title: Chlorination of N-methylacetamide and amide-containing pharmaceuticals. Quantum-chemical study of the reaction mechanism.
abstract: Chlorination of amides is of utmost importance in biochemistry and environmental chemistry. Despite the huge body of data, the mechanism of reaction between amides and hypochlorous acid in aqueous environment remains unclear. In this work, the three different reaction pathways for chlorination of N-methylacetamide by HOCl have been considered: the one-step N-chlorination of the amide, the chlorination via O-chlorinated intermediate, and the N-chlorination of the iminol intermediate. The high-level quantum chemical G3B3 composite procedure, double-hybrid B2-PLYPD, B2K-PLYP methods, and global hybrid M06-2X and BMK methods have been employed. The calculated energy barriers have been compared to the experimental value of ΔG(#)298 ≈ 87 kJ/mol, which corresponds to reaction rate constant k(r) ≈ 0.0036 M(-1) s(-1). Only the mechanism in which the iminol form of N-methylacetamide reacts with HOCl is consistent (ΔG(#)298 = 87.3 kJ/mol at G3B3 level) with experimental results. The analogous reaction mechanism has been calculated as the most favorable pathway in the chlorination of small-sized amides and amide-containing pharmaceuticals: carbamazepine, acetaminophen, and phenytoin. We conclude that the formation of the iminol intermediate followed by its reaction with HOCl is the general mechanism of N-chlorination for a vast array of amides.
authors.affiliation: Faculty of Pharmacy and Biochemistry, University of Zagreb , A. Kovačića 1, 10000 Zagreb, Croatia.
authors.forename: Davor
authors.initials: D
authors.lastname: Šakić
authors.forename: Pavica
authors.initials: P
authors.lastname: Šonjić
authors.forename: Tana
authors.initials: T
authors.lastname: Tandarić
authors.forename: Valerije
authors.initials: V
authors.lastname: Vrček
mesh_terms: D000081:Acetamides / Q000737:chemistry*; D000082:Acetaminophen / Q000737:chemistry; D000577:Amides / Q000737:chemistry*; D002220:Carbamazepine / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D002713:Chlorine / Q000737:chemistry*; D003198:Computer Simulation; D054879:Halogenation; D008956:Models, Chemical; D015394:Molecular Structure; D010672:Phenytoin / Q000737:chemistry; D011789:Quantum Theory; D012997:Solvents / Q000737:chemistry; D014867:Water / Q000737:chemistry
chemical_list: D000081:Acetamides; D000577:Amides; D012997:Solvents; D014867:Water; D002220:Carbamazepine; D000082:Acetaminophen; D002713:Chlorine; D010672:Phenytoin; C018595:N-methylacetamide