Mechanism engineering of polyphenol antioxidants: DFT/TD-DFT evidence for HAT?SPLET switching via targeted functional blocking in curcumin, quercetin, and resveratrol derivatives

Polyphenolic antioxidants (curcumin, quercetin, resveratrol) were probed alongside purpose-built derivatives that selectively block key H-donor sites (Cur-OMe; Q-diOMe; RSV-4S) to engineer radical-scavenging pathways. DFT/TD-DFT (B3LYP/6-31G(d,p), PCM ethanol/water; single-point 6?311++G (d,p)) delivered site-resolved thermodynamics for HAT, SET?PT, and SPLET. We find that (i) quercetin?s catechol (3?,4?-OH) exhibits the lowest BDE and most favorable SPLET in polar media; (ii) blocking the catechol (Q-diOMe) suppresses HAT and switches the preference to SPLET via stabilized phenolates; (iii) curcumin?s enolic OH competes effectively via HAT, but Cur-OMe shifts the balance toward SPLET; and (iv) RSV-4S displays solvent-dependent behavior with a modest SPLET gain in water. NBO/MEP analyses show charge relocation to oxygen centers and strengthened LP ? ?* interactions underlying these switches. TD-DFT reproduces experimental UV?Vis/IR trends (after standard frequency scaling) and reconciles bathochromic/hypsochromic shifts with changes in ?E(HOMO?LUMO). Overall, targeted functional blocking enables HAT?SPLET control in polyphenols, offering a rational route to mechanism-tailored antioxidants for specific environments.