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

Abstract

Abstract A 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 β nuc = 0.52 and 0.55 for pyridines 1a and 1b , respectively, indicating that the reaction proceeds through a S N Ar 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) = s N ( 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.