9.7. Enolate alkylation

The anions from ketones, called enolates, can act as a nucleophile in S_N2 type reactions. Overall an α hydrogen is replaced with an alkyl group and a new carbon-carbon bond is formed. These alkylations are affected by the same limitations as S_N2 reactions previously discussed. A good leaving group, chloride, bromide, iodide or tosylate, should be used. Also, secondary and tertiary leaving groups should not be used because of poor reactivity and possible competition with elimination reactions. Lastly, it is important to use a strong base, such as LDA, for preparing the enolate from the ketone. Using a weaker base such as hydroxide or an alkoxide leaves the possibility of multiple alkylations occurring, and competing S_N2 reactions with the base.

Example 1: Alpha Alkylation

Mechanism

1) Formation of the enolate via an acid-base reaction:

Formation of an enolate by deprotonation of a ketone with LDA

2) S_N2 reaction of the enolate (as nucleophile) with a primary or secondary alkyl halide.

Mechanism of the SN2 reaction of an enolate with an alkyl halide

Alkylation of Unsymmetrical Ketones

Unsymmetrical ketones can be regioselctively alkylated to form one major product depending on the reagents.

Treatment with LDA in THF at -78^oC tends to form the less substituted kinetic enolate.

Using sodium ethoxide in ethanol at room temperature forms the more substituted thermodynamic enolate, though yields of alkylation product are likely to be poorer because of the side reactions mentioned above.