Modeling the Alkaline Hydrolysis of Diaryl Sulfate Diesters: A Mechanistic Study

Phosphate
and sulfate esters have important roles in regulating
cellular processes. However, while there has been substantial experimental
and computational investigation of the mechanisms and the transition
states involved in phosphate ester hydrolysis, there is far less work
on sulfate ester hydrolysis. Here, we report a detailed computational
study of the alkaline hydrolysis of diaryl sulfate diesters, using
different DFT functionals as well as mixed implicit/explicit solvation
with varying numbers of explicit water molecules. We consider the
impact of the computational model on computed linear free-energy relationships
(LFER) and the nature of the transition states (TS) involved. We obtain
good qualitative agreement with experimental LFER data when using
a pure implicit solvent model and excellent agreement with experimental kinetic isotope effects
for all models used. Our calculations suggest that sulfate diester
hydrolysis proceeds through loose transition states, with minimal
bond formation to the nucleophile and bond cleavage to the leaving
group already initiated. Comparison to prior work indicates that these
TS are similar in nature to those for the alkaline hydrolysis of neutral
arylsulfonate monoesters or charged phosphate diesters and fluorophosphates.
Obtaining more detailed insights into the transition states involved
assists in understanding the selectivity of enzymes that hydrolyze
these reactions.

磷酸酯与硫酸酯在调控细胞进程中发挥着重要作用。尽管学界已针对磷酸酯水解的相关机制与过渡态开展了大量实验与计算研究，但针对硫酸酯水解的相关工作却相对匮乏。本研究针对二芳基硫酸二酯的碱性水解开展了详细的计算研究，采用了多种密度泛函理论（Density Functional Theory, DFT）泛函，以及包含不同数目显性水分子的混合隐式/显性溶剂化模型。我们考察了计算模型对所得到的线性自由能关系（Linear Free-Energy Relationship, LFER）以及相关过渡态（Transition State, TS）性质的影响。当采用纯隐式溶剂模型时，我们的计算结果与实验测得的LFER数据可达到良好的定性一致性；而对于所有所用模型，其计算结果与实验动力学同位素效应均展现出极佳的匹配度。本研究的计算结果表明，硫酸二酯的水解反应经由松散过渡态进行：亲核试剂的成键作用极弱，而离去基团的键断裂过程已初步启动。与已有研究对比可知，此类过渡态在性质上与中性芳基磺酸单酯、带电荷磷酸二酯以及氟代磷酸酯的碱性水解所涉及的过渡态相似。对相关过渡态获得更细致的认知，有助于理解催化此类水解反应的酶的选择性机制。