An aldol reaction may also be carried out between an aldehyde and a ketone or between two different aldehydes and ketones. Such a reaction is called a cross aldol reaction. Now in cases where both the coupling partners possess α-H are not of any synthetic value as four different products may be produced. However, where one of the coupling partners is only capable of enolizing and is more electrophilic than the other partner, the aldol reaction may be fruitful in giving only one preferential product. Thus, the Claisen-Schmidt condensation of aromatic aldehydes with aliphatic aldehydes or methyl ketones using a base may be considered as of this type (Scheme 5).

Scheme 5

Similarly the importance of high electrophilicity of the non enolizing partner can be understood from the following example.

The reaction proceeds via the usual base catalyzed pathway. In the first step, the enolizable partner undergoes enolization in the presence of the base.

Next, the enolate attacks the electrophile benzaldehyde to form an aldol which then dehydrates by E1cB pathway.

The enolate (1) formed in this step could attack another molecule of unenolized ketone but did not since ketones are less reactive than aldehydes.  Thus, the enolate chooses to attack the better electrophile (4-nitrobenzaldehyde).

Lithium enolates derived from carbonyl compounds in THF at low temperature by using lithium diisopropylamide (LDA) as base. The reaction is kinetically controlled and therefore converted fast enough to prevent the enolate to react with a molecule of unenolized carbonyl compound.

Now, if a second carbonyl compound is added, then it also complexes with the lithium cation allowing the aldol reaction to take place from a six membered transition state.

The reaction works well even if the electrophilic partner is an enolizable aldehyde. Thus, the lithium enolate of propiophenone can react with propan-1-al to form 3-hydroxy-2-methyl-1-phenylpentan-1-one selectively even when propan-1-al is an enolizable aldehydes (Scheme 6). But it must be noted that the reaction is actually carried out in two steps. In the first step, lithium enolate of propiophenone is formed, then, the electrophilic partner is added.

Scheme 6