Substitution Reactions

What is a substitution reaction?

The atom or group that is substituted or eliminated in

these reactions is called a leaving group (X-)
 CH3Br + OH– CH3OH + Br–

Because a nucleophile substitutes for the halogen,

these reactions are known as nucleophilic
substitution reactions

The reaction mechanism which predominates

depends on the following factors:
• the structure of the alkyl halide
• the reactivity of the nucleophile
• the concentration of the nucleophile
• the solvent of the reaction
Bimolecular nucleophilic
substitution
 The Mechanism of an SN2 Reaction

CH3Br + OH– CH3OH + Br–

Consider the kinetic of the reaction:

Rate = k[alkyl halide][nucleophile]

a second-order reaction
 Three Experimental Evidences Support an SN2
Reaction Mechanism

1. The rate of the reaction is dependent on the

concentration of the alkyl halides and the nucleophile

2. The rate of the reaction with a given nucleophile

decreases with increasing size of the alkyl halides

3. The configuration of the substituted product is

inverted compared to the configuration of the reacting
chiral alkyl halide
1. The rate of the reaction is dependent on the
concentration of the alkyl halides and the nucleophile
Why does the nucleophile attack from the back side?
2. The rate of the reaction with a given nucleophile
decreases with increasing size of the alkyl halides
A bulky substituent in the alkyl halide reduces the
reactivity of the alkyl halide: steric hindrance
 Reaction coordinate diagrams

(a) the SN2 reaction of methyl bromide (b) an SN2 reaction of a

sterically hindered alkyl
bromide
3. The configuration of the substituted product is
inverted compared to the configuration of the reacting
chiral alkyl halide

Inversion of configuration (Walden inversion) in an

SN2 reaction is due to back side attack
The Stereochemistry of SN2 Reactions
SN2 Reactions Are Affected by the Leaving Group
The weaker the base, the better it is as a leaving group
 The Nucleophile Affects an SN2 Reaction
• Nucleophilicity is a measure of how readily a
compound (a nucleophile) is able to attack an
electron-deficient atom
• Nucleophilicity is measured by a rate constant (k)

UNLIKE

• Basicity is a measure of how well a compound (a

base) shares its lone pair with a proton
• Basicity is measured by the acid dissociation
constant (Ka)
When comparing molecules with the same
attacking atom

stronger base, weaker base,

better nucleophile poorer nucleophile
OH– > H2O
CH3O– > CH3OH
–NH > NH3
2
CH3CH2NH– > CH3CH2NH2
When comparing molecules with attacking groups that
are very different in size,

more bonding

little bonding
If the reaction is carried out in the gas phase, the
stronger bases are the best nucleophiles, but, if a
protic solvent is used
 The Effect of Solvent on Nucleophilicity

How does a protic solvent make strong bases less

nucleophilic?
Consider the ion–dipole interaction
It is easier to break the ion-dipole interactions
between a weak base and the solvent than between
a strong base and the solvent

Therefore, fluoride is a better nucleophile in

nonpolar solvent

Also, aprotic polar solvents such as DMSO and

DMF facilitate the reaction of ionic compounds
because they solvate cations
Nucleophilicity is affected by steric effects

Steric effects affect nucleophilicity, but not basicity

Unimolecular Nucleophilic
Substitution
Experimental Evidence for an SN1 Reaction

1. The rate of the reaction depends only on the

concentration of the alkyl halide

2. The rate of the reaction is favored by the bulkiness of

the alkyl substituent

3. In the substitution of a chiral alkyl halide, a racemic

mixture of product is obtained
1. The rate of the reaction depends only on the
concentration of the alkyl halide
Reaction Coordinate Diagram for an SN1
Reaction
2. The rate of the reaction is favored by the bulkiness of
the alkyl substituent
The carbocation reaction intermediate leads to the
formation of two stereoisomeric products
3. In the substitution of a chiral alkyl halide, a racemic
mixture of product is obtained
The Effect of the Leaving Group on an SN1
Reaction

The nucleophile has no effect on the rate of an SN1

reaction
When a reaction forms a carbocation intermediate,
always check for the possibility of a carbocation
rearrangement
The Stereochemistry of SN1 Reactions
Sometimes extra inverted product is formed in an SN1
reaction because …
Benzylic and allylic halides readily undergo SN2,
unless they are tertiary

Tertiary benzylic and tertiary allylic halides are

unreactive in SN2 because of steric hindrance
 Benzylic and allylic halides also undergo SN1

Benzylic and allylic halides form stable carbocations

More than one product may result from an SN1
reaction of an allylic halide
 Vinyl and aryl halides do not undergo SN2 because

Cl Br
R
C C
H H
X
X Nu
Nu

Vinyl and aryl halides do not undergo SN1 because

RCH CH Cl X RCH CH + Cl-

X + Br-
Br
Some Biological Methylating Reagents