15.31:
α-Alkylation of Ketones via Enolate Ions
A ketone, in the presence of a strong base like LDA, loses an acidic α hydrogen to give an enolate ion, which is stabilized by resonance.
Its hybrid structure reveals negative charges on the carbonyl oxygen and the α carbon.
The ambident enolate nucleophile can attack an electrophile via two potential reactive sites: the anionic oxygen or the anionic α carbon.
Reactions through O-attack are less preferred than C-attack. This is because the oxygen site is less accessible, as the positive counterpart of the base stays more strongly attached to the oxygen than to the α carbon.
Moreover, in the O-attack product, the strong carbonyl bond is lost, which is otherwise retained in the C-attack product.
In summary, to alkylate a ketone, the ketone is first reacted with a strong base to give an enolate, which undergoes a C-attack with an alkyl halide in an SN2 reaction to produce an α-alkylated ketone.
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 SN2 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.