Stereochemistry of Nucleophilic substitution reactions

Under the guidance of:

Sri Shahin Begum madam
(M.Pharm, Ph.D.). Submitted by:
M.Vidya Rani
2017MPH40042,
SPMVV
 STEREOCHEMISTRY OF
NUCLEOPHILIC SUBSTITUTION
REACTIONS

Contents:
 Stereochemistry of SN1 reactions
 Stereochemistry of SN2 reactions
SN2 reactions:
(Nucleophilic substitution bimolecular)
 In SN2 process , there is attack by the nucleophile
from the opposite side of the carbon atom of substrate
bearing the leaving group.
 SN2 process proceeds in one step by a transition state
 In SN2 reactions , the rate of reaction is proportional
to both the concentrations of substrate and
nucleophile. Thus SN2 reaction follows second order
kinetics.
 Rate expression is described as
Rate=k[R-X][Nuˉ]
R-X + Nuˉ [Nu---R---X] Nu-R + X
 Nucleophile attacks from the back side of carbon
atom; such that C-X bond of substrate breaks only as
the C-Nu bond of the product is forming. So, in
transition state, the nucleophile-carbon bond is
partially formed and the C-X bond is partially broken.
 Approach of nucleophile from the side of the
molecule bearing the leaving group is unfavourable
due to electrostatic repulsion and steric factors.
 In transition state, the 3 non reacting substituents on
carbon lie in a plane with the carbon undergoing the
reaction. This plane is between incoming and outgoing
groups.
 Since, no free carbocation is generated separately, so SN2
displacements afford un rearranged products.
Stereochemistry of SN2 reaction:
 Most of SN2 reactions proceed with “complete inversion
of configuration of substrate”.
 The inversion of SN2 reaction means Nucleophile must
attack from the side opposite to the leaving group, such
an attack flip the other 3groups from one side of carbon
atom to other. This process is known as “Walden
inversion”.
SN2 reaction produces a product of opposite
configuration.
1
1 1 R 2
R R R 2 R

Nu + R
2
C X Nu C + X
Nu C X 3
3 R
R 3
R

Transition state
Example:
H13C6 C6H13
H13C6

C Br
HO CH Br HO C + Bromide ion
OH CH3
H H2N Br H
CH3
S-2-bromo octane R-2-Octanol
Transition state
 Here 2-Bromo octane and 2-Octanol are chiral ,that is
they have molecules that are non superimposable
mirror images.
 When (-)-2-Bromo octane is allowed to react with
sodium hydroxide under conditions where second
order kinetics are followed, there is (+)-2-Octanol is
formed.
 Example:
H13C6 H13C6
H13C6
NaOH
H3C C Br HO CH Br HO CH + Br

H CH3 H CH3
CH3

(-)-2-bromo octane Transition state (+)-2-Octanol

 Here , -OH group has not taken the position occupied
by –Br. So the obtained product has a configuration
opposite to that of initial product.
 When a reaction yields a product whose configuration
is opposite to that of the reactant is said to proceed
with “Inversion of configuration”.
 It happens to be accompanied by a change in
specification from S to R or vice versa.(i.e.,
configuration of every molecule is inverted and
reaction proceeds with complete inversion).
 Sample of optically pure bromide were found to yield
optically pure alcohol.
 As –OH becomes attached to carbon, 3 bonds are forced
to apart, until they reach planar “spoke” rearrangement of
the transition state, then as bromide expelled, they move
on to tetrahedral arrangement opposite to original one.
Example:

H2 H CH 2CH 3
H3CH 2C H3CH 2C
Na+ OH-
C Br HO C Br HO C H + Br
CH3 CH3 CH3
S-2-bromobutane Transition state R-2-butanol

 In above reaction, nucleophile attacks the carbon atom

from the back side of leaving group.
 SN2 reaction occurs in single step, and hence bond-
making and bond breaking occurs simultaneously in a
concerted fashion.
 Every molecule of substrate faces the same stereo
chemical fate – Inversion.
 Specificity is completely consistent with the
mechanism:
leaving group is still attached to carbon atom when
nucleophile attack begins and controls the direction
from which attack occurs
Example:
Br
OH
H3C Na+ OH-
CH3 H3C
CH3
Inversion of configuration
Ex : Effect of structure of alkyl halide
H H
Nu H C H
H C H
H C X
Nu C X C
H
H C H
H H
H
H
1° - alkyl halide 3° - alkyl halide

In the above condition, it is easy for nucleophile to

attack the carbon in primary alkyl halide than carbon
in tertiary alkyl halide.
Order of reactivity towards SN2 displacement is
CH3-X>1̊ >2̊ >3̊
Ex: a). 2-Bromo-2-methyl butane, b). 1-bromo pentane,
c). 2-bromo pentane.
CH3
H

H3C CH2 C CH3 H3C CH2 CH2 CH2 C H

Br
Br

3°- alkyl halide 1°- alkyl halide

H3C CH2CH2 CH CH3

Br
 order is b>c>a
2°- alkyl halide
:Ex a). 1-Bromo-3-methyl butane, b). 2-bromo-2-methyl
butane ,c)3-bromo-2-methyl butane

CH3 CH3
H
H3C CH2 C CH3
H3C C CH2 C H

Br Br
H

CH3

H3C CH2 C CH3

CH3

Order is a>c>b.
 SN1 (Substitution nucleophilic unimolecular):
 SN1 reactions proceeds in 2 steps.
Formation of carbocation
Nucleophilic reagent attaches to the carbocation.
Here the formation of carbocation is rate determining
step.
(It involves the ionization of reactant to form carbocation
intermediate).
In second step, the intermediate carbocation is attacked
by the nucleophile to give the final product.
SN1 reactions follows the first order kinetics, as rate of
reaction depends only on the concentration of substrate,
not on nucleophile concentration.
 Rate of expression is:
Rate =k [R-X]
 In most reactions, nucleophile is a solvent molecule
such as water, ammonia or alcohol, here the
substitution is called as “solvolysis”
CH3 CH3
CH3
slow H2O
H3C C Cl H3C C + Cl H3C C OH +H
fast
CH3
CH3 CH3

t- butyl chloride t- butyl carbocation t-butyl alcohol

 In the above reaction, tertiary-butyl chloride ionizes
to a tertiary butyl carbocation, which is captured by a
nucleophilic solvent water, to give protonated alcohol
and then alcohol itself.
  Ionisation step:
CH3
CH3
slow
H3C C Cl H3C C + Cl

CH3 CH3
t- butyl chloride t- butyl carbocation
 Capture of ion by nucleophile:
CH3 H3C
fast
+
H3C C + H2O H3C C OH + H

CH3
CH3
t-butyl alcohol
 SN1 reaction involves 2 transition states. Transition
state for slow step is higher in energy than the
transition state for the fast step.
 In SN1 reactions, nucleophile does not attacks the
substrate but the carbocation, here the leaving group
already become detached, so it can no longer effect
the spacial orientation of attack.
 In first step, optically active substrate- alkyl halide
dissociates to form halide ion and carbocation.
 Nucleophilic reagent, then attaches itself to the
carbocation.
 It may attaches to either the face of flat ion and
depending on the face; yield one/other of 2
enantiomeric products, these constitute the racemic
modification. So, racemization that accompanies
these reactions is consistant with SN1 mechanism and
formation of intermediate carbocation.
Stereochemistry of SN1 reaction:
 Ionisation of optically pure alkyl halide molecule
leads to planar, achiral(symmetrical) carbon atom
with empty P-orbital perpendicular to the plane.
 Addition of nucleophile can take place from the both
sides of the carbocation , resulting in formation of
racemic mixture (equal amounts of R and S
configurations).
 In some cases, there may be a predominant side for its
attack by the nucleophile, here, the product will
contain unequal amounts of enantiomers, yielding
partially optically active product.
 Optically pure starting material contains only one
enantiomer, but the product must contain the both.
The product is thus a mixture of inverted product and
racemic modification. So,SN1 reaction has proceed
with inversion plus partial racemization.
Example:
Optically pure substrate gives a product of opposite
configuration and 50% optical purity; of every 100
molecules of product,75 are formed with Inversion of
configuration and 25 with retention.
These 25 of retained configuration cancel the rotation
of 25 molecules of inverted configuration, leaving an
excess of 50mlecules of inverted configuration.
 Here, the carbocation and leaving group exist for a while
as “Intimate ion pair” and so, the attack of nucleophile
during this time takes place only on the back side of
carbocation – giving rise to Inversion.
 Then those ions diffuse apart as solvent interveins, and
becomes free ions, now attack of nucleophile on free
symmetrical carbocation occurs from backside /front side
with equal probabilities.
R X R X R X R + X

 So, the reaction said to be proceed with

75% of inversion
25% of retention.
Also,accurately50% inversion and 50% racemization
 %of racemization is a measure of stereochemical
randomness.
 %of net inversion is a measure of stereo selectivity.
Example:
C6H13
OH
HO C H
H13C6 H13C6 H CH3

C X
H C X

H3C CH3 C6H13

HO C OH

CH3
  If the carbocation is less stable, It is more likely to be
attacked by nucleophile before leaving group
separates from it, giving rise to Inversion.
 So, in this case, reaction proceeds with racemization
plus net inversion.
Example: (Racemization +net inversion).

CH3
CH3 CH3
H2O
R C R C + HO C
CH3COCH3 R
Cl OH
H5C2 H5C2 H5 C2

3-chloro-3,7 dimethyl octane Retention Inversion

When 3-chloro-3,7-di methyl octane is hydrolised in presence of acetone, there

is 21% excess of product resulting from inversion of configuration.
 If the carbocation is stable enough to survive through
attack of nucleophile during ion pair stage, resulted
product becomes completely racemized.
Example:

CH3 CH3
CH3
H2O
H HO
H + H
Cl OH
Ph Ph
Ph
Retention(51%) Inversion(49%)

Hydrolysis of 1-chloro-1-phenyl ethane occurs with extensive racemization

as reactant ionizes to give benzylic carbocation that is stabilized because of
resonance and ions diffused before nucleophilic attack. So, the attack can
takes place from the both sides of carbocation to give racemic mixture.
 So, SN1 mechanism proceeds via an intermediate
carbocation that is not completely free to react with
nucleophile on both sides.
 The leaving group is still close enough to shield the
sides of carbon atom of carbocation for some time to
which it was attached from nucleophile attack. So,
excess product with inverted configuration observed
in most SN1 reactions.
OH
R
C
X
CH3 H5C2 H
R Retention(<50%)
R C C H2O
H
H H3C
H5C2 H
C
R
H5 C2
OH
Inversion(>50%)
Examples for SN1 reactions:
Nu

C Nu
C

X
C

X Nu

CH3
SH

H3C o ve
+
Na SH- ab
Br
Retention
SH
bel
ow
CH3

Inversion
Order of reactivity towards SN1 displacement is
CH3-X<1̊ <2̊ <3̊
Ex: a). 2-Bromo-2-methyl butane, b). 1-bromo pentane, c). 2-
bromo pentane.
CH3
H

H3C CH2 C CH3 H3C CH2 CH2 CH2 C H

Br
Br

H3C CH2CH2 CH CH3

Br Order is B<c<a
References:

 Organic reaction mechanisms by

V.K.Ahluwalia, Rakesh kumar Parashar.
 Morrison and boyd , Organic chemistry .