Premium
The Uncatalyzed Direct Amide Formation Reaction – Mechanism Studies and the Key Role of Carboxylic Acid H‐Bonding
Author(s) -
Charville Hayley,
Jackson David A.,
Hodges George,
Whiting Andrew,
Wilson Mark R.
Publication year - 2011
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201100714
Subject(s) - chemistry , amide , carboxylic acid , carboxylate , salt (chemistry) , toluene , hydrogen bond , reaction mechanism , ammonium , peptide bond , computational chemistry , molecule , catalysis , organic chemistry , enzyme
Abstract Calorimetric studies of the mixing of a series of carboxylic acids and amines have been carried out to measure heat output, which has been compared with their ability to react to form carboxylate ammonium salts and amides. In order to identify which species (salt or H‐bonded species) were formed, 1 H NMR studies were also carried out by mixingcarboxylic acids and amines in [D 8 ]toluene and monitoring the resulting reactions. These experiments were also compared to DFT computational studies, from which the relative merits of different mechanistic schemes for direct amide formation could be assessed. A reaction mechanism involving zwitterionic intermediates could be eliminated on the basis of calculated energies in toluene, however, a neutral intermediate pathway, involving carboxylic acid dimerization by mutual hydrogen bonding was found to be accessible and may explain how the direct amide formation reaction occurs. Such a mechanism is not inconsistent with kinetic modelling of direct amide formation under different reactions conditions.