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
Pages (from-to)75-84
JournalPure and Applied Chemistry
Volume92
Issue number1
Early online date29 Jul 2019
DOIs
Publication statusPublished - 1 Jan 2020

Cite this

Computational simulation of mechanism and isotope effects on acetal heterolysis as a model for glycoside hydrolysis. / Williams, Ian; Glancy, John H.; Lee, Daniel M.; Read, Emily O.

In: Pure and Applied Chemistry, Vol. 92, No. 1, 01.01.2020, p. 75-84.

Research output: Contribution to journalArticle

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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.",
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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.

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