Carbonyl Condensations versus Alpha Substitutions

Carbonyl condensation reactions are a type of alpha-substitution reaction. Both occur through an enolate ion intermediate under basic conditions and involve substitution at the carbon alpha to the carbonyl group. However, in a carbonyl condensation reaction the electrophile (E⁺) being attacked is another carbonyl compound.

In a carbonyl condensation a catalytic amount of base is used to generate the enolate ion which attacks any unreacted carbonyl compound to form the carbon-carbon bond at the alpha site. The resulting alkoxide is then protonated, which regenerates the base that will produce more enolate ion in the next cycle.

These steps are all reversible and it should be noted that reactants and products that are close in energy level can potentially undergo the reverse reaction if conditions change enough. While from a synthetic point of view in the laboratory this may mean increasing yields by driving the reaction to completion (e.g. adding heat, removing product), in biological systems it can have more drastic consequences. Indeed, depending on metabolic conditions, retro-aldol reactions (the reverse of aldol condensations, in which carbon-carbon bonds are broken) can occur.

In contrast, the alpha-substitution reaction is often more directional by design. To reduce unwanted competition from carbonyl condensation, the enolate ion intermediate is generated all at once with a full equivalent of strong base at low temperature. The reactive enolate intermediate generated is then quenched with rapid addition of the electrophile to complete the substitution. In Section 22.7, under direct alkylation, the use of strong bases like NaNH₂ and LDA to generate the enolate intermediate followed by addition of an alkylhalide was discussed.