In Silico Structure-Reactivity Analysis of Lignin-Derived Phenolics: O-H Bond Dissociation Enthalpies, Spin...

Plant phenolics represent a prospective source of renewable antifungal drugs, yet the molecular mechanisms underlying their activity within the structurally varied phenolic components of natural products like wood vinegar remain ambiguous. Nine phenolic compounds from corncob (Zea mays) and Areca catechu wood vinegars, encompassing the phenol, guaiacol, syringol, and benzenediol categories were examined by in silico methods. Geometries and global reactivity descriptors were derived using density functional theory at the B3LYP-D3BJ/def2-TZVP/CPCM-(water) level, homolytic O-H bond dissociation enthalpies (BDEs) and phenoxyl-radical spin-density distributions were calculated to evaluate and elucidate radical-scavenging capacity, while consensus lipophilicity (log P) was estimated to assess membrane permeability. To establish the reactivity trend on a quantitative and transferable basis, the dataset was expanded to include 12 para-, meta-, and ortho-substituted phenols (totaling 21 compounds), the O-H bond dissociation energy in the para-series exhibits a linear correlation with the Hammett constant σ⁺ (ρ ≈ +8.3 kcal mol^-1, r = 0.987). Computed bond dissociation energies (BDEs) were compared with experimental literature values (phenol, 83.2 vs 86.7 ± 0.7 kcal mol^-1), validating a consistent B3LYP deviation that neutralizes in the relative assessments upon which the analysis depends. The initial O-H bond dissociation energies for the nine natural compounds varied between 73.7 and 83.2 kcal mol^-1, with phenol exhibiting the lowest reactivity and the two benzenediols demonstrating the highest reactivity. log P and BDE exhibited statistical independence (r = 0.15), establishing two orthogonal axes of structure-activity, however the Hirshfeld oxygen spin population of the phenoxyl radical showed a strong correlation with BDE (r = 0.911), indicating that spin delocalization is the underlying physical cause of the observed reactivity trend. Docking with Candida albicans sterol 14α-demethylase (CYP51, PDB 5TZ1) revealed phenolic affinities ranging from -5.0 to -7.6 kcal mol^-1, which are inferior to the clinical azole fluconazole (-8.4 kcal mol^-1) and the native inhibitor VT-1161 (-12.2 kcal mol^-1), the affinity correlated with log P (r = -0.76) but not with BDE, suggesting that direct inhibition of CYP51 is at best a secondary factor. The diminished second O-H bond dissociation energies of benzenediols facilitate a quinone redox cascade that, when measured against a peroxyl reference bond, categorizes the phenols into radical-terminating monophenols and redox-cycling propagators. The framework offers a structural justification for the antifungal properties of lignin-derived phenolics at the individual component level and emphasizes the unexploited low-BDE/high-log P area as a focus for enhancement.