Aldehydes and ketones react with secondary amines to form compounds called enamines. The general reaction for enamine formation can be written as follows:
Since enamine formation requires the loss of a molecule of water, enamine preparations are usually carried out in a way that allows water to be removed as an azeotrope or by a drying agent. This removal of water drives the reversible reaction to completion. Enamine formation is also catalyzed by the presence of a trace of an acid. The secondary amines most commonly used to prepare enamines are cyclic amines such as pyrrolidine, piperidine, and morpholine:
Cyclohexanone, for example, reacts with pyrrolidine in the following way:
Enamines are good nucleophiles. Examination of the resonance structures that follow show that we should expect enamines to have both a nucleophilic nitrogen and a nucleophilic carbon. A map of electrostatic potential highlights the nucleophilic region of an enamine.
The nucleophilicity of the carbon of enamines makes them particularly useful reagents in organic synthesis because they can be acylated, alkylated, and used in Michael additions. Enamines can be used as synthetic equivalents of aldehyde or ketone enolates because the alkene carbon of an enamine reacts the same way as does the α carbon of an aldehyde or ketone enolate and, after hydrolysis, the products are the same. Development of these techniques originated with the work of Gilbert Stork of Columbia University, and in his honor they have come to be known as Stork enamine reactions.
When an enamine reacts with an acyl halide or an acid anhydride, the product is the Cacylated compound. The iminium ion that forms hydrolyzes when water is added, and the overall reaction provides a synthesis of β-diketones:
Although N-acylation may occur in this synthesis, the N-acyl product is unstable and can act as an acylating agent itself:
As a consequence, the yields of C-acylated products are generally high.
Enamines can be alkylated as well as acylated. Although alkylation may lead to the formation of a considerable amount of N-alkylated product, heating the N-alkylated product often converts it to a C-alkyl compound. This rearrangement is particularly favored when the alkyl halide is an allylic halide, benzylic halide, or a-haloacetic ester:
Enamine alkylations are SN2 reactions; therefore, when we choose our alkylating agents, we are usually restricted to the use of methyl, primary, allylic, and benzylic halides. α-Halo esters can also be used as the alkylating agents, and this reaction provides a convenient synthesis of γ-keto esters: