15.22 : Crossed Aldol Reaction Using Weak Bases

This lesson deals with the crossed aldol reaction using weak bases. The self-condensation of an aldehyde having α hydrogen is prevented by adding it slowly to a mixture of formaldehyde and weak bases like hydroxide and alkoxide. Upon slow addition of the aldehyde, the base deprotonates the α carbon of the aldehyde to form the corresponding enolate. The enolate subsequently attacks the formaldehyde to form a single crossed product. Figure 1 depicts the aforementioned reaction.

Figure 1. The formation of a single crossed product

In a reaction between a β-keto ester and a ketone, the β-keto ester with lower pK_a is a stronger acid than the ketone. Hence, a weak base like sodium ethoxidepreferentially deprotonates the β-keto ester to form an enolate. The enolate then attacks the ketone to form the corresponding crossed aldol product in good yield. Figure 2 shows an example of the crossed aldol reaction using a weak base.

Figure 2. The formation of the crossed aldol product