Integrated Experimental and Theoretical Exploration of Bioactive 2‐Naphthol‐Based Acetamides: Solvent‐Free Synthesis, DFT/NLO/QTAIM Characterization, and Protein‐Ligand Interaction

Abstract A sustainable, solvent‐free multicomponent protocol was employed for the synthesis of two novel 2‐naphthol‐based acetamide derivatives, NPD‐1 and NPD‐2, using trichloroacetic acid and montmorillonite K10 clay as catalysts. The optimized conditions yielded NPD‐1 and NPD‐2 in 78% and 76%, respectively. Structural elucidation was achieved through FT‐IR, UV–vis, 1 H/ 13 C‐NMR, and QTOF‐MS analyses. DFT and TD‐DFT calculations provided comprehensive insights into electronic structures, optical transitions, and chemical reactivity. Theoretical IR, NMR, and UV–vis spectra closely matched experimental data, validating the optimized geometries. Topological (QTAIM, NCI, RDG) and electronic (ELF, LOL) analyses clarified the nature of intra/intermolecular interactions and charge delocalization. The HOMO–LUMO gaps (4.59 eV for NPD‐1; 3.98 eV for NPD‐2) and hyperpolarizabilities (526.5 and 1271.3 a.u.) confirmed the enhanced NLO activity of NPD‐2. Antibacterial assays exhibited inhibition zones up to 19 mm with MIC values of 7.8–31.2 µg/mL, while antioxidant evaluation showed 75.6% DPPH scavenging efficiency. Molecular docking revealed strong protein–ligand affinities (−6.8 to −7.7 kcal·mol −1 ). The combined experimental and computational results highlight the multifunctional potential of NPD‐1 and NPD‐2 as promising candidates for biomedical and nonlinear optical applications.