Chapter 11: Nucleophilic Substitution and Elimination ...

Chapter 11: Nucleophilic Substitution and Elimination Walden Inversion

HO O

O

OH OH

(S)-(-) Malic acid [a]D= -2.3 ?

Ag2O, H2O

PCl5

O HO

OH O Cl (+)-2-Chlorosuccinic acid

Ag2O, H2O

O HO

OH O Cl (-)-2-Chlorosuccinic acid

PCl5

HO O

O

OH OH

(R)-(+) Malic 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

Nu:

CX

O Cl S O

C OH +

CH3

O

Nu:

COS

O

X= Cl, Br, I

Nu C

+ X-

O

COS

CH3

O

tosylate

O -O S O

CH3

Nu C +

CH3

1

H OH

Tos-Cl pyridine

[a]D= +33.0

HO-

O

TosO - +

HO

H3C

O-

O CH3

[a]D= -7.0

O

H3C

O-

H O Tos

[a]D= +31.1

OH Tos

[a]D= -31.0

Tos-Cl pyridine

OH

+ TosO -

O CH3

[a]D= -7.06

HO-

OH H

[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: HO _

H C Br

H H

H

HO C H

Br _

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

HO _

H C Br

H H

H

HO C H

Br _

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= substitution N= nucleophilic 2= biomolecular

SN1

S= substitution N= nucleophilic 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

realtive reactivity

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

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