A Simple Method To Determine Kinetic Deuterium Isotope Effects Provides Evidence that Proton Transfer to Carbon Proceeds over and Not through the Reaction Barrier

Tsang, Wing-Yin; Richard, John P.

doi:10.1021/ja073679g

Cited by 17 publications

(27 citation statements)

References 11 publications

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“…7 To demonstrate the applicability of our approach, the KP2 method is used to estimate the KIE (protium/deuterium) for the addition of a proton to a series of arylsubstituted (R) -methoxystyrenes from chloroacetic acid in water. 25 In this case, we quantized about 90 degrees of freedom in our computation (Fig. 1).…”

Section: Kinetic Isotope Effects (Kies) In Proton Transfer Reactionsmentioning

confidence: 99%

An automated integration-free path-integral method based on Kleinert’s variational perturbation theory

Wong

Gao

2007

The Journal of Chemical Physics

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Based on Kleinert's variational perturbation (KP) theory [Path Integrals in Quantum Mechanics, Statistics, Polymer Physics, and Financial Markets, 3rd ed. (World Scientific, Singapore, 2004)], we present an analytic path-integral approach for computing the effective centroid potential. The approach enables the KP theory to be applied to any realistic systems beyond the first-order perturbation (i.e., the original Feynman-Kleinert [Phys. Rev. A 34, 5080 (1986)] variational method). Accurate values are obtained for several systems in which exact quantum results are known. Furthermore, the computed kinetic isotope effects for a series of proton transfer reactions, in which the potential energy surfaces are evaluated by density-functional theory, are in good accordance with experiments. We hope that our method could be used by non-path-integral experts or experimentalists as a "black box" for any given system.

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Section: Kinetic Isotope Effects (Kies) In Proton Transfer Reactionsmentioning

confidence: 99%

An automated integration-free path-integral method based on Kleinert’s variational perturbation theory

Wong

Gao

2007

The Journal of Chemical Physics

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“…Recently Tsang and Richard reported a fast and general method for determining primary product (PIE) and kinetic isotope effects on proton transfer at carbon in hydroxylic solutions 7. That work has been extended to include a broader range of substituents both on the proton donor and on the vinyl ether proton acceptor X-1 6.…”

Section: Introductionmentioning

confidence: 99%

Theoretical Analysis of Kinetic Isotope Effects on Proton Transfer Reactions between Substituted α-Methoxystyrenes and Substituted Acetic Acids

2009

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Primary kinetic isotope effects (KIEs) on a series of carboxylic acid-catalyzed protonation reactions of aryl-substituted α-methoxystyrenes (X-1) to form oxocarbenium ions have been computed using the Kleinert variational second-order perturbation theory (KP2) in the framework of Feynman path integrals (PI) along with the potential energy surface obtained at the B3LYP/6-31+G(d,p) level. Good agreement with the experimental data was obtained, demonstrating that this novel computational approach for computing KIEs of organic reactions is a viable alternative to the traditional method employing Bigeleisen equation and harmonic vibrational frequencies. Although tunneling makes relative small contributions to the lowering of the free energy barriers for the carboxylic acid catalyzed protonation reaction, it is necessary to include tunneling contributions to obtain quantitative estimates of the KIEs. Consideration of anharmonicity can further improve the calculated KIEs for the protonation of substituted α-methoxystyrenes by chloroacetic acid, but for the reactions of the parent and 4-NO2 substituted α-methoxystyrene with substituted carboxylic acids, the correction of anharmonicity overestimates the computed KIEs for strong acid catalysts. In agreement with experimental findings, the largest KIEs are found in nearly ergoneutral reactions, ΔGo ≈ 0, where the transition structures are nearly symmetric and the reaction barriers are relatively low. Furthermore, the optimized transition structures are strongly dependent on the free energy for the formation of the carbocation intermediate, i.e., the driving force ΔGo, along with a good correlation of Hammond shift in the transition state structure.

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“…By contrast, a product isotope effect (PIE) determined in experiments in which H and D in a mixed solvent of H 2 O/D 2 O compete for reaction with enzyme-bound OMP to form UMP labeled at C-6 (Scheme 2) would provide insight into the changes in bonding at the transferred hydron that occur on proceeding to the transition state for the product-determining step. 10 PIEs are more precise and easier to interpret than SKIEs determined as the ratio of rate constants for reactions in H 2 O and D 2 O because (1) A significant primary product isotope effect is expected for a reaction in which there is moVement of the proton in the transition state for the product-determining step, 17a and there is no precedent for PIEs as small as 1.0 when carbanion protonation is the productdetermining step. 17a,18 The observed PIE of 1.0 requires that all of the zero-point energy present in the N-L + bonds of Lys-93 be maintained at the transition state for the step that determines whether the UMP product is labeled at C-6 with H or D. This PIE is not consistent with a mechanism in which proton transfer from Lys-93 to C-6 of OMP provides electrophilic push to the loss of CO 2 in a concerted reaction that avoids formation of an unstable vinyl carbanion intermediate (bottom pathway, Scheme 3).…”

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confidence: 99%

Product Deuterium Isotope Effect for Orotidine 5‘-Monophosphate Decarboxylase: Evidence for the Existence of a Short-Lived Carbanion Intermediate

et al. 2007

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We report that equal yields of [6-1 H]-uridine 5′-monophosphate (50%) and [6-2 H]-uridine 5′-monophosphate (50%) are obtained from the decarboxylation of orotidine 5′-monophosphate (OMP) catalyzed by orotidine 5′-monophosphate decarboxylase in a solvent of 50/50 (v/v) H 2 O/D 2 O. This observation of an unusually small product isotope effect of unity eliminates a proposed mechanism in which proton transfer from Lys-93 1 to C-6 provides electrophilic push to the loss of CO 2 from OMP in a concerted reaction. 2,3 It provides evidence that proton transfer from the ammonium cation side chain of Lys-93 to a vinyl carbanion intermediate is faster than the bond rotation that exchanges the positions of the acidic N-L + hydrons of this side chain.Orotidine 5′-monophosphate decarboxylase (OMPDC) is a remarkable enzyme because it employs no metal ions or other cofactors but yet effects an enormous 10 17 -fold acceleration of the chemically very difficult decarboxylation of OMP to give uridine 5′-monophosphate (UMP). 4,5 It has been shown that a large fraction of the enzymatic rate acceleration results directly from utilization of the intrinsic binding energy of the remote nonreacting 5′-phosphodianion group of OMP in transition state stabilization. 6 The decarboxylation reaction is often proposed to proceed in two steps through a vinyl carbanion intermediate (Scheme 1). However, it has also been suggested that this unstable intermediate might be avoided in a concerted reaction in which decarboxylation and proton transfer to C-6 occur in a single step. 2,3 Experimental and computational studies on OMPDC have focused largely on the partly rate-determining and highly unfavorable loss of CO 2 from OMP. [7][8][9] There are few data pertaining to the proton transfer to C-6 of the pyrimidine ring. Experimental characterization of this proton-transfer step is essential for insight into the existence and lifetime of the putative enzyme-bound vinyl carbanion intermediate.OMPDC catalyzes incorporation of a hydron from solvent into the UMP product and it has been reported that the decarboxylation of saturating OMP is 30% faster in H 2 O than in D 2 O. 7 While the origin of this solvent isotope effect on k cat is unclear, it may represent a secondary solvent kinetic isotope effect (SKIE). By contrast, a product isotope effect (PIE) determined in experiments in which H and D in a mixed solvent of H 2 O/D 2 O compete for reaction with enzyme-bound OMP to form UMP labeled at C-6 (Scheme 2) would provide insight into the changes in bonding at the transferred hydron that occur on proceeding to the transition state for the product-determining step. 10 PIEs are more precise and easier to interpret than SKIEs determined as the ratio of rate constants for reactions in H 2 O and D 2 O because (1) there are no complications from any secondary SKIE when the H-and D-labeled products are formed in the same mixed H 2 O/D 2 O solvent and (2) there are no errors due to differences in the conditions for separate reactions in H 2 O and D 2 O, such as enzy...

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A Simple Method To Determine Kinetic Deuterium Isotope Effects Provides Evidence that Proton Transfer to Carbon Proceeds over and Not through the Reaction Barrier

Cited by 17 publications

References 11 publications

An automated integration-free path-integral method based on Kleinert’s variational perturbation theory

An automated integration-free path-integral method based on Kleinert’s variational perturbation theory

Theoretical Analysis of Kinetic Isotope Effects on Proton Transfer Reactions between Substituted α-Methoxystyrenes and Substituted Acetic Acids

Product Deuterium Isotope Effect for Orotidine 5‘-Monophosphate Decarboxylase: Evidence for the Existence of a Short-Lived Carbanion Intermediate

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