Hofmann rearrangement

Hofmann rearrangement
Named after	August Wilhelm von Hofmann
Reaction type	Rearrangement reaction
Identifiers
RSC ontology ID	RXNO:0000410

The Hofmann rearrangement (Hofmann degradation) is the

amines.

The reaction is named after its discoverer,

.

Mechanism

The reaction of bromine with sodium hydroxide forms sodium hypobromite in situ, which transforms the primary amide into an intermediate isocyanate. The formation of an intermediate nitrene is not possible because it implies also the formation of a hydroxamic acid as a byproduct, which has never been observed. The intermediate isocyanate is hydrolyzed to a primary amine, giving off carbon 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 an N-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 a carbamic acid (aka urethane).
6. The carbamic acid spontaneously loses CO₂, yielding the amine product.

Variations

Several reagents can be substituted for bromine.

can affect a Hofmann rearrangement.

The intermediate isocyanate can be trapped with various nucleophiles to form stable carbamates or other products rather than undergoing decarboxylation. In the following example, the intermediate isocyanate is trapped by methanol.^[7]

In a similar fashion, the intermediate isocyanate can be trapped by

(Boc)-protected amine.

The Hofmann Rearrangement also can be used to yield carbamates from

in good yields (≈70%).

Applications

• In the preparation of anthranilic acid from phthalimide^[10]
• Nicotinamide is converted into 3-Aminopyridine^[11]
• The symmetrical structure^{[clarification needed]} of α-phenyl propanamide does not change after Hofmann reaction.
• In the synthesis of gabapentin, beginning with the mono-amidation of 1,1-cyclohexane diacetic acid anhydride with ammonia to 1,1-cyclohexane diacetic acid mono-amide, followed by a Hofmann rearrangement^[12]

See also

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

References

Bibliography

• 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.