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<p>Phosphate and sulfate esters have important roles as biological building blocks and 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 (in particular computational) work on sulfate ester hydrolysis. Here, we report a
detailed computational study of the alkaline hydrolysis of diaryl sulfate diesters, using different
DFT functionals and both pure implicit solvation as well as mixed implicit/explicit solvation with
varying numbers of explicit water molecules. We consider both the impact of how the system is
modeled on computed linear free energy relationships (LFER) and the nature of the transition
states. Although our calculations consistently underestimate the absolute activation free energies,
we obtain good agreement with experimental LFER data when using pure implicit solvent, and
excellent agreement with experimental kinetic isotope effects for all models used. Our calculations
suggest that the hydrolysis of sulfate diesters proceeds through loose transition states, with
minimal bond formation to the nucleophile and with bond cleavage to the leaving group already
initiated. Comparison to prior work indicates that these transition states are similar in nature to
those of analogous reactions such as the alkaline hydrolysis of neutral arylsulfonate monoesters or
charged phosphate diesters and fluorophosphates. Obtaining more detailed insight into the
transition states involved assists in understanding the selectivity of enzymes that hydrolyze these
reactions; however, this work also highlights the methodological challenges involved in reliably
modeling sulfate ester hydrolysis.
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Modeling the Alkaline Hydrolysis of Diaryl Sulfate Diesters: A Mechanistic Study