SNAr reactions of substituted pyridines with secondary amines in aqueous solution: Kinetic and reactivity indices in density functional theory

Abstract

AbstractA kinetic study is reported for the reactions of 2‐methoxy‐3‐nitropyridine 1a and 2‐methoxy‐5‐nitropyridine 1b with three secondary amines 2a–c (morpholine, piperidine, and pyrrolidine) in aqueous solution at 20°C. The Brønsted‐type plots are linear with βnuc = 0.52 and 0.55 for pyridines 1a and 1b, respectively, indicating that the reaction proceeds through a SNAr mechanism in which the first step is the rate‐determining step. Additional theoretical calculations using the DFT/B3LYP method confirm that the C‐2 carbon being the most electrophilic center for the both pyridines 1a and 1b. The second‐order rate constants have been used to evaluate the electrophilicity parameters E of 1a and 1b according to the linear free energy relationship log k (20°C) = sN (N + E). The E parameters thus derived are compared with the electrophilic reactivities of a large variety of anisoles. The validity of these E values has been satisfactorily verified by comparison of calculated and experimental second‐order rate constants for the reactions of pyridines 1a and 1b with anion of ethyl benzylacetate.