Synthesis of esters
The Yamaguchi Esterification allows the mild synthesis of highly functionalized esters. After formation of a mixed anhydride between the Yamaguchi Reagent (2,4,6-trichlorobenzoyl chloride) and the carboxylic acid, the volatiles are removed and the reaction of the anhydride with an alcohol in presence of a stoichiometric amount of DMAP generates the desired ester.
Mechanism of the Yamaguchi Esterification
Addition of the carboxylate to the carboxylic acid chloride forms the mixed anhydride:
DMAP is an acyl transfer reagent that reacts regioselectively at the less hindered carbonyl site:
DMAP is a stronger nucleophile than the alcohol. The newly formed intermediate is less hindered, the acyl group is still polarized and DMAP is a good leaving group, all of which enable a fast reaction with the alcohol.
In reactions with aliphatic carboxylic acids, there is no need for a two step-procedure. It has been shown by SantaLucia, Jr that slight reactivity differences in this case can even lead to the formation of the symmetric aliphatic anhydrides, as shown in the following reaction pathway:
I. Dhimitruka, J. SantaLucia, Jr, Org. Lett., 2006, 8, 47-50.
The assumption is that aliphatic carboxylates are better nucleophiles than either aromatic carboxylates or alcohols. However, the aliphatic anhydride is also more electrophilic towards DMAP (not shown in the scheme) or the alcohol than is the aromatic carbonyl of the mixed anhydride produced in situ. A more detailed description can be found in the work by J. SantaLucia, Jr.
A New Condensation Reaction for the Synthesis of Carboxylic Esters from Nearly Equimolar Amounts of Carboxylic Acids and Alcohols Using 2-Methyl-6-nitrobenzoic Anhydride
I. Shiina, R. Ibuka, M. Kubota, Chem. Lett., 2002, 286-287.
Investigation of the Yamaguchi Esterification Mechanism. Synthesis of a Lux-S Enzyme Inhibitor Using an Improved Esterification Method
I. Dhimitruka, J. SantaLucia, Org. Lett., 2006, 8, 47-50.