Proton‐Coupled Electron Transfer in Reaction of Catecholamines: Experimental and Computational Approach

Biogenic catecholamines (dopamine, noradrenaline, adrenaline) exhibit a dual role in biological systems, acting as both endogenous antioxidants and potential sources of oxidative stress. The core of their antiradical activity is the catechol moiety that enables efficient radical scavenging via hydrogen and/or electron transfer. In this study, the reactivity of catecholamines toward the DPPH• radical was investigated experimentally and computationally in predominantly nonpolar 1,4-dioxane-water media. Experimental rate constants, kinetic isotope effects, and thermodynamic activation parameters suggest that, under these conditions, the reactions proceed via a concerted hydrogen transfer mechanism, best described as proton-coupled electron transfer (PCET). The proposed PCET-like reaction mechanism is supported by intrinsic bond orbital analysis along the intrinsic reaction coordinate path. Average local ionization energy (ALIE) analysis showed that the most reactive electron-donating sites are associated with π electrons above and below the aromatic ring of the catecholamine compounds. Additionally, kinetic isotope effects and anomalous Arrhenius parameters provide evidence for the involvement of hydrogen tunneling. Complementary pH-dependent kinetic studies with dopamine suggest a mechanistic shift toward a faster sequential proton loss-electron transfer pathway with increasing catecholate formation. These findings offer new insight into the antioxidant mechanisms of catecholamines and provide the first experimental indication of hydrogen tunneling in their radical-scavenging reactions.