Solvent Effects on C–H Abstraction by Hydroperoxyl Radicals: Implication for Antioxidant Strategies

Kinetic solvent effects (KSE) on hydrogen atom transfer (HAT) reactions play a pivotal role in processes such as photoredox catalysis, electrochemical synthesis, and antioxidant defense. While general principles of KSE are well established, the influence of solvent-radical interactions on the reactivity of the hydroperoxyl radical (HOO^•) remains largely uncharacterized. Here, we examine the effects of noncovalent interactions and acid–base equilibria on HOO^• reactivity, using the autoxidation of 1,4-cyclohexadiene (CHD) as convenient HOO^• source in chlorobenzene (PhCl) or acetonitrile solutions containing cosolvents (S) with varying hydrogen bond acceptor basicities (β₂^H). Equilibrium (K_S) and CHD + HOO^• (k_p^S) rate constants in PhCl were determined for cosolvents including MeOH, MeCN, DMSO, pyridine, and DABCO. As β₂^H increased from 0.41 (MeOH) to ∼0.70 (DABCO), K_S increased from 50 to 3 × 10⁶ M^–1, while k_p^S decreased from 90 to 0.1 M^–1 s^–1. MeCN (β₂^H = 0.44) gave K^S = 70 M^–1 and k_p^S = 130 M^–1 s^–1. For DMSO (β₂^H = 0.78) and pyridine (β₂^H = 0.62) K_S values were 2.0 × 10³ and 3 × 10⁵ M^–1, respectively, with corresponding k_p^S values of 20 and 5 M^–1 s^–1. The observed K_S values show a qualitative correlation with the solvent β₂^H values of the solvents. Moreover, the calculated α₂^H values for HOO^• in nonbasic cosolvents (MeOH, MeCN, DMSO) cluster around 0.87 ± 0.07, consistent with prior estimates. Experiments in MeCN solution suggest HOO^• deprotonation with alkylamines, and the pK_a of HOO^• is estimated as 18–19. These findings provide mechanistic insight into HOO^• reactivity in complex media and suggest new strategies for modulating oxidative radical chemistry in both synthetic and biological contexts.