Comparative Study of the Alkyl and Peroxy Radical-scavenging Activity of 2-t-Butyl-4-methoxyphenol (BHA) and its Dimer, and their Theoretical Parameters

Abstract

Background: 2-t-Butyl-4-methoxyphenol (BHA) has considerable toxicity and undesirable potential tumor-promoting activities. To clarify the free radical mechanism of BHA-induced toxicity, the comparative radical-scavenging activity of BHA and its dimer (bis-BHA, 3,3′-ditert-butyl-5,5′-dimethoxy-1,1′-biphenyl-2,2′-diol) with or without 2-mercapto-1-methylimidazole (MMI) was studied using the induction period method. Materials and Methods: The induction period and propagation rate (Rp) were determined by differential scanning calorimetry (DSC) monitoring of polymerization of methyl methacrylate, initiated by the thermal decomposition of benzoyl peroxide (a source of the peroxy radical, PhCOO^.) or 2,2′-azobisisobutyronitrile (a source of the alkyl radical, R^.) under nearly anaerobic conditions. The anti-1,1′-diphenyl-2-picrylhydrazyl (DPPH) radical- and O₂^--scavenging activities were also investigated. Furthermore, theoretical parameters were calculated from the DEFT/B3LYP and HF/6-31G*//B3LYP levels. Results: For both PhCOO^. and R^. the inhibition rate constant (k_inh) for BHA and bis-BHA was almost identical, but a marked decrease in the Rp_inh/Rp_con was found for the former. The BHA/MMI mixture (1:1 molar ratio) oxidized by R^. reduced the total radical-scavenging activity by approximately 20% . BHA showed lower anti-DPPH radical- and higher O₂^--scavenging activity. Conclusion: Upon PhCOO^. or R^. scavenging, BHA with a lower BDE, IP _koopman's, electronegativity, and electrophilicity value, but not bis-BHA with higher corresponding values, highly suppressed propagation. This may be due to the formation of highly reactive free-radical intermediates, which are potentially toxic.