Carbonyl compounds with an α hydrogen atom deprotonate to give enolates: Base mediates the process, but
Lewis acidity plays a key role in stabilizing the product. Often the (weak) Lewis acid is simply the
alkali counterion to an
Arrhenius base (
1.); unsurprisingly, reactivity with such salts varies from lithium to cesium. Alternatively, enolates can be generated from a molecular Lewis acid and a weak Brønsted base (a
frustrated Lewis pair;
2.): Most substrates have multiple α hydrogen atoms, and in principle could give multiple enolate isomers. For example, with
methylcyclohexanone: However, reaction conditions can control both the resulting enolate's regio- and stereochemistry. This provides one of the best understood synthetic strategies to introduce chemical complexity in
total syntheses. Alternatively, an enone can serve as a
protecting group, masking a specific enol. Reaction with a hydride or
dissolving-metal reduction then forms an enol, as in this total synthesis of progesterone:
Regiochemistry The
kinetic-versus-thermodynamic distinction is key to regiocontrol during deprotonation. Substitution improves alkene thermodynamics through additional
hyperconjugation, but hinders initial proton loss. In the methylcyclohexanone example above, the trisubstituted enolate deprotonates more quickly: it is the
kinetic enolate. The tetrasubstituted enolate is more stable, and dominant in thermodynamic equilibrium. Base strength determines the regioisomeric ratio. With strong bases and weak Lewis acids, deprotonation is quantitative and irreversible, trapping the kinetic enolate. Typically kinetic enolates are generated using
lithium diisopropylamide (LDA), often in slight excess and at low temperature. Weaker alkoxide bases and stronger Lewis acids instead reversibly deprotonate the substrate, affording thermodynamically-favored enolates.
Stereochemistry Most enolization conditions give
Z enolates from ketones and
E enolates from
esters, but
HMPA is known to reverse the
stereoselectivity of deprotonation. Likewise different Lewis acids give different enolate geometries: with a six-membered, cyclic, monomeric
transition state proposal. For
deprotonation to occur, an α C-H
σ bond must overlap the π* orbital of the
carbonyl: In the Ireland model, the larger substituent on the electrophile (for the ester above, methyl)
adopts an equatorial disposition in the transition state, leading to a preference for E enolates. The Ireland model fails often. It is not known when, if ever, the intermediates are
monomeric and cyclic like the model proposes. ==Reactions==