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 atoms.[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 or the Harmon Process, 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 via a formation of a nitrene. The intermediate isocyanate is hydrolyzed to a primary amine, giving off carbon dioxide.

Hofmann rearrangement mechanism.

Variations[edit]

Several reagents can substitute for bromine. Sodium hypochlorite,[4] Lead tetraacetate,[5] N-bromosuccinimide, (bis(trifluoroacetoxy)iodo)benzene,[6] 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.[7]

The Hofmann rearrangement using NBS.

In a similar fashion, the intermediate isocyanate can be trapped by tert-butyl alcohol, yielding the tert-butoxycarbonyl (Boc)-protected amine.

Hoffmann Rearrangement also can be used to yield carbamates from α,β-unsaturated or α-hydroxy amides[8][9] or nitriles from α,β-Acetylenic amides[10][9] in good yields (≈70%).

Applications[edit]

See also[edit]

References[edit]

  1. ^ Hofmann, A. W. v. (1881). Ber. 14: 2725. 
  2. ^ Wallis, E. S.; Lane, J. F. (1949). Org. React. 3: 267–306. 
  3. ^ Shioiri, T. (1991). Comp. Org. Syn. 6: 800–806. 
  4. ^ Mohan, Ram S.; Monk, Keith A. (1999). "The Hofmann Rearrangement Using Household Bleach: Synthesis of 3-Nitroaniline". Journal of Chemical Education 76 (12): 1717. doi:10.1021/ed076p1717. 
  5. ^ Baumgarten, Henry; Smith, Howard; and Staklis, Andris (1975). "Reactions of amines. XVIII. Oxidative rearrangement of amides with lead tetraacetate". The Journal of Organic Chemistry 40 (24): 3554–3561. doi:10.1021/jo00912a019. Retrieved 19 December 2013. 
  6. ^ Almond, M. R.; Stimmel, J. B.; Thompson, E. A.; Loudon, G.M. (1993), "Hofmann Rearrangement under Mildly Acidic Conditions using [I,I-Bis(Trifluoroacetoxy)]iodobenzene: Cyclobutylamine Hydrochloride from Cyclobutanecarboxamide", Org. Synth. ; Coll. Vol. 8: 132 
  7. ^ Keillor, J. W.; Huang, X. (2004), "Methyl Carbamate Formation via Modified Hofmann Rearrangement Reactions: Methyl N-(p-Methoxyphenyl)carbamate", Org. Synth. ; Coll. Vol. 10: 549 
  8. ^ Weerman, R.A. (1913). "Einwirkung von Natriumhypochlorit auf Amide ungesättigter Säuren". Justus Liebigs Annalen der Chemie 401 (1): 1–20. doi:10.1002/jlac.19134010102. 
  9. ^ a b Adams, Rodger (1946). Organic Reactions Volume III. Newyork: John Wiley and Sons Inc. pp. 275 & 276. ISBN 9780471005285. Retrieved 15 June 2014. 
  10. ^ Rinkes, I. J. (1920). "De l'action de l'Hypochlorite de Sodium sur les Amides D'Acides". Recueil des Travaux Chimiques des Pays-Bas 39 (12): 704–710. doi:10.1002/recl.19200391204. 

External links[edit]

Bibliography[edit]

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