The scavenging mechanism of hydrazone compounds towards HOO˙ and CH3OO˙ radicals: a computational mechanistic and kinetic study

Abstract

In this study, a detailed DFT investigation was conducted to systematically analyze the scavenging activity of six hydrazone compounds (1–6) against HOO˙ and CH₃OO˙ radicals. Three mechanistic pathways were explored: hydrogen atom transfer (HAT), single electron transfer followed by proton transfer (SETPT), and sequential proton loss electron transfer (SPLET). These mechanisms were evaluated based on thermodynamic parameters, including bond dissociation enthalpy (BDE), ionization potential (IP), proton dissociation enthalpy (PDE), proton affinity (PA), and electron transfer enthalpy (ETE) in the gas phase, water, and pentyl ethanoate. HAT was identified as the most favorable mechanism in the gas phase, while SPLET was preferred in water. Among the studied compounds, compound 2 showed the highest rate constants for HOO˙ scavenging following the HAT mechanism in the gas phase observed at the O2′–H bond with a k_Eck value of 6.02 × 10⁴ M⁻¹ s⁻¹. For CH₃OO˙ scavenging, the same compound exhibited the highest rate constants at the N8–H (9.03 × 10⁴ M⁻¹ s⁻¹) and O2′–H (7.22 × 10⁴ M⁻¹ s⁻¹) sites. The calculated overall rate constant values of compound 2 are k_overall (HOO˙) = 6.86 × 10⁴ M⁻¹ s⁻¹ and k_overall (CH₃OO˙) = 1.63 × 10⁵ M⁻¹ s⁻¹. These results suggest that compound 2 exhibits antioxidant activities comparable to butylated hydroxyanisole (BHA), consistent with experimental findings, indicating its potential as an effective scavenger of hydroperoxyl and methoxy peroxyl radicals. In aqueous solution, the anionic form of compound 2 showed the greatest HOO˙ and CH₃OO˙ radical scavenging activity among all of the studied compounds with rate constants of k_app = 1.8 × 10⁷ M⁻¹ s⁻¹ and k_app = 3.3 × 10⁶ M⁻¹ s⁻¹, respectively. Compared with some typical antioxidants such as rubiadin, natural fraxin, and natural anthraquinones, compound 2 showed higher HOO˙ and CH₃OO˙ radical scavenging activity in water. Thus, compound 2 is a promising antioxidant in aqueous physiological environments.