involved.
16.9 MOLECULAR REARRANGEMENTS

Rearrangements which are very common with carbocation intermediates are rare in the case
of free radicals (Scheme 16.37). Infact the migration of a saturated group is highly unlikely.
CH3 CH3 H CH3 CH3

+
.
CH3—C—CH2 CH3—C C—H CH3—C—CH2 CH3—C—CH
. 2
+
CH3 CH3 CH3 CH3
The migration of a methyl group
Common Most uncommon
SCHEME 16.37
In the case of cationic intermediates, migration occurs through a bridged transition state (or
intermediate) which involves a three center two electron bond (I, Scheme 16.38). In the case of
a free radical there is a third electron in the system. It however, cannot occupy the same
orbital as the two other electrons. It shall then have to be in an antibonding level. Thus the
transition state for migration is less favourable compared to that in a carbocation.
In the case of free radicals, migrations however, can occur with aryl, vinyl, acyl and
other unsaturated groups. The migration of an aryl group (Scheme 16.38) e.g., involves the
formation of bridged intermediate by an addition process and the intermediate is a
cyclohexadienyl radical. The substrate (I, Scheme 16.39) adds an acyl radical (acyl radicals are
formed by the abstraction of the formyl hydrogen from an aldehyde). The phenyl group migration
then gives another free radical (II, Scheme 16.39) which abstracts a hydrogen atom from the
R
. .
C + C C—C C C C—C
(I)
SCHEME 16.38
O
Ph . . Ph
RCO Phenyl group
R
migrates
Ph Ph
(I) Carbon-carbon
bond formation
O Ph O O Ph
O
Ph Ph
. R—C—H
+ .
R R R—C
(II)
SCHEME 16.39
aldehyde. Migration of phenyl groups have been observed during decarbonylation of suitable
aldehydes under free radical conditions. Consider the example of 3-methyl-3-phenylbutanal
(Scheme 16.40) and consider the following points:
• Free radicals react with aldehydes by selective attack at the hydrogen bonded to the
carbonyl group to form acyl radicals (I, Scheme 16.40).
hn .
AIBN In + N2
C 6H5 O C 6H 5
O C6H5
. . .
CH3—C—CH2—C—H In CH3—C—CH2—C –CO CH3—C—CH2
–InH
CH3 CH3 CH3
(I) (II)
H C6H5
(1) Rearrangement .
C6H5 . CH3—C—CH2 + R—C O
(2) H Abstraction
C6H5 CH3—C—CH2CHO
CH3
. CH3 Rearranged product
CH3—C—CH2
H (III)
CH3
(i.e.,) R—C O
C6H5
(II) .
. + R—C O
H abstraction CH3—C—CH3
CH3
Decarbonylation of aldehyde
(IV)
SCHEME 16.40
• AIBN or organic peroxides can be used as radical initiators.

• The acyl radicals usually lose CO to form alkyl or aryl radicals (II, Scheme 16.40).
• Migration of a phenyl group followed by abstraction of hydrogen atom from the
aldehyde gives the rearranged product (III). One may note that only phenyl but not
methyl migrates.
• When the radical (II, Scheme 16.40) abstract only a hydrogen atom one get the product
of decarbonylation of the reactant aldehyde.
PROBLEM 16.4
Write the product formed from the reaction (Scheme 16.41) with mechanism
CH3 Ph CH2CHO
CHO
Peroxide Peroxide
CH3CH2—C—CHO Peroxide
D D
CH3 D
CH3
(I) (II) (III)
SCHEME 16.41
ANSWER. From (I), CH3CH2CH(CH3)2 due to decarbonylation, no rearrangement
CH3
possible; (II), due to decarbonylation and no rearrangement;
CH2C6H5
(III), due to free radical formation on methylene group in the chain, Ph
migration and hydrogen atom abstraction.
Migrations have also been observed for chloro groups. Thus in the reaction of (I, Scheme
16.42) with bromine in the presence of peroxides a rearrangement to (II) was observed, which
was formed along with the normal addition product Cl3CCHBrCH2Br. Migration of a halogen
could occur via a transition state in which the odd electron is accommodated in a vacant d
orbital of the halogen.
Cl ClBr Cl Br Br Cl Br
Br2 . . Br2
Cl—C—CH CH2 Cl—C—CH—CH2 Cl—C—CH—CH2 Cl—C—CH—CH2
Peroxides
Cl Cl Cl Cl
(I) (II)
SCHEME 16.42
16.10 SOME FURTHER SUBSTITUTION AND OTHER REACTIONS

(i) Nitration of Alkanes (Formation of carbon-nitrogen bonds)
This is carried out in the gas phase around 400°C. It has been shown that nitric acid itself
does not react at a saturated carbon unless nitrogen dioxide (this is a stable free radical) is
present. Thus the purpose of nitric acid is the supply of nitrogen dioxide and the key steps of
nitration are (Scheme 16.43).
RH + .NO2 R. + HNO2
R. + .NO2 RNO2
Nitration of alkanes
SCHEME 16.43
(ii) Cyclic Ether Formation

Alcohols which have δ-hydrogens get cyclized with lead tetracetate to give tetrahydrofurans
in high yields (Scheme 16.44). The reaction is carried out by heating (~ 80°C) or at room
temperature on irradiation with UV light. Evidence has been given to show that the last step
in cyclic ether formation is through a carbocation intermediate. The four and six membered
cyclic ethers (oxetanes and tetrahydropyrans) are not formed by this method.
Pb(OAc)4
+ HOAc .
.
H OH H O H O OH
Pb(OAc)3 .Pb(OAc) .Pb(OAc)
3 3
+
–H .
+
O :OH Pb(OAc)3 OH . OH
Tetrahydrofuran –
Pb(OAc)3 Pb(OAc)3
Pb(OAc)2
AcOH
Cyclic ether formation
SCHEME 16.44
(iii) SRN1 Mechanism For Substitution on Hindered Alkyl Halides

The SRN1 mechanisms are now known to occur with a variety of substrates (for example on
aryl halides, see Scheme 16.17). The operation of this mechanism with hindered alkyl halides
reflect both on the synthetic utility of the reaction and geometry of free radical intermediates
(Scheme 16.45).
– hn – hn
(CH3)3CCH2Br + PhS (CH3)3CCH2SPh Br + P(Ph)2 P(Ph)2
NH3 NH3
SCHEME 16.45
The mechanism involves similar steps as in Scheme 16.17, i.e., initiation by the supply
of electrons to the alkyl halide; formation of an alkyl free radical and its reaction with nucleophile
etc.
(iv) Polymerization of Olefins

In the presence of free radical initiators (a peroxide or an azo compound) several olefins are
polymerized (Scheme 16.46). The chains continuously grow and termination occurs by
dimerization or disproportionation. Coordination polymerization of olefins is gainfully brought
about using Ziegler-Natta catalysts which gives isotactic (stereoregular) polymers (Chapter 7).
.
Y. + CH2 CH2 Y—CH2—CH2
. . etc. .
YCH2CH2 + CH2 CH2 YCH2CH2CH2CH2 Y(CH2CH2)nCH2CH2
SCHEME 16.46
In free radical polymerization chain branching occurs when the growing end of the polymer
chain abstracts a hydrogen atom from its own chain. A new chain brand then starts growing
at this point (see arrow Scheme 16.47).
CH2CH2CH2CH3
CH2
Y(CH2CH2)n—CH CH2 Y(CH2CH2)nCH
.
H CH2
.CH Chain branching occurs here
2
SCHEME 16.47
Nitrosation of cyclohexane with nitrosyl chloride (NOCl) is a photochemical reaction of

great commercial significance for the manufacture of nylon. The NO radical is not reactive,
however chlorine readily abstracts a hydrogen atom from cyclohexane to yield cyclohexyl radical.
This radical combines with NO radical to give nitrosocyclohexane (Scheme 16.48). Note that it
is not a chain reaction, and nitrosocyclohexane in other steps gives oxime. The cyclohexanone
oxime undergoes a Beckman rearrangement to the ε-lactam which is then converted into nylon
(see, Scheme 15.22).
hn . .
Cl—N O Cl + NO O OH
N N
. .
. –HCl NO H
+
+ Cl
Nitrosocyclohexane Oxime
Beckman +
rearrangement H
O
O O
NH
N D H2N H2O
H –H2O OH
n
Nylon 6 6-aminohexanoic acid e-caprolactam
SCHEME 16.48
(v) Radical Inhibitors

Some compounds are highly reactive towards radicals and react with these immediately on
their generation to give inactive products. A low concentration of these inhibitors is sufficient,
to arrest a free radical reaction. These inhibitors may be stable free radicals like nitric oxide
(NO reacts with organic radicals e.g., R• to give nitroso compounds R—NO) or these may be
compounds which react with radicals to generate radicals of a stability so that these do not
perpetuate the chain. An example of this is quinol (Scheme 16.49). Thus to achieve a good
efficiency from a radical catalysed reaction it is necessary to carry out radical reactions with
reactants of high purity. One must appreciate that a chain propagating step cannot be achieved
till all the inhibitor (if present) is consumed. In case an inhibitor is present, the reaction
mechanism then instead may take up the ionic pathway which is not effected by an inhibitor.
.
OH O O –O
. .
R
–RH
OH OH OH +OH
.
SCHEME 16.49
Inhibitors are required for storage of some organic compounds which are highly susceptible
to radical catalysed polymerisation. The inhibitor will then act to eliminate efficiently any
stray radicals which may originate through the action of light or oxygen.
PROBLEMS
16.1 Explain the following reactions in terms of yield of the products.
Cl2
(CH3)3CH (CH3)2CHCH2Cl + (CH3)3CCI (CH3)3CH + Br2 (CH3)3C—Br + HBr
–HCl
1-chloro- 2-chloro- t-butyl bromide
2-methylpropane 2-methylpropane over 99%
(Isobutyl chloride) (tert-Butyl chloride)
64% 36%
16.2 Devise a method for the synthesis of α-tetralone from tetralin. How can one synthesis the
compounds (I and II)?
O OH H
OH
O O
tetralin a-tetralone H
(I) (II)
16.3 Bromotrichloromethane adds to cyclooctene according to expectations. However, the

addition of carbon tetrachloride gives the unusual product (II) as well as the expected
product (I). Explain.
Br
BrCCl3
CCl3
CCl4 Cl Cl CCl3
Cyclooctene +
CCl3
(I) (II)
16.4 Why in the free radical rearrangement of the vinyl group in (I) to give (III) one invokes
the formation of the intermediate cyclopropyl species?
.
CH2
CH CH2
.
(CH3)2C—CH2. CH3 (CH3)2CCH2CH CH2
(I) CH3 (III)
16.5 Why the radical initiated decarbonylation of optically active (I) leads to a racemic product?
Give mechanism.
C 2H 5
CH3 O
C—C
(CH3)2CH H
Optically active
(I)
16.6 Predict the radical catalysed addition of carbon tetrachloride to β-pinene.
b-pinene

16.1 Bromine atoms are significantly more selective than chlorine atoms in their reactions
at primary, secondary and tertiary C—H groups.
16.2 It can be achieved via hydroperoxide and its subsequent E2 elimination with base. The
cyclic acyloins (I and II) can be made from the corresponding esters (III and IV) by
treatment with sodium, chlorotrimethylsilane followed by acid hydrolysis.
–
OH O
H O—OH
+ O2 Initiator
Tetralin a-tetralyl
hydroperoxide
CO2Et CO2Et
CO2Et CO2Et
(III) (IV)
16.3 The radical intermediate from addition of (CCl4) faces two competing reactions i.e.,
intramolecular hydrogen abstraction (compare with intramolecular free radical reactions
e.g., Barton reaction) as well as abstraction of a chlorine atom from carbon tetrachloride.
In the medium sized ring under study, transannular hydrogen abstraction is not observed
during the addition of BrCCl3, as the bromine atom abstraction is rapid and this prevents
a competition by the intramolecular hydrogen abstraction.
CCl3 CCl3 Cl CCl3

. CCl4
H . H
16.4 The migration occurs through addition to give a cyclopropyl species. The involvement of
the usual transition state for a radical 1, 2 shift will have three electrons and electrons
in excess of two can be accommodated only in an anti bonding molecular orbital of much
higher energy. This in fact is a cyclization fragmentation reaction and the overall driving
force is the conversion of a primary to a tertiary radical. D.A. Lindsay, J. Lusztyk, and
K.U. Ingold, J. Am. Chem. Soc. 106, 7087 (1984).
16.5 The process involves the formation of a free radical at the stereogenic carbon.
C 2H 5 C2H5
. CH3 . .
(I) + (CH3)3CO C—C O + (CH3)3COH C—CH(CH3)2 + CO
(CH3)2CH CH3
CH3
RCHO .
C2H5—CH—CH(CH3)2 + RCO
16.6 The initial addition affords a radical which undergoes molecular rearrangement whereby
the ring strain associated with the cyclobutane ring is relieved.
CH2CCl3 CH2CCl3 CH2CCl3

.
.
CCl3 CCl4
(I) + .CCl
3
.
Cl
+0)26-4 17
Pericyclic Reactions
In a pericyclic reaction, there is a concerted bond reorganization and the essential bonding
changes occur within a cyclic array of the participating atomic centers. These reactions do not
involve the intermediate formation of either ions or radicals. Pericyclic reactions are also largely
unaffected by polar reagents, solvent changes, radical initiators etc. These can however, be
influenced only thermally i.e., reactants are in their ground state or photochemically, i.e., the
excited state of a reactant is involved in the reaction.
1,3-Butadiene
CH2 CH—CH CH2
4* 4*
Antibonding MO’s
3* 3*
Energy
(LUMO) (HOMO)
node
2 2
Bonding MO’s
(HOMO)
Bonding
1 1
Ground Excited
state state
The four molecular orbitals of 1,3-butadiene
(asterisk denotes an antibonding orbital)
SCHEME 17.1
605
1,3,5-hexatriene
CH2 CH—CH CH—CH CH2
+ –
– – + +
6*
+ + – –
– +
+ +
– – – –
5 * LUMO
+ + + +
– –
– +
– + – +
LUMO 4* HOMO
+ + – –
Energy
– +
– –
+ + + +
HOMO 3
– + + –
– –
+ –
+ – + –
2
– + – +
– +
+ +
+ – – +
1
– + + –
Ground Excited
state – – state
The six molecular orbitals of 1, 3, 5-hexatriene

SCHEME 17.2
Pericyclic Reactions 607
A consideration of the phase of orbitals of 1, 3-butadiene and 1, 3, 5-hexatriene are

presented (Schemes 17.1 and 17.2) has significance, since only orbitals of the same phase will
overlap to result in bonding. The orbitals of the different phase lead to a repulsive anti-bonding
situation.
• The normal electronic configuration of a molecule is called its ground state. When
one combines four adjacent p atomic orbitals e.g., in 1, 3-butadiene a set of four π
molecular orbitals, two of which are bonding and two of which are antibonding are
obtained. The four π electrons occupy the two bonding orbitals to leave the antibonding
orbitals vacant.
• The lowest-energy π molecular orbital (ψ1, Greek psi) is a fully additive combination
with no nodes between the nuclei and is thus bonding. The π MO of the next lowest
energy ψ2, with one node between nuclei is also bonding. Above ψ1 and ψ2 in energy
there are two antibonding π MO’s, ψ3∗ and ψ4∗. (The asterisks indicate antibonding
orbitals.) One may note that the number of nodes between nuclei increases as the
energy level of the orbital increases. The ψ3∗ orbital has two nodes between nuclei
while ψ4∗, the highest-energy MO, has three nodes between nuclei.
• When one considers the ground state of 1, 3-butadiene (Scheme 17.1) the highest
occupied molecular orbital (HOMO) is ψ2 and the lowest unoccupied molecular orbital
(LUMO) is ψ3∗.
• Ultraviolet irradiation of a polyene excites an electron which is promoted from its
ground state HOMO to its LUMO i.e., from ψ2 to ψ3∗. The molecule is then in an
excited state. In the excited state the HOMO of 1, 3-butadiene is ψ3∗.
• The electronic excitation changes the symmetries of HOMO and LUMO and it also
changes the reaction stereochemistry.
• In a thermal reaction the reactant is in its ground state while in a photochemical
reaction the reactant is in its excited state.
• To show the different phases of the two lobes of a p orbital one phase may be shaded
and other left as such (Scheme 17.1) or different phases may be represented by
mathematical signs (+) or (–). Thus the ground state HOMO and excited state HOMO
of a conjugated diene are depicted (Scheme 17.3).
SCHEME 17.3
A consideration of the six π molecular orbitals of 1, 3, 5-hexatriene (Scheme 17.2) shows

that ψ3 is the HOMO in the ground state and ψ4∗ is the LUMO. In the excited state of 1, 3, 5-
hexatriene ψ4∗ is the HOMO and ψ5∗ is the LUMO.
17.1 CONSERVATION OF MOLECULAR ORBITAL SYMMETRY

The resulting stereochemistry of the concerted pericyclic reactions depends on whether the
reaction is thermal or photochemical. Woodward and Hofmann in 1965 pointed out that sym-
metry of the molecular orbitals which participate in the chemical reaction determines the
course of the reaction and they proposed the principle of the conservation of orbital symmetry
in concerted reactions. A pericyclic reaction can take place only provided the symmetry of all
reactant molecular orbitals is the same as the symmetry of the product molecular orbitals
(symmetry allowed reaction). In other words the lobes of the reactant molecular orbitals must
be of correct algebraic sign for bonding overlap to take place in the transition state to give the
product.
In a concerted reaction, the symmetry present in the reactants is maintained during the
course of the reaction and is present in the product as well (principle of conservation of orbital
symmetry). For example, in the Diels-Alder reaction, the reactants, the diene and the dienophile
each has a plane of symmetry which is maintained in the transition state as well as in the
product cyclohexene (Scheme 17.4).
Plane of Plane of Plane of

symmetry symmetry symmetry
Bisected by a plane
of symmetry
ä
ä
ä
(the diene) (the dienophile) (product)

(the transition state)
The conservation of symmetry e.g. in Diels-Alder reaction
SCHEME 17.4
17.2 METHODS TO EXPLAIN PERICYCLIC REACTIONS

Three approaches have been employed to explain the pericyclic reactions and these are:
1. Woodward-Hofmann Rules—Correlation Diagrams
These rules require the smooth passage of the participating molecular orbitals of the reactants
into the molecular orbitals of the product. The process is described by a correlation diagram. In
case the conversion of the reactant orbitals into the product orbitals is favoured in terms of
energy and if orbital symmetry is conserved in the process, the reaction is called symmetry
allowed (The symmetries of the orbitals to be maintained are around the mirror plane and the
two fold axis of rotation as a symmetry element). In case either of these conditions (energy and
orbital symmetry) is not met the reaction is called symmetry-forbidden.
2. HOMO-LUMO Method—FMO Approach

The Fuki’s method concentrates on the so called frontier molecular orbitals, the HOMO (highest
occupied molecular orbital) and the LUMO (lowest unoccupied molecular orbital). In the ground
state of 1,3-butadiene ψ2 is HOMO and ψ3* is the LUMO (Scheme 17.1). The Fuki’s FMO
approach examines as to how the orbitals of HOMO or in some cases, the orbitals of HOMO of
one component and the LUMO of other overlap to form new bonds. If the overlaps are favourable
(bonding overlaps) then the reaction is allowed and if not favourable (antibonding overlaps)
then the reaction is forbidden.
3. Möbius-Hückel Analysis (PMO Method)
The idea behind this method is that a pericyclic reaction which proceeds through a transition
state which has aromatic characteristics (electron interactions is energetically favourable) is
allowed process. For system of 4n + 2 electrons Hückel transition states are aromatic; for
systems of 4n electrons Möbius transition states are aromatic.
17.3 ELECTROCYCLIC REACTIONS (FMO-APPROACH)

These are pericyclic reactions (intramolecular) which under the influence of heat or
light involve either the formation of a ring, with the generation of one new sigma-bond and the
consumption of one pi-bond or the reverse (Scheme 17.5). The reverse reaction, ring opening
proceeds by the same mechanism, but in reverse.
cis-1,3,5-hexatriene 1,3-cyclohexadiene Cyclobutene 1,3-butadiene

(Electron movement)
Electrocyclic reactions
SCHEME 17.5
The stereochemistry of electrocyclic reactions can be studied by using suitably substituted

molecules. An intriguing feature of electrocyclic reaction is the stereochemistry of the product
which depends on whether the reaction is thermally induced or photo-induced.
Electrocyclic reactions are brought about by heat or light and are concerted and
stereospecific. A symmetry-allowed pathway requires in-phase orbital overlap.
When the HOMO is symmetric which has the end orbitals identical e.g., (II, Scheme
17.6) the rotation will have to be disrotatory to achieve the in-phase overalap (a
symmetry allowed process). When however, the HOMO is asymmetric e.g.,
(I, Scheme 17.6) the rotation must be conrotatory to achieve an in-phase overlap.
A symmetry-allowed pathway requires an in-phase orbital overlap.
Regarding Electron Movement

In electrocyclic reactions conjugated polyenes close to give rings or rings open to
polyenes shown by having electrons “chase each other’s tails” around in a circle.
These are among the conceptually simplest organic reactions. (It doesn’t matter in
which direction the curved arrows depicting electron motions are drawn in
electrocyclic reactions, as long as they all move in the same direction (Scheme 17.5).

• All the electrocyclic reactions are accounted for by orbital-symmetry arguments (FMO
approach) by looking only at the symmetries of the two outermost lobes of the polyene.
Thus the inner lobes of a reactant may not be shown (Scheme 17.6) and if shown,
these may not be labelled +ve or –ve. The lobes of like sign can be either on the
opposite side or on same side of the molecule (I and II respectively; Scheme 17.6). For
bond formation the outermost lobes must rotate—a positive lobe overlapping a positive
lobe or a negative lobe overlapping a negative lobe. When the two lobes of like sign
are on the same side of the molecule (symmetric arrangement) the two orbitals (on
the ends of the pi system) must rotate in different direction (clockwise and
counterclockwise) and this motion is termed Disrotatory (Scheme 17.7). When,
however, the lobes of like sign are on opposite side of the molecule (asymmetric
arrangement) both orbitals must rotate in the same direction (both clockwise or both
counter-clockwise) and this motion is termed Conrotatory.
SCHEME 17.6
• The stereochemical outcome of an electrocyclic reaction depends on the number of

double bonds in a polyene and on whether the reaction is thermal or photochemical.
A thermal electrocyclic reaction involving 4n pi electrons (n = 1, 2, 3,...) proceeds
with conrotatory motion (i.e., a motion in which the bonds rotate in the same direction)
while the photochemical reaction involves disrotatory motion (a motion, in which the
bonds rotate in opposite directions).
A thermal reaction involving (4n + 2) pi electrons (where n = 0, 1, 2,...) proceeds with

disrotatory motion while the photochemical reaction proceeds with conrotatory motion.
+ –
Conrotatory A bonding -molecular orbital
– + + – between C1 and C4 is formed
motion
– when the p-orbitals rotate via
+
conrotatory motion i.e., rotation
Ground state HOMO in the same direction either both
Symmetry allowed
2 of butadiene symmetry preserved
(Homo is asymmetric)
The p orbitals at the end of the molecular orbital are not identical, in one, (+) lobe is at top
while in other it is below. The molecular orbital is asymmetric. The ring closure is conrotatory.
+ – Disrotatory
– + – + With the two end p-orbitals non-
motion identical i.e., when the molecular
– + orbital is asymmetric a disrotatory
motion is symmetry forbidden.
Ground state HOMO
Symmetry-forbidden
2 of butadiene
(HOMO is asymmetric)
+ + The new -bond is formed by rotation

Disrotatory of the p orbitals at the end of
– + + –
motion conjugated system (head to head
– – 3
overlap and rehybridization to sp ).
Excited state HOMO Thus ring closure must be disrotatory.
Symmetry allowed
3* of butadiene
(HOMO is now symmetric)
The p orbitals at the end of the molecular orbital are identical i.e., both have (+) lobes on the
top and (–) lobes at the bottom thus the HOMO is symmetric. The ring closure in disrotatory.
SCHEME 17.7
• The direction taken by an electrocyclic reaction is dependent on the relative stabilities

of the ring and open-chain reactants. In the case of cyclobutanes the open chain
structure is favoured because of the strain in the ring, during the thermal reaction.
A. Thermally Induced Interconversion of a Conjugated Diene and a Cyclobutene
• The symmetry of the HOMO of a conjugated polyene undergoing ring closure
determines the outcome of the electrocyclic reaction. All conjugated polyenes with
asymmetric HOMO’s undergo conrotatory ring closure. The ground state HOMO of a
conjugated compound with an even number of double bonds e.g., in a conjugated
diene is asymmetric and should undergo conrotatory ring closure (Scheme 17.8).
Moreover the reaction is remarkably stereospecific (Scheme 17.8). One may recall
that there are always two conrotatory modes clockwise and anticlockwise and both
are equally probable. It is obvious that neither of the two possible disrotatory modes
can be a favourable process each being an antibonding situation.
H CH3
CH3 CH3
CH3 Heat H H Heat H
H CH3 H H
H CH3
CH3 CH3
(electron movement) (electron movement)
2E,4Z-hexadiene Cis-3,4-dimethylcyclobutene 2E,4E-hexadiene trans-3,4-dimethyl cyclobutene
CH3
+ – H3C CH3
H
– + + –
H3C H H3C H Conrotatory
– + motion H H
CH3
Clockwise Clockwise cis-3,4-dimethyl-cyclobutene H
(movement of p-orbitals)
(2E, 4Z)-2, 4-hexadiene 2
Same molecule!
OR
H
+ – H H
CH3
+ – – +
H3C H H3C H Conrotatory H
– + motion CH3 CH3
CH3
Counter- Counter- cis-3,4-dimethylcyclobutene
clockwise clockwise
(2E, 4Z)-2, 4-hexadiene 2
SCHEME 17.8
EXERCISE 17.1
Depict the conrotatory ring closure of 2E, 4E-hexadiene and predict the
stereochemistry of the product.
ANSWER. Conrotatory ring closure is depicted in the counterclockwise fashion,
the product is trans-3, 4-dimethylcyclobutene (Scheme 17.9). Same product would
result by conrotation via clockwise motion.
CH3
+ – H CH3
H
+ – – +
H 3C – H H + CH3 Conrotatory H
motion CH3 H
C2-symmetry
CH3
trans-3,4-dimethylcyclobutene
Counter- Counter-
clockwise clockwise
(2E, 4E-hexadiene)
SCHEME 17.9
More on Electrocyclic Reactions

• The diene must assume a s-cis-conformation for the terminal carbons p orbitals
overlap.
• The alkyl substituents (as an approximation) do not effect the π molecular-orbital
structure of a conjugated alkene. Thus the π molecular structure of 2, 4-hexadiene
is very close to that of parent 1,3-butadiene.
• The relative orbital phase at the terminal carbon atoms of the HOMO (the orbital
symmetry) is what that determines if the reaction would occur by conrotation or
disrotation.
B. Thermal Ring Opening of Cyclobutenes

In keeping with the principle of microscopic reversibility the reverse process of thermal ring
opening takes exactly the same path.
Due to conrotatory motion (Scheme 17.10). A σ bond will open so as to give the resulting
p orbitals which will have the symmetry of the highest occupied π orbital of the product. Since
in the case of cyclobutenes the HOMO of the product (i.e., a butadiene) in the thermal reaction
is ψ2 therefore, the cyclobutene must open so that on one side the positive lobe lies above the
plane, which on the other side it is below it. This process also forces the stereochemistry in the
product from a substituted cyclobutene (Scheme 17.10).
Conrotatory
H H H H + –
– + + – H H
CH3 CH3
CH3 CH3 CH3 CH3 – +
cis-3,4-Dimethylcyclobutene (2E,4Z)-Hexadiene
Conrotatory
H 3C H H 3C H + –
– + + – H 3C H
H CH3
H CH3 H CH3 – +
trans-3,4-Dimethylcyclobutene (2E,4E)-Hexadiene
Thermal ring opening of cis- and trans-dimethylcyclobutene involves conrotatory motions
SCHEME 17.10
One may depict the opening of cyclobutane rings directly along with the stereochemistry.
Consider the thermal electrocyclic ring opening in cis-3, 4-dimethylcyclobutene to 2E,
4Z-hexadiene. This is a concerted 4n-electron reaction in which two of electron pairs are
involved ; the sigma bond and the pi bond of the reactant are converted to the two pi bonds of
the product. (Scheme 17.11). Recall that a conrotation involving 4 electrons is thermally allowed.
The conrotation in anticlockwise fashion will yield the same compound as already seen (see,
Scheme 17.8).
SCHEME 17.11
EXERCISE 17.2
Depict two possible conrotatory (thermal) modes of ring opening in trans-3,
4-dimethylcyclobutene.
ANSWER. The two conrotatory modes lead to different products. (The two disrotatory
modes on cis- and trans-disubstituted cyclobutenes are in Scheme 17.20a).

H3C H
conrotatory H H
CH3 CH3
H CH3
cis, cis (Z, Z)
trans-3,4-dimethylcyclobutene (movement of electrons)
(rotation of p-orbitals
clockwise)

H3C H
conrotatory
H 3C CH3
H H
H CH3
trans, trans (E, E)
(rotation of p-orbitals)
Anticlockwise
SCHEME 17.12
Thus one can also easily depict these conrotations (and also disrotations) directly without
drawing molecular orbitals (Scheme 17.13). When a polyene undergoes an electrocyclic ring
closure to give a cycloalkene, the terminal carbons of the polyene chain must rotate about 90°
to convert the p orbitals on these carbons into the sp3 orbitals forming the new σ bond. The
substituents on these carbons are to be rotated into a plane which is approximately at right
angles to the newly formed ring. Conversely, during the ring opening of a cycloalkene, the
substituents on the atoms forming the bond undergoing cleavage will rotate into the plane of
the new double bonds.
D
CH3 CH3
conrotation
CH3 CH3
H H H H
cis-3,4-dimethylcyclobutene
(2E,4Z)-hexadiene
(Group rotations)
D
CH3 H
conrotation
CH3 H
H CH3 H CH3
(2E,4E)-hexadiene
(Group rotations)
SCHEME 17.13
C. Thermal Electrocyclic Interconversion of 1, 3, 5-Hexatriene and 1,3-Cyclohexadiene
Thermal Electrocyclic Ring Closure or Ring Opening—Conrotatory or

Disrotatory Motions
One has already seen that the ground state HOMO of a compound with an even
number of conjugated double bonds is asymmetric and involves conrotatory mo-
tion e.g., in interconversion of a conjugated diene and cyclobutene (involvement of
4n pi electrons).
On the other hand the ground state HOMO of a compound with an odd number of
conjugated double bonds is symmetric and involves disrotatory motion e.g., in
interconversion of 1, 3, 5-hexatriene and 1, 3-cyclohexadiene (involvement of
4n + 2 electrons).
A thermal electrocyclic reaction involving (4n + 2) π electrons where (n = 0, 1, 2,...)

proceeds with disrotatory motion.
The HOMO for the ground state of a hexatriene is ψ3 and when compared with the
HOMO of the ground state of butadiene i.e., ψ2 one finds that the relative symmetry about the
terminal carbons is opposite (Scheme 17.14). Thus unlike the thermal opening of a cyclobutene
(or the reverse reaction—the ring closure) which requires conrotatory motion, in the thermal
opening of a 1,3-cyclohexadiene and likewise the ring closure requires a disrotatory motion.
Based on these arguments 2E, 4Z, 6E-octatriene gives specifically cis-5,6-dimethyl-
cyclohexadiene (Scheme 17.15).
+ –
The diene and triene HOMO’s
+ + have different symmetries.
– +
– –
Ground state diene HOMO 2
Ground state triene HOMO 3
A conjugated diene and a conjugated triene react in opposite stereochemical senses. The diene
opens and closes by conrotatory motion while a triene opens and closes by disrotatory motion.
SCHEME 17.14

+ + CH3 H3C CH3 H3C
Disrotatory
motion – + + –
H 3C HH CH3
– –
H H H H
3, ground state HOMO cis-5,6-dimethyl-1,3-cyclohexadiene
2E, 4Z, 6E-octatriene
(4n + 2) -electron system
OR
Heat
CH3 H3C
(disrotatory)
H3C H H CH3
H H
SCHEME 17.15
Similarly one finds that in the thermal cyclization of (2E, 4Z, 6Z)-octatriene as well the
methyl groups rotate in the disrotatory fashion (Scheme 17.16).
heat
CH3 H
(disrotatory
H 3C H CH H motion)
3
H CH3
(2E,4Z,6Z)-octatriene
trans-5,6-dimethyl-1,
3-cyclohexadiene
SCHEME 17.16
A thermal ring opening e.g., in the case of cis-5, 6-dimethyl-1, 3-cyclohexadiene (see
Scheme 17.15) must also be disrotatory. The ground state HOMO of the derived triene is to be
ψ3 (Scheme 17.17).
Disrotatory
motion
CH3 H 3C
+ +
– + + –
H 3C – H H – CH3
H H
cis-5,6-dimethyl-1,3-cyclohexadiene (2E, 4Z, 6E)-2,4,6-octatriene
or
Disrotatory
motion
CH3 H3C

H3C H H CH3
H H (2E, 4Z, 6E)-2,4,6-octatriene
cis-5,6-dimethyl-1,3-cyclohexadiene
SCHEME 17.17
EXERCISE 17.3
What stereochemistry of the allyl carbocation is
expected under thermal conditions from cis- H
dimethylcyclopropyl carbocation (Scheme 17.18)? +

ANSWER. The allyl carbocation will be formed by
electrocyclic ring opening. Since the reactant involves
two electrons it is a (4n + 2, n = 0, 1, ...) system and H3C CH3
thus disrotatory opening is thermally allowed SCHEME 17.18
(Scheme 17.19).
H
+ H 3C CH3 H3C CH3
disrotatory + +
H H H H
H 3C CH3
H
+
H3C CH3
H H
SCHEME 17.19
D. Summary—Electrocyclic Thermal Reactions

Electrocyclic closure of a conjugated diene is conrotatory, while that of a conjugated triene is
disrotatory. This is due to the difference is the phase relationships within the HOMO at the
terminal carbons of these π systems. In the diene the HOMO has opposite phase at these two
carbons while in the triene the HOMO has the same phase.
Conjugated alkenes with 4n π electrons (n = any integer) have antisymmetric

HOMOs and undergo conrotatory ring closure while those with (4n + 2) π electrons
have symmetric HOMOs and undergo disrotatory ring closure. Thus a conrotatory
ring closure is allowed for systems with 4n π electrons and it is forbidden for systems
with (4n + 2) π electrons. Conversely, disrotatory ring closure is allowed for systems
with (4n + 2) π electrons and is forbidden for systems with 4n π electrons.
E. Excited State (Photochemical) Electrocyclic Reactions

On absorption of light a molecule reacts through its excited state. Recall that the HOMO of the
excited state is different from the HOMO of the ground state and therefore, has different
symmetry (thermal electrocyclic reactions occur through electronic ground states).
Consider for comparison the thermal or photochemical cyclization of (2E, 4Z) hexadiene
which gives cis or trans 3,4-dimethylcyclobutene respectively. Under thermal cyclization the
ground state HOMO is ψ2 which is asymmetric, the reaction has to be conrotatory in order to
achieve in-phase overlap (Scheme 17.20).
+ – H 3C CH3

– + + –
H3C H H 3C H conrotatory
– + motion H H
(2E,4Z)-hexadiene cis-3,4-dimethylcyclobutene
Ground state HOMO 2

(asymmetric)
+ + H 3C H
disrotatory
– + + –
H3C H H 3C H h
– – H CH3
Excited state HOMO 3* trans-3,4-dimethylcyclobutene
(2E, 4Z)-hexadiene
(symmetric)
SCHEME 17.20
Similarly when (2E, 4E)-hexadiene on heating cyclizes to form trans-3, 4-dimethyl-

cyclobutene, none of the cis-isomer is formed. In the reverse reaction the cyclobutene opens to
produce only the (E, E)-isomer of the hexadiene. When the same isomer is photolyzed rather
than heated, only cis-3, 4-dimethylcyclobutene is produced as the only product (Scheme 17.20a).
Thus the reaction is completely stereospecific and involves conrotation under thermal condi-
tions and disrotation on photochemical cyclization.
CH3 CH3 H
H
H CH3 H CH3
h
H conrotatory
H H disrotatory
CH3
CH3 CH3 CH3 H
(2E,4E)-hexadiene trans-3,4-dimethyl- (2E,4E)-hexadiene cis-3,4-dimethyl-
cyclobutene cyclobutene
(Electron movement)
SCHEME 17.20a
EXERCISE 17.4
Depict the stereochemistry of the product from two disrotatory modes involved in
the photochemical reaction of cis and trans-disubstituted cyclobutene.
ANSWER. The products will be formed by disrotation, a cis-disubstituted
cyclobutene opens to give cis, cis and trans, trans isomers of butadiene (Scheme
17.20b), while a trans-disubstituted cyclobutene gives the same product (in which
there is one cis and one trans double bond).
Disrotation
H H hn
H H
X X X X
cis cis, cis (Z, Z)
Disrotation
H H hn
X X
X X H H
cis trans, trans (E, E)
X H Disrotation
hn X H
H X H X
trans trans, cis (E, Z)
Same
X H
Disrotation
hn
H X
H X X H
trans cis, trans (Z, E)
SCHEME 17.20b
When photocyclization is carried out the excited state HOMO of (2E, 4Z)-hexadiene is
now ψ3*, because this HOMO is symmetric (this HOMO has the same phase at each end of the
π system) thus the bonding overlap can occur only provided the ring closure is disrotatory
(Scheme 17.20).
One quickly gets to the same stereochemical out come by avoiding writing of the p orbit-
als at the ends of the conjugated system (Scheme 17.21).
CH3 CH3
Heat
The ground state HOMO of a
Conrotatory compound with an even number
H3C H H 3C H H H
motion of conjugated double bonds is
cis,trans-2,4-hexadiene cis-3,4-dimethylcyclobutene asymmetric (4n) -electron
(2E-4Z-isomer) system (conrotatory ring closure).
(HOMO is asymmetric) The ground state HOMO of a
compound with odd number of
heat conjugated double bonds (4n + 2)
CH3 H -electron system is symmetric
(disrotatory (disrotatory ring closure).
H 3C H CH H motion)
3
H CH3
trans, cis cis (2E,4Z,6Z)-octatriene trans
(HOMO is symmetric) 3
CH3 CH3
h
H 3C H H CH3 Disrotatory H H
motion
cis-3,4-dimethylcyclobutene In reactions under photochemical
trans,trans-2,4-hexadiene conditions every thing is reversed.
(2E-4E)-isomer The ground state and excited state
(HOMO is symmetric) HOMO’s have opposite symmetries.
If the ground state HOMO is
symmetric the excited state HOMO
is asymmetric.
h
CH3 H
H H (Conrotatory
H 3C CH3 motion)
H CH3
trans,cis,trans
(2E,4Z,6E)-octatriene trans
(HOMO is asymmetric) 4*
SCHEME 17.21
EXERCISE 17.5
Predict the stereochemical outcome from the electrocyclic reactions (Scheme 17.22)?
CH3
H h
H 3C H H CH3 H
(2E,4Z,6E)-octatriene
CH3
(I) (II)
SCHEME 17.22
ANSWER. (I) Reactant has odd number of double bonds (4n + 2) π electron system,
ground state HOMO of the triene (ψ3) is symmetric. Ring closure is disrotatory.
D
Disrotatory CH3 H3C
CH3 H H CH3
H H
HOMO symmetric
cis-5,6-dimethyl-1,
3-cyclohexadiene
SCHEME 17.23
(II) Reactant is a (4n + 2) π electron system, photochemically it involves a conrotatory

motion.
SCHEME 17.24
The selection rules for electrocyclic reactions which are given again (Table 17.1) will
thus help to know the outcome of an electrocyclic reaction. Compound (I, scheme 17.25) is a
4nπ system, therefore, a thermal cyclization via a conrotatory motion is an allowed process.
Table 17.1. Selection Rules for Electrocyclic Reactions
Number of Mode of Allowed

electrons* activation stereochemistry
4n thermal conrotatory
photochemical disrotatory
4n + 2 thermal disrotatory
photochemical conrotatory
*n = an integer. These selection rules are based on the orbital symmetry of the open-chain (conjugated
alkene) reactant.
CH3
H CH3 D H
CH3 Conrotatory H H3C CH3
H
H 3C H H CH3
(I) H
CH3 H
SCHEME 17.25
F. Stereochemical Rules—Electrocyclic Reactions—Problem Solving Hint
A conjugated diene and a conjugated triene react in opposite (alternating)

stereochemical senses during thermal reaction. The diene opens and closes by a
conrotatory path while the triene opens and closes by a disrotatory path. These
results are due to different symmetries of the HOMO of a diene and a triene.
On electronic excitation (photochemical reactions) the symmetries of HOMO and

LUMO change and with it changes the reaction stereochemistry (which is reversed)
and stereochemical rules for electrocyclic reactions are given (Table 17.1).
Problem Solving Hint 1
If in a reactant the bonds to the substituents point in opposite directions then these
substituents will have cis stereochemistry in the product provided the motion is
disrotatory (Scheme 17.25a)
CH3 CH3
H h
H (Disrotatory)
CH3 CH3
(4n) -electron system cis-stereochemistry

substituents point in
opposite directions
CH3
CH3
H
H
Disrotatory
CH3
CH3
(4n + 2) -electron system cis-stereochemistry
opposite directions
CH3
CH3
H h H
H CH3
Disrotatory
H
CH3
(4n) -electron system cis-stereochemistry
opposite directions
H
H
h
Disrotatory
H
H
4n and (Z, Z)
Substituents point in
opposite directions
SCHEME 17.25a

If in a reactant the bonds to the substitutents point in opposite directions then
these substituents will have trans stereochemistry in the product provided the
motion is conrotatory (Scheme 17.26).
CH3
H
H Conrotatory H H3C
CH3
CH3 H
Substituents point in trans-stereochemistry
opposite directions
(4n) electron system
CH3
CH3
H h
H
Conrotatory
CH3
CH3
Substituents point in trans-stereochemistry
different directions
(4n + 2) electron system
CH3
CH3
H
H
H Conrotatory H
CH3
CH3
trans-stereochemistry
Substituents point in
different directions
(4n) electron system
SCHEME 17.26

If in a reactant the bonds to the substituents point in the same direction then these
substituents will have cis-stereochemistry in the product provided the motion is
conrotatory (Scheme 17.27).
CH3 CH3
H Heat
CH3
Conrotatory
H CH3
cis-stereochemistry
The substituents point in
the same direction
(4n) p electron system
CH3
CH3
H hn
CH3
Conrotatory CH3
H
cis-stereochemistry
the same direction
(4n + 2) p-electron system
CH3
CH3
H D
H
CH3 Conrotatory CH3
H
H cis-stereochemistry
the same direction
(4n) p-electron system
SCHEME 17.27

If in a reactant the bonds to substituents point in the same direction then the
substituents will have trans-stereochemistry in the product provided the motion is
disrotatory (Scheme 17.28).
CH3
CH3
H
CH3
Disrotatory
CH3
H
The substituents point in the same trans-stereochemistry
direction (4n + 2) electron system
CH3
H
H h CH3
CH3 CH3
Disrotatory
H
H trans-stereochemistry
The substituents point in the same
direction (4n) electron system
H
h
H Disrotatory
H
4n and (E, Z) H
the same direction
SCHEME 17.28
Example 1: Consider, firstly the photochemical ring closure of precalciferol which gives ergos-
terol and lumisterol (I and II respectively; Scheme 17.29) in which hydrogen and methyl
substituents are trans to one another.
The reactant precalciferol has three conjugated π bonds (4n + 2) π electron system thus
ring closure under photochemical conditions is conrotatory (see Table 17.1). The methyl and
hydrogen at C-10 and C-9 respectively point in opposite directions in precalciferol (the H atom
at C-9 is not shown which if drawn is in opposite direction to CH3 at C-10, note that ring
residue at C-9 and CH3 substituent at C-10 are in the same direction).
Thus in precalciferol a conrotatory ring closure will cause the substituents which point
in opposite directions in the reactant to be trans in the product. On disrotatory ring closure of
precalciferol, however, these substituents will assume a cis relationship. The reason for the
formation of two cis and two trans products is that e.g., in the case of disrotatory ring closure
(Scheme 17.29) two cis products arise due to the outward disrotatory or inward disrotatory
motion.
CH3 CH3
Conrotatory
H + H
h
CH3 HO HO
Erogsterol Lumisterol
CH3 9
10
H CH3 CH3
HO

Precalciferol H + H
Disrotatory
HO HO
Isopyrocalciferol Pyrocalciferol
SCHEME 17.29
Example 2: On heating 1,3,5-cyclononatriene (I, Scheme 17.30) gives a bicyclic product with
cis-ring fusion. In (I) when the hydrogens are drawn, these point in opposite directions (II).
The reactant has three π bonds (4n + 2) π electron system thus under thermal conditions the
ring closure is disrotatory (table 17.1) and therefore, the hydrogen atoms in the product will
have a cis relationship.
SCHEME 17.30
Example 3: Consider the photochemical ring opening electrocyclic reaction of (I, scheme 17.31).
The product (II) undergoing ring closure has three conjugated double bonds and thus under
photochemical conditions (see Table 17.1) ring closure or ring opening is conrotatory. To get a
product with cis hydrogens in (I, Scheme 17.31) the substituent hydrogens have to point in the
same direction (II). Thus compared to 1,3,5-cyclononatriene (I, Scheme 17.30) in which all the
three double bonds have Z geometry in (II, Scheme 17.31) one of the double bonds has E
configuration.
H
Conrotatory
hn
H H
H H H
(I) (II) (III)
SCHEME 17.31
Example 4: 1,3-Cycloheptadiene (I, Scheme 17.32) closes to the cyclobutene by a disrotatory

motion under photochemical conditions with expected cis ring fusion. A conrotatory opening of
cyclobutene (II) is thermally allowed, since the hydrogens in (II, Scheme 17.32) are cis, these
must point in the same direction in the ring opened product (III) i.e., one of the double bonds in
III must be cis and the other must be trans. However, a trans-double bond cannot be
accommodated in a seven membered ring and thus (II, Scheme 17.32) is stable under thermal
conditions. Similar arguments prove that compound (IV, Scheme 17.32) does not undergo ring
opening under thermal conditions while (V) does.
H H
H
Too strained to be formed. A
Disrotatory conrotatory ã trans double bond can not
h H be accommodated in a
tra seven membered ring.
ns
H
H
(I) (II) (III)
(not formed)
H H
H H
(IV) (V)
SCHEME 17.32
EXERCISE 17.6
Predict if the conversion shown (Scheme 17.33) is allowed or forbidden?
H H
H
(I) (II)
SCHEME 17.33
ANSWER. I t is a concerted 4n electron reaction. The ring opening shall have to
be conrotatory (Table 17.1). Thermal process is allowed but the product is strained
and is therefore, not formed (see Scheme 17.32). However, the conversion
(Scheme 17.33) to unstrained all cis-diene is a disrotatory process as shown and
is forbidden by the selection rules (Table 17.1).
EXERCISE 17.7
One of the cyclobutenes (Scheme 17.34) on heating reacts very fast while the other
reacts at an extremely slow rate and at much higher temperature. Explain.
H H H H
(I) (II)
SCHEME 17.34
ANSWER. Recall problem solving hints 1–4. Compound (I) reacts faster.
Conrotation Both the H atoms point in

opposite directions, these
fast
are to be trans in the reactant.
D H H
H H
(4n) electron system (III)
(I)
Both the H atoms point in the same direction,

Conrotation these are to be cis in the reactant, however (IV)
very slow
H
has a trans double bond in a six membered
D H ring. Its formation is very slow if at all.
H H
(II) (IV)
SCHEME 17.35
The compound (II) can however, undergo an easy photochemical opening to the
butadiene (III see Problem 17.9), involving disrotation. One may recall that e.g.,
on ring closure a butadiene under thermal or photochemical conditions gives
cyclobutenes with opposite configurations. (see, Scheme 17.20a)
EXERCISE 17.8
How one can convert trans-5, 6-dimethyl-1, 3-cyclohexadiene into its cis isomer?
ANSWER. This may be achieved by electrocyclic ring opening followed by
electrocyclic ring closure under appropriate conditions (Scheme 17.36).
h heat
CH3 H (Conrotatory) (Disrotatory) CH3 H3C
CH3 H H CH3
H CH3 H H
trans, cis, trans-2,4,6-octatriene
trans-5,6-dimethyl-1, cis-5,6-dimethyl-1,
3-cyclohexadiene 3-cyclohexadiene
SCHEME 17.36
Example 5: Dewar benzene has been synthesized and is stable at room temperature (at 25°C,
the half life for its conversion to benzene is two days). It is much less stable than benzene due
to angle strain and no stabilization due to aromaticity. Dewar benzene could therefore, easily
isomerize to benzene. However, this conversion is an electrocyclic reaction (Scheme 17.37), it
involves two pair of electrons one pair of π electrons and one pair of sigma electrons of the
Dewar benzene, the third pair of electrons is located in exactly the same place both in the
reactant and the product and is thus not involved in the reaction).
H
H
H t C
Conrotation ran C H
s

H H H H
H
“Strained benzene”
H
H C C H
Dewar benzene H
H H

Disrotatory
(forbidden)
H
Benzene
SCHEME 17.37
A thermally allowed electrocyclic reaction with two pairs of electrons (4n) π electron
system must be conrotatory and the opening of the cyclobutene ring in Dewar-benzene
(Scheme 17.37) would result in strained isomer of benzene (“strained benzene”) with a trans
double bond in six membered ring. (In strained benzene two hydrogens on the newly created
diene moiety which point to the same side are circled. Thus the otherwise thermally allowed
conversion of Dewar benzene into benzene is geometrically impossible since low energy pathway
for this conversion is not available.
Example 6: The tetraene (Scheme 17.38) has an even number of π bonds (4n) π electron system
and therefore, under thermal conditions (– 10°C) it will undergo conrotatory ring closure.
Since the two methyl substituents on the tetraene point to opposite directions these will be
trans in the ring closed cyclooctatriene. In cyclooctatriene one now has three double bonds in
conjugation (an odd number, 4n + 2 system) and therefore, the second thermal ring closure
will now be disrotatory. Since the hydrogen substituents at the ends of the triene system
(which are not drawn) are in opposite directions (Compare with Scheme 17.30), these must be
cis in the final bicyclo product.
H
CH3 CH3
CH3
Conrotatory Disrotatory
(– 10ºC) (20ºC)
CH3 CH3 CH3
(2E, 4Z, 6Z, 8E)- trans-dimethyl- H
decatetraene cyclooctatriene cis ring junction
(electron movement)
SCHEME 17.38
Example 7: A remarkable distinction between photochemical and thermal reactions is displayed

by all cis-cyclodecapentaene (Scheme 17.39). One may consider its reacting system with three
conjugated π bonds. A conrotatory ring closure under photochemical conditions with hydrogen
substituents at the end of the considered triene system in opposite directions will end up in a
trans ring junction. Thermal ring closure of a three π bond system is disrotatory, and with
hydrogen atoms in opposite directions will end up in a cis ring junction.
Two cyclodecapentaenes are shown. All

H H cis isomer (known) is not aromatic. Infact it
is a tub shaped molecule. All double bonds
cannot be considered as conjugated.
cis,cis,cis,cis,cis- trans,cis,trans,cis,cis-
Cyclodecapentaene Cyclodecapentaene
(angle strain) (strain caused by the
inside hydrogens)
H H
Disrotatory Conrotatory
h
H H
SCHEME 17.39
17.4 CYCLOADDITIONS (FMO-APPROACH)

The reactions of alkenes (the dienophiles) and polyenes (conjugated dienes) in which two
molecules react to form a cyclic product, with π electrons being used to form two new σ bonds
are called cycloaddition reactions. These reactions are classified on the basis of π electrons
involved, in each component, the [4 + 2] cycloaddition being the well known Diels-Alder reaction
(Scheme 17.40). The reaction of two alkenes to form a cyclobutane derivative is termed a [2 + 2]
cycloaddition reaction (Scheme 17.40). A cycloaddition reaction requires only heat or light for
initiation, radical and ionic intermediates are not involved.
H2C CH2 hn H2C—CH2

A [2 + 2] cycloaddition
H2C CH2 H2C—CH2
+ A [4 + 2] cycloaddition
Diels-Alder reaction
Diene Alkene Cyclohexene

(dienophile)
SCHEME 17.40
Molecular Orbitals of Ethylene

On heating ethylene its π electrons are not promoted, but remain in the ground
state ψ1. Irradiation with UV light excites an electron from ψ1, the ground-state
HOMO, to ψ2*, which becomes the excited-state HOMO. Interaction between the
excited-state HOMO of one alkene and the LUMO of the second alkene indicates
that a photochemical [2 + 2] cycloaddition reaction can occur by a suprafacial
pathway (Scheme 17.41).
+ – + –
2 * LUMO HOMO
– + – +
h
+ + + +
1 HOMO
– – – –
(Ground state) (Excited state)

Molecular orbitals of ethylene
SCHEME 17.41
A. Diels-Alder Reaction—[4 + 2] Cycloadditions

These are concerted, thermal [4 + 2] cycloadditions. A consideration of orbital interactions
(two combinations) accounts for this (Scheme 17.42), i.e., the overlap can take place between
the HOMO of one component and the LUMO of the other and vice versa.
As with electrocyclic reactions in cycloadditions as well, one is only concerned wih the
terminal lobes. The simplest [4 + 2] system involves the cycloaddition of 1, 3-butadiene (the
diene) and ethylene (the dienophile) which is a thermally induced reaction. This thermally
allowed reaction involves e.g., the HOMO of 1, 3-butadiene (ψ2) with the LUMO of ethylene
ψ2* (one could equally well use the diene LUMO and the alkene HOMO).
+
HOMO
–
1,3-butadiene 2
–
(ground state) Suprafacial
+
–
LUMO
+
ethylene 2*
+ (ground state)
–
Symmetry-allowed thermal [4 + 2] cycloaddition : 1,3-butadiene and ethylene
SCHEME 17.42
In either case, the overlap brings together lobes of the same phase. Addition to the lobes
on the same side of a π system is called suprafacial addition, while addition to lobes on opposite
sides of a π system is termed antarafacial addition (for an example of antarafacial addition see
Scheme 17.57). These modes of addition are identified by the symbols s and a respectively.
Thus cycloaddition of two π bonds each reacting suprafacially would be called [π2s + π2s] reaction.
EXERCISE 17.9
Explain by orbital drawings that [4 + 2] cycloaddition is photochemically forbidden.
ANSWER. Usually the absorption of a photon will promote an electron from HOMO
to LUMO. In the case of a photochemical Diels-Alder reaction (which is the most
uncommon) the lower energy HOMO–LUMO gap is in the diene partner. Thus on
absorption of light a new photochemical HOMO for the diene (ψ3*) is generated
and now the HOMO–LUMO interaction with the dienophile partner involves one
antibonding overlap. Thus the new bonds cannot be formed at the same time and
the photochemical Diels-Alder reaction is forbidden by orbital symmetry (I, Scheme
17.43). However, one may note that photoinduced [4 + 2] cycloaddition cannot
occur if either the diene or the dienophile is excited (II, Scheme 17.43).
– –
– + – +
photochemical + LUMO 3* +
HOMO 3* + (ground state) +
+ – + –
– –
Bonding Bonding
– –
Antibonding Antibonding
+ LUMO 2* + HOMO 2*
+ (ground + (excited)
– state) –
(I) (II)
SCHEME 17.43
When in the dienophile there is conjugation to a group of – M type e.g., carbonyl, nitro
etc, the reaction occurs under milder conditions and gives good yields. The substituent lowers
the energy of the LUMO of the dienophile so as to bring it closer in energy to the HOMO of the
diene. Consequently the bonding interaction in the transition state increases. As expected, the
reactivity is also increased by an electron releasing group in the diene. Conversely, when the
diene contains an electron-withdrawing substituent the dienophile requires an electron-
releasing substituent for ready reaction. In this situation the interaction is between diene’s
LUMO and the dienophile’s HOMO. Thus, the bonding at the transition state is more effective
when the HOMO of one reactant and the LUMO of other are more closely matched in energy.
• s-cis Conformation of the Diene. As correctly shown (Scheme 17.40) the diene reacts
in the s-cis conformation, which allows the ends of the conjugated system to reach the
doubly bonded carbons of the dienophile. That the s-cis geometry of the diene is
essential is shown by the unreactive nature of the fixed transoid dienes (I and II,
Scheme 17.44). Moreover, as expected the substituents in the diene may also effect
the cycloaddition sterically. The substituents effect the equilibrium proportion of the
diene in the required cisoid form (Scheme 17.44). Consequently Z alkyl or aryl
substituents in the 1-position (III, Scheme 17.44 of the diene slow down the reaction
by sterically hindering formation of the cisoid conformation, while bulky 2-substituents
(IV) make it fast.
Required for
Diels-Alder
ã
reaction
Cisoid Transoid (I) (II)
(s-cis) (s-trans)
1
R R R
2 R
3
H
H H H
4
(III) (IV)
SCHEME 17.44
Cyclic dienes are among the useful dienes and particularly reactive in Diels-Alder reac-
tions as the two double bonds are held in the s-cis conformation in five or six membered rings.
Cyclopentadiene is highly reactive and forms a Diels-Alder adduct with itself. On heating, the
commercially available dimer undergoes a retro-Diels-Alder reaction (The term retro means
the reverse) to give cyclopentadiene (Scheme 17.45).
H

+ H

Diene Dienophile
Cyclopentadiene Dicyclopentadiene
dimer
SCHEME 17.45
• syn-Stereochemistry. That the Diels-Alder reaction is concerted (both the new bonds
are formed in the same transition state) is shown by the fact, that it proceeds with
retention of configuration of both the diene and the dienophile (Schemes 17.46 and
17.47) i.e., it proceeds stereoselectively syn with respect to both the diene and the
dienophile as expected of a concerted (supra, supra) mode of addition. One may note
that if in a diene both groups e.g., methyls are “outside”, these ends up cis in the
product (Scheme 17.47) and if one methyl is “inside” and one “outside” these end up
trans in the product.
H
H CO2CH3 CO2CH3

+
H CO2CH3 CO2CH3
cis-dienophile
H
Dimethyl maleate cis-product
H
CH3O2C H CO2CH3

+
H CO2CH3 CO2CH3
trans-dienophile
H
Dimethyl fumarate trans-product
The stereochemistry of the dienophile is retained

SCHEME 17.46
• The Endo Rule. The Diels-Alder reaction takes place generally to give the less stable
endo adduct as the major product. For the endo addition e.g., with cyclopentadiene
and methyl acrylate (Scheme 17.48), the transition state can be stabilized (speeding
up the reaction) through secondary interactions. These interactions involve the lobes
of HOMO and LUMO of the same phase which themselves are not involved directly
in the formation of bonds. One sees that for the endo addition the π-system lies more
completely over the other. These secondary interactions are not possible in the
transition state for exo addition since the relevant set of centers in the diene and the
CH3
COOCH3 H CH3
C COOCH3
H C
+
H C
C COOCH3
COOCH3 H CH3
CH3
trans, trans-2, 4-hexadiene (methyls end up cis)
(Both methyls “outside”)
CH3
COOCH3 H CH3
C COOCH3
H C
+
CH3 C
C COOCH3
COOCH3 H 3C H
H
cis, trans-2, 4-hexadiene (methyls end up trans)
(One methyl “inside” one methyl “outside”)
The stereochemistry of the diene is retained
SCHEME 17.47
5
ä
1 1
H
2
heat
5 ä + H 4
3 COCH3 H
4
O secondary O OCH3
Cyclopentadiene overlap
+ endo
H
Methyl acrylate H (major)
CH3O
O H
O
O O O
O
O
O Exo-product
O O
Endo-product
O O
Maleic anhydride
+
Cyclopentadiene
SCHEME 17.48
dienophile are now too far apart, from each other. Thus the preference for endo
selectivity (which infact is due to several steric and electronic influences on the
transition state—the endo transition state is lower in energy) is observed when the
dienophile has a π bond in its electron withdrawing group e.g., CN or C O. The
p orbitals of this group approach the central carbon atoms C2 and C3 of the diene and
the resulting proximity leads to an overlap of the p orbitals and secondary overlap
effects between the p orbitals of the diene and the dienophile (Scheme 17.48).
• The endo Rule to Predict General Stereochemical Outcome. One can use the endo rule
to predict the stereochemical outcome of a reaction as detailed (Scheme 17.49). One
can imagine the “inside” ligands of a diene to be the “CH2” of cyclopentadiene and
these will have a cis-relationship and shown on thick wedges. In keeping with the
endo product formation when the product is a cyclohexene derivative the group on
the dienophile (which is electron withdrawing) will be down (on a dotted wedge) due
to it being inside the pocket of ring as a result of stability of the transition state
(secondary overlap).
OCH3
ä
OCH3 CH3O
H H
COOCH3 COOCH3
Hä heat
+ H
CH3OCO
H
(I)
In (I) the H at C-1 ends “up” in the product (thick wedge) just like C5 methylene of cyclopentadiene
(see, scheme 17.48) on its reaction with methyl acrylate. Based on endo rule COOCH3 is below
the diene in the transition state, thus it ends “down” (dotted wedge) in the product.
OCH3 CH3O H
H OCH3
H
H
+
CH3 H H
H C OCH3
C—CH3
OCH3 O C CH3O H
O CH3
(II) O
Relation with endo
product formation
In (II) since both OCH3 groups are outside these end up cis in the product. As in (I) both
the inside H atoms end up on thick wedges. The COCH3 group being under the pi system
in the transition state is down (dotted wedge).
SCHEME 17.49
Stereochemistry Solving Hint

Considering schemes 17.47 and 17.49 one can evolve an useful stereochemistry
solving hint of syn addition of concerted Diels-Alder reaction.
Two inner substituents always end up with a cis relationship in the product, and
same is the case with two outer substituents. An inner substituent on one carbon
ends up always trans to an outer substituent on the other.
When a ring junction is created then as expected the stereochemistry at the ring
junction must be cis for a syn addition. Thus when maleic anhydride adds to
trans, trans-2, 4-hexadine two diastereomeric syn addition products are possible
(Scheme 17.49a).
SCHEME 17.49a
• Regioselectivity. Cycloaddition of an unsymmetrically substituted diene and an

unsymmetrically substituted dienophile can lead to regioisomers (Scheme 17.50).
CO2H CO2H
CO2H CO2H
HOMO LUMO
C6H5 C6H5
CO2Me CO2Me
HOMO LUMO
SCHEME 17.50
One has already seen that in a normal Diels-Alder reaction i.e., between an electron
rich diene and electron-deficient dienophile, the main interaction is between the HOMO of the
diene and LUMO of the dienophile (In this situation these orbitals are more closely matched in
energy, the better is the overlap and thus the reaction occurs more readily). However, the
orientation of the product from an unsymmetrical diene and an unsymmetrical dienophile
depends mostly on the atomic orbital coefficients at the reacting termini. The atoms with the
larger terminal coefficients on each reactant, bond preferentially in the transition state, because
of better orbital overlap. Consequently with 1-substituted butadienes the major product is 1,2
(“ortho”) adduct while with 2-substituted butadienes, the major adduct is 1,4 (“para”).
In the case of butadiene-1 carboxylic acid and acrylic acid the frontier orbitals are
polarized as shown (Scheme 17.50). The size of the circles as shown is roughly proportional to
the size of the coefficients and an allowed reaction leads to 1,2-adduct. Similarly, now with
2-phenyl-butadiene and methyl acrylate the major product formed would be 1,4.
• Lewis Acid Catalysts. Some Diels-Alder reactions are catalysed by Lewis acid catalysts.
These catalysts form complexes with the polar groups on the dienophile which lower
the energies of the frontier orbitals of the dienophile. Consequently, the energy
difference between the HOMO of the diene and the LUMO of dienophile is reduced
and the reaction becomes faster.
EXERCISE 17.10
Write the structure of the products from the reactions (Scheme 17.50a).
COOH COOH
+ +
COOH COOH
(I) (II)
SCHEME 17.50a
ANSWER.
SCHEME 17.50b
B. Asymmetric Diels-Alder Reaction

In asymmetric Diels-Alder reaction generally camphor based chiral auxiliaries are employed
and this is due to the reason that both geometrically possible stereoisomeric forms of camphor
are readily available. The following points may be noted:
• In the case of a monosubstituted alkene there are two enantiotopic faces Re or Si.
• A diene e.g., buta-1,3-diene thus can add either to Re or Si face of a dienophile like
acrylic acid to give a cyclohexene in which the stereocenter generated via this Diels-
Alder reaction could be either S (Re approach of the diene) or R (Si approach of the
diene, Scheme 17.51).
• Diels-Alder reaction, therefore, creates stereocenters and when both reactants are
achiral and no other chiral influence is there, racemic mixtures are obtained.
COOH
H
2
COOH
S COOH
Diene attacks
the Re face
Enantiomers
2 H
COOH COOH
R HOOC
Diene attacks
the Si face
SCHEME 17.51
• When there is chiral influence, e.g., in the dienophile as is so in chiral acrylate (optically
active, Scheme 17.52) derived from acrylic acid and optically active alcohol (I, Scheme
17.52) derived from camphor, one of the faces of the double bond in the dienophile
gets hindered.
SCHEME 17.52
• The top Re face of the carbon-carbon double bond of the dienophile is hindered by the
t-butyl group of neopentyl unit. This forces the addition to occur preferentially from
the Si-face (back of the double bond to give (III) almost exclusively, to give only one of
the enantiomers.
• One knows that Diels-Alder cycloadditions follow the endo-rule.
• Reduction of the ester with lithium aluminium hydride gives the product (IV) in an
optically pure form and regenerates the camphor derived chiral auxiliary.
Another example is in (Scheme 17.53). The dienophile (E)-methyl crotonate becomes

chiral when optically active alkyldichloroborane (I) complexes with it to yield (II). Now the
approach of diene from the rear face of the dienophile is blocked (naphthyl group). Attack
occurs from front to give (IV) in optically pure state (trans-geometry of dienophile is preserved
in IV).
C. Hydrophobic Effects
It has been shown that some intermolecular Diels-Alder reactions are accelerated under
hydrophobic effects in aqueous media. This was the case when cyclopentadiene reacted with
methylvinyl ketone (Scheme 17.54) and it was observed that any additive which increased the
hydrophobic effect also increased the rate e.g., lithium chloride increases the hydrophobic effect
by salting out nonpolar material.
O Cl – Cl
BCl2 B
+
OMe O
O
Me
(I) (II)
Me
Cl – Cl
B
+
O
O O
O
Me
Me
(III) (IV)
One enantiomer
SCHEME 17.53
Hydrophilic and hydrophobic effects are water attractive and water repellant
respectively. Soaps e.g., sodium oleate have a hydrophilic site (COO –) and a
hydrophobic site (the hydrocarbon chain).
β-Cyclodextrin has a hydrophobic cavity and if the system of a particular Diels-Alder

combination can fit within the cavity a significant rate enhancement is observed. This is found
in the case of methyl vinyl ketone and cyclopentadiene system in aqueous medium with
β-cyclodextrin as additive. α-Cyclodextrin, however, has a smaller cavity which is not able to
accommodate the reactive species and the rate is significantly diminished in its presence
compared to that in β-cyclodextrin.
SCHEME 17.54
D. [2+2] Cycloadditions
In the dimerization of ethylene, a thermal [2+2] cyclization would involve overlap of HOMO, of
one molecule with the LUMO, of the other (see, Scheme 17.41). If in this concerted reaction
both bonds to a component are formed on the same face i.e., the process is suprafacial, the
lobes of opposite phase would approach each other (Scheme 17.55). This interaction which is
suprafacial with respect to both components [π2s + π2s] is therefore, antibonding and repulsive
and the concerted reaction, does not take place (symmetry forbidden process).
+
Ground state HOMO 1
+
of alkene 1 (ethylene) –
–
Bonding
–
Antibonding
+
Symmetry-forbidden thermal
+ 2s 2s
Ground state LUMO of [2+2] cycloaddition, [ + ]
alkene 2 (ethylene) –
SCHEME 17.55
The photochemical [2+2] cycloadditions which are suprafacial with respect to both the
components [π2s + π2s] will, however, permit a previously forbidden reaction to become a
symmetry allowed process. During [2 + 2] cycloadditions, irradiation of an alkene with UV
light excites an electron from ψ1, the ground state HOMO to ψ2∗ which now becomes the excited
state HOMO. The interaction between the excited state HOMO of one alkene and LUMO of
the second alkene is now a symmetry allowed process (Scheme 17.56).
The stereochemistry of the Diels-Alder reaction reveals that these are also π4s + π2s
processes. However, a thermal [2+2] cycloaddition could occur provided it is suprafacial with
respect to one component and antarafacial with respect to the other i.e., it is π2s + π2a (Scheme
17.57). This process, through symmetry allowed is geometrically very difficult.
Thus the photochemical [2+2] cycloaddition reaction occurs smoothly and represents
one of the best techniques to synthesize cyclobutane rings and cage compounds (Scheme 17.58).
The CO double bond of an aldehyde or a ketone can act as one component in [2+2] cycloaddition
with an alkene to form an oxetane (Scheme 17.58). The reaction can occur inter-or
intramolecularly.
SCHEME 17.56
+
+
–
A thermal [2+2] cycloaddition
– suprafacial with respect to one
component and antarafacial with
+ respect to other is symmetry allowed
but geometrically very difficult.
–
–
2s 2a
[ + ] cycloaddition
SCHEME 17.57
Both thermal as well as photochemical cycloaddition reactions take place by opposite

stereochemical pathways. As with electrocyclic reactions one can categorize cycloadditions
according to the total number of electron pairs (double bonds) taking part in the rearrange-
ment. Thus, a Diels-Alder [4+2] reaction between a diene and a dienophile involves an odd
number (three) of electron pairs and takes place by a ground state (thermal) suprafacial path-
way. A [2+2] thermal reaction between two alkenes involves an even number (two) of electron
Table 17.2 Cycloaddition Reactions Stereochemical Rules
Electron pairs Thermal Photochemical

(double bonds) reaction reaction
Even number Antarafacial Suprafacial

Odd number Suprafacial Antarafacial
pairs and must takes place by an antarafacial pathway. However, it may be said that both
suprafacial and antarafacial cycloaddition pathways are symmetry allowed. Only the geometric
constraints inherent in twisting a conjugated pi electron system out of planarity make

antarafacial reaction geometrically difficult in most of the cases. One may note that preferences
for cycloadditions may be summarized further (Table 17.3) to quickly know the success of a
particular cycloaddition and provides a rule of thumb.
Table 17.3 Cycloaddition Reactions
Number of Electron Pairs Allowed Cycloaddition
Odd Thermal
Even Photochemical
As a last example of cycloaddition, cyclopentadiene reacts with cycloheptatriene system

to give a product—which is [6+4] suprafacial process (Scheme 17.59, this would include an
aromatic transition state with 10 electrons).
O O
H
+
h
H
CH3
O H3C CH3
h O CH3
+
C Ph CH3
Ph Ph H3C CH3
Ph CH3
OH OH
h
CH3 CH3
O
O
Br Br
h Br
O O
Br
SCHEME 17.58

+
Cyclopentadiene Cycloheptatrienone (95%) O

O
This is a [6+4] suprafacial cycloaddition reaction, which involves 10 electrons. The Diels-Alder
reaction involves six electrons (4n+2 system), but the Hückel rule is also fulfilled with two, ten, etc.
electrons, also see Schemes 17.98 and 17.99)
SCHEME 17.59
EXERCISE 17.11
Indicate if the following reactions (Scheme 17.59a) are allowed or forbidden.
SCHEME 17.59a
Hint. If in a reactant more π electrons are involved in the cyclization, the

nonparticipating π electrons are not counted for the classification (see Table 17.3).
A reaction involving odd number of electron pairs requires heat while a reaction
involving even number of electron pairs requires light.
ANSWER. (I) A[4 + 4] cycloaddition, involves 4 electron pairs is photochemically

allowed (see Table 17.3).
(II) A[6 + 2] cycloaddition, involves 4 electron pairs is photochemically allowed
and thermally forbidden.
(III) Since it is a [10 + 2] cycloaddition and involves 6 electron pairs, is
photochemically allowed.
(IV) It is the allowed thermal dimerization [4 + 2].
EXERCISE 17.12
One of the reactions (Scheme 17.59b) requires heat and the other light. Which is
which ? Explain.
O COOCH3 CO2CH3
(I) + + CO2
O
COOCH3 CO2CH3
C6H5 C6H5
C6H5
(II) 2
C6H5
C6H5 C6H5
SCHEME 17.59b
ANSWER. (I) This reaction is thermally allowed ; it being a [4 + 2] cycloaddition.

The initially formed intermediate then undergoes a thermally allowed reverse Diels
Alder reaction (Scheme 17.59c).
SCHEME 17.59c
(II) This is a photochemical [2 + 2] dimerization with the stereochemistry as dictated
from end-to-end overlap of p-orbital components (Scheme 17.59d).
SCHEME 17.59d
17.5 1, 3-DIPOLAR CYCLOADDITIONS

These cycloadditions are analogous to the Diels-Alder – + + –
:
reaction in that they are concerted [π4s + π2s] reactions. : N N CH2 : N N CH2
The 1,3-dipolar components are compounds whose ‘1,3-dipolar’ compound
representation requires ionic structures which include diazomethane
ones with charges on atoms bearing 1,3-relationship, as SCHEME 17.60
in diazomethane (Scheme 17.60). These type of molecules
which are called, 1,3-dipoles are isoelectronic with allyl anion. These have four π electron and
each has at least one charge separated resonance structure with opposite charges in a 1,3
relationship. The other reactant (dipolarophile) in a dipolar cycloaddition has unsaturated
bonds like, C C, C ≡≡ C, C O and C ≡≡ N. The 1,3-dipolar cycloadditions form useful reactions
for the synthesis of five membered heterocyclic rings.
Mechanistically the transition state for 1, 3-dipolar cycloaddition is not very polar and the
reaction rate is not strongly sensitive to solvent polarity. The loss of charge separation which is
implied, is more apparent rather than real, since most 1, 3-dipolar compounds are not highly
polar. The polarity associated with a single structure is balanced by other contributing
structures.
A 1, 3-dipole represents a structural variant of the diene component in the Diels-Alder
reaction; in the dipolar compound, four π-electrons are distributed over three atoms instead of
the four in a diene. Moreover, the HOMO and LUMO of a 1, 3-dipole are similar in symmetry
to that in a diene with respect to the two-fold axis and to the mirror plane which bisects the
molecule (Scheme 17.61), a concerted cycloaddition e.g., to an alkene is a symmetry allowed
process. The reaction of an alkene with diazomethane to give a pyrazoline (Scheme 17.62
pyrazole derivative) belongs to this class.
node
ã
1,3-dipolar 1,3-diene
Compound HOMO
LUMO
SCHEME 17.61
Dipolarophile CO2Me CO2Me

ä
CO2Me
N NH
Pyrazoline
+ – N N
:N
:
N—CH2
SCHEME 17.62
17.6 CHELETROPIC REACTIONS

In a cheletropic reaction two σ bonds that terminate at a single atom are made or broken
during a concerted reaction (Scheme 17.63). In the case of molecules, sulphur dioxide or carbon
monoxide the HOMO is that which has a lone pair of electrons in the plane having the atoms,
while the LUMO represents the p orbital perpendicular to this plane (Scheme 17.64).
+ SO2 SO2
3-Sulpholene
(a cheletropic reaction)
SCHEME 17.63
For a symmetry allowed cycloaddition of e.g., SO2 to a diene, the molecule of SO2 must
lie in a plane which bisects the s-cis conformation of the diene (Scheme 17.64). The interaction
is suprafacial for diene and SO2. In the transition state, the terminal carbon atoms of the diene
must move in the disrotatory manner in order that the HOMO of SO2 can interact with the
LUMO of the diene, or the LUMO of SO2 with the HOMO of the diene.
ã
LUMO
+ O O
HOMO ã
+ S – S
–
O O
Sulphur dioxide
LUMO HOMO
HOMO
S LUMO S
O O O O
SCHEME 17.64
In keeping with these arguments the trans, trans-1,4-disubstituted dienes give specifi-
cally more crowded cis-substituted 3-sulphones (Scheme 17.65). By similar arguments cis,
trans-disubstituted dienes, on the other hand afford trans-substituted-3-sulphones. As with
electrocyclic reactions, the opposite stereochemistry is observed when the reaction is photo-
chemical rather than thermochemical (Scheme 17.65).
CH3 CH3 CH3 H
disrotatory conrotatory CH3

+ SO2 SO2 SO2 + SO2
D hn
CH3 CH3 CH3 CH3

ä
E, E-1,4-disubstituted diene E, Z-1,4-disubstituted diene
SCHEME 17.65
3-Sulpholene, a solid, is a convenient substitute for geseous butadiene. Butadiene is

generated at high temperatures from 3-sulpholene in a reverse reaction (Scheme 17.66) and
when a dienophile is present it is trapped in a Diels-Alder reaction. The Diels-Alder reaction in
itself is usually reversible and has been used to protect double bonds (see Exercise 17.11).
Z
D
SO2 + ZHC CHZ
Z
3-Sulpholene The dienophile
SCHEME 17.66
17.7 SIGMATROPIC REARRANGEMENTS

A sigmatropic rearrangement is a concerted intramolecular shift of an atom or a group of
atoms. During this arrangement a σ bond is broken in the reactant and a new σ bond is formed
in the product and the π bonds rearrange. The following points may be noted:
• The number of π bonds does not change, both the reactant and the product contain
the same number of π bonds.
• The σ bond that cleaves can be in the middle of the π system or at end of the π system
(Scheme 17.67).
2 2
1 3 R 1 3 R
The sigma bond is ã New sigma bond is
broken in the middle ã formed i.e., new position
of the pi system of the sigma bond
1 3 R 1 3 R
2 2
a [3,3] sigmatropic rearrangement
3 3
2 4 2 4
1 5 1 5
R H R H
ã
ã
1 1
New sigma bond
The sigma bond is
broken at the end of
the pi system
SCHEME 17.67
• The σ bond that breaks is bonded to an allylic carbon.

• To identify the order of a sigmatropic shift [i, j] first
identify the σ bond which is broken in the reaction. This bond cleaves
Then assign number 1 to both the atoms involved in CH3
ä
1
H3C H
this bond, then the atoms in each direction from the
2 1 [1, 5]
bond being cleaved, upto and including the atoms
which form the new σ bond in the product are 3 5
numbered as atoms 2,3 and so on. The numbers 4

SCHEME 17.68
assigned to the atoms that form the new bond,
separated by commas are put within the brackets to show the reaction order (Scheme
17.67). Similarly the migration of hydrogen (Scheme 17.68) is another example of
[1,5] sigmatropic shift. The order [1,5] is not due to the fact that hydrogen migrates
from C1 to C5 but since the hydrogen (one of the two atoms given the number 1)
forms part of the new σ bond and had also formed part of the old σ bond. Only all the
atoms taking part in the reaction have to be counted. Thus the rearrangement of
cyclohexadiene (Scheme 17.68) cannot be labelled as [1,3] shift since the methylene
group linking 1 and 5 is not involved in the reaction.
• Since in these reactions a change in the position of one σ bond takes place, Woodward
and Hofmann coined the term “sigmatropic shifts”.
• A [3,3] sigmatropic rearrangement of a 1,5-diene (when the six atoms involved are all
carbons) is known as the Cope rearrangement (I, Scheme 17.69).
• The oxygen analog of the Cope rearrangement is called the Claisen rearrangement.
Often one of the π bonds is part of an aromatic ring (II, Scheme 17.69). Allyl vinyl
ethers also undergo Claisen rearrangement.
C 6H5 1
[3,3] sigmatropic tautomeri-
1
:OH
:
:
2 O : rearrangement O zation
A [3,3] 2
sigmatropic 3
CH3 3
(I) rearrange-
H
ment
C 6H5 a Cope
rearrange- Allyl phenyl ether o-Allylphenol
ment
(II) a Claisen rearrangement
CH3
SCHEME 17.69
• More examples of sigmatropic rearrangements are in (Scheme 17.69a).
2 2
2 2
1 CH 3 1 CH 3 1 1
O CH2 O CH2 3
3
H2C CH2 H 2C CH2 3 3

3 1 1
1 CH 1 CH 3 2 2
2 2
a [3,3] sigmatropic rearrangement a [3,3] sigmatropic rearrangement
1
1 2
1 2
1 2 3
2 CR3 CH2—CR3
2
3 4 1 CH2 CH2 CH—CR2
3 1 2 3
5
4 3 1 CH2—CH CR2
1 2 3
5 2
SCHEME 17.69a
A. Sigmatropic Migration of Hydrogen

(i) Introduction.
A hydrogen atom is reported to migrate from one end of a system of π bonds to the other,
under thermal or photochemical rearrangements. In the transition state the hydrogen must
be in contact with both ends of the chain at the same time. There are two distinct processes by
which a sigmatropic migration can occur. If the hydrogen moves along the top or bottom face of
the π-system i.e., migrating group remains associated with same face of the conjugated system
throughout the process, the migration is termed suprafacial. When the hydrogen moves across
the π system either from top to bottom or vice versa i.e., the migrating group moves to the
opposite face of the π-system during the course of migration then it is called antarafacial.
In a given sigmatropic rearrangement, the migrating group is bonded to both the
migration source and the migration termini in the transition state. It is imagined that the
migrating H atom breaks away from the rest of the system which is treated as a free radical.
Thus in a simplest case involving a [1,3] shift of hydrogen (Scheme 17.70), the frontier orbital
analysis treats this system as a hydrogen atom interacting with an allyl radical. The electron
of the hydrogen atom is in a 1s orbital which has only one lobe. The HOMO of an allylic free
radical depends on the number of carbons in the π-framework (Scheme 17.71).
. Imaginary transition state for a

. [1,3] sigmatropic hydrogen shift.
H H H
SCHEME 17.70
1 2 3 1 2 3 4 5 1 2 3 4 5 6 7
(I) (II) (III)
The HOMO of the allylic radicals
SCHEME 17.71
(ii) [1,3] Sigmatropic Rearrangement (Hydrogen Shift).

In the migration of hydrogen the H must move from a plus to plus or from minus to a
minus lobe of the HOMO, it cannot move to a lobe of opposite sign.
H1s orbital
Phases incorrect
ã
+ for overlap
1H H
+ –
2 3
1 CH2CH CD2 CH2 CHCD2
The [1,3] sigmatropic rearrangement – +
is thermally forbidden
HOMO
[1,3] thermal suprafacial migration
of H is symmetry forbidden
H1s orbital
+
–
The [1,3] thermal antarafacial H
+ migration of H is symmetry allowed H —CH3
C
but geometrically impossible. H
– + H
(I)
SCHEME 17.72
During a thermal [1,3] sigmatropic migration of a hydrogen, the overlap of the hydrogen
1s orbital with the HOMO of the allyl radical (I, Scheme 17.71, asymmetric) is bonding at one
end and antibonding at the other end for the suprafacial migration (Scheme 17.72). Thus [1,3]
sigmatropic suprafacial migration of hydrogen (under thermal conditions) is symmetry-
forbidden (Scheme 17.72). However, in the antarafacial process (Scheme 17.72) the hydrogen
atom shall have to cross over the pi system to the other face to form a four membered ring
transition state, a geometrically very difficult situation. Thus over all thermal [1,3] sigmatropic
rearrangements are rare. The stability of the triene (I, Scheme 17.72) which is not thermally
isomerized to toluene, which is thermodynamically more stable is due to a symmetry-forbidden
process (suprafacial H migration is symmetry forbidden, antarafacial H migration though
symmetry allowed but sterically forbidden).
In a photochemical reaction promotion of an electron means that now (I, Scheme 17.73)
becomes the HOMO. Suprafacial pathway for [1,3] shift now becomes an allowed process and
antarafacial pathway forbidden. Thus, the compound (II, Scheme 17.73) displays a [1,3]
hydrogen shift under photochemical conditions.
Photochemical [1,3]
+
ã
suprafacial process
(symmetry allowed)
H CH3 CH3
+ + 1 H
H h
–
2
– –
3
+ CH3 H CH3
(I) (II)
The [1,3] sigmatropic rearrangement is photochemically allowed
SCHEME 17.73
A [1,3] sigmatropic rearrangement involves a π bond and a pair of σ electrons so in all two
pairs electrons are involved similarly a [1,5] sigmatropic rearrangement involves three pairs of
electrons. Woodward Hoffmann rules for sigmatropic rearrangements are given in Table 17.4.
Table 17.4 Woodward-Hoffmann Rules for Sigmatropic Rearrangements
Number of pairs of electrons Reaction condition Allowed mode

in the reacting system
Even number Thermal Antarafacial

Photochemical Suprafacial
Odd number Thermal Suprafacial
Photochemical Antarafacial
Thus, since a [1,3] sigmatropic migration involves two pairs of electrons, an antrafacial
rearrangement for a 1,3-shift under thermal conditions does not take place due to geometrical
constraints. 1,3-Shifts do take place photochemically [Table 17.4, moreover, since under
photochemical conditions HOMO becomes symmetric (see, Scheme 17.73) hydrogen can migrate
by suprafacial pathway].
(iii) [1,5] Sigmatropic Hydrogen Shift.
The [1,5] sigmatropic shift of hydrogen or deuterium atoms is well known. These involve
three pairs of electrons, thus these occurs via a suprafacial pathway under thermal conditions
(see Table 17.4). These shifts can be analyzed by examining a hydrogen atom and a pentadienyl
radical whose HOMO (see III, Scheme 17.71) is bonding at both the migration origin and the
migration terminus. Thus the migration maintains orbital symmetry when the migrating group
remains on the same side of the conjugated system (suprafacial process, Scheme 17.74).
SCHEME 17.74
Another remarkable example of suprafacial [1,5] hydrogen shift thermally, is in the

1,3-diene (I, Scheme 17.75) of known stereochemistry both at the double bond and at the
stereocenter. This 1,3-diene gave a two component mixture compatible with only suprafacial
migration. These results are explained as under:
• One has to consider two rotational isomers (I and Ia, Scheme 17.75) for the reaction.
• Recall, a compound can have an infinite number of conformations but only one
configuration.
• In (I) the methyl group is directed toward C4-C5 double bond while in (Ia) it is now
ethyl group that is directed toward C4-C5 bond.
(E) CH
3 (R) CH3
D [1,5]
D
CH3CH2 CH3 Suprafacial H
(S) (bottom to bottom) CH3
(E)
H
(I) CH2CH3
(II)
(E) CH
3 H
(S)
H D [1,5]
(S) D CH3
Suprafacial
H 3C (top to top) CH2CH3
CH2CH3 (Z)
(Ia) CH3
(I) = (Ia) rotamers (III)
SCHEME 17.75
• There are two suprafacial [1,5] pathways for the hydrogen in these two conformations
(I and Ia Scheme 17.75) “top to top” as in (I) or “bottom to bottom” as in (Ia).
• Each of these suprafacial pathways gives a product with specific stereochemistry and
both are formed.
• Considering the two stereogenic units in (I, Scheme 17.75) 4 stereoisomers could be
considered. Two (II and III) are formed during suprafacial migration by the symmetry
allowed pathway.
• If one considers, the antarafacial pathway the remaining two stereoisomers (as a
diastereomeric pair) would have been formed (Scheme 17.76) which however, is not
the case.
H
(E) CH (S)
3
CH3
D D
CH3CH2 CH3 Antarafacial CH3
(S) [1,5] (E)
H CH2CH3
(I, scheme 8.75) (not formed)
(E) CH (R) CH3

3
D
H D H
Antarafacial CH2CH3
[1,5] (Z)
H3C (S) CH2CH3
CH3
(Ia, scheme 8.75) (not formed)
SCHEME 17.76
Heating of indene (Scheme 17.77) causes the scrambling of the label to all the three non-
aromatic positions. It is only via [1,5] shift of H or D (by including the p-orbitals of the benzene
ring) that one can account for the results.
H D H D
1
2 [1, 5] D [1, 5]
3 5 D H D
4
D D
[1, 5] H
H H
SCHEME 17.77
(iv) [1,7] Sigmatropic Hydrogen Shift

In the case of [1,7] hydrogen shifts, in a triene, the orbital symmetry rules (see III,
Scheme 17.71) predict that the transfer of hydrogen must be antarafacial compared to [1,3]
shift, the transition state is not much strained and the shift is sterically feasible. This is seen
in the thermal interconversion of vitamin D series (Scheme 17.78).
CH3 CH3
R R

H 3C
[1,7] H shift
HO HO
H H
Previtamin D Vitamin D3
CH2 CH3
H
H
HO
SCHEME 17.78
More on sigmatropic rearrangements (Degenerate rearrangements)

1, 3–Pentadiene on heating regenerates itself via a [1, 5] shift of hydrogen, this
kind of process in which a reactant rearranges to itself is termed degenerate
rearrangement (Scheme 17.78a). Significantly as expected the [1, 3] shift is
symmetry forbidden.
4
3 5 [1,3] [1,5]
H
2 H H H
CH2 CH2 CH2 CH2
1
not formed 1,3-pentadiene 1,3-pentadiene
A degenerate rearrangement
SCHEME 17.78a
The degenerate rearrangement can be established either by isotopically labeled

molecules or suitably substituted molecules (Scheme 17.78b).
CH2D
[1,5]
CD3 CD2
5,5,5-trideuterio-1, 1,1,5-trideuterio-1,
3-pentadiene 3-pentadiene
CH3
CH3 CH3 CH3
H
H
CH3 CH3
[1,5] [1,5]
CH2—H CH2
H H H
SCHEME 17.78b
Three membered rings can often play the role of a double bond and a [1, 5] H shift
can take place just like in 1, 3-pentadiene and involves the opening of the
cyclopropane (Scheme 17.78c).
1
2 CH2
D H
[1,5] 3 CH2
4 5
SCHEME 17.78c
B. Sigmatropic Migrations of Carbon

As compared to a hydrogen atom which has its electrons in a 1s orbital that has only one lobe,
a carbon free radical (free imaginary transition state) has its odd electron in a p orbital which
has two lobes of opposite sign. Recall that a [1,3] sigmatropic suprafacial migration of hydrogen
(thermally) is symmetry forbidden while an antarafacial reaction though allowed is
geometrically improbable (see Schemes 17.72–17.74). Interestingly an additional possibility
would exist if an alkyl group (carbon) rather than a hydrogen was potential migrator. A [1,3]
shift can now be suprafacial migration (I, Scheme 17.79) if the migrating group does so
antarafacially i.e., it would result in inversion of configuration of the migrating group. Thus
carbon can simultaneously interact with the migration source and the migration terminus
using either one of its lobes or both of its lobes (Scheme 17.79). Considering suprafacial
rearrangement, carbon will migrate using one of its lobes if the HOMO is symmetric (II, Scheme
17.79). This happens during a thermal suprafacial [1,5] process. When carbon migrates with
only one of its lobes interacting with migration source and migration terminus, the migrating
group retains its configuration since bonding is always to the same lobe. When the carbon
migrates using both of its lobes. (asymmetric HOMO, I Scheme 17.79), a [1,3] thermal suprafacial
migration would involve opposite lobes. Thus, if the migrating carbon was originally bonded
via its positive lobe, it must now use its negative lobe to form the new C—C bond. The
stereochemical outcome of such a process is the inversion of configuration in the migrating group.
+
+ –
+
+ – + – + +
–
– + – + – –
A thermal [1,3] suprafacial A thermal suprafacial +

shift of H is forbidden [1,3] shift of carbon is
however allowed with A thermal suprafacial [1,5]
inversion of configuration shift of carbon is allowed
with retention of configuration
(I)
(II)
SCHEME 17.79
In summary, a suprafacial [1,5] thermal rearrangement proceeds with retention of

configuration at the migrating carbon, while the related [1,3] suprafacial process proceeds
with inversion. In the thermal conversion of (I, Scheme 17.80) to (II) a carbon atom migrates
across an allyl system to leave C-1 and ending up at C-3 via a [1,3] shift. The inversion
of configuration is observed using suitable substrates (Scheme 17.81). The [1,3] shifts of carbon
2
3
1
C
[1,3]-shift
C C
Bicyclo[3.2.0]- Bicyclo[2.2.1]-
hept-2-ene hept-2-ene
(I) (II)
SCHEME 17.80
SCHEME 17.81
(i.e., alkyl groups) in such reactions involve expansions of strained three-or four-membered
rings. As predicted by orbital symmetry conservation rules these reactions proceed almost
entirely with inversion of configurations in the migrating group as in (I, Scheme 17.81). In this
case, a label deuterium was placed at C7 which was trans to the acetoxy group. After the
reaction, it was found to be exclusively cis due to inversion of configuration at C7. The transition
state (II, Scheme 17.81) shows that it is a [1,3] sigmatropic shift of carbon. Similarly (III,
Scheme 17.81) gives (IV) via the transition state (V) by a suprafacial [1,3] shift with inversion
at the migrating carbon under thermal conditions.
C. The Cope Rearrangement
A 1,5-diene on heating is rearranged to another 1,5-diene by concerted formation of a 1, 6-bond,
breaking of the 3,4-bond and migration of both double bonds in a [3,3] sigmatropic
rearrangement known as Cope rearrangement (see, Scheme 17.69). The compound rearranges
by a [3,3] sigmatropic pathway and is also hypothetically pictured as split into two allyl radicals
(Scheme 17.82). Interaction of the HOMO’s of these allyl radicals is bonding at both ends, so
the reaction is thermally allowed. The stereochemical outcome of this rearrangement is in
keeping with their occurrence generally through the chair-shaped transition states (Scheme
17.83). Meso 3,4-dimethyl-1, 5-hexadiene gives cis, trans-2, 6-octadiene (in the starting
compound the two methyl groups are having cis-relationship, in the chair form of a cyclohexane
only 1, 2-axial, equatorial relationship is cis) while a boat shaped transition state would give
cis, cis-product or trans, trans-product (Scheme 17.84).
H H H H
+ –
C CH3 C CH3 C CH3 C CH3
H 2C CH H2C CH H 2C CH
. H2C CH
CH2 CH2 – +
H 2C H2C
C C
H H – +
.
H 2C CH2 H2C CH2
C +
C –
H H
The [3,3] sigmatropic rearrangement is thermally allowed

SCHEME 17.82
‡
CH3
CH3 CH3
pyrolysis
CH3 CH3
CH3
99.7%
CH3 CH3
CH3 CH3
CH3
H 3C H 3C
CH3
Chair shaped 99.7%
meso-3,4-dimethyl-1,
transition state Z, E-2,6-octadiene
5-hexadiene
(cis, trans)
Cope rearrangement occurs via a chair shaped transition state
SCHEME 17.83
H3C CH3
H 3C
H 3C H 3C
H3C
meso-3,4-dimethyl-1, boat shaped cis, cis-product
5-hexadiene transition state not formed
SCHEME 17.84
EXERCISE 17.13
Which diene you expect on pyrolysis of trans-3, 4-dimethylcyclohexadiene ?
ANSWER. A Cope rearrangement occurs through a chair shaped transition state
and the diene expected is E, E isomer of 2, 6-octadiene (Scheme 17.85).
H
H 3C CH3 CH3
H3C
H3C
H 3C
H
E, E-isomer
trans-3,4-dimethylcyclohexadiene (2,6-octadiene)
SCHEME 17.85
EXERCISE 17.14
Why Z, Z-2, 6-octadiene is not the product of pyrolysis of trans-3,4-dimethylcyclo-
hexadiene ?
ANSWER. The transition state (I, Scheme 17.86) with two pseudoequatorial groups
is far more stable than (II) with two pseudoaxial groups. The Z, Z-isomer would
arise from the less stable chair shaped transition state (II, Scheme 17.86).
SCHEME 17.86
On introducing strain into the reactant, rate accelerations are observed and cis-
divinylcyclopropane rapidly undergoes Cope rearrangement (Scheme 17.87). Similar reaction
is however, not observed with trans-isomer where the reacting ends of the double bonds are
too far apart. Thus the Cope rearrangement occurs at low temperatures in cis-1, 2-divinyl
cyclopropane compared to Cope rearrangement of 1, 5-hexadiene itself which requires
temperatures in the range of 200–300°C.
H H 10°C H

H H H
cis-1,2-divinyl- 1,4-cycloheptadiene trans-1,2-divinyl-
cyclopropane cyclopropane
SCHEME 17.87
EXERCISE 17.15
Which two conformations of cis-1, 2-divinylcyclopropane can be considered for a
possible Cope rearrangement ?
Which of these conformations is capable of undergoing this rearrangement ?
ANSWER. See Scheme 17.87a. Two conformations can be adopted (I and II, Scheme
17.87a), (I) is less stable due to steric strain between double bond and a H atom
and only this conformation can undergo Cope rearrangement. The conformation
(II) will be unreactive since then the product will have two trans double bonds in
a seven membered ring (an impossible geometrical situation).
H H H
H
Clash H H
Cope Cope
H
H
H H
H H
H H H H H H
H H
both double bonds
(I) (II) trans, impossible to be
both double Less stable, “coiled” Less stable, “extended” accommodated in a seven
bonds cis (conformation) (conformation) membered ring
SCHEME 17.87a
D. Fluxional Molecules—A Degenerate Rearrangement

Divinylcyclopropane rearrangements can proceed even with more ease in case the entropy of
activation is made still negative by incorporating both vinyl groups into a ring. The system then
becomes homotropilidene (Scheme 17.88) which undergoes a degenerate Cope rearrangement
SCHEME 17.88
A degenerate rearrangement leads to a product which is indistinguishable from the reactant.

By bridging the two methylene groups in homotropilidene one gets a molecule of bullvalene
(Scheme 17.89). This is converted into itself at 25°C. At 100°C the 1HNMR spectrum of bullvalene
shows a single peak at 4.22 ppm. Bullvalene has a three fold rotational axis; thus all the three
double bonds are equivalent. The Cope rearrangement can occur in each of the three faces of
the molecule and is degenerate in every case (Bullvalene is a fluxional molecule—a molecule
which undergoes rapid degenerate rearrangement).
SCHEME 17.89
E. Oxy-Cope Rearrangement
As seen in other pericyclic reactions Cope rearrangement is also reversible and the position of
equilibrium depends on the relative stability of the isomers. This problem can be checked and
the forward reaction can be made to predominate provided the product reacts further. This is
so in oxy-Cope rearrangement when the reactant contains an oxygen group on C3 or C4 position.
The alcohol variant of Cope rearrangement (Scheme 17.90) is called the oxy-Cope rearrangement
and when the alkoxide derivative is used it is referred to as the “anionic oxy-Cope
rearrangement. The rates of sigmatropic rearrangements are enhanced and the temperatures
for the reactions are drammatically decreased compared to parent alcohols.
H
HO HO
O C
3-hydroxy-1,5-diene enol
“oxy-Cope rearrangement”
+ +
O K O K
– –
H3C C
H3C
“anionic-oxy Cope rearrangement”
SCHEME 17.90
F. Aza-Cope Rearrangement
It is well known that the presence of oxygen atom adjacent to the π bond accelerates the Cope
rearrangement. Similarly a nitrogen usually as an iminium salt fragment in the diene also
induces an aza-Cope rearrangement. Thus the reactant (II, Scheme 17.91) derived from (I)
underwent a fast aza-Cope rearrangement at low temperature.
H O—SO2CH3
–5°C
+
:
N N N
+
H
CH3 (II) CH3
reactant for aza-Cope
(I) rearrangement
Aza-Cope rearrangement
SCHEME 17.91
EXERCISE 17.16
Write the structure of products from the reactions (Scheme 17.92).
OH
H D D D
OH
H
H
(I) (II) (III)
SCHEME 17.92
ANSWER. Always look for the presence of a 1, 5-diene unit which will hint towards
a Cope rearrangement (draw the arrow to form a bond between C1 and C6 and
breaking a bond between C3 and C4, Scheme 17.93).
2
1
3 Cope
5
4 6
(I)
H H H
1 oxy-Cope H
3 OH OH O
2 4 OH
5 H H
6 Enol Ketone
(II)
OH OH O
oxy-Cope
H
H H
(III)
SCHEME 17.93
G. The Claisen Rearrangement

Claisen rearrangement also involves a [3,3] sigmatropic pathway like Cope rearrangement,
however, in Claisen rearrangement the substrates incorporate one or more heteroatoms in
place of carbon in the 1,5-hexadiene system. The simplest example of Claisen rearrangement
is the thermal conversion of allyl vinyl ether to 4-pentenal (Scheme 17.94). The transition
state involves a cycle of six orbitals and six electrons. With six electrons the transition state
has aromatic character. Similarly allyl aryl ethers on heating rearrange to o-allyl phenols.
O Heat O O
H 2C CHCH2OCH CH2 H2C CHCH2CH2CH O
Allyl vinyl ether
Aromatic 4-pentenal
transition state
Claisen rearrangement
SCHEME 17.94
Studies using migrating groups labelled with 14C or with substituents show that the
allylic group is end-interchanged during the ortho rearrangement (Scheme 17.95). These and
other results which show that the Claisen rearrangement is intramolecular provide strong
support for a concerted mechanism. When both o-positions are occupied the allyl group mi-
grates to the p-position (Scheme 17.96).
I
CH2
O CH O OH
I I
CH2 CH2CH CH2 CH2CH CH2
H

Allyl aryl ether o-allylphenol

Allyl group normally migrates to the ortho position
(the allylic group is end-interchanged)
CH3
OCH—CH CH2 OH
CH2CH CHCH3

SCHEME 17.95
Like Cope rearrangement reliable stereochemical predictions can be made from a

chair-like transition state (Scheme 17.96a). In (I) the methyl groups occupy pseudoequatorial
positions in the transition state. Similarly in (II) the major product will have E configuration
of the newly created double bond due to placement of the bulkier substituent in the pseudo
equatorial position.
OCH2CH CHCH3 ‡
O O
CH3 CH3 CH3 CH3 CH3 CH3 CH3
CH3 CH
CH
D
CH
CH
CH2
CH2
O OH
CH3 CH3 CH3 CH3 Two successive allylic
rearrangements restore
the original orientation
of the allylic group
H CH2CH CHCH3
CH2CH CHCH3
SCHEME 17.96
Me O
O Me O Me
Me Me
Me
(I) transition state threo-2,3-dimethylpentenal
H
R2 R2 H R
2 H
O—C CH3
R1—C C R1 O CH3 1 O
R CH3
C H
H CH2 transition state H
R1 > R2
(II)
SCHEME 17.96a
H. [5, 5] Sigmatropic Shifts

Thermal [5, 5] shifts are facile, however the compounds undergoing such rearrangement are
not common. One type of substrates are pentadienyl ethers which give 4-pentadienylphenols
as the major products along with minor products arising from ortho-Claisen rearrangement
(Scheme 17.96b). With the help of deuterium labeling it has been shown that major products
arise from direct [5, 5] sigmatropic shifts and not by two consecutive [3, 3] shifts.
It is proved that [5, 5] shifts occur very fast in negatively charged compounds. An
interesting reaction is oxy-Cope rearrangement of (I, Scheme 17.96c) the arrangement does
not proceed by a sequence of consecutive [3, 3] shifts, however it is indeed a result of [5, 5]
shifts, (Scheme 17.96c).
D D D
O OH OH D
+
D
D
D D
O O OH
[5,5]
D
D
H
D
D
[5,5] Sigmatropic shifts
SCHEME 17.96b
– +
OH O K O
KH
(I)
– +
O K
SCHEME 17.96c
17.8 THE ENE REACTION

In this reaction an alkene having an allylic hydrogen atom reacts thermally with a dienophile
(C C, C O, N N etc., called enophile) with the formation of a new σ bond to the terminal
carbon of the allyl group. This is followed by the 1,5-migration of the allylic hydrogen and
subsequent change in the position of allylic double bond. The reaction thus resembles both
cycloaddition and a [1,5]-sigmatropic shift of hydrogen.
Mechanistically, the reaction is a concerted process, there being little charge development
in the transition state. It shows a primary kinetic isotope effect to show C—H bond breaks in
the rate determining step (the reverse process occurs in the pyrolysis of esters). The interaction
of a hydrogen atom with the HOMO of the allyl radical and the LUMO of the enophile (Scheme
17.97) is a symmetry allowed process. A good example of ene reaction is found during allylic
oxidation of alkenes with selenium dioxide.
The reaction shows a primary kinetic isotope effect of C—H bond breaking in the rate
determining step. The ene reaction of β-pinene with maleic anhydride (Scheme 17.97) gives
the product without skeletal rearrangement of the strained four membered ring in the β-pinene,
to show the concerted nature of the reaction (rather than the formation of a cationic
intermediate). The ene reaction, however requires higher temperature than in Diels-Alder
reaction, but occurs faster with conjugated enones with Lewis acid catalysts. Coordination of
the Lewis acids with the enophile lowers the energy of LUMO.
ã Allyl HOMO
H ã H(1s) H
ã LUMO of enophile
– H H –
H
O O O O
–H2O Sigmatropic
+
+
Se Se Se Se
HO HO HO HO
OH OH
O
O CH2
O
H
O
O
(I) O
Ene reaction
SCHEME 17.97
17.9 AROMATIC TRANSITION STATES

The reactions with aromatic transition states (2, 6, 10, 14 ... 4n + 2) delocalized electrons are
permitted, while the anti-aromatic systems (4, 8, 12 ... 4n) delocalized electrons are the forbidden
ones. It is clear that the Diels-Alder reaction has a 6π aromatic transition state isoelectronic
with benzene while the forbidden cyclobutane formation has the unfavourable 4π transition
state, isoelectronic with cyclobutadiene. This is the reason that although [4+2] reactions are
common and general, the analogous concerted [2+2] and [4+4] thermal cycloaddition reactions
generally do not occur, since the corresponding transition states involve 4 and 8 electrons
respectively (Scheme 17.98 also see Table 17.3). However, the other hand, cycloaddition reactions
which involve 6 or 10 electrons occur readily (Scheme 17.99). It may be mentioned that e.g., a
[4+2] cycloaddition involves four π electrons of one system and two on another.
Most pericyclic reactions involve six electrons, but the Huckel rule is also obeyed with
two, ten etc. electrons. An important pericyclic reaction with two electrons is the rearrangement
of carbocations. The pericylic nature of such a transition state is shown (Scheme 17.100). The
cation with a total of two electrons has a filled shell and relative stability. The corresponding
transition state for a carbanion involves four electrons and an unfilled shell. Accordingly,
carbocation rearrangements are common, while carbanion rearrangements are not. Moreover,
Wagner-Meerwien and related rearrangement order [1,2], occur in carbocation because of the
allowed s, s pathway, but not in carbanions which would requires s,a. The migrating group
retains its chirality. By contrast, the [1,3] shift (see, Scheme 17.79) is a accompanied with
inversion of configuration.
CH2 CH2 D D
+ +
CH2 CH2
[2 + 2] [4 + 4]
SCHEME 17.98
COOC2H5
COOC2H5
+
COOC2H5
COOC2H5
[4+2]-cycloaddition
COOCH3
+ COOCH3
Heptafulvene COOCH3
COOCH3
[8+2]-cycloaddition
SCHEME 17.99
17.10 MÖBIUS-HÜCKEL ANALYSIS (PMO) APPROACH

The concerted reactions are analyzed by the classification of transition states as aromatic or
antiaromatic. These predictions yield the same results as by other methods. In the previous
section a mention was made of aromatic transition states. Hückel’s rule of aromaticity states
that a monocyclic planar conjugated system with (4n + 2)π electrons is aromatic and therefore,
stable in the ground state. On the other hand a system with (4n) π electrons is unstable and is
called antiaromatic. Further it has been shown that these rules are reversed by the presence
of a node (a phase dislocation) in the array of atomic orbitals. The Möbius-Hückel concept is
used to analyze the pericyclic reactions without using the actual molecular orbitals. The
following points may be noted:
• Each atom of the interacting system is assigned a p orbital with one lobe black and
one white (or some other designation). A hydrogen atom is represented by a circle of
one color representing an s orbital.
• One draws each reactant with the black lobes on one side and the white on the other.
Then one considers the transition state of a particular reaction, counts the number of
electrons and the nodes in the array to reach the conclusion if that reaction is symmetry
allowed or forbidden.
SCHEME 17.100
• A Hückel system has zero (or any even number) of nodes (phase changes) around the
orbital array. A Hückel system with 4n + 2 electrons is aromatic and with 4n electrons
is antiaromatic. An array with an odd number of phase dislocations is called an anti
Hückel system (Mobius system). An anti-Hückel system with 4n electrons is aromatic
and with 4n + 2 electrons is antiaromatic.
• The condition for aromaticity in anti-Hückel system is opposite to that for Hückel
system.
1. Electrocyclic Reactions
(a) Thermal Ring Opening of Cyclobutenes—4n Systems
On the basis of FMO approach under thermal conditions the observed stereochemistry of the
products indicates a conrotatory motion. Consider the thermal ring opening in cis 3,4-dimethyl-
cyclobutene which on the basis of FMO method gives 2E, 4Z-hexadiene (Schemes 17.6 and 17.10).
The Hückel-Möbius approach also predicts conrotatory motion under thermal conditions and
predicts the formation of same diene. Consider the basis set for the starting butadiene
(Scheme 17.101), the tilt at C-1 and C-4 as the butadiene system rotates toward the transition
state is different for conrotatory and disrotatory modes. The transition state for conrotatory
ring opening has one sign inversion (phase dislocation) and with four electrons it is aromatic.
The conrotatory transition state for cyclobutene ring opening is therefore, aromatic. The
transition state for disrotatory cyclobutene ring opening however, is anti-aromatic (no phase
dislocation with 4 electrons). Thus the PMO approach like FMO method also predicts that for
butadiene-cyclobutene interconversion the conrotatory transition state is the favoured aromatic
transition state and thus thermal conrotatory ring opening in cyclobutenes is allowed and
disrotatory opening is forbidden.
Transition state phase

relationships
‡
CH3
Conrotatory H
CH3 CH3 CH3 CH3 CH3
ã
Phase
H
H H dislocation H H
(2E,4Z)-hexadiene
Cis-3,4-dimethylcyclobutene One phase dislocation Mobius
Basis set for conrotatory system 4 electrons in cyclic array
cyclobutene ring opening of orbitals aromatic (thermally
allowed process)
‡
CH3
Disrotatory H
CH3 CH3 H 3C
CH3 H
H CH3
H H H
(2E,4E)-hexadiene
Cis-3,4-dimethylcyclobutene No phase dislocation Hückel system
Basis set for disrotatory 4 electrons in cyclic array of orbitals-
cyclobutene ring opening antiaromatic thermally forbidden
process (photochemically allowed)
SCHEME 17.101
(b) Thermal Ring Closure of an Octatetraene—4n Systems

In this case also a conrotatory ring closure (Scheme 17.102) is allowed since in the transition
state basis set there is one phase dislocation at the forming σ bond. The transition state is
therefore, aromatic (8 electrons Möbius system). Disrotatory ring closure for the reaction
(Scheme 17.102) will be however, antiaromatic eight electron Hückel system.
As with FMO approach the general statement is that thermal electrocyclic reactions in
the conrotatory mode are allowed for 4n electron transition states.
The stereochemistry and other aspects are just the same as already discussed during
FMO approach. Moreover, since Woodward-Hoffmann rules for photochemical reactions are
always the reverse for thermal reactions, one can always predict the outcome of a reaction
under photochemical conditions (Schemes 17.101 and 17.102).
CH3 CH3 CH3 CH3

h
conrotatory disrotatory
CH3 CH3 CH3 CH3
(2E,4Z,6Z,8E)- (2E,4Z,6Z,8E)-
decatetraene decatetraene
Conrotatory
ring closure
ã
One phase dislocation at
the forming bond, Mobius
pattern, eight electrons,
aromatic transition state.
No phase dislocation
Hückel system 8
electrons, antiaromatic
The basis set for an

ã
electrocyclic ring closure

of an octatetraene Disrotatory
ring closure
SCHEME 17.102
(c) Thermal Hexatriene Ring Closure—4n + 2 Systems

In FMO approach for 4n + 2 electron transition states, in electrocyclic reactions, the disrotatory
mode is allowed for thermal reactions and the conrotatory mode for photochemical reactions.
In PMO method as well, this is found to be true. Starting from hexatriene basis set (I, Scheme
17.103), the transition state for disrotatory ring closure is a six-electron Hückel system and
thus aromatic (II). The conrotatory ring closure proceeds through an antiaromatic anti-Hückel
transition state. It is, therefore, correctly predicted that thermal ring closure of substituted
hexatrienes should be disrotatory and the photochemical reaction should proceed via the
opposite conrotatory path.
2. Diels-Alder Reaction
The selection rules may also be derived by the consideration of the aromaticity of the transition
state of a Diels-Alder reaction. Same conclusions (as in the case of FMO approach) are again
reached and these are summarized in Scheme 17.104).
(I) (II) (III)

The hexatriene Transition state for hexatriene Transition state for hexatriene
basis set disrotatory ring closure, 6 conrotatory ring closure (one
electrons Hückel system (no phase dislocation) 6 electrons
phase dislocation) aromatic antiaromatic.
(thermally allowed) (Photochemically allowed)
CH3
CH3
H
CH3 D
CH3
H
(2E,4Z,6Z)-octatriene trans-5,6-dimethyl-1,
3-cyclohexadiene
CH3
CH3
H
CH3 hn
CH3
H
(2E,4Z,6Z)-octatriene cis-5,6-dimethyl-1,
3-cyclohexadiene
SCHEME 17.103
SCHEME 17.104
Antarafacial-Suprafacial cycloaddition is highly sterically hindered and is, therefore,

less common. In case two ethylene molecules are brought together in such a way that a Mobius
activated complex can be realized (see Scheme 17.104) the process become a suprafacial/
antarafacial addition. This process should be allowed since it is a Mobius system with four
electron and a node. For this process to be realized the ethylene molecules have to approach
each other in a perpendicular geometry. The completion of this addition involves distortion of
the carbon framework. The process, therefore, is difficult although allowed. For this reason
simple alkenes do not display this addition. The highly strained triene (Scheme 17.105) how-
ever, spontaneously dimerizes thermally and represents [π2a + π2s] transition state. Reaction
of heptafulvalene with tetracynoethylene is a remarkable example of a [π14a + π2s] thermal
cycloaddition leading to a product of anti addition. The transition state involves a negative
overlap which corresponds to a Mobius cyclic electronic system, a favourable transition state
for a 16-electron (4n) cyclic system (Scheme 17.105).
As already discussed many known cycloadditions [p + q] involve pericyclic electrons
equal to 6, 10, 14 etc., and involve Hückel aromatic transition states. The [14 + 2] cycloaddition,
however, does not fit the Hückel rule.
HH
H H D
H + H
[p2a + p2s] Thermal cycloaddition HH
NC CN H
D (CN)2
+
(CN)2 ä Negative
NC CN H overlap
CN
CN
Heptafulvalene Tetracyanoethylene NC
NC
[p14a + p2s] Thermal cycloaddition
SCHEME 17.105
3. Sigmatropic Shifts
Consider the simplest case of 1,3-sigmatropic shift of a hydrogen. In the FMO approach the
hydrogen 1s orbital interacts with an allyl radicals HOMO. A thermal [1,3] suprafacial shift is
symmetry forbidden, the antarafacial is symmetry allowed, but energetically very unfavour-
able (see, Scheme 17.72). A consideration of basis set atomic orbitals and their classification as
aromatic or antiaromatic reaches the same conclusions (Scheme 17.106). The 1,3-suprafacial
shift of hydrogen is forbidden, but the suprafacial 1,5-shift is allowed. The 1,7-shifts should be
antarafacial, when an alkyl group (carbon) migrates, an additional stereochemical feature has
to be considered. Again in agreement with FMO approach, the allowed processes include, the
suprafacial 1,3-shift with inversion and the suprafacial 1,5-shift with retention (Scheme 17.107).
SCHEME 17.106
SCHEME 17.107
17.11 CORRELATION DIAGRAM METHOD

In this method a correlation of the geometrical symmetry of the orbitals between reactants
and the products is involved. Based on this, a correlation diagram is developed which com-
pares the symmetry characteristics from this comparison. A reaction can be easily predicted to
be symmetry allowed or symmetry forbidden. The following points may be noted:
• Molecular orbitals (of the reactant and the product) are either symmetric or
antisymmetric around the mirror plane or around a two fold axis of rotation (C2).
Thus π orbital of ethylene in the ground state is symmetric (S) with respect to mirror
plane (I, Scheme 17.108) while it is antisymmetric (A) with respect to rotational axis
C2 (II, Scheme 17.108). A two fold axis of rotation may be regarded as a pin at right
angles passing in the middle. If a molecular orbital is spun 180° (i.e., C2 axis 360°/2),
around this axis it would either yield an identical orbital i.e., symmetric or an orbital
with all signs the opposite of what these were originally i.e., antisymmetric (A). Thus
when the π orbital of ethylene is rotated it is found that the symmetry around the axis of
rotation is not maintained. One would see that after the rotation the shaded lobes
would be instead on the bottom rather than at the top (as was so in the original). Thus
π orbital of ethylene is antisymmetric (A) in relation to its axis of rotation (II Scheme
17.108).
C2
m Asymmetrical (A)
around the axis of p
Symmetrical (S) rotation (C2)
around the p
ã
mirror plane
C2 Axis
(I) (II)
SCHEME 17.108
• On the other hand the same operations show that the antibonding π* orbital of ethylene
is antisymmetric around the mirror plane but symmetric around the C2 axis of rotation
(Scheme 17.109).
Symmetrical (S)
around the axis p* p*
Asymmetrical (A) of rotation (C2)
around the mirror p*
ã
plane.
C2
SCHEME 17.109
• Similarly the orbitals of the reactant and the product can be labelled. Thus the sigma
orbital of a C-C covalent bond has a mirror plane of symmetry as well as C2 symmetry,
a σ* orbital is antisymmetric both with respect to plane of symmetry as well as
rotational axis of symmetry (Scheme 17.110).
Symmetrical with
Anti-symmetrical with
respect to both
respect to both mirror
mirror plane and
plane and rotational
s rotational axis of s* axis of symmetry.
symmetry.
SCHEME 17.110
• During a disrotatory electrocyclic conversion, a plane of symmetry is maintained

throughout (Scheme 17.111). If the reaction proceeds by a conrotatory motion a two
fold axis of Symmetry (C2) is preserved throughout (Scheme 17.112).
Mirror plane
Disrotatory motion (terminal orbitals) a mirror plane of symmetry is maintained throughout
SCHEME 17.111
C2
Conrotatory motion (terminal orbitals) a C2 axis of symmetry is preserved throughout
SCHEME 17.112
• The most stable transition state is the one that conserves the symmetry of the reactant
orbitals in passing to product orbitals—a symmetric (S) orbital in the reactant must
transform to a symmetric orbital in the product, and an antisymmetric (A) orbital
must transform to an antisymmetric orbital.
Example 1: Correlation Diagrams For Electrocyclic Interconversion of 1,3-Butadiene and
Cyclobutene.
These correlation diagrams are now developed involving a plane of symmetry as well as
an axis of symmetry. The four molecular orbitals of butadiene and cyclobutane are inspected
for the two symmetry elements. [In Scheme 17.113, the symmetric properties (plane of symme-
try) of molecular orbitals of butadiene and cyclobutene along with the correlation diagram are
depicted together. However, these symmetry properties can be translated onto a correlation
diagram (as shown on the bottom of Scheme 17.113) for its study.] Firstly one considers the
correlation diagram for the disrotatory ring closure of 1,3-butadiene to cyclobutene during
which the mirror plane of symmetry is preserved (Scheme 17.113). The following points may
be considered:
• ψ1 can be converted to σ, however, ψ2 cannot be converted to π which is the second-
lowest orbital of cyclobutene.
• In order to conserve symmetry around the mirror plane, ψ2 must instead be converted
to π*, while it is ψ3 which is converted to π.
• This symmetry correlation requires crossover between bonding and antibonding
orbitals (Scheme 17.113). This is thermally an unfavourable energetic process (i.e.,
symmetries of the molecular orbitals with respect to mirror plane do not show ground
state correlation) and thus the disrotatory process is forbidden.
• When one considers the correlation diagram for the thermal conrotatory ring closure
of 1,3-butadiene (Scheme 17.114) considering the symmetries of the orbitals in relation
to the axis of rotation the following results arise.
• ψ1 is now antisymmetric in relation to its axis of rotation (if the ψ1 orbital is rotated
180° around the axis, the shaded lobes would come on the bottom instead of on top)
similar is the case with π (Scheme 17.114).
s*
A A
y4
Antibonding
p*
y3 S A
p
A S
y2
Bonding
y1 S S
s
Cyclobutene
1,3-Butadiene
Symmetry properties of molecular orbitals and correlation diagram for disrotatory

interconversion of butadiene-cyclobutene
A y 4— —s* A
S y 3— —p* S Correlation diagram for disrotatory
interconversion of butadiene-cyclobutene
(Mirror plane of symmetry is preserved)
A y 2— —p S
S y 1— —s S
Thermal disrotatory ring closure-1,3-butadiene (mirror symmetry maintained) symmetry forbidden
SCHEME 17.113
• However, ψ2 and π* are symmetric as in both the cases a 180° rotation would bring
shaded lobes back to the top left and bottom right of the orbital.
• Similar operations reveal that σ is symmetric while σ* is antisymmetric around the
axis of rotation.
• These data show that correlation exists between the ground state bonding orbitals,
therefore, a thermal conrotatory motion is symmetry allowed process.
s*
S A
y4
p*
y3 A S
p
S A
y2
y1 A S
s
Cyclobutene
1,3-Butadiene
S y 4— —s* A
A y 3— —p* S Correlation diagram for conrotatory
ä interconversion of butadiene-cyclobutene
(Axis of symmetry)
S y 2— —p A
A y 1— —s S
Thermal conrotatory ring closure-1, 3-butadiene (C2 axis of symmetry maintained) symmetry allowed
SCHEME 17.114
Example 2: [4 + 2] Cycloaddition of Ethylene to Butadiene to Give Cyclohexene Suprafacial

Suprafacial Thermal Cycloaddition.
The orbital symmetry relationships are given (Scheme 17.115) with respect to the mirror
plane of symmetry of the whole reacting system. The two σ-bonds of the product are considered
as a symmetric and antisymmetric combination. After the classification of the orbitals with
respect to symmetry these are arranged according to energy and the correlation lines can be
drawn. (Scheme 17.115). It is found that all bonding levels of the reactants correlate with
product ground state orbitals (orbital symmetry is conserved within the bonding orbitals and
also within the antibonding set and no cross over between the two sets occurs). This therefore,
is an allowed reaction.
A y4 A s2*
The correlation diagram

for [4s+2s] cycloaddition
(Diels-Alder reaction) for
ethylene, butadiene and
A p* cyclohexene. Thermal S s1*
concerted cycloaddition
between butadiene and
ethylene is allowed.
S y3 A p*
Anti-bonding
E
Bonding
A y2 S p
S p A s2
S y1 S s1
m m
p
s s
SCHEME 17.115
PROBLEMS
17.1. Write the stereostructure of the compound obtained by the Diels-Alder reaction of
dimethyl maleate with butadiene.
17.2. Which diene and dienophile one would employ to synthesize the following compounds?
Give alternative route for one of these.
H H
COOEt
H H Norbornadiene
(I) (II) (III) (IV)
17.3. Furan and maleimide undergo a Diels-Alder reactions at 25°C to give endo adduct as
the major product. When the reaction is carried out at 90°C, however, the major product
is the exo isomer. The endo adduct isomerizes to the exo adduct when it is heated to
90°C. Propose an explanation.
O
O
O
25°C
O O + NH
90°C NH
O NH
less stable O more stable O
(endo) (exo)
90°C via the reactants
17.4. (Z)-1,3-pentadiene reacts with maleic anhydride at 100°C to give the adduct in 4% yield,
while (E)-isomer gives the adduct in quantitative yield at 0°C. Explain.
17.5. What are the preferences for cycloaddition reactions ?
17.6. Give a classification of pericyclic reactions.
17.7. The transition state of the Diels-Alder pericyclic reaction is aromatic and compares
with Cope rearrangement. Explain.
17.8. Predict the structure of photochemical electrocyclic cyclization product of (2E, 4Z)-
hexadiene and compare the results with the thermal cyclization of the same compound.
1
CH3
H CH3
2
3 H hn CH3 H
4 CH3 CH3 CH3
5 6
H H
H (I) (II)
(2E,4Z)-hexadiene
17.9. Give the stereostructure of the products from the following electrocyclic reactions of (I
and II) carried out under photochemical reactions. Discuss if each reaction takes place
in a conrotatory or disrotatory fashion.
hn
hn
HH
(I) (II)
17.10. On thermal ring opening cis 3,4-dimethylcyclobutene gives two dienes (I and II). One of
these is formed almost exclusively which is this diene and how it is formed?
CH3
D
+
(I) (II)
CH3
cis-3,4-dimethyl-
cyclobutene
17.11. Predict whether conrotatory or disrotatory motion will take place under the conditions
mentioned against each compound. Write the structure of the product with stereo-
chemistry in each case.
CH3
CH3
hn D D
hn
CH3 CH3
(I) (II) (III) (IV)
17.12. Explain briefly, taking one common example as to how FMO (frontier molecular orbital),
method, PMO method and correlation diagram can be used for analyzing a pericyclic
reaction.
17.13. Draw a correlation diagram for disrotatory conversion of butadiene to cyclobutene. Is
the process allowed or forbidden? Explain.
17.14. A [3,3] sigmatropic rearrangement is thermally allowed via hypothetically formed allyl
radicals. Explain by drawing appropriate bonding interactions.
17.15 (a) Explain briefly as to how a conjugated diene under photochemical conditions under-
goes cyclization via a disrotatory path?
(b) Under which conditions, thermal or photochemical, the following ring closure will
take place? Explain the stereochemistry at the ring fusion.
H
O O
O
O
H
17.16. Which of the following statements are true or false.
(i) A conjugated diene with an even number of double bonds undergoes conrotatory ring
closure under thermal conditions.
(ii) A conjugated diene with asymmetric HOMO undergoes conrotatory ring closure under
thermal conditions.
(iii) A concerted antarafacial [1,3]-sigmatropic shift of hydrogen is thermally allowed.
(iv) The HOMO of a conjugated diene with an odd number of double bonds is symmetric.
(v) A [1,3] sigmatropic shift of carbon can occur under thermal conditions.
17.17. Fill in the blanks:
(i) A 1, 3-migration of carbon can take place thermally with ...... of configuration.
(ii) Pericyclic reactions are concerted, unaffected by catalysts or solvents and have ......
transition states.
(iii) [1,5] Sigmatropic shift of hydrogen involves three pairs of electrons and occurs by
...... pathway thermally.
(iv) A [1,7] sigmatropic shift of hydrogen occurs thermally by an ...... pathway.
(v) Frontier orbital analysis of a [4 + 2] cycloaddition shows that overlap of in phase
orbitals to form new sigma bonds requires a ...... orbital overlap.
17.18.(a) Draw the transition states for suprafacial and antarafacial 1, 3 hydrogen shift by
drawing the phase interactions in the basis sets. Show which process is thermally
forbidden and which thermally allowed?
(b) Explain the results of the following photochemical reaction.
hn
+
17.19.(a) Benzocyclobutene on heating with dimethyl trans-2-butene dioate (I) gives a bicyclic
product of shown stereochemistry. Explain the reaction.
CO2CH3 CO2CH3
+

CH3O2C CO2CH3
(I)
(b) Write the product with stereochemistry of the Diels-Alder reactions (II and III).
CH3 CH3
O
H H
+ O +
CH3 H CH3O2C
H O CH3
(II) (III)

17.1. The reaction follows a stereospecifically syn pathway. The product is cis-dimethyl
cyclohexene-4, 5-dicarboxylate. Therefore, the groups which are cis in the olefin also
occupy cis-positions in the cyclohexene ring.
O
O
H COCH3
COCH3
C
+
C
COCH3
H COCH3
O
O
17.2. Cyclopentadiene and acetylene.
H H
hn hn hn
+ or
[2 + 2] disrotation conrotation
H H
(I) (4n+2) (II)
D
+ +
COOEt
(III) [4 + 2] (IV)
17.3. The exo product is thermodynamically more stable. The less stable endo isomer
(kinetically favoured adduct) is formed faster and predominates at 25°C, the reaction is
effectively irreversible. At 90°C this product is in rapid equilibrium with the reactants,
consequently, the less rapidly formed but more stable exo isomer accumulates with time.
17.4. The bulky 1-cis (Z-) methyl substituent, sterically hinders formation of the cisoid con-
formation with a hydrogen at C-4. In the E-isomer the cisoid conformation is attained
easily due to only tiny H, H interaction.
H CH3
CH3 H
H H
H H
(Z)-1,3-pentadiene (E)-1,3-pentadiene
17.5. The rule of thumb is that when the reactants involve odd number of electron pairs, the
cycloaddition is allowed thermally, while with even number of electron pairs, the
cycloaddition is allowed photochemically.
17.6. Electrocyclic reactions are stereochemically classified as conrotatory and disrotatory,
cycloadditions and sigmatropic rearrangements are classified as suprafacial or
antarafacial.
17.7. In both the cases, the transition states involve six orbitals and six electrons.
Aromatic Aromatic
transition state transition state
the Cope rearrangement the Diels-Alder reaction
17.8. In the photochemical cyclization disrotatory motion is required for bond formation, one
methyl rotates up while the other down to give trans-3, 4-dimethylecyclohexene (I). The
reverse would occur in thermal reaction (see Scheme 17.6) to give (II).
17.9. (I) hn
HH
H H
Butadiene system,
disrotatory ring closure. Hydrogen atoms on the
same side of the ring.
(II) It is a 4n + 2 electrocyclic reaction; n = 1, therefore, conrotatory in the excited state,

the hydrogen atoms at the ring junctions in dihydrophenanthrene will be trans to
one another.
17.10. It is diene (I). Thermally a compound with two π bonds undergoes conrotatory ring
closure. Since in the product the two methyls are cis placed, these point in the same
direction in the reactant. In diene (I) the methyls point in the same direction.
17.11. The stereostructures of product in each case is presented (refer to Table 17.1).
H CH3
CH3 H
CH3 H
H CH3
(I) (II) (III) (IV)
(I) The reactant being a (4n) π electron system will undergo disrotatory ring closure
under photochemical conditions. Since the two methyl groups point in opposite
directions these will be cis in the product.
(III) The reactant is (2E, 4Z) hexadiene (4n) π electron system. Photochemically it will
undergo ring closure by disrotation. Since the methyl substituents point in the same
direction, the product will have these in trans relationship.
(IV) The reactant 1, 3, 5-cycloheptatriene is a (4n + 2) π electron system. It will undergo
disrotatory ring closure under thermal conditions, since in the triene, the hydrogen
substituents (not shown) point in opposite directions these will be cis in the product
norcaradiene. However, due to the strain, norcaradiene cannot be isolated and it

reverts back to the starting material. In case the ring size of the starting triene is
large as in 1, 3, 5-cyclononatriene (Scheme 17.30) the product is stable and is iso-
lated as the exclusive product.
17.15.(b) The electrocyclization will be under photochemical conditions (see table 17.1). Since
in the reactant α-pyrone, the hydrogens on the diene system are pointing in opposite
directions these will be cis in the product on disrotatory motion.
17.16. (i) True; (ii) true; (iii) true; (iv) true; (v) true.
17.17. (i) Inversion; (ii) cyclic; (iii) suprafacial; (iv) antarafacial; (v) suprafacial.
17.18. (b) This is a photochemical 1, 3-hydrogen shift (see, Scheme 17.34). Two products are
expected since two different allylic hydrogens can undergo this shift.
hn H
hn
17.19 (a) It is a combination of electrocyclic reaction (to give IV) followed by Diels-Alder reaction.
(b) The reaction (II) gives the product (V) with the stereochemistry at centres other
than ring junction as shown. This is deriveable from the discussion presented
(Scheme 17.49a). Maleic anhydride is a cis-alkene, since the Diels-Alder reaction is a
syn addition, the stereochemistry at the ring junction must be cis. The product from
reactin (III) is (VI, campare with Scheme 17.49).
CH3 H H CH3
O
O
CO2CH3
H H O
CH3 CH3
(IV) (V) (VI)
References and Further Reading
1. T.A. Albright, J.K. Burdett, and M.H. Whangbo, Orbital Interactions in Chemistry, John Wiley
and Sons, New York, 1985.
2. P.J. Garratt, Aromaticity, Wiley, New York, 1986.
3. M. Sainsbury, Aromatic Chemistry, Oxford University Press, Oxford, 1992.
4. B.K. Carpenter, Determination of Organic Reaction Mechanisms, Wiley-Interscience, New York,
1984.
5. K.A. Connors, Chemical Kinetics, VCH Publishers, New York, 1990.
6. C. Reichardt, Solvents and Solvent Effects in Organic Chemistry, Wiley-VCH, Weinhem, 2003.
7. E. Erdik, Organozinc Reagents in Organic Synthesis, CRC Press, Boca Raton, FL, 1996.
8. P. Knochel and P. Jones, Editors, Organozinc Reagents, Oxford University Press, Oxford, 1999.
9. H.G. Richey, Jr., ed., Grignard Reagents; New Developments, Wiley, New York, 2000.
10. M. Schlosser, ed., Organometallic in Synthesis; A Manual, Wiley, New York, 1994.
11. B.J. Wakefield, Organomagnesium Methods in Organic Synthesis, Academic Press, London, 1995.
12. R.M. Crabtree, The Organometallic Chemistry of the Transition Metals, Wiley-Interscience, New
York, 2005.
13. J.K. Kochi, Organometallic Mechanisms and Catalysis, Academic Press, New York, 1979.
14. E. Negishi and A. de Mejeire, eds., Handbook of Organopalladium Chemistry for Organic Synthesis,
Vol. 1 and 2, Wiley-Interscience, New York, 2002.
15. H.C. Brown, Organic Synthesis via Boranes, Wiley, New York, 1975.
16. A. Pelter, K. Smith, and H.C. Brown, Borane Reagents, Academic Press, New York, 1988.
17. D.R. Arnold, N.C. Baird, J.R. Bolton, J.C.D. Brand, P.W.M. Jacobs, P. de Mayo, and W.R. Ware,
Photochemistry; An Introduction, Academic Press, New York, 1974.
18. A Gilbert and J. Baggott, Essentials of Molecular Photochemistry, CRC Press, Boca Raton, FL,
1991.
19. W. Horspool and D. Armester, Organic Photochemistry: A Comprehensive Treatment, Ellis
Horwood/Prentice-Hall, Chichester, 1992.
20. W. H. Horspool and P.-S. Song, eds., Organic Photochemistry and Photobiology, CRC Press, Boca
Raton, FL, 1995.
21. W. Horspool and F. Lenci, eds., CRC Handbook of Organic Photochemistry and Photobiology,
2nd Edition, CRC Press, Boca Raton, FL, 2004.
22. P.B. de la Mare and R. Bolton, Electrophilic Additions to Unsaturated Systems, 2nd ed., Elsevier,
New York, 1982.
23. P.V. Ramachandran and H.C. Brown, Organoboranes for Synthesis, American Chemical Society,
Washington, 2001.
24. A.L.J. Beckwith and K.U. Ingold, in Rearrangements in Ground and Excited States, P. de Mayo,
ed., Academic Press, New York, 1980, Chap. 4.
683
References and Further Reading 684
25. M. Birkhofer, H.-D. Beckhaus, and C. Rüchardt, Substituent Effects in Radical Chemistry, Reidel,
Boston, 1986.
26. J. Fossey, D. Lefort, and J. Sorba, Free Radicals in Organic Chemistry, Wiley, Chichester, 1995.
27. B. Giese, Radicals in Organic Synthesis: Formation of Carbon-Carbon Bonds, Pergamon Press,
Oxford, 1986.
28. W.B. Motherwell and D. Crich, Free Radical Chain Reactions in Organic Synthesis, Academic
Press, London, 1992.
29. P. Renaud and M.P. Sibi, Radicals in Organic Synthesis, Vol. 1, Basic Principles, P. Renaud and
M.P. Sibi, editors, Wiley-VCH, Weinheim, 2001.
30. M.B. Smith and J. March, March’s Advanced Organic Chemistry, Wiley, New York, 2001.
31. Fleming, Frontier Orbitals and Organic Chemical Reactions, Wiley, London, 1976.
32. R.B. Woodward and R. Hoffmann, The Conservation of Orbital Symmetry, Verlag Chemie,
Weinheim, 1971.
33. F.A. Carey and R.M. Sundberg, Advanced Organic Chemistry; 5th ed; Springer, 2007.
Index
A dihydropyran, 437
photoaddition, 400
Aci form, 82 syn additions, 146
Acidity: Alcohols
alcohol, 95 acidity, 95, 97
of imides, 101 reactions:
constant Ka, 88 esterification with organic
of carboxylic acids, 96 acids, 252
of α-hydrogens, 104 oxidation, 463
of C—H groups, 102 Aldol condensation, 103, 220
of C—H bond, 93 directed, 222
of cyclopentadiene, 65, 103 stereochemistry, 223
of O—H groups, 95 Alkanes:
of N—H groups, 101 rearrangements, 554
and structure, 91 nitration, 599
of sulphonic acids, 100 Alkenes:
Acids: acidity, 94
acid-base reactions, 94, 116 addition, 421
Bronsted-Lowry concepts, 87 metathesis, 272
Lewis, 90 reduction, 501
Acid strength: 91 oxidation, 474–486
leveling effect, 118 ozonolysis, 485
solvent effect, 117 Alkyl boranes, 488
Acetonitrile, 111 Alkyl halides
Activated complex, (see Transition state), 135 reactions:
Activation and deactivation of benzene ring, 340, elimination, 125
350
nucleophilic substitution, 176
Activation energy, 135
Alkynes:
Acyl anion equivalent, 166
acidity, 94
Acyl-iron complexes, 275
coupling, 595
Acylium ion, 337
Allylic oxidation, 470
Acyloin condensation, 592
Allylic rearrangement, 51
Adamantane, 554
Allylic substitution, 575
Addition reactions, 124
Allylic species, 46
1,4-additions, 140
Allylsilanes, 301
to alkenes, 429
Amibdent nucleophile, 216
to alkynes, 430
Amides, 110, 436
antarafacial and suprafacial, 631
acidity, 101
anti additions, 150
$&#
$&$ Organic Reactions and their Mechanisms
basicity, 110 Basicity:

hydrolysis, 257 of amines, 107
reduction, 525 constants Kb and pKb, 106
Ammonia (structure), 6 in gas phase, 107
Anchimeric assistance, 205 and nucleophilicity, 185
Angle strain, 9, 55 of pyridine, 111
Aniline: effect of solvent, 117
basicity, 108 effect of structure, 106
[18] Annulene, 57, 596 9-BBN, 306
Anthracene, 72, 353 Beckmann rearrangement, 558
Antiaromatic, 57, 61 Benzene, 42
Anti-Markovnikov addition, 305, 586 sigma (σ) complex, 331
Arbuzov reaction, 282 electrophilic substitution, 329
Arenechromium-carbonyl complexes, 376 protonation, 333
Arenium ion, 174, 329 resonance, 42
Arndt-Eistert Synthesis, 553 Benzidine rearrangement, 565, 566
Aromatic compounds, 57 Benzilic acid rearrangement, 552
Aromatic ions, 63 Benzoin, 493
Aromatic heterocyclic compounds, 70 Benzoin condensation, 238
Aromaticity, 53, 57, 61 Benzvalene 43
and acidity, 103 Benzylic position:
and carbocation, 156 halogenation, 577
and NMR, 56 oxidation, 469
annulenes, 57, 59 Benzyne, 126, 174, 370, 372, 400
azulene, 68 Birch reduction, 515
benzene, 56 Biphenyls:
Aromatic compounds, 54 synthesis, 590
Arrhenius equation, 136 Bonding, 1
Aryl bromides, 195 delocalized, 39
Asymmetric induction, 535 Bond angles, 6
Atactic, 272 in reaction mechanism, 9
Atomic orbitals, 1 shapes of molecules, 6
Aza enolates, 244 Bond length and strength, 9
Aza-Cope rearrangement, 659 Bonds:
Azulene, 68 pi (π) and sigma (σ), 11
Borane:
B hydroboration, 304
Baeyer-Villiger reaction, 492 reduction of epoxides, 537
Baeyer-Villiger rearrangement, 559 reduction of ketones, 522
Bakers yeast, 538 Borohydrides, 522, 524
Barton reaction, 594 Bredt rule, 34, 37
Bredt rule, 37 Bridgehead, 201
9BBN, 307 Bridgehead carbon, 37
Bases Brönsted-Lowry concept, 87 Bromination of benzene, 333
Lewis, 90 Bromonium ion, 130, 150, 423, 430
N-Bromosuccinimide (NBS), 52, 575
Index $&%
Bulky boranes, 306 Claisen (ester) condensation, 236

1,3-butadiene, 39, 41 Claisen rearrangement, 661
Bulvalene, 658 Claisen-Schmidt reaction, 226
Butadiene, 39 Clemmensen reduction, 520
Butyl lithium, 113 Collins reagent, 463
Conjugated diene, 39
C Cope reaction, 457
Cope rearrangement, 399, 655
Claisen reaction, 229
Corrannulene, 45
Camphor, 529
Crams rule, 536
Cannizzaro reaction, 535
Crown ethers, 22, 194, 483
Canonical forms, 42
Carbanion, 10, 164 Cryptates, 22
acetylide anion, 95 Cryptands, 24
allylic, 140 Curtin-Hammett principle, 144
from organometallics, 165 Curtius rearrangement, 556
Carbenes, 171, 433 Cycloaddition reaction, 630, 668
Carbenoids, 434 Cyclobutadiene, 55, 58
Carbocations, 10, 154 Cyclobutane, 36
allyl, 46, 156 Cyclodextrin, 25
benzylic, 156 Cycloheptatriene, 54
bridgehead, 160 Cycloheptatrienyl ions, 66
nonclassical, 204 Cyclooctatetraene, 55, 60
rearrangement, 162 dianion, 68
vinyl, 160 Cyclopentadienyl ions, 64
Carbonyl groups:
reduction, 523 D
Carboxylic acids:
Dakin reaction, 492
acidity, 96
Darzens condensation, 231
decarboxylation, 250
DCC, 464
Catalysis:
DDQ, 473
electrophilic, 193
Decarbonylation, 599
nucleophilic, 193
Decarboxylation, 250, 493
Catalytic hydrogenation, 501
Dehydrogenation, 474
Catecholborane, 306
Dewar benzene, 42
Catenanes, 28
Diazomethane, 398, 553
Charge transfer complex, 21
Diazonium ions:
Chichibabin reaction, 376
coupling, 361
Chloranil, 468
DIBAL, 532
Chloronium ion, 425
β-Dicarbonyl compounds, 103, 227
Cholesterol, 503
Dieckmann condensation, 237
Chromium arene complexes, 277
Diels-Alder reaction, 360, 630
Chromium (VI) oxide, 463
of furan, pyrrole and thiophene, 360
s cis., 41
Diimide, 509
Cine substitution, 372
Diisobutylaluminum hydride (DIBAL), 533
Clathrate compounds, 28
$&& Organic Reactions and their Mechanisms
Dimethyl sulfoxide (DMSO), in oxidation, 464, Enantioselective recognition, 23

465 Endo rule, 633
Diol, 481 Ene reaction, 663
Di-pi-methane rearrangement, 409 Energy profile diagram, 137
Dioxirane, 476, 495 Enolates, 44, 114, 216, 220
Dipolar cycloaddition, 644 regiospecific generation, 220
Dipole moment, 12 Entropy, 132
Epoxides (reactions)
Disiamylborane, 306
acid-catalyzed, 478
1, 3-Dithianes, 105, 295
base-catalyzed, 479
Double bond, 5,7
formation, 475-78
DMDO, 476
reactions, 480-83
DMP, 467 reduction, 538
DMSO, 465, 471 Esterification, 252
Ester:
E hydrolysis, 252
Ether formation, 600
Electrocyclic reaction, 609
Electron
deficient systems, 543 F
rich systems, 544 Favorskii rearrangement, 560
18-rule, 264 Ferrocene, 71
spin resonance spectroscopy (esr), 53 Field effects, 14
transfer steps, 596 Fluorene, 590
Electronegativity, 12 Fluxional molecules, 659
Electrophile, 130 FR (D), 477
Electrophilic catalysis, 193 FR (L), 477
Electrophilic addition Franck-Condon principle, 341
alkenes, 430 Free energy, 132
alkynes, 429 Free radicals, 168, 597
metal ions, 431 Free radical rearrangements, 545, 597
Electrophilic substitution, 329 Friedel-Crafts reactions:
aromatic, 329 acylation, 336
heteroaromatic, 358 alkylations, 249, 334
substituent effect, 342 limitations, 355
α-eliminations, 438 Fries rearrangement.
β-eliminations, 438 Frost circle, 62
Cope elimination, 457 Fullerene, 75
E1 and E2 mechanisms, 439, 452 Furan(s), 71
E1cB, 439
ester pyrolysis, 455 G
Hoffmann rule, 441
Gatterman Aldehyde synthesis, 357
Saytzeff rule, 441
Gatterman-Koch reaction, 357
Syn elimination, 451
Gilman reagents, 48, 195, 323
xanthate esters, 457
Glycols, 482
Enamine (Stork) reaction, 199, 239
Gomberg reaction, 590
Index $&'
Grignard reagents, 316, 317 of alkynes, 508-512

allylic Grignard reagent, 319 mechanism, 502
basicity, 317 Hydrogen-bonding (H-bonding), 18
limitations, 317 Hydrogenolysis, 501, 516, 518
preparation, 316 Hydrolysis, 252-57
reactions; Hydroxylation, 477
with acid chlorides, 318 Hyperconjugation, 11, 78
with alcohols and water, 317
with aldehydes, epoxides and I
ketones, 317, 320
Inclusion compounds, 27
with amides, 318
Inductive effects, 14
with carbon dioxide, 319
on acidity of carboxylic acid, 96
with esters, 317
Intersystem crossing, 384
with ethylorthoformate, 318
Ion-pairs, 202
with nitriles, 318
Ipc2BH, 308
with pyrrole, 320
Ipso attack, 128, 232, 366
other reactions, 319, 321
Ipso substitution, 123, 353
steric effects, stereoselectivity, 321
Isomerisation (of olefins), 555
Guanidine, 111
Isotope effect, 462
Isotopic labelling, 154
H
Halogenation of benzene, 333 J
Hammett equation, 30
Jablonski diagram, 382
Hammond postulate, 141
Jones reagent, 462
Hard acids and bases, 118
Heck reaction, 267
Hexahelicene, 79 K
Hexamethylenetetramine, 469 Kinetic control, 139
Hofmann elimination, 442 Kinetic enolate, 219
Hofmann rearrangement, 554 Kinetic isotope effects, 150
Hofmann Loffler-Freytag reaction, 593 Knoevenagel reaction, 232
HOMO and LUMO, 605 Kolbe electrolytic reaction, 591
Homoaromatic compounds, 77
Hückel’s rule, 57
L
and antiaromaticity, 59
and aromaticity, 57 LDA, 112, 115, 199, 511
Hunsdiecker reaction, 590 Leveling effect, 118
Hybrid orbitals, 2 Lead tetraacetate, 486, 600
Hybridization, 2, 9 Lindlar’s catalyst, 508
Hydroboration, 304 Linear molecules, 8
enantioselective, 308 Lithium alkoxyaluminum hydrides:
Hydroformylation, 269 diisobutylaluminium hydride (DIBAL), 532
Hydrogenation, 501 Lithium aluminum hydride, 522
of alkenes, 501-508 Lithium diisopropylamide (LDA), 111, 199, 217
Lossen rearrangement, 556
$' Organic Reactions and their Mechanisms
M SN1 and SN2, comparison, 176

Nucleophilic aromatic substitution, 366
Manganese dioxide, 468 addition, elimination, 366
Mannich reaction, 247 elimination addition (benzyne), 370
Markovnikov addition, 587 Nucleophilic catalysis, 193
Meerwein-Ponndorf-Verley reaction, 534 Nucleophilicity, 184
Meisenheimer complex, 368
Mercurinium ion, 431
O
Metallocenes, 71
Mechael addition, 234 O2, 569
Mitsunobu reaction, 288 Oppenauer oxidation, 467
Migratory aptitudes, 550 Organic lithium compounds, 322
Molecular orbitals, 2 Organoboranes, 304
Molecular rearrangements, 126, 543 from alkenes, 305, 307, 308
isomerization of, 307
N with carbon, monoxide, 310
with carboxylic acids, 309
Napthalene, 72 with cyanide ion, 312
electrophilic substitution, 352 with α-haloesters, 313
Naphthalene-1-sulfonic acid, 352 oxidation, 308
NBS, 575 protonolysis, 309
Neber rearrangement, 563 sterically congested, 306
Neighbouring group participation, 204 synthesis of alkynes, 315
Neopentyl cation, rearrangement, 545 synthesis of conjugated dienes, 315
Nickel complexes, 278 synthesis of E and Z alkenes, 313
Nitration, electrophilic aromatic substitution, Organocuparate, 195, 323
332
Organotransition metal complexes, 263
Nitriles, 436
chromium arene, 277
Nitrenes, 173
Iron, 276
Nonaromatic, 57, 59
Nickel, 278
Non-benzenoid aromatic compounds, 68
Palladium, 267
Nonclassical carbocations, 204
Rhodium, 266
Norcamphor, 529
Titanium, 271
Norrish type reactions, 393, 396
Organosilicon compounds, 297
Nucleophiles, 130
Osmium tetroxide, 482
Nucleophilic addition
Oxidative coupling, 392
alkenes, 432
Oxygen singlet triplet, 496, 569
alkynes, 432
Oxaphosphetane, 281
carbonyl compounds, 434
Oxaspiropentane, 292
carboxilic acid derivative, 435
Oxiranes (see Epoxides)
Nuclophilic aliphatic substitution, 176
Oxo reaction, 269
bimolecular (SN2), 182
Oxy-Cope rearrangement, 659
electrophilic and nucleophilic catalysis, 193
Oxymercuration-demercuration, 431
nucleophilicity, 184
Ozonolysis:
solvent effects, 188
of alkenes, 486
substrate structure, 182, 194
Index $'
P Potassium permanganate, 481

Prevost reaction, 484
Palladium chloride, 488 Primary isotope effect, 151
Paracyclophanes, 45 Prins reaction, 246
Partial bond fixation, 73 Prismane, 43
Parterno-Büchi reaction, 400 Protonation of benzene, 333
Pauson-Khand reaction, 270 Pschorr synthesis, 590, 591
Periodic acid, 487 Pyridine(s), 70
Perkin reaction, 230 basicity, 111
Peroxide effect, 586 reactions, 361, 376
Peroxyacids, 475 Pyridine N-oxide, 466, 495
Peterson reaction, 298 Pyridinium chlorochromate (PCC), 463
pH, 88 Pyridinium dichromate PDC, 463
Phase transfer catalysis, 194 Pyrrole(s), 71, 109
Phenanthrene, 72 basicity, 109
Phenol coupling, 494 reactions, 359
Phosphorane, 280
Phosphorescence, 382
Q
Photochemical elimination, 400, 403
Photochemical aromatic nucleophilic Quantum yield, 380
substitution, 414 Quadricyclane, 410
Photochemical eliminations, 400
Photochemical rearrangement, 409 R
Photochemistry of:
Dienes, Radical addition:
alkenes and to multiple bonds, 572, 580
aromatic compounds, 406 orientation and reactivity, 579
Photocyclization, 409 Radical rearrangements, 597
Photodimerization, 406, 410 Radicals, 10, 168
Photoenolization, 387 allylic, 46, 52, 574
Photo-Fries rearrangement, 355, 413 bridgehead, 169
Photoisomerization, 390 inhibitors, 602
Photolysis, 399 preparation, 569
Photolytic reduction, 343 reactivity of, 574
Photooxidation, 388, 495 selectivity, 575
Photoreduction, 385 stability, 169, 570
Photosensitization, 344 Rate enhancement, 184
Picolines, 104 Rate determining step, 138
Pi bond, 11 Rate of reaction, 134
Pi(π) complex, 21, 284 Rearrangements, 354
Pinacol rearrangement, 549 Redox reactions, 572
Piperidine, 111 Reduction, 500
Polymerization, 601 of aldehyde, 522
Polymers: of amides, 525
atactic, 271 of carboxylic acids, 527
isotactic, 271 catalytic, 501
syndiotactic, 272 via, diimide, 510
$' Organic Reactions and their Mechanisms
via, dissolving metals, 510 Singlet-methylene insertion, 433

of esters, 524 SN1 (substitution, nucleophilic, internal)
via, hydride transfer, 522 mechanism, 200
mechanism, 503 SN1 reactions, 51, 196
Wilkinson’s catalyst, 506 comparison with SN2, 198
of nitriles 528 nucleophilic aromatic substitution, 369
reductive coupling, 515 rearrangement during, 157, 181
stereochemistry, 531 with Silyl enol ethers, 243
via, zinc metal, 516 SN2 mechanism, 95,
Reformatsky reaction, 230 at an allytic position, 195
Reimer-Tiemann reaction, 355 at an aryl substrate, 194
Resonance, effect:
hybrid, 43, 52 of crown ether, 194
rules for, 44 of leaving group, 190, 193
steric inhibition of, 44, 102 of nucleophile, 184
structures, 44, 46 of substrate structure, 182
Resonance effects, 47, 49 SN1′, 52, 200
on acid base strength, 50 SN2′ mechanism, 52
on reactivity, 47, 50 SNAr mechanism, 366, 368
Resonance energy, 50 Sodium cyanoborohybride, 540
Retinal, 351 Solvation of ion, 97, 194
Retro-Aldol reaction, 229 Sommelet reaction, 468
Rhodium catalyst, in hydrogenation, 507 Sommelet-Hauser rearrangement, 564
Ring contraction, 162, 399 SRN1 mechanism, 600
Ring enlargement 162, 172 Strained molecules, 8
Robinson annulation, 235 Steric effects, 34
Rosenmund reaction, 508 Steric hindrance, 34, 183
Rotaxanes, 28 Steric strain (I-strain), 34
Stevens rearrangement, 563
S Stobbe condensation, 231
Stork enamine reaction, 199, 239
Saytzeff rule, 441 Sulfonation:
Schmidt rearrangement, 557 of benzene, 333
SE2 reactions, 200, 329 Sulphonic acid, 100
SET mechanism, 201 Super acid, 101
Selectrides, 531 Suzuki reaction, 340
Selenides, 458 Swern oxidation, 465
Selenium dioxide, 469, 470
Selenoxide, 458
T
Shapiro reaction, 521
Sigma bonds, 12 Taft equation, 33
Sigma (σ) complex, 329 Tautomerism, 79
Sily enol ethers in SN1 reactions, 243 Tebbe, reagent, 273
Silyl ether protection with, 302 TEMPO, 467
Silver oxide, 463 Tetrahedral structure, 5
Simmons-Smith synthesis, 434 Thermodynamic control, 139
Index $'!
Thexylborane, 306 W
Thermodynamic enolate, 218
Thioketals reduction, 522 Wacker reaction, 269
Thorpe reaction, 238 Wadswarth-Emmons reaction, 281, 285
Tosylate esters, 180 Wagner–Meerwein rearrangement, 545
Tosylhydrazones, 520 Water (structure), 6
s-trans, 41 Wilkinson’s catalyst, 266, 505
Transfer hydrogenation (see Hydrogenation) Williamson synthesis, 133
Transition state (TS, activated complex), 135, Wittig reaction, 280
144 Wittig rearrangement, 563
stabilization, 142 Wolff-Kishner reduction, 520
Tributyltin hybride, 582 Wolff rearrangement, 553
Triflate anion, 195 Woodward reaction, 484
Trimethylsilyl iodide, 303
Triphenylmethyl radical, 170, 570 X
Triplet carbenes (see Carbenes), 398
Xanthate ester, 454
Tropylium ion, 67
Y
U
Ylide
Ullman reaction 591
phosphorous, 166, 280
Umpolung, 295
sulphur, 290, 292
Unactivated C—H group (Oxidation), 472
Z
V
Z (see E/Z notation)
Vibrational level, 381
Ziegler-Natta catalyst, 271
Vilsmeier reaction, 358
Zinc metal, 516
Vinylsilanes, 300
VSEPR model, 6

Kalsi P S Organic Reactions and Their Mechanisms New Age Science

Uploaded by

Copyright:

Available Formats

Kalsi P S Organic Reactions and Their Mechanisms New Age Science

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Kalsi P S Organic Reactions and Their Mechanisms New Age Science

Uploaded by

Copyright:

Available Formats

3rd Edition

The Control Centre, 11 A Little Mount Sion

ISBN : 978 1 78183 175 5

British Library Cataloguing in Publication Data

Shapiro reaction, 521 Tiffeneau-Demjanov reaction, 293

Acyl-iron complexes, 275 Lithium dialkylcuparates, 323

Chapter 1 Fundamental Principles and Special Topics 1–38

1.1 Structure and Bonding in Organic Compounds 1

Chapter 2 Delocalized Chemical Bonding 39–86

2.1 1, 3-butadiene a Typical Conjugated System 39

Chapter 3 Organic Acids and Bases 87–121

Chapter 4 Organic Reactions and the Determination of 122–175

Chapter 5 Aliphatic Nucleophilic Substitution and 176–215

5.1 Introduction 176

Chapter 6 Common Organic Reactions and their 216–262

6.1 Base Catalysed Reactions (Formation of Carbon-Carbon Bonds) 216

Chapter 7 Reagents in Organic Synthesis and Relevant 263–328

7.1 Organotransition Metal Reagents 263

Chapter 8 Electrophilic Aromatic Substitution 329–365

8.1 General View—The Arenium Ion—The Arenium Ion

Chapter 9 Aromatic Nucleophilic Substitution 366–379

9.1 The SNAr Mechanism—The Addition—Elimination Mechanism— 366

Chapter 10 Photochemistry 380–420

10.1 Absorption of Electromagnetic Radiation—Quantum Yield 380

Chapter 11 Addition to Carbon-Carbon and Carbon-Hetero 421–437

11.1 Addition of Electrophiles to a Multiple Bond 421

Chapter 12 Elimination Reactions 438–461

12.1 The Bimolecular Mechanism for Elimination—E2 Process 439

Chapter 13 Oxidation Methods 462–499

13.1 Oxidation of Alcohols to Aldehydes, Ketones or Carboxylic Acids 462

Chapter 14 Reduction Methods 500–542

14.1 Catalytic Reduction-Reduction with Diimide and Hydroboration 501

Chapter 15 Molecular Rearrangements 543–568

15.1 Rearrangements to Electron Deficient Carbon 545

Chapter 16 Free Radical Reactions 569–604

16.1 Structure, Stability and Geometry 569

16.4 Aromatic Nucleophilic Substitution—SRN1 Substitution 588

Chapter 17 Pericyclic Reactions 605–682

17.1 Conservation of Molecular Orbital Symmetry 608

References and Further Reading 683-684

1.1 STRUCTURE AND BONDING IN ORGANIC COMPOUNDS

B. Molecular Orbitals and Bonding

(I) (II) (III)

C. Hybrid Orbitals: Bonding in Complex Molecules

(I) Hybridization Back lobe

Hybridization in beryllium to create two sp hybrids

Triangular structure of BH3

‡ The p bond is electron rich and borane electron poor. In

(iii) sp3 Hybridization gives Tetrahedral Shape

D. Bond Angles, Shapes of Molecules (VSEPR model) and Reactivity

Methanal trigonal planar

Ethene trigonal planar

Linear carbon dioxide (Ethyne) Linear acetylene

The orbitals forming the

VSEPR MODEL/SHAPE OF MOLECULES

(v) Strained Molecules

(vi) Role of Bond Angles in Reaction Mechanism

Table 1.1 Relative reactivities of cycloalkyl

E. Hybridization and Length and Strength of a Bond

F. Shapes of Some Reactive Intermediates

1.2 ELECTRONEGATIVITYDIPOLE MOMENT

A : B → A· + B· DH° = Homolytic bond dissociation energy or D(A B)

HH 104 CH3H 104

1.7 THE HAMMETT EQUATIONLINEAR FREE ENERGY RELATIONSHIP

NH2 0.16 0.66

(B) Resonance Structures of BenzeneDewar Structures

(C) Canonical FormsClaus Benzene

(D) Writing One Best StructureRepresentation of Resonance Hybrid Structure