Computational study of maleamic acid cyclodehydration with acetic anhydride

Abstract

AbstractThe reaction mechanisms of N‐substituted maleamic acids (MA) cyclodehydration (CDH) to the corresponding maleimides (M) and isomaleimides (IM) and IM rearrangement to M were studied by the PM3 Hamiltonian with charge model 1 (CM1P) of the AMSOL computational method with solvation effect in order to establish the most probable pathways. CDH was considered in the presence of acetic anhydride in the presence of an acetate anion or triethylamine as the dehydrating agent in CH2Cl2 as the solvent. In the first step, our computational results supported carboxylic proton losses, provided by a nucleophilic center on the dehydrating agent. In the next step, maleamic acid anion could either add a molecule of a dehydrating agent (path A) or cyclicize (path B). Our results indicate the path B to require more energy than path A, so path B is considered less likely to occur. The formation (path A) of an anion complex I2 between the anion of MA and the dehydration agent was supported as well as acetate anion loss to form the neutral mixed anhydride I3. The ring closure to M or IM occurs only after I3 amide proton loss, meaning that the dehydrating agent necessitate another nucleophilic center. The cyclization of I4 anion over amide nitrogen or oxygen to the reaction outcome depends on the electronic effect of amide nitrogen substituent. The same results were obtained studying CDH of N‐substituted ophthalmic acids with acetic anhydride and for MA with N,N′‐dicyclohexylcarbodiimide as dehydrating agent, in the same solvent. In such circumstances, one can consider them the common features of a general CDH reaction mechanism of MA. Our computational results found the IM to M rearrangement to correspond to the reversible final path of synthesis mechanism although the other investigators considered it to take place under a different reaction. They also supported the importance of the acetate anion in both cyclization and rearrangement mechanisms; the presence of tertiary amine blocks the acetic acid formed during reaction, determines I3 amide proton loss and prevents rearrangement. The theoretical conclusions are consistent with the experimental results. © 2005 Wiley Periodicals, Inc. Int J Quantum Chem, 2006