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

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The Hofmann rearrangement is the organic reaction of a primary amide to a primary amine with one fewer carbon atom.[1][2][3]

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[edit]

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.

Hoffmann rearrangement mechanism.svg

Variations[edit]

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.[4]

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.[5]

References[edit]

  1. Hofmann, A. W. v. Ber. 1881, 14, 2725.
  2. Wallis, E. S.; Lane, J. F. Org. React. 1949, 3, 267-306. (Review)
  3. Shioiri, T. Comp. Org. Syn. 1991, 6, 800-806. (Review)
  4. Keillor, J. W.; Huang, X. - Organic Syntheses (2004, 549pp)
  5. Almond, M. R.; Stimmel, J. B.; Thompson, E. A.; Loudon, G.M. - Organic Syntheses (1993, 132pp)

Bibliography[edit]

  • Clayden, Jonnathan (2007). Organic Chemistry. Oxfort University Press Inc.. pp. 1073. ISBN 978-0-19-850346-0. 
  • Fieser, Louis F. (1962). Advanced Organic Chemistry. Reinhold Publishing Corporation, Chapman & Hall, Ltd.. pp. 499-501.