A density functional theory study of the hydrolysis mechanism of phosphodiester catalyzed by a mononuclear Zn(II) complex

Density functional theory (DFT) calculations were used to explore the hydrolysis mechanism of the DNA analog BNPP (BNPP = bis(4-nitrophenyl)phosphate) catalyzed by the mononuclear zinc(II):OH− complex of 1,5,9-triazacyclododecane (Zn:([12] aneN3)). We present a binding mode in which one terminal phosphoryl oxygen atom as well as the nucleophilic group (hydroxyl anion) binds to zinc center. Two potential mechanisms were found as follows: one is a concerted mechanism with a reaction barrier of 18.1 kcal/mol in liquid phase of implicit solvent and 13.8 kcal/mol in liquid phase of explicit solvent of water molecules; the other is a stepwise mechanism with a hydroxylated phosphate reaction intermediate of a quasi-trigonal bipyramid configuration but is less feasible. Both the concerted reaction pathway and stepwise reaction pathway are SN2 manner of nucleophilic substitution reactions. Meanwhile polar protic solvents like water, methanol and ethanol are favored in the catalyst-assisted hydrolysis mechanism. We explore the rationality of deprotonation of mono-anionic phosphates in the transient products and find that it is difficult to dissociate a proton and the ultimate product is NPP− rather than NPP2−. These results are consistent with and systematically interpret the experimental observations, more importantly, provide useful suggestions in the catalyst design and solvent selection.

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► The hydrolysis of phosphodiester catalyzed by zinc complex was explored.
► A stepwise pathway and a concerted pathway were found and the latter is favored.
► The two mechanisms are SN2 manner of nucleophilic substitution reactions.
► Polar protic solvents are favorable in the catalyst-assisted SN2 reaction.
► The phosphate in the product would not dissociate a proton at neutral pH solution.