Aldol Condensation

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Some ketones also undergo it. In general, the reaction is an equilibrium shifted toward the starting materials.

The aldol condensation gives an aldol or β-hydroxyaldehyde, in low proportion.

However, heating the aldol brings about its dehydration to an α,β-unsaturated aldehyde. The loss of water "pulls" the equilibria toward the final product.

The self-condensation of an aldehyde with α hydrogens leads to a new, α,β-unsaturated aldehyde.

However, this reaction has some limitations…

First limitation

As already mentioned, the equilibria of an aldol condensation are usually shifted toward the starting material. One way of shifting them toward the products is to avoid continuous contact between the aldehyde and the base. This can be achieved with the so-called Soxhlet apparatus.

Solution to the first limitation

The starting aldehyde or ketone boils in the round-bottomed flask and, after condensing in the condenser, accumulates in the Soxhlet reservoir, where it comes into temporary contact with the base and the equilibrium is established. When the Soxhlet is full, the siphon empties it and the equilibrium liquid returns to the flask. The small amount of aldol formed is no longer in contact with the base, so it cannot revert to the starting material, and it stays in the flask because its boiling point is much higher. The cycle is repeated many times (overnight, for example) and the liquid in the flask ends up highly enriched in the aldol.

Second limitation

Generally speaking, the aldol condensation cannot be performed between different aldehydes or ketones (cross aldol condensation) because a mixture of products would be obtained:

A solution to the second limitation

If one of the reactants has no α hydrogens, like pivalaldehyde or benzaldehyde, and the other aldehyde is added very slowly, the crossed aldol condensation can be achieved in high yield, giving a single product.

In this reaction only one enolate can be formed, that of acetaldehyde, because pivalaldehyde has no α hydrogens. To avoid the self-condensation of acetaldehyde, it must be added very slowly, so that its concentration remains as low as possible. In this way, the acetaldehyde enolate is more likely to react with the most abundant species in the reaction mixture: pivalaldehyde.

Another solution to the second limitation

Use enamines or trap the enolate with a silicon derivative:

For instance, the enolate of acetone can be generated quantitatively with a very strong base such as LDA (lithium diisopropylamide) and made to react with chlorotrimethylsilane. Perhaps unexpectedly, silicon halides react predominantly with the oxygen of the enolate and not with the carbon: they trap the enolate, so to speak "freezing" it. The silyl enol ether can then react with any aldehyde or ketone, with or without α hydrogens, in the presence of TiCl₄, which binds to the carbonyl group and activates it further. In this way, aldols can be obtained from any pair of aldehydes or ketones. The final dehydration can even be avoided by keeping the reaction mixture as cold as possible.

The aldol condensation can be carried out intramolecularly, with suitable dialdehydes or diketones.

This allows highly functionalized five- or six-membered cyclic compounds to be obtained.

As an example, 2,5-hexanedione can give two different enolates. The one formed at a terminal methyl group can attack the other carbonyl group intramolecularly, giving a stable five-membered cyclic ketol. The other enolate (top) would give a three-membered ring, far too strained to be formed. On heating, the cyclic ketol dehydrates to the α,β-unsaturated 3-methylcyclopent-2-en-1-one.