What Is an Enamine?

Vincent Summers

In organic chemistry, an "enamine" is the rearrangement product of an imine, itself the reaction product of a carbonyl compound — an aldehyde or ketone — with either ammonia or an amine — primary or secondary. Derivation of the term is from the words "alkene" and "amine" — the two functionalities that constitute an enamine, if they are located adjacent to each other. The complete, overall reaction sequence is RCH2-C(R1)=O + N(H)R2R3RCH2-C(R1)=NR2R3 → RCH=C(R1)-NR2R3. Each "R" in this reaction can be hydrogen or some carbon-based alkyl or aromatic attachment — for example, methyl, isopropyl or phenyl.

Drug developmentis one of the most important areas of enamine chemistry application.
Drug developmentis one of the most important areas of enamine chemistry application.

In the above reaction, the double bond, once between carbon and oxygen, now links carbon to nitrogen and represents the major change in the first step. Next is the reversible change of an imine into an enamine, analogous to the reversible transformation of a ketone into an "enol," or alkene-alcohol. The conversion of the well-known ketone, acetone, well illustrates keto-enol tautomerism: CH3-C(=O)-CH3 → CH2=C(-OH)-CH3. The nitrogen analog of acetone, dimethylimine, changes according to a similar reaction pathway CH3-C(=NH)-CH3CH2=C(-NH2)-CH3. Close scrutiny of the two product structures reveals the reaction parallels.

The ready interchangeability of isomers — sometimes spontaneous or with only a minor change in chemical environment — is called tautomerism, and the individual structures, tautomers. Initiating the change from an imine to an enamine can be as simple as adding a little mineral acid (HX). This action results in protonation, the installment of a positive hydrogen ion (H+) on the nitrogen atom, forcing the double shift: -CH2-CH=NR1R2; plus protonation → -CH2-CH=N+HR1R2; with rearrangement → -C+H2=CH-NHR1R2; with deprotonation → -CH2=CH-NR1R2.

The ability of tautomers to so readily interchange increases the range of possible reactions considerably, making them especially useful intermediates in chemical synthesis — most notably for organic structures in which a rather large carbon skeleton must be developed in as few steps as possible. Lengthy carbon chains, and hence enamines, are of special importance for the development of biologically active, chiral substances. This is because in organic chemistry, any given reaction often results in a collection of optical isomers, and these isomers may require separation — a task not easily accomplished. On the other hand, when it is possible to produce only one isomer, the yield can be twice as great, plus there is no need for separation. Drug development, notably in alkaloids, is certainly one of the most important areas of enamine chemistry application, as is the important and thoroughly researched use of enamines as non-metallic, and hence "green," catalysts.

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