ZnO Nanocatalyst-Enabled Microwave-Assisted Solvent-Free Synthesis of Functional Amidoalkyl-2-naphthol Derivatives: A Synergistic Experimental and Quantum Chemical Study.

Novel N-methyl-1-amidoalkyl-2-naphthol derivatives (HNM-1 and HNM-2) were synthesized via a solvent-free, microwave-assisted one-pot condensation of 2-naphthol, N-methylacetamide, and functionalized benzaldehydes. A recyclable ZnO nanoparticle catalyst (20 mol %) enabled the reactions to proceed efficiently, affording yields ≥80% within 15-18 min at 300 W, significantly outperforming montmorillonite K10 clay under comparable green conditions. The synthesized compounds were fully characterized using FT-IR, 1H- and 13C NMR, HR-ESI-MS, and UV-vis spectroscopies. Density functional theory (DFT) calculations (B3LYP/6-311G-(d,p)) provided optimized geometries and electronic structures. The HOMO and LUMO energy levels were determined as -5.97/-2.68 eV for HNM-1 and -5.95/-2.95 eV for HNM-2, corresponding to moderate energy gaps of 3.29 and 3.00 eV, respectively. Time-dependent DFT (TD-DFT) simulations accurately reproduced the experimental UV-vis spectra, revealing a distinct intramolecular charge transfer band at 379 nm for HNM-2. Mulliken population analysis, DOS, ELF/LOL maps, and MEP surfaces confirmed pronounced electron migration from the donor (naphthol-acetamide moiety) to the nitro-substituted aryl acceptor. Quantum Theory of Atoms in Molecules (QTAIM) and noncovalent interaction (NCI) analyses identified stabilizing hydrogen bonds (up to -59 kJ/mol) and van der Waals interactions, consistent with high predicted chemical hardness (η = 1.50-1.65 eV) and kinetic stability. Molecular docking studies against the SARS-CoV-2 main protease (PDB ID: 7U0N) revealed strong binding affinities (-7.0 and -6.2 kcal/mol for HNM-1 and HNM-2, respectively). HNM-1 formed five hydrogen bonds with residues Leu351, Lys403, and Gln409, while HNM-2 engaged in a single, well-oriented hydrogen bond with Asn322, highlighting effective complementarity with the viral active site.