Dr Rafiq Zakaria Campus,

Maulana Azad College,

Dr Ahmad Zaheer
Lecture Series

Nucleophillic Substitution
Reaction
Dr Mohsin Abdul Aziz
 2

Nucleophilic substitution at saturated carbon atom

The replacement of one group by another is called substitution
reaction. There are three main types of these reactions: radical, electrophilic
and nucleophilic substitution. In this section we will deal with nucleophilic
substitution at saturated carbon atom.
Attack of a nucleophile at a saturated carbon atom bearing a
substituent, known as leaving group, results in substitution reaction. The group
that is displaced (leaving group) carries its bonding electrons. The new bond is
formed between nucleophile and the carbon using the electrons supplied by the
nucleophilic reagent.
 5

This is exemplified by the displacement of halogen atom with a

hydroxide ion in the conversion of alkyl halide into an alcohol. Alkyl halides
undergo substitution reactions with a variety of different nucleophilic reagents
and are extremely important synthetically, as can be seen by the wide variety of
compounds which can be prepared by its applications. The halogen is lost as a
halide ion.
 6

The compound on which substitution takes place is called the

substrate and the group that becomes displaced from carbon, taking the
electron pair with it, is called leaving group. The leaving group often leaves
as an anion but may also be a neutral molecule. The substrate consists of two
parts, alkyl group and leaving group. For example, reaction of methyl bromide
with sodium hydroxide affords methanol and sodium bromide. In this reaction
methyl bromide is substrate, bromide is leaving group and hydroxide ion is the
nucleophile.
 10

Nucleophilic substitution reactions have been studied extensively

from a mechanistic viewpoint. Many factors influence the course of
nucleophilic substitution reactions. including the nature of the nucleophile, its
strength and concentration, the solvent. the nature of substrate, and the nature
of leaving group.
Substitution reactions at saturated carbon can be mechanistically categorized
as unimolecular (SN1) or bimolecular (SN2).
 11

SN1 (Substitution Nucleophilic Unimolecular)

An SN1 reaction proceeds in two steps. The first step (slow step) is the
rate determining step and involves the ionization of the reactant to form a
carbocation intermediate. The breaking of C-X bond in RX takes place in a
heterolytic fashion, in which both the bonding electrons go to the leaving group.
In the second step (fast step), the intermediate carbocation is attacked by the
nucleophile to give the final product.
Step 1. Formation of carbocation

Step 2. Capture of the carbocation by the nucleophile

The SN1 reaction shows first-order kinetics as rate of the reaction depends only on
the concentration of the substrate (RX) and does not depend on the concentration
of the nucleophile reacting with it. The rate expression is therefore:

where k is rate constant and quantity in square brackets represents concentration.

 12

In several reactions, nucleophile is a solvent molecule such as water,

ammonia or alcohol such substitution reactions are called solvolysis.

For example, hydrolysis of tert-butyl chloride to tert-butyl alcohol follows SN1

process. In the first step, tert-butyl chloride ionizes to a tert-butyl carbocation,
which is captured in a second step by the nucleophilic solvent, water, to give the
protonated alcohol first and then alcohol itself.
 14

An energy diagram (Following figure) for SN1 reaction involves two

transition states. The transition state for the slow step (the ionization step) is
higher in energy than the transition state for the fast step (second step, the capture
of the ion by a nucleophile).
 Solvolysis Reactions

Tertiary alkyl halides are very unreactive in

substitutions that proceed by the SN2 mechanism.

• But they are highly reactive in solvolysis

reactions where the solvent is generally one of
the reactants.
 Hydrolysis of tert-butyl bromide.

CH3 CH3
H H
CH3 CH3
.. +
C Br : + : O : C O :
..

CH3 H CH3 H

+
.. –
CH3
CH3 : Br :
.. .. ..
C OH + H Br :
.. ..

CH3
 Hydrolysis of tert-butyl bromide.

CH3 CH3
H H
CH3 CH3
.. +
C Br :
..
+ : O : C O :

CH3 H H
CH3

+
.. –
This is the nucleophilic substitution
stage of the reaction; the one with : Br :
which we are concerned. ..
 Hydrolysis of tert-butyl bromide.

CH3 CH3
H H
CH3 CH3
.. +
C Br :
..
+ : O : C O :

CH3 H H
CH3

+
.. –
The reaction rate is independent
of the concentration of the nucleophile : Br :
and follows a first-order rate law. ..
rate = k[(CH3)3CBr]
 Hydrolysis of tert-butyl bromide.

CH3 CH3
H H
CH3 CH3
.. +
C Br :
..
+ : O : C O :

CH3 H H
CH3

+
.. –
The mechanism of this step is
not SN2. It is called SN1 and : Br :
begins with ionization of (CH3)3CBr. ..
 Kinetics and
Mechanism
rate = k[alkyl halide]
First-order kinetics implies a unimolecular
rate-determining step.

• Proposed mechanism is called SN1, which

stands for
substitution nucleophilic unimolecular
 CH3
CH3
.. Mechanism
C Br :
..

CH3

unimolecular
slow

H3C CH3
+ .. –
C + : Br :
..

CH3
H3C
+
CH3
H Mechanism
C
: O :

CH3
H

bimolecular
fast
CH3
H
CH3
+
C O :

CH3 H
carbocation
formation
carbocation
capture
R+

proton
transfer

RX

+
ROH2 ROH
Characteristics of the SN1 mechanism

•first order kinetics: rate = k[RX]

▫unimolecular rate-determining step
•carbocation intermediate
▫rate follows carbocation stability
▫rearrangements sometimes observed
•reaction is not stereospecific
▫racemization occurs in reactions of
optically active alkyl halides
Carbocation Stability and
SN1 Reaction Rates
Electronic Effects Govern SN1 Rates

The rate of nucleophilic substitution

by the SN1 mechanism is governed
by electronic effects.

Carbocation formation is rate-determining.

The more stable the carbocation, the faster
its rate of formation, and the greater the
rate of unimolecular nucleophilic substitution.
Reactivity toward substitution by the SN1
mechanism
RBr solvolysis in aqueous formic acid

•Alkyl bromide Class Relative rate

•CH3Br Methyl 1
•CH3CH2Br Primary 2
•(CH3)2CHBr Secondary 43
•(CH3)3CBr Tertiary 100,000,000
 Decreasing SN1
Reactivity

(CH3)3CBr

(CH3)2CHBr

CH3CH2Br

CH3Br
 30

Stereochemistry of the SN1 reaction

Ionization of optically pure alkyl halide molecule leads to the planar,

achiral (symmetrical) carbocation with an empty p-orbital perpendicular to the
plane. Addition of nucleophile can take place at both sides of the carbocation with
equal ease owing to the symmetry of carbocation, resulting in a racemic mixture
(equal amounts of R and S products). But in actual practice, depending on the
nature of substrate, solvent and leaving group, there may be a preferred side for its
attack by nucleophile, in which case the product will contain unequal amounts of
the two enantiomers, yielding partially optically active product.
 Generalization

•Nucleophilic substitutions that exhibit

first-order kinetic behavior are
not stereospecific.
 Stereochemistry of an SN1 Reaction
H
CH3

R-(–)-2-Bromooctane C Br

CH3(CH2)5

H
H CH3
CH3
H2O
C OH
HO C

CH3(CH2)5
(CH2)5CH3

(S)-(+)-2-Octanol (83%) (R)-(–)-2-Octanol (17%)

Figure

Ionization step
gives carbocation; three
bonds to chirality
center become coplanar
+

Leaving group shields

one face of carbocation;
nucleophile attacks
faster at opposite face.
Structure of tert-Butyl Cation

CH3

+
C
H3C
CH3

• Positively charged carbon is sp2 hybridized.

• All four carbons lie in same plane.
• Unhybridized p orbital is perpendicular to
plane of four carbons.
 +

More than 50% Less than 50%

Carbocation Capture

H3C CH3
H3 C CH3
–
C + Cl C Cl

CH3 H3C
Lewis acid Lewis base

Electrophile Nucleophile
Carbocation
Rearrangements
in SN1 Reactions
 Because...

•carbocations are intermediates

in SN1 reactions, rearrangements
are possible.
 Example
CH3 CH3
H2O

CH3 C CHCH3 CH3 C CH2CH3

(93%)
H Br OH

H2O

CH3 CH3

CH3 C CHCH3 CH3 C CHCH3

+ +

H H
Effect of Solvent
on the
Rate of Nucleophilic
Substitution
 In general...

•SN1 Reaction Rates Increase

in Polar Solvents
 SN1 Reactivity versus
Solvent Polarity
Solvent Dielectric Relative
constant rate

acetic acid
methanol
formic acid
water

Most polar Fastest rate

 transition R 
X 
state
stabilized by
polar solvent

R+

energy of RX
not much
affected by
polarity of
RX
solvent
 transition activation energy
state decreases;
stabilized by R 
X  rate increases
polar solvent

R+

energy of RX
not much
affected by
polarity of
RX
solvent
 46

It is believed that carbocation and leaving group exist for a while as an

intimate ion pair and the attack of nucleophile during this time takes place only on
the back side of carbocation, but not on the front side, giving rise to inversion.
Then these ions diffuse apart as solvent intervenes, and become free ions. Now
attack of nucleophile on free symmetrical carbocation occurs from the back side or
from the front side with equal probability.
Nucleophilic substitution
bimolecular (SN2) Reaction
 Introduction
SN2 correspond to substitution Nucleophilic Bimolecular.

 This Reaction is a concerted reaction in which bond forming and bond

breaking occur simultaneously.

 Energy required to break the bond is compensated by bond

formation.
Concerted One Step - Bimolecular
Reactions
Example

Example
 Kinetics
 The rate of the reaction is found to be vary linearly with non zero slope with
respect to electrophile as well as nucleophile .

Rate=K [elec][Nucl] K= equilibrium constant

2 in the SN2 correspond to bimolecular.

In presence of large excess of nucleophile kinetics is found to be first
order experimentally even though mechanism is bimolecular.

rate=K[elec]

 Nucleophile affect the rate even being in large excess but concentration does
not vary significantly and rate is found to be determined alone by electrophile.
Such kinetics are known as “Pseudo first order reaction”.
Bimolecular
mechanism

one step
concerted
HO – + CH3Br HOCH3 + Br –
Bimolecular
mechanism

one step
concerted
HO – + CH3Br HOCH3 + Br –
Bimolecular
mechanism 

HO CH3 Br

transition state

one step
••one
onestep
step

concerted
concerted
concerted

HO – + CH3Br HOCH3 + Br –
 Mechanism
 During SN2 reaction nucleophile first approaches to antibonding orbital of
C-Y bond.
 Attractive interaction between orbital, develop bond between incoming
group and carbon. Simultaneously the leaving group start to depart away
from carbon center.
 Substitution may be possible either via front side or backside attack of
nucleophile.

 In SN2 substitution backside attack is preferred in which approach of

nucleophile is 180⁰ away from the leaving group.
 56

Rearrangement in SN2
Since no free carbocation is generated, therefore, SN2 displacement afford
unrearranged products. However, some times SN2 reaction, leads to allylic
rearrangement. The attack of nucleophile takes place at the end of the π-system
i.e. on C-3 of the allylic-system, with simultaneous expulsion of a leaving group.
Such reactions are referred to as SN2', to distinguish them from the normal SN2
process.
3 2 1
 57

SN2' mechanism leads to the same product as SN2, however, if the allylic halide is
unsymmetrically substituted, we can tell which mechanism operates and the
product formed will be from the nucleophilic attack at the less hindered end of the
allylic system. Prenyl bromide, for example, reacts entirely via SN2 process. If we

react the secondary butenyl chloride with an amine we get the product from S N2'
mechanism. 1

3
Stereochemistry of SN2
Reactions
Generalization

•Nucleophilic substitutions that exhibit

second-order kinetic behavior are
stereospecific and proceed with
inversion of configuration.
Inversion of Configuration

nucleophile attacks carbon

from side opposite bond
to the leaving group
Inversion of Configuration

nucleophile attacks carbon three-dimensional

from side opposite bond arrangement of bonds in
to the leaving group product is opposite to
that of reactant
Inversion of configuration (Walden inversion) in an SN2
reaction is due to back side attack
 Walden Inversion
 Complete Inversion in stereochemistry is observed during aliphatic
nucleophilic substitution via SN2 pathway, confirming that backside
attack is preferred over front side attack.
 Stereochemical outcome of the SN2 reaction is termed as Walden
inversion in honor of his discovery.

Only backside attack of nucleophile provide the most favorable interaction

between antibonding orbital of C-Y bond and orbital of incoming nucleophile.
A conceptual view of SN2
reactions
Why does the nucleophile attack from the back side?
Why does the nucleophile attack from the back side?
“Roundabout” SN2 Reaction
Mechanism
 SN2 Reaction Mechanisms: Gas Phase (2008)
http://pubs.acs.org/cen/news/86/i02/8602notw1.html

Traditional Physicist Roland Wester and his team in Matthias Weidemüller's group at the
Roundabout
University of Freiburg, in Germany, in collaboration with William L. Hase's
group at Texas Tech University, provide direct evidence for this mechanism in
the gas phase. However, they also detected an additional, unexpected
mechanism. In this new pathway, called the roundabout mechanism, chloride
bumps into the methyl group and spins the entire methyl iodide molecule 360°
before chloride substitution. Data at lower collision energies support the
traditional SN2 mechanism. However, at higher collision energies, about 10%
of the iodide ions fell outside of the expected distribution.

"We saw a group of iodide ions with a much slower velocity than the rest,"
says Wester. "Since energy is conserved, if iodide ions are slow, the energy
has to be somewhere else."

On the basis of calculations performed by their colleagues at Texas Tech, the

team concluded that the energy missing from the iodide transfers to the methyl
chloride product in the form of rotational excitation, supporting the proposed
roundabout mechanism.
 Fig. 3. View of a typical trajectory for the indirect roundabout reaction mechanism at 1.9 eV that
proceeds via CH3 rotation

J. Mikosch et al., Science 319, 183 -186 (2008)

Published by AAAS
Steric Effects in SN2
Reactions
Crowding at the Reaction Site
The rate of nucleophilic substitution
by the SN2 mechanism is governed
N
by steric effects.

Crowding at the carbon that bears

the leaving group slows the rate of

bimolecular nucleophilic substitution.

Reactivity toward substitution by the
SN2 mechanism
RBr + LiI RI + LiBr

•Alkyl Class Relative

bromide rate
•CH3Br Methyl 221,000
•CH3CH2Br Primary 1,350
•(CH3)2CHBr Secondary 1
•(CH3)3CBr Tertiary too small
to measure
A bulky substituent in the alkyl halide reduces the
reactivity of the alkyl halide: steric hindrance
 Decreasing SN2
Reactivity

CH3Br

CH3CH2Br

(CH3)2CHBr

(CH3)3CBr
 Decreasing SN2
Reactivity
CH3Br

CH3CH2Br

(CH3)2CHBr

(CH3)3CBr
Reaction coordinate diagrams for (a) the SN2 reaction of
methyl bromide and (b) an SN2 reaction of a sterically
hindered alkyl bromide
Crowding Adjacent to the Reaction
Site
The rate of nucleophilic substitution
by the SN2 mechanism is governed

by steric effects.

Crowding at the carbon adjacent

to the one that bears the leaving group

also slows the rate of bimolecular

nucleophilic substitution, but the

effect is smaller.
Effect of chain branching on rate of
SN2 substitution
RBr + LiI RI + LiBr

•Alkyl Structure Relative

bromide rate
•Ethyl CH3CH2Br 1.0
•Propyl CH3CH2CH2Br 0.8
•Isobutyl (CH3)2CHCH2Br 0.036
•Neopentyl (CH3)3CCH2Br 0.00002
 Effect of Solvent
 Solvent may play a vital role in the rate of SN2 reaction as it involves either
creation or dispersion of charge.
 Charged species are more stabilized in the polar solvent than non-polar
solvent.
 Difference between the solvation capacity of reactant and transition state in
various solvent lead to the solvent effect in a reaction.
Reactants Transition State Charge Effect of
Creation/Dispersion Increasing the
Polarity of Solvent
δ δ Charge dispersion Retard the reaction
Nuc R-LG Nuc R LG

δ δ Charge creation speed the reaction

Nuc R-LG Nuc R LG

Nuc R-LG δ δ Charge dispersion Retard the reaction

Nuc R LG
δ δ Charge dispersion Retard the reaction
Nuc R-LG Nuc R LG
  In case of negative nucleophile a remarkable change in rate of SN2 reaction
is observed while changing the solvent from polar protic to polar non-protic

solvent.
 In polar aprotic solvent negatively charged nucleophile are less soluble but
solvent are polar enough to solubilize the nucleophile making them highly
reactive.
Solvent K relative
Methanol 0.9
Water 1.0
Formamide 14.1
Acetonitrile 3.58 x 104
Acetone 1.41 x 106

 Solubility of nucleophile is a major problem in substitution reaction,

particularly in less polar aprotic solvent.
Structure Function Correlation With Nucleophile

 In SN2 reaction stronger the nucleophile faster the reaction will occur.
 Strength of a nucleophile can be determined by given principle-
1.A nucleophile with negative charge is more powerful than its conjugate acid.
Example: NH2─ >NH3, OH─ >H2O,
2. Nucleophilicity is almost in same order as basicity in row.
Example: R3C ─ > R2N ─ > RO ─ > F ─
NH2 ─ > RO ─ >R2NH ─ > ArO ─ > NH3 > Pyridine > F ─ > H2O > ClO4 ─

3. Going down in a group nucleophilicity increase while basicity decrease.

Example: I ─ >Br ─ > Cl ─ > F ─(less solvation, Higher polarization)
S ─ >O ─
Structure Function Correlation With Nucleophile

4. More free nucleophile, more nucleophilicity.

Example 1: Rate of reaction using NaOH can be largely enhanced by
specifically solvating cation Na+. (use of crown ether).
Example 2: NaOHDMSO >NaOHwater (basicity)
In water Na+ and HO ─ both are solvated while in DMSO
Na+ is solvated preferably than HO ─ leaving HO ─ as free
nucleophile.
Structure function correlation with leaving group
 Negative charge develops on leaving group during the rate determining step.
Thus, reaction proceed faster with a leaving group which stabilize better
negative charge.
 Better leaving group are mostly weak bases which stabilize the negative
charges.
Example: TsO ─ , MsO ─, TfO ─

 In presence of better leaving group, SN1 reaction do not require strong base,
but for SN2 reaction it is required.
Example:
1. XH is always a weaker base than X ─. Thus XH is a better leaving group which
facilitate the SN2 reaction.
HS─ > H2S, HO ─ > H2O, I ─ > HI, NH2 ─ >NH3
2. Acidic medium also protonate the base making them weaker.
ROH is converted to ROH + in acid medium which is a better leaving group.
 Structure Function Correlation With R Group
 R group plays vital role on the rate of reaction as well as in determination of the
reaction.
 R group may have stearic, electronic and neighboring group effect.
 Stearic hindrance may slower the rate of reaction, as nucleophile adds to the
carbon centre in rate determining step.
 During transition state incoming nucleophile(Nuc) and leaving group(LG) are
90⁰ to the R group. Thus placing larger group at 90⁰ to LG and Nuc, transition
state will be more strained which causes lesser rate of reaction.

R R

X Y

90 0 R 900
Bulkier R group increase steric hindrance
Structure Function Correlation With R Group
A bulkier adjacent group may bend the trajectory of nucleophile away from

the linear approach which leads to a strained transition state.

R
R R

LG
Nuc
R R
Strained transition state due to adjacent group steric effect

 electron withdrawing nature of groups having sp2 carbon(vinyl and phenyl)

make the adjacent carbon more electrophilic and hence reactivity towards
nucleophile increases.
Example:
Higher rate for nucleophilic substitution at allyl and benzyl system.
 Neighboring Group Participation
 In presence of electron donor neighboring group, reaction undergo with higher
rate of reaction than expected and neither inversion nor racemisation is
observed.
 It shows the neighboring group participation in the reaction.

 Two consecutive SN2 substitution, leads to retention of

configuration.
Example 1
 Neighboring Group Participation
Example 2

The most likely neighboring group participation in three, five, six

membered ring.
 Four membered ring neighboring group participation is higher in case
of alkyl substitution on α or β carbon.
 The effect of halogen increase as going down the group ( I> Br> Cl ).
Example 3

Example 4

Some neighboring groups are COO ─, COOR, COAr, OCOR, OR, OH, O─,
NH2 , NHR , NHCOR, SH, SR, I, Br, S ─
 SN2’ Reaction
 allylic rearrangement in SN2 condition is known as SN2’ reaction.

Simultaneous movement of three electron pair during transition state

SN2' attack Usual attack(SN2)

Attack at γ carbon with SN2 condition is SN2’ reaction.

 SN2’ Reaction
 Increasing the size of nucleophile as well as stearic hindrance at α- carbon
increases the extent of SN2 reaction.
 Leaving group also affect the extent of reaction in certain cases.
Example:
PhCH=CHCH2X treated with LiAlH4 when X=Br,Cl only SN2 reaction
=P(Ph)3+Br ─ only SN2’ reaction
 Stereochemistry depends upon the nature of incoming group and leaving group
in SN2’ reaction, still syn-substitution is preferred over anti.
•Mechanism Summary
SN1 and SN2
When...
•primary alkyl halides undergo nucleophilic
substitution, they always react by the SN2
mechanism
•tertiary alkyl halides undergo nucleophilic
substitution, they always react by the SN1
mechanism
•secondary alkyl halides undergo nucleophilic
substitution, they react by the
▫SN1 mechanism in the presence of a weak
nucleophile (solvolysis)
▫SN2 mechanism in the presence of a good
nucleophile
SN1 vs. SN2 – The Leaving Group

•The most commonly used leaving groups are halides

and sulfonate ions.
 SN2 vs. SN1 – Solvent
SN2 reaction, use a polar, aprotic solvent

•To promote an SN1 reaction, use a polar, protic

solvent: The protic solvent will hydrogen bond with
the nucleophile, stabilizing it, while the leaving group
leaves first.
 95

SNi (Substitution Nucleophilic internal)

In this process part of leaving group which attacks the substrate detaches
itself from the rest of the leaving group. This is exemplified by the conversion of
(R)-2-butanol to (R)-2-chlorobutane with SOCl2 in nonpolar solvent and absence
of base. The product formed is with complete retention of configuration, i.e., in
which the starting material and product have the same configuration. The
mechanism appears to involve the formation of intermediate chlorosulfite ester,
ROSOCl (R = sec-butyl group), which dissociates into an intimate ion pair, R+:
-
OSOCl as in SN1 mechanism. The Cl, with pair of electrons, of the anion attacks
the R+ from the same side of the carbocation from which –OSOCl departed and the
product (RCl) is formed with complete retention of configuration.
 96

It is interesting to note that if a tertiary amine such as pyridine is added to the

reaction mixture, the product RCl is found now to have undergone inversion of
configuration. The pyridine co-ordinates with the HCl, produced during the
formation of intermediate chlorosulfite from ROH and SOCl2, to form pyridine
hydrochloride and the Cl– is an effective nucleophile. The displacement of the
chlorosulfite ester by Cl- via SN2 mechanism gives product with complete
inversion of configuration. The reaction of alcohols with thionyl chloride in
presence of pyridine is known as Darzen's procedure.
•Thank You