The Hofmann Rearrangement

CHAPTER 13 Hofmann Rearrangement

BY, G.DEEPA The Hofmann Rearrangement

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

O Br2 RCNH RNH + CO 2– 2 HO– 2 3 Examples

O Br2, NaOH (CH3)3CCH2CNH2 (CH3)3CCH2NH2 H O 2 (94%)

O Br2, KOH CNH2 NH2

H2O Br Br (87%) Mechanism of the Hofmann Rearrangement

O O

RCNH2 RCNHBr RNCO RNH2

•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) Step 1

•• O• – •• RC • O H ••

• N H H Step 1

•• – ••• • O• • O• – •• •• RC • O H RC • O H •• • • N H • N H H H Step 2

•• – • • O•

• •• •• • N • • Br Br• •• •• H Step 2

•• – ••• • O• • O•

RC RC •• • N • •• – • •• •• • Br • • • • N • •• • Br• • Br Br• •• •• •• H H Step 3

•• O•

RC •• • N Br • • •• H

– •• • O H •• Step 3

•• – ••• • O• • O•

RC R C •• •• • • • • N Br • • N Br • •• •• H H – •• • • O H •O H •• •• Step 4

•• – • • •• O• • O•

C R C

• •• R N • N Br • •• •• •• – •Br• •• Steps 5 and 6

••• •• O• •O H2O •• – C C O • •• • R N • R N •

HO– H

•• + 2– R NH2 CO3 Mechanism of Diazonium salt formation

H + HONO+ H + O NO H H + + O NO H 2 O + NO H nitrosonium ion H + + RNH2 + NO RNNO H N-nitrosoammonium ion H + + RNN O + H 2 O RNNO+H3 O H H N-nitrosamine

RNNO RNN OH tautomerization H a diazenol

+ H RNN OH+ H + RNN O H

+ H + RNN O RNN + H 2 O H a diazonium ion Basicity of amines

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

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

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