Hofmann rearrangement

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The Hofmann rearrangement (also Hofmann degradation or Hofmann acid amide degradation ) is a name reaction in organic chemistry , which was named after its discoverer August Wilhelm von Hofmann (1818-1892). Here, an unsubstituted carboxamide is reacted with bromine Br 2 in the presence of a base in water . This creates an amine shortened by the carbonyl group . This elimination of the carbonyl group of the amide is closely related to the Curtius reaction , the Lossen degradation and the Schmidt reaction .

Overview reaction

The Hofmann rearrangement is a breakdown of carboxamides to primary amines :

Overview of the Hofmann rearrangement

mechanism

In the first step, the hydroxide ion attacks a proton of the amino group . In the next step, a positively polarized bromine atom binds to the negatively charged nitrogen atom. These two reaction steps can also be combined into one: In an alkaline environment, the reactive hypobromite is formed from bromine , which attacks the nucleophilic amino group with its partial positive charge , creating an N -bromamide. Because of its NH acidity, this can be deprotonated by another hydroxide ion . From this anion is bromide cleaved and the rest of R ( alkyl - or aryl group ) of the nitrene migrates to form an isocyanate to the nitrogen . The isocyanate accumulates water and reacts to form a carbamic acid . This is not stable in an aqueous alkaline solution and is decarboxylated . A primary amine is formed .

Mechanism of the Hofmann rearrangement

In the related reactions such as the Curtius rearrangement , the Schmidt reaction or the Lossen degradation , the intermediate nitrene cannot actually be formulated as an intermediate in the corresponding reaction step. Rather, the isocyanate is formed directly from the N- bromoamide in a concerted reaction via a rearrangement .

variants

Bromine can be replaced by other reagents such as chlorine (Cl 2 ) or N- bromo succinimide (NBS) with 1,8-diazabicyclo [5.4.0] undec-7-en (DBU) as the base. In the following example, the intermediate isocyanate is converted to a urethane by methanol :

The Hofmann rearrangement using NBS

As an alternative to bromine, (bis (trifluoroacetoxy) iodine) benzene can also be used.

Individual evidence

  1. ↑ AW Hofmann: About the action of bromine in alkaline solution on amides . In: Reports of the German Chemical Society . tape 14 , no. 2 , July 1881, p. 2725-2736 , doi : 10.1002 / cber.188101402242 .
  2. ^ Everett S. Wallis, John F. Lane: The Hofmann Reaction . In: Organic reactions . tape 3 , no. 7 , 1946, pp. 267-306 , doi : 10.1002 / 0471264180.or003.07 (review article).
  3. ↑ T. Shioiri: The Hofmann reaction . In: Comprehensive Organic Synthesis . Volume 6: Heteroatom Manipulation, 1991, p. 800-806 (review). The article is a subsection in: Takayuki Shioiri: Degradation Reactions . In: Ian Fleming, Barry M. Trost (Eds.): Comprehensive Organic Synthesis . Volume 6: Heteroatom Manipulation. Pergamon, Oxford 1991, ISBN 978-0-08-052349-1 , pp. 795-828 , doi : 10.1016 / B978-0-08-052349-1.00172-4 .
  4. ↑ T. Laue, A. Plagens: Name and catchword reactions of organic chemistry . Teubner Verlag, 2006, ISBN 3-8351-0091-2 , p. 189-190 .
  5. ↑ JW Keillor, X Huang: Methyl Carbamate Formation via modified Hofmann Rearrangement Reactions: Methyl N- (p-Methoxyphenyl) carbamate In: Organic Syntheses . 78, 2002, p. 234, doi : 10.15227 / orgsyn.078.0234 ; Coll. Vol. 10, 2004, p. 549 ( PDF ).
  6. ↑ MR Almond, JB Stimmel, EA Thompson, GM Loudon: Hofmann Rearrangement under mildly acidic Conditions using (I, I-bis (Trifluoroacetoxy)) iodobenzene: Cyclobutylamine Hydrochloride from Cyclobutanecarboxamide In: Organic Syntheses . 66, 1988, p. 132, doi : 10.15227 / orgsyn.066.0132 ; Coll. Vol. 8, 1993, p. 132 ( PDF ).