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

Abstract

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(N)2-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.

Mechanistic investigation of the cleavage of phosphodiester catalyzed by a symmetrical oxyimine-based macrocyclic dinuclear zinc complex: a DFT study

“…65,66 The popular B3LYP suite of density functionals is known to exhibit good performance on various systems. Besides, our previous related studies 22,50,67,68 demonstrate that B3LYP functionals appear sufficient to describe several phosphate ester hydrolysis reactions. Therefore, the B3LYP hybrid functionals are adopted in consideration of their data accuracy and relatively low computational expense.…”

Nuclease-like metalloscissors: Biomimetic candidates for cancer and bacterial and viral infections therapy

“…These methodologies are able to probe the mechanism of cleavage reaction through analysis of all the involved intermediates and transition states throughout the catalytic process. These methods are able to predict the effective factors on the nuclease activity of AMSs [164] , [165] , [166] , [167] , [168] , [169] , [170] , [171] , [172] , [173] , [174] . Moreover, the photophysical properties of metal complexes suitable for the use in PDT have been investigated by DFT and time-dependent DFT (TD-DFT) approaches [175] .…”

Mechanistic Studies of Homo- and Heterodinuclear Zinc Phosphoesterase Mimics: What Has Been Learned?

“…In contrast to the large number of studies on the catalysis of phosphodiester hydrolysis, the cleavage mechanism of phosphomonoesters by biomimetic zinc(II) complexes is little investigated (Anbu et al, 2012; Zhang et al, 2014a,c; Sanyal et al, 2015). In recent years, various studies have been aimed at elucidating the role of the heterodimetallic Fe(III)-Zn(II) site in PAP.…”

“…Phosphomonoester hydrolysis by dizinc(II) complexes is usually studied using 4-nitrophenyl phosphate as an ester with a good leaving group (NPP, Figure 3). The mechanism of the hydrolysis of the NPP 2− dianion is generally believed to be concerted with a loose transition state, while for phosphomonoester monoanions a dissociative mechanism involving metaphosphate as the intermediate has not been ruled out (Cleland and Hengge, 2006; Klähn et al, 2006; Kamerlin and Wilkie, 2007; Zhang et al, 2014a,c; Sanyal et al, 2015). The dianion is less reactive than the monoanion due to the higher negative charge of the transition state.…”

“…The reaction kinetics showed a change in the reaction order at higher complex concentrations. Zhao and coworkers carried out DFT calculations to investigate the reaction mechanism (Zhang et al, 2014a,c). Different competitive catalytic mechanisms were found, depending on the concentration of the complex.…”