title: Mechanistic Elucidation of Zirconium-Catalyzed Direct Amidation.
abstract: The mechanism of the zirconium-catalyzed condensation of carboxylic acids and amines for direct formation of amides was studied using kinetics, NMR spectroscopy, and DFT calculations. The reaction is found to be first order with respect to the catalyst and has a positive rate dependence on amine concentration. A negative rate dependence on carboxylic acid concentration is observed along with S-shaped kinetic profiles under certain conditions, which is consistent with the formation of reversible off-cycle species. Kinetic experiments using reaction progress kinetic analysis protocols demonstrate that inhibition of the catalyst by the amide product can be avoided using a high amine concentration. These insights led to the design of a reaction protocol with improved yields and a decrease in catalyst loading. NMR spectroscopy provides important details of the nature of the zirconium catalyst and serves as the starting point for a theoretical study of the catalytic cycle using DFT calculations. These studies indicate that a dinuclear zirconium species can catalyze the reaction with feasible energy barriers. The amine is proposed to perform a nucleophilic attack at a terminal η2-carboxylate ligand of the zirconium catalyst, followed by a C-O bond cleavage step, with an intermediate proton transfer from nitrogen to oxygen facilitated by an additional equivalent of amine. In addition, the DFT calculations reproduce experimentally observed effects on reaction rate, induced by electronically different substituents on the carboxylic acid.
authors.affiliation: Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University , SE-106 91 Stockholm, Sweden.
authors.forename: Helena
authors.initials: H
authors.lastname: Lundberg
authors.affiliation: Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University , SE-106 91 Stockholm, Sweden.
authors.forename: Fredrik
authors.identifier: 0000-0003-1271-4601
authors.initials: F
authors.lastname: Tinnis
authors.affiliation: Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University , SE-106 91 Stockholm, Sweden.
authors.forename: Jiji
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University , SE-106 91 Stockholm, Sweden.|Departamento de Ciencia de los Materiales e Ingeniería Metalúrgica y Química Inorgánica, Universidad de Cádiz , Campus Universitario de Puerto Real, 11510 Puerto Real, Spain.
authors.forename: Andrés G
authors.identifier: 0000-0002-5062-2858
authors.initials: AG
authors.lastname: Algarra
authors.affiliation: Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University , SE-106 91 Stockholm, Sweden.
authors.forename: Fahmi
authors.identifier: 0000-0002-1012-5611
authors.initials: F
authors.lastname: Himo
authors.affiliation: Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University , SE-106 91 Stockholm, Sweden.|Department of Chemistry, Umeå University , SE-901 87 Umeå, Sweden.
authors.forename: Hans
authors.identifier: 0000-0001-5887-4630
authors.initials: H
authors.lastname: Adolfsson