Chemistry:Hofmann rearrangement

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Short description: Type of chemical reaction
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 organic reaction of a primary amide to a primary amine with one less carbon atom.[1][2][3] The reaction involves oxidation of the nitrogen followed by rearrangement of the carbonyl and nitrogen to give an isocyanate intermediate. The reaction can form a wide range of products, including alkyl and aryl amines.

The Hofmann rearrangement

The reaction is named after its discoverer, August Wilhelm von Hofmann, and should not be confused with the Hofmann elimination, another name reaction for which he is eponymous.

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]

Hoffman rearrangement.png

  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,[4] lead tetraacetate,[5] N-bromosuccinimide, and (bis(trifluoroacetoxy)iodo)benzene[6] 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]

The Hofmann rearrangement using NBS.

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[2][8] or nitriles from α,β-acetylenic amides[2][9] in good yields (≈70%).

Applications

See also

References

  1. Hofmann, A. W. (1881). "Ueber die Einwirkung des Broms in alkalischer Lösung auf Amide". Berichte der Deutschen Chemischen Gesellschaft 14 (2): 2725–2736. doi:10.1002/cber.188101402242. https://zenodo.org/record/1425242. 
  2. 2.0 2.1 2.2 2.3 Everett, Wallis; Lane, John (1946). The Hofmann Reaction. 3. 267–306. doi:10.1002/0471264180.or003.07. ISBN 9780471005285. 
  3. Shioiri, Takayuki (1991). "Degradation Reactions". Comprehensive Organic Synthesis. 6. pp. 795–828. doi:10.1016/B978-0-08-052349-1.00172-4. ISBN 9780080359298. 
  4. Mohan, Ram S.; Monk, Keith A. (1999). "The Hofmann Rearrangement Using Household Bleach: Synthesis of 3-Nitroaniline". Journal of Chemical Education 76 (12): 1717. doi:10.1021/ed076p1717. Bibcode1999JChEd..76.1717M. https://digitalcommons.iwu.edu/chem_scholarship/51. 
  5. Baumgarten, Henry; Smith, Howard; 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. 
  6. Almond, Merrick R.; Stimmel, Julie B.; Thompson, Alan; Loudon, Marc (1988). "Hofmann Rearrangement under Mildly Acidic Conditions using [I,I-Bis(Trifluoroacetoxy)]iodobenzene: Cyclobutylamine Hydrochloride from Cyclobutanecarboxamide". Organic Syntheses 66: 132. doi:10.15227/orgsyn.066.0132. 
  7. Keillor, Jeffrey W.; Huang, Xicai (2002). "Methyl Carbamate Formation via Modified Hofmann Rearrangement Reactions: Methyl N-(p-Methoxyphenyl)carbamate". Organic Syntheses 78: 234. doi:10.15227/orgsyn.078.0234. 
  8. Weerman, R.A. (1913). "Einwirkung von Natriumhypochlorit auf Amide ungesättigter Säuren". Justus Liebigs Annalen der Chemie 401 (1): 1–20. doi:10.1002/jlac.19134010102. https://zenodo.org/record/1427615. 
  9. Rinkes, I. J. (1920). "De l'action de l'Hypochlorite de Sodium sur les Amides D'Acides". Recueil des Travaux Chimiques des Pays-Bas 39 (12): 704–710. doi:10.1002/recl.19200391204. 
  10. Maki, Takao; Takeda, Kazuo (2000). "Benzoic Acid and Derivatives". Ullmann's Encyclopedia of Industrial Chemistry. doi:10.1002/14356007.a03_555. ISBN 3527306730. .
  11. Allen, C. F. H.; Wolf, Calvin N. (1950). "3-Aminopyridine". Organic Syntheses 30: 3. doi:10.15227/orgsyn.030.0003. http://www.orgsyn.org/demo.aspx?prep=CV4P0045. ; Collective Volume, 4, pp. 45 
  12. "Process For Synthesis Of Gabapentin" US patent 20080103334

Bibliography