Kinetic Isotope Effect Studies Research Articles

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.

Noncovalent interaction with a spirobipyridine ligand enables efficient iridium-catalyzed C–H activation

Exploitation of noncovalent interactions for recognition of an organic substrate has received much attention for the design of metal catalysts in organic synthesis. The CH–π interaction is especially of interest for molecular recognition because both the C–H bonds and the π electrons are fundamental properties of organic molecules. However, because of their weak nature, these interactions have been less utilized for the control of organic reactions. We show here that the CH–π interaction can be used to kinetically accelerate catalytic C–H activation of arenes by directly recognizing the π-electrons of the arene substrates with a spirobipyridine ligand. Computation and a ligand kinetic isotope effect study provide evidence for the CH–π interaction between the ligand backbone and the arene substrate. The rational exploitation of weak noncovalent interactions between the ligand and the substrate will open new avenues for ligand design in catalysis.

Regio- and Diastereoselective Annulation of α,β-Unsaturated Aldimines with Alkenes via Allylic C(sp3)-H Activation by Rare-Earth Catalysts.

The [3 + 2] or [4 + 2] annulation of α,β-unsaturated aldimines with alkenes via β'- or γ-allylic C(sp3)-H activation is, in principle, an atom-efficient route for the synthesis of five- or six-membered-ring cycloalkylamines, which are important structural motifs in numerous natural products, bioactive molecules, and pharmaceuticals. However, such a transformation has remained undeveloped to date probably due to the lack of suitable catalysts. We report herein for the first time the regio- and diastereoselective [3 + 2] and [4 + 2] annulations of α,β-unsaturated imines with alkenes via allylic C(sp3)-H activation by half-sandwich rare-earth catalysts having different metal ion sizes. The reaction of α-methyl-substituted α,β-unsaturated aldimines with alkenes by a C5Me4SiMe3-ligated scandium catalyst took place in a trans-diastereoselective [3 + 2] annulation fashion via C(sp3)-H activation at the α-methyl group (β'-position), exclusively affording alkylidene-functionalized cyclopentylamines with excellent trans-diastereoselectivity. In contrast, the reaction of β-methyl-substituted α,β-unsaturated aldimines with alkenes by a C5Me5-ligated cerium catalyst proceeded in a cis-diastereoselective [4 + 2] annulation fashion via γ-allylic C(sp3)-H activation, selectively yielding multisubstituted 2-cyclohexenylamines with excellent cis-diastereoselectivity. The mechanistic details of these transformations have been elucidated by deuterium-labeling experiments, kinetic isotope effect studies, and the isolation and transformations of key reaction intermediates. This work offers an efficient and selective protocol for the synthesis of a new family of cycloalkylamine derivatives, featuring 100% atom efficiency, high regio- and diastereoselectivity, broad substrate scope, and an unprecedented reaction mechanism.

Anion-Bridged Dual Hydrogen Bond Enabled Concerted Addition of Phenol to Glycal.

A noncovalent organocatalytic concerted addition of phenol to glycal is developed for the stereoselective and regioselective construction of biologically important phenolic 2-deoxyglycosides, featuring wide substrate tolerance. The method relies on an anion-bridged dual hydrogen bond interaction which is experimentally proved by Nuclear Magnetic Resonance (NMR), Ultraviolet and visible (UV-vis), and fluorescence analysis. Experimental evidence including kinetic analysis, Kinetic Isotope Effect (KIE) studies, linear free energy relationship, Hammett plot, and density functional theory (DFT) calculations is provided for a concerted mechanism where a high-energy oxocarbenium ion is not formed. In addition, the potential utility of this method is further demonstrated by the synthesis of biologically active glycosylated flavones. The benchmarking studies demonstrate significant advances in this newly developed method compared to previous approaches.

Cu(II) Promoted C(sp3 )-H Activation in Unactivated Cycloalkanes: Oxo-Alkylation of Styrenes to Synthesize β-Disubstituted Ketones.

We report the Cu(II) catalyzed synthesis of β-disubstituted ketones from styrene via oxo-alkylation with unactivated cycloalkanes as the alkylating agent in presence of tert-butylhydroperoxide (TBHP) and 1-methylimidazole as oxidant and base respectively. β-disubstituted ketones are known to be synthesized by using either expensive Ru/Ir complexes, or low-cost metal complexes (e. g., Fe, Mn) with activated species like aldehyde, acid, alcohol, or phthalimide derivatives as the alkylating agent, however, use of unactivated cycloalkanes directly as the alkylating agent remains challenging. A wide range of aliphatic C-H substrates as well as various olefinic arenes and heteroarene (35 substrates including 14 new substrates) are well-tolerated in this method. Hammett analysis shed more light on the substitution effect in the olefinic part on the overall mechanism. Furthermore, the controlled experiments, kinetic isotope effect study, and theoretical calculations (DFT) enable us to gain deeper insight of mechanistic intricacies of this new simple and atom-economic methodology.

“Stepwise or concerted or a hybrid mechanism for berberine bridge enzyme?”: A computational mechanistic study by QM-MM and QM methods

Berberine bridge enzyme (BBE) is a plant-based amine oxidase that catalyzes conversion of (S)-reticuline into (S)-scoulerine using flavin as cofactor in a stereospecific way in an alkaloid biosynthesis pathway. Based on the active site enzyme variants, a concerted mechanism was proposed involving hydride transfer, proton transfer, and substrate cyclization processes in a single step. In this mechanism, Glu417 residue acts as the catalytic base which deprotonates the phenolic proton of the substrate while a hydride ion transfers from the substrate to flavin and the substrate cyclizes. However, based on solvent and substrate deuterium kinetic isotope effect studies, it was proposed that the oxidation process occurs in a stepwise fashion in which a hydride ion transfer from substrate to flavin first, then cyclization of the substrate occurs together with the proton transfer process. In this study, we formulated computational models to elucidate the oxidation mechanism of (S)-reticuline into (S)-scoulerine using the crystal structure of enzyme complexed with (S)-reticuline. Both QM and QM-MM calculations revealed that a hybrid of concerted and stepwise mechanisms might be operative during the catalysis. It was found that a concerted hydride-proton transfer processes occurs forming a reactive intermediate which subsequently cyclize without an energy barrier as a decoupled step.

Aerobic oxidation of alkyl aromatics to ketones catalyzed by biomimetic copper complex and N-hydroxyphthalimide (NHPI) under mild conditions

A galactose oxidase-like copper complex (CuIIL) (Ligand: N, N′-bis(2-hydroxy-3,5-di-tert-butylphenyl)-2,2′-diaminobiphenyl) was synthesized and used to catalyze the aerobic oxidation of alkyl aromatics to ketones in presence of N-hydroxyphthalimide (NHPI). The catalytic system exhibited excellent performance and tolerance under mild conditions. Mechanistic studies indicated that NHPI could be activated smoothly to generate phthalimide N-oxyl (PINO) radical in the presence of CuIIL. The kinetic isotope effect (KIE) studies showed that the generation of PINO radical was the rate-determining step.

Transition from Sequential to Concerted Proton-Coupled Electron Transfer of Water Oxidation on Semiconductor Photoanodes.

Accelerating proton transfer has been demonstrated as key to boosting water oxidation on semiconductor photoanodes. Herein, we study proton-coupled electron transfer (PCET) of water oxidation on five typical photoanodes [i.e., α-Fe2O3, BiVO4, TiO2, plasmonic Au/TiO2, and nickel-iron oxyhydroxide (Ni1-xFexOOH)-modified silicon (Si)] by combining the rate law analysis of H2O molecules with the H/D kinetic isotope effect (KIE) and operando spectroscopic studies. An unexpected and universal half-order kinetics is observed for the rate law analysis of H2O, referring to a sequential proton-electron transfer pathway, which is the rate-limiting factor that causes the sluggish water oxidation performance. Surface modification of the Ni1-xFexOOH electrocatalyst is observed to break this limitation and exhibits a normal first-order kinetics accompanied by much enhanced H/D KIE values, facilitating the turnover frequency of water oxidation by 1 order of magnitude. It is the first time that Ni1-xFexOOH is found to be a PCET modulator. The rate law analysis illustrates an effective strategy for modulating PCET kinetics of water oxidation on semiconductor surfaces.

Electrocatalytic Hydrogen Evolution using a Nickel-based Calixpyrrole Complex: Controlling the Secondary Coordination Sphere on an Electrode Surface.

Incorporating design elements from homogeneous catalysts to construct well defined active sites on electrode surfaces is a promising approach for developing next generation electrocatalysts for energy conversion reactions. Furthermore, if functionalities that control the electrode microenvironment could be integrated into these active sites it would be particularly appealing. In this context, a square planar nickel calixpyrrole complex, Ni(DPMDA) (DPMDA=2,2'-((diphenylmethylene)bis(1H-pyrrole-5,2-diyl))bis(methaneylylidene))bis(azaneylylidene))dianiline) with pendant amine groups is reported that forms a heterogeneous hydrogen evolution catalyst using anilinium tetrafluoroborate as the proton source. The supported Ni(DPMDA) catalyst was surprisingly stable and displayed fast reaction kinetics with turnover frequencies (TOF) up to 25,900 s-1 or 366,000 s-1 cm-2 . Kinetic isotope effect (KIE) studies revealed a KIE of 5.7, and this data, combined with Tafel slope analysis, suggested that a proton-coupled electron transfer (PCET) process involving the pendant amine groups was rate-limiting. While evidence of an outer-sphere reduction of the Ni(DPMDA) catalyst was observed, it is hypothesized that the control over the secondary coordination sphere provided by the pendant amines facilitated such high TOFs and enabled the PCET mechanism. The results reported herein provide insight into heterogeneous catalyst design and approaches for controlling the secondary coordination sphere on electrode surfaces.

Kinetic isotope effect study of N-6 methyladenosine chemical demethylation in bicarbonate-activated peroxide system.

N-6 methyladenosine is the most abundant nucleic acid modification in eukaryotes and plays a crucial role in gene regulation. The AlkB family of alpha-ketoglutarate-dependent dioxygenases is responsible for nucleic acid demethylation. Recent studies have discovered that a chemical demethylation system using hydrogen peroxide and ammonium bicarbonate can effectively demethylate nucleic acids. The addition of ferrous ammonium sulfate boosts the oxidation rate by forming a Fenton reagent with hydrogen peroxide. However, the specific mechanism and key steps of this process remain unclear. In this study, we investigate the influence of ferrous ammonium sulfate concentration on the kinetic isotope effect (KIE) of the chemical demethylation system using LC-MS. As the concentration of ferrous ions increases, the observed KIE decreases from 1.377 ± 0.020 to 1.120 ± 0.016, indicating a combination of the primary isotope effect and inverse α-secondary isotope effect with the ion pairing effect. We propose that the initial hydrogen extraction is the rate-limiting step and observe a tight transition state structure in the formation of the hm6A process through the analysis of KIE trends. The concentration-dependent KIE provides a novel perspective on the mechanism of chemical demethylation and offers a chemical model for enzyme-catalyzed demethylation.

Computational Insights on the Hydride and Proton Transfer Mechanisms of D-Arginine Dehydrogenase.

D-Arginine dehydrogenase from Pseudomonas aeruginosa (PaDADH) is an amine oxidase which catalyzes the conversion of D-arginine into iminoarginine. It contains a non-covalent FAD cofactor that is involved in the oxidation mechanism. Based on substrate, solvent, and multiple kinetic isotope effects studies, a stepwise hydride transfer mechanism is proposed. It was shown that D-arginine binds to the active site of enzyme as α-amino group protonated, and it is deprotonated before a hydride ion is transferred from its α-C to FAD. Based on a mutagenesis study, it was concluded that a water molecule is the most likely catalytic base responsible from the deprotonation of α-amino group. In this study, we formulated computational models based on ONIOM method to elucidate the oxidation mechanism of D-arginine into iminoarginine using the crystal structure of enzyme complexed with iminoarginine. The calculations showed that Arg222, Arg305, Tyr249, Glu87, His 48, and two active site water molecules play key roles in binding and catalysis. Model systems showed that the deprotonation step occurs prior to hydride transfer step, and active site water molecule(s) may have participated in the deprotonation process.

Electrochemical Activation of Nitromethane to Construct Isoxazoline Aldoximes.

Activation of nitromethane to endow new reactivity is an interesting and meaningful but also challenging topic. Herein, we report an electrochemical activation of nitromethane to serve as both the heterocyclic skeleton and oxime sources for the construction of isoxazoline aldoximes. The isoxazoline aldoximes that are prepared by four steps with the reported strategy are synthesized in a single step from low-cost and readily available nitromethane and olefins with moderate to excellent yields under our electrochemical conditions. The reaction also takes advantage of high atom-economy and E-selectivity. Moreover, the mechanism is studied by control experiments, a kinetic isotope effect (KIE) study, cyclic voltammogram (CV) experiments, and density functional theory (DFT) calculations. The mechanistic results reveal that nitromethane may be activated under electrochemical conditions to deliver a 1,2,5-oxadiazole 2-oxide intermediate, which undergoes [3+2] cycloaddition with olefins to yield isoxazoline aldoximes.

Electrochemical Activation of Nitromethane to Construct Isoxazoline Aldoximes

AbstractActivation of nitromethane to endow new reactivity is an interesting and meaningful but also challenging topic. Herein, we report an electrochemical activation of nitromethane to serve as both the heterocyclic skeleton and oxime sources for the construction of isoxazoline aldoximes. The isoxazoline aldoximes that are prepared by four steps with the reported strategy are synthesized in a single step from low‐cost and readily available nitromethane and olefins with moderate to excellent yields under our electrochemical conditions. The reaction also takes advantage of high atom‐economy and E‐selectivity. Moreover, the mechanism is studied by control experiments, a kinetic isotope effect (KIE) study, cyclic voltammogram (CV) experiments, and density functional theory (DFT) calculations. The mechanistic results reveal that nitromethane may be activated under electrochemical conditions to deliver a 1,2,5‐oxadiazole 2‐oxide intermediate, which undergoes [3+2] cycloaddition with olefins to yield isoxazoline aldoximes.

Defective PrOx for Efficient Electrochemical NO2−-to-NH3 in a Wide Potential Range

Electrocatalytic reduction of nitrite (NO2−) is a sustainable and carbon-neutral approach to producing green ammonia (NH3). We herein report the first work on building defects on PrOx for electrochemical NO2− reduction to NH3, and demonstrate a high NH3 yield of 2870 μg h−1 cm−2 at the optimal potential of –0.7 V with a faradaic efficiency (FE) of 97.6% and excellent FEs of >94% at a wide given potential range (−0.5 to −0.8 V). The kinetic isotope effect (KIE) study suggested that the reaction involved promoted hydrogenation. Theoretical calculations clarified that there was an accelerated rate-determining step of NO2− reduction on PrOx. The results also indicated that PrOx could be durable for long-term electrosynthesis and cycling tests.

Rapid laser synthesis of surfactantless tantalum‐based nanomaterials as bifunctional catalysts for direct peroxide–peroxide fuel cells

AbstractEfficient and durable electrocatalysts are instrumental in enabling next‐generation fuel cell technologies. At present, expensive precious metals are used as state‐of‐the‐art catalysts. In this report, cost‐effective nanosized tantalum‐based alternatives are synthesized for the first time via a green and scalable laser pyrolysis method as bifunctional catalysts for direct peroxide–peroxide fuel cells. This rapid laser pyrolysis strategy allows for the production of nanoparticles at a laboratory scale of grams per hour, compatible with a detailed exploration of the functional properties of as‐synthesized nanoparticles. By varying the precursor ratio between ammonia and tantalum ethanolate, five tantalum‐based nanomaterials (TaNOC) are prepared with crystalline phases of Ta2O5, Ta4N5, Ta3N5, and TaN in tunable ratios. Electrochemical studies in neutral and alkaline conditions demonstrate that Ta4N5 is the active component for both H2O2 oxidation and reduction. Kinetic isotope effect studies show that protons are involved at or before the rate‐determining step. Long‐term stability studies indicate that Ta3N5 grants surfactant‐free TaNOC‐enhanced longevity during electrocatalytic operations. Taken together, bifunctional TaNOC can act as active and robust electrocatalysts for H2O2 reduction and oxidation. Laser pyrolysis is envisioned to produce refractory metal nanomaterials with boosted corrosion resistance for energy catalysis.

Folding-Induced Promotion of Proton-Coupled Electron Transfers via Proximal Base for Light-Driven Water Oxidation.

Proton-coupled electron-transfer (PCET) processes play a key role in biocatalytic energy conversion and storage, for example, photosynthesis or nitrogen fixation. Here, we report a series of bipyridine-containing di- to tetranuclear Ru(bda) macrocycles 2 C-4 C (bda: 2,2'-bipyridine-6,6'-dicarboxylate) to promote O-O bond formation. In photocatalytic water oxidation under neutral conditions, all complexes 2 C-4 C prevail in a folded conformation that support the water nucleophilic attack (WNA) pathway with remarkable turnover frequencies of up to 15.5 s-1 per Ru unit respectively. Single-crystal X-ray analysis revealed an increased tendency for intramolecular π-π stacking and preorganization of the proximal bases close to the active centers for the larger macrocycles. H/D kinetic isotope effect studies and electrochemical data demonstrate the key role of the proximal bipyridines as proton acceptors in lowering the activation barrier for the crucial nucleophilic attack of H2 O in the WNA mechanism.

Folding‐Induced Promotion of Proton‐Coupled Electron Transfers via Proximal Base for Light‐Driven Water Oxidation

AbstractProton‐coupled electron‐transfer (PCET) processes play a key role in biocatalytic energy conversion and storage, for example, photosynthesis or nitrogen fixation. Here, we report a series of bipyridine‐containing di‐ to tetranuclear Ru(bda) macrocycles 2 C–4 C (bda: 2,2′‐bipyridine‐6,6′‐dicarboxylate) to promote O−O bond formation. In photocatalytic water oxidation under neutral conditions, all complexes 2 C–4 C prevail in a folded conformation that support the water nucleophilic attack (WNA) pathway with remarkable turnover frequencies of up to 15.5 s−1 per Ru unit respectively. Single‐crystal X‐ray analysis revealed an increased tendency for intramolecular π‐π stacking and preorganization of the proximal bases close to the active centers for the larger macrocycles. H/D kinetic isotope effect studies and electrochemical data demonstrate the key role of the proximal bipyridines as proton acceptors in lowering the activation barrier for the crucial nucleophilic attack of H2O in the WNA mechanism.

Two-Dimensional Bimetallic Hydroxide Nanostructures for Catalyzing Low-Temperature Aerobic C–H Bond Activation in Alkylarene and Alcohol Partial Oxidation

Two-dimensional (2D) bimetallic NixMn1–x(OH)y layered double hydroxide (LDH) nanostructures were synthesized and optimized as a remarkably active catalytic platform for low-temperature aerobic C–H bond activation in alkylarenes and partial oxidation of alcohols using a wide substrate (i.e., reactant) and diverse solvent scope. The NixMn1–x(OH)y structure consists of nonprecious and earth-abundant metals that can effectively operate at low catalyst loadings, requiring only molecular oxygen as the stoichiometric oxidant. Structurally diverse alkylarenes as well as primary and secondary alcohols were shown to be competent substrates where oxidation products were obtained in excellent yields (93–99%). Comprehensive catalyst structural characterization via XRD, ATR-IR, TEM, EDX, XPS, BET, and TGA indicated that the ultimately optimized Ni0.6Mn0.4(OH)y-9S catalyst possessed not only particular rotational faults in its β-Ni0.6Mn0.4(OH)y domains but also distinct α/β-Ni0.6Mn0.4(OH)y interstratification disorders, in addition to a relatively high specific surface area of 125 m2/g, a 2D platelet morphology, and an average Mn oxidation state of +3.5, suggesting the presence of both Mn3+ and Mn4+ species in its structure working in a synergistic fashion with the Ni2+/x+ cations (the latter is justified by the lack of catalytic activity in the monometallic LDH catalysts Ni(OH)2 and Mn(OH)2). Kinetic isotope effect studies carried out in the fluorene oxidation reaction (kH/kD = 5.7) revealed that the rate-determining step of the catalytic oxidation reaction directly involved the scission of a C–H bond. Moreover, the optimized catalyst was demonstrated to be reusable through the application of a regeneration protocol, which can redeem the full initial activity of the carbon-poisoned spent catalyst in the fluorene oxidation reaction.

Inverse kinetic isotope effects in the oxygen reduction reaction at platinum single crystals.

Although the oxygen reduction reaction (ORR) involves multiple proton-coupled electron transfer processes, early studies reported the absence of kinetic isotope effects (KIEs) on polycrystalline platinum, probably due to the use of unpurified D2O. Here we developed a methodology to prepare ultra-pure D2O, which is indispensable for reliably investigating extremely surface-sensitive platinum single crystals. We find that Pt(111) exhibits much higher ORR activity in D2O than in H2O, with potential-dependent inverse KIEs of ~0.5, whereas Pt(100) and Pt(110) exhibit potential-independent inverse KIEs of ~0.8. Such inverse KIEs are closely correlated to the lower *OD coverage and weakened *OD binding strength relative to *OH, which, based on theoretical calculations, are attributed to the differences in their zero-point energies. This study suggests that the competing adsorption between *OH/*OD and *O2 probably plays an important role in the ORR rate-determining steps that involve a chemical step preceding an electrochemical step (CE mechanism).

Cobalt(III)-Catalyzed Regioselective [4 + 2]-Annulation of N-Chlorobenzamides with Substituted Alkenes.

A Co(III)-catalyzed redox-neutral [4 + 2] annulation of N-chlorobenzamides/acrylamides with substituted alkenes at ambient temperature is demonstrated. Using this protocol, pharmaceutically important 3,4-dihydroisoquinolinone derivatives were synthesized in good yields. Intriguingly, the synthetically useful functional group of allylic coupling partners such as sulfonyl, carbonate, acetate, phosphate, amide, nitrile, and silane were retained in the final cyclized product. The present annulation reaction was compatible with various substituted benzamides and allylic coupling partners. To support the proposed reaction mechanism, competition experiments, deuterium labeling studies, and kinetic isotope effect studies were performed.