In many cases, self-condensation is an unwanted side-reaction. Therefore, chemists have adopted many ways to prevent this from occurring when performing a crossed aldol reaction.
The use of a more reactive electrophile, and a non-enolizable partner If
acetophenone and
benzaldehyde are put together in the presence of aqueous
NaOH, only one product is formed: : This occurs because benzaldehyde lacks any enolizable protons, so it cannot form an enolate, and the benzaldehyde is much more electrophilic than any unenolized acetophenone in solution. Therefore, the enolate formed from acetophenone will always preferentially attack the benzaldehyde over another molecule of acetophenone.
Making enolate ion quantitatively When
nitromethane and
acetophenone are combined using aqueous NaOH, only one product is formed: : Here, the acetophenone never gets a chance to condense with itself, because the nitromethane is so much more acidic that the nitro "enolate" is made quantitatively. There is no known published procedure for the condensation between Acetophenone and Nitromethane. A similar process can also be used to prevent self-condensation between two ketones. In this case, however, the base used needs to be more powerful. A common base used is
Lithium diisopropyl amide (LDA). Here it is used in order to perform the crossed condensation between
acetone and
cyclohexanone. : The deprotonation step using LDA is so fast that the enolate formed never gets a chance to react with any unreacted molecules of cyclohexanone. Then the enolate reacts quickly with acetone.
Silyl enol ether formation Using LDA will not work when attempting to make enolate ion from aldehydes. They are so reactive that self-condensation will occur. One way to get around this is to turn the aldehyde into a silyl enol ether using
trimethylsilyl chloride and a base, such as
triethylamine, and then perform the aldol condensation. Here this tactic is employed in the condensation of
acetaldehyde and
benzaldehyde. A Lewis acid, such as
TiCl4, must be used in order to promote condensation. : == References ==