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23.2 Carbonyl Condensations versus Alpha Substitutions

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  • Objectives

    After completing this section, you should be able to describe the difference between a carbonyl condensation reaction and an alpha‑substitution reaction, and determine which of these two types of reaction is most likely to occur, given the appropriate experimental data.

    Study Notes

    So far we have discussed three of the four general reactions of carbonyl compounds: nucleophile additions of aldehydes and ketones (Chapter 19), nucleophilic acyl substitution reactions of carboxylic acid derivatives (Chapter 21) and alpha‑substitution reactions (Chapter 22). The fourth general reaction, carbonyl condensation, is similar to the alpha‑substitution reaction, so you need to appreciate how it differs from the other three and the conditions under which it occurs.

    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.

    Example 22.7.1: Alpha Alkylation