Stabilized carbanions Claisen condensation

The Claisen condensation is initiated by deprotonation of an ester molecule by sodium ethanolate to give a carbanion that is stabilized, mostly by resonance, as an enolate. This carbanion makes a nucleophilic attack at the partially positively charged carbon atom of the e.ster group, leading to the formation of a C-C bond and the elimination ofan ethanolate ion, This Claisen condensation only proceeds in strongly basic conditions with a pH of about 14. 

Related chemistry not covered in this chapter includes the acylation of stabilized organometallics and the broad category of enolate or metalloenamine C-acylation (Volume 2), the Claisen or Dieckman condensations (Chapter 3.6, Volume 2), the acylation of heteroatom-stabilized carbanions (Part 2, Volume... 

As we have seen in the section on thiolases, Claisen condensations normally involve activation of the electrophilic carhonyl through formation of a thioester and stabilization of the attacking carbanion also as a thioester. Dihydroxynaphthoyl-CoA synthase (MenB) catalyzes an intramolecular Claisen condensation reaction in which only the nucleophilic portion of the molecule has been converted to a thioester. This reaction is a component of the menaquinone biosynthetic pathway, and most studies have focused on the enzyme from M. tuberculosis based on the premise that this pathway may be a valid target for the development of novel compounds that inhibit both replicating and nonreplicating bacteria. ... 

Scheme 9.145. A representation of proton removal from the methyl group of ethyl ethanoate (ethyl acetate, CH3CO2CH2CH3) generating a resonance-stabilized carbanion. Attack of the latter at the carbonyl of ethyl benzenecarboxylate (ethyl benzoate, C6H5CO2CH2CH3) and ethyl ethanoate (ethyl acetate, CH3CO2CH2CH3) to yield, respectively, ethyl 3-phenyl-3-oxopropanoate and 3-oxobntanoate (ethyl acetoacetate, CH3COCH2CO2CH2CH3). An example of the Claisen condensation.

Because we are left with a carbanion after the Claisen condensation, acidification of the reaction mixture is required in order to form the neutral P-keto ester. What prevents this product, thermodynamically unstable with respect to the starting ester molecules, from re-forming the starting esters Certainly the Claisen condensation is reversible. But the p-keto ester that is formed in the basic conditions is much more likely to form the resonance-stabilized enolate than go back to starting material. And once the stable enolate is formed it is not likely to react with alkojdde, a nucleophile + nucleophile reaction. And after acidification there is no base present Without the base, there can be no reverse Claisen condensation, and the product ester is obtained (Fig. 19.104). 

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