Computational simulation of mechanism and isotope effects on acetal heterolysis as a model for glycoside hydrolysis.

Ian Williams, John H. Glancy, Daniel M. Lee, Emily O. Read

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Abstract

DFT calculations for the equilibrium isotope effect for deuterium substitution at the anomeric centre Cα in 2-(p-nitrophenoxy)tetrahydropyran with continuum solvation show significant variation in the range of relative permittivity 2 ≤ ε ≤ 10. One-dimensional scans of potential energy (with implicit solvation by water) or of free energy (from QM/MM potentials of mean force with explicit aqueous solvation with a hybrid AM1/OPLS method) for heterolysis of the bond between Cα and the nucleofuge do not show a transition state. A two-dimensional free-energy surface that considers also the distance between Cα and a nucleophilic water indicates a pre-association DN*ANint mechanism with a transition state involving nucleophilic attack upon an ion-pair intermediate, and this is supported by good agreement between the mean values of the calculated and experimental α-D KIEs. However, the magnitudes of the standard deviations about the mean values for the making and breaking C–O bonds suggest that the transition state is rather plastic, with Cα–Onu ≈ 2 ± 0.4 Å and Cα–Olg ≈ 3 ± 0.5 Å. Not only is nucleophilic solvent assistance necessary, but there is also evidence for electrophilic assistance through specific hydrogen bonding to the nucleofuge.
Original languageEnglish
JournalPure and Applied Chemistry
Early online date29 Jul 2019
DOIs
Publication statusE-pub ahead of print - 29 Jul 2019

Cite this

@article{486ee0d7d1344812b6af331ce810bc27,
title = "Computational simulation of mechanism and isotope effects on acetal heterolysis as a model for glycoside hydrolysis.",
abstract = "DFT calculations for the equilibrium isotope effect for deuterium substitution at the anomeric centre Cα in 2-(p-nitrophenoxy)tetrahydropyran with continuum solvation show significant variation in the range of relative permittivity 2 ≤ ε ≤ 10. One-dimensional scans of potential energy (with implicit solvation by water) or of free energy (from QM/MM potentials of mean force with explicit aqueous solvation with a hybrid AM1/OPLS method) for heterolysis of the bond between Cα and the nucleofuge do not show a transition state. A two-dimensional free-energy surface that considers also the distance between Cα and a nucleophilic water indicates a pre-association DN*ANint‡ mechanism with a transition state involving nucleophilic attack upon an ion-pair intermediate, and this is supported by good agreement between the mean values of the calculated and experimental α-D KIEs. However, the magnitudes of the standard deviations about the mean values for the making and breaking C–O bonds suggest that the transition state is rather plastic, with Cα–Onu ≈ 2 ± 0.4 {\AA} and Cα–Olg ≈ 3 ± 0.5 {\AA}. Not only is nucleophilic solvent assistance necessary, but there is also evidence for electrophilic assistance through specific hydrogen bonding to the nucleofuge.",
author = "Ian Williams and Glancy, {John H.} and Lee, {Daniel M.} and Read, {Emily O.}",
year = "2019",
month = "7",
day = "29",
doi = "10.1515/pac-2019-0221",
language = "English",
journal = "Pure and Applied Chemistry",
issn = "0033-4545",
publisher = "IUPAC Secretariat",

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TY - JOUR

T1 - Computational simulation of mechanism and isotope effects on acetal heterolysis as a model for glycoside hydrolysis.

AU - Williams, Ian

AU - Glancy, John H.

AU - Lee, Daniel M.

AU - Read, Emily O.

PY - 2019/7/29

Y1 - 2019/7/29

N2 - DFT calculations for the equilibrium isotope effect for deuterium substitution at the anomeric centre Cα in 2-(p-nitrophenoxy)tetrahydropyran with continuum solvation show significant variation in the range of relative permittivity 2 ≤ ε ≤ 10. One-dimensional scans of potential energy (with implicit solvation by water) or of free energy (from QM/MM potentials of mean force with explicit aqueous solvation with a hybrid AM1/OPLS method) for heterolysis of the bond between Cα and the nucleofuge do not show a transition state. A two-dimensional free-energy surface that considers also the distance between Cα and a nucleophilic water indicates a pre-association DN*ANint‡ mechanism with a transition state involving nucleophilic attack upon an ion-pair intermediate, and this is supported by good agreement between the mean values of the calculated and experimental α-D KIEs. However, the magnitudes of the standard deviations about the mean values for the making and breaking C–O bonds suggest that the transition state is rather plastic, with Cα–Onu ≈ 2 ± 0.4 Å and Cα–Olg ≈ 3 ± 0.5 Å. Not only is nucleophilic solvent assistance necessary, but there is also evidence for electrophilic assistance through specific hydrogen bonding to the nucleofuge.

AB - DFT calculations for the equilibrium isotope effect for deuterium substitution at the anomeric centre Cα in 2-(p-nitrophenoxy)tetrahydropyran with continuum solvation show significant variation in the range of relative permittivity 2 ≤ ε ≤ 10. One-dimensional scans of potential energy (with implicit solvation by water) or of free energy (from QM/MM potentials of mean force with explicit aqueous solvation with a hybrid AM1/OPLS method) for heterolysis of the bond between Cα and the nucleofuge do not show a transition state. A two-dimensional free-energy surface that considers also the distance between Cα and a nucleophilic water indicates a pre-association DN*ANint‡ mechanism with a transition state involving nucleophilic attack upon an ion-pair intermediate, and this is supported by good agreement between the mean values of the calculated and experimental α-D KIEs. However, the magnitudes of the standard deviations about the mean values for the making and breaking C–O bonds suggest that the transition state is rather plastic, with Cα–Onu ≈ 2 ± 0.4 Å and Cα–Olg ≈ 3 ± 0.5 Å. Not only is nucleophilic solvent assistance necessary, but there is also evidence for electrophilic assistance through specific hydrogen bonding to the nucleofuge.

U2 - 10.1515/pac-2019-0221

DO - 10.1515/pac-2019-0221

M3 - Article

JO - Pure and Applied Chemistry

JF - Pure and Applied Chemistry

SN - 0033-4545

ER -