Selective Alkane Hydroxylation Research Articles

Selective Alkane Hydroxylation in a Fluorous Solvent System Catalyzed by a Fluorocarbon-Soluble Transition-Metal Catalyst

Selective Alkane Hydroxylation in a Fluorous Solvent System Catalyzed by a Fluorocarbon-Soluble Transition-Metal Catalyst

Selective alkane hydroxylation and alkene epoxidation using H2O2 and Fe(II) catalysts electrostatically attached to a fluorinated surface.

Fe(II) complexes with pentadentate ligands, including N-heterocyclic carbene moieties, were prepared and electrostatically attached onto the perfluorinated surface of a mesoporous aluminosilicate. The heterogeneous catalysts were applied to the catalytic oxidation of cyclohexane and cyclohexene using H2O2 as an oxidant in CH3CN, demonstrating high performance and selectivity in alkane hydroxylation and cyclohexene epoxidation.

Selective Hydroxylation of Alkanes Catalyzed by Cytochrome P450 Enzymes

Selective Hydroxylation of Alkanes Catalyzed by Cytochrome P450 Enzymes

Direct reactivity studies of non-heme iron-oxo intermediates toward alkane oxidation

Iron complexes [((S,S)-PDP*)FeIII(μ-OH)2FeIII((S,S)-PDP*)](OTf)4 (6), (S,S)-PDP* = N,N′-bis(3,5-dimethyl-4-methoxypyridyl-2-methyl)-(S,S)-2,2′-bipyrrolidine, and [(TPA*)FeIII(μ-OH)2FeIII(TPA*)](OTf)4 (7), TPA* = tris(3,5-dimethyl-4-methoxypyridyl-2-methyl)amine, catalyze the selective hydroxylation of alkanes with H2O2 and peroxycarboxylic acids. Using in situ EPR spectroscopy, direct kinetic data on the reactivity of the iron-oxo intermediates formed in the catalyst systems 6,7/oxidant/RCOOH (RCOOH = acetic acid (AA) or 2-ethylhexanoic acid (EHA)) toward cyclohexane have been obtained for the first time, thus corroborating their key role in the selective CH oxidation. Intermediates 6aAA, 6aEHA and 7a2EHA with proposed structures [((S,S)-PDP*)FeVO(OC(O)CH3)]2+, [((S,S)-PDP*)FeVO(OC(O)R)]2+ and [(TPA*)FeVO(OC(O)R)]2+ (RCOOH = EHA) display similar EPR spectra (g1 = 2.07, g2 = 2.01, g3 = 1.96) and have close reactivities toward cyclohexane at −70 °C (k2 = 2–3 × 10−3 M−1 s−1).

Engineering of P450pyr Hydroxylase for the Highly Regio‐ and Enantioselective Subterminal Hydroxylation of Alkanes

Terminal-selective cytochrome P450pyr has been successfully engineered through directed evolution for the subterminal hydroxylation of alkanes with excellent regio- and enantioselectivity. A sensitive colorimetric high-throughput screening (HTS) assay was developed for the measurement of both the regioselectivity and the enantioselectivity of a hydroxylation reaction. By using the HTS assay and iterative saturation mutagenesis, sextuple-mutant P450pyrSM1 was created for the hydroxylation of n-octane (1) to give (S)-2-octanol (2) with 98 % ee and >99 % subterminal selectivity. The engineered P450 is the first enzyme for this type of highly selective alkane hydroxylation, being useful for the C-H activation and functionalization of alkanes and the preparation of enantiopure alcohols. Molecular modeling provided structure-based understanding of the fully altered regioselectivity and the excellent enantioselectivity. Another sextuple-mutant P450pyrSM2 catalyzed the hydroxylation of propylbenzene (3) to afford (S)-1-phenyl-2-propanol (4) with 95 % ee and 98 % subterminal selectivity.

Engineering of P450pyr Hydroxylase for the Highly Regio‐ and Enantioselective Subterminal Hydroxylation of Alkanes

AbstractTerminal‐selective cytochrome P450pyr has been successfully engineered through directed evolution for the subterminal hydroxylation of alkanes with excellent regio‐ and enantioselectivity. A sensitive colorimetric high‐throughput screening (HTS) assay was developed for the measurement of both the regioselectivity and the enantioselectivity of a hydroxylation reaction. By using the HTS assay and iterative saturation mutagenesis, sextuple‐mutant P450pyrSM1 was created for the hydroxylation of n‐octane (1) to give (S)‐2‐octanol (2) with 98 % ee and >99 % subterminal selectivity. The engineered P450 is the first enzyme for this type of highly selective alkane hydroxylation, being useful for the CH activation and functionalization of alkanes and the preparation of enantiopure alcohols. Molecular modeling provided structure‐based understanding of the fully altered regioselectivity and the excellent enantioselectivity. Another sextuple‐mutant P450pyrSM2 catalyzed the hydroxylation of propylbenzene (3) to afford (S)‐1‐phenyl‐2‐propanol (4) with 95 % ee and 98 % subterminal selectivity.

A non-heme cationic Fe(iii)-complex intercalated in montmorillonite K-10: synthesis, characterization and catalytic alkane hydroxylation with H2O2 at room temperature

An efficient catalyst for highly selective hydroxylation of alkanes with environmentally benign H2O2 at room temperature has been designed by the intercalation of a non-heme iron(iii) complex into smectite montmorillonite K-10.

Diiron(III) complexes of tridentate 3N ligands as functional models for methane monooxygenases: Effect of the capping ligand on hydroxylation of alkanes

A series of non-heme (μ-oxo)bis(μ-benzoato)-bridged diiron(III) complexes of the type [Fe2(O)(OBz)2(L)2]2+ (1–6), where OBz=benzoate, L=bis(pyridin-2-ylmethyl)amine (L1), N-((6-methylpyridin-2-yl-)methyl)(pyridin-2-yl)methanamine (L2), N,N-dimethyl-N′-(pyrid-2-ylmethyl)ethylenediamine (L3), (1-methyl-1H-imidazol-2-yl)-N-(pyridin-2-ylmethyl)-methanamine (L4), (1H-benzo[o]imidazol-2-yl)-N-(pyridin-2-ylmethyl)methanamine (L5) and bis((1H-benzo[o]imidazol-2-yl)methyl)amine (L6), have been isolated and characterized by means of elemental analysis, spectral and electrochemical methods. They have been studied as catalysts for selective hydroxylation of alkanes using m-choloroperbenzoic acid (m-CPBA) as the oxidant. In acetonitrile/dichloromethane mixed solvent all the complexes display a d–d band characteristic of a triply bridged diiron(III) core, revealing that they retain their identity in solution. Upon replacing a donor atom on the capping ligand by a stronger donor, the E1/2 value of the one-electron FeIIIFeIII→FeIIIFeII reduction becomes more negative. All the complexes function as efficient catalysts for hydroxylation of cyclohexane, with 390–410 total turnover numbers and good alcohol selectivity (A/K, 9.3–12.8). Adamantane is selectively oxidized (3°/2°, 15.7–28.1) to 1-adamantanol and 2-adamantanol, along with a small amount of 2-adamantanone (Total TON, 336–437), and interestingly the 3N capping ligands with the pyridyl donor around the diiron(III) center lead to high 3°/2° bond selectivity.

Engineered catalytic biofilms for continuous large scale production of n‐octanol and (S)‐styrene oxide

This study evaluates the technical feasibility of biofilm-based biotransformations at an industrial scale by theoretically designing a process employing membrane fiber modules as being used in the chemical industry and compares the respective process parameters to classical stirred-tank studies. To our knowledge, catalytic biofilm processes for fine chemicals production have so far not been reported on a technical scale. As model reactions, we applied the previously studied asymmetric styrene epoxidation employing Pseudomonas sp. strain VLB120ΔC biofilms and the here-described selective alkane hydroxylation. Using the non-heme iron containing alkane hydroxylase system (AlkBGT) from P. putida Gpo1 in the recombinant P. putida PpS81 pBT10 biofilm, we were able to continuously produce 1-octanol from octane with a maximal productivity of 1.3 g L ⁻¹(aq) day⁻¹ in a single tube micro reactor. For a possible industrial application, a cylindrical membrane fiber module packed with 84,000 polypropylene fibers is proposed. Based on the here presented calculations, 59 membrane fiber modules (of 0.9 m diameter and 2 m length) would be feasible to realize a production process of 1,000 tons/year for styrene oxide. Moreover, the product yield on carbon can at least be doubled and over 400-fold less biomass waste would be generated compared to classical stirred-tank reactor processes. For the octanol process, instead, further intensification in biological activity and/or surface membrane enlargement is required to reach production scale. By taking into consideration challenges such as biomass growth control and maintaining a constant biological activity, this study shows that a biofilm process at an industrial scale for the production of fine chemicals is a sustainable alternative in terms of product yield and biomass waste production.

Selective hydroxylation of alkanes by an extracellular fungal peroxygenase

Fungal peroxygenases are novel extracellular heme-thiolate biocatalysts that are capable of catalyzing the selective monooxygenation of diverse organic compounds, using only H(2)O(2) as a cosubstrate. Little is known about the physiological role or the catalytic mechanism of these enzymes. We have found that the peroxygenase secreted by Agrocybe aegerita catalyzes the H(2)O(2)-dependent hydroxylation of linear alkanes at the 2-position and 3-position with high efficiency, as well as the regioselective monooxygenation of branched and cyclic alkanes. Experiments with n-heptane and n-octane showed that the hydroxylation proceeded with complete stereoselectivity for the (R)-enantiomer of the corresponding 3-alcohol. Investigations with a number of model substrates provided information about the route of alkane hydroxylation: (a) the hydroxylation of cyclohexane mediated by H(2)(18)(2) resulted in complete incorporation of (18)O into the hydroxyl group of the product cyclohexanol; (b) the hydroxylation of n-hexane-1,1,1,2,2,3,3-D(7) showed a large intramolecular deuterium isotope effect [(k(H)/k(D))(obs)] of 16.0 ± 1.0 for 2-hexanol and 8.9 ± 0.9 for 3-hexanol; and (c) the hydroxylation of the radical clock norcarane led to an estimated radical lifetime of 9.4 ps and an oxygen rebound rate of 1.06 × 10(11) s(-1). These results point to a hydrogen abstraction and oxygen rebound mechanism for alkane hydroxylation. The peroxygenase appeared to lack activity on long-chain alkanes (> C(16)) and highly branched alkanes (e.g. tetramethylpentane), but otherwise exhibited a broad substrate range. It may accordingly have a role in the bioconversion of natural and anthropogenic alkane-containing structures (including alkyl chains of complex biomaterials) in soils, plant litter, and wood.

Selective hydroxylation of alkanes catalyzed by iron(IV)corrole

The complex meso-tris(pentafluorophenyl)corrolatoiron(IV)chloride [(F 15TPC)FeCl] emerged as efficient catalyst in hydroxylating alkanes at room temperature. Cyclohexane and adamantane have been oxidized to the corresponding alcohols using m-chloroperbenzoic acid ( m-CPBA) as terminal oxidant. Cyclohexane has been converted to cyclohexanol in 50% yield with 100% selectivity. Adamantane has also been hydroxylated up to 75% overall yield under identical reaction condition. Significantly high regioselectivity in adamantane oxidation has been observed. The reactive intermediates have been quantitatively trapped by 2,4,6-tri- t-butylphenol (TTBP). Kinetic analysis of the (F 15TPC)FeCl-catalyzed oxidation of TTBP has found consistent with rapid reaction of organic substrate with an intermediate formed in the first and rate-determining step.

Highly selective hydroxylation of alkanes catalyzed by (μ-oxo)bis(μ-carboxylato)-bridged diiron(iii) complexes: involvement of mononuclear iron(iii) species in catalysis

A few diiron(III) complexes [Fe2(O)(OAc)2(L1)2](ClO4)2, [Fe2(O)(OBz)2(L1)2](ClO4)2, [Fe2(O)(OAc)2(L2)2](ClO4)2 and [Fe2(O)(OBz)2(L2)2](ClO4)2, where L1=N,N-bis(pyrid-2-ylmethyl)-iso-butylamine, L2=N,N-bis(pyrid-2-ylmethyl)benzylamine, AcO=acetate and BzO=benzoate, have been isolated and characterized by means of elemental analysis and spectral and electrochemical methods. The molecular structures of the complexes and have been determined by single-crystal X-ray diffraction analysis and they possess a distorted bioctahedral geometry in which each iron atom is coordinated to the oxygen atom of the micro-oxo bridge, two oxygen atoms of the micro-benzoato bridges and three nitrogen atoms of L1 and L2 ligands capping the two ends of the diiron(III) cluster. The ESI-MS spectral data of the complexes reveal that the complexes remain intact in dichloromethane (DCM) solution. Upon adding one equivalent of Et3N to a mixture of one equivalent of the diiron(III) complexes and excess of m-chloroperbenzoic acid (m-CPBA) in DCM, an intense absorption band (lambdamax, 670-700 nm) appears, which corresponds to the species [Fe2(O)(OAc)(m-CPBA)(L)2]2+ (ESI-MS, m/z 466) suggested as the intermediate involved in the oxygenation reactions. All the present complexes show efficient alkane hydroxylation with 300-400 turn over numbers and good selectivities for cyclohexane (A/K, 10-14) and adamantane (3 degrees/2 degrees, 9-11). Interestingly, the formation of monoiron(III) species has been discerned in the alkane hydroxylation reactions beyond approximately 50 turnovers. The mononuclear 1:1 iron(III) complexes of L1 and L2 ligands generated in situ are also found to catalyze the oxygenation reactions with high selectivity and efficiency for cyclohexane (A/K, 10-14). Upon their reaction with m-CPBA in DCM, a characteristic absorption band (lambdamax, 600 nm, epsilonmax, 355 M(-1) cm(-1)) appears and decays at room temperature. This spectral feature is consistent with the mononuclear high-valent iron-oxo species suggested as an intermediate in the oxygenation reactions.

A study of the mechanism of alkane hydroxylation using the Fepy4Cl2-PhNHNHPh-O2 system

Abstract Selective alkane hydroxylation has been investigated employing O2 in the presence of PhNHNHPh, PhCO2H and the catalyst, [Fepy4Cl2]. The conversion of cyclohexane to cyclohexanol and the direct reaction between PhNHNHPh and O2 were studied kinetically in the presence of the catalyst. These studies, together with an examination of a range of potential reaction intermediates, suggest that the active species for alkane hydroxylation is an iron-hydroperoxide complex. Hydrazobenzene plays an essential role in the formation of this intermediate. However, a competitive reaction of the hydroperoxide complex leads to the formation of a [Fe(II)(H2O2)]-complex which reacts further with PhNHNHPh. A comparison of the efficiency of a range of iron complexes and a range of substituted hydrazobenzenes in promoting alkane hydroxylation is reported. This oxidation system cannot be viewed as a model for cytochrome P450.

ChemInform Abstract: Shape Selective Alkane Hydroxylation by Metalloporphyrin Catalysts

A series of manganese and iron porphyrins with sterically protected pockets are shown to be shape selective alkane hydroxylation catalysts. With iodosobenzene as oxidant, good regioselectivity is observed for hydroxylation of alkanes at the least hindered methyl group by using the very sterically hindered (5,10,15,20-tetrakis(2',4',6'-triphenylphenyl)-porphyrinato)manganese(III) acetate (MnTTPPP(OAc)) as catalyst; the moderately hindered (5,10,15,20-tetrakis(2',4',6'-trimethoxyphenyl)porphyrinato)manganese(III) acetate shows little selectivity toward terminal CH/sub 3/ hydroxylation but does show enhancement for the adjacent, omega-1, CH/sub 2/ site. Primary selectivity is dependent on the size and shape of the alkane substrate, with more bulky substituents giving greater primary selectivity. Substituting pentafluoroiodosobenzene or m-chloroperbenzoic acid as oxidants yields similar selectivity, thus conclusively demonstrating metal based oxidation via a common intermediate for these three systems. In contrast, tert-butyl hydroperoxide or 2,2,2-trifluoroethanol solubilized pentafluoroiodosobenzene show no primary carbon selectivity, and reaction product ratios are independent of the metalloporphyrin catalyst; this demonstrates that the site of oxidation with these oxidants is not metal based. The iron porphyrin derivatives also show good primary selectivity, although to a lesser degree than with the Mn derivatives, proving that these oxidations too are metal based.

Shape-selective alkane hydroxylation by metalloporphyrin catalysts

A series of manganese and iron porphyrins with sterically protected pockets are shown to be shape selective alkane hydroxylation catalysts. With iodosobenzene as oxidant, good regioselectivity is observed for hydroxylation of alkanes at the least hindered methyl group by using the very sterically hindered (5,10,15,20-tetrakis(2',4',6'-triphenylphenyl)-porphyrinato)manganese(III) acetate (MnTTPPP(OAc)) as catalyst; the moderately hindered (5,10,15,20-tetrakis(2',4',6'-trimethoxyphenyl)porphyrinato)manganese(III) acetate shows little selectivity toward terminal CH/sub 3/ hydroxylation but does show enhancement for the adjacent, omega-1, CH/sub 2/ site. Primary selectivity is dependent on the size and shape of the alkane substrate, with more bulky substituents giving greater primary selectivity. Substituting pentafluoroiodosobenzene or m-chloroperbenzoic acid as oxidants yields similar selectivity, thus conclusively demonstrating metal based oxidation via a common intermediate for these three systems. In contrast, tert-butyl hydroperoxide or 2,2,2-trifluoroethanol solubilized pentafluoroiodosobenzene show no primary carbon selectivity, and reaction product ratios are independent of the metalloporphyrin catalyst; this demonstrates that the site of oxidation with these oxidants is not metal based. The iron porphyrin derivatives also show good primary selectivity, although to a lesser degree than with the Mn derivatives, proving that these oxidations too are metal based.