Hofmann reaction side reactions

The Hofmann and Curtius reactions as applied to both the mono-and diamides and hydrazides have been reported. Marquardt found that a low yield of the amine can be obtained in the Hofmann reaction of l,2,5-thiadiazole-3-carboxamide. The main side reaction was hydrolysis of the electron-deficient amide to the carboxylic acid. Under the same conditions the dicarboxamide (78) formed the amino acid (16b). Attempts to prepare diaminothiadiazole via the Hofmann reaction of the amino amide (16a) resulted only in amide hydrolysis and the formation of the same amino acid. 

Weinstock and Boekelheide introduced Amberlite IRA-400 (OH ) for conversion of alkyltrimethylammonium iodides into the corresponding quaternary ammonium hydroxides. The procedure is simpler than the conventional silver oxide method and avoids undesirable side reactions sometimes encountered. In the case of a derivative of /3-erythroidine, this technique raised the yield in a Hofmann degradation from 40 to 78%. 

The second side reaction is the Hofmann degradation, a destruction of the quaternary ammonium alcoholate by p hydrogen abstraction. This reaction takes place when the hydroxyalkyl group linked to the amine is longer, having a minimum of two PO units (reaction 13.13). 

Exhaustive methylation of a-methyltropidine followed by a Hofmann degradation eliminates the nitrogen as trimethylamine and the low boiling cycloheptatriene (tropilidene) was isolated in good yield (22,121). Tropane may be converted through the intermediate methyltropane to A -cyclo-heptadiene (hydrotropilidene) by a similar process. In the conversion of methyltropane methohydroxide to cycloheptadiene (139), 20% of the methyltropane is reformed by the loss of methanol, a side reaction which occurs in most Hofmann degradations to a greater or lesser extent. Cycloheptatriene and cycloheptadiene have been reduced to cycloheptane (194) which in turn has been oxidized (nitric acid) to pimelic acid. 

More than 100 years ago, Hofmaim reported in a series of papers the conversion of primary amides to amines with bromine in aqueous sodium hydroxide. The occasional side reaction leading to nitrile formation was also observed by Hofmann. Another early observed side reaction is the formation of ureas from the combination of isocyanate with unreacted amide. This particular side reaction can be circumvented by employing sodium methoxide in place of sodium hydroxide to afford the corresponding methyl carbamate, which upon distillation from calcium hydroxide affords the corresponding primary amine, as first described by Jeffreys. ... 

The Hofmann reaction, shown in (79) (discovered 1882) gives excellent (80-90%) yields with lower alkyl and aryl amides, but side-reactions intrude with higher homologues. The discoverer elucidated the mechanism except for the details of the migration. He isolated 76, showed that the corresponding iV chloro, but not the... 

One of the most common reasons for lowyields is an incomplete reaction. Rates of organic reactions can vary enormously, some are complete in a few seconds whereas rates of others are measured on a geological timescale. Consequently, to ensure that the problem of low yields is not simply due to low reactivity, reaction conditions should be such that some or all of the starting material does actually react. If none of the desired product is obtained, but similar reactions of related compounds are successful, the mechanistic implications should be considered. This situation has been referred to as Limitation of Reaction, and several examples have been given [32 ] the Hofmann rearrangement, for example, does not proceed for secondary amides (RCONHR ) because the intermediate anion 28 cannot form (Scheme 2.11). Sometimes, a substrate for a mechanistic investigation may be chosen deliberately to exclude particular reaction pathways for example, unimolecular substitution reactions of 1-adamantyl derivatives have been studied in detail in the knowledge that rear-side nucleophilic attack and elimination are not possible and hence not complications (see Section 2.7.1). 

The results of Eqs. 10.2.b-7 and 10.2.b-10 have been represented by Schoenemann and Hofmann [2] in convenient diagranK Fig. 10.2b-l is the diagram for first-order reactions with constant density. The conversion for more complex kinetic forms must often be obtained numerically, by solving the algebraic Eq. 10.2.b-l with the appropriate rate function on the right-hand side. 

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