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 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

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.

Variations

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

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

Applications

  • Aliphatic & Aromatic amides are converted into aliphatic and aromatic amines, respectively
  • In the preparations of Anthranilic Acid from Phthalimide
  • Nicotinic acid is converted into 3-Amino pyridine
  • The Symmetrical structure of α-phenyl propanamide does not change after Hofmann reaction.

See also

References

  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. ↑ 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. 
  5. ↑ 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 
  6. ↑ 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 

External links

Bibliography

  • 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. 
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