Solvent Dependence of Carboxylic Acid Condensations with Dicyclohexylcarbodiimide

Article abstract of DOI:10.1021/jo00269a032

The kinetics of a model dicyclohexylcarbodiimide (DCC)-carboxylic acid condensation have been studied in six organic solvents at low concentrations of DCC and acid.The first bimolecular rate constant for acid addition to DCC (k₁), to give an O-acylisourea, and the second bimolecular rate constant (k₃) for acid addition to this intermediate, to give an anhydride, are both dependent on the interaction between acid molecules and solvent.These rate constants correlate extremely well with measures of the solvent's hydrogen-bond accepting ability.The rate constant forintramolecular rearrangement from the O-acylisourea to the N-acylurea (k₂) is, by contrast, independent of the solvent.Formation of dimers of the acid is not important at these low concentrations, but it appears the reaction favors formation of anhydride whenever retardation of the k₁ and k₃ rate constants is minimized.This occurs in solvents in which the acid is least soluble.There is, therefore, a delicate interplay between the conditions that favor the pathway producing anhydride: on the one hand high concentrations are favorable while on the other solvents that offer limited solubility are desirable.For synthetic purposes, where anhydride is the more useful product, a careful optimization of solubility and fast k₁ and k₃ rate constants are required.