Mixed aldol reaction and condensations

The previous examples of aldol reactions and condensations used a common reactant as both the enolic donor and the electrophilic acceptor. The product in such cases is always a dimer of the reactant carbonyl compound. Aldol condensations between different carbonyl reactants are called crossed or mixed reactions, and under certain conditions such crossed aldol condensations can be effective.

Example 4: Mixed Aldol Reactions

The success of these mixed aldol reactions is due to two factors. First, aldehydes are more reactive acceptor electrophiles than ketones, and formaldehyde is more reactive than other aldehydes. Second, aldehydes lacking alpha-hydrogens can only function as acceptor reactants, and this reduces the number of possible products by half. Mixed aldols in which both reactants can serve as donors and acceptors generally give complex mixtures of both dimeric (homo) aldols and crossed aldols. Because of this most mixed aldol reactions are usually not performed unless one reactant has no alpha hydrogens.

The following abbreviated formulas illustrate the possible products in such a case, red letters representing the acceptor component and blue the donor. If all the reactions occurred at the same rate, equal quantities of the four products would be obtained. Separation and purification of the components of such a mixture would be difficult.

AACH₂CHO   +   BCH₂CHO   +   NaOH  →  A–A   +   B–B  +  A–B   +   B–A

The aldol condensation of ketones with aryl aldehydes to form α,β-unsaturated derivatives is called the Claisen-Schmidt reaction.  This relies on the fact that the addition of an enolate to a ketone is not particularly favorable, whereas the addition of an enolate to an aldehyde is favorable; this means that the aldehyde is consumed, while the ketone serves to provide the enolate part for the reaction.

Example 4: Claisen-Schmidt Reaction

Another approach is to use LDA on one ketone to form the enolate quantitatively, then to react that enolate with the other carbonyl compound. Here, the use of LDA gives control of which compound forms the enolate, though it cannot be used to form aldehyde enolates.