CHAPTER 13

Hofmann Rearrangement

BY,

G.DEEPA

The Hofmann Rearrangement

Treatment of amides with bromine in basic solutiongives an amine with loss of the carbonyl carbon.

RCNH2

OBr2

HO–RNH2 + CO3

2–

Examples

(94%)

(CH3)3CCH2CNH2

OBr2, NaOH

H2O(CH3)3CCH2NH2

Br

CNH2

OBr2, KOH

H2O

Br

NH2

(87%)

Mechanism of the Hofmann Rearrangement

•The Hofmann rearrangement involves 6 steps in 3 stages.• 1.  formation of an N‐bromo amide (2 steps)• 2.  conversion of the N‐bromo amide to an 

isocyanate (2 steps)• 3.  hydrolysis of the isocyanate (2 steps)

RCNH2

O

RCNHBr

O

RNCO RNH2

Step 1

O•• ••

– ••H

••

RC

O

N

••

•• H

H

Step 1

O•• ••

– ••H

H

O••••

H

••

RC

O

N

••

•• H

H

RC

O

N

••

••

–

H

••••

Step 2

••••

••Br Br•• ••

••

RC

O

N

••

••

–

H

••••

Step 2

••••

••

••

RC

O

N

••

•• Br

H••••

••Br Br•• ••

••Br•••• ••••

–

RC

O

N

••

••

–

H

••••

Step 3

••

RC

O

N

••

•• ••••

••Br

H

O•• ••

– ••H

Step 3

••

RC

O

N

••

•• ••••

••Br

H

O•• ••

– ••H

••

H

O•• H

C

O

N

••

••

–••••

••••

••Br

R

Step 4

••

C

O

N

••

••R

Br•••• ••••

–

C

O

N

••–

••

••

••••

••Br

R

••

Steps 5 and 6

••

C

O

N

••

••R

H2O

HO–

••

C

O

N

••

••R

O

H

••••••

–

+ CO32–NH2R

••

Mechanism of Diazonium salt formation

H O N O + H +

H 2 O

+

nitrosoniumion

R NH 2

N O++

R NH

H

N O+

N-nitrosoammoniumion

R NH

H

N O+

+ H 2 O R N

H

N O + H 3 O +

N-nitrosamine

R N

H

N Otautomerization

R N N OH

a diazenol

R N N OH + H + R N N OH

H

R N N OH

HR N N + H 2 O

+

a diazoniumion

N OOH

H

+

N OOH

H

+

+

+

N O+

Basicity of amines

The greater the availability of the lone pair electrons on nitrogen, the greater the base.

Kb = [RNH3+] [OH-] / RNH2

In the old days, pKb was a measure of base strength.

pKb = - log Kb

The stronger the base the lower the pKb

EFFECTS ON AMINE BASICITY

1. INDUCTIVE EFFECT - ALKYL SUBSTITUTION

METHYL GROUP INCREASES ELECTRON DENSITY ON N

3.36 3.28 2 METHYLS ARE BETTER THAN ONE

WATCH OUT THREE METHYL GROUPS DECREASES BASICITY pKb = 4.26 - Steric inhibition of solvation of HOH with the NH+ of the R3NH+ cation.

The greater the availability of the lone pair electrons on nitrogen, the greater the base.

Kb = [RNH3+] [OH-] / RNH2

In the old days, pKb was a measure of base strength.

pKb = - log Kb

The stronger the base the lower the pKb

EFFECTS ON AMINE BASICITY

1. INDUCTIVE EFFECT - ALKYL SUBSTITUTION

METHYL GROUP INCREASES ELECTRON DENSITY ON N

3.36 3.28 2 METHYLS ARE BETTER THAN ONE

WATCH OUT THREE METHYL GROUPS DECREASES BASICITY pKb = 4.26 - Steric inhibition of solvation of HOH with the NH+ of the R3NH+ cation.

Reimer‐Tiemann Reaction Mechanism

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