1. 20.17 The Hofmann Rearrangement

2. 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

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

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

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

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

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

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

9. Step 3 •• RC O N
• • Br H – 8

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

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

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

13. 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

14. 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

15. 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