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Enamines are rearrangement products of imines, formed from a carbonyl compound and ammonia or an amine. They are useful intermediates in chemical synthesis, particularly for developing biologically active chiral substances. Enamines can be protonated to form tautomers, which can easily exchange and increase the range of possible reactions. Enamines are important in drug development and as non-metallic catalysts.
In organic chemistry, an “enamine” is the rearrangement product of an imine, itself the reaction product of a carbonyl compound – an aldehyde or a ketone – with ammonia or an amine – primary or secondary. The derivation of the term is from the words “alkene” and “amine” – the two functionalities that make up an enamine, if they are located adjacent to each other. The complete and overall reaction sequence is RCH2-C(R1)=O + N(H)R2R3 → RCH2-C(R1)=NR2R3 → RCH=C(R1)-NR2R3. Each “R” in this reaction can be hydrogen or some carbon-based alkyl or aromatic bond, such as methyl, isopropyl, or phenyl.
In the above reaction, the double bond, once between carbon and oxygen, now connects carbon to nitrogen and represents the major change in the first step. Next is the reversible change of an imine to an enamine, analogous to the reversible change of a ketone to an “enol,” or alkene-alcohol. The conversion of the well-known ketone, acetone, illustrates well the keto-enol tautomerism: CH3-C(=O)-CH3 → CH2=C(-OH)-CH3. The nitrogenous analogue of acetone, dimethylimine, changes in a similar reaction pathway CH3-C(=NH)-CH3 → CH2=C(-NH2)-CH3. Close examination of the two product structures reveals the parallels of reaction.
The ready interchangeability of isomers – sometimes spontaneous or with only a small change in the chemical environment – is called tautomerism and the individual structures, tautomers. Initiating the transition from an imine to an enamine can be as simple as adding some mineral acid (HX). This action causes protonation, the installation of a positive hydrogen ion (H+) on the nitrogen atom, forcing the double displacement: -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 exchange so easily increases the range of possible reactions considerably, making them particularly useful intermediates in chemical synthesis, particularly for organic structures where a sizable carbon skeleton must be developed in as few steps as possible. Long carbon chains, and thus enamines, are of particular 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 only one isomer can be produced, the yield can be doubled, furthermore there is no need for separation. Drug development, particularly in alkaloids, is certainly one of the most important areas of application of enamine chemistry, as is the important and carefully studied use of enamines as non-metallic and therefore “green” catalysts.
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