Organic Chemistry

5th Edition
Paula Yurkanis Bruice

Chapter 8

Substitution Reactions
of Alkyl Halides
 What is a substitution reaction?

The atom or group that is substituted or eliminated in

these reactions is called a leaving group
 Alkyl halides have relatively good leaving groups

How do alkyl halides react?

Alternatively…
 The substitution is more precisely called a nucleophilic
substitution because the atom or group replacing the
leaving group is a nucleophile

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
The Mechanism of an SN2 Reaction

Consider the kinetic of the reaction:

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
As SN2 is a one-step reaction

A nucleophile attacks the back side of the carbon that is

bonded to the leaving group
Why does the nucleophile attack from the back side?
A bulky substituent in the alkyl halide reduces the
reactivity of the alkyl halide: steric hindrance

Tertiary alkyl halides cannot undergo SN2 reactions

Reaction coordinate diagrams for (a) the SN2 reaction of
methyl bromide and (b) an SN2 reaction of a sterically
hindered alkyl bromide
Inversion of configuration (Walden inversion) in an SN2
reaction is due to back side attack
SN2 Reactions Are Affected by
the Leaving Group
The weaker the base, the better it is as a leaving group

Stable bases are weak bases

 Carbon and iodide have the same electronegativity

Why is RI the most reactive?

Large atoms are more polarizable than small atoms

The high polarizability of a large iodide atom causes it to

react as if it were polar
 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 atoms of
approximately the same size, the stronger bases are the
better nucleophiles
When comparing molecules with attacking groups that
are very different in size,
Does the greater polarizability that helps the larger atoms
to be better nucleophiles make up for the decreased
basicity that causes them to be poor nucleophiles?

a hydrogen
bond donor
The Effect of Solvent on Nucleophilicity
In a protic solvent, the smallest atom is the poorest
nucleophile even if it is the strongest base

How does a protic solvent make strong bases less

nucleophilic?

Protic solvents are hydrogen bond donors that shield the

nucleophiles by ion–dipole interactions
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

An SN2 reaction proceeds in the direction that allows
the strongest base to displace the weaker base
The reaction will be reversible if the difference between
the basicities of the nucleophile and the leaving group
is not very large
 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 mixture of

stereoisomeric product is obtained
An SN1 is a two-step reaction and the leaving group
departs before the nucleophile approaches
Reaction Coordinate Diagram for an
SN1 Reaction
The carbocation reaction intermediate leads to the
formation of two stereoisomeric products
 The Effect of the Leaving Group on an
SN1 Reaction

The rate of the reaction is affected by:

1) the ease with which the leaving group dissociates
from the carbon

2) the stability of the carbocation that is formed

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 SN2 Reactions
The Stereochemistry of SN1 Reactions
Sometimes extra inverted product is formed in an SN1
reaction because…
The products resulting from substitution of cyclic
compounds
Benzylic and allylic halides 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
Vinyl and aryl halides do not undergo SN1 because
When an alkyl halide can undergo either SN1 or SN2,

the concentration of the nucleophile,

the reactivity of the nucleophile,

and the solvent of the reaction

will determine which reaction will predominate

An SN2 reaction is favored by a high concentration of a

good nucleophile

An SN1 reaction is favored by a low concentration of a

nucleophile or by a poor nucleophile
 The Role of Solvent in SN2 and in SN1
Reactions

one or more reactants charged none of the reactants is charged

in the rate-limiting step in the rate-limiting step

increase the polarity increase the polarity

of the solvent of the solvent

decrease the rate increase the rate

of the reaction of the reaction
Solvents Can Stabilize Organic Molecules
The dielectric constant is a measure of how the solvent
can insulate opposite charges from one another
Polar solvents have high dielectric constants and are
very good at insulating (solvating) charges

An SN1 reaction cannot take place in a non-polar

solvent or in the gas phase
The greater the charge on a solvated molecule, the
stronger will be its interaction with a polar solvent and…
If the charge on the transition state is greater than the
charge on the reactants, a polar solvent will stabilize the
transition state more…
The effect of a solvent on the rate of an SN1 reaction
 The effect of a solvent on an SN2 reaction

When a neutral halide reacts with a charged nucleophile,

increasing the polarity of the solvent will decrease the
rate of the reaction

When a neutral halide reacts with a neutral nucleophile,

increasing the polarity of the solvent will increase the
rate of the reaction
 Intermolecular Versus
Intramolecular Reactions
An intramolecular reaction is favored when a five- or six-
membered ring product is formed
 Competition Between
Substitution and Elimination
Alkyl halides can undergo SN2, SN1, E2, and E1

1) decide whether the reaction conditions favor S N2/E2 or SN1/E1

•SN2/E2 reactions are favored by a high concentration of a

good nucleophile/strong base

•SN1/E1 reactions are favored by a poor nucleophile/weak

base

2) decide how much of the product will be the substitution product

and how much of the product will be the elimination product
Consider the SN2/E2 conditions
A bulky alkyl halide or a sterically hindered nucleophile
encourages elimination over substitution
A strong or a bulky base encourages elimination over
substitution
A high temperature favors elimination over substitution
Tertiary alkyl halides undergo only elimination under
SN2/E2 conditions
Consider SN1/E1 conditions

Primary alkyl halides do not form carbocations; therefore

they cannot undergo SN1 and E1 reactions
In synthesizing an ether, the less hindered group should
be provided by the alkyl halide
However, the most hindered alkyl halide
should be used if you want to synthesize an alkene