Design and In Silico Evaluation of Organometallic-Enhanced Chromone- Thiazole Hybrid Antioxidants: A DFT Investigation of HAT/SPLET Mechanism Switching and Solvent-Corrected Radical Scavenging Thermodynamics

Abstract Context: Chromone- and thiazole-containing scaffolds are compact antioxidant and drug-design motifs, yet the extent to which organometallic modification 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 chromone-thiazole hybrids is still limited. This study addresses that gap by designing HCT base, MeO-HCT, NO 2 -HCT, HCT-CuCl 2 , and HCT-ZnCl 2 models and testing whether substituent effects and metal coordination promote solvent-dependent switching between HAT/SPLET mechanisms. Methods Geometry optimizations and harmonic frequency calculations were performed using omega B97X-D/def2-SVP, followed by single-point SMD calculations at omegaB97X-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 The merged reanalysis contained 219 raw SMD single-point blocks, including superseded failed attempts; after duplicate resolution, 208 unique system-state-solvent records were successful, and no unresolved solvent single-point failure remained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 markedly stabilize proton-loss terms, making SPLET competitive or dominant in several systems. 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 findings establish a compact in silico framework for solvent-aware design of organometallic-enhanced chromone-thiazole antioxidants.