Dual Oxidation in the Amino Acid-Mediated Copper-Catalyzed Fenton-like System: Effects of Ligand Structure and pH-Dependent Speciation

Abstract The Cu(II)/H2O2 system has attracted increasing interest as a Cu-catalyzed advanced oxidation process and serves as a useful biomimetic model for investigating Cu-mediated biomolecule redox interactions. In this system, reactive oxidants can operate in a dual-oxidation mode, where the oxidant flux partitions between coordinated ligands and coexisting bulk-phase substrates. In this study, we systematically investigated this behavior over a wide pH range (3–12), using 17 structurally diverse amino acids (AAs) as model ligands and benzoic acid (BA), which exhibits negligible Cu(II) complexation, as a model bulk-phase substrate. Speciation-based kinetic analysis identified the bis-chelated complex, [Cu(AA)2], as a key catalytic species associated with effective dual oxidation, namely, balanced oxidant allocation between ligand-centered AA oxidation and bulk-phase BA oxidation, at pH 7–10. Using quantitative structure–activity/efficiency relationships, we demonstrate that the partitioning of oxidant flux is governed by two ligand-associated properties: (i) Cu(II)-binding strength, which promotes ligand-centered oxidation, and (ii) oxidative stability (proxied by the highest occupied molecular orbital (HOMO)–lowest unoccupied molecular orbital (LUMO) gap), which favors the oxidant flux to the bulk phase. At higher pH, the possible formation of mixed hydroxo species, [Cu(AA)2(OH)]−, was associated with a shift toward ligand-centered oxidation and attenuated bulk-phase BA oxidation. Integrated machine-learning models combining ligand descriptors with pH-dependent speciation indicators further supported these trends and predicted AA and BA oxidation kinetics across pH 7–11. These results provide a predictive framework for understanding how ligand structure and pH-dependent speciation jointly control oxidant allocation in the Cu(II)/H2O2 system.