Evaluating the Solvent and pH Effect in the Inversion of the Circular Dichroism Signal of S ‐Naproxen

ABSTRACT

S ‐Naproxen (NPX) exhibits an unusual inversion of its ECD spectrum upon solvent change, a phenomenon that this work analyzes both experimentally and theoretically. By evaluating NPX in water, ethanol, and acetonitrile, it was observed that pH variation shifts the chemical equilibrium between protonated and deprotonated forms, making this transition the direct cause of the ECD signal inversion. Molecular dynamics and TD‐DFT (CAM‐B3LYP/aug‐cc‐pVDZ) calculations corroborated the experimental data, demonstrating that structural changes alter the predominant electronic transitions from π → π* in NPX to n → π* in the NPX ⁻ anion, as evidenced by transition density differences and natural transition orbitals (NTOs). These findings demonstrate that explicit solvent treatment and statistical analysis are requisite to accurately reproduce the data, validating that the negative signal in water and the positive signal in acetonitrile is governed by the predominant species dictated by the chemical equilibrium.