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Aldol Reactions and Aldol-like Reactions

Crossed Aldol Reactions

A crossed aldol reaction.

In a crossed aldol reaction, two different carbonyl compounds are applied. If both carbonyl compounds contain an α hydrogen atom, both may act as electrophilic carbonyl compound, as well as nucleophilic enol or enolate. In addition, each enol may nucleophilically attack the two different carbonyl compounds. As a result, such a crossed aldol reaction yields four different products. Therefore, crossed aldol reactions of this kind are synthetically less valuable. The starting products depicted in the illustration are symmetric ketones. If this were not the case additional products would be possible, due to the problem of regioselectivity.

If a starting product does not contain any α hydrogen atom, the variety of possible products is reduced to two, as this starting product can only act as an electrophilic carbonyl compound, though it cannot act as a nucleophilic enolate. Benzaldehyde, which contains no α hydrogen atoms, is such an aldehyde.

Claisen-Schmidt reaction.

If benzaldehyde is converted with acetone, for instance, two different products (aside from different stereoisomers) may principally be formed, as acetone may react with benzaldehyde (product "A+B") as well as another acetone molecule (product "A+A"). However, practically speaking, the reaction basically yields product "A+B", as the electrophilicity and, thus, the reactivity of the aldehyde are considerably higher than that of the ketone. The reaction is known as Claisen-Schmidt reaction (after Ludwig Claisen). If tert-butyl methyl ketone is applied in this reaction in place of acetone, only one product is usually obtained, as, due to strong steric interactions, tert-butyl methyl ketone virtually never reacts with any other tert-butyl methyl ketone molecule.

Claisen-Schmidt reaction with tert-butyl methyl ketone.
Stability of enolates.

The product distribution in a crossed aldol reaction, as well as in a "normal" aldol reaction of a unsymmetrical ketone also depends on and can be controlled by the enolates' stabilities. If, for instance, butyl methyl ketone is applied in an aldol reaction, two different enolates are conceivable, as the ketone is asymmetrical. The enolate that contains the higher substituted double bond is relatively more stable than the other one. Thus, the enolate with the terminal double bond is less stable than that with the "internal" double bond. As a result, the product in an aldol condensation is mainly established by the reaction of the more stable enolate. If the less stable enolate with the terminal double bond ought to be the mainly occuring nucleophile, a considerably bulky base, such as lithium diisopropylamide (LDA), must be applied. Due to steric interactions, a sufficiently bulky base tends to abstract the terminal methyl proton.


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