Small Kinetic Isotope Effect Research Articles

Hydrogen Tunneling Exhibiting Unexpectedly Small Primary Kinetic Isotope Effects

Hydrogen Tunneling Exhibiting Unexpectedly Small Primary Kinetic Isotope Effects

Hydrogen Tunneling Exhibiting Unexpectedly Small Primary Kinetic Isotope Effects.

Probing quantum mechanical tunneling (QMT) in chemical reactions is crucial to understanding and developing new transformations. Primary H/D kinetic isotopic effects (KIEs) beyond the semiclassical maximum values of 7-10 (room temperature) are commonly used to assess substantial QMT contributions in one-step hydrogen transfer reactions, because of the much greater QMT probability of protium vs. deuterium. Nevertheless, we report here the discovery of a reaction model occurring exclusively by H-atom QMT with residual primary H/D KIEs. 2-Hydroxyphenylnitrene, generated in N2 matrix, was found to isomerize to an imino-ketone via sequential (domino) QMT involving anti to syn OH-rotamerization (rate determining step) and [1,4]-H shift reactions. These sequential QMT transformations were also observed in the OD-deuterated sample, and unexpected primary H/D KIEs between 3 and 4 were measured at 3 to 20 K. Analogous residual primary H/D KIEs were found in the anti to syn OH-rotamerization QMT of 2-cyanophenol in a N2 matrix. Evidence strongly indicates that these intriguing isotope-insensitive QMT reactivities arise due to the solvation effects of the N2 matrix medium, putatively through coupling with the moving H/D tunneling particle. Should a similar scenario be extrapolated to conventional solution conditions, then QMT may have been overlooked in many chemical reactions.

Carbon Atom Reactivity with Amorphous Solid Water: H2O-Catalyzed Formation of H2CO.

We report new computational and experimental evidence of an efficient and astrochemically relevant formation route to formaldehyde (H2CO). This simplest carbonylic compound is central to the formation of complex organics in cold interstellar clouds and is generally regarded to be formed by the hydrogenation of solid-state carbon monoxide. We demonstrate H2CO formation via the reaction of carbon atoms with amorphous solid water. Crucial to our proposed mechanism is a concerted proton transfer catalyzed by the water hydrogen bonding network. Consequently, the reactions 3C + H2O → 3HCOH and 1HCOH → 1H2CO can take place with low or without barriers, contrary to the high-barrier traditional internal hydrogen migration. These low barriers (or the absence thereof) explain the very small kinetic isotope effect in our experiments when comparing the formation of H2CO to D2CO. Our results reconcile the disagreement found in the literature on the reaction route C + H2O → H2CO.

Insertion products in the reaction of carbonyl oxide Criegee intermediates with acids: Chloro(hydroperoxy)methane formation from reaction of CH2OO with HCl and DCl

The reactions of carbonyl oxide Criegee intermediates with acids proceed predominantly by an insertion mechanism. We characterise the products from one of the simplest reactions of carbonyl oxides with inorganic acids, CH2OO + hydrogen chloride, which occurs via a 1,2-insertion in the H–Cl bond. Reactions of both HCl and DCl isotopologues yield product signal at the mass of the insertion product chloro(hydroperoxy)methane and a dissociative ionisation peak at the mass of the protonated (or deuteronated) Criegee intermediate. The isotopic composition of the insertion product has been measured for reaction mixtures where both HCl isotopologues are present, and the H/D ratio of the product is consistently higher (by a factor of 1.6 ± 0.3) than that of the reactants. This isotope selectivity in the products has smaller uncertainty than the ratio of measured rate coefficients and suggests a normal (k H > k D) kinetic isotope effect in the reaction. Theoretical kinetics calculations predict a small normal kinetic isotope effect for the overall reaction (k H / k D = 1.35 at 20 Torr N2 and k H / k D = 1.2 at 1 atm N2) but predict a substantial inverse kinetic isotope effect (k D > k H) for the stabilisation fraction, in disagreement with the experimental observation.

A meta-Selective C-H Alumination of Mono-Substituted Benzene by Using An Alkyl-Substituted Al Anion through Hydride-Eliminating SN Ar Reaction.

Reaction of an Al-centered anion with toluene proceeded to form C-H cleaved product with a perfect meta-selectivity and a relatively small kinetic isotope effect (KIE, kH /kD =1.51). DFT calculations suggested a two-step reaction mechanism and electronically controlled meta-selectivity arising from the electron-donating methyl group. The reaction with other mono-substituted arenes was also investigated.

A meta‐Selective C−H Alumination of Mono‐Substituted Benzene by Using An Alkyl‐Substituted Al Anion through Hydride‐Eliminating SNAr Reaction

AbstractReaction of an Al‐centered anion with toluene proceeded to form C−H cleaved product with a perfect meta‐selectivity and a relatively small kinetic isotope effect (KIE, kH/kD=1.51). DFT calculations suggested a two‐step reaction mechanism and electronically controlled meta‐selectivity arising from the electron‐donating methyl group. The reaction with other mono‐substituted arenes was also investigated.

Ageing mechanisms of nitroethylbenzenes

ABSTRACTSimulated ageing of 2,4-dinitro-1-ethylbenzene (DNEB) in DMSO in the presence of O2 in a closed system at 85–105°C gave benzylic oxidised products 1-(2,4-dinitrophenyl)ethanol (DNPE) and 2,4-dinitroacetophenone (DNAP), with the latter as the major product. Evidence for the formation of 3-methyl-6-nitro-2,1-benzoisoxazole (an ‘anthranil’), suggested in the literature as a likely decomposition product, is scant. A mechanism with initial H-abstraction to yield an electron-rich benzylic radical as the rate-limiting step is suggested, supported by a small kinetic isotope effect kH/kD ~2 and a reactivity in the order 2,4,6-trinitro-1-ethylbenzene TNEB > DNEB > 4-nitro-1-ethylbenzene (NEB). The activation energy for DNEB oxidation is 40 kJ mol−1, a value that translates to 1% oxidative decomposition of DNEB after ~ 14 d under an O2 atmosphere, or 70 d in air at ambient temperature.

Large Solvent Isotope Effect Associated with the Hydrolysis of Allylindium Iodide.

Allylindium halides are valuable allylating reagents, which can even be applied in aqueous solutions. Previous 1H NMR spectroscopic investigations suggested that these reagents are stable for several hours in D2O, whereas ESI-mass spectrometric experiments in H2O pointed to much shorter lifetimes. To resolve this seeming discrepancy, the present study systematically examines the solvolysis of allylindium iodide in H2O, D2O, and mixtures thereof by both analytical methods. Kinetic measurements find a large kinetic isotope effect (KIE = 12.0 ± 1.5 at 298 K), which fully explains the different behavior in H2O and D2O. Moreover, new intact and partially hydrolyzed allylindium intermediates are detected. Additional experiments on solutions of allylindium iodide in CH3OH, CH3OD, and EtOH observe ions identical or similar to those present in aqueous solutions, but determine a somewhat smaller kinetic isotope effect.

Earth-Abundant Mixed-Metal Catalysts for Hydrocarbon Oxygenation.

The oxygenation of aliphatic and aromatic hydrocarbons using earth-abundant Fe and Cu catalysts and "green" oxidants such as hydrogen peroxide is becoming increasingly important to atom-economical chemical processing. In light of this, we describe that dinuclear CuII complexes of pyrrolic Schiff-base macrocycles, in combination with ferric chloride (FeCl3), catalyze the oxygenation of π-activated benzylic substrates with hydroperoxide oxidants at room temperature and low loadings, representing a novel design in oxidation catalysis. Mass spectrometry and extended X-ray absorption fine structure analysis indicate that a cooperative action between CuII and FeIII occurs, most likely because of the interaction of FeCl3 or FeCl4- with the dinuclear CuII macrocycle. Voltammetric measurements highlight a modulation of both CuII and FeIII redox potentials in this adduct, but electron paramagnetic resonance spectroscopy indicates that any Cu-Fe intermetallic interaction is weak. High ketone/alcohol product ratios, a small reaction constant (Hammett analysis), and small kinetic isotope effect for H-atom abstraction point toward a free-radical reaction. However, the lack of reactivity with cyclohexane, oxidation of 9,10-dihydroanthracene, oxygenation by the hydroperoxide MPPH (radical mechanistic probe), and oxygenation in dinitrogen-purge experiments indicate a metal-based reaction. Through detailed reaction monitoring and associated kinetic modeling, a network of oxidation pathways is proposed that includes "well-disguised" radical chemistry via the formation of metal-associated radical intermediates.

Concerted One-Electron Two-Proton Transfer Processes in Models Inspired by the Tyr-His Couple of Photosystem II.

Nature employs a TyrZ-His pair as a redox relay that couples proton transfer to the redox process between P680 and the water oxidizing catalyst in photosystem II. Artificial redox relays composed of different benzimidazole–phenol dyads (benzimidazole models His and phenol models Tyr) with substituents designed to simulate the hydrogen bond network surrounding the TyrZ-His pair have been prepared. When the benzimidazole substituents are strong proton acceptors such as primary or tertiary amines, theory predicts that a concerted two proton transfer process associated with the electrochemical oxidation of the phenol will take place. Also, theory predicts a decrease in the redox potential of the phenol by ∼300 mV and a small kinetic isotope effect (KIE). Indeed, electrochemical, spectroelectrochemical, and KIE experimental data are consistent with these predictions. Notably, these results were obtained by using theory to guide the rational design of artificial systems and have implications for managing proton activity to optimize efficiency at energy conversion sites involving water oxidation and reduction.

Prehydrated One-Electron Attachment to Azido-Modified Pentofuranoses: Aminyl Radical Formation, Rapid H-Atom Transfer, and Subsequent Ring Opening.

Methyl 2-azido-2-deoxy-α-d-lyxofuranoside (1a) and methyl 2-azido-2-deoxy-β-d-ribofuranoside (2) were prepared from d-xylose or d-arabinose, respectively. Employing ESR and DFT/B3LYP/6-31G* calculations, we investigated (i) aminyl radical (RNH·) formation and (ii) reaction pathways of RNH·. Prehydrated electron attachment to 1a and 2 at 77 K produced transient azide anion radical (RN3·-) which reacts via rapid N2 loss at 77 K, forming nitrene anion radical (RN·-). Rapid protonation of RN·- at 77 K formed RNH· and -OH. 15N-labeled-1a confirmed this mechanism. Investigations employing in-house synthesized site-specifically deuterated derivatives of 1a (e.g., CH3 (1b), C4 (1c), and C5 (1d)) established that (a) a facile intramolecular H atom transfer from C5 to RNH· generated C5· and RNH2. C5· formation had a small deuterium kinetic isotope effect suggesting that this reaction does not occur via direct H atom abstraction. (b) Subsequently, C5· underwent a facile unimolecular conversion to ring-opened C4·. Identification of ring-opened C4· intermediate confirms the mechanism of C5'· mediated unaltered base release associated with DNA-strand break. However, for 2, ESR studies established thermally activated intermolecular H atom abstraction by RNH· from the methyl group at C1. Thus, sugar ring configuration strongly influences the site and pathway of RNH· mediated reactions in pentofuranoses.

Hydrogenation and Deuteration of C2H2 and C2H4 on Cold Grains: A Clue to the Formation Mechanism of C2H6 with Astronomical Interest

Abstract We quantitatively investigated the hydrogen addition reactions of acetylene (C2H2) and ethylene (C2H4) on amorphous solid water (ASW) at 10 and 20 K relevant to the formation of ethane (C2H6) on interstellar icy grains. We found that the ASW surface enhances the reaction rates for C2H2 and C2H4 by approximately a factor of 2 compared to those on the pure-solid C2H2 and C2H4 at 10 K, probably due to an increase in the sticking coefficient and adsorption energy of the H atoms on ASW. In contrast to the previous proposal that the hydrogenation rate of C2H4 is orders of magnitude larger than that of C2H2, the present results show that the difference in hydrogenation rates of C2H2 and C2H4 is only within a factor of 3 on both the surfaces of pure solids and ASW. In addition, we found the small kinetic isotope effect for hydrogenation/deuteration of C2H2 and C2H4 at 10 K, despite the requirement of quantum tunneling. At 20 K, the reaction rate of deuteration becomes even larger than that of hydrogenation. These unusual isotope effects might originate from a slightly larger number density of D atoms than H atoms on ASW at 20 K. The hydrogenation of C2H2 is four times faster than CO hydrogenation and can produce C2H6 efficiently through C2H4 even in the environment of a dark molecular cloud.

Dynamical barrier and isotope effects in the simplest substitution reaction via Walden inversion mechanism

Reactions occurring at a carbon atom through the Walden inversion mechanism are one of the most important and useful classes of reactions in chemistry. Here we report an accurate theoretical study of the simplest reaction of that type: the H+CH4 substitution reaction and its isotope analogues. It is found that the reaction threshold versus collision energy is considerably higher than the barrier height. The reaction exhibits a strong normal secondary isotope effect on the cross-sections measured above the reaction threshold, and a small but reverse secondary kinetic isotope effect at room temperature. Detailed analysis reveals that the reaction proceeds along a path with a higher barrier height instead of the minimum-energy path because the umbrella angle of the non-reacting methyl group cannot change synchronously with the other reaction coordinates during the reaction due to insufficient energy transfer from the translational motion to the umbrella mode.

Ultrafast Dissociation Dynamics of 2-Ethylpyrrole.

To explore the effects of ring substitution on dissociation dynamics, the primary photochemistry of 2-ethylpyrrole was explored using ultrafast ion imaging techniques. Photoexcitation to the S1 state, a πσ* state, in the range from 238 to 265 nm results in cleavage of the N-H bond with an H atom appearance lifetime of ca. 70 fs. The insensitivity of this lifetime to photon energy, combined with a small kinetic isotope effect, suggests that tunneling does not play a major role in N-H bond cleavage. Total kinetic energy release spectra reveal modest vibrational excitation in the radical counter-fragment, increasing with photon energy. At wavelengths less than or equal to 248 nm, an additional low kinetic energy H atom loss mechanism becomes available with an appearance lifetime of ∼1.5 ps, possibly due to the population of higher-lying 1ππ* states.

Kinetic Isotope Effects as a Probe for the Protonolysis Mechanism of Alkylmetal Complexes: VTST/MT Calculations Based on DFT Potential Energy Surfaces

Protonolysis by platinum or palladium complexes has been extensively studied because it is the microscopic reverse of the C-H bond activation reaction. The protonolysis of (COD)PtIIMe2, which exhibits abnormally large kinetic isotope effects (KIEs), is proposed to occur via a concerted pathway (SE2 mechanism) with large tunneling. However, further investigation of KIEs for the protonolysis of ZnMe2 and others led to a conclusion that there is no noticeable correlation between the mechanism and magnitude of KIE. In this study, we demonstrated that variational transition state theory including multidimensional tunneling (VTST/MT) could accurately predict KIEs and Arrhenius parameters of the protonolysis of alkylmetal complexes based on the potential energy surfaces generated by density functional theory. The predicted KIEs, EaD - EaH values, and AH/AD ratios for the protonolysis of (COD)PtIIMe2 and ZnIIMe2 by TFA agreed very well with experimental values. The protonolysis of ZnMe2 with the concerted pathway has a very flat potential energy surface, which produces a very small tunneling effect and therefore a small KIE. The predicted KIE for the stepwise protonolysis (SE(ox) mechanism) of (COD)PtIIMe2 was much smaller than that of the concerted pathway, but greater than the KIE of the concerted protonolysis of ZnMe2. A large KIE, which entails a significant tunneling effect, could be used as an experimental probe of the concerted pathway. However, a normal or small KIE should not be used as an indicator of the stepwise mechanism, and the interplay between experiments and reliable theory including tunneling would be essential to uncover the mechanism correctly.

Long-range electron transfer triggers mechanistic differences between iron(IV)-oxo and iron(IV)-imido oxidants.

Nature often utilizes molecular oxygen for oxidation reactions through monoxygenases and dioxygenases. In many of these systems, a high-valent iron(IV)-oxo active species is found. In recent years, evidence has accumulated of possible iron(IV)-imido and iron(V)-nitrido intermediates in enzymatic catalysis, although little is known about their activity. In this work, we report a detailed combined kinetics and computational study on the difference in reactivity and chemical properties of nonheme iron(IV)-oxo compared with iron(IV)-tosylimido. We show here that iron(IV)-tosylimido complex is much more reactive with sulfides than the corresponding iron(IV)-oxo complex; however, the reverse trend is obtained for hydrogen atom abstraction reactions. The latter proceed with a relatively small kinetic isotope effect of kH/kD = 7 for the iron(IV)-tosylimido complex. Moreover, a Hammett analysis of hydrogen atom abstraction from para-X-benzyl alcohol reveals a slope of close to zero for the iron(IV)-oxo, whereas a strong negative slope is found for the iron(IV)-tosylimido complex. These studies implicate dramatic changes in the reaction mechanisms and suggest a considerable charge transfer in the transition states. Density functional theory calculations were performed to support the experiments and confirm an initial long-range electron transfer for the iron(IV)-tosylimido complex with substrates, due to a substantially larger electron affinity compared with the iron(IV)-oxo species. As a consequence, it also reacts more efficiently in electrophilic addition reactions such as those with sulfides. By contrast, the long-range electron transfer for the iron(IV)-tosylimido complex results in a rate constant that is dependent on the π*xz → σ*z(2) excitation energy, which raises the hydrogen atom abstraction barrier above that found for the iron(IV)-oxo. On the other hand, sulfimidation has much earlier electron transfer steps with respect to sulfoxidation. All data has been analyzed and rationalized with valence bond models and thermochemical cycles. Our studies highlight the catalytic potential of iron(IV)-tosylimido complexes in chemistry and biology.

Alcohol-assisted base-free hydrogenation of acetophenone catalyzed by OsH(NHCMe2CMe2NH2)(PPh3)2

The hydrido–amido complex OsH(NHCMe2CMe2NH2)(PPh3)2 (1) catalyzes the base-free hydrogenation of ketones in benzene. Kinetic studies using acetophenone revealed that the system has an induction period, after which the rate of the reaction increases. A constant rate was observed when a critical amount of the product alcohol was added, indicating that the reaction is autocatalytic in 1-phenylethanol. Varying the initial conditions showed that the reaction rate is dependent on hydrogen and catalyst concentration and independent of ketone concentration. Above the critical concentrations of 1-phenylethanol, the reaction rate is independent of alcohol concentration. The rate law for pressures up to 5 atm was found to be rate = d[alcohol]/dt = −d[ketone]/dt = k[Os][H2], with k = 30 mol L−1 s−1 at 293 K and the temperature dependence provided energy of activation parameters. Therefore, the heterolytic splitting of dihydrogen is rate determining under these conditions. Only small kinetic isotope effects were measured in contrast with the analogous ruthenium system. Complex 1 reacts with the product alcohol 1-phenylethanol and is partially converted into the dihydride complex trans-OsH2(NH2CMe2CMe2NH2)(PPh3)2 and acetophenone; with excess alcohol, an osmium alkoxide is observed at low temperature. As expected from these results, 1 is a ketone transfer hydrogenation catalyst in isopropanol.

Substrate‐Dependent H/D Kinetic Isotope Effects and the Role of the Di(μ‐oxo)diiron(IV) Core in Soluble Methane Monooxygenase: A Theoretical Study

Soluble methane monooxygenase (sMMO) is an enzyme that converts alkanes to alcohols using a di(μ-oxo)diiron(IV) intermediate Q at the active site. Very large kinetic isotope effects (KIEs) indicative of significant tunneling are observed for the hydrogen transfer (H-transfer) of CH4 and CH3 CN; however, a relatively small KIE is observed for CH3NO2. The detailed mechanism of the enzymatic H-transfer responsible for the diverse range of KIEs is not yet fully understood. In this study, variational transition-state theory including the multidimensional tunneling approximation is used to calculate rate constants to predict KIEs based on the quantum-mechanically generated intrinsic reaction coordinates of the H-transfer by the di(μ-oxo)diiron(IV) complex. The results of our study reveal that the role of the di(μ-oxo)diiron(IV) core and the H-transfer mechanism are dependent on the substrate. For CH4 , substrate binding induces an electron transfer from the oxygen to one Fe(IV) center, which in turn makes the μ-O ligand more electrophilic and assists the H-transfer by abstracting an electron from the C-H σ orbital. For CH3CN, the reduction of Fe(IV) to Fe(III) occurs gradually with substrate binding and H-transfer. The charge density and electrophilicity of the μ-O ligand hardly change upon substrate binding; however, for CH3NO2, there seems to be no electron movement from μ-O to Fe(IV) during the H-transfer. Thus, the μ-O ligand appears to abstract a proton without an electron from the C-H σ orbital. The calculated KIEs for CH4, CH3CN, and CH3NO2 are 24.4, 49.0, and 8.27, respectively, at 293 K, in remarkably good agreement with the experimental values. This study reveals that diverse KIE values originate mainly from tunneling to the same di(μ-oxo)diiron(IV) core for all substrates, and demonstrate that the reaction dynamics are essential for reproducing experimental results and understanding the role of the diiron core for methane oxidation in sMMO.

Pb(II)-Promoted Amide Cleavage: Mechanistic Comparison to a Zn(II) Analogue

Two new Pb(II) complexes of the amide-appended nitrogen/sulfur epppa (N-((2-ethylthio)ethyl)-N-((6-pivaloylamido-2-pyridyl)methyl)-N-((2-pyridyl)methyl)amine) chelate ligand, [(epppa)Pb(NO3)2] (4-NO3) and [(epppa)Pb(ClO4)2] (4-ClO4), were prepared and characterized. In the solid state, 4-NO3 exhibits κ(5)-epppa chelate ligand coordination as well as the coordination of two bidentate nitrate ions. In acetonitrile, 4-NO3 is a 1:1 electrolyte with a coordinated NO3(-), whereas 4-ClO4 is a 1:2 electrolyte. Treatment of 4-ClO4 with 1 equiv Me4NOH·5H2O in CH3CN:CH3OH (3:5) results in amide methanolysis in a reaction that is akin to that previously reported for the Zn(II) analogue [(epppa)Zn](ClO4)2 (3-ClO4). (1)H NMR kinetic studies of the amide methanolysis reactions of 4-ClO4 and 3-ClO4 as a function of temperature revealed free energies of activation of 21.3 and 24.5 kcal/mol, respectively. The amide methanolysis reactions of 4-ClO4 and 3-ClO4 differ in terms of the effect of the concentration of methanol (saturation kinetics for 4-ClO4; second-order behavior for 3-ClO4), the observation of a small solvent kinetic isotope effect (SKIE) only for the reaction of the Zn(II)-containing 3-ClO4, and the properties of an initial intermediate isolated from each reaction upon treatment with Me4NOH·5H2O. These experimental results, combined with computational studies of the amide methanolysis reaction pathways of 4-ClO4 and 3-ClO4, indicate that the Zn(II)-containing 3-ClO4 initially undergoes amide deprotonation upon treatment with Me4NOH·5H2O. Subsequent amide protonation from coordinated methanol yields a structure containing a coordinated neutral amide and methoxide anion from which amide cleavage can then proceed. The rate-determining step in this pathway is either amide protonation or protonation of the leaving group. The Pb(II)-containing 4-ClO4 instead directly forms a neutral amide-containing, epppa-ligated Pb(II)-OH/Pb(II)-OCH3 equilibrium mixture upon treatment with Me4NOH·5H2O in methanol. The rate-determining step in the amide methanolysis pathway of 4-ClO4 is nucleophilic attack of the Pb(II)-OCH3 moiety on the coordinated amide. Overall, it is the larger size of the Pb(II) center and the availability of coordination positions that enable direct formation of a Pb(II)-OH/Pb(II)-OCH3 mixture versus the initial amide deprotonation identified in the reaction of the Zn(II)-containing 3-ClO4.

Advances in Kinetic Isotope Effect Measurement Techniques for Enzyme Mechanism Study

Kinetic isotope effects (KIEs) are a very powerful tool for investigating enzyme mechanisms. Precision of measurement is the most important factor for KIE determinations, especially for small heavy atom KIEs. Internal competition is commonly used to measure small KIEs on V/K. Several methods, including such as liquid scintillation counting, mass spectrometry, nuclear magnetic resonance spectroscopy and polarimetry have been used to determine KIEs. In this paper, which does not aspire to be an exhaustive review, we briefly review different experimental approaches for the measurement of KIEs on enzymatic reaction with an emphasis on newer techniques employing mass spectrometry and nuclear magnetic resonance spectrometry as well as some corresponding examples.