TheHofmann rearrangement (Hofmann degradation) is theorganic reaction of a primaryamide to a primaryamine with one lesscarbon atom.^[1][2][3] The reaction involvesoxidation of the nitrogen followed byrearrangement of the carbonyl and nitrogen to give anisocyanate intermediate. The reaction can form a wide range of products, includingalkyl andaryl amines.

The reaction is named after its discoverer,August Wilhelm von Hofmann, and should not be confused with theHofmann elimination, anothername reaction for which he iseponymous.

The reaction ofbromine withsodium hydroxide formssodium hypobromitein situ, which transforms the primaryamide into an intermediate isocyanate. The formation of an intermediatenitrene is not possible because it implies also the formation of ahydroxamic acid as a byproduct, which has never been observed. The intermediate isocyanate is hydrolyzed to a primary amine, giving offcarbon dioxide.^[2]

1. Base abstracts an acidic N-H proton, yielding an anion.
2. The anion reacts with bromine in an α-substitution reaction to give anN-bromoamide.
3. Base abstraction of the remaining amide proton gives a bromoamide anion.
4. The bromoamide anion rearranges as the R group attached to the carbonyl carbon migrates to nitrogen at the same time the bromide ion leaves, giving an isocyanate.
5. The isocyanate adds water in a nucleophilic addition step to yield acarbamic acid (akaurethane).
6. The carbamic acid spontaneously loses CO₂, yielding the amine product.

Several reagents can be substituted for bromine.Sodium hypochlorite,^[4]lead tetraacetate,^[5]N-bromosuccinimide, and(bis(trifluoroacetoxy)iodo)benzene^[6] have all been used for Hofmann rearrangements.

The intermediateisocyanate can be trapped with variousnucleophiles to form stablecarbamates or other products rather than undergoing decarboxylation. In the following example, the intermediate isocyanate is trapped bymethanol.^[7]

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

The Hofmann Rearrangement also can be used to yield carbamates fromα,β-unsaturated or α-hydroxy amides^[2][8] or nitriles from α,β-acetylenic amides^[2][9] in good yields (≈70%).

• The preparation ofanthranilic acid fromphthalimide^[10]
• The conversion ofNicotinamide into3-Aminopyridine^[11]
• In the synthesis ofgabapentin, beginning with the mono-amidation of 1,1-cyclohexane diacetic acid anhydride withammonia to 1,1-cyclohexane diacetic acid mono-amide, followed by a Hofmann rearrangement^[12]

• Beckmann rearrangement
• Curtius rearrangement
• Iodoform reaction
• Lossen rearrangement
• Schmidt reaction
• Weerman degradation

• Clayden, Jonathan (2007).Organic Chemistry. Oxford 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.