α-Substitution Reactions in Carboxylic Acids and Derivatives

Abstract

The chemistry of carboxylic acid derivatives containing at least one hydrogen α to the carbonyl group is the focus of this chapter. The synthesis of β-ketoesters by the Claisen condensation illustrates the enolization and condensation processes guided by the pKa difference between the nucleophile and the product. The importance of malonic and acetoacetic esters for the preparation of carboxylic acids and derivatives (malonic ester synthesis) and ketones (acetoacetic ester synthesis) is presented. The biosynthetic relevance of the Claisen and Dieckmann condensations in the metabolism and the synthesis of natural products is also addressed. The alkylation of esters, tertiary amides and nitriles via the corresponding enolates is presented. The stereochemical control in the formation of enolates from carboxylic acid derivatives and their use in aldol reactions is discussed by taking into account the Zimmerman–Traxler transition-state model. The Perkin, Knoevenagel, and Reformatsky reactions are also addressed as a route to carboxylic acids and derivatives. Asymmetric aldol reactions using chiral auxiliaries and asymmetric catalysis are discussed.