Hofmann rearrangement, mechanism

The Hofmann rearrangement mechanism is long and complicated, but it can be broken down ... 

Carboxylic acid derivatives can be converted into primary amines with loss of one carbon atom by both the Hofmann rearrangement and tire Curtius rearrangement. Although the Hofmann rearrangement involves a primary-amide and the Curtius rearrangement involves an acyl azide, both proceed through similar mechanisms. 

Figure 24.5 MECHANISM Mechanism of the Hofmann rearrangement of an amide to an amine. Each step is analogous to a reaction studied previously.

When an a-hydroxy amide is treated with Br2 in aqueous NaOH under Hofmann rearrangement conditions, loss of C02 occurs and a chain-shortened aldehyde is formed. Propose a mechanism. 

In 1882 Hofmann discovered that when amides are treated with bromine in basic solution, they are converted to amines with one carbon less than the starting amide.180 He also isolated the N-bromo amine (114) and the isocyanate (115) as intermediates on the reaction path. The mechanism in Equation 6.56 accounts for the products and the intermediates. This reaction (or the analogous rearrangement of the N-chloro amine) is now known as the Hofmann rearrangement or, because of its synthetic usefulness in eliminating a carbon atom, the Hofmann degradation. 

The conversion of an amide in this way is termed the Hofmann reaction or the Hofmann rearrangement. The mechanism of the reaction involves an intramolecular 1,2-carbon-to-nitrogen nucleophilic shift of the alkyl (or aryl) group... 

The Hofmann rearrangement also involves a migration to an electron-deficient nitrogen. In this case, an amide is treated with Cl2 or Br2 in aqueous base, resulting in the formation of an amine with one less carbon. The original carbonyl carbon is lost as carbon dioxide. The mechanism is shown in Figure 22.7 and an example is provided by the following equation ... 

The following reaction is known as the Curtius rearrangement. Its mechanism is similar to the Hofmann rearrangement. Show the mechanism of this reaction. 

The Curtius rearrangement starts with an acyl azide and occurs by a mechanism very similar to that of the Hofmann rearrangement. 

Hofmann rearrangement (the mechanism is shown in Section 24.6) of an a-hydroxy amide produces a carbinolamine intermediate that expels ammonia to give an aldehyde. 

The rearrangement has a mechanism similar to those of the Hofmann rearrangement of amides, the Lossen rearrangement of acylhydroxamic esters, the Schmidt rearrangement of carbonyl compounds and the Wolff rearrangement of diazoketones. Evidence concerning the mechanism of one can often be applied to the others, and the whole family has been reviewed briefly . Sometimes the distinction is made that the conversion of an acyl azide into an isocyanate or urethane is the Curtius rearrangement whereas the overall sequence is the Curtius reaction, but usually the former name is used for both processes. 

In the mechanism outlined above, the Hofmann rearrangement is shown as intramolecular. How do we know that this is so To answer this question, T. J. Prosser and E. L. Eliel (of the University of Notre Dame) carried out degradation of a mixture of m-deuteriobenzamide and benzamide- N. When they analyzed the product with the mass spectrometer, they found only w-deuterioaniline and... 

The first intermediates of the Hofmann reaction are A -haloamides e.g. 1), which are subsequently converted to alkaline salts e.g. 2). Both intermediates can be isolated under carefully controlled conditions. Kinetic evidence on both the substituent and isotope effects in the Hofmann rearrangement of various IV-halobenzamides (1) in an aqueous sodium hydroxide solution strongly support a concerted mechanism, involving the bridged anion (3), shown in Scheme 6. 

Grillot, G. F. Hofmann-Martius rearrangement. Mechanisms of Molecular Migrations 1971, 3, 237-270. 

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