Hydrogen exchange carboxylic acid derivatives

The enolates of aldehydes and ketones undergo deuterium exchange, bromination, and alkylation reactions (Sections 22.4—22.6). Carboxylic acid derivatives react similarly. However, the added possibility of a competing nucleophilic acyl substitution reaction limits some of the substitution reactions at the a-carbon atom of acid derivatives. For example, acyl halides react with most bases in substitution reactions at the carbonyl carbon atom rather than by abstraction of the a-hydrogen atom. On the other hand, the pA of the a-hydrogen atoms of amides is very large, and these derivatives would require a very strong base for formation of enolates for synthetic reactions. Esters are the most convenient acyl derivatives for enolate formation and subsequent substitution at the a-carbon atom. The substituted ester can subsequently be converted into other acyl derivatives. 

Related to the pyridine studies are the results of base-catalyzed hydrogen exchange in cyclobutabenzene derivatives, which suggest that cyclobutyl annelation increases both the kinetic and thermodynamic acidity at the a-position. The most significant study is the thermodynamic deprotonation/carboxylation reaction of cyclobutabenzene with amyl sodium/COj, in which only the a-carboxy isomer is formed (Figure 6). This is consistent with the value for the a-proton being several p units lower than that for the P-proton in cyclobutabenzene (38). 

Silylation is without a doubt the most employed derivation procedure today. It is particularly effective with alcohols, phenols, sugars, amines, thiols, steroids, and carboxylic acids. ° The reaction of an alcohol presented in Fignre 1.1 replaces an exchangeable hydrogen with a silicon. The operational conditions depend obviously on the analytes and the reagents used, but most silylation reactions are performed in an oven, at temperatures ranging from 60 to 80°C and with reaction times ranging from 20 to 30 minutes. 

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