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15.24: Crossed Aldol Reaction Using Strong Bases: Directed Aldol Reaction

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Organic Chemistry

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Crossed Aldol Reaction Using Strong Bases: Directed Aldol Reaction

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.


Crossed Aldol Reaction Strong Bases Lithium Diisopropylamide (LDA) Directed Aldol Reaction Aldehyde Ketone Aqueous Sodium Hydroxide Self-condensation Reaction Ketone Enolate Single Crossed Aldol Product Unsymmetrical Ketone Kinetic Enolate Thermodynamic Enolate

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