An Integrated DFT and Experimental Approach to Investigate the Structural, Electronic, and Spectroscopic Properties...

Nobiletin, a polymethoxylated flavonoid with known antioxidant, anti-inflammatory, and anticancer potentials, is investigated, along with three derivatives, using an integrated experimental and computational approach. Density Functional Theory (DFT) is employed to evaluate the structural, electronic, and vibrational spectroscopic properties. To determine the most suitable computational conditions, we compared three functionals─B3LYP, M06-2X, and PBE0 using basis sets 6-31++G(d,p), def2-TZVP, and cc-PVDZ. The B3LYP/6-31++G(d,p) level was identified as the most reliable in terms of accuracy and computational efficiency and was subsequently used in combination with experimental infrared and Raman spectroscopic analyses. Vibrational mode assignments are carried out using the Potential Energy Distribution analysis, and theoretical spectra are validated against experimental results. Solvent effects in water and dimethyl sulfoxide are examined by using the Integral Equation Formalism Polarizable Continuum Model to assess the environmental influences on molecular properties. Frontier molecular orbital analysis suggests that the demethylated derivatives exhibit enhanced electronic behavior, including increased electron affinity, ionization, and electronegativity, indicating greater potential for molecular interaction. Potential (MESP) mapping identifies C═O and hydroxyl-substituted regions as key reactive sites susceptible to nucleophilic and electrophilic attack, respectively. Furthermore, a DFT guided derivatization scheme is proposed to generate NM1-NM3 from the parent compound with intermediate states evaluated through Gibbs free energy calculations to confirm thermodynamic feasibility. The findings offer comprehensive insights into the physicochemical behavior of Nobiletin and its derivatives and support their potential utility in anticancer drug development and biophysical research.