Primary Kinetic Isotope Effect Research Articles

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. A 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.

Cobalt(II)-Catalyzed Synthesis of γ-Diketones from Aryl Alkenes and Its Utilization in the Synthesis of Various Heterocyclic Compounds.

An earth-abundant Co(II) salt-catalyzed mild and affordable synthetic route has been developed for the synthesis of industrially relevant 1,4-dicarbonyl compounds (or γ-diketones) via oxidative coupling between aryl alkenes and ketones (both cyclic and acyclic) using TBHP and DBU as the oxidant and base, respectively. 1,4-Dicarbonyl compounds are known to be synthesized using expensive metal catalysts, dual catalysts, or low-cost metal complexes combined with an additive or ligand template, which further needs to be synthesized. Herein, we report the synthesis of 1,4-dicarbonyl compounds using cobalt(II) acetate as a catalyst without any expensive co-catalyst or ligand templates. This methodology has a broad substrate scope with significant yields and good functional group tolerance. Generation of unsymmetrical 1,4-dicarbonyls at room temperature and its versatile synthetic expansion to produce synthetically and biologically valuable heterocyclic compounds are salient features of this novel methodology. In addition, various controlled experiments such as primary kinetic isotope effect study, Hammett analysis with variation of the nature of the substituents on the styrene ring, and theoretical calculations (density functional theory) unravel the mechanistic intricacies involved in this new, simple, and atom-economic methodology.

Intramolecular carbon isotopic rollover in propane from natural gas reservoirs of the Santanghu Basin: Insights into chemical structure of kerogen

An intramolecular isotopic study was conducted on natural gases from the Santanghu Basin in China. Propane samples spanned a wide range of ΔC-T (δ13Ccentral-δ13Cterminal) values from –8.4 to 8.5 ‰, δ13Ccentral and δ13Cterminal values varied from –37.3 to –25.8 ‰ and –35.7 to –28.9 ‰, respectively. During thermal maturation, the position-specific carbon isotopic composition of propane shifted from δ13Ccentral < δ13Cterminal to δ13Ccentral > δ13Cterminal, and the δ13Cterminal decreased by 6.8 ‰ within a Ro range of 0.46–0.50 %. The intramolecular carbon isotopic rollover and a decrease in δ13Cterminal with a slight increase in maturation could be explained by kinetic effects in thermal cracking of kerogen with a low proportion of branched chains. As isomeric groups were rapidly exhausted, propane generation pathway rapidly changed and primary kinetic isotope effect completely shifted from central carbon position to terminal carbon positions in propane. These changes increased carbon isotope fractionation at terminal carbon positions, thereby reducing δ13Cterminal values and shifting δ13Ccentral < δ13Cterminal to δ13Ccentral > δ13Cterminal within a small maturity range. This work demonstrated that position-specific isotope distribution of propane can be applied to elucidate the chemical structure of kerogen.

Superior electrocatalytic hydrogen evolution activity of a triply bridged diruthenium(II) complex on a carbon cloth support.

This article describes the structural authentication of a unique triply bridged [1](ClO4)2 and monomeric [2]ClO4/[3]ClO4. Electrochemical HER on a carbon cloth support demonstrated the superior performance of [1](ClO4)2 with high TON (>105) and its long-term stability. The primary kinetic isotope effect of [1](ClO4)2 revealed the involvement of PCET in the rate-determining step.

Effect of α-Substitution on the Reactivity of C(sp3)-H Bonds in Pd0-Catalyzed C-H Arylation.

We report mechanistic studies on the reactivity of different α-substituted C(sp3)-H bonds, -CHnR (R = H, Me, CO2Me, CONMe2, OMe, and Ph, as well as the cyclopropyl and isopropyl derivatives -CH(CH2)2 and -CHMe2) in the context of Pd0-catalyzed C(sp3)-H arylation. Primary kinetic isotope effects, kH/kD, were determined experimentally for R = H (3.2) and Me (3.5), and these, along with the determination of reaction orders and computational studies, indicate rate-limiting C-H activation for all substituents except when R = CO2Me. This last result was confirmed experimentally (kH/kD ∼ 1). A reactivity scale for C(sp3)-H activation was then determined: CH2CO2Me > CH(CH2)2 ≥ CH2CONMe2 > CH3 ≫ CH2Ph > CH2Me > CH2OMe ≫ CHMe2. C-H activation involves AMLA/CMD transition states featuring intramolecular O → H-C H-bonding assisted by C-H → Pd agostic bonding. The "AMLA coefficient", χ, is introduced to quantify the energies associated with these interactions via natural bond orbital 2nd order perturbation theory analysis. Higher barriers correlate with lower χ values, which in turn signal a greater agostic interaction in the transition state. We believe that this reactivity scale and the underlying factors that determine this will be of use for future studies in transition-metal-catalyzed C(sp3)-H activation proceeding via the AMLA/CMD mechanism.

Synthesis of the 3,3'-(Ethane-1,2-diylidene)bis(indolin-2-one) Unit Promoted by Thermally-activated Electron Transfer andPhotoreduction of CO2 to CH4and CO.

A Sonogashira coupling reaction leads to the formation of a serendipitous product C with the 3,3'-(ethane-1,2-diylidene)bis(indolin-2-one) unit. To our knowledge, our study provides the first example demonstrating that electron transfer between isoindigo and triethylamine can be thermally activated and be employed in synthesis. The physical properties of C suggest that C possesses decent photo-induced electron-transfer capabilities. Under the illumination of 136 mW cm-2 intensity, C furnishes ~2.4 mmol gcat-1 (per gram of catalyst) of CH4 and ~0.5 mmol gcat-1 of CO in 20 hours in the absence of additional metal, co-catalyst, and amine sacrificial agent. The primary kinetic isotope effect suggests that the bond cleavage of water is a rate-determining step in the reduction. Moreover, the CH4 and CO production can be boosted as the illuminance increases. This study demonstrates that organic donor-acceptor conjugated molecules are potential photocatalysts for CO2 reduction.

Estimation of frequency factors for the calculation of kinetic isotope effects from classical and path integral free energy simulations.

We use the modified Bigeleisen-Mayer equation to compute kinetic isotope effect values for non-enzymatic phosphoryl transfer reactions from classical and path integral molecular dynamics umbrella sampling. The modified form of the Bigeleisen-Mayer equation consists of a ratio of imaginary mode vibrational frequencies and a contribution arising from the isotopic substitution's effect on the activation free energy, which can be computed from path integral simulation. In the present study, we describe a practical method for estimating the frequency ratio correction directly from umbrella sampling in a manner that does not require normal mode analysis of many geometry optimized structures. Instead, the method relates the frequency ratio to the change in the mass weighted coordinate representation of the minimum free energy path at the transition state induced by isotopic substitution. The method is applied to the calculation of 16/18O and 32/34S primary kinetic isotope effect values for six non-enzymatic phosphoryl transfer reactions. We demonstrate that the results are consistent with the analysis of geometry optimized transition state ensembles using the traditional Bigeleisen-Mayer equation. The method thus presents a new practical tool to enable facile calculation of kinetic isotope effect values for complex chemical reactions in the condensed phase.

Kinetic isotope effect and reaction pathways of thermogenic propane generation at early maturation stage: Insights from position-specific carbon isotope distribution

An intramolecular isotopic study was conducted on natural gases from the Turpan-Hami Basin of China. The set of natural gases exhibits larger δ13C values of the terminal position compared with those at the central position of propane, with ΔC-T (δ13Ccentral-δ13Cterminal) values ranging from −3.8‰ to −0.7‰. During the thermal cracking of kerogen, the primary kinetic isotope effect is on the terminal carbon position to generate n-propyl radicals and on the central carbon position to produce i-propyl radicals. Therefore, distinct reaction pathways significantly influence the position-specific carbon isotope distribution in thermogenic propane. In the early stage of maturation, propane is preferentially generated from the i-propyl radicals by capturing hydrogen atoms owing to the lower dissociation energies of i-propyl radicals cleavage from kerogen compared with those of n-propyl radicals, resulting in larger δ13C values in the terminal position compared with those at the central position of generated propane. The position-specific 13C isotope composition of propane could provide new insights into revealing the generation mechanism of natural gas in the geological period at the atomic level.

Structure-reactivity relation in the oxidation of some aliphatic aldehydes by Tripropylammonium chlorochromate

The oxidation of six aliphatic aldehydes by tripropylammonium chlorochromate (TPACC) in dimethyl sulfoxide (DMSO) leads to the formation of corresponding carboxylic acids. The reaction is of first order each in TPACC. A Michaelis-Menten type of kinetics is observed with respect to the aldehydes. The reaction is catalysed by hydrogen ions. The hydrogen-ion dependence has the form: kobs = a + b[H+]. The oxidation of deuteriated acetaldehyde MeCDO exhibited a substantial primary kinetic isotope effect (kH/kD = 5.75 at 298 K). The oxidation of acetaldehyde has been studied in nineteen different organic solvents. The solvent effect has been analysed using Taft's and Swain's multiparametric equations. The rate constants correlate well with Taft’s * values, reaction constants being negative. A mechanism involving transfer of hydride ion has been suggested.

Dissociative Transition State in Hepatitis Delta Virus Ribozyme Catalysis.

Ribonucleases and small nucleolytic ribozymes are both able to catalyze RNA strand cleavage through 2'-O-transphosphorylation, provoking the question of whether protein and RNA enzymes facilitate mechanisms that pass through the same or distinct transition states. Here, we report the primary and secondary 18O kinetic isotope effects for hepatitis delta virus ribozyme catalysis that reveal a dissociative, metaphosphate-like transition state in stark contrast to the late, associative transition states observed for reactions catalyzed by specific base, Zn2+ ions, or ribonuclease A. This new information provides evidence for a discrete ribozyme active site design that modulates the RNA cleavage pathway to pass through an altered transition state.

Measurement of kinetic isotope effects on peptide hydroxylation using MALDI-MS.

Primary kinetic isotope effects (KIEs) provide unique insight into enzymatic reactions, as they can reveal rate-limiting steps and detailed chemical mechanisms. HIF hydroxylases, part of a family of 2-oxoglutarate (2OG) oxygenases are central to the regulation of many crucial biological processes through O2-sensing, but present a challenge to monitor due to the large size of the protein substrate and the similarity between native and hydroxylated substrate. MALDI-TOF MS is a convenient tool to measure peptide masses, which can also be used to measure the discontinuous kinetics of peptide hydroxylation for Factor Inhibiting HIF (FIH). Using this technique, rate data can be observed from the mole-fraction of CTAD and CTAD-OH in small volumes, allowing noncompetitive H/D KIEs to be measured. Slow dCTAD substrate leads to extensive uncoupling of O2 consumption from peptide hydroxylation, leading to enzyme autohydroxylation, which is observed using UV-vis spectroscopy. Simultaneously measuring both the normal product, CTAD-OH, and the uncoupled product, autohydroxylated enzyme, the KIE on the microscopic step of hydrogen atom transfer (HAT) can be estimated. MALDI-MS analysis is a strong method for monitoring reactions that hydroxylate peptides, and can be generalized to other similar reactions, and simultaneous kinetic detection of branched products can provide valuable insight on microscopic KIEs at intermediate mechanistic steps.

Employing deuterium kinetic isotope effects to uncover the mechanism of (R)-3-hydroxybutyrate dehydrogenase.

Short-chain dehydrogenases/reductases (SDR) form a large enzyme superfamily playing important roles in health and disease. Furthermore, they are useful tools in biocatalysis. Unveiling the nature of the transition state for hydride transfer is a crucial undertaking toward defining the physicochemical underpinnings of catalysis by SDR enzymes, including possible contributions from quantum mechanical tunneling. Primary deuterium kinetic isotope effects can uncover the contribution from chemistry to the rate-limiting step and potentially provide detailed information on the hydride-transfer transition state in SDR-catalyzed reactions. For the latter, however, one needs to determine the intrinsic isotope effect: that which would be measured if hydride transfer were rate determining. Alas, as is the case for many other enzymatic reactions, those catalyzed by SDRs are often limited by the rate of isotope-insensitive steps, such as product release and conformational changes, which masks the expression of the intrinsic isotope effect. This can be overcome by the powerful yet underexplored method of Palfey and Fagan via which intrinsic kinetic isotope effects can be extracted from pre-steady-state kinetics data. SDRs are ideal systems to which this method can be applied. We have employed this approach to elucidate the transition states for hydride transfer catalyzed by NADH-dependent cold- and warm-adapted (R)-3-hydroxybutyrate dehydrogenase. Experimental conditions which simplify the analysis are discussed.

Pathways in permanganate oxidation of mandelic acid: reactivity and selectivity of intermediate manganese species.

We report a comprehensive kinetic and product study of the oxidation of mandelic acid (MA) by permanganate in the pH range of 1-13, including a full account of total oxidizing equivalents (five and three-electron change in acidic and basic media, respectively). In the entire pH range, the reaction shows a primary kinetic deuterium isotope effect (kH/kD ≥8-9), indicating rate-limiting hydride transfer. The deuterium label in α-deutero-mandelic acid is retained in benzaldehyde. Benzaldehyde (BZ) is formed in post-rate limiting steps due to reactions involving manganese intermediates. In alkaline pH (≥13), in the presence of barium acetate, Mn(VI) is removed as insoluble blue barium manganate; the stoichiometry of the first step of reduction was found to be: MA + 2Mn(VII) → PGA + 2Mn(VI). Manganate, MnO42-, is directly reduced to MnO2 giving an additional mole of phenylglyoxylic acid (PGA). The experimentally observed ratio of benzaldehyde to phenylglyoxylic (BZ/PGA) provides a basis for discrimination between mechanistic choices that include direct reduction of Mn(V) to Mn(III) (in an acidic medium), disproportionation to Mn(IV) and Mn(VI) or oxidation to Mn(VI) by a second mole of permanganate. Interestingly, at pH 4, a stoichiometric, soluble Mn(IV) is observed for the first time for hydroxy-acid oxidation, reminiscent of the Guyard reaction. Because of the widespread use of permanganate as an environmentally green oxidant, results from mandelic acid oxidation have implications for the remediation of dissolved organic matter (DOM) including hydrocarbons and nitroaromatics in waste and groundwater.

Organocatalytic Enantioselective Pictet-Spengler Reaction of α-Ketoesters: Development and Application to the Total Synthesis of (+)-Alstratine A.

We report herein an asymmetric Pictet-Spengler reaction of α-ketoesters. In the presence of a catalytic amount of simple alanine-derived squaramide and p-nitrobenzoic acid, reaction of tryptamines with methyl 2-oxoalkanoates afforded the corresponding 1-alkyl-1-methoxycarbonyl tetrahydro-β-carbolines (THBCs) in high yields and ee values. A primary kinetic isotope effect (KIE=4.5) using C2-deteurium-labelled tryptamine indicates that rearomatization through deprotonation of the pentahydro-β-carbolinium ion could be the rate- and enantioselectivity-determining step. A concise enantioselective total synthesis of (+)-alstratine A, a hexacyclic cagelike monoterpene indole alkaloid, featuring this reaction as a key step, was subsequently accomplished. Remeasurement of the [a]D value of the natural product indicates that natural alstratine A is dextrorotatory rather than levorotatory as it was initially reported in the isolation paper.

Organocatalytic Enantioselective Pictet–Spengler Reaction of α‐Ketoesters: Development and Application to the Total Synthesis of (+)‐Alstratine A

AbstractWe report herein an asymmetric Pictet–Spengler reaction of α‐ketoesters. In the presence of a catalytic amount of simple alanine‐derived squaramide and p‐nitrobenzoic acid, reaction of tryptamines with methyl 2‐oxoalkanoates afforded the corresponding 1‐alkyl‐1‐methoxycarbonyl tetrahydro‐β‐carbolines (THBCs) in high yields and ee values. A primary kinetic isotope effect (KIE=4.5) using C2‐deteurium‐labelled tryptamine indicates that rearomatization through deprotonation of the pentahydro‐β‐carbolinium ion could be the rate‐ and enantioselectivity‐determining step. A concise enantioselective total synthesis of (+)‐alstratine A, a hexacyclic cagelike monoterpene indole alkaloid, featuring this reaction as a key step, was subsequently accomplished. Remeasurement of the [a]D value of the natural product indicates that natural alstratine A is dextrorotatory rather than levorotatory as it was initially reported in the isolation paper.

A Common Active Intermediate in the Oxidation of Alkenes, Alcohols and Alkanes with H2O2 and a Mn(II)/Pyridin-2-Carboxylato Catalyst.

The mechanism and the reactive species involved in the oxidation of alkenes, and alcohols with H2O2, catalysed by an in situ prepared mixture of a MnII salt, pyridine-2-carboxylic acid and a ketone is elucidated using substrate competition experiments, kinetic isotope effect (KIE) measurements, and atom tracking with 18O labelling. The data indicate that a single reactive species engages in the oxidation of both alkenes and alcohols. The primary KIE in the oxidation of benzyl alcohols is ca. 3.5 and shows the reactive species to be selective despite a zero order dependence on substrate concentration, and the high turnover frequencies (up to 30 s-1) observed. Selective 18O labelling identifies the origin of the oxygen atoms transferred to the substrate during oxidation, and is consistent with a highly reactive, e. g., [MnV(O)(OH)] or [MnV(O)2], species rather than an alkylperoxy or hydroperoxy species.

Fast Au-Ni@ZIF-8-catalyzed ammonia borane hydrolysis boosted by dramatic volcano-type synergy and plasmonic acceleration

Production of hydrogen (H2) from H2 storage materials is very attractive as a source of sustainable energy. We report that AuNi@ZIF-8 alloys are very efficient nanocatalysts for H2 evolution upon ammonia borane hydrolysis under visible-light illumination with turnover frequency 3.4 times higher than with the monometallic Ni catalyst in the dark. This improvement is attributed to dramatic volcano-type positive synergy optimized in Au0.5Ni0.5 @ZIF-8, for which ZIF-8 is by far the superior support, as well as to the localized surface plasmon resonance induced between 450 and 620 nm. Infrared spectra analysis and tandem reaction confirm the origin of the hydrogen atoms, reveal the reaction mechanism, and suggest how the cleavage of the B–H and O–H bonds proceeds in this reaction. Deuteration experiments with D2O including primary kinetic isotope effects and density functional theory calculation under both dark and visible light conditions show that activation of H2O always is the rate-determining step.

Iridium-Catalyzed Stereoselective Transfer Hydrogenation of 1,5-Benzodiazepines.

An iridium-catalyzed highly stereoselective transfer hydrogenation of N-protected 2,4-disubstituted-1,5-benzodiazepines as well as dibenzo[1,5]oxa/thiazepines is realized in an aqueous solvent under acidic conditions, with formic acid as the hydride donor. Only trans-products are obtained in all the cases where diastereoselective issues are associated. The catalyst efficiency is highly dependent on the electronic and steric properties of the substrates. Topologically analyzing the angle of attack for hydride delivering revealed, stereoelectronically, that the steric interaction between the N-protecting group and the sterically large iridium hydride intermediate constitutes the main contributor to the excellent stereochemical control. Highly deuterated products can also be accessible with DCO2D as the deuteride donor. The observed primary kinetic isotope effect (kH/kD = 4.24) suggests that the formation of iridium hydride through β-hydride elimination should be the rate-determining step (with C-H bond cleavage). The potential use of the chirally modified iridium catalysts in a chemical resolution of racemic 1,5-benzodiazepines is also conceptually demonstrated.

Correlation analysis of reactivity in the oxidation of some vicinal and non-vicinal diols by Tributylammonium chlorochromate: A kinetic and mechanistic approach

The kinetics of oxidation of four vicinal, four non-vicinal diols by tributylammonium chlorochromate (TBACC) has been studied in dimethylsulphoxide (DMSO). The main product of oxidation is the corresponding hydroxycarbonyl compound. The reaction is first order each in TBACC. Michaelies-Menten type of kinetics is observed with respect to the diols. The reaction is catalysed by hydrogen ions. The hydrogen ion dependence is taking the form: kobs = a + b[H+]. The oxidation of [1,1,2,2-2H4] ethanediol exhibits a substantial primary kinetic isotope effect (kH/kD = 5.81 at 298 K). The reaction has been studied in nineteen different organic solvents and the solvent effect has been analysed using Taft's and Swain's multiparametric equations. The temperature dependence of the kinetic isotope effect indicates the presence of a symmetrical transition state in the rate-determining step. A suitable mechanism has been proposed.

Heteroatom modified polymer immobilized ionic liquid stabilized ruthenium nanoparticles: Efficient catalysts for the hydrolytic evolution of hydrogen from sodium borohydride

Ruthenium nanoparticles stabilised by polymer immobilized ionic liquids catalyse the hydrolytic release of hydrogen from sodium borohydride. The composition of the polymer influences performance and ruthenium nanoparticles stabilised by an amine-decorated imidazolium-based polymer immobilised ionic liquid (RuNP@NH2-PIILS) was the most efficient with a maximum initial turnover frequency (TOF) of 177 moleH2.molRu−1.min−1, obtained at 30°C with a catalyst loading of 0.08 mol%; markedly higher than that of 69 molH2.molRu−1.min−1 obtained with 5 wt% Ru/C and one of the highest to be reported for a RuNP catalyst. The apparent activation energy (Ea) of 38.9 kJ mol−1 for the hydrolysis of NaBH4 catalysed by RuNP@NH2-PIILS is lower than that for the other polymer immobilized ionic liquid stabilised RuNPs, which is consistent with its efficacy. Comparison of the initial rates of hydrolysis in H2O and D2O catalysed by RuNP@NH2-PIILS gave a primary kinetic isotope effect (kH/kD) of 2.3 which supports a mechanism involving rate limiting oxidative addition of one of the O-H bonds in a strongly hydrogen-bonded surface-coordinated [BH3H−]—-H2O ensemble. The involvement of a surface-coordinated borohydride is further supported by an inverse kinetic isotope effect of 0.65 obtained from a comparison of the initial rates for the hydrolysis of NaBH4 and NaBD4 under the conditions of catalysis i.e., at a high hydride/catalyst mole ratio. Interestingly though, when the comparison of the initial rates of hydrolysis of NaBH4 and NaBD4 was conducted in dilute solution with a hydride/catalyst mole ratio of 1 a kinetic isotope effect (kH/kD) of 2.72 was obtained; this would be more consistent with concerted activation of both an O-H and B-H bond in the rate limiting step, possibly via a concerted oxidative addition-hydride transfer in the surface-coordinated hydrogen-bonded ensemble. Catalyst stability and reuse studies showed that RuNP@NH2-PIILS retained 71% of its activity over five runs; the gradual drop in the initial TOF with run number appears to be due to passivation of the catalyst by the sodium borate by-product as well as an increase in viscosity of the reaction mixture rather than leaching of the catalyst.