Organic Chemistry
4th Edition
Paula Yurkanis Bruice
Chapter 10
Substitution Reactions
of Alkyl Halides
Irene Lee
Case Western Reserve University
Cleveland, OH
©2004, Prentice Hall
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?
+ RCH2 X
Nu:- +
X= F, Cl, Br, I
C Nu + X-
C X
+ -
Alternatively …
C X
+ -
Nu:- +
C+
C+
+
X-
C Nu
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
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
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
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
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,
better nucleophile
OH–
CH3O–
–NH
2
CH3CH2NH–
weaker base,
poorer nucleophile
>
>
>
>
H2O
CH3OH
NH3
CH3CH2NH2
When comparing molecules with attacking atoms of
approximately the same size,
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
An SN2 reaction proceeds in the direction that allows
the strongest base to displace the weaker base
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
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 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
Both the cis- and trans-4-methylcyclohexanol are
obtained in the SN1 reaction
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
Br
Cl
R
C C
H
H
X
Nu
X
Nu
Vinyl and aryl halides do not undergo SN1 because
RCH CH Cl
X
X
Br
RCH CH
+ Cl+ Br-
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
in the rate-limiting step
none of the reactants is charged
in the rate-limiting step
increase the polarity
of the solvent
increase the polarity
of the solvent
decrease the rate
of the reaction
increase the rate
of the reaction
Some Biological Methylating Reagents