Elucidating the Roles of Distinct Chemical Factors in the Hydrolytic Activities of Hetero- and Homonuclear Synthetic Analogues of Binuclear Metalloenzymes

In this study, hydrolytic activities of hetero- and homobinuclear metallovariants of an asymmetric (I) or symmetric (II) ligand with the Fe^III-Zn^II, Zn^II-Zn^II, and Cu^II-Cu^II cores (i.e., I_FZ, I_ZZ, and I_CC or II_FZ, II_ZZ, and II_CC, respectively) are investigated using DFT calculations through four distinct mechanisms: dissociative (DA), substrate-assisted (SA), water-assisted (WA), and associative (AS). Additionally, the effects of different nucleophiles (μ-OH, terminal-OH, and -O₂H₃), coordination numbers, para substituents (-CH₃, -Cl, and -NO₂) of the linker, and an external electric field on the energetics of these reactions are computed. The geometries, spin ground states, and substrate binding modes of the three metal centers for both asymmetric (I) and symmetric (II) ligands differ from each other. There is no Lewis acid activation of the bis(2,4-dinitrophenyl) phosphate (BDNPP) substrate, and hydrolysis is predominantly controlled by the nucleophilicity of the metal-bound hydroxyl ion. The electronic nature of the metal ions determines the activities of their complexes, and the homobinuclear I_ZZ is found to be the most active complex. However, complexes formed with ligand I are not more active than their ligand-II-containing counterparts for all metal ions. The DFT calculations suggest that the DA pathway is the energetically most feasible among the four pathways. The terminal hydroxyl group is the strongest nucleophile, and the electron-donating -CH₃ group is the most suitable para substituent in the linker. Whereas the introduction of an external electric field along the reaction axis lowers the barrier for I_FZ, it leaves that unchanged for I_ZZ and increases that for I_CC. These combined results in this study highlight the influence of distinct critical chemical factors such as the electronic nature of the metal ions, the ligand environment, as well as the linker and nucleophile on phosphoester hydrolysis. Insights gained will guide the design of the next generation of versatile metal complexes for a wide range of reactions and applications.