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 (en-) and alcohol (-ol). Enamines are nitrogen analogs of enols.<ref>Imines and Enamines | PharmaXChange.info</ref>
Enamines are both good nucleophiles and good bases. Their behavior as carbon-based nucleophiles is explained with reference to the following resonance structures.
Enamines can be easily produced from commercially available starting reagents. Commonly enamines are produced by condensation of secondary amines with ketones and aldehydes..<ref name=Cook/><ref>Template:OrgSynth</ref> 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 pKaH of the reacting amine is sufficiently high (for example, pyrrolidine, which has a pKaH of 11.26). If the pKaH of the reacting amine is low, however, then acid catalysis is required through both the addition and the dehydration steps.<ref>Template:Cite journal</ref> Common dehydrating agents include MgSO4 and Na2SO4.<ref name="scripps_Lockner_Nov_07">Template:Cite web</ref>
Methyl ketone self-condensation is a side-reaction which can be avoided through the addition of TiCl4<ref>Template:Cite journal</ref> into the reaction mixture (to act as a water scavenger).<ref name="scripps_Lockner_Nov_07"/><ref>Template:Cite journal</ref>
Primary amines are usually not used for enamine synthesis.<ref name="chemwiki_Enamine_Reactions">Template:Cite web</ref> Instead, such reactions give imines:
E vs Z geometry affects the reactivity of enamines.<ref name="scripps_Lockner_Nov_07"/>
Reactions
Enamines are nucleophiles. Ketone enamines are more nucleophilic than their aldehyde counterparts.<ref>Template:Cite book</ref>
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 (the seven membered ring being the least reactive). 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 (will pyramidalize) and compromise donation into the adjacent π C-C bond.<ref>Template:Cite journal</ref>
Alkylation and acylation
Alkylation 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 (a starting material in enamine synthesis):
Template:Chem2 (hydrolysis of the resulting iminium salt, giving a 2-alkylated aldehyde)
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.<ref>Template:Cite book</ref>
Similar to their alkylation, enamines can be acylated. Hydrolysis of this acylated imine forms a 1,3-dicarbonyl.<ref>Template:Cite journal</ref><ref name="chemwiki_Enamine_Reactions"/>
Template:Chem2 (hydrolysis of chloroiminium, giving a chloroaldehyde)
In addition to chlorination, bromination and even iodination have been demonstrated.<ref>Template:Cite journal</ref>
Oxidative coupling
Enamines can be efficiently cross-coupled with enol silanes through treatment with ceric ammonium nitrate.<ref>Template:Cite journal</ref> Oxidative dimerization of aldehydes in the presence of amines proceeds through the formation of an enamine followed by a final pyrrole formation.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>
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 (commonly abbreviated to MVK) 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.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref><ref>Template:Cite web</ref>
Metalloenamines
Lithiated enamines (also known as aza enolates, imine anions, enamides, or metallated Schiff bases) are nitrogen analogues to enolates,<ref name="uk">Template:Cite thesis</ref> formed when imines get treated with strong bases such as LiNR2:
That reaction is one of the key steps in the synthesis of the Oulema melanopus' male aggression pheromone:<ref name= 'hormone'>Template:Cite journal</ref>
Most prominently, these reactions have allowed for asymmetric alkylations of ketones through transformation to chiral intermediate metalloenamines.<ref>Template:Cite journal</ref>
