| Abstract
| - The kinetics of formation of amide, 4, from the corresponding carboxylic acid by reaction with the isopropylester of methionine (MIPE), mediated by carbodiimide EDCI, 1, and HOBt, 2, have been studied in1-methyl-2-pyrrolidinone (NMP) using reaction calorimetry. The reaction rates have been found to beindependent of the concentration of HOBt, showing that the rate-determining step is the reaction betweenthe carboxylic acid and EDCI to give the corresponding O-acylisourea. The pH dependence of the observedrate constants for O-acylisourea formation is consistent with a second-order reaction between doublyprotonated EDCI (EDCIH22+, 6) and the carboxylate group. The observed rate constants fall sharply athigh pH, as the fraction of EDCI as EDCIH22+ continues to fall strongly, whereas the carboxylic acidgroup is already fully ionized. The rate constant, kP, for reaction between the carboxylate group of acid,3, and EDCIH22+ has a value of kP = 4.1 × 104 M-1 s-1 at 20 °C, some 105 times higher than similarrate constants measured in water. The subsequent catalytic cycle, involving reaction of O-acylisoureawith HOBt to give HOBt ester, which then reacts with the amine to give the amide with regeneration ofHOBt, determines the product distribution. In the case of the amino acid, 3, reaction of the O-acylisoureawith MIPE to give amide, 4, is increasingly favored at higher pH values over that with the less basicinternal aromatic amine of 3 to give the diamide 5.
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