20.17 The Hofmann Rearrangement

The Hofmann Rearrangement Treatment of amides with bromine in basic solution gives an amine with loss of the carbonyl carbon. RCNH2 O Br2 RNH2 + CO32– HO– 5

Examples O Br2, NaOH (CH3)3CCH2CNH2 (CH3)3CCH2NH2 H2O (94%) Br CNH2 O Br2, KOH Br NH2 H2O (87%) 4

Mechanism of the Hofmann Rearrangement RCNH2 O RCNHBr O 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) 5

Step 1 •• RC O N • • H O • • •• – H 8

Step 1 RC O N • • – H •• •• RC O N • • H O • • •• – H H O • • •• 8

Step 2 RC O N • • – H •• • • •• Br 8

Step 2 RC O N – H RC O N Br H Br – Br •• •• • • • • •• • • •• • • • • 8

Step 3 •• RC O N • • Br H – 8

Step 3 C O N • • – •• Br R •• RC O N • • Br H – •• H O • • 8

Step 4 C O N • • – •• Br R •• C O N • • R Br • • •• – 8

Steps 5 and 6 C O N R C O N R H – H2O HO– NH2 R + CO32– •• •• • • • • 8

alkyl group migrates with retention of configuration Stereochemistry CNH2 O H C6H5CH2 H3C C alkyl group migrates with retention of configuration Br2, NaOH, H2O NH2 H C6H5CH2 H3C C 5

Isocyanates are intermediates When the reaction is carried out in methanol instead of water, the product shown is isolated. CH3(CH2)14CNH2 O CH3(CH2)14NHCOCH3 O Br2 NaOCH3 CH3OH 5

Isocyanates are intermediates When the reaction is carried out in methanol instead of water, the product shown is isolated. CH3(CH2)14CNH2 O CH3(CH2)14NHCOCH3 O Br2 NaOCH3 CH3OH via: CH3(CH2)14N C O 5