Chapter 11: Nucleophilic Substitution and Elimination

Walden Inversion
O
O
PCl5
HO HO
OH
OH
O OH
O Cl
(S)-(-) Malic acid (+)-2-Chlorosuccinic acid
[a]D= -2.3 °
Ag2O,
H2O
Ag2O,
H2O

O
O HO
PCl5 OH
HO
OH O OH
O Cl (R)-(+) Malic acid
(-)-2-Chlorosuccinic acid [a]D= +2.3 °

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

C X Nu C + X-
Nu:
X= Cl, Br, I

O
Cl S O
O
C OH + C O S CH3
O

CH3 tosylate
O
-
O S O
O
Nu: C O S CH3 Nu C +
O

CH3

1
 O

Tos-Cl H3C O- O H + TosO -

H O H pyridine H O Tos
O CH3

[a]D= +33.0 [a]D= +31.1 [a]D= -7.06

HO- HO-

H3C O- Tos-Cl
H O
TosO - + O H O H
pyridine
Tos H
O CH3

[a]D= -7.0 [a]D= -31.0 [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)
H H
Consider: _ C Br HO C Br _
HO H H
H H

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)

2
 H H
_ C Br HO C Br _
HO H H
H H

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
mol•sec
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 N1

S= substitution S= substitution
N= nucleophilic N= nucleophilic
2= biomolecular 1= unimolecular

rate = k [R-X] [Nu:] rate = k [R-X]

3
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.

4
 Increasing reactivity in the SN2 reaction

CH3 CH3 CH3 CH3 H

H3C C Br < H3C C CH2 Br < H3C C Br < H C Br < H C Br
CH3 CH3 H H H

tertiary neopentyl secondary primary methyl

realtive
<< 1 1 500 40,000 2,000,000
reactivity

Vinyl and aryl halides do not react in nucleophilc substitution reactions

X Nu
R3 R1

X
R3 X

R2 R1
+ Nu:
R2 Nu
+ Nu:
X
R3 X R3 CH3 From Chapter 10:
+ (CH3)2CuLi NOT a nucleophilc
R2 R1 R2 R1 substitution reaction

The nature of the nucleophile in the SN2 Reaction:

The measure of nucleophilicity is imprecise.
_ _
Anionic Nu: + R-X Nu-R + X:
+ _
Neutral Nu: + R-X Nu-R + X:

Nu + H3C-Br Nu-CH3 + Br -
Nu = H2O relative reactivity= 1
CH3CO2- 500
NH3 700
Cl- 1,000
HO- 16,000
CH3O- 25,000
I- 100,000
N≡C- 125,000
HS- 125,000

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Nucleophiles are Lewis bases

Nucleophilicity roughly parallels basicity when comparing nucleophiles

that have the same attacking atom

Nu: CH3O- HO- CH3CO2- H2O

relative reactivity: 25,000 16,000 500 1
pKa of the conj. acid: 15.5 15.7 4.7 -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
C X Nu C + X_
Nu _ H H
H H

H H
_ C X+ HO C + X
Nu H H
H H

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.

6
 d- H d- ‡ H
H
C X Nu C X Nu C + X_
Nu _ H H
H H H H

Increasing reactivity in the SN2 reaction

LG: HO-, H2N-, RO- F- Cl- Br- I- TosO-
Relative <<1 1 200 10,000 30,000 60,000
Reactivity:
pKa: >15 3.45 -7.0 -8.0

Charged Leaving Groups: conversion of a poor leaving group to

a good one
Nu _ H H
H H+ + pKa of
C OH C OH Nu C + OH2
H H H H H3O+= -1.7
H H H

The role of the solvent in SN2 reactions:

Descriptor 1:
polar: “high” dipole moment
_
d_ d_ O
+ O + O + S
d H Hd R Hd +
water alcohols DMSO

non-polar: low dipole moment (hexanes)

Descriptor 2:
protic: acidic hydrogens that can form hydrogen bonds
(water, alcohols)
aprotic: no acidic hydrogens
O
+ _
_ O CH3
[(CH3)2N]3P O CH3C N H N
S
+ CH3
hexamethylphosphoramide acetonitrile dimethylformamide
DMSO
(HMPA) (DMF)

7
 Solvation: solvent molecules form “shells” around reactants and
dramatically influence their reactivity.
H H
O d+ d+
H H H O
_
Od d+ H H
H O H O d_
+
H
H d _
_ d+ _ d
H d+
_ H d
d_ O H X H Od d+ O Y+ O
H H d+ H H d+
d+ H H
H O d+ Od_
O
H H O
d_ H
H

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 + N3- CH3CH2CH2CH2CH2Br + Br-

Solvent: CH3OH H2O DMSO DMF CH3CN HMPA

relative
reativity: 1 7 1,300 2,800 5,000 200,000

DE‡ DE‡

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 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 expression-

changing 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

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 DG‡step 2

step 1

DG‡ˇstep 1 >> DG‡step 2

DG‡ˇstep 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
+ H R
H C+ R C+ C
C C+ R C+ R C+
H H R R

Methyl < Primary (1°) < Allylic ~

_ 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

Cl H2O
H3C
H3C CH2CH2CH2CH3
CH2CH2CH2CH3 H3CH2C
H3CH2C

OH2

Carbocation is achiral
OH

H3C CH2CH2CH2CH3
H3CH2C
enantiomers: produced
in equal amount
H3CH2C
H3C CH2CH2CH2CH3

OH

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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
R H+ R -H2O R
+ R + Nu:
C OH C OH C R C Nu
R R R R
R R H 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 e = 1.9
nonpolar
(CH3CH2)2O 4.3
HMPA 30 aprotic
DMF 38
DMSO 48
CH3CH2OH 24 polar
CH3OH 34 protic
H2O 80

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 CH3 CH3
+ ROH H3C C OR + HCl
H3C C Cl
CH3 CH3

Solvent: Ethanol 40% H2O 80% H2O H2O

60% Ethanol 20% Ethanol
Rel. reactivity: 1 100 14,000 100,000

Increasing reactivity in the SN1 reaction

H
‡ H H
H
_
d _O H O
H O H H Od H d+
R R + d_ H d _ +
H
O d _ O H d _ d+
C Cl H C Cl H O H d C H
R O + O H Cl H O
R H
O R R d_
H d_ H H
H O d+ H
H O H O
sp 3 O H O
H H H H
tetrahedral H

sp2
trigonal planar

Solvent stablization of Solvent stablization of

the transition state the intermediates

Stabilization of the intermediate carbocation and the transition state

by polar protic solvents in the SN1 reaction

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Elimination Reactions: Nucleophiles are Lewis bases. In the reaction
with alkyl halides, they can also promote elimination reactions
rather than substitution.

R SN2
_ R C C CH2R
R C C:
X

1° alkyl
halide

_ H elimination H R
R C C: H R

R H
R X
H
2° alkyl
halide

Elimination is a competitive reaction with nucleophilic substitution.

Zaitsev’s 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.

H CH3 H3C H
Br CH3CH2O - Na+
C C + C C
H3CH2C C CH3
CH3CH2OH H3CH2C CH3 H3CH2CH2C H
CH3
81% 19%

Br
CH3CH2O - Na+ H CH3 H H H H
H3CH2C C CH3 C C + C C
+ C C
H CH3CH2OH H3CH2C H H3CH2C CH3 H3CH2CH2C H

70% 30%

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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 X H

XH H

Syn periplanar: Anti periplanar:

the H and X the H and X are
are eclipsed anti staggered
dihedral angle = 0 ° dihedral angle = 180 °

Generally, the anti periplanar geometry is energetically preferred

(staggered conformation vs eclipsed)

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 In the periplanar conformation, the orbitals are already aligned for
p-bond formation

The E2 elimination has a defined geometric (stereochemical)

outcome:

B: H H
H H H Br H
Ph will be H Ph will be
cis on the cis on the
Br Br Br alkene Br Ph alkene
Ph Ph Ph Br Ph Ph
Br

meso anti periplanar

E
favored
BrH Br Ph
H Br

Br Ph Br H Ph H
Ph H Ph will be
will be Ph
cis on the
cis on the
alkene
Z
syn periplanar alkene

Anti periplanar geometry is usually preferred for E2 elimination

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E2 elimination with halocyclohexane reactants

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

No geometric requirements for E1 elimination.

Usually follows Zaitsev’s Rule

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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 SN2 CH3 C H
CH3
_ H
H3C C O
H
C X X H3C C O C
H
H

H CH3 H
CH3

H C E2 H CH3
CH3 C
_ H + H3C C OH
H3C C O C X C
H H H CH3
CH3 H

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

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