Department of Chemistry - BMC, Uppsala University, BMC Box 576, S-751 23 Uppsala, Sweden.
Department of Chemistry, University of Sheffield, Sheffield S3 7HF, U.K.
J Org Chem. 2020 May 15;85(10):6489-6497. doi: 10.1021/acs.joc.0c00441. Epub 2020 Apr 30.
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.
磷酸盐和硫酸盐酯在调节细胞过程中起着重要作用。然而，尽管已经对涉及磷酸盐酯水解的机制和过渡态进行了大量的实验和计算研究，但对硫酸盐酯水解的研究却少得多。在这里，我们使用不同的 DFT 泛函以及具有不同数量的显式水分子的混合隐式/显式溶剂化，对二芳基硫酸盐二酯的碱性水解进行了详细的计算研究。我们考虑了计算模型对计算线性自由能关系（LFER）和涉及的过渡态（TS）的性质的影响。当使用纯隐式溶剂模型时，我们与实验 LFER 数据取得了良好的定性一致性，并且所有模型的实验动力学同位素效应都非常吻合。我们的计算表明，硫酸盐二酯的水解通过松散的过渡态进行，与亲核试剂的键形成最小，并且已经开始对离去基团进行键裂解。与之前的工作相比，这些 TS 的性质与碱性水解中性芳基磺酸盐单酯或带电荷的磷酸二酯和氟代磷酸酯的 TS 相似。更详细地了解涉及的过渡态有助于理解水解这些反应的酶的选择性。
