Mechanistic Investigation into the Cleavage of a Phosphomonoester Mediated by a Symmetrical Oxyimine‐Based Macrocyclic Zinc(II) Complex

Density functional calculations are utilized to explore the hydrolysis mechanisms of the phosphomonoester 4‐nitrophenyl phosphate catalyzed by a symmetrical zinc(II) complex. The formation process and properties of the active catalyst are verified. Eight plausible mechanisms are proposed and categorized into three groups. All of the proposed mechanisms, except for Mechanism 7 (see text), are S_N2‐type addition–substitution reaction pathways. Nucleophilic attack at the ortho position occurs in Mechanism 7 with a relatively high reaction barrier. Mechanisms 1 and 2 in the monocatalyst model, Mechanisms 5 to 7 in the sandwich‐dual‐catalyst model, as well as the nucleophilic addition–substitution step in Mechanism 8 are concerted reaction pathways, whereas the rest appear to occur in a stepwise manner. Meanwhile, the explicit solvent model is utilized to consider direct hydrogen bonds and solvation interactions and these results indicate that the added water molecule is involved in the hydrolysis process, but does not change the mechanisms significantly. Mechanism 8, with the lowest reaction barrier, is the most favored reaction pathway of the eight proposed mechanisms, although Mechanisms 1, 4, and 6 are in competition with Mechanism 8. In consideration of the zinc(II) complex concentration, Mechanism 1 is only the predominant reaction pathway at a low zinc(II) complex concentration; Mechanisms 4 and 6 tend to be more competitive with increasing concentration of the zinc(II) complexes, and Mechanism 8 is favored at high zinc(II) complex concentrations. Our calculated results are consistent with, and can be used to systematically interpret, experimental observations. More importantly, insightful suggestions are made regarding the catalyst design and selection of the reaction environment.