Density functional calculations on the effect of sulfur substitution for 2′-hydroxypropyl-p-nitrophenyl phosphate: C[sbnd]O vs. P[sbnd]O bond cleavage

Abstract

Density functional theory calculations have been used to investigate the intra-molecular attack of 2′-hydroxypropyl-p-nitrophenyl phosphate (HPpNP) and its analogous compound 2-thiouridyl-p-nitrophenyl phosphate (s-2′pNP). Bulk solvent effect has been tested at the geometry optimization level with the polarized continuum model. It is found that the P-path involving the intra-molecular attack at the phosphorus atom and C-path involving the attack at the beta carbon atom proceed through the SN2-type mechanism for HPpNP and s-2′pNP. The calculated results indicate that the P-path with the free energy barrier of about 11kcal/mol is more accessible than the C-path for the intra-molecular attack of HPpNP, which favors the formation of the five-membered phosphate diester. While for s-2′pNP, the C-path with the free energy barrier of about 21kcal/mol proceeds more favorably than the P-path. The calculated energy barriers of the favorable pathways for HPpNP and s-2′pNP are both in agreement with the experimental results.