Enamines are formed when aldehydes or ketones react with secondary amines. The mechanism below shows how they react with alkylating agents to form new carbon–carbon bonds: the enamine here is the one derived from cyclohexanone and pyrrolidine. The product is at first not a carbonyl compound: it’s an iminium ion or an enamine (depending on whether an appropriate proton can be lost). But a mild acidic hydrolysis converts the iminium ion or enamine into the corresponding alkylated carbonyl compound.

The overall process, from carbonyl compound to carbonyl compound, amounts to an enolate alkylation, but no strong base or enolates are involved so there is no danger of self-condensation. The example below shows two specifi c examples of cyclohexanone alkylation using an enamine. Note the relatively high temperatures and long reaction times: enamines are among the most reactive of neutral nucleophiles, but they are still a lot less nucleophilic than enolates.

The choice of the secondary amine for formation of the enamine is not completely arbitrary even though it does not end up in the final alkylated product. Simple dialkyl amines can be used but cyclic amines such as pyrrolidine, piperidine, and morpholine are popular choices as the ring structure makes both the starting amine and the enamine more nucleophilic (the alkyl groups are ‘tied back’ and can’t get in the way). The higher boiling points of these amines allow the enamine to be formed by heating. α-Bromo carbonyl compounds are excellent electrophiles for SN2 reactions because of the rate-enhancing effect of the carbonyl group. The protons between the halogen and the carbonyl are significantly more acidic than those adjacent to just a carbonyl group and there can be a serious risk of an enolate nucleophile acting as a base. Enamines are only very weakly basic, but react well as nucleophiles with α-bromo carbonyl compounds, and so are a good choice.

The starting ketone here is unsymmetrical, so two enamines are possible. However, the formation of solely the less substituted enamine is typical. The outcome may be explained as the result of thermodynamic control: enamine formation is reversible so the less hindered enamine predominates. For the more substituted enamine, steric hindrance forces the enamine to lose planarity, and destabilizes it. The less substituted enamine, on the other hand, is rather more stable.

There is, however, a major problem with enamines: reaction at nitrogen. Less reactive alkylating agents—simple alkyl halides such as methyl iodide, for example—react to a significant degree at N rather than at C. The product is a quaternary ammonium salt, which hydro lyses back to the starting material and leads to low yields.

●Enamines work best with reactive alkylating agents:

• allylic halides

• benzyl halides

• αα-halo carbonyl compounds.

That said, enamines are a good solution to the aldehyde enolate problem. Aldehydes form enamines very easily (one of the advantages of the electrophilic aldehyde) and these are immune to attack by nucleophiles—including, most importantly, the enamines themselves. Below are two examples of aldehyde alkylation using the enamine method. Both again use highly SN2-reactive electrophiles, and this is the main limitation of enamines.

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مواضيع ذات صلة

The Claisen ester condensation and other self-condensations

Problems with acylation at carbon

Cross-condensations

The aldol reaction

Nitroalkanes are superb nucleophiles for conjugate addition

A variety of electrophilic alkenes will accept enol(ate) nucleophiles

Conjugate addition of silyl enol ethers leads to the silyl enol ether of the product

Enamines are convenient stable enol equivalents for conjugate addition

Alkali metal (especially Na, K) enolates can undergo conjugate addition

1,3-Dicarbonyl compounds undergo conjugate addition

Using Michael acceptors as electrophiles

Conjugate addition to enones gives enolates regiospecifically