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Chapter 15: α-Carbon Chemistry: Enols, Enolates, and Enamines Back To Chapter

15.32: Factors Affecting α-Alkylation of Ketones: Choice of Base

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Factors Affecting α-Alkylation of Ketones: Choice of Base

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15.31: α-Alkylation of Ketones via Enolate Ions

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Recall that α-alkylation of ketones occurs via the generation of an enolate ion followed by a substitution reaction.

The enolate formation from ketones takes place in the presence of a base that plays a crucial role in deciding the reaction outcome.

A base whose conjugate acid is stronger than the ketone favors the reverse reaction, resulting in an equilibrium mixture with a higher ketone and lower enolate concentration.

As a result, self-condensation of ketones and nucleophilic attack of the base on alkyl halide competes with α-alkylation.

Conversely, reactions involving a base whose conjugate acid is weaker than the ketone ensures complete and irreversible conversion of the ketone to its corresponding enolate.

This eliminates the chances of other undesirable side reactions, and the resulting enolate acts as a nucleophile that can undergo substitution reactions with the alkyl halide to give substituted ketones.

15.32: Factors Affecting α-Alkylation of Ketones: Choice of Base

α-Alkylation of ketones is achieved in the presence of alkyl halides and a base. The reaction proceeds via the formation of an enolate ion followed by nucleophilic substitution. The choice of base employed is essential as it is the key factor in determining the reaction outcome.

The reaction involving bases like EtO⁻ whose conjugate acid EtOH (pK_a = 15.9) is stronger than the ketone (pK_a = 19.2) results in an equilibrium mixture with higher ketone concentration. As a consequence, side reactions become predominant over α-alkylation. Using bases like LDA, whose conjugate acid NH(CHMe₂)₂ is weaker (pK_a = 36) than the ketones, leads to an irreversible enolate ion formation, excluding undesirable side reactions. Hence, the nucleophilic enolate further undergoes substitution with alkyl halides to produce the desired α-alkylated ketone.

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Î±-alkylation Ketones Base Alkyl Halides Enolate Ion Nucleophilic Substitution Reaction Outcome EtO- EtOH PKa Equilibrium Mixture Side Reactions LDA NH(CHMe2)2 Irreversible Enolate Ion Formation Nucleophilic Enolate Alkylated Ketone

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