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Modeling the Alkaline Hydrolysis of Diaryl Sulfate Diesters: A Mechanistic Study
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry. (Kamerlin)ORCID iD: 0000-0003-0079-6304
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry. (Karmelin)ORCID iD: 0000-0002-3190-1173
(English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904Article in journal (Refereed) Submitted
Abstract [en]

Phosphate and sulfate esters have important roles as biological building blocks and in regulatingcellular processes. However, while there has been substantial experimental and computationalinvestigation of the mechanisms and the transition states involved in phosphate ester hydrolysis,there is far less (in particular computational) work on sulfate ester hydrolysis. Here, we report adetailed computational study of the alkaline hydrolysis of diaryl sulfate diesters, using differentDFT functionals and both pure implicit solvation as well as mixed implicit/explicit solvation withvarying numbers of explicit water molecules. We consider both the impact of how the system ismodeled on computed linear free energy relationships (LFER) and the nature of the transitionstates. Although our calculations consistently underestimate the absolute activation free energies,we obtain good agreement with experimental LFER data when using pure implicit solvent, andexcellent agreement with experimental kinetic isotope effects for all models used. Our calculationssuggest that the hydrolysis of sulfate diesters proceeds through loose transition states, withminimal bond formation to the nucleophile and with bond cleavage to the leaving group alreadyinitiated. Comparison to prior work indicates that these transition states are similar in nature tothose of analogous reactions such as the alkaline hydrolysis of neutral arylsulfonate monoesters orcharged phosphate diesters and fluorophosphates. Obtaining more detailed insight into thetransition states involved assists in understanding the selectivity of enzymes that hydrolyze thesereactions; however, this work also highlights the methodological challenges involved in reliablymodeling sulfate ester hydrolysis.

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American Chemical Society (ACS).
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Chemical Sciences Theoretical Chemistry Physical Chemistry
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URN: urn:nbn:se:uu:diva-407493OAI: oai:DiVA.org:uu-407493DiVA, id: diva2:1416759
Available from: 2020-03-25 Created: 2020-03-25 Last updated: 2020-03-30Bibliographically approved
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Szeler, KlaudiaKamerlin, Shina C. Lynn

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