Understanding the nucleophilicity of para-substituted anilines in methanol: reactivity and computational analyses

Abstract

We investigated the nucleophilic reactivity of a series of para-substituted anilines 2a-2e through a combined kinetic and theoretical approach, employing their reactions with thiophenes 1a-1c as electrophilic references in methanol at 20 °C. The satisfactorily correlations observed between the reaction rates and the oxidation potentials of the anilines provide compelling evidence for a single-electron transfer (SET) mechanism. Nucleophilicity parameters (N, s_N) were determined in methanol following Mayr's empirical eq. A particularly compelling finding of our study is the good correlation observed between the nucleophilicity parameters (N) of anilines 2a-2e measured in methanol and those reported by Mayr in acetonitrile, demonstrating the role of solvent polarity in nucleophilic reactivity. Utilizing this correlation and the established relationship between N and the Hammett constant (σ_p), we predicted N values for five additional 4-X-anilines 2f-2j (X = NO₂, CN, CF₃, F, and N(CH₃)₂). In addition, density functional theory (DFT) transition-state (TS) analyses provided activation free energies (ΔG^≠) for each para-substituent (X = OH, OCH₃, CH₃, H, Cl), all confirmed by a single imaginary frequency along the reaction coordinate. The computed ΔG^≠ values inversely correlate with N: electron-donating groups decrease, and electron-withdrawing groups increase the activation barrier. Furthermore, DFT calculations were conducted to explore relationships between N and various reactivity descriptors, including the global nucleophilicity index (ω⁻¹), dipole moment (μ), polarizability (α), and hyperpolarizability (β) for the ten para-X-substituted anilines 2a-2j. The data reveal a clear structure–property framework for tuning the NLO response of substituted anilines. Molecules substituted with strong EWGs are superior candidates for NLO applications due to their high dipole moments, elevated polarizabilities, and exceptionally large hyperpolarizabilities.