Enamine

An enamine is a functional group with the formula. Enamines are reagents used in organic synthesis and are intermediates in some enzyme-catalyzed reactions.
The word "enamine" is derived from the affix en-, used as the suffix of alkene, and the root amine. This can be compared with enol, which is a functional group containing both alkene and alcohol. Enamines are nitrogen analogs of enols.
Enamines are both good nucleophiles and good bases. Their behavior as carbon-based nucleophiles is explained with reference to the following resonance structures.

Formation

Enamines can be easily produced from commercially available starting reagents. Commonly enamines are produced by condensation of secondary amines with ketones and aldehydes.. The condensing ketone and aldehyde must contain an α-hydrogen. The associated equations for enamine formation follow:
In some cases, acid-catalysts are employed. Acid catalysis is not always required, if the pK_aH of the reacting amine is sufficiently high. If the pK_aH of the reacting amine is low, however, then acid catalysis is required through both the addition and the dehydration steps. Common dehydrating agents include MgSO₄ and Na₂SO₄.
Methyl ketone self-condensation is a side-reaction which can be avoided through the addition of TiCl₄ into the reaction mixture.
Primary amines are usually not used for enamine synthesis. Instead, such reactions give imines:
Imines are tautomers of enamines. The enamine-imine tautomerism is analogous to the keto-enol tautomerism.

Structure

As shown by X-ray crystallography, the portion of enamines is close to planar. This arrangement reflects the sp² hybridization of the core.
E vs Z geometry affects the reactivity of enamines.

Reactions

Enamines are nucleophiles. Ketone enamines are more nucleophilic than their aldehyde counterparts.
Compared to their enolate counterparts, their alkylations often proceed with fewer side reactions. Cyclic ketone enamines follow a reactivity trend where the five membered ring is the most reactive due to its maximally planar conformation at the nitrogen, following the trend 5>8>6>7. This trend has been attributed to the amount of p-character on the nitrogen lone pair orbital - the higher p character corresponding to a greater nucleophilicity because the p-orbital would allow for donation into the alkene π- orbital. Analogously, if the N lone pair participates in stereoelectronic interactions on the amine moiety, the lone pair will pop out of the plane and compromise donation into the adjacent π C-C bond.

Alkylation and acylation

is the predominant reaction sought with enamines. When treated with alkyl halides enamines give the alkylated iminium salts, which then can be hydrolyzes to regenerate a ketone :
Owing to the pioneering work by Gilbert Stork, this reaction is sometimes referred to as the Stork enamine alkylation. Analogously, this reaction can be used as an effective means of acylation. A variety of alkylating and acylating agents including benzylic, allylic halides can be used in this reaction.
Similar to their alkylation, enamines can be acylated. Hydrolysis of this acylated imine forms a 1,3-dicarbonyl.

Halogenation

of enamines followed by hydrolysis gives α-halo ketones and aldehydes:
In addition to chlorination, bromination and even iodination have been demonstrated.

Oxidative coupling

Enamines can be efficiently cross-coupled with enol silanes through treatment with ceric ammonium nitrate. Oxidative dimerization of aldehydes in the presence of amines proceeds through the formation of an enamine followed by a final pyrrole formation. This method for symmetric pyrrole synthesis was developed in 2010 by the Jia group, as a valuable new pathway for the synthesis of pyrrole-containing natural products.

Annulation

Enamines chemistry has been implemented for the purposes of producing a one-pot enantioselective version of the Robinson annulation. The Robinson annulation, published by Robert Robinson in 1935, is a base-catalyzed reaction that combines a ketone and a methyl vinyl ketone to form a cyclohexenone fused ring system. This reaction may be catalyzed by proline to proceed through chiral enamine intermediates which allow for good stereoselectivity. This is important, in particular in the field of natural product synthesis, for example, for the synthesis of the Wieland-Miescher ketone – a vital building block for more complex biologically active molecules.

Metalloenamines

Lithiated enamines are nitrogen analogues to enolates, formed when imines get treated with strong bases such as LiNR₂:
They can also be formed with Grignard reagents and react with other soft electrophiles, including Michael receptors.
Aza enolates are highly nucleophilic at the β carbon, but scarcely electrophilic. They do not undergo self-condensation in a basic or neutral solution. Thus, aza enolates are convenient to alkylate the β carbon with epoxides and alkyl halides:
That reaction is one of the key steps in the synthesis of the Oulema melanopus' male aggression pheromone:
Most prominently, these reactions have allowed for asymmetric alkylations of ketones through transformation to chiral intermediate metalloenamines.

Biochemistry

Nature processes sugars using enzymes called aldolases. These enzymes act by reversible formation of enamines.