Claisen condensation
/ KLY-zen /
The Claisen condensation is the aldol's cousin for esters. Take two molecules of an ester, deprotonate one at its alpha-carbon to make an ester enolate, and let that nucleophile attack the carbonyl of the second ester. But where the aldol stops at an alcohol, the ester does something extra: it has a leaving group (the -OR alkoxy group). After the enolate adds, that alkoxide is expelled, and the product is a beta-keto ester — a ketone and an ester separated by a single carbon.
The mechanism is nucleophilic acyl substitution rather than simple addition. Base (typically the matching alkoxide, like sodium ethoxide for an ethyl ester) removes an alpha-proton; the ester enolate attacks the carbonyl carbon of a second ester to give a tetrahedral intermediate; that intermediate collapses, kicking out the alkoxide leaving group and rebuilding a C=O. The new compound has a CO next to a CO2R, i.e. a beta-keto ester such as ethyl acetoacetate.
One subtle but essential point: the simple addition steps of a Claisen are only mildly favorable, but the product beta-keto ester has a very acidic doubly-activated proton (pKa ~11). The base deprotonates that product to its stabilized enolate, and THAT irreversible deprotonation pulls the whole equilibrium forward. So you need a full equivalent of base, and you need the ester to have at least two alpha-hydrogens. The beta-keto ester product is gold: it feeds the acetoacetic ester synthesis and many ring-forming and chain-building strategies.
Two molecules of ethyl acetate, CH3-CO2Et, with sodium ethoxide give ethyl acetoacetate, CH3-CO-CH2-CO2Et (a beta-keto ester), plus one molecule of ethanol. This is the textbook Claisen condensation.
Two esters condense to a beta-keto ester, expelling an alkoxide.
An ester with only ONE alpha-hydrogen (like ethyl 2-methylpropanoate, with a single alpha-H) cannot run a normal Claisen, because there is no acidic doubly-activated proton in the product to deprotonate and drive the equilibrium forward.