Hofmann rearrangement

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.

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. Sodium hypochlorite, lead tetraacetate, N-bromosuccinimide, and (bis(trifluoroacetoxy)iodo)benzene have all been used for Hofmann rearrangements.

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.

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

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

In the Schestakov rearrangement, the substrate is a urea and the product a diacyl hydrazide.

Applications

• The preparation of anthranilic acid from phthalimide
• The conversion of Nicotinamide into 3-Aminopyridine
• 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

References

Bibliography

References

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2. (1946). "The Hofmann Reaction". Organic Reactions.
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5. (1975). "Reactions of amines. XVIII. Oxidative rearrangement of amides with lead tetraacetate". The Journal of Organic Chemistry.
6. (1988). "Hofmann Rearrangement under Mildly Acidic Conditions using [I,I-Bis(Trifluoroacetoxy)]iodobenzene: Cyclobutylamine Hydrochloride from Cyclobutanecarboxamide". Organic Syntheses.
7. (2002). "Methyl Carbamate Formation via Modified Hofmann Rearrangement Reactions: Methyl ''N''-(''p''-Methoxyphenyl)carbamate". Organic Syntheses.
8. (1913). "Einwirkung von Natriumhypochlorit auf Amide ungesättigter Säuren". Justus Liebigs Annalen der Chemie.
9. (1970). "The Chemistry of Amides". Interscience (Wiley).
10. (2000). "Ullmann's Encyclopedia of Industrial Chemistry".
11. (1950). "3-Aminopyridine".
12. "Process For Synthesis Of Gabapentin".