CH221 CLASS 19
CHAPTER 11: REACTIONS OF ALKYL HALIDES – NUCLEOPHILIC
SUBSTITUTIONS AND ELIMINATIONS
Synopsis. Class 19 begins considering the substitution and elimination reactions
of alkyl halides by discussing the SN2 mechanism and the factors that influence
it. At the end, there is a short discussion of substitution reactions in synthesis.
Introduction
Because of the electrophilic nature of the halogen-containing carbon atom and
the corresponding slightly acidic nature of the hydrogen atoms on the adjacent
carbon (the “-hydrogens”), the reactions of alkyl halides are dominated by
nucleophilic substitution (SN) and elimination (E):
SN
Nu:-
E
Nu:acting as a
protic base
+
C
X
Nu
C
+
:X-
Nu-H
H
C
C
C
X
C
:X-
[Nu:- may or may not be involved in the rate determining step]
Indeed, nucleophilic substitutions and eliminations are two of the most important
reaction types in organic chemistry, where X is not necessarily (though it is
frequently) halogen.
It was discovered, by Paul Walden in the late 19th century, that certain reactions
occur with inversion of configuration at the reaction site. This is now called the
“Walden inversion”. Some years later, Kenyon and Phillips demonstrated that
certain substitution reactions occur with inversion of configuration, but it wasn’t
until the 1930s that Hughes and Ingold showed that complete inversion of
configuration accompanies all bimolecular nucleophilic substitutions, which were
now called SN2 reactions. The work (described above) of all these pioneers was
with primary or secondary alkyl halides or their equivalents, such as tosylates
(see later).
The SN2 Reaction
Many primary and secondary alkyl halides react with strong nucleophiles (see
later) in substitution reactions that involve just one step, in which the new bond is
made and the old one is broken in a synchronous manner:
.. HO
.. :
SN2
+
CH3
Br
HO
CH3
.. :Br
..
+
The kinetic rate law for such a reaction is
Rate = k[CH3Br][OH-]
Or, more generally, rate = k[RX][Nu-]
The term SN2 was first used by Hughes and Ingold: it stands for bimolecular
nucleophilic substitution.
The chief features of the SN2 reaction are summarized below for the
displacement of bromide from 2-bromobutane by hydroxide to give 2-butanol.
"backside attack"
(180o reaction line)
5-co-ordinate trigonal
bipyramidal transition state
CH3
H
HO incoming
nucleophile
+
C
Br
HO
C2H5
H CH3
C
=/
Br
C2H5
(S)-2-bromobutane
tetrahedral
inversion of
configuration
CH3
H
HO
+
C
C2H5
(R)-2-butanol
tetrahedral
Any factor that increases G at a particular temperature will lead to a slower SN2
reaction at that temperature. This includes factors that lower the reactant energy
(such as effective solvation of the nucleophilic reagent) and those that increase
the transition state energy (such as steric hindrance or unfavorable electronic
interactions). In a similar way, any factor that decreases G will result in a faster
SN2 reaction
Br-
Characteristics of SN2 Reactions
As implied above, some SN2 reactions occur readily (i.e. they are fast), whereas
others occur only slowly, or not at all. It is now time to examine the factors that
influence the rates of SN2 reactions.
These factors are inherent in the nature of the substrate
structure, the nucleophile, the leaving group and the solvent.
Influence of the Substrate: Electronic and Steric Effects
It has long been known that in the reaction
R-Br
+
Cl-

R-Cl + Br-,
Methyl bromide reacts most readily, followed by bromoethane, 1-bromopropane
(and other primary halides) and then various simple secondary alkyl halides. The
following is a reactivity sequence:
Substrate (CH3)3CBr (CH3)3CCH2Br (CH3)2CHBr CH3CH2Br CH3Br
3o
Rel. rate
hindered 1o
(neopentyl)
<1
1
2o
1o
methyl
4 x 10 4
500
2 x 106
SN2 reactions are NOT favored by branched substrates: the best
substrates are methyl halides, primary halides and some simple
secondary halides
The effect of branching can be explained by a combination of electronic and
steric effects:
=/
CH3 CH3
Cl
C
Br
CH3
too high electron density
at C due to 3 x +I effect
gives higher transition state
energy
=/
CH3
Cl
CH3
C
Br
CH3
crowded transition state
gives higher transition state
energy
The lack of reactivity of vinyl and aryl halides can be explained in a similar
manner:
Nu:Cl
high energy transition state
Similarly, the lack of SN2 reactivity at bridgehead carbon atoms can be explained
by a high-energy transition state, this time arising partly from steric hindrance
and partly by the inability of the reaction carbon to invert its configuration,
because of ring strain:
Nu:Cl
1-chloronorbornane
The above examples all illustrate ways in which certain structural features can
destabilize the transition state, that is to say, increase its energy (with respect to
the reactant ground state energy), thereby increasing G, so that the rate of
reaction is decreased. Other structural aspects can stabilize the transition state,
thereby making the SN2 reaction more favorable. This can occur particularly
when there are favorable electronic interactions in the transition state, such as
when there is an unsaturated group conjugated with the reaction site. Consider
the data below for the following reaction, in acetone:
R-Cl
+
R
Rel. rate
I-

R-I
+
Cl-
CH3CH2 CH2=CH-CH2
1
33
PhCH2
93
PhCOCH2
10 5
The transition state in the last case above is strongly stabilized by delocalization,
via p- orbital overlap:
Influence of the Nucleophile
Under a given set of conditions, different nucleophiles have different reactivities
(nucleophilic strengths or “nucleophilicities”), resulting in different SN2 reaction
rates. For example, examine the data for the following reaction in aqueous
ethanol:
CH3-Br + NuNucleophile
Rel. rate

CH3-Nu + Br-
H2O
CH3COO-
Cl-
1
500
103
Br-
OH-
I-
8x103 16x103 11x104
CN-
SH-
12.5x104
It is evident from the above data that the best nucleophiles are generally those
with the following characteristics.
1. The presence of a negative charge: anions are the best
nucleophiles.
2. Basic strength. When comparing nucleophiles that have
the same reacting atom (e.g. oxygen), those that are the
stronger bases are generally the better nucleophiles, e.g.
OH- is better than CH3COO-, which in turn, is better than
H2O.
3. Size: larger simple anions are better nucleophiles than
smaller ones, e.g. I- is better than Br- , which in turn, is
better than Cl-. This is mainly because of higher
polarizability and lower solvation requirements of larger
anions.
Cl-
small anion - high solvation
l-
large anion – low solvation
Influence of the Leaving Group
The better the leaving group, the faster the SN2 reaction. The best leaving groups
(X) are those that are best able to stabilize a negative charge: those that are the
weakest bases and, consequently, those that are derived from the strongest
acids (HX). The following general scale of reactivities is applicable to most SN2
reactions.
Leaving group X
CN- OH- NH2- OR- F- Cl-
Rel. reactivity
<<1
1 200
Br104
I-
TosO-*
3x104
6x104
O
O
TosO- = "tosylate" (p-toluenesulfonate,
O
S
)
CH3
It can be seen that the poor leaving groups are CN-, OH-, NH2-, OR- and F-. This
means that nitriles, alcohols, amines, ethers and alkyl fluorides do not normally
undergo SN2 reactions. However, it is possible to convert some of these poor
leaving groups into good leaving groups by simple chemical reactions. For
example, the hydroxyl group of alcohols can be “activated” in acidic solution or
(better) by reaction with tosyl chloride (p-toluenesulfonyl chloride):
O
O
S
CH 3
Cl
CH3CH2CH2CH2
+
OH2
CH3CH2CH2CH2OH
tosyl
chloride
(TosCl)
HBr
Br-
CH3CH2CH2CH2
Br-
Br-
/amine base
CH3CH2CH2CH2
+OH is a good
2
leaving group
Br
no reaction in neutral
solution (OH is a poor
leaving group)
-OTos is a good
leaving group
See later for examples of activation of hydroxyl groups using PBr3.
OTos
Influence of the Solvent
The rates of SN2 reactions are affected by the solvent in different ways,
depending much upon the nature of the nucleophile and the leaving group, but
we will consider here only the displacement of one anionic group by another.
Consider the data below for the reaction
CH3CH2CH2CH2-Br + N3-

Solvent
CH3OH
H2O
DMSO
DMF
CH3CN
HMPA
Rel. rate
1
7
1300
2800
5000
2x10 5
CH3CH2CH2CH2N3 + Br-
It can be seen from the data that polar protic solvents, like water and methanol
are the poorest, whereas the best are that are called polar aprotic solvents
(DMSO to HMPA, above). This is because polar protic solvents readily solvate
anionic nucleophiles, thereby stabilizing them and lowering their ground state
energies, as shown below.
O
H
R
O
R
H
Nu:H
R
H
O
R
O
Polar aprotic solvents, on the other hand, although they dissolve salts (from
whence anionic nucleophiles are derived), they solvate cations only, leaving the
anions almost free of solvation and hence with higher ground state energies:
Na+N3-(s) + nHMPA(l)
Na+(HMPA)n (solv) + N3-(l)
It can be seen overleaf that the structures of polar aprotic solvents can readily
interact with cations, but not with anions.
..
:O
..
O:
H
C
S
..
CH3
N
..
CH3
CH3
Dimethyl sulfoxide
DMSO
CH3
CH3
C
Acetonitrile
..
N
[(CH3)2N]3 P
..
O:
Hexamethylphosphoramide
HMPA
Dimethylformamide
DMF
CH3 CH3
S
E.g.
CH3
O
S
O
CH3
Na+
O
S
CH3
CH3
O
S
CH3
CH3
..
:O: -
DMSO can also be written
S+
..
CH3
CH3
Summary of SN2 Characteristics
Substrate. Branching raises the energy of the transition state, increases G and
decreases the rate of reaction. The best substrates are methyl and primary alkyl.
Nucleophile. More reactive nucleophiles are less stable, have higher ground
state energies, thereby decreasing G and increasing the reaction rate. The
best nucleophiles are large basic anions.
Leaving group. Good leaving groups (more stable anions) lower the energy of the
transition state, decreasing G and increasing the reaction rate.
Solvent. Protic solvents solvate the nucleophile, lower its ground state energy,
which increases G and decreases the rate of reaction. Polar aprotic solvents
do not solvate the nucleophilic anion, leaving it with a higher ground state
energy, decreasing G and increasing the reaction rate.
Nucleophilic Substitution Reactions and Synthesis
Nucleophilic substitutions are important reactions in organic chemistry – they
occupy prominent positions in many organic syntheses. Indeed, we have seen a
number of examples already, but it will be useful to examine the following two
examples again.
C3H7
1.
C2H5C
C:
Li+
+
C3H7
CH2
Br
C2H5C
C
CH2
+
Li+Br-
lithio 1-butyne
A very useful way of extending carbon frameworks and still retaining
a reactive functional group ( C C) for further synthesis.
2.
R
PBr3
if R is secondary
or primary
OH
R
HBr if R is tertiary
Br
Two useful ways of converting alcohols to alkyl bromides.
These examples will now serve both to illustrate a problem associated with S N
reactions, arising from competitive elimination (E) reactions and to introduce the
difference between SN2 and SN1 reactions. Accordingly, the same two examples
also give a short preview of the topics of the final two classes, SN1 reactions and
elimination reactions.
In example 1, note that the alkyl halide used is primary: good yields of
substitution product are obtained in this case. However, if the halide is secondary
or tertiary, elimination competes successfully with substitution, especially as this
nucleophile is also a very strong base.
E.g.
C4H9C
Br
C:
Na+
+
CH3
CH
SN2
C4H9C
C
CH(CH3)2
7%
CH3
E2
C4H9C
CH + CH3CH
CH2
93%
In the second example, tertiary alcohols react rapidly with HBr because the
substitution mechanism is not SN2 but SN1, which involves the generation of a
carbocation intermediate – 3o cations are more stable than 2o or 1o cations:
SN1
..
OH
+ H
..
(CH3)3C
+
OH2
(CH3)3C
Br
(CH3)3C
+
H2O
2-Methyl-2-propanol
Br-
(CH3)3C
Br
2-bromo-2-methylpropane
On the other hand, 1o and 2o alcohols react readily with PBr3 because this
reagent converts the poor leaving group OH into a very good one:
H
C5H11CH2
..
OH
..
+
PBr3
C5H11CH2
O
+
SN2
C5H11CH2
PBr2
Br
Br-
Class Questions
1. What product would you expect from an SN2 reaction of (R)-1- bromo-1phenylethane with cyanide ion (-CN)?
H
: NC-:
CH3
+
C
H
inversion
Br
C6H5
(R)-1-bromo-1-phenylethane
NC
CH3
+
C
Br-
C6H5
(S)-2-phenylpropanenitrile
2. Which substance of the following pairs is more reactive as a nucleophile?
(a) (CH3)2N- or (CH3)2NH (b) (CH3)3B or (CH3)3N (c) H2O or H2S
(a) (CH3)2N(b) (CH3)3N
(c) H2S
3. Rank the following compounds in order of their expected reactivity toward
the SN2 reaction:
CH3Br, CH3OTos, (CH3)3CCl, (CH3)2CHCl
CH3OTos > CH3Br >(CH3)2CHCl > (CH3)3CCl