Kinetic Isotope Effect Studies Research Articles

Hydrogen by Deuterium Substitution in an Aldehyde Tunes the Regioselectivity by a Nonheme Manganese(III)–Peroxo Complex

AbstractMononuclear nonheme MnIII‐peroxo complexes are important intermediates in biology, and take part in oxygen activation by photosystem II. Herein, we present work on two isomeric biomimetic side‐on MnIII‐peroxo intermediates with bispidine ligand system and reactivity patterns with aldehydes. The complexes are characterized with UV/Vis and mass spectrometric techniques and reaction rates with cyclohexane carboxaldehyde (CCA) are measured. The reaction gives an unusual regioselectivity switch from aliphatic to aldehyde hydrogen atom abstraction upon deuteration of the substrate, leading to the corresponding carboxylic acid product for the latter, while the former gives a deformylation reaction. Mechanistic details are established from kinetic isotope effect studies and density functional theory calculations. Thus, replacement of C−H by C−D raises the hydrogen atom abstraction barriers and enables a regioselectivity switch to a competitive pathway that is slightly higher in energy.

Cu-Catalyzed Direct C-P Bond Formation through Dehydrogenative Cross-Coupling Reactions between Azoles and Dialkyl Phosphites.

A direct dehydrogenative cross-coupling of azoles [C(sp2)-H] with dialkyl phosphites [P(O)-H] to access 2-phosphonated azoles using Cu(I)/Cu(II) as catalyst and K2S2O8/di- tert-butylperoxide as oxidant has been achieved. A remarkable advantage over reported procedures includes that oxazoles, imidazoles, benz(ox/othi/imid)azoles, and indole are found to react under optimized reaction conditions to provide corresponding adducts in high yields. The mechanistic insight of cross-coupling was obtained by deuterium kinetic isotope effect studies.

(Physical and Analytical Electrochemistry Division David C. Grahame Award Address) Electroanalytical Techniques for Studying Nitrogenase Enzyme Mechanisms

Nitrogenase is the only enzyme known to reduce nitrogen to ammonia. This intriguing enzyme is typically studied spectroscopically and due to the complexity of the nitrogenase system (including the dynamics of both a catalytic protein containing a FeMo-cofactor and an Fe protein), it is hard to directly study enzyme mechanism with standard spectroscopic techniques. This talk will discuss electroanalytical techniques for studying the enzyme mechanism of nitrogenase, including mediated bioelectrocatalysis and direct bioelectrocatalysis. The talk will discuss materials innovation for interfacing these complex proteins with electrode surfaces as well as the use of square wave voltammetry and amperometric titrations to evaluate mechanism, including inhibition studies, mutant enzyme studies, and kinetic isotope effect studies.

Modulating the mechanism of electrocatalytic CO2 reduction by cobalt phthalocyanine through polymer coordination and encapsulation

The selective and efficient electrochemical reduction of CO2 to single products is crucial for solar fuels development. Encapsulating molecular catalysts such as cobalt phthalocyanine within coordination polymers such as poly-4-vinylpyridine leads to dramatically increased activity and selectivity for CO2 reduction. In this study, we use a combination of kinetic isotope effect and proton inventory studies to explain the observed increase in activity and selectivity upon polymer encapsulation. We provide evidence that axial-coordination from the pyridyl moieties in poly-4-vinylpyridine to the cobalt phthalocyanine complex changes the rate-determining step in the CO2 reduction mechanism accounting for the increased activity in the catalyst-polymer composite. Moreover, we show that proton delivery to cobalt centers within the polymer is controlled by a proton relay mechanism that inhibits competitive hydrogen evolution. These mechanistic findings provide design strategies for selective CO2 reduction electrocatalysts and serve as a model for understanding the catalytic mechanism of related heterogeneous systems.

The Mechanism of Sugar C-H Bond Oxidation by a Flavoprotein Oxidase Occurs by a Hydride Transfer Before Proton Abstraction.

Understanding the reaction mechanism underlying the functionalization of C-H bonds by an enzymatic process is one of the most challenging issues in catalysis. Here, combined approaches using density functional theory (DFT) analysis and transient kinetics were employed to investigate the reaction mechanism of C-H bond oxidation in d-glucose, catalyzed by the enzyme pyranose 2-oxidase (P2O). Unlike the mechanisms that have been conventionally proposed, our findings show that the first step of the C-H bond oxidation reaction is a hydride transfer from the C2 position of d-glucose to N5 of the flavin to generate a protonated ketone sugar intermediate. The proton is then transferred from the protonated ketone intermediate to a conserved residue, His548. The results show for the first time how specific interactions around the sugar binding site promote the hydride transfer and formation of the protonated ketone intermediate. The DFT results are also consistent with experimental results including the enthalpy of activation obtained from Eyring plots, as well as the results of kinetic isotope effect and site-directed mutagenesis studies. The mechanistic model obtained from this work may also be relevant to other reactions of various flavoenzyme oxidases that are generally used as biocatalysts in biotechnology applications.

Quantum dynamics study of kinetic isotope effects of OD with HBr and DBr.

We carried out a time-dependent, full dimensional, quantum dynamics wave-packet calculation to study the isotope effects for the OD + HBr and OD + DBr reactions. Reaction cross sections and rate constants for the OD + HBr (k2) and OD + DBr (k4) reactions are compared with the ones of OH + HBr (k1) and OH + DBr (k3). The comparisons of cross sections and rate constants show that OH/OD + HBr almost has the same reactivity, as does OH/OD + DBr. Nonetheless, the OH + HBr reaction still has the largest reactivity, then OD + HBr, OH + DBr, and OD + DBr has the smallest. Furthermore, the rate constants of OD + HBr/DBr reactions have a strong negative temperature dependence below 200 K and a nearly constant temperature dependence above 200 K, agreeing with the experimental results both qualitatively and quantitatively. Our calculated quantum primary kinetic isotope effects (k1/k3 = 1.56 and k2/k4 = 1.80) and secondary kinetic isotope effects (k1/k2 = 1.11 and k3/k4 = 1.29) are temperature independent, confirming the experimental measurements, and are in very good agreement with the experimental data.

Copper-Mediated Amination of Aryl C-H Bonds with the Direct Use of Aqueous Ammonia via a Disproportionation Pathway.

The direct amination of C-H bonds with ammonia is a challenge in synthetic chemistry. Herein, we present a copper-mediated approach that enables a chelation-assisted aromatic C-H bond amination using aqueous ammonia. A key strategy was to use soft low-valent Cu(I) species to avoid the strong coordination of ammonia. Mechanistic investigations suggest that the catalysis is initiated by a facile deprotonation of bound ammonia, and the C-N coupling is achieved by subsequent reductive elimination of the resultant copper-amido intermediate from a Cu(III) intermediate that is readily generated by disproportionation of low-valent copper analogues. This mechanistic postulate was supported by a preliminary kinetic isotope effect study and computations. This new chelation-assisted, copper-mediated C-H bond amination with aqueous ammonia was successfully applied to a broad range of substrates to deliver primary anilines. Moreover, the mild conditions required for this transformation allowed the reaction to operate even under substoichiometric conditions to enable a late-stage application for the preparation of pharmaceutical agents.

Metal-Free Radical Cyclization of Vinyl Isocyanides with Alkanes: Synthesis of 1-Alkylisoquinolines

A metal-free radical cyclization reaction of vinyl isocyanides with alkanes is developed, allowing convenient access to a diverse range of potentially valuable 1-alkylisoquinolines. The methodology is simple and efficient, demonstrating excellent functional group tolerance and broad substrate scope. A mechanism involving a radical process is supported by kinetic isotope effect and radical inhibition studies.

Iridium-Catalyzed Highly Efficient and Site-Selective Deoxygenation of Alcohols

An iridium-catalyzed, highly efficient, and site-selective deoxygenation of primary, secondary, and tertiary alcohols has been realized, under the assistance of a 4-(N-substituted amino)aryl directing group. Only the hydroxyl adjacent to the directing group can be deoxygenated. The deoxygenation is performed in water, with formic acid as both the promoter and hydride donor. Excellent yields and functionality tolerance, as well as high efficiency (S/C up to 1 000 000, TOF up to 445 000 h–1), are obtained. The kinetic isotope effect studies show that hydride formation is the rate-determining step, and the deoxygenation follows an SN1-type pathway. The deoxygenation protocol has been demonstrated useful in the structural modification of naturally occurring ketones and steroids.

Stereoretentive Intramolecular Glycosyl Cross-Coupling: Development, Scope, and Kinetic Isotope Effect Study.

A series of cyclic C-glycosides were synthesized using the palladium-catalyzed stereoretentive intramolecular glycosylation of aryl iodides by employing a bulky phosphine ligand. A variety of functional groups are tolerated in the reaction, and enantioenriched anomeric nucleophiles could be coupled without erosion of optical purity. This study offers a unified method to access both cis- and trans-fused rings by capitalizing on the stereoretentive nature of the Stille reaction. In addition, competition experiments for intermolecular and intramolecular cross-couplings revealed secondary KIEs of 1.43 and 0.81, respectively, suggesting a profoundly different steric congestion at the transition state.

Concerted nucleophilic aromatic substitutions.

Nucleophilic aromatic substitution (SNAr) is one of the most widely applied reaction classes in pharmaceutical and chemical research, providing a broadly useful platform for the modification of aromatic ring scaffolds. The generally accepted mechanism for SNAr reactions involves a two-step addition–elimination sequence via a discrete, non-aromatic Meisenheimer complex. Here we use 12C/13C kinetic isotope effect (KIE) studies and computational analyses to provide evidence that prototypical SNAr reactions in fact proceed through concerted mechanisms. The KIE measurements were made possible by a new technique that leverages the high sensitivity of 19F as an NMR nucleus to quantitate the degree of isotopic fractionation. This sensitive technique permits the measurement of KIEs on 10 mg of natural abundance material in one overnight acquisition. As a result, it provides a practical tool for performing detailed mechanistic analyses of reactions that form or break C–F bonds.

Stereospecific sp3 C–H oxidation with m-CPBA: A CoIII Schiff base complex as pre-catalyst vs. its CoIIICdII heterometallic derivative

The mono- and binuclear Schiff base complexes [CoL3]·DMF (1) and [CoCdL3Cl2]·0.5H2O (2) were facilely synthesized using zerovalent cobalt and cadmium chloride (for 2) as starting materials and the pre-formed pro-ligand HL (2-methoxy-6-[(methylimino)methyl]phenol, the product of condensation of o-vanillin and methylamine) in air. The compounds were characterized by single crystal X-ray diffraction analysis and spectroscopic methods in solution and in the solid state. Both complexes demonstrate a profound catalytic activity in the stereoselective oxidation of cis-1,2-dimethylcyclohexane (model substrate) with m-CPBA (m-chloroperbenzoic acid) under mild conditions in the presence of promoters of various acidity (HNO3, TFA and HOAc). The heterometallic binuclear CoIIICdII pre-catalyst (2) was more active than the mononuclear CoIII one (1), exhibiting higher products yields up to 51% and excellent stereospecificity (up to 99.2% retention of stereoconfiguration). This result could be associated with a synergistic effect of two different metals in 2. Based on the large obtained kinetic isotope effect and H218O labeling studies, the overall reaction mechanism was proposed to proceed without the participation of free alkyl radicals. The acidity of the promoter was shown to influence catalytic parameters for both 1 and 2 so that the better parameters are achieved with the acid possessing lower pKa values (a stronger acid). The comparison of the catalytic behaviours of 1 and 2 is discussed in detail considering relevant examples from the literature.

Ultrathin and Vacancy-Rich CoAl-Layered Double Hydroxide/Graphite Oxide Catalysts: Promotional Effect of Cobalt Vacancies and Oxygen Vacancies in Alcohol Oxidation

Co-containing layered double hydroxides (LDHs) are potential non-noble-metal catalysts for the aerobic oxidation of alcohols. However, the intrinsic activity of bulk LDHs is relatively low. In this work, we fabricated ultrathin and vacancy-rich nanosheets by exfoliating bulk CoAl-LDHs, which were then assembled with graphite oxide (GO) to afford a hybrid CoAl-ELDH/GO catalyst. TEM, AFM, and positron annihilation spectrometry indicate that the thickness of the exfoliated LDH platelets is about 3 nm, with a large number of vacancies in the host layers. Fourier transformed XAFS functions show that the Co–O and Co····Co coordination numbers (5.5 and 2.8, respectively) in the hybrid CoAl-ELDH/GO material are significantly lower than the corresponding values in bulk CoAl-LDHs (6.0 and 3.8, respectively). Furthermore, in addition to the oxygen vacancies (VO) and cobalt vacancies (VCo), CoAl-ELDH/GO also contains negatively charged VCo–Co–OHδ− sites and exposed lattice oxygen sites. CoAl-ELDH/GO shows excellent performance as a catalyst for the aerobic oxidation of benzyl alcohol, with a TOF of 1.14 h–1; this is nearly five times that of the unexfoliated bulk CoAl-LDHs (0.23 h–1) precursor. O2-TPD and DRIFT spectroscopy declare that the oxygen storage capacity and mobility are facilitated by the oxygen vacancies and surface lattice oxygen sites. Meanwhile, DFT calculations of adsorption energy show that benzyl alcohol is strongly adsorbed on the oxygen vacancies and negatively charged VCo–Co–OHδ− sites. A kinetic isotope effect study further illustrates that the vacancy-rich CoAl-ELDH/GO catalyst accelerates the cleavage of the O–H bond in benzyl alcohol. Finally, we show that the hybrid CoAl-ELDH/GO material exhibits excellent catalytic activity and selectivity in the oxidation of a range of other benzylic and unsaturated alcohols.

Adsorbed Hydrogen as a Site-Occupying Species in the Electrocatalytic Oxidation of Formate on Pd/C in Alkaline Medium

We investigate the mechanistic origin of oxidation of HCOO− on Pd/C in alkaline media using H/D kinetic isotope effect studies and electrochemical experiments, such as cyclic voltammetry, step-linear sweep voltammetry, and stripping voltammetry. We reveal that HCOO− is oxidized to CO2 through a direct pathway, and the oxidation of Hads is the rate determining step. The slow oxidation kinetics of Hads, which causes a site-occupying effect, suppress the oxidation of HCOO−, and a more distinct phenomenon is observed in the potential region for Hads. These observations provide clues to understanding the significant electrocatalytic activity of Pd and rational approaches for the development of more active catalysts for the oxidation of HCOO− in alkaline media.

Nonradiative dynamics determined by charge transfer induced hydrogen bonding: a combined femtosecond time-resolved fluorescence and density functional theoretical study of methyl dimethylaminobenzoate in water.

As a case study of the interplay and the consequence of the interplay between intramolecular charge transfer (ICT) and intermolecular hydrogen (H)-bonding, a combined femtosecond time-resolved fluorescence (fs-TRF) and density functional theoretical (DFT) and time-dependent DFT (TDDFT) study has been conducted on methyl dimethylaminobenzoate (MDMABA) largely in a water solvent. Direct observation of the broadband spectra, anisotropy, and kinetic decays of fs-TRF from photo-excited MDMABA revealed a rapid ICT reaction occurring with a time constant of ∼0.7 ps from an initial locally excited (LE) state identified to have the Laππ* character; this produced a weakly emissive ICT state featuring radiative rate constant decreased by more than two orders of magnitude. The fluorescence of the ICT state is strongly quenched exhibiting a decay time of ∼49.7 ps, unusually faster than the nanosecond range lifetime in a polar aprotic solvent when intersystem crossing (ISC) is the major deactivation channel. This, according to the study of the solvent kinetic isotope effect, is identified to originate from an instantly enhanced strong solute-solvent H-bonding induced by the ICT reaction which allows elimination of the ISC, and enables the nonradiative decay to proceed almost entirely through the otherwise inaccessible internal conversion from the ICT state. The enhancement of H-bonding is verified by the calculation which presents theoretical evidence for not only the binding site and binding energy of the H-bonding configuration but also the electronic and structural characterization, lending support to the twisted ICT (TICT) description of the photo-excited MDMABA. This study contributes a prominent example for the extraordinary ability of water and a decisive role of ICT promoted H-bonding in offering a highly effective molecular mechanism for rapid elimination of the electronic excitation energy. The results contain an important insight for the in-depth understanding of the excited state H-bonding dynamics, and also have significant implication for clarifying the "sunscreen controversy" of the DMABA type of UVB sunscreen molecule.

Full-dimensional analytical potential energy surface describing the gas-phase Cl + C2H6 reaction and kinetics study of rate constants and kinetic isotope effects.

Within the Born-Oppenheimer approximation a full-dimensional analytical potential energy surface, PES-2017, was developed for the gas-phase hydrogen abstraction reaction between the chlorine atom and ethane, which is a nine body system. This surface presents a valence-bond/molecular mechanics functional form dependent on 60 parameters and is fitted to high-level ab initio calculations. This reaction presents little exothermicity, -2.30 kcal mol-1, with a low height barrier, 2.44 kcal mol-1, and intermediate complexes in the entrance and exit channels. We found that the energetic description was strongly dependent on the ab initio level used and it presented a very flat topology in the entrance channel, which represents a theoretical challenge in the fitting process. In general, PES-2017 reproduces the ab initio information used as input, which is merely a test of self-consistency. As a first test of the quality of the PES-2017, a theoretical kinetics study was performed in the temperature range 200-1400 K using two approaches, i.e. the variational transition-state theory and quasi-classical trajectory calculations, with spin-orbit effects. The rate constants show reasonable agreement with experiments in the whole temperature range, with the largest differences at the lowest temperatures, and this behaviour agrees with previous theoretical studies, thus indicating the inherent difficulties in the theoretical simulation of the kinetics of the title reaction. Different sources of error were analysed, such as the limitations of the PES and theoretical methods, recrossing effects, and the tunnelling effect, which is negligible in this reaction, and the manner in which the spin-orbit effects were included in this non-relativistic study. We found that the variation of spin-orbit coupling along the reaction path, and the influence of the reactivity of the excited Cl(2P1/2) state, have relative importance, but do not explain the whole discrepancy. Finally, the activation energy and the kinetics isotope effects reproduce the experimental information.

Density functional theory study of thermodynamic and kinetic isotope effects of H2/D2 dissociative adsorption on transition metals

Thermodynamic/kinetic isotope effects for H2/D2 dissociative adsorption calculated on metal surfaces offer a means to identify active sites.

P4VP-RuII(bda) polyelectrolyte-metal complex as water oxidation catalyst: on the unique slow-diffusion and multi-charge effects of the polyelectrolyte ligand.

In this work, we analyze the catalytic mechanism of P4VP–RuII(bda) polyelectrolyte–metal complex (PMC) as a water oxidation catalyst and elucidate how the unique slow diffusion and multi-charge properties of the polyelectrolyte ligand dominate the catalytic process. Four poly(4-vinyl pyridine)–Ru(bda) (P4VP–Ru) PMCs with different chain lengths and controlled Ru loading amounts were prepared and used as catalysts for catalytic water oxidation. These catalysts present excellent catalytic performance with turnover numbers (TON) from ∼1200 to ∼1700 because of the good hydration properties. Surprisingly, the combined catalysis kinetics and kinetic isotope effect (KIE) studies for P4VP–Ru PMCs confirm the single-site water nucleophilic attack (WNA) mechanism in catalysis, rather than the interaction between two metal oxide units (I2M). A combination of dynamic light scattering characterization, zeta-potential measurement and molecular dynamics simulation reveals that the slow diffusion and multi-charge properties of the polyelectrolyte ligand are responsible for the observed mechanism difference between the P4VP–Ru PMC system and small-molecule multi-nuclear system, though the two systems actually own a similar structural feature (flexible linkages between Ru centers). Our experimental and simulation results highlight the fact that though the existence of flexible linkages between Ru centers could provide large conformation entropy for the occurrence of Ru-dimerization in small-molecule and neutral polymer systems, the entropy elasticity could not overcome the electrostatic interaction energy in the PMC system. Clearly, this work unambiguously clarified why both intra-chain and inter-chain Ru-dimerization (I2M) are prohibited for the PMC system from a perspective of macromolecular chemistry and physics.

Mechanistic study on iodine-catalyzed aromatic bromination of aryl ethers by N-Bromosuccinimide

Although iodine-catalyzed reaction has rapid advances in recent years, examples on iodine-catalyzed bromination are rare and the mechanism of these reactions remains unclear. Herein, we reported an I2-catalyzed aromatic bromination of aryl ethers by NBS and presented the details of the mechanistic study including kinetic study and the study of kinetic isotope effects. The study revealed that the reaction was actually catalyzed by IBr formed in the induction period, and the rate-determining step was the HBr-elimination of the Wheland intermediate assisted by IBr.

Enhancement of photocatalytic decarboxylation on TiO2 by water-induced change in adsorption-mode

Decarboxylation is an important process in the photocatalytic degradation of organic pollutants. In this study, the adsorption and photocatalytic decarboxylation of acetic acid and trichloroacetic acid were investigated by in-situ diffuse reflectance Fourier transform infrared spectroscopy (DRIFTS), which can distinguish carboxylate groups with different adsorption modes. We found that water molecules promote photocatalytic decarboxylation reaction and the promotional effect of water is attributed to the changed adsorption mode of the carboxylate group by the co-adsorbed water molecules. The IR study shows that degradation of the monodentate-coordinated acetic acids is much faster than that of the bidentate-coordinated one. The kinetic isotope effect studies and analysis of the intermediate products indicates that the degradation of acetic acids originates from the direct oxidation by holes even in the presence of water, rather than from the reaction of OH radicals as generally believed. DFT-based molecular dynamics calculations revealed that the formation of the monodentate-coordinated carboxylate group in the presence of water is attributed to competition between the O atom of the carboxylate group and water for the surface Ti sites. Because of its higher electron density, the monodentate carboxylate group is easier to be directly oxidized by holes than the bidentate group.