Chemical Sciences: A Manual for CSIR-UGC National Eligibility Test for Lectureship and JRF/Named Reactions/Hofmann Rearrangement

The Hofmann rearrangement is the organic reaction of a primary amide to a primary amine with one fewer carbon atom.Hofmann, A. W. v. Ber. 1881, 14, 2725.Wallis, E. S.; Lane, J. F. Org. React. 1949, 3, 267-306. (Review)Shioiri, T. Comp. Org. Syn. 1991, 6, 800-806. (Review) 400px|The Hofmann rearrangment The reaction is named after its discoverer: August Wilhelm von Hofmann. This reaction is also sometimes called the Hofmann degradation, and should not be confused with the Hofmann elimination. Mechanism The reaction of bromine with sodium hydroxide forms sodium hypobromite in situ, which transforms the primary amide into an intermediate isocyanate. The intermediate isocyanate is hydrolyzed to a primary amine giving off carbon dioxide. 400px Variations Several reagents can substitute for bromine. N-Bromosuccinimide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) can effect a Hofmann rearrangement. In the following example, the intermediate isocyanate is trapped by methanol forming a carbamate.Keillor, J. W.; Huang, X. - Organic Syntheses (2004, 549pp) 400px|The Hofmann rearrangement using NBS In a similar fashion the intermediate isocyanate can be trapped by tert-butanol yielding the t-butoxycarbonyl (Boc)-protected amine. A mild alternative to bromine is also (bis(trifluoroacetoxy)iodo)benzene.Almond, M. R.; Stimmel, J. B.; Thompson, E. A.; Loudon, G.M. - Organic Syntheses (1993, 132pp) References Bibliography Clayden Jonnathan Organic Chemistry Oxfort University Press Inc. 2007 1073 978-0-19-850346-0 Fieser Louis F. Advanced Organic Chemistry Reinhold Publishing Corporation, Chapman & Hall, Ltd. 1962 499-501