23.8 Mixed Claisen Condensations

Mixed Claisen condensations bring together two different carbonyl compounds to create new carbon-carbon bonds. This reaction pairs an ester or formate as the electrophile with a ketone or aldehyde as the nucleophile, forming β-diketones under carefully controlled conditions.

The process hinges on enolate formation from the ketone, which then attacks the ester's carbonyl. Strong bases, anhydrous conditions, and specific solvents and temperatures are crucial. The resulting β-diketones feature two carbonyls separated by a methylene group.

Mixed Claisen Condensations

Components of mixed Claisen condensation

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• Two different carbonyl compounds react together
  • Ester (ethyl acetate) or formate serves as the electrophilic carbonyl acceptor
  • Ketone (acetone) or aldehyde acts as the nucleophilic carbonyl donor providing the enolate
• Strong base deprotonates the α-carbon of the ketone to form the enolate nucleophile
  • Common bases include sodium ethoxide or sodium hydride
• Anhydrous conditions prevent hydrolysis of the ester or the product
  • Moisture can react with the ester or product leading to undesired side reactions
• Polar aprotic solvent facilitates the reaction by stabilizing charged intermediates
  • Examples include tetrahydrofuran (THF) or diethyl ether
• Typical reaction temperature range from 0°C to room temperature (25°C)
  • Low temperatures favor formation of the kinetic enolate and minimize side reactions

Products of ester-ketone condensations

• The enolate of the ketone acts as a nucleophile attacking the electrophilic carbonyl carbon of the ester
• The alkoxide group of the ester is eliminated forming a new carbon-carbon bond
  • Bond forms between the α-carbon of the ketone and the carbonyl carbon of the ester
• The resulting intermediate undergoes proton transfer to form the β-diketone product
  • The α-hydrogen of the ketone is more acidic than the α-hydrogen of the ester
  • Favors formation of the ketone enolate and the β-diketone product
• The β-diketone product has two carbonyl groups separated by a methylene ($CH_2$) group
  • Reaction between acetophenone and ethyl acetate yields 1-phenylbutane-1,3-dione
  • Two carbonyl groups flank the central $CH_2$ in the 1,3-diketone product

Effective electrophilic acceptor esters

• Ethyl benzoate has a highly electrophilic carbonyl carbon
  • Electron-withdrawing effect of the aromatic ring
  • Resonance effect of the benzene ring delocalizes electrons away from the carbonyl group
  • Increased electrophilicity makes it more susceptible to nucleophilic attack
• Ethyl formate has a highly electrophilic carbonyl carbon
  • Absence of an α-carbon prevents competing enolate formation
  • Carbonyl group is more electrophilic compared to other esters
  • Effective acceptor in mixed Claisen condensations
• The ethoxide group is a good leaving group
  • Facilitates the elimination step
  • Enables efficient formation of the β-diketone product

Reaction Mechanism and Key Concepts

• Mixed Claisen condensation is a type of condensation reaction
• It is a base-catalyzed reaction involving nucleophilic addition followed by elimination
• The enolate acts as the nucleophile, while the ester carbonyl serves as the electrophile
• The alkoxide group of the ester functions as the leaving group during the reaction