15.22:
Crossed Aldol Reaction Using Weak Bases
Recall that an efficient crossed aldol reaction requires one of the two reacting unique carbonyl compounds to lack an α hydrogen, as illustrated in the reaction of formaldehyde with another aldehyde containing an α-hydrogen.
The self-condensation of the aldehyde comprising an α hydrogen is prevented by adding it slowly to the reaction mixture of formaldehyde and a weak base.
Recollect that hydroxides and alkoxides with relatively smaller pKa values function as weak bases.
In this reaction, the hydroxide ion deprotonates the α hydrogen of the aldehyde to form a nucleophilic enolate, which attacks the formaldehyde to produce a single crossed aldol product.
Similarly, in a solution of a β-ketoester and a ketone, the β-ketoester with a lower pKa is more acidic. Hence, sodium ethoxide, a weak base, preferentially deprotonates the β-ketoester, which then reacts with the ketone to form a single product in good yield.
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 pKa is a stronger acid than the ketone. Hence, a weak base like sodium ethoxide preferentially 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