15.24:
Crossed Aldol Reaction Using Strong Bases: Directed Aldol Reaction
The crossed aldol reaction between an aldehyde and a ketone – both containing an alpha-hydrogen, in aqueous sodium hydroxide forms a mixture of products.
Alternatively, a strong base like lithium diisopropylamide, abbreviated as LDA, minimizes the number of products.
The slow, dropwise addition of a ketone to the LDA solution irreversibly generates a ketone enolate.
Next, with the slow addition of the aldehyde to this solution, the nucleophilic addition of the ketone enolate to the carbonyl group of the aldehyde produces a single crossed aldol product. This is called a directed aldol addition reaction.
In unsymmetrical ketones, LDA preferentially deprotonates at the less-substituted carbon to form the kinetic enolate.
15.24:
Crossed Aldol Reaction Using Strong Bases: Directed Aldol Reaction
The reaction between two different carbonyl compounds comprising α hydrogen in the presence of a strong base like lithium diisopropylamide (LDA) to form a crossed aldol product is known as a directed aldol reaction. The directed aldol reaction is depicted in Figure 1.
Figure 1. Directed aldol reaction
Let us consider the reaction between an aldehyde and a ketone in the presence of aqueous sodium hydroxide. As the aldehyde and ketone comprise α hydrogen, the reaction yields a mixture of products. This is due to the self-condensation reaction of both the aldehyde and ketone.
However, replacing sodium hydroxide with a stronger base like lithium diisopropylamide (LDA) minimizes the number of products in the reaction. The reaction is performed by slowly adding the ketone to an LDA solution. LDA being a strong base, promotes the irreversible formation of a ketone enolate. Next, the dropwise addition of aldehyde to the ketone enolate solution results in a single crossed aldol product.
Suppose an unsymmetrical ketone is used in the reaction. In that case, the deprotonation at the less-substituted carbon forms a kinetic enolate, while the deprotonation at the more-substituted carbon generates a thermodynamic enolate. Here, the LDA deprotonates preferably at the less-substituted carbon to form the kinetic enolate.