NUCLEOPHILIC SUBSTITUTION, THE CARBON-CARBON
DOUBLE BOND AND THE CHEMISTRY OF ALKENES
Text references: McMurry (5th Edition) Chapters 6, 7 and 11.
Some Important Definitions:
BASE: Any species that can 'accept' (i.e. form a bond with) a proton.
Since a proton has no electrons the base must be able to provide both
electrons for the proton-base bond. Therefore the atom in the base
which acts as the actual basic site must bear a lone pair of electrons.
The ease with which a base accepts a proton is referred to as its
basicity.
B : + H+
[ B:H ] +
NUCLEOPHILE: ('nucleus-loving') an electron-rich species with a
tendency to 'attack' (i.e. donate an electron pair to) an electron-poor site
in another molecule (called an ELECTROPHILE). The nucleophilic
site in many - though not all - nucleophiles will be an atom bearing a
lone pair of electrons.
The rapidity with which a nucleophile reacts with a given type of
electrophile is referred to as its nucleophilicity towards that kind of
electrophile. Good nucleophiles (high nucleophilicity) react rapidly
while poor nucleophiles (low nucleophilicity) react slowly.
Notice that a molecule behaving as a base (i.e. donating an electron pair
to a proton) is simply a special category of nucleophilic behaviour
where the electrophile is a proton.
Therefore a base is also usually (though not always) a nucleophile in
the more general sense. Strong bases are usually (though not always)
also strong nucleophiles and vice-versa.
Alkyl halides, RX, and related compounds are a group of very
important electrophiles in organic chemistry:
X
This carbon atom
is electrophilic
C
+
When alkyl halides react with nucleophiles two different kinds of
reaction can occur:
(1) Nucleophilic substitution:
X
C
+
Nu
+ Nu:-
C
+ X-
(2) Elimination:
X
C
- HX
C
H
-
:Nu
C
C
+ NuH + X-
Alkene
Here the nucleophile behaves as a base and removes a proton from a
carbon atom adjacent to the carbon bearing the halogen. The
consequence of the reaction is that the elements of a small molecule
(H+, X- = HX) are split out or eliminated from the alkyl halide and a
new compound with a carbon-carbon double bond is formed.
Nucleophilic substitution reactions:
Depending on the compounds involved nucleophilic substitution
reactions can involve one of two different kinds of stereochemical
change:
Consider the following reaction:
H
C6 H5
C
Br
CN
H
-
CH3
C
CN
C6 H5
CH3
(R)-1-Bromo-1-phenylethane
(S)-1-Cyano-1-phenylethane
The stereochemical configuration at the electrophilic carbon in the
starting material has changed from R- in the starting material to S- in
the product - the nucleophilic substitution occurs with an inversion of
configuration known, after its original discoverer, as the Walden
Inversion.
The kinetic behaviour of this reaction is also of significance. The rate
depends on both the concentration of the alkyl halide and on the
concentration of the nucleophile - i.e. the reaction follows a second
order rate law:
Rate = k x [RX] x [Nucleophile]
Second-order kinetics tell us that the reaction is bimolecular - i.e. two
molecules - the alkyl halide and the nucleophile - are involved in the
slowest (i.e. rate-determining) step of the nucleophilic substitution
reaction.
A mechanism accounting for the stereochemistry and kinetic
behaviour of this class of nucleophilic substitution reactions was put
forward in 1937 by Hughes and Ingold.
Hughes and Ingold labelled the process SN2 to indicate that it was a
substitution, involved a nucleophile and was bimolecular.
The crucial feature of the SN2 mechanism is that the nucleophile attacks
the electrophilic carbon from the rear of the group - called the leaving
group - which will be displaced. There is no intermediate - just a
single step in which the nucleophile forms a bond to carbon while the
leaving group departs:
H
N
C: Ph
C
Br
(R)-1-Bromo-1-phenylethane
Br
Transition state
CH3
N
C
H
C
Ph
CH3
H
N
C
C
Ph
CH3
+ Br-
(S)-1-Cyano-1-phenylethane
H
Nu-:
C
Ph
X
sp3
CH3
sp2
X
H
Nu
C
Ph
CH3
sp3
H
Nu
C
Ph
CH3
+ X-
As the nucleophile approaches it
repels the electrons in the bonds at
the central carbon forcing them
back in the direction of the
departing leaving group.
In the transition state the
hybridisation at carbon has
changed from tetrahedral sp3 to
planar sp2 with both nucleophile
and leaving group sharing an
unhybridised p orbital.
As the nucleophile moves even
closer to carbon - and the leaving
group moves off - the sp2
transition state collapses to sp3
again in the direction of the
departing leaving group forming
the substitution product with
inverted configuration at carbon.
The fact that both nucleophile and substrate are involved in the
transition state explains the bimolecular kinetics while the requirement
that the nucleophile attack from the rear of the departing leaving group
explains the inversion of configuration at the reacting centre.
Variables in the SN2 reaction
(1) Steric effects:
H
CH3
C
H
Br
C
H
H
CH3
Br
H
C
CH3
CH3
Br
CH3
H
Methyl
Primary
Secondary
2 x 106
4 x 104
500
High
C
Br
CH3
Tertiary
<1
Low
Relative SN 2 reactivity
As the degree of substitution on the halogen-bearing carbon increases
the reactivity towards SN2 substitution falls off dramatically.
Increasing substitution hinders the approach of the nucleophile to the
halogen-substituted carbon.
(2) The nucleophile:
H2O
Cl
HO
CH3O
1 x 103
HS
1 x 105
1.6 x 104
1
I
2.5 x 104
1.2 x 105
Weak
Powerful
Relative nucleophilicity (relative reactivity in S N 2 substitution)
(i) Nucleophilicity parallels basicity - stronger base = better nucleophile
(ii) Negatively charged nucleophiles are more reactive than neutral
(iii) For related species 4th row nucleophiles > 3rd row nucleophiles >
2nd row nucleophiles
An unexpected experimental result:
Relative SN 2 reactivity
High
Low
C
H
C
Br
H
H
R
C
Br
H
CH3
Primary
<1
1
R
C
Br
CH3
H
Br + H2 O
Methyl
Less
reactive
CH3
CH3
CH3
H
Br
CH3
OH + HBr
Secondary
12
Relative rate of reaction with water:
Tertiary
1.2 x 106
More
reactive
Q: How can this discrepancy be explained?
A: The one-step SN2 process is not the only possible reaction pathway nucleophilic substitution can also proceed by a two-step SN1
mechanism - unimolecular nucleophilic substitution - with a first order
rate law:
Rate = k x [RX]
Mechanism:
Slow
(CH3 )3C
Br
Rate-determining
step.
+
(CH3)3 C + Br
Rapid Nu-
(CH3 )3C
CARBOCATION
intermediate
Nu
Stereochemical consequences of the SN1 reaction:
H
+
Slow
C
Ph
H
Br
C
Ph
CH3
CH3
PLANAR
+ Br
sp2 hybridised
CARBOCATION
-
(R)-1-Bromo-1phenylethane
N
H
Ph
C
_
C
H
+
CN
CH3
(R)-1-Cyano-1phenylethane
50%
_
C
C
Ph
N
H
NC
C
CH3
RACEMISATION
Ph
CH3
(S)-1-Cyano-1phenylethane
50%
Where the SN2 mechanism leads to inversion at the reacting carbon
atom the SN1 mechanism leads to racemisation, i.e. to the complete loss
of optical activity .
Variables in the SN1 Reaction
(1) The structure of the substrate (i.e. the reactant which is attacked by
the nucleophile)
Energy
Transition State
Free energy
G‡
of
activation
R+ + X
Carbocation
intermediate
RX + Nu
RNu + X
-
Progress of reaction
Transition State Theory: Any factor which stabilises an
intermediate will also stabilise the transition state for the formation
of the intermediate and increase the rate of the reaction concerned.
So - what factors stabilise a carbocation?
H
CH3
CH3
CH3
C
C
C
C
+
H
+
H
H
<
Methyl
+
H
H
<
1°
+
CH3
CH3 CH3
<
2°
3°
Increasing carbocation stability
+
Filled C-H 
bonding orbital
H
C
C
H
H
Hyperconjugation
Donating electrons
via -overlap to:
Empty p-orbital
of carbocation
H
CH3
C
H
H
Methyl
Less
reactive
Br
CH3
C
H
Br
H
Primary
CH3
C
CH3
Br
H
Secondary
Increasing SN1 reactivity
C
CH3
Br
CH3
Tertiary
More
reactive
Note that the structural factors which promote the SN1 pathway are
exactly the same factors which inhibit the SN2 mechanism.