Experimental Demonstration and Density Functional Theory Mechanistic Analysis of Arene C-H Bond Oxidation and Product Protection by Osmium Tetroxide in a Strongly Basic/Nucleophilic Solvent.

Reactions that result in the oxy-functionalization of sp2 C-H bonds to give phenols are relatively rare. Here we report experiments and density functional theory (DFT) calculations that demonstrate selective C-H bond hydroxylation of nitroarenes to their corresponding mono-phenoxide as the exclusive product using OsO4 in a highly basic solvent mixture of water, hydroxide, and pyridine. DFT calculations using a mixed explicit/continuum solvent approach indicate that there is likely a mixture of OsO4-hydroxide/pyridine ground-state structures that have competitive reactivity and that the mechanism involves the nucleophilic addition of an anionic metal-oxo species to the arene followed by a hydride transfer process that is different from the standard [3 + 2] mechanism often invoked for the OsO4 oxidation of σ and π bonds. This work demonstrates the utility of using a strongly basic solvent for C-H bond oxidation reactions as this effectively converts any reactive phenolic product into the corresponding phenoxide, which is protected and essentially inert to further oxidation by the nucleophilic metal-oxo species.

Theory and Experiment Demonstrate that Sb(V)-Promoted Methane C-H Activation and Functionalization Outcompete Superacid Protonolysis in Sulfuric Acid.

Sb(V) in strong Brønsted acid solvents is traditionally assumed to react with light alkanes through superacid protonolysis, which results in carbocation intermediates, H2, and carbon oligomerization. In contrast to this general assumption, our density functional theory (DFT) calculations revealed an accessible barrier for C-H activation between methane and Sb(V) in sulfuric acid that could potentially outcompete superacid protonolysis. This prompted us to experimentally examine this reaction in sulfuric acid with oleum, which has never been reported because of presumed superacid reactivity. Reaction of methane at 180 °C for 3 h resulted in very high yields of methyl bisulfate without significant overoxidation. Our DFT calculations show that a C-H activation and Sb-Me bond functionalization mechanism to give methyl bisulfate outcompetes methane protonolysis and many other possible reaction mechanisms, such as electron transfer, proton-coupled electron transfer, and hydride abstraction. Our DFT calculations also explain experimental hydrogen-deuterium exchange studies and the absence of methane carbo-functionalization/oligomerization products. Overall, this work demonstrates that in very strong Brønsted acid solvent, Sb(V) can induce innersphere reaction mechanisms akin to transition metals and outcompete superacid reactivity.

Supermetal: SbF5-mediated methane oxidation occurs by C-H activation and isobutane oxidation occurs by hydride transfer.

SbVF5 is generally assumed to oxidize methane through a methanium-to-methyl cation mechanism. However, experimentally no H2 is observed, and the mechanism of methane oxidation has remained unsolved for several decades. To solve this problem, density functional theory calculations with multiple chemical models (mononuclear and dinuclear) were used to examine methane oxidation by SbVF5 in the presence of CO leading to the methyl acylium cation ([CH3CO]+). While there is a low barrier for methane protonation by [SbVF6]-[H]+ (the combination of SbVF5 and HF) to give the [SbVF5]-[CH5]+ ion pair, H2 dissociation is a relatively high energy process, even with CO assistance, and so this protonation pathway is reversible. While Sb-mediated hydride transfer has a reasonable barrier, the C-H activation/σ-bond metathesis mechanism with the formation of an SbV-Me intermediate is lower in energy. This pathway leads to the acylium cation by functionalization of the SbV-Me intermediate with CO and is consistent with no observation of H2. Because this C-H activation/metal-alkyl functionalization pathway is higher in energy than methane protonation, it is also consistent with the experimentally observed methane hydrogen-to-deuterium exchange. This is the first time that evidence is presented demonstrating that SbVF5 acts beyond a Bronsted superacid and involves C-H activation with an organometallic intermediate. In contrast to methane, due to the much lower carbocation hydride affinity, isobutane significantly favors hydride transfer to give the tert-butyl carbocation with concomitant SbV to SbIII reduction. In this mechanism, the resulting highly acidic SbV-H intermediate provides a route to H2 through protonation of isobutane, which is consistent with experiments and resolves the longstanding enigma of different experimental results for methane versus isobutane.

Selective C-H Functionalization of Methane and Ethane by a Molecular SbV Complex.

Owing to the strong nonpolar bonds involved, selective C-H functionalization of methane and ethane to esters remains a challenge for molecular homogeneous chemistry. We report that the computationally predicted main-group p-block SbV (TFA)5 complex selectively functionalizes the C-H bonds of methane and ethane to the corresponding mono and/or diol trifluoroacetate esters at 110-180 °C with yields for ethane of up to 60 % with over 90 % selectivity. Experimental and computational studies support a unique mechanism that involves SbV -mediated C-H activation followed by functionalization of a SbV -alkyl intermediate.

Comment on "Selective anaerobic oxidation of methane enables direct synthesis of methanol".

Sushkevich et al (Reports, 5 May 2017, p. 523) report on the use of water to oxidize methane to methanol. This seems problematic because the reaction of CH4 and water to generate methanol and H2 is highly unfavorable at any temperature (ΔG of reaction ≈ +28 kcal/mol at 200°C, equilibrium constant K ≈ 10-13). Consequently, even if the reaction is separated into two steps, it seems inconceivable to carry out such a net reaction in a practical manner.

Homogeneous Functionalization of Methane.

One of the remaining "grand challenges" in chemistry is the development of a next generation, less expensive, cleaner process that can allow the vast reserves of methane from natural gas to augment or replace oil as the source of fuels and chemicals. Homogeneous (gas/liquid) systems that convert methane to functionalized products with emphasis on reports after 1995 are reviewed. Gas/solid, bioinorganic, biological, and reaction systems that do not specifically involve methane functionalization are excluded. The various reports are grouped under the main element involved in the direct reactions with methane. Central to the review is classification of the various reports into 12 categories based on both practical considerations and the mechanisms of the elementary reactions with methane. Practical considerations are based on whether or not the system reported can directly or indirectly utilize O2 as the only net coreactant based only on thermodynamic potentials. Mechanistic classifications are based on whether the elementary reactions with methane proceed by chain or nonchain reactions and with stoichiometric reagents or catalytic species. The nonchain reactions are further classified as CH activation (CHA) or CH oxidation (CHO). The bases for these various classifications are defined. In particular, CHA reactions are defined as elementary reactions with methane that result in a discrete methyl intermediate where the formal oxidation state (FOS) on the carbon remains unchanged at -IV relative to that in methane. In contrast, CHO reactions are defined as elementary reactions with methane where the carbon atom of the product is oxidized and has a FOS less negative than -IV. This review reveals that the bulk of the work in the field is relatively evenly distributed across most of the various areas classified. However, a few areas are only marginally examined, or not examined at all. This review also shows that, while significant scientific progress has been made, greater advances, particularly in developing systems that can utilize O2, will be required to develop a practical process that can replace the current energy and capital intensive natural gas conversion process. We believe that this classification scheme will provide the reader with a rapid way to identify systems of interest while providing a deeper appreciation and understanding, both practical and fundamental, of the extensive literature on methane functionalization. The hope is that this could accelerate progress toward meeting this "grand challenge."

Selective electrocatalytic oxidation of a re-methyl complex to methanol by a surface-bound Ru(II) polypyridyl catalyst.

The complex [Ru(Mebimpy)(4,4'-((HO)2OPCH2)2bpy)(OH2)](2+) surface bound to tin-doped indium oxide mesoporous nanoparticle film electrodes (nanoITO-Ru(II)(OH2)(2+)) is an electrocatalyst for the selective oxidation of methylrhenium trioxide (MTO) to methanol in acidic aqueous solution. Oxidative activation of the catalyst to nanoITO-Ru(IV)(OH)(3+) induces oxidation of MTO. The reaction is first order in MTO with rate saturation observed at [MTO] > 12 mM with a limiting rate constant of k = 25 s(-1). Methanol is formed selectively in 87% Faradaic yield in controlled potential electrolyses at 1.3 V vs NHE. At higher potentials, oxidation of MTO by nanoITO-Ru(V)(O)(3+) leads to multiple electrolysis products. The results of an electrochemical kinetics study point to a mechanism in which surface oxidation to nanoITO-Ru(IV)(OH)(3+) is followed by direct insertion into the rhenium-methyl bond of MTO with a detectable intermediate.

Selective CH functionalization of methane, ethane, and propane by a perfluoroarene iodine(III) complex.

Direct partial oxidation of methane, ethane, and propane to their respective trifluoroacetate esters is achieved by a homogeneous hypervalent iodine(III) complex in non-superacidic (trifluoroacetic acid) solvent. The reaction is highly selective for ester formation (>99%). In the case of ethane, greater than 0.5 M EtTFA can be achieved. Preliminary kinetic analysis and density functional calculations support a nonradical electrophilic CH activation and iodine alkyl functionalization mechanism.

A mechanistic change results in 100 times faster CH functionalization for ethane versus methane by a homogeneous Pt catalyst.

The selective, oxidative functionalization of ethane, a significant component of shale gas, to products such as ethylene or ethanol at low temperatures and pressures remains a significant challenge. Herein we report that ethane is efficiently and selectively functionalized to the ethanol ester of H2SO4, ethyl bisulfate (EtOSO3H) as the initial product, with the Pt(II) "Periana-Catalytica" catalyst in 98% sulfuric acid. A subsequent organic reaction selectively generates isethionic acid bisulfate ester (HO3S-CH2-CH2-OSO3H, ITA). In contrast to the modest 3-5 times faster rate typically observed in electrophilic CH activation of higher alkanes, ethane CH functionalization was found to be ~100 times faster than that of methane. Experiment and quantum-mechanical calculations reveal that this unexpectedly large increase in rate is the result of a fundamentally different catalytic cycle in which ethane CH activation (and not platinum oxidation as for methane) is now turnover limiting. Facile Pt(II)-Et functionalization was determined to occur via a low energy ß-hydride elimination pathway (which is not available for methane) to generate ethylene and a Pt(II)-hydride, which is then rapidly oxidized by H2SO4 to regenerate Pt(II)-X2. A rapid, non-Pt-catalyzed reaction of formed ethylene with the hot, concentrated H2SO4 solvent cleanly generate EtOSO3H as the initial product, which further reacts with the H2SO4 solvent to generate ITA.

Selective monooxidation of light alkanes using chloride and iodate.

We describe an efficient system for the direct partial oxidation of methane, ethane, and propane using iodate salts with catalytic amounts of chloride in protic solvents. In HTFA (TFA = trifluoroacetate), >20% methane conversion with >85% selectivity for MeTFA have been achieved. The addition of substoichiometric amounts of chloride is essential, and for methane the conversion increases from <1% in the absence of chloride to >20%. The reaction also proceeds in aqueous HTFA as well as acetic acid to afford methyl acetate. (13)C labeling experiments showed that less than 2% of methane is overoxidized to (13)CO2 at 15% conversion of (13)CH4. The system is selective for higher alkanes: 30% ethane conversion with 98% selectivity for EtTFA and 19% propane conversion that is selective for mixtures of the mono- and difunctionalized TFA esters. Studies of methane conversion using a series of iodine-based reagents [I2, ICl, ICl3, I(TFA)3, I2O4, I2O5, (IO2)2S2O7, (IO)2SO4] indicated that the chloride enhancement is not limited to iodate.

Main-group compounds selectively oxidize mixtures of methane, ethane, and propane to alcohol esters.

Much of the recent research on homogeneous alkane oxidation has focused on the use of transition metal catalysts. Here, we report that the electrophilic main-group cations thallium(III) and lead(IV) stoichiometrically oxidize methane, ethane, and propane, separately or as a one-pot mixture, to corresponding alcohol esters in trifluoroacetic acid solvent. Esters of methanol, ethanol, ethylene glycol, isopropanol, and propylene glycol are obtained with greater than 95% selectivity in concentrations up to 1.48 molar within 3 hours at 180°C. Experiment and theory support a mechanism involving electrophilic carbon-hydrogen bond activation to generate metal alkyl intermediates. We posit that the comparatively high reactivity of these d(10) main-group cations relative to transition metals stems from facile alkane coordination at vacant sites, enabled by the overall lability of the ligand sphere and the absence of ligand field stabilization energies in systems with filled d-orbitals.

Using reduced catalysts for oxidation reactions: mechanistic studies of the "Periana-Catalytica" system for CH4 oxidation.

Designing oxidation catalysts based on CH activation with reduced, low oxidation state species is a seeming dilemma given the proclivity for catalyst deactivation by overoxidation. This dilemma has been recognized in the Shilov system where reduced Pt(II) is used to catalyze methane functionalization. Thus, it is generally accepted that key to replacing Pt(IV) in that system with more practical oxidants is ensuring that the oxidant does not over-oxidize the reduced Pt(II) species. The "Periana-Catalytica" system, which utilizes (bpym)Pt(II)Cl2 in concentrated sulfuric acid solvent at 200 °C, is a highly stable catalyst for the selective, high yield oxy-functionalization of methane. In lieu of the over-oxidation dilemma, the high stability and observed rapid oxidation of (bpym)Pt(II)Cl2 to Pt(IV) in the absence of methane would seem to contradict the originally proposed mechanism involving CH activation by a reduced Pt(II) species. Mechanistic studies show that the originally proposed mechanism is incomplete and that while CH activation does proceed with Pt(II) there is a solution to the over-oxidation dilemma. Importantly, contrary to the accepted view to minimize Pt(II) overoxidation, these studies also show that increasing that rate could increase the rate of catalysis and catalyst stability. The mechanistic basis for this counterintuitive prediction could help to guide the design of new catalysts for alkane oxidation that operate by CH activation.

Designing catalysts for functionalization of unactivated C-H bonds based on the CH activation reaction.

In an effort to augment or displace petroleum as a source of liquid fuels and chemicals, researchers are seeking lower cost technologies that convert natural gas (largely methane) to products such as methanol. Current methane to methanol technologies based on highly optimized, indirect, high-temperature chemistry (>800 °C) are prohibitively expensive. A new generation of catalysts is needed to rapidly convert methane and O(2) (ideally as air) directly to methanol (or other liquid hydrocarbons) at lower temperatures (~250 °C) and with high selectivity. Our approach is based on the reaction between CH bonds of hydrocarbons (RH) and transition metal complexes, L(n)M-X, to generate activated L(n)M-R intermediates while avoiding the formation of free radicals or carbocations. We have focused on the incorporation of this reaction into catalytic cycles by integrating the activation of the CH bond with the functionalization of L(n)M-R to generate the desired product and regenerate the L(n)M-X complex. To avoid free-radical reactions possible with the direct use of O(2), our approach is based on the use of air-recyclable oxidants. In addition, the solvent serves several roles including protection of the product, generation of highly active catalysts, and in some cases, as the air-regenerable oxidant. We postulate that there could be three distinct classes of catalyst/oxidant/solvent systems. The established electrophilic class combines electron-poor catalysts in acidic solvents that conceptually react by net removal of electrons from the bonding orbitals of the CH bond. The solvent protects the CH(3)OH by conversion to more electron-poor [CH(3)OH(2)](+) or the ester and also increases the electrophilicity of the catalyst by ligand protonation. The nucleophilic class matches electron-rich catalysts with basic solvents and conceptually reacts by net donation of electrons to the antibonding orbitals of the CH bond. In this case, the solvent could protect the CH(3)OH by deprotonation to the more electron-rich [CH(3)O](-) and increases the nucleophilicity of the catalysts by ligand deprotonation. The third grouping involves ambiphilic catalysts that can conceptually react with both the HOMO and LUMO of the CH bond and would typically involve neutral reaction solvents. We call this continuum base- or acid-modulated (BAM) catalysis. In this Account, we describe our efforts to design catalysts following these general principles. We have had the most success with designing electrophilic systems, but unfortunately, the essential role of the acidic solvent also led to catalyst inhibition by CH(3)OH above ~1 M. The ambiphilic catalysts reduced this product inhibition but were too slow and inefficient. To date, we have designed new base-assisted CH activation and L(n)M-R fuctionalization reactions and are working to integrate these into a complete, working catalytic cycle. Although we have yet to design a system that could supplant commercial processes, continued exploration of the BAM catalysis continuum may lead to new systems that will succeed in addressing this valuable goal.

The para-substituent effect and pH-dependence of the organometallic Baeyer-Villiger oxidation of rhenium-carbon bonds.

We studied the Baeyer-Villiger (BV) type oxidation of phenylrhenium trioxide (PTO) by H(2)O(2) in the aqueous phase using Quantum Mechanics (density functional theory with the M06 functional) focusing on how the solution pH and the para-substituent affect the Gibbs free energy surfaces. For both PTO and MTO (methylrhenium trioxide) cases, we find that for pH > 1 the BV pathway having OH(-) as the leaving group is lower in energy than the one involving simultaneous protonation of hydroxide. We also find that during this organometallic BV oxidation, the migrating phenyl is a nucleophile so that substituting functional groups in the para-position of phenyl with increased electron-donating character lowers the migration barrier, just as in organic BV reactions. However, this substituent effect also pushes electron density to Re, impeding HOO(-) coordination and slowing down the reaction. This is in direct contrast to the organic analog, in which para-substitution has an insignificant influence on 1,2-addition of peracids. Due to the competition of the two opposing effects and the dependence of the resting state on pH and concentration, the reaction rate of the organometallic BV oxidation is surprisingly unaffected by para-substitution.

Iridium complexes bearing a PNP ligand, favoring facile C(sp3)-H bond cleavage.

Hydrogen iodide is lost upon reaction of PNP with IrI(3), where PNP = 2,6-bis-(di-t-butylphosphinomethyl)pyridine to give crystallographically characterized Ir(PNP)*(I)(2), which reacts with H(2) to give Ir(PNP)(H)(I)(2). Ir(PNP)(Cl)(3) is relatively inert towards the intramolecular C-H activation of the tert-butyl's of the PNP ligand.

Rhodium complexes bearing tetradentate diamine-bis(phenolate) ligands.

Using tetradentate, dianionic ligands, several new rhodium complexes have been prepared. Some of these diamine-bis(phenolate) compounds, are active for C-H activation of benzene. These complexes are air and thermally stable. All four complexes were characterized by X-ray diffraction.

Acceleration of nucleophilic CH activation by strongly basic solvents.

(IPI)Ru(II)(OH)(n)(H(2)O)(m), 2, where IPI is the NNN-pincer ligand, 2,6-diimidizoylpyridine, is shown to catalyze H/D exchange between hydrocarbons and strongly basic solvents at higher rates than in the case of the solvent alone. Significantly, catalysis by 2 is accelerated rather than inhibited by increasing solvent basicity. The evidence is consistent with the reaction proceeding by base modulated nucleophilic CH activation.

Product protection, the key to developing high performance methane selective oxidation catalysts.

Selective, direct conversion of methane to methanol might seem an impossible task since the C-H bond energy of methane is 105 kcal mol(-1) compared to the C-H bond energy for methanol of 94. We show here that the Catalytica catalyst is successful because the methanol is protected as methyl bisulfate, which is substantially less reactive than methanol toward the catalyst. This analysis suggests a limiting performance for systems that operate by this type of protection that is well above the Catalytica system.

Transition-state charge transfer reveals electrophilic, ambiphilic, and nucleophilic carbon-hydrogen bond activation.

Absolutely localized molecular orbital energy decomposition analysis of C-H activation transition states (TSs), including Pt, Au, Ir, Ru, W, Sc, and Re metal centers, shows an electrophilic, ambiphilic, and nucleophilic charge transfer (CT) continuum irrespective of the bonding paradigm (oxidative addition, sigma-bond metathesis, oxidative hydrogen migration, 1,2-substitution). Pt(II) insertion and Au(III) substitution TSs are highly electrophilic and dominated by C-H bond to metal/ligand orbital stabilization, while Ir-X and Ru-X (X = R, NH(2), OR, or BOR(2)) substitution TSs are ambiphilic in nature. In this ambiphilic activation regime, an increase in one direction of CT typically leads to a decrease in the reverse direction. Comparison of Tp(CO)Ru-OH and Tp(CO)Ru-NH(2) complexes showed no evidence for the classic d(pi)-p(pi) repulsion model. Complexes such as and Cp(CO)(2)W-B(OR)(2), (PNP)Ir(I), Cp(2)ScMe, and (acac-kappaO,kappaO)(2)Re(III)-OH were found to mediate nucleophilic C-H activation, where the CT is dominated by the metal/ligand orbital to C-H antibonding orbital interaction. This CT continuum ultimately affects the metal-alkyl intermediate polarization and possible functionalization reactions. This analysis will impact the design of new activation reactions and stimulate the discovery of more nucleophilic activation complexes.