Chapter 11: Nucleophilic Substitution and Elimination

Walden Inversion
O

PCl5

HO

HO

OH
O

OH

OH

(S)-(-) Malic acid

[a]D= -2.3

Cl

(+)-2-Chlorosuccinic acid
Ag2O,
H2O

Ag2O,
H2O

O
O
HO

HO

PCl5

OH
O

OH
Cl

OH

(R)-(+) Malic acid

[a]D= +2.3

(-)-2-Chlorosuccinic acid

The displacement of a leaving group in a nucleophilic substitution

reaction has a defined stereochemistry

Stereochemistry of nucleophilic substitution

p-toluenesulfonate ester (tosylate): converts an alcohol into
a leaving group; tosylate are excellent leaving groups.
abbreviates as Tos
+ X-

Nu C

C X

Nu:

X= Cl, Br, I
O
Cl S O
O
C OH

C O S

CH3

O
CH3

tosylate
O
-

O
Nu:

C O S

CH3

Nu C

S O

O
CH3

O
Tos-Cl
H O H

H3C
H

pyridine

O-

[a]D= +31.1

[a]D= +33.0

O Tos

+ TosO -

CH3

[a]D= -7.06
HO-

HOO
H3C

H O

TosO - +

Tos-Cl

O-

Tos

CH3

[a]D= -7.0

[a]D= -31.0

pyridine

[a]D= -33.2

The nucleophilic substitution reaction inverts the

Stereochemistry of the carbon (electrophile)- Walden inversion

Kinetics of nucleophilic substitution

Reaction rate: how fast (or slow) reactants are converted into product
(kinetics)
Reaction rates are dependent upon the concentration of the reactants.
(reactions rely on molecular collisions)
Consider:

H
HO

C Br
H

HO C
H

Br _

At a given temperature:
If [OH-] is doubled, then the reaction rate may be doubled
If [CH3-Br] is doubled, then the reaction rate may be doubled
A linear dependence of rate on the concentration of two reactants is
called a second-order reaction (molecularity)

H
HO

HO C

C Br

Br _

Reaction rates (kinetic) can be expressed mathematically:

reaction rate = disappearance of reactants (or appearance of products)
For the disappearance of reactants:
rate = k [CH3Br] [OH-]
[CH3Br] = CH3Br concentration
[OH-] = OH- concentration
k= constant (rate constant)

L
molsec

For the reaction above, product formation involves a collision

between both reactants, thus the rate of the reaction is
dependent upon the concentration of both.

Nucleophilic Substitution comes in two reaction types:

SN2
S= substitution
N= nucleophilic
2= biomolecular
rate = k [R-X] [Nu:]

S N1
S= substitution
N= nucleophilic
1= unimolecular
rate = k [R-X]

The SN2 Reaction: Mechanism

Steric effects in the SN2 reaction:

For an SN2 reaction, the nucleophile approaches the electrophilic
carbon at an angle of 180 from the leaving group (backside attack)
the rate of the SN2 reaction decrease as the steric hindrance
(substitution) of the electrophile increases.

Increasing reactivity in the SN2 reaction

CH3

CH3

H3C C Br

<

CH3

realtive
reactivity

CH3

H3C C CH2 Br

<

H3C C Br

CH3

CH3

<

<

H C Br

H C Br

tertiary

neopentyl

secondary

primary

<< 1

500

40,000

methyl
2,000,000

Vinyl and aryl halides do not react in nucleophilc substitution reactions

X
R3

R2

R1

R3

R1

R2

Nu

Nu
+

X
+

R2

Nu:

R3

R3

CH3

R2

R1

(CH3)2CuLi

R1

Nu:

From Chapter 10:

NOT a nucleophilc
substitution reaction

The nature of the nucleophile in the SN2 Reaction:

The measure of nucleophilicity is imprecise.
Anionic

Nu:

Neutral

Nu:

R-X

Nu-R

X:

R-X

+
Nu-R

X:

Nu + H3C-Br
Nu = H2O
CH3CO2NH3
ClHOCH3OINCHS-

Nu-CH3 + Br relative reactivity=

1
500
700
1,000
16,000
25,000
100,000
125,000
125,000

Nucleophiles are Lewis bases

Nucleophilicity roughly parallels basicity when comparing nucleophiles
that have the same attacking atom
Nu:
CH3Orelative reactivity:
25,000
pKa of the conj. acid: 15.5

HO16,000
15.7

CH3CO2500
4.7

H2O
1
-1.7

Nucleophilicity usually increases going down a column of the periodic

chart. Thus, sulfur nucleophiles are more reactive than oxygen
nucleophiles. I- > Br- > Cl-.
Negatively charges nucleophiles are usually more reactive than neutral
nucleophiles.

The role of the leaving group in SN2 reactions:

H

H
Nu _

Nu C

C X

H
Nu

C X+

HO C

X_

The leaving group is usually displaced with a negative charge

The best leaving groups are those with atoms or groups that can
best stabilize a negative charge.
Good leaving groups are the conjugate bases of strong acids
H-X

H+

X-

the lower the pKa of H-X, the stronger the acid.

H
Nu _

C X

d-

Nu

dX

H
Nu C
H

H H

X_

Increasing reactivity in the SN2 reaction

HO-, H2N-, RO-

LG:

Relative
Reactivity:
pKa:

F-

Cl-

<<1

200

>15

3.45

-7.0

Br-

I-

TosO-

10,000 30,000

60,000

-8.0

Charged Leaving Groups: conversion of a poor leaving group to

a good one
H
H

H+

Nu _

+
C OH
H
H
H

C OH
H

Nu C
H

pKa of
H3O+= -1.7

OH2

The role of the solvent in SN2 reactions:

Descriptor 1:
polar: high dipole moment
+

d H

d_
O

Hd

water

d_
O

O
Hd

alcohols

S
+

DMSO

non-polar: low dipole moment (hexanes)

Descriptor 2:
protic: acidic hydrogens that can form hydrogen bonds
(water, alcohols)
aprotic: no acidic hydrogens
O
_

+
_
[(CH3)2N]3P O

hexamethylphosphoramide
(HMPA)

DMSO

S
+

CH3C N

CH3

CH3

acetonitrile

dimethylformamide
(DMF)

Solvation: solvent molecules form shells around reactants and

dramatically influence their reactivity.
H
H

d
H
d_ O H
H
H O

d+
H
_
Od

H
H O
d+
_
H Od
H d+

d+ H
O
H O
H
d_

d+

d+
H
d+
H O d_

_
H d
O

H
d+

d
H d+
O

Y+
H
Od_
H

H d+

Polar protic solvents stabilize the nucleophile, thereby lowering its

energy. This will raise the activation energy of the reactions.
SN2 reactions are not favored by polar protic solvents.
Polar aprotic solvents selectively solvate cations. This raises the
energy of the anion (nucleophile), thus making it more
reactive. SN2 reactions are favored by polar aprotic solvents.

CH3CH2CH2CH2CH2Br + N3Solvent: CH3OH

relative
reativity:
1

CH3CH2CH2CH2CH2Br + Br-

H2O

DMSO

DMF

CH3CN

1,300

2,800

5,000

DE

HMPA
200,000

DE

The SN1 Reaction:

kinetics: first order reaction (unimolecular)
rate = k [R-X]
[R-X]= alkyl halide conc.
The nucleophile does not appear in the rate expressionchanging the nucleophile concentration does not affect
the rate of the reaction!
Must be a two-step reaction
The overall rate of a reaction is dependent upon the slowest
step: rate-limiting step

The Mechanism of the SN1 Reaction

DGstep 2

step 1

DGstep 1 >> DGstep 2

DGstep 1 is rate-limiting

Reactivity of the Alkyl Halide in the SN1 Reaction:

Formation of the carbocation intermediate is rate-limiting.
Thus, carbocation stability greatly influence the reactivity.
H

H C+

R C+

Methyl

<

Primary (1)

<

Allylic

R
R C+

R C+

C+

~
_

Benzylic

~
_

Secondary (2)

<

Tertiary (3)

Increasing carbocation stability

The order of reactivity of the alkyl halide in the SN1 reaction
exactly parallels the carbocation stability

10

Allylic and benzylic carbocations are stablized by resonance

Stereochemistry of the SN1 Reaction: it is actually a complicated issue.

For the purpose of Chem 220a, sect. 2 the stereochemistry of
the SN1 reaction gives racemization. A chiral alkyl halide will
undergo SN1 substitution to give a racemic product
OH2
H2O

Cl
H3C
CH2CH2CH2CH3
H3CH2C

H3C
H3CH2C

CH2CH2CH2CH3

OH2
OH
H3C
CH2CH2CH2CH3
H3CH2C
H3CH2C
CH2CH2CH2CH3
H3C

Carbocation is achiral

enantiomers: produced
in equal amount

OH

11

The role of the leaving group in SN1 reactions:

same as for the SN2 reaction
TosO- > I- > Br- > Cl- ~_ H2O
Charged Leaving Groups: conversion of a poor leaving group to
a good one
H+

R
R

C OH
R

+
C OH
R
R H

-H2O

R
R

+
C

Nu:
R

C Nu
R

The role of the nucleophile in SN1 reactions: None

Involvement of the nucleophile in the SN1 reaction is after the
rate-limiting step. Thus, the nucleophile does not appear in the
rate expression. The nature of the nucleophile plays no role in
the rate of the SN1 reaction.

The role of the solvent in SN1 reactions:

polar solvents are fovored over non-polar for the SN1 reaction
protic solvents are favored over aprotic for the SN1 reaction
Solvent polarity is measured by dielectric constant (e)
Hexane
(CH3CH2)2O
HMPA
DMF
DMSO
CH3CH2OH
CH3OH
H2O

e = 1.9
4.3
30
38
48
24
34
80

nonpolar
aprotic
polar
protic

12

CH3

CH3

H3C C Cl

ROH

+ HCl

H3C C OR
CH3

CH3

Solvent:

Ethanol

Rel. reactivity:

40% H2O
60% Ethanol
100

80% H2O
20% Ethanol
14,000

H2O
100,000

Increasing reactivity in the SN1 reaction

H

H
H
R
R

C Cl
H

R
3

sp
tetrahedral

O H
R + d_
d
C
Cl

R R

H
H

H
H O
H
O

H
_
H Od
_
H d
O

d _O H
H

d
C
+
d_
H O

d_
H
O
H

H
H

O H

O
H

Cl

d+

_ d+
H O

d+ H
O
H

sp2
trigonal planar

Solvent stablization of
the transition state

Solvent stablization of
the intermediates

Stabilization of the intermediate carbocation and the transition state

by polar protic solvents in the SN1 reaction

13

Elimination Reactions: Nucleophiles are Lewis bases. In the reaction

with alkyl halides, they can also promote elimination reactions
rather than substitution.

R C C:

SN2

R C C CH2R

X
1 alkyl
halide

R C C:

H
R

elimination

R
X

2 alkyl
halide

Elimination is a competitive reaction with nucleophilic substitution.

Zaitsevs Rule: When more than one alkene product is possible

from the base induced elimination of an alkyl halide, the
most highly substituted (most stable) alkene is usually the
major product.
Br
H3CH2C C CH3
CH3

CH3CH2O - Na+
CH3CH2OH

CH3
C C

H3CH2C

H3C

+
H3CH2CH2C

CH3
81%

Br
H3CH2C C CH3
H

CH3CH2O - Na+

CH3CH2OH

H3CH2C

H
19%

CH3
C C

H
C C

H3CH2C

70%

H
C C
CH3

H
C C

H3CH2CH2C

30%

14

The E2 Elimination:
rate = k [R-X] [Base]

The E2 elimination takes place in a single step with no intermediate

Stereochemistry of the E2 Elimination:

The H being abstracted and the leaving group must be in
the same plane
H

H
X

XH

Syn periplanar:
the H and X
are eclipsed
dihedral angle = 0

Anti periplanar:
the H and X are
anti staggered
dihedral angle = 180

Generally, the anti periplanar geometry is energetically preferred

(staggered conformation vs eclipsed)

15

In the periplanar conformation, the orbitals are already aligned for

p-bond formation

The E2 elimination has a defined geometric (stereochemical)

outcome:

H
Br
Ph

B:

H
Br
Ph

meso

H
Br
Ph

will be
cis on the
alkene

Ph

Br

Ph
Ph

Br
Br

Br

will be
cis on the
alkene

Ph

Ph

anti periplanar

favored

Br

Br

Ph

Ph

syn periplanar

Br

BrH

will be
cis on the
alkene

Br
Ph

H
Ph

will be
cis on the
alkene

Ph

Ph

Anti periplanar geometry is usually preferred for E2 elimination

16

E2 elimination with halocyclohexane reactants

17

The E1 Elimination:
rate = k [R-X]

No geometric requirements for E1 elimination.

Usually follows Zaitsevs Rule

18

SN2 vs E2
For primary alkyl halides SN2 is favored with most nucleophiles
E2 is favored with bulky bases (t-butoxide)
CH3
H3C C O

t-butoxide is too bulky to undergo SN2

CH3

H C
_ H
C X
H3C C O
H
H
CH3
CH3

CH3
H3C C O
CH3

H C
H
H

SN2

CH3

E2

H3C C O C
CH3

C X
H

CH3
+ H3C C OH

C
C

C H
H
H

CH3

Secondary halides: E2 is competitive with SN2 and often gives a

mixture of substitution and elimination products
Tertiary Halides:
E2 elimination occurs with strong bases such as
HO-, RO-, H2N- (strongly basic conditions)
E1 elimination occurs with heat and weak bases such as
H2O or ROH. (neutral conditions)
The E1 elimination product is often a minor product with the
major product arising from SN1 reaction.
SN2 reaction does not occur with 3 halides

19