It has been shown that the major reactive oxygen species (ROS) generated by the aqueous reaction of Fe(II) and H₂O₂ (i.e., the Fenton reaction) are high-valent oxoiron(IV) species, whereas the hydroxyl radical plays a role only in very acidic conditions. Nevertheless, when the Fenton reaction is conducted in phosphate buffer solutions, the resulting ROS turns into hydroxyl radical even in neutral pH conditions. The present density functional theory (DFT) study discloses the underlying principle for this phenomenon. Static and dynamic DFT calculations indicate that in phosphate buffer solutions, the iron ion is highly coordinated by phosphoric acid anions. Such a coordination environment substantially raises the pK_a of coordinated water on Fe(III). As a consequence, the Fe(III)–OH intermediate, resulting from the reductive decomposition of H₂O₂ by ferrous ion is relatively unstable and will be readily protonated by phosphoric acid ligand or by free proton in solution. These proton-transfer reactions, which become energetically favorable when the number of phosphate coordination goes up to three, prevent the Fe(III)–OH from hydrogen abstraction by nascent ^•OH to form Fe(IV)═O species. On the basis of this finding, a ligand design strategy toward controlling the nature of ROS produced in the Fenton reaction is put forth. In addition, it is found that while phosphate buffers facilitate ^•OH radical generation in the Fenton reaction, phosphoric acid anions can act as ^•OH radical scavengers through hydrogen atom transfer reactions.

The reaction of iron(II) and hydrogen peroxide, namely the Fenton reaction, is well-known for its strong oxidizing capability. While the Fenton reactions are ubiquitous and have wide applications in many areas, the detailed mechanism, especially the nature of the reactive intermediates responsible for oxidation, is not completely clear. In this work, the performances of various density functional theory (DFT) methods on the relative energies of key Fenton intermediates are evaluated. The DFT method selected from the benchmark study is then exploited to investigate the aqueous Fenton reactions in different pH conditions. The results show that at pH > 2.2, the major Fenton oxidants are high-valent oxoiron(IV) aquo complexes. However, depending on the pH conditions, these complexes can exist in three protonation states that display quite different oxidation reactivities. The oxidizing power of Fe^IV O is found to be principally determined by the total charge of the ligands and is less influenced by the axial ligand effect. Moreover, the calculations reveal that the presence of the hydronium ion can stabilize the intermediate of the hydroxyl radical and further inhibit oxoiron(IV) formation via proton transfer. The contribution of hydroxyl radicals could compete with the oxoiron(IV) species at pH below 2.2. In addition, high-level ab initio calculations question the existence of the iron(IV)-dihydroxo intermediate suggested in the literature. The implications of the computational results for the Fenton oxidation process, cytochrome P450, and catalyst design are discussed.