15.31 : α-Alkylation of Ketones via Enolate Ions

Ketones with α protons are deprotonated by strong bases like lithium diisopropylamide (LDA) to form enolate ions. The anion is stabilized by resonance, and its hybrid structure exhibits negative charges on the carbonyl oxygen and the α carbon. This ambident nucleophile can attack an electrophile via two possible sites: the carbonyl oxygen, known as O-attack, or the α carbon, known as C-attack. The nucleophilic attack via the carbanionic site is preferred. This is due to the strong interaction of the positive counterpart of the base with the anionic oxygen, which restricts the approaching electrophile, making the reaction less favorable. Also, the product obtained through C-attack is more stable than that obtained through O-attack, as the stronger C=O π bond is retained in the former, whereas a weaker C=C π bond is preserved in the latter.

A subsequent reaction of the enolate with electrophiles such as alkyl halides produces an α-alkylated ketone via the S_N2 pathway. The α-alkylation of ketones is achieved with the halides of primary alkyl, benzyl, and allylic groups. With secondary and tertiary alkyl halides, elimination predominates over substitution.