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 or the Harmon Process, and should not be confused with the Hofmann elimination.

Contents

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.

Hoffmann rearrangement mechanism.svg

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.[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]

Applications

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. ^ Keillor, J. W.; Huang, X. (2004), "Methyl Carbamate Formation via Modified Hofmann Rearrangement Reactions: Methyl N-(p-Methoxyphenyl)carbamate", Org. Synth., http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=v78p0234 ; Coll. Vol. 10: 549 
  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., http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv8p0132 ; Coll. Vol. 8: 132 

External links

Bibliography