Alkane Hydroxylation Research Articles

Perspectives on some challenges and approaches for developing the next generation of selective, low temperature, oxidation catalysts for alkane hydroxylation based on the CH activation reaction

The development of selective, energy efficient direct alkane oxidation chemistry could lead to a new paradigm in materials and energy technologies in the 21st century that is environmentally and economically superior and allow the vast reserves of natural gas to be employed directly as feedstocks for fuels and chemicals. The use of homogeneous catalysts that activate and functionalize the CH bonds of unactivated hydrocarbons is of particular interest from a scientific as well as an economic viewpoint. This results from the strong potential for these catalysts to carry out oxidative hydrocarbon conversions with high atom and energy efficiency and under mild conditions. Despite the large body of work on the CH activation reaction that has been produced over the last three decades, to date relatively few catalyst systems that are based on this approach have been developed that allow the functionalization of hydrocarbons and there are still large gaps in our fundamental knowledge of how to rationally design such catalysts. Addressed in this paper are some of the key challenges and approaches to the de novo, rational development of the next generation of organometallic, alkane functionalization catalysts based on the CH activation reaction with emphasis on our own research.

A convenient preparation of polymer-supported manganese porphyrin and its use as hydrocarbon monooxygenation catalyst

A supported tetra(4-pyridyl)porphyrinato manganese(III) was prepared very easily in one step by a quaternerization reaction and is found to be an efficient catalyst for alkene epoxidation and alkane hydroxylation by sodium periodate. This catalyst showed high selectivity in epoxidation of stilbenes and R-(+)-limonene and exhibits a particular ability to epoxidize linear alkenes. Very inert saturated hydrocarbons as well as alkylbenzene derivatives can be oxidized in the presence of this supported catalyst. The new heterogenized metalloporphyrin catalyst is of high stability and reusability.

Alkane Oxidation Catalyzed by Manganese‐tmtacn Complexes with H2O2.

AbstractFor Abstract see ChemInform Abstract in Full Text.

The “Rebound Controversy”: An Overview and Theoretical Modeling of the Rebound Step in C—H Hydroxylation by Cytochrome P450

AbstractFor Abstract see ChemInform Abstract in Full Text.

Toward delineating the structure and function of the particulate methane monooxygenase from methanotrophic bacteria.

The particulate methane monooxygenase (pMMO) is a complex membrane protein complex that has been difficult to isolate and purify for biochemical and biophysical characterization because of its instability in detergents used to solubilize the enzyme. In this perspective, we summarize the progress recently made toward obtaining a purified pMMO-detergent complex and characterizing the enzyme in pMMO-enriched membranes. The purified pMMO is a multi-copper protein, with ca. 15 copper ions sequestered into five trinuclear copper clusters: two for dioxygen chemistry and alkane hydroxylation (catalytic or C-clusters) and three to provide a buffer of reducing equivalents to re-reduce the C-clusters following turnover (electron transfer or E-clusters). The enzyme is functional when all the copper ions are reduced. When the protein is purified under ambient aerobic conditions in the absence of a hydrocarbon substrate, only the C-clusters are oxidized; there is an apparent kinetic barrier for electron transfer from the E-cluster copper ions to the C-clusters under these conditions. Evidence is provided in support of both C-clusters participating in the dioxygen chemistry, but only one C-cluster supporting alkane hydroxylation. Acetylene modification of the latter C-cluster in the hydrophobic pocket of the active site lowers or removes the kinetic barrier for electron transfer from the E-clusters to the C-clusters so that all the copper ions could be fully oxidized by dioxygen. A model for the hydroxylation chemistry when a hydrocarbon substrate is bound to the active site of the hydroxylation C-cluster is presented. Unlike soluble methane monooxygenase (sMMO), pMMO exhibits limited substrate specificity, but the hydroxylation chemistry is highly regioselective and stereoselective. In addition, the hydroxylation occurs with total retention of configuration of the carbon center that is oxidized. These results are consistent with a concerted mechanism involving direct side-on insertion of an active singlet "oxene" from the activated copper cluster across the "C-H" bond in the active site. Finally, in our hands, both the purified pMMO-detergent complex and pMMO-enriched membranes exhibit high NADH-sensitive as well as duroquinol-sensitive specific activity. A possible role for the two reductants in the turnover of the enzyme is proposed.

Non-heme iron polyazadentate complexes as catalysts for oxidations by H2O2: particular efficiency in aromatic hydroxylations and beneficial effects of a reducing agent

Four iron(II) complexes, bearing hexa-, penta- or tetra-azadentate ligands, whose redox potentials (for the FeIII/FeII couple) vary from +280 to +1023 mV (versus saturated calomel electrode), were compared as catalysts for the oxidation of various substrates by H2O2. These complexes were bad catalysts for alkene epoxidation or alkane hydroxylation, whereas those exhibiting the highest redox potentials were interesting catalysts for the hydroxylation of aromatic compounds. For most of them, addition of an appropriate reducing agent, such as hydroquinones, PhSH or tetrahydropterins, in the medium, led to spectacular increases of the yields of hydroxylation of aromatic compounds such as anisole, toluene, ethylbenzene, benzene and naphthalene (with final yields based on H2O2 up to 69, 33, 18, 40 and 47%, respectively). Such systems catalyzed the transfer of an oxygen atom from H2O2, as shown by experiments using H218O2 and H218O, into anisole with yields based on starting H2O2 up to 69%.

The “Rebound Controversy”: An Overview and Theoretical Modeling of the Rebound Step in C−H Hydroxylation by Cytochrome P450

AbstractC−H hydroxylation by the enzyme cytochrome P450 is one of Nature’s important and most ubiquitous processes. There is strong evidence that the mechanism proceeds by initial hydrogen abstraction, from the alkane, by the high‐valent iron−oxo species of the enzyme, followed by a rebound of the alkyl radical to form the ferric−alcohol product complex (the Groves “rebound” mechanism). Nevertheless, the “rebound” mechanism is still controversial due to the ultrashort radical lifetimes deduced from radical‐clock experiments. This review describes the main elements of the controversy and its updated resolution by theory, with an emphasis on the controversial rebound step. The theoretically derived model for alkane hydroxylation is found to involve two‐state reactivity (TSR). In TSR, radicals are produced on two different spin‐state surfaces, and thereafter they react differently; on the low‐spin surface, the rebound proceeds with no product rearrangement and the lifetime of the radicals is ultrashort (or zero), while on the high‐spin surface the barrier for rebound is substantial and the lifetime of the radical is sufficiently long that rearrangement may compete with product formation by rebound. A new valence‐bond model is developed to model the rebound barrier on the high‐spin surface and conceptualize its dependence on the nature of the alkyl radical. The possible intermediacy of carbocationic intermediates alongside radicals is discussed. It is shown that the TSR scenario provides a satisfactory rationale for the controversial findings in the field, and makes verifiable predictions. One of the predictions of TSR is that the ratio of unrearranged to rearranged products, [U/R], will be subject to an intrinsic isotope effect that is substrate‐dependent. This prediction and its possible verification by experiment are discussed. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

Nonheme FeIVO complexes that can oxidize the C-H bonds of cyclohexane at room temperature.

Nonheme oxoiron(IV) complexes of two pentadentate ligands, N4Py (N,N-bis(2-pyridylmethyl)-bis(2-pyridyl)methylamine) and Bn-tpen (N-benzyl-N,N',N'-tris(2-pyridylmethyl)-1,2-diaminoethane), have been generated and found to have spectroscopic properties similar to the closely related tetradentate TPA (tris(2-pyridylmethyl)amine) complex reported earlier. However, unlike the TPA complex, the pentadentate complexes have a considerable lifetime at room temperature. This greater thermal stability has allowed the hydroxylation of alkanes with C-H bonds as strong as 99.3 kcal/mol to be observed at room temperature. Furthermore, a large deuterium KIE value is found in the oxidation of ethylbenzene. These observations lend strong credence to postulated mechanisms of mononuclear nonheme iron enzymes that invoke the intermediacy of oxoiron(IV) species.

Alkane Oxidation Catalyzed by Manganese-tmtacn Complexes with H2O2

The C-H bond activation of alkanes for selective hydroxylation by metal complexes has been the subject of intense research for application in synthetic chemistry and industrial processes. As metal-containing enzymes functionalize the energetically difficult C-H bonds of alkanes, biomimetic alkane hydroxylations using the model complexes of the enzymes have received much attention in the communities of bioinorganic and oxidation chemistry. Among the reported model complexes, manganese complexes using N, N’,N”-trimethyl-1,4,7-triazacyclononane (tmtacn) are known to catalyze various oxidation reactions, such as epoxidation of olefins, hydroxylation of saturated and aromatic hydrocarbons, and oxidation of alcohols, by peroxides. In the oxidation reactions of alkane and alkene, the nature of carboxylate buffers was reported to have a significant effect on the activities of the Mn-tmtacn catalysts. The differences in the activity observed in different carboxylate buffers were suggested perhaps to arise from differences in the structures of the active Mn species involved in the oxidation reactions. As an attempt to get an additional insight into the reactivity and selectivity features of the catalytic alkane oxidation process based on our experience with porphyrin catalysts, we have studied the alkane oxidation using the Mn-tmtacn catalyst and H2O2 in the presence of an oxalate buffer under mild conditions. We now report that this Mn catalyst is able to oxidize alkanes with moderate yields at 0 C and perform a stereospecific hydroxylation via a mechanism involving metal-based oxidants.

First direct evidence for stereospecific olefin epoxidation and alkane hydroxylation by an oxoiron(IV) porphyrin complex.

We report in this study that an oxoiron(IV) porphyrin complex bearing electron-deficient porphyrin ligand, (TPFPP)FeIV=O (TPFPP = meso-tetrakis(pentafluorophenyl)porphinato dianion), shows reactivities similar to those found in oxoiron(IV) porphyrin pi-cation radicals. In the epoxidation of olefins by the (TPFPP)FeIV=O complex, epoxides were yielded as major products; cyclohexene oxide was the sole product formed in the epoxidation of cyclohexene, and stilbenes were stereospecifically oxidized to the corresponding epoxide products. More striking results were obtained in alkane hydroxylation reactions; the hydroxylation of adamantane afforded a high degree of selectivity for tertiary C-H bonds over secondary C-H bonds, and the hydroxylation of cis-1,2-dimethylcyclohexane yielded a tertiary alcohol product with >99% retention of stereochemistry. The latter result demonstrates that an oxoiron(IV) porphyrin complex hydroxylates alkanes with a high stereospecificity. Isotope labeling studies performed with H218O and 18O2 in the olefin epoxidation and alkane hydroxylation reactions demonstrated that oxygen atoms in oxygenated products derived from the oxoiron(IV) porphyrin complex.

Immobilized Osmium Clusters in the Processes of Liquid-Phase Oxidation of Cycloxehene

The reaction of catalytic hydroxylation of olefins by organic hydroperoxides in the presence of osmium carbonyl clusters supported on polymer matrices is studied. The process occurs with the predominant formation of unsaturated alcohols. The oxidative coupling of olefins with the formation of nonconjugated dienes and in which the double bonds remain intact occurs in parallel. In the course of the reaction, changes in the chemical structures of the initial osmium clusters are not observed.

Regio- and enantioselective alkane hydroxylation with engineered cytochromes P450 BM-3.

Cytochrome P450 BM-3 from Bacillus megaterium was engineered using a combination of directed evolution and site-directed mutagenesis to hydroxylate linear alkanes regio- and enantioselectively using atmospheric dioxygen as an oxidant. BM-3 variant 9-10A-A328V hydroxylates octane at the 2-position to form S-2-octanol (40% ee). Another variant, 1-12G, also hydroxylates alkanes larger than hexane primarily at the 2-position but forms R-2-alcohols (40-55% ee). These biocatalysts are highly active (rates up to 400 min(-1)) and support thousands of product turnovers. The regio- and enantioselectivities are retained in whole-cell biotransformations with Escherichia coli, where the engineered P450s can be expressed at high levels and the cofactor is supplied endogenously.

Can a single oxidant with two spin states masquerade as two different oxidants? A study of the sulfoxidation mechanism by cytochrome p450.

Density functional calculations were performed on the sulfoxidation reaction by a model compound I (Cpd I) of cytochrome P450. By contrast to previous alkane hydroxylation studies, which exhibit a dominant low-spin (LS) pathway, the sulfoxidation follows a dominant high-spin (HS) reaction. Thus, competing hydroxylation and sulfoxidation processes as observed for instance by Jones et al. (Volz, T. J.; Rock, D. A.; Jones, J. P. J. Am. Chem. Soc. 2002, 124, 9724) are the result of a two-state reactivity scenario, whereby the hydroxylation originates from the LS pathway and the sulfoxidation from the HS pathway. In this manner, two spin states of a single oxidant (Cpd I) can be disguised as two different oxidants. The calculations rule out the possibility that a second oxidant (the ferric peroxide, Cpd 0 species) interferes in the observed results of Jones et al.

A proton-shuttle mechanism mediated by the porphyrin in benzene hydroxylation by cytochrome p450 enzymes.

Benzene hydroxylation is a fundamental process in chemical catalysis. In nature, this reaction is catalyzed by the enzyme cytochrome P450 via oxygen transfer in a still debated mechanism of considerable complexity. The paper uses hybrid density functional calculations to elucidate the mechanisms by which benzene is converted to phenol, benzene oxide, and ketone, by the active species of the enzyme, the high-valent iron-oxo porphyrin species. The effects of the protein polarity and hydrogen-bonding donation to the active species are mimicked, as before (Ogliaro, F.; Cohen, S.; de Visser, S. P.; Shaik, S. J. Am. Chem. Soc. 2000, 122, 12892-12893). It is verified that the reaction does not proceed either by hydrogen abstraction or by initial electron transfer (Ortiz de Montellano, P. R. In Cytochrome P450: Structure, Mechanism and Biochemistry, 2nd ed.; Ortiz de Montellano, P. R., Ed.; Plenum Press: New York, 1995; Chapter 8, pp 245-303). In accord with the latest experimental conclusions, the theoretical calculations show that the reactivity is an interplay of electrophilic and radicalar pathways, which involve an initial attack on the pi-system of the benzene to produce sigma-complexes (Korzekwa, K. R.; Swinney, D. C.; Trager, W. T. Biochemistry 1989, 28, 9019-9027). The dominant reaction channel is electrophilic and proceeds via the cationic sigma-complex,( 2)3, that involves an internal ion pair made from a cationic benzene moiety and an anionic iron porphyrin. The minor channel proceeds by intermediacy of the radical sigma-complex, (2)2, in which the benzene moiety is radicalar and the iron-porphyrin moiety is neutral. Ring closure in these intermediates produces the benzene oxide product ((2)4), which does not rearrange to phenol ((2)7) or cyclohexenone ((2)6). While such a rearrangement can occur post-enzymatically under physiological conditions by acid catalysis, the computations reveal a novel mechanism whereby the active species of the enzyme catalyzes directly the production of phenol and cyclohexenone. This enzymatic mechanism involves proton shuttles mediated by the porphyrin ring through the N-protonated intermediate, (2)5, which relays the proton either to the oxygen atom to form phenol ((2)7) or to the ortho-carbon atom to produce cyclohexenone product ((2)6). The formation of the phenol via this proton-shuttle mechanism will be competitive with the nonenzymatic conversion of benzene oxide to phenol by external acid catalysis. With the assumption that (2)5 is not fully thermalized, this novel mechanism would account also for the observation that there is a partial skeletal retention of the original hydrogen of the activated C-H bond, due to migration of the hydrogen from the site of hydroxylation to the adjacent carbon (so-called "NIH shift" (Jerina, D. M.; Daly, J. W. Science 1974, 185, 573-582)). Thus, in general, the computationally discovered mechanism of a porphyrin proton shuttle suggests thatthere is an enzymatic pathway that converts benzene directly to a phenol and ketone, in addition to nonenzymatic production of these species by conversion of arene oxide to phenol and ketone. The potential generality of protonated porphyrin intermediates in P450 chemistry is discussed in the light of the H/D exchange observed during some olefin epoxidation reactions (Groves, J. T.; Avaria-Neisser, G. E.; Fish, K. M.; Imachi, M.; Kuczkowski, R. J. Am. Chem. Soc. 1986, 108, 3837-3838) and the general observation of heme alkylation products (Kunze, K. L.; Mangold, B. L. K.; Wheeler, C.; Beilan, H. S.; Ortiz de Montellano, P. R. J. Biol. Chem. 1983, 258, 4202-4207). The competition, similarities, and differences between benzene oxidation viz. olefin epoxidation and alkanyl C-H hydroxylation are discussed, and comparison is made with relevant experimental and computational data. The dominance of low-spin reactivity in benzene hydroxylation viz. two-state reactivity (Shaik, S.; de Visser, S. P.; Ogliaro, F.; Schwarz, H.; Schröder, D. Curr. Opin. Chem. Biol. 2002, 6, 556-567) in olefin epoxidation and alkane hydroxylation is traced to the loss of benzene resonance energy during the bond activation step.

Highly effective ironporphyrin-immobilized catalytic systems for the processes of hydroxylation and epoxidation of lower alkanes and alkenes

The catalytic activity of the following samples in the hydroxylation reaction were studied: PPFe 3+ OH/AlSiCr, PPFe 3+ OH/AlSiMg, PPFe 3+ OH/Al 2 O 3 , and per-FTPhPFe 3+ OH/Al 2 O 3 . PPFe 3+ OH/AlSiMg-catalyzed methane hydroxylation yielded 46.5 wt% of methanol at a 48% methane conversion, at a maximum of 180°C. Per-FTPhPFe 3+ OH/Al 2 O 3 testing in propane hydroxylation by H 2 O 2 yielded 39.3 mol% of isopropanol. Per-FTPhPFe 3+ OH/Al 2 O 3 -catalyzed propylene oxidation by H 2 O 2 yielded 30 mol% of propylene oxide. PPFe 3+ OH/Al 2 O 3 -catalyzed propylene epoxidation yielded the following: the selectivity on the monooxygenase products is about 100%, the selectivity on propylene oxide - 59.2%, propylene conversion - 93.3%. The experimental research data revealed the fact that during the reaction of epoxidation per-FTPhPFe 3+ OH/Al 2 O 3 proved to be more stable under the influence of oxidizer and temperature than PPFe 3+ OH/Al 2 O 3 .

A theoretical study on the mechanism of camphor hydroxylation by compound I of cytochrome p450.

Mechanistic and energetic aspects for the conversion of camphor to 5-exo-hydroxycamphor by the compound I iron-oxo species of cytochrome P450 are discussed from B3LYP DFT calculations. This reaction occurs in a two-step manner along the lines that the oxygen rebound mechanism suggests. The activation energy for the first transition state of the H atom abstraction at the C5 atom of camphor is computed to be more than 20 kcal/mol. This H atom abstraction is the rate-determining step in this hydroxylation reaction, leading to a reaction intermediate that involves a carbon radical species and the iron-hydroxo species. The second transition state of the rebound step that connects the reaction intermediate and the product alcohol complex lies a few kcal/mol below that for the H atom abstraction on the doublet and quartet potential energy surfaces. This energetic feature allows the virtually barrierless recombination in both spin states, being consistent with experimentally observed high stereoselectivity and brief lifetimes of the reaction intermediate. The overall energetic profile of the catalytic mechanism of camphor hydroxylation particularly with respect to why the high activation energy for the H atom abstraction is accessible under physiological conditions is also considered and calculated. According to a proton source model involving Thr252, Asp251, and two solvent water molecules (Biochemistry 1998, 37, 9211), the energetics for the conversion of the iron-peroxo species to compound I is studied. A significant energy over 50 kcal/mol is released in the course of this dioxygen activation process. The energy released in this chemical process is an important driving force in alkane hydroxylation by cytochrome P450. This energy is used for the access to the high activation energy for the H atom abstraction.

Enantiocomplementary Preparation of (S)‐ and (R)‐1‐Pyridylalkanols via Ketone Reduction and Alkane Hydroxylation Using Whole Cells of Pseudomonas putida UV4.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Manganese(III) Porphyrin Supported on Polystyrene as a Heterogeneous Alkene Epoxidation and Alkane Hydroxylation Catalyst.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Kinetic Simulation of Methane and Ethane Hydroxylation by Methane Monooxygenase

According to the mechanism of alkane hydroxylation, whose main postulate is the formation of an intermediate complex containing pentacoordinated carbon, the hydroxylation of methane and ethane by methane monooxygenase was kinetically simulated by the numerical method. The published data on the kinetic isotope effects of oxidation of deuterium-substituted methane molecules (CHD3, CH2D2, and CH3D) and the distribution of products of chiral ethane (R- and S-MeCHDT) oxidation by methane monooxygenase were examined. The kinetic models proposed for the oxidation of isotopically substituted methane and ethane are in good agreement with experimental data.

Bioinspired Iron Catalysts for Degradation of Aromatic Pollutants and Alkane Hydroxylation

Bioinspired Iron Catalysts for Degradation of Aromatic Pollutants and Alkane Hydroxylation