Organometallic-enhanced chromone-thiazole hybrid antioxidants: a DFT study of solvent-dependent HAT/SPLET switching

Hydroxychromone-thiazole (HCT) and related chromone-/thiazole-containing scaffolds are compact antioxidant and drug-design motifs, yet the extent to which metal coordination can redirect their radical-scavenging pathways remains insufficiently resolved. In particular, systematic Q-Chem-based evaluation of hydrogen atom transfer (HAT), sequential proton-loss electron transfer (SPLET), and single-electron transfer followed by proton transfer (SET-PT) for hydroxychromone-thiazole hybrids remains limited. This study addresses that gap by designing HCT base, MeO-HCT, NO₂-HCT, HCT-CuCl₂, and HCT-ZnCl₂ models and testing whether substituent effects and metal coordination promote solvent-dependent changes in the relative thermodynamic accessibility of HAT and SPLET.

Geometry optimizations and harmonic frequency calculations were performed using ωB97X-D/def2-SVP, followed by single-point SMD calculations at ωB97X-D/def2-TZVP in water, methanol, ethanol, DMSO, and trichloromethane. Neutral ArOH, HAT radical ArO^•, SPLET anion ArO^⁻, SET-PT radical cation ArOH^•⁺, and Cu spin-coupling candidates were evaluated. Thermochemical corrections from the frequency calculations were combined with solvent-specific H^⁺ and e⁻ carrier conventions to obtain BDE, IP, PDE, PA, and ETE descriptors. The originally incomplete solvent calculations were re⁻run and integrated into the final audit. The merged reanalysis contained 219 raw SMD single-point blocks, including superseded failed attempts; after duplicate resolution, 208 unique system-state⁻solvent records were successful, and no unresolved solvent single-point failure remained for descriptor construction. The results show that gas-phase descriptors favor HAT, whereas polar solvents stabilize proton-loss terms and make SPLET thermodynamically competitive or lower in the supported polar-solvent descriptors. Electron-donating MeO substitution facilitates radical stabilization, NO₂ substitution perturbs charge⁻separation energetics, and Cu/Zn coordination modulates both descriptor ordering and convergence sensitivity. These calculations provide a compact in silico framework for solvent-aware design of organometallic-enhanced chromone-thiazole antioxidants.