SCHOOL OF SCIENCE & HUMANITIES

DEPARTMENT OF CHEMISTRY

UNIT – I - ORGANIC SYNTHESIS – SCYA5101

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 UNIT 1

ORGANIC SYNTHESIS

1.1 Synthetic analysis and planning:

Synthetic planning is a construction process that involves converting simple and
commercially available molecules into complex molecules using specific reagents associated
with known reactions in the retrosynthetic scheme. The overall yield in a multistep synthesis
is the product of the yields for each separate step.

1.2 Guidelines for Retrosynthesis:

1. Recognize the functional group in the TM.
2. Disconnect the TM into fragments with known reliable chemical reactions using
FGI.
3. During FGI, changing one Functional group to another may alter its reactivity
dramatically.
i. Alcohols and aldehydes are converted by redox reactions with the
carbonyl groups are electron withdrawing and alcohols are electron
donating groups.
4. Disconnections in the TM proceeds with
i. Disconnect at the middle of the TM
ii. Disconnect at the branch point
iii. Disconnect rings from the chains.
b. Bonds next to carbonyl group
c. Bonds joining the aromatic ring to the rest of the molecule.
d. Using two group disconnections.
5. Some substituents (OMe) are difficult to add in that case it is best to retain them for
the synthesis.
6. Some groups are added to the aromatic ring by electrophilic substitution reaction
which requires an electron withdrawing group like nitro (o to leaving group).
7. When a series of reactions has been proposed, start a reaction which gives a single
product rather than a mixture.
8. When two groups are of equal reactivity, one group is selectively reacted by suitable
reagents.
9. When two groups of unequal reactivity, the more reactive can be made to react first.

1.3 Classification:

Synthesis can be grouped into three broad categories: (i) Linear synthesis (ii)
Convergent synthesis (iii) Divergent Synthesis.

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1.3.1 Linear Synthesis:
In linear synthesis, the target molecule (TM) is synthesized through a series of linear
transformations. The TM is assembled in a stepwise manner. E.g.,
A B C D E F G H
For the above seven step synthesis, there are total eight components (A to H). If the yield of
the intermediate at each step is 80% then,
Overall yield of H = 80/100*80/100*80/100*80/100*80/100*80/100 =0.21
Therefore, overall yield % of H = 21%.

1.3.2 Convergent Synthesis

A convergent synthesis is a strategy that aims to improve the efficiency of multistep
organic synthesis. In this case, the key fragments of the target molecule are synthesized
separately or independently and then joined together at a later stage in the synthesis to make
the target molecule. E.g.,
In this sequences of convergent synthesis:
A B
C D E
There are five components in two steps (A to E) each with a yield of 50%
The overall yield is given by (50/100)*(50/100) =0.21 =21%

1.3.3 Divergent Synthesis

A divergent synthesis is a strategy with the aim to improve the efficiency of chemical
synthesis. It is often an alternative to convergent synthesis or linear synthesis. In this
strategy divergent synthesis aims to generate a chemical compound (1) by first reacting a
molecule with a set of reactants. The next generation of compounds is generated by further
reactions with each compound in generation 1. This methodology quickly diverges to large
numbers of new compounds.

1.4 Definitions
Target Molecule: The molecule to be synthesized.
Retrosynthesis: The logical processes of analysing the structure of the target molecule to
discern a possible synthesis step by step and is represented by
Disconnection: A conceptual cleavage of a bond to break the molecule into possible starting
materials.
Transformations (tfs): A disconnection of a strategic bond in the target molecule.
Synthons: the charged species formed during the disconnection process.
Retron: The functional group containing portion of the target material.
Synthetic equivalents: A chemical compound available commercially for a synthon.
FGA( Functional group Addition)- addition of Functional group during a strategic bond
breaking.
FGI (Functional Group Interchange)-Changing of one functional to another to disconnect
a bond.
Functional group Removal(FGR): Deletion of functional group in the target molecule for
the successive steps to form synthons.

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Ring Disconnection (RGD): cyclic ring structure is disconnected to form aliphatic
molecules.
Chain Disconnection(CHD):Acyclic structure or appendage in the ring structure is
removed.

Arrow Notations

Reaction Arrow is denoted by “ ”

Delocalization arrow by “ ”
Equilibrium arrow by “ ”
Curved arrow (electron movement) “ ”

Fish-Hook arrow (one electron) “ ”

Retrosynthetic arrow “ ”
TM can be made from the substrate. (Reverse of the synthetic reaction).

Test for Knowledge

Predict the conversions:

1.5 Synthons:
Depending on nucleophilic and electrophilic role, synthons are classified as electron
donors (d) and electron acceptors (a) and are numbered with respect to the relative position
of the FG and the reactive carbon atom.
Donor synthons: Neagtive polarized synthons denoted by ‘d’

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 Eg: Alkyl anions, R-; cyanide CN- ; acetylide RCΞC-
Acceptor synthons: Positive polarized synthons denoted by ‘a’
Eg; Alkyl R+; Acyl cation Ar+; acylinium RCO+;

According to the position of FG,

Alkyl synthons: Alkyl synthons without functional groups and are used as alkylating
agents.
d0: Electronegative heteroatom of the FG forms a covalent bond with acceptor synthons.
a1d1: If the C1 atom of the FG itself is reacting then it is a1 (for acceptor synthons) and d1
(for donor synthons)
a2d2: If the C-2 carbon atom ( mainly relative to carbonyl group) to the FG is reactive.
a3d3: If the C-3 carbon atom is reactive relative to FG

Type synthons Synthetic equivalents

d0 MeS- MeSH

d1 CN- KCN

d2 -
CH2CHO CH3CHO

d3 -
C=CCOOMe CH2=CHCOOMe

Acceptor synthons

Type synthons Synthetic equivalents

a0 +
PMe2 ClPMe2

a1

a2

a3

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1.6 Retrosynthesis of MonoFunctional Disconnections

Example 1
Consider the formation of primary alcohol, ,it can be formed by
disconnecting the alcoholic bond to form

Leads to the formation of synthon and ethylene oxide.

Synthon can be formed by,

The R- synthon is formed by,

The synthetic equivalents are HCHO, ethylene oxide and ROH

Synthesis of

Example 2-Tertiary alcohol disconnection:

The target molecule is

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The disconnection can be of

The formation of the synthon is difficult.

Hence, the disconnection can be

Retrosynthesis

Synthon, Ph- can be obtained

Starting materials are cyclohexanol, acetaldehyde and bromobenzene.

Synthesis:
1)Phenyl magnesium bromide from Bromobenzene.

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2) Cyclohexanol to methyl Ketone

Alcohol to ketone

3)Reaction of ketone with PhMgBr to form TM

Example 3- Alkene disconnection

By FGI of an alkene to alcohol and then followed by alcohol disconnection.
By Wittig reaction. ( the reaction is not applicable if the double bond is a part of the
ring)
a) By alcohol disconnection:

The target molecule is,

The disconnection proceeds by conversion to 30 alcohol and then disconnected.

Retrosynthesis:

Synthon, Ph- is obtained by

The synthetic equivalents or starting materials for the reaction is cyclohexanone and
bromobenzene.

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Synthesis of the TM,
Reaction of cyclohexanone with phenyl magnesium bromide followed by dehydration.

b) Alkene disconnection by Wittig reaction.

The Target Molecule,
Retrosynthesis:

Phosphorane is obtained by

The starting materials for the reaction are benzyl alcohol,acetone, ethylene oxide.

Synthesis:
1) Phosphorane is prepared from benzyl alcohol.

2) Reaction of phosphorane with acetone to form TM

Example 4- Ketones disconnection

Methyl ketones are disconnected by acetonylation reaction (introduction of CH3COCH
group).
Symmetrical ketones are disconnected through ethylformate.
Unsymmetrical ketones are disconnected via alcohol disconnection.

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a) Methyl ketones disconnection,
Target molecule is

Retrosynthesis approach:
a) Introduction of Functional group (COOR) followed by disconnection

The synthetic equivalents or starting materials for the reaction are ethyl acetoacetate and
benzyl bromide.
Synthesis:

b) Symmetrical Ketones
Target Molecule is

Retrosynthesis:
By FGI to 20 alcohol and then disconnected.

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The synthetic equivalents or starting materials for the reaction are ethyl formate, methanol
and ethylene oxide
Synthesis:
Preparation of Propyl Magnesium bromide from methanol and ethylene oxide.

Reaction of Propyl Magnesium bromide with ethyl formate to form aldehyde.

c) Unsymmetrical Ketones
Target Molecule is

Retrosynthesis:
Conversion of 20 alcohol and disconnection

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The synthetic equivalents or starting materials for the reaction are propanal, bromobenzene
and ethylene oxide.
Synthesis:
Reaction to phenyl ethyl magnesium bromide

Reaction with propanal to 20 alcohol and oxidation

Example 5 Carboxylic acid disconnection

a) Conversion to aldehyde cyanodhydrin
b) Disconnection to CO2
Example1 :
The target acid molecule is
Retrosynthesis
By CO2 disconnection

The synthon is further disconnected,

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The synthetic equivalents or starting materials for the reaction are CO2, bromobenzene and
ethylene oxide.
Synthesis:

Formation to phenyl ethyl Magnesium Bromide

Reaction with CO2

Second approach:
Target molecule:

Retrosynthetic approach:

The synthetic equivalents or starting materials for the reaction are HCN, bromobenzene and
ethylene oxide.
Synthesis:

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Example 6- Alkane Disconnection
FGA to form alcohol disconnection.
Eg 1:
Target Molecule:

Retrosynthesis approach:
FGA to form alcohol followed by disconnection

The starting materials or synthetic equivalents for the reaction are Ethanol, Ethylene oxide
and bromo benzene.
Synthesis:
Formation of butanal, Phenyl Magnesium bromide followed by their reaction to form TM

Formation of Butanal

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Reaction of Butanal with Phenyl Magnesium bromide

Eg: 2
Target Molecule:

Retrosynthesis:

The starting materials or synthetic equivalents for the reaction are m-xylene, acetyl chloride
and Isopropyl bromide.

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Synthesis:
Acetylation of m-xylene by Friedel-craft’s reaction

Alcohol undergoes dehydration followed by hydrogenation

1.7 Retrosynthesis of Bi functional disconnections

The alcoholic –OH group can be easily disconnected hence bifunctional disconnections are
described for oxygen containing functional groups only. The bifunctional disconnections are
further classified based on the relative distance between two functional groups
like 1,2; 1,3; 1,4; 1,5; 1,6-bifunctional disconnections. Since they are oxygen containing
functional groups they are abbreviated as 1,3-di O, 1,5-di O, 1,6-di O

Example 1 1,3-di O functional group disconnections

Represents aldol and can be applied to α,β unsaturated carbonyl compound.
Target Molecule:

The above aldol can be synthesized by aldolization of butanal. Starting materials are Butanal
Retrosynthetic approach:

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Synthesis:

Target Molecule:

Retrosynthetic approach:

Disconnected to form two aldehydes

Synthon is further disconnected

The starting materials are ethanol and formaldehyde.

Further reactions of butan-2 magnesium bromide with formaldehyde

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Example 2 1,5 –di functional disconnection
Disconnection takes place by Michael addition reaction. (Addition of carbanion of
nucleophile to carbon of an α,β unsaturated carbonyl compound to form conjugate addition
compound.)
Target Molecule:

Retrosynthesis:

Starting materials are ethyl acetoactetate and methyl vinyl ketone (acetone, dimethylamine,
formaldehyde)
Synthesis:
Methylvinyl ketone can be prepared by Mannich reaction

Michael reaction:

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Target Molecule:

Retrosynthesis:
Formation of carbanion of Michael addition reaction and a MVK(Methyl vinyl ketone)

The synthon MVK can be obtained from acetone by Mannich reaction.

Starting materials are Resorcinol, methylchoride and methyl vinyl ketone (acetone,
dimethylamine, formaldehyde)

Synthesis:

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Example 3 1,6-Di O disconnection
Oxidative ring opening of cyclohexene
Chemical reactions:

Target Molecule:

Retrosynthesis:
Ozonolysis of di substituted cyclohexene

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Starting materials for the reaction are cyclohexanone, methyl chloride and methyl
magnesium bromide.
Synthesis:

Target Molecule:

Retrosynthesis:
Oxidative ring opening of monosubstituted cyclohexene ring.

Starting materials for the reaction are cyclohexanone, phenyl magnesium bromide.

Synthesis:

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Example 4-1,4-di O disconnection
Heterolysis of carbon-carbon bond.
Target Molecule:

Retrosynthesis:

The synthon, can be prepared as

Starting materials for the reaction are Ethylacetoacetate, Bromoacetone.

Synthesis:

Target molecule:

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Retrosynthesis:

The synthon, can be prepared as

Starting materials for the reaction are cyclohexanone, Bromoacetone

Synthesis:

Example 5- 1.2-di O disconnection

Often involve illogical synthon
Target Molecule:

Retrosynthesis:

Starting materials for the reaction are Acetophenone, HCN

Synthesis:

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Target Molecule:

Retrosynthesis:

Starting materials for the reaction are Acetone, acetylene

Synthesis:

Test for Knowledge 2

Propose a retrosynthetic pathway
Compound

Retrosynthesis:

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The synthon,

Synthetic equivalents: Butanal , MVK and methyl acrylate.

Synthesis:

Michael addition with MVK

Compound

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Compound is a bifunctional group – with carboxylic acid groups at 1 an6 position. Hence
the retrosynthetic pathway proceeds by cleavage of cyclohexene ring with oxidizing agents
like Cr(VI) along with transformations.
Disconnection takes place next to the carbonyl functional group.
Retrosynthesis:

The synthetic equivalents or the raw materials for the reaction are anisole and 1,3 butadiene.
Synthesis:

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1,6-diO cleavage

1.8 Protecting Agents

Organic synthesis involves polyfunctional substrates. It is therefore necessary to
protect a functional group in order to carry out a reaction at some other functional group
without any interference. After the reaction is completed, the protected group can be
deprotected.

1.8.1 Protection Reagent: A molecular framework used to block the reactivity of a

particular functional group in a substrate with polyfunctional groups under specified
conditions.
Eg: alcohols are protective agent for acids.

1.8.2 Characteristics of Protective agent:

It should be chemoselective in its reaction with the functional group to be protected.
The protected group should be stable/resistant enough to survive the reaction conditions
maintained for performing the desired reactions.
After the reaction, the protected group should be easily and chemoselectively removed under
mild conditions without affecting the rest of the molecule.

Example 1 :
Protection of active C-H bond.
Terminal alkynes are protected with chloro trimethyl silane and deprotected by AgNO3/KCN
–Corey’ s method.

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Alkenes can be protected by epoxidation reaction and deprotected by treatment with ZnI-NaI
acetic acid.

Example 2
Protection of Amino groups:
1) Trifluoroacetic anhydride:

2) tert-butylazido formate:

3)Carbobenzoxy chloride:

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Example 3
Protection of alcohol group:
1)Acetic anhydride:

2)MEMCl

3) Benzyl chloride

4) Dihydropyran (DHP)

5) Butyl dimethylsilyl chloride

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Example 4:
Protection of aldehydes and ketones
1) 1,2 glycol

2) Mercaptoethanol

3)1,3-Dithiane

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Example 5
Protection of acid group
1) Benzylalcohol

2)Trichloro ethylalcohol

TEXT / REFERENCE BOOKS

1. March J., and Smith M., Advanced Organic Chemistry, 5th Edition, John-Wiley and Son,
2001.
2. Gould E. S., Mechanism and Structure in Organic Chemistry Holt, Rinehart and Winston
Inc., 1959.
3. Carey A. Francis, and Sundberg J Richard., Part A and Part B Advanced Organic
chemistry, 5th edition, Springer, 2007.
4. Jonathan Clayden, Nick Greeves and Stuart Warren., Organic Chemstry, 2nd Edition,
Oxford Publishers, 2012.
5. Finar I. L., Organic Chemistry, 6th Edition, Pearson Education Asia, 2004.
6. House H.O., Modern Synthetic Reactions, W.A. Benjamin Inc, 1972.

30
 SCHOOL OF SCIENCE & HUMANITIES
DEPARTMENT OF CHEMISTRY

UNIT – II -REAGENTS IN ORGANIC CHEMISTRY– SCYA5101

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 UNIT 2

REAGENTS IN ORGANIC CHEMISTRY

2..1 Oxidising agents

2.1.1 Potassium dichromate in acidic medium- K2Cr2O7
1) Oxidation of alcohols:

Mechanism:

2) Oxidation of cyclic alcohols:

3) Oxidation of cyclic diols:

1
4) Oxidation of aromatic alcohols

5) Oxidation of aromatic side chains:

6) Oxidation of aromatic side chains:

2.1.2 Jones Reagent:

It is a CrO3 –acetate in acid medium. It is used for oxidation of alcohol with double and
triple bond, allylic or benzylic CH bonds. The reaction is carried out at 0-20oC.

1) Oxidation of alcohol

2
2) Oxidation of aromatic alcohols

3) Oxidation of aromatic side chains:

2.1.3 Chromium trioxide-Pyridine complex

a) Sarett Reagent:

b) Collins reagent: Chromium trioxide-Pyridine complex in dicholromethane solvent.

1) Oxidation of alcohols:

c) Pyridinium chlorochromate [PCC]

It is prepared by dissolving CrO3 in pyridine solution and HCl.

1) Oxidation of alcohols:

3
d) Pyridium dichromate:PDC-
Oxidation of alcohol:

2.1. 4 Periodic acid : HIO4

Used for the cleavage of adjacent 1,2 diols.

Periodic acids:

2..1.5 DDQ- 2,3 dichloro 5,6 dicyano 1,4 benzoquinone

Preparation:
By treating with 1,4 hydroquinone with HCN followed by oxidation and acid treatment.

4
It decomposes in water and inert towards THF and dioxane.

Chemical Reactions:
1) Aromatisation or Dehydrogenation: Solutions of DDQ in benzene are red in colour.

2) Bicyclic systems:

3) Forms salts of aromatic cations.

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4) Oxidation of Phenols

5) Oxidation cyclization:

6) Intramolecular cyclization:

2.1.6 SeO2
Oxidation of allylic benzylic C-H fragments to allylic and benzylic alcohols (α,β unsaturated
carbonyl compounds)
Mechanism: Initial ene reaction of allylic compound to SeO2 to give allylic selenic acid,
undergoes a 2,3 sigmatropic rearrangement followed by hydrolysis –allylic alcohols.

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1) Reactions with allylic compound:

2) In aromatic heterocycles, the methyl group in α position with respect to nitrogen is

oxidised to aldehyde.

3) Oxidation of acetylenes:

4) Oxidation of carbonyl compound:

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2.1.7 Osmium tetroxide OsO4
Toxic, volatile and its vapours are dangerous to eyes. It is a reagent used mostly for cis-
hydroxylation of C-C double bonds.

2.1.8 1,3-dithiane
The carbonyl carbon of aldehyde is partially positive i.e.,electrophilic therefore
attacked by the nucleophile. Reaction of an aldehyde with 1,3 propane dithiol and further
reaction with butyl lithium the carbon becomes negatively charged –Umpolung (polarity
reversal).

Reactions:
1) Conversion of aldehyde to ketone

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2) Conversion of dihalides to 3-7 membered cyclic ketones

3) Reaction with aldehyde it gives α-hydroxy ketones.

4) Act as nucleophile

2.1.9 Woodward and Prevost Hydroxylation

Alkene is reacted with iodine and silver salt in wet conditions ( Woodward Method)-Cis
diols; dry conditions (Prevost method)- trans diols.

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Woodward prevost

2.1.10 Swern oxidation

Mild reagent used for the oxidation of alcohol to aldehyde/ ketones in the presence of
oxalyl chloride, dimethylsulphoxide and a base (trimethyl amine) at low temperatures.
The first step is the replacement of one chlorine atom by the oxygen atom of DMSO
followed by attack of alcohol at the electrophilic sulphur atom to give alkoxy sulfonium salt.

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The salt undergoes proton abstraction by the base to form an ylide which fragments to
aldehyde and ketone by an intramolecular concerted process.

2.2 Reducing Agents

2.2.1 Lithium Aluminum hydride-LiAlH4
Preparation: Treating LiH to AlCl3 in THF medium.

Act as Reducing agent: Reduces aldehydes, ketones, acids, esters ,acid chlorides and
epoxides to alcohols. Reduces amides, nitriles, azides, nitro groups to amines.
Reduces polar functional groups except alkenes and alkynes.
1) Reduction of carbonyl group:

Mechanism:

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2) Reduction of acids and its derivatives:
The reactivity is RCOCl> RCOOR>RCONR2> RCN> RCOOH
Mechanism:

3) Reduction of acids and its derivatives:

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4) Reduction of amide to amine
Mechanism:

5) Reduction of epoxide: The Nucleophile attacks the less hindered carbon atom to form
corresponding alcohol.

6) Reduction of azides, nitriles

13
7) Reduction of alkyl halides:

2.2.2 Sodium borohydride-NaBH4

Preparation: reacts with sodium hydride with methyl borate.

Reacts in aqueous medium and reacts slowly.Reduces aldehydes and ketones. Inert towards
cyano, nitro, amido, ester, acids, lactones. Epoxides.

1) Reduction of aldehyde and ketone

Mechanism:

Reduction of aldehyde and ketone

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2) Reduction of alkylhalide:

3) Reduction of α ,β unsaturated carbomnyl compound

2.2.3 Luche’s reagent –Mixture of sodium borohydride and cerium chloride. In a cyclic
unsaturated ketones, the unsaturation remains unaffected with this reagent.

2.2.4 Borane-BH3
Preparation:
Borane exists as its gaseous dimer, Diborane B2H6. It is commercially available in the form
of complexes with THF and is prepared from borohydride and boron trifluoride.

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Properties:
Reacts with C=C, CΞC bond and adds hydrogen by hydroboration reaction.

1) Hydroboration of olefins:
Borane reacts with olefins to form alkyl boranes.

Mixed alkyl boranes can be obtained.

16
Mechanism:

2) Hydroboration and oxidation- Regioselective reaction.

Olefin is converted to alcohol-AntiMarkownikoff’s rule.

Hydroboration and oxidation:

Mechanism:

17
3) Hydroboration with dichromate as oxidising reagent.
Olefins to ketones

4) Hydroboration of acetylenes: Acetylene bond is converted to ketone.

5) Carbonylation: Organoboranes can be converted to acids by treating with CO followed by

oxidation

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2.2.5 Aluminum hydride-AlH3
Preparation: Reaction of lithium aluminum hydride with aluminum chloride.

Reaction:
Reduces ketone, acid derivatives to alcohol. Unaffected by halogens and nitro group.
1) Ketone:

2) Halides and nitro group containing acid derivatives:

3) Epoxides:

2.2.6 DIBAL-Diisobutylaluminumhydride
DIBAL can be prepared by heating triisobutylaluminium (itself a dimer) to induce beta-
hydride elimination:
(i-Bu3Al)2 → (i-Bu2AlH)2 + 2 (CH3)2C=CH.

Chemical properties:
1) Esters:

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DIBAL is an hydride donor at low temperature -780C and act as an electrophilic reducing
agent.
Mechanism:

2) Nitriles to aldehydes

3) Esters to alcohol

2.3 Grignard’s Reagent-Organometallic Reagent

Organic compounds with a carbon-metal bond. CH3Li, C2H5MgBr.Excludes
compound where the metal atom is bonded through heteroatom.CH3ONa. Electro negativity
of carbon is 2.5 which is much higher than most of the metals which lie between 0.9-1.8
Preparation:
By direct reduction of alkyl halide with the metal.

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Properties: Colourless, hygroscopic solids. Fairly stable in air. The carbon-metal bond is
highly polar. The carbanion with an unshared pair of electrons act as nucleophile thereby
Grignard reagent undergoes both Nucleophilic substitution and addition reactions.
Nucleophilic Substitution Reactions:
The general pattern of reaction is,

1) Reactions with active hydrogen compounds: Compounds in which hydrogen is attached to

highly electronegative atom can be easily dissociated as proton are known as active
hydrogen.

In case of ammonia and primary amine,

2) Reaction with acetylene and enolic form of acetoacetic ester

3) Reaction with organic halides

21
4) Reaction with cyanogen chloride and chloramines:

b) Nucleophilic Addition:
Grignard Reagents reacts with compounds having carbon-oxygen, carbon-sulphur, carbon-
nitrogen multiple bonds to form addition products which on hydrolysis forms variety of
compounds
General Mechanism of Nucleophilic addition

1) Addition to aldehydes
a) Formaldehyde: forms primary alcohols

b) acetaldehyde – forms secondary alcohols

22
c) ketones-forms tertiary alcohols

2) Addition to CO2: Forms acids

3) Addition to Esters:
a) Formic esters: forms aldehyde

b) esters- forms ketones

23
c) Acid chlorides- Forms ketones

3) Addition to CS2- forms dithioic acids

4) Addition to SO2 –forms sulphinic acids

5) Addition to ethylene oxide- forms alcohols

6) Addition to alkyl cyanides-forms ketones.

24
7) Addition to carbon-carbon double bonds:

2.3.1 Organolithium Compounds

Alkyl lithium: Heating alkyl halide with Lithium in the presence of benzene or ether.

Properties- Colourless liquids; mainly covalent in nature, Reacts with Lewis base. More
reactive than Grignard Reagent.
Nucleophilic Substitution Reaction:
1) Reaction with active hydrogen : Forms alkanes

2) Nucleophilic Addition Reaction: Reacts with aldehydes, ketones similar to Grignard’s

reagent
Addition to formaldehyde- forms primary alcohol

2) Addition to aldehyde-forms secondary alcohol

25
3) Addition to ketone- forms tertiary alcohol

4) Addition to CO2- forms acids

5) Addition to epoxide- forms alcohols.

2.4 Lithium diisopropyl amide-LDA

Prepared by treating a solution of diisopropylamine in THF with n-butyllithium.

Properties:
Basic in nature, relatively soluble in ether. Converts carbonyl compound to corresponding
enolates
Alkylation of carbonyl compound by SN2 reaction

26
2.5 Tributyl tin hydride (Bu3SnH)
Converts alkyl halide to alkane. Reaction proceeds with an radical initiator AIBN. The
tributyl tin radical abstracts a halogen from alkyl halide since Sn-H bond is weak can't
abstract C-H bond from the alkyl group. The reaction is energetically favoured as it form Sn-
Br and C-H bond which are far stronger than the Sn-H and C-Br bond.

Tributyl tin radical reaction with alkyl halide

27
1) Converts alkyl halide to alkane

2) Converts alkylhalide to aldehyde

3) Intramolecular addition of a free radical to alkene to from 5membered ring

4) Intramolecular addition from aldehyde to alcohol

28
2.6 Phase transfer catalysis
Compounds whose addition to a two-phase organic water system transfers a water soluble
reactant to the organic phase where a homogeneous reaction takes place thus enhancing the
rate of the reaction.

Chloroform reacts with base to yield dichlorocarbenes which adds to a double bond to form
dihydrocyclopropane.

Small amounts of benzyl triethyl ammonium chloride is added.

Example 2 oxidation of alkene in benzene with KMnO4 in the presence of quaternary

ammonium ion.

2.7 Crown ethers

Large ring polyethers able to transport ionic compounds into the organic phase. They
are polymers of ethylene glycols prepared by reacting a mixture of triethylene glycol and its
corresponding dichloride in aqueous KOH.

29
Relationship between crownether and ion is called host-guest relationship forming a species
with hydrocarbon like exterior. The complexed ion is soluble in nonpolar organic solvents.
Reactions:

Hence, salts like KF,KCN can be transferred into aprotic solvents by using catalytic amount
of 18-crown-6. In the organic phase, the realtively unsolvated anions of these salts can carry
nucleophilic substitution reaction on an organic substrate.

2.8 Meerifield solid phase reaction

Solid support is used for the synthesis of polypeptides

30
2.9 Baker’s yeast
It is an enzyme which bring about the reduction of ketone to optically active
secondary alcohol. The enzyme is a chiral catalyst however does not provide the hydrogen
atom for reduction. The hydrogen atom is provided by coenzyme NADH. The reduction is
carried out using whole cells where both the enzyme and coenzyme are provided by the
organism.

31
TEXT / REFERENCE BOOKS
1. March J., and Smith M., Advanced Organic Chemistry, 5th Edition, John-Wiley and Son,
2001.
2. Gould E. S., Mechanism and Structure in Organic Chemistry Holt, Rinehart and Winston
Inc., 1959.
3. Carey A. Francis, and Sundberg J Richard., Part A and Part B Advanced Organic
chemistry, 5th edition, Springer, 2007.
4. Jonathan Clayden, Nick Greeves and Stuart Warren., Organic Chemstry, 2nd Edition,
Oxford Publishers, 2012.
5. Finar I. L., Organic Chemistry, 6th Edition, Pearson Education Asia, 2004.
6. House H.O., Modern Synthetic Reactions, W.A. Benjamin Inc, 1972.

32
 SCHOOL OF SCIENCE & HUMANITIES
DEPARTMENT OF CHEMISTRY

UNIT – I -Named Reactions – SCYA5101

1
 UNIT 3

NAMED REACTIONS

3.1 Appel Reaction:

Conversion of alcohol to alkyl halide in the presence of triphenyl phosphine and CCl4.

3.2 Corey Chaykovsky reaction

Reaction of sulphur ylides with carbonyl compounds to form epoxides and with imines it
form azridines.

1
The overall reaction can be summarized as

3.3 Ene Reaction:

Addition of an olefin having an allylic hydrogen to a compound containing double bond
(C=C, C=O, C=N) with the formation of new sigma bond to the terminal carbon of the allyl
group.

2
3.4 Strok enamine Reaction

Enamines are α,β unsaturated amines and are obtained by the reaction of
aldehyde/ketone having α –hydrogen atom with secondary amine in the presence of
dehydrating agnet p-TSH. The reaction proceeds in the forward direction by the removal of
water.

3
3.5 Mannich Reaction:
It is a condensation reaction between HCHO, ammonia or a primary or secondary
amine and a compound containing one or more active hydrogens.
Active hydrogen: ketones, keto-acids, acetoacetic ester, cyano acids and their esters, phenol,
nitro, alkynes etc.,
Secondary amines: Dialkyl amines,piperdine or pyrrolidine.
Aldehydes other than HCHO can also be used.

Mechanism:

4
With primary amine:

3.6 Michael Reaction:

Addition of carbanion of nucleophile to carbon of an α,β unsaturated carbonyl compound to
form conjugate addition compound(C-C bond).

5
Mechanism:

Michael addition Malonic ester

3.7 Robinson Annulation:

Michael addition and intramolecular aldol reaction

6
Robinson annulation:

7
3.8 Wittig Reaction:
Direct conversion of carbonyl group of aldehyde and ketone to alkene using phosphorane or
ylide.
The ylide is prepared by treating the alkyl halide with triphenylphosphine having α-
hydrogen atom. The resulting phosphonium halide on treatment with alkali in the inert
solvent forms the ylide.

The ylide reacts with a carbonyl group to form oxaphosphetane which undergoes cyclo
elimination to give alkene. Elimination.

High affinity of P to oxygen favours cyclo elimination. Stabilised ylides reacts with
aldehydes to form E-isomer while the unstabilised ylides forms z-isomer.

3.9 Arbuzov Reaction:

The Phosphonates required for the formation of alkene is prepared by this reaction.

8
3.10 Horner-Wordsworth-Emmons Reaction
Phosphonates on warming with a base and treating in an inert solvent it forms a stabilised
carbanion. The carbanion reacts with carbonyl compound to form alkene (E-isomer).

3.11 Barton Reaction

The methyl group δ to OH group is converted to oxime.

9
3.12 Nef Reaction
Formation of aldehydes and ketones from nitro group.

Reactions:

Reactions:

10
3.13 Henry Reaction
The Henry Reaction is a base-catalyzed C-C bond-forming reaction between
nitroalkanes and aldehydes or ketones. It is similar to the aldol reaction, and also referred to
as the Nitro Aldol Reaction.If acidic protons are available (i.e. when R = H), the products
tend to eliminate water to give nitroalkenes. Therefore, only small amounts of base should
be used if the isolation of the β-hydroxy nitro-compounds is desired.

Mechanism:

11
3.14 Stetter Reaction
The Stetter Reaction is a 1,4-addition (conjugate addition) of an aldehyde to an a,β-
unsaturated compound, catalyzed by cyanide or a thiazolium salt.

Mechanism:

12
3.15 Vilsmeier-Haack Reaction
Aromatic /Heterocyclic compounds reacts with disubstituted formamide and POCl3
to give aldehyde.

Mechanism:

13
3.14 Sharpless asymmetric Epoxidation.
Oxidation of allylic alcohol to epoxides.
Substrate: Allyl alcohol
Oxidant: t-Butylhydroperoxide
Catalyst: Titanium tetraisopropoxde/Diethyl tartrate
Solvent: Dichloromethane at 20oC.
Stereochemistry: Right [Alcohol] Left
(+)DET Wedge Dash
(-)DET) Dash Wedge

Reactions:

Mechanism:

14
15
Test your Knowledge:

(a) Predict the products:

3.15 Grubb’s metathesis

The process can be used to close or open or to interchange between double bond
components.. The catalyst used is the benzylidene complex of Ru [RuCl2(P c-(C6H11)3)2
which is a metal carbene- Grubb’s catalyst.

Grubb’s catalyst are

16
Mechanism:
Olefin co-ordination to the metal center. Dissociation of ligand.Formation of
metallocyclobutane ring followed by cyclo revision to form olefin.

Intramolecular metathesis:

17
3.16 Bischler–Napieralski Reaction
The Bischler–Napieralski reaction is an intra molecular electrophilic aromatic
substitution reaction that allows for the cyclization of β-arylethylamides or β-
arylethylcarbamates.. The reaction is most notably used in the synthesis of
dihydroisoquinolines, which can be subsequently oxidized to isoquinolines.

.
Test your Knowledge:

1. Corey-Chaykovsky reaction

18
2. Intramolecular Michael reaction

3. Wittig reaction

4. Diel Alder and Nef Reaction

5. Stetter Reaction:

6. Sharpless epoxidation

7. Appel Reaction:

19
8. Barton Reaction

9.Mannich reaction

10.Henry reaction:

11. Strokenamine Reaction:

REFERENCE BOOKS
1. March J., and Smith M., Advanced Organic Chemistry, 5th Edition, John-Wiley and Son,
2001.
2. Gould E. S., Mechanism and Structure in Organic Chemistry Holt, Rinehart and Winston
Inc., 1959.
3. Carey A. Francis, and Sundberg J Richard., Part A and Part B Advanced Organic
chemistry, 5th edition, Springer, 2007.
4. Jonathan Clayden, Nick Greeves and Stuart Warren., Organic Chemstry, 2nd Edition,
Oxford Publishers, 2012.
5. Finar I. L., Organic Chemistry, 6th Edition, Pearson Education Asia, 2004.
6. House H.O., Modern Synthetic Reactions, W.A. Benjamin Inc, 1972.

20
 SCHOOL OF SCIENCE & HUMANITIES
DEPARTMENT OF CHEMISTRY

UNIT – IV METAL CATALYSED NAMED REACTIONS – SCYA5101

1
 UNIT 4

METAL CATALYSED NAMED REACTIONS

4.1 Heck reaction:

It is the chemical reaction of an unsaturated halide with an alkene in the presence of
abase and a palladium catalyst or (Pd nanomaterial –based catalyst to form substituted
alkene. This reaction was the first example of a carbon-carbon bond-forming reaction that
followed a Pd(0)/Pd(II) catalytic cycle, the same catalytic cycle that is seen in other Pd(0)-
catalyzed cross-coupling reactions. The Heck reaction is a way to substitute trans- alkenes

Mechanism

1
 The mechanism involves organopalladium intermediates. The palladium(0)
compound required in this cycle is generated in situ from a palladium(II) precursor.
Palladium(II) acetate is reduced by triphenylphosphine to bis(triphenylphosphine)
palladium(0) and triphenylphosphine is oxidized to triphenylphosphine oxide.
Step 1: Oxidative addition :It increases both the oxidation state and co ordination number
of the metal centre.The metal must have a vacant CN site. The reaction in which palladium
inserts itself in the aryl to bromide bond.
Step 2: Insertion: Palladium then forms a π complex with the alkene and in the alkene
inserts itself in the palladium - carbon bond in a syn addition step. Then follows a torsional
strain relieving rotation to the trans isomer (not shown) and
Step 3: Beta-hydride elimination: Reaction in which the alkyl group bonded to the metal
centre is converted to metal-hydridebond and alkene. The alkyl group must have a hydrogen
atom. In this step, with the formation of a new palladium - alkene π complex. This complex
is destroyed in the next step.
Step 4: Reductive Elimination: It is an elementary step in organometallic chemistry in
which the oxidation state of the metal center decreases while forming a new covalent
bond between two ligands. The palladium(0) compound is regenerated by potassium
carbonate in the final step.

4.2 Metal Coupling Reactions

Palladium catalyst involving cross coupling reactions:

a)Suzuki coupling- Arylboronic acid + aryl halide

b)Stille coupling- Aryl tin+ aryl halide
c) Negishi coupling- Aryl zinc + aryl halide
d)Hiyama coupling- Aryl silyl + aryl halide
e) Kumada coupling-Aryl Li/Mg + aryl halide

Mechanism:

2
Oxidative addition:
In this oxidation step, the electron count of central metal is increased, the oxidation
state is increased and its coordination number is also increased. The conditions for the metal
to undergo oxidative addition are:
Metal must be electron rich to donate electrons.
Metal must be co-ordinationally unsaturated. (CN<6)
Metal must be either d8 or d10 system.
Metals with d0 system doesn't participate in the reaction.
Ligands with EWG (∏-acceptors) decrease the rate of oxidative addition by decreasing the
electron density of the metal.

Reductive elimination: In this step, the electron count of central metal is decreased, the
oxidation state is decreased and its coordination number is also decreased. The conditions
for the metal to undergo reductive elimination are:
Metal must be electron deficient.
Ligands with EWG (∏-acceptors) increase the rate of elimination by decreasing the electron
density of the metal.
Ligands undergoing elimination must be cis to each other.
The products formed in elimination must be stable.

Transmetallation:
Occurs when an organo metallic reagent reacts with metal halide whose electronegativity is
close to the metal.
There is no change in the formal change in the oxidation satte.
The groups exchanged are cis to each other.

4.3 Suzuki Reaction

It is an organic reaction, classified as a cross-coupling reaction, where the coupling
partners are a boronic acid and an organohalide and the catalyst is a palladium(0) complex It
is widely used to synthesize polyolefins, styrenes, and biphenyls. The general scheme for
the Suzuki reaction is shown below, where a carbon-carbon single bond is formed by
coupling an organoboron species (R1-BY2) with a halide (R2-X) using a palladium catalyst
and a base.

3
Mechanism:

The first step is the oxidative addition of palladium to the halide to form
the organopalladium species Reaction (metathesis) with base gives intermediate , which
via transmetalation with the boron-ate complex (produced by reaction of the boronic
acid with base) forms the organopalladium species Reductive elimination of the desired
product restores the original palladium catalyst which completes the catalytic cycle.
The oxidative addition is the rate determining step of the catalytic cycle. During this step,
the palladium catalyst is oxidized from palladium(0) to palladium(II). The palladium
catalyst is coupled with the alkyl halide to yield an organopalladium complex.
The oxidative addition step breaks the carbon-halogen bond where the palladium is now
bound to both the halogen and the R group.
Transmetalation is an organometallic reaction where ligands are transferred from one species
to another. In the case of the Suzuki coupling the ligands are transferred from the
organoboron species to the palladium(II) complex where the base that was added in the
prior step is exchanged with the R1 substituent on the organoboron species to give the new
palladium(II) complex . The organoboron compounds do not undergo transmetalation in the
absence of base and it is therefore widely believed that the role of the base is to activate the
organoboron compound as well as facilitate the formation of R2-Pdll-OtBu from R2-Pdll-X
The final step is the reductive elimination step where the palladium(II) complex eliminates
the product and regenerates the palladium(0) catalyst. The order of elimination is Ar-Ar>
Ar-R > R-R

4
4.4 Stille Coupling
The Stille reaction is a chemical reaction widely used in organic synthesis. The
reaction involves the coupling of two organic groups, one of which is carried as an organotin
compound (also known as organostannanes).

Transmetallation is the rate determining step.

Mechanism:

Oxidative addition to the 14-electron Pd(0) complex gives a 16-electron Pd(II)

species. the anionic ligands, such as OAc, accelerate this step by the formation of
[Pd(OAc)(PR3)n]−, making the palladium species more nucleophillic. In some cases,
especially when an sp3-hybridized organohalide is used, an SN2 type mechanism tends to
prevail.
Transmetallation: First, when the organostannane initially adds to the trans metal complex,
the X group can coordinate to the tin, in addition to the palladium, producing a
cyclic transition state. Breakdown of this adduct results in the loss of R3Sn-X and a
trivalent palladium complex with R1 and R2 present in a cis relationship.

5
Reductive Elimination:In order for R1-R2 to reductively eliminate, these groups must occupy
mutually cis coordination sites. Any trans-adducts must therefore isomerize to
the cis intermediate

4.5 Negishi coupling

It is a metal catalyzed cross-coupling reaction. The reaction couples organic
halides or triflates with organozinc compounds, forming carbon-carbon bonds (c-c) in the
process. A palladium (0) species is generally utilized as the metal catalyst.

Rate determining step is the transmetallation. . Organozincs are moisture and air sensitive,
so the Negishi coupling must be performed in an oxygen and water free environment, a fact
that has hindered its use relative to other cross-coupling reactions that require less robust
conditions (i.e. Suzuki reaction). However, organozincs are more reactive than both
organostannanes and organoborates

Mechanism:

The reaction mechanism is proceeds via a standard Pd catalyzed cross-coupling

pathway, starting with a Pd(0) species, which is oxidized to Pd(II) in an oxidative addition
step involving the organohalide species. This step proceeds with aryl, vinyl, alkynyl, and
acyl halides, acetates, or triflates, with substrates following standard oxidative
addition relative rates (I>OTf>Br>>Cl).Next, the transmetalation step occurs where the
organozinc reagent exchanges its organic substituent with the halide in the Pd(II) complex,
generating the trans- Pd(II) complex and a zinc halide salt. The organozinc substrate can be

6
aryl, vinyl, allyl, benzyl, homoallyl, or homopropargyl. Transmetalation is usually rate
limiting step. The last step in the catalytic pathway of the Negishi coupling is reductive
elimination, which is thought to proceed via a three coordinate transition state, yielding the
coupled organic product and regenerating the Pd(0) catalyst.

4.6 Kumada Coupling

It is useful for generating carbon–carbon bonds by the reaction of a Grignard

reagent and an organic halide. The procedure uses transition metal catalysts, typically nickel
or palladium, to couple a combination of two alkyl, aryl or vinyl groups Kumada Coupling
is the method of choice for the low-cost synthesis of unsymmetrical biaryls. The advantage
of this reaction is the direct coupling of Grignard reagents, which avoids additional reaction
steps such as the conversion of metal complexes.

Mechanism:

4.7 Hiyama Coupling

It is a palladium-catalyzed cross-coupling reaction of organosilanes with organic

halides used in organic chemistry to form carbon–carbon bonds (C-C bonds).

7
A) Oxidative addition step, in which the organic halide adds to the palladium oxidizing the
metal from palladium(0) to palladium(II); a
B) Transmetalation step, in which the C-Si bond is broken and the second carbon fragment is
bound to the palladium center; and finally
C) Reductive elimination step, in which the C-C bond is formed and the palladium returns to
its zero-valent state to start the cycle. over again

Mechanism:

4.8 Fukuyama coupling

It is a coupling reaction taking place between a thioester and an organozinc halide in

the presence of a palladium catalyst. The reaction product is a ketone.

8
Tolerates wide functional groups to yield the product.

Mechanism: Oxidative addition of the thioester is followed by transmetalation from the zinc
compound. Reductive elimination leads to the coupled product.

4.9 Trost-Tsuji coupling

It is a palladium-catalysed substitution reaction involving a substrate that contains

a leaving group in an allylic position. The palladium catalyst first coordinates with the allyl
group and then undergoes oxidative addition, forming the π-allyl complex. This allyl
complex can then be attacked by a nucleophile, resulting in the substituted product..

Mechanism:
Trost reaction proceeds with the addition of alkene in which the palladium
coordinates to the alkene, forming a π-allyl-Pd0 Π complex. The next step is oxidative
addition in which the leaving group is expelled with inversion of configuration and a π-

9
allyl-PdII is created (also called ionization). The nucleophile then adds to the allyl group
regenerating the π-allyl-Pd0 complex. At the completion of the reaction, the palladium
detaches from the alkene and can start again in the catalytic cycle.
Stabilized or "soft" nucleophiles invert the stereochemistry of the π-allyl complex.
This inversion in conjunction with the inversion in stereochemistry associated with the
oxidative addition of palladium yields a net retention of stereochemistry. Unstabilized or
"hard" nucleophiles, on the other hand, retain the stereochemistry of the π-allyl complex,
resulting in a net inversion of stereochemistry.

4.10 Songosharia Reaction

It is a cross-coupling reaction used in organic synthesis to form carbon–carbon

bonds. It employs a palladium catalyst as well as copper co-catalyst to form a carbon–carbon
bond between a terminal alkyne and an aryl or vinyl halide.

10
Mechansim:

The active Pd0 catalyst is involved in the oxidative addition step with
the aryl or vinyl halide substrate to produce PdII species .The structure depends on the
employed ligands. This step is believed to be the rate-limiting step of the reaction.
The Pd complex reacts with copper acetylide, in a transmetallation step, yielding
complex and regenerating the copper catalyst.
For the facile reductive elimination to occur, the substrate motifs need to be in close
vicinity, i.e. cis-orientation, so there can be trans-cis isomerisation involved. In reductive
elimination the product s expelled from the complex and the active Pd catalytic species is
regenerated.

4.11 Buckwald-Hartwig reaction

It is a chemical reaction used in organic chemistry for the synthesis of carbon–

nitrogen bonds via the palladium-catalyzed coupling reactions of amines with aryl halides.
The reaction's synthetic utility stems primarily from the shortcomings of typical methods
(nucleophilic substitution, reductive amination, etc.) for the synthesis of aromatic C–N
bonds, with most methods suffering from limited substrate scope and functional group
tolerance.

11
Mechanism:

The reaction mechanism include oxidative addition of the aryl halide to a Pd(0)
species, addition of the amine to the oxidative addition complex, deprotonation followed
by reductive elimination. An unproductive side reaction can compete with reductive
elimination wherein the amide undergoes beta hydride elimination to yield the
hydrodehalogenated arene and an imine product.
For chelating ligands, the monophosphine palladium species is not formed; oxidative
addition, amide formation and reductive elimination occur from L2Pd complexes. The
Hartwig group found that "reductive elimination can occur from either a four-coordinate
bisphosphine or three-coordinate monophosphine arylpalladium amido complex.
Eliminations from the three-coordinate compounds are faster. Second, β-hydrogen
elimination occurs from a three-coordinate intermediate. Therefore, β-hydrogen elimination
occurs slowly from arylpalladium complexes containing chelating phosphines while
reductive elimination can still occur from these four-coordinate species

12
4.12 Pauson-khand Reaction

The Pauson-Khand reaction is an organic reaction used to convert an alkyne and

alkene to a substituted cyclopentenone under an atmosphere of carbon monoxide and a
dicobalt complex catalyst.

Mechanism
This 2+2+1 cycloaddition reaction begins with the addition of the alkyne to the metal
complex followed by ligand substitution of the alkene to expel a CO molecule. Alkene
insertion follows and a subsequent CO insertion results in the formation of a carbonyl group.
A series of reductive eliminations then yield the final cyclopentenone product and
regenerates the cobalt catalyst.
Two steps:
The insertion of the alkene is followed by insertion of carbon monoxide and reductive
elimination of one Co unit
Dissociation of the second Co unit gives the resulting cyclopentenone product.

13
14
4.13 Kulinkovich Cyclopropanation Reaction

The Kulinkovich Reaction allows the preparation of cyclopropanol derivatives by the

reaction of Grignard reagents (ethyl or higher) with esters in the presence of titanium(IV)
isopropoxide as catalyst.

Mechanism:

The generally accepted reaction mechanism initially utilizes two successive stages
of transmetallation of the committed Grignard reagent, leading to an intermediate
dialkyldiisopropyl oxytitanium complex. This complex undergoes a dismutation to give an
alkane molecule and a titanacyclopropane bond leads to an oxatitana cyclopentane being
rearranged to ketone . Lastly, the insertion of the carbonyl group in the residual carbon-
titanium connection forms a cyclopropane ring. tetraalkyloxytitanium compound able to
play a part similar to that of the starting tetraisopropyloxytitanate, which closes the catalytic
cycle. At the end of the reaction, the product is mainly in the shape of the magnesium
alcoholate , giving the cyclopropanol after hydrolysis by the reaction medium.

15
4.14 Mukiyama reaction

It is an organic reaction used to convert an aldehyde and a silyl enol ether to a 1,3
ketol using a Lewis acid catalyst (such as TiCl4), followed by aqueous work-up.

Mechanism begins by coordination of the aldehyde's oxygen to Titanium, which activate the
carbonyl for attack while also releasing a chloride ion. The chloride attacks the silicon of the
silyl enol ether to form TMSCl and an enolate. The enolate then attacks the activated
carbonyl and subsequent aqueous work-up provides the final 1,3 ketol product.

Mechanism

4.15 Wacker oxidation

The Wacker oxidation refers generally to the transformation of a terminal or 1,2-

disubstituted alkene to a ketone through the action of catalytic palladium(II), water, and a
co-oxidant. Variants of the reaction yield aldehydes, allylic/vinylic ethers, and allylic/vinylic
amines. Because of the ease with which terminal alkenes may be prepared and the versatility
of the methyl ketone group installed by the reaction, the Wacker oxidation has been
employed extensively in organic synthesis.

16
 Mechanism

4.16 Miyaura borylation

The Miyaura borylation reaction enables the synthesis of boronates by cross-

coupling of bis(pinacolato)diboron (B2pin2) with aryl halides and vinyl halides.

17
Mechanism:

Oxidative addition:
In this oxidation step, the electron count of central metal is increased, the oxidation
state is increased and its coordination number is also increased.
Transmetallation:
Occurs when an organo boron reagent reacts with metal halide whose electronegativity is
close to the metal. The groups exchanged are cis to each other.
Reductive elimination: In this step, the electron count of central metal is decreased, the
oxidation state is decreased and its coordination number is also decreased. Ligands (organo
boron) undergoing elimination must be cis to each other. The products formed in elimination
must be stable.

18
REFERENCES

1. March J., and Smith M., Advanced Organic Chemistry, 5th Edition, John-Wiley and Son,
2001.
2. Gould E. S., Mechanism and Structure in Organic Chemistry Holt, Rinehart and Winston
Inc., 1959.
3. Carey A. Francis, and Sundberg J Richard., Part A and Part B Advanced Organic
chemistry, 5th edition, Springer, 2007.
4. Jonathan Clayden, Nick Greeves and Stuart Warren., Organic Chemstry, 2nd Edition,
Oxford Publishers, 2012.
5. Finar I. L., Organic Chemistry, 6th Edition, Pearson Education Asia, 2004.
6. House H.O., Modern Synthetic Reactions, W.A. Benjamin Inc, 1972.

19
 SCHOOL OF SCIENCE AND HUMANITIES
DEPARTMENT OF CHEMISTRY

UNIT –V - MOLECULAR REARRANGEMENTS – SCYA5101

1
 UNIT-5
MOLECULAR REARRANGEMENTS

5.0 INTRODUCTION
Rearrangement: Reactions in which the carbon skeleton of the molecule is rearranged
to give a structural isomer of the original molecule.
Sequence of steps involving substitution, elimination and addition reactions.
Atom or group which is migrates- Migrating Group.
Atom which is initially attached – Migration origin
Atom or group which it finally joins- Migration terminus.

Intermolecular Rearrangement:
When the migratory group is completely detached from the molecule and go the migration
terminus of the other molecule.

Intramolecular rearrangement:
When the migratory group remains attached to the molecule in some or the other way
throughout the process of rearrangement.
1. Anionotropic Migration:
If the migratory atoms or groups may occur with the pair of electrons.

2. Cationotropic Migration:
If the migratory atoms or groups may occur without this pair of electrons.

1
3. Free Radical Migration:
If the migratory group moves with one unpaired electron.

5.1 C-C Migration-

5.1.1Pinacol-Pinacolone Rearrangement
The acid-catalyzed elimination of water from pinacol gives t-butyl methyl ketone.

Mechanism: This reaction occurs with a variety of fully substituted 1,2-diols, and can be
understood to involve the formation of a carbenium ion intermediate that subsequently
undergoes a rearrangement. The first generated intermediate, an α-hydroxycarbenium ion,
rearranges through a 1,2-alkyl shift to produce the carbonyl compound. If two of the
substituents form a ring, the Pinacol Rearrangement can constitute a ring-expansion or ring-
contraction reaction

2
5.1.2 Benzil-Benzilic Rearrangement
The benzilic acid rearrangement is the rearrangement reaction of benzil with potassium
hydroxide to benzilic acid.

3
Mechanism:
A hydroxide anion attacks one of the ketone groups in 1 in a nucleophilic addition to
the hydroxyl anion 2. The next step requires a bond rotation to conformer 3 which places the
migrating group R in position for attack on the second carbonyl group in a concerted step
with reversion of the hydroxyl group back to the carbonyl group. This sequence resembles
a nucleophilic acyl substitution.

5.1.3 Wagner-Meerwein rearrangement

The Wagner-Meerwein rearrangement is an organic reaction used to convert an
alcohol to an olefin using an acid catalyst. The mechanism begins with protonation of the
alcohol by the acid which is then released as water to forms a carbocation. A 1,2-shift then
occurs to form a more substituted and stabilized carbo-cation. A final deprotonation with
water produces the final olefin product and regenerates the acid catalyst

4
5.1.4 Demjanov Rearrangement
The Demjanov rearrangement is the chemical reaction of primary amines with nitrous
acid to give rearranged alcohols.

The reaction process begins with diazotization of the amine by nitrous acid. The
diazonium group is a good leaving group, forming nitrogen gas when displaced from the
organic structure. This displacement can occur via a rearrangement (path A), in which one of
the sigma bonds adjacent to the diazo group migrates. This migration results in an expansion
of the ring. The resulting carbocation is then attacked by a molecule of water. Alternately, the
diazo group can be displaced directly by a molecule of water in an SN2 reaction (path B).
Both routes lead to formation of an alcohol.

5
Mechanism-Demjanov Rearrangement

5.1.5 Favorskii rearrangement

Favorskii rearrangement, is most principally a rearrangement
of cyclopropanones and α-halo ketones which leads to carboxylic acid derivatives. In the case
of cyclic α-halo ketones, the Favorski rearrangement constitutes a ring contraction. This
rearrangement takes place in the presence of a base, sometimes hydroxide, to yield a
carboxylic acid but most of the time either an alkoxide base or an amine to yield an ester or
an amide, respectively. α,α’-Dihaloketones eliminate HX under the reaction conditions to
give α,β-unsaturated carbonyl compounds.

Mechanism-Favorskii rearrangement
It involve the formation of an enolate on the side of the ketone away from
the chlorine atom. This enolate cyclizes to a cyclopropanone intermediate which is then
attacked by the hydroxide nucleophile.

6
5.2 C-N Migration
5.2.1 Hoffmann Reaction:
The Hofmann rearrangement (Hofmann degradation) is the organic reaction of a
primary amide to a primary amine with one fewer carbon atom.The reaction
involves oxidation of the nitrogen followed by rearrangement of the carbonyl and nitrogen to
give an isocyanate intermediate.

Mechanism: The reaction involves the migration of aryl or aryl group from adjacent carbon
atom to electron deficient nitrogen atom forming isocyanates.

5.2.2 Curtius Rearrangement

The Curtius Rearrangement is the thermal decomposition of carboxylic azides to
produce an isocyanate. These intermediates may be isolated, or their corresponding reaction
or hydrolysis products may be obtained.

7
 Preparation of azides:

Mechanism-Curtius Rearrangement
Decomposition:

Reaction with water to the unstable carbamic acid derivative which will undergo
spontaneous decarboxylation:

5.2.3 Lossen rearrangement

The Lossen rearrangement is the conversion of a hydroxamate ester to
an isocyanate. Typically O-acyl, sulfonyl, or phosphoryl O-derivative are employed. The
isocyanate can be used further to generate ureas in the presence of amines or generate amines
in the presence of H2O.

8
Mechanism:

5.2.4 Schmidt Reaction

The acid-catalysed reaction of hydrogen azide with electrophiles, such as carbonyl
compounds, tertiary alcohols or alkenes. After a rearrangement and extrusion of N2, amines,
nitriles, amides or imines are produced.

Mechanism Reaction of carboxylic acids gives acyl azides, which rearrange to isocyanates,
and these may be hydrolyzed to carbamic acid or solvolysed to carbamates. Decarboxylation
leads to amines.

9
5.2. 5 Beckmann Rearrangement
An acid-induced rearrangement of oximes to give amides.

Mechanism:
Conversion of ketoxime to better leaving group in the presence of H+.

Mechanism:

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5.2.6 Neber Rearrangement
The Neber rearrangement in which an oxime is converted into an alpha-
aminoketone in a rearrangement reaction. The oxime is first converted to a
ketoxime tosylate by reaction with tosyl chloride. Added base forms a carbanion which
displaces the tosylate group in a nucleophilic displacement to an azirine and added water
subsequently hydrolyses it to the aminoketone

5.2.7Arndt-Eistert Synthesis
The Arndt-Eistert Synthesis allows the formation of homologated carboxylic acids or
their derivatives by reaction of the activated carboxylic acids with diazomethane and
subsequent Wolff-Rearrangement of the intermediate diazoketones in the presence of
nucleophiles such as water, alcohols, or amines.

Mechanism of the Arndt-Eistert Synthesis

In the first step of this one-carbon homologation, the diazomethane carbon is acylated
by an acid chloride or mixed anhydride, to give an α-diazoketone. Formation of
diazoketone,on warmed with Ag2O loses N2 to form carbene where alkyl group migrates to
form ketene which reacts with water to form acids.

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5.3 C-O Migration
5.3.1 Baeyer-Villiger Oxidation
The Baeyer-Villiger Oxidation is the oxidative cleavage of a carbon-carbon bond
adjacent to a carbonyl, which converts ketones to esters and cyclic ketones to lactones. It is
carried out with peracids, such as MCBPA, or with hydrogen peroxide and a Lewis acid.

Mechanism-Baeyer-Villiger Oxidation

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5.3.2 Shapiro Reaction
The Shapiro Reaction, a variation on the Bamford-Stevens Reaction, is the base-
induced reaction of tosylhydrazones to afford alkenes. This reaction is carried out with two
equivalents of an organolithium compound.

Mechanism: The resulting dianion does not tend to rearrange, which can occur with
intermediate carbenes and carbenium ions.

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5.4 Miscellaneous Rearrangements:
5.4.1 Fries Rearrangement
The Fries Rearrangement enables the preparation of acyl phenols

Mechanism of the Fries Rearrangement

The reaction is catalyzed by Brønsted or Lewis acids such as HF, AlCl 3, BF3, TiCl4 or
SnCl4. The acids are used in excess of the stoichiometric amount, especially the Lewis acids,
since they form complexes with both the starting materials and products. The complex can
dissociate to form an acylium ion. Depending on the solvent, an ion pair can form, and the
ionic species can react with each other within the solvent cage
After hydrolysis, the product o and p acyl phenol is liberated

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5.4.2 Cope Rearrangement (Anionic) Oxy-Cope Rearrangement
The Cope Rearrangement is the thermal isomerization of a 1,5-diene leading to a
regioisomeric 1,5-diene. The main product is the thermodynamically more stable
regioisomer. The Oxy-Cope has a hydroxyl substituent on an sp3-hybridized carbon of the
starting isomer.

The driving force for the neutral or anionic Oxy-Cope Rearrangement is that the product is an
enol or enolate (resp.), which can tautomerize to the corresponding carbonyl compound. This
product will not equilibrate back to the other regioisomer.

5.4.3 Claisen Rearrangement:

The Claisen rearrangement is a powerful carbon–carbon bond-forming chemical
reaction discovered by Rainer Ludwig Claisen. The heating of an allyl vinyl ether will initiate
a [3,3]-sigmatropic rearrangement to give a γ,δ-unsaturated carbonyl.

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Reaction:
The [3,3]-sigmatropic rearrangement of an allyl phenyl ether to intermediate 1, which
quickly tautomerizes to an ortho-substituted phenol.

5.4.4 Sommelet–Hauser rearrangement

The Sommelet–Hauser rearrangement is a rearrangement reaction of
certain benzyl quaternary ammonium salts. The reagent is sodium amide or another alkali
metal amide and the reaction product a N-dialkyl benzyl amine with a new alkyl group in
the aromatic ortho position.

Mechanism
The benzylic methylene proton is acidic and deprotonation takes place to produce the
benzylic ylide . This ylide is in equilibrium with a second ylide that is formed by
deprotonation of one of the ammonium methyl groups Though the second ylide is present in
much smaller amounts, it undergoes a 2,3-sigmatropic rearrangement and subsequent
aromatization to form the final product

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Mechanism-Sommelet–Hauser rearrangement

5.4.5 Stevens Rearrangement

The Stevens rearrangement is an organic reaction converting quaternary ammonium
salts and sulfonium salts to the corresponding amines or sulfides in presence of a
strong base in a 1,2-rearrangement.

Mechanism-Stevens Rearrangement
Stevens Rearrangement involving 1,2 hydride shift:

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5.4.6 Von-Richter rearrangement
It is the chemical reaction of aromatic nitro compounds with potassium cyanide giving
carboxylation ortho to the position of the former nitro group.

First, the cyanide attacks the carbon-atom in ortho-position to the nitro-group 1. After
this the compound is aromatic again 2. In the next step, the negative charged oxygen-atom
attacks the neighbor carbon-atom and an five-membered ring is build 3. It opens under
building a carconlylic-group 4. Next, an other five-membered ring is built 5. After
acondensation, a double bond is build between the two nitrogen-atoms 6. Elemental nitrogen
is cut of for opening the ring 7. In the last step, the compound is protonated and the 3-
halogenbenzoic acid 8 is built.

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 Mechanism-Von-Richter rearrangement

TEXT / REFERENCE BOOKS

1. March J., and Smith M., Advanced Organic Chemistry, 5th Edition, John-Wiley and Son,
2001.
2. Gould E. S., Mechanism and Structure in Organic Chemistry Holt, Rinehart and Winston
Inc., 1959.
3. Carey A. Francis, and Sundberg J Richard., Part A and Part B Advanced Organic
chemistry, 5th edition, Springer, 2007.
4. Jonathan Clayden, Nick Greeves and Stuart Warren., Organic Chemstry, 2nd Edition,
Oxford Publishers, 2012.
5. Finar I. L., Organic Chemistry, 6th Edition, Pearson Education Asia, 2004.
6. House H.O., Modern Synthetic Reactions, W.A. Benjamin Inc, 1972.

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