Conformer-audited full-panel DFT refinement of frontier-orbital heterogeneity in classical sulfonamides: Beyond...

Classical sulfonamides share a formal SO₂NH motif, yet their molecular environments impose distinct frontier-orbital responses. We examined thirteen classical sulfonamides and dapsone using a staged, quality-controlled workflow that separated exploratory GFN2-xTB/Composite-SEPI (the study-specific exploratory electronic-prioritization score) screening from full-panel B3LYP-D3BJ/def2-SVP optimization/frequency analysis, canonical PBE0-D4/def2-TZVP refinement with the conductor-like polarizable continuum model for water (CPCM(water)), and an orthogonal ωB97X-D4 sensitivity layer. Revision-stage robustness tests additionally challenged geometry, additive D4 dispersion, population partitioning, and the basis-set dependence of charged-state Fukui descriptors. Corrected B3LYP and fixed-geometry PBE0 gaps preserved the same lower-gap regime (Pearson r = 0.935; Spearman ρ = 0.934). Full-panel PBE0 reoptimization showed modest but measurable gap sensitivity (mean absolute error (MAE) = 0.0595 eV; root-mean-square error (RMSE) = 0.0696 eV; 7/14 with |Δgap| ≥ 0.050 eV) while preserving the lower-gap top-three identity. PBE0 and ωB97X-D4 retained the relative gap landscape (r = 0.959; ρ = 0.978), and Mulliken-Löwdin cross-checks preserved the dominant HOMO and LUMO fragments for 14/14 molecules. In sulfadiazine, sulfamerazine, and sulfamethazine, the occupied and virtual frontier orbitals remained spatially separated between the aryl/aniline and diazine-containing regions. Diffuse-basis def2-TZVPD tests yielded negative vertical electron affinities and positive anion α-spin singly occupied molecular orbital (SOMO) energies for 14/14 molecules, making f+ and the dual descriptor basis-sensitive while f- remained comparatively robust. Formal SO₂NH identity therefore masks reproducible electronic heterogeneity, but the reported quantities remain method-dependent isolated-molecule descriptors and do not establish charge-transfer states or biological activity predictions.