15.31
β-Dicarbonyl Compounds via Crossed Claisen Condensations
Crossed Claisen condensations are base-promoted reactions between two different ester molecules producing β-dicarbonyl compounds. The reaction involvi…
Claisen condensation between two different esters is termed crossed Claisen condensation.
If both esters contain α hydrogens, then four different types of ꞵ-ketoesters are formed. Of these, two are self-condensation products and the other two are crossed-condensation products.
A successful crossed Claisen condensation requires at least one ester molecule with no α hydrogen or the use of LDA base.
For instance, aryl esters have no α hydrogen and, therefore, cannot form enolates. They give crossed Claisen condensation products with other enolate-forming ester molecules.
Formate esters, in addition to containing no α hydrogen, are highly reactive compared to other esters, making them suitable for crossed Claisen condensation.
If a less reactive, no α-hydrogen-containing ester is used, an excess of it is required for a feasible reaction.
If α-hydrogen-containing esters are used, then a strong base like LDA facilitates a directed crossed Claisen condensation by generating an irreversible ester enolate, followed by its reaction with another ester molecule.
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Q1: What is a crossed Claisen condensation and how does it differ from regular Claisen condensation?
A crossed Claisen condensation is a base-promoted reaction between two different ester molecules that produces β-dicarbonyl compounds. Unlike regular Claisen condensation between identical esters, crossed condensation involves distinct ester partners. This approach solves the problem of multiple product formation that occurs when both esters contain α hydrogens, making the reaction more synthetically useful and easier to isolate desired products.
Q2: Why do aryl esters work well in crossed Claisen condensations?
Aryl esters are effective in crossed Claisen condensations because they contain no α hydrogen atoms and therefore cannot form enolates. This property makes them excellent electrophilic partners that react with enolate-forming ester molecules. Since aryl esters cannot self-condense, they selectively produce crossed-condensation products rather than unwanted self-condensation byproducts.
Q3: What role does LDA play in directed crossed Claisen condensations?
LDA (lithium diisopropylamide) is a strong, sterically hindered base that facilitates directed crossed Claisen condensations when both esters contain α hydrogens. LDA irreversibly deprotonates one ester to form an enolate, while the other ester acts as the electrophile. This controlled approach prevents formation of multiple products and ensures selective formation of the desired β-dicarbonyl compound.
Q4: How do formate esters contribute to successful crossed Claisen condensations?
Formate esters are highly reactive molecules that lack α hydrogen atoms, making them ideal electrophilic partners in crossed Claisen condensations. Their enhanced reactivity compared to other esters allows them to readily accept the nucleophilic attack from enolate-forming ester molecules. This combination of high reactivity and absence of α hydrogens ensures selective product formation.
Q5: What happens when you use a less reactive ester with no α hydrogen in crossed Claisen condensation?
When a less reactive ester lacking α hydrogens is used, an excess quantity of that ester is required to make the reaction feasible. The excess drives the equilibrium toward product formation by increasing the concentration of the electrophilic partner. This strategy allows less reactive esters to participate effectively in crossed Claisen condensations despite their lower reactivity.
Q6: Can ketones react with esters in crossed Claisen condensations?
Yes, ketones can react with esters in a variation of crossed Claisen condensation. The enolate of the ketone acts as the nucleophile and attacks the carbonyl carbon of the ester, producing β-dicarbonyl compounds. This ketone-ester variant expands the scope of crossed Claisen condensations beyond ester-ester reactions.
Q7: Why do both esters containing α hydrogens create synthetic problems in crossed Claisen condensation?
When both esters contain α hydrogens, four different β-ketoester products form: two self-condensation products and two crossed-condensation products. This mixture is difficult to isolate and reduces synthetic utility. Using esters without α hydrogens or employing LDA eliminates this problem by preventing self-condensation and ensuring selective formation of the desired crossed-condensation product.