Regioselective preparation of (R)-2-(4-hydroxyphenoxy)propionic acid with a fungal peroxygenase

The extracellular heme-thiolate peroxygenase of Agrocybe aegerita catalyzed the H₂O₂-dependent hydroxylation of 2-phenoxypropionic acid (POPA) to give the herbicide precursor 2-(4-hydroxyphenoxy)propionic acid (HPOPA). The reaction proceeded regioselectively with an isomeric purity near 98%, and yielded the desired R-isomer of HPOPA with an enantiomeric excess of 60%. ¹⁸O-labeling experiments showed that the phenolic hydroxyl in HPOPA originated from H₂O₂, which establishes that the reaction is mechanistically a peroxygenation. Our results raise the possibility that fungal peroxygenases may be useful for a variety of organic oxidations.     

Selective Activation of C−H Bonds in a Cascade Process Combining Photochemistry and Biocatalysis

Selective oxyfunctionalizations of inert C−H bonds can be achieved under mild conditions by using peroxygenases. This approach, however, suffers from the poor robustness of these enzymes in the presence of hydrogen peroxide as the stoichiometric oxidant. Herein, we demonstrate that inorganic photocatalysts such as gold–titanium dioxide efficiently provide H₂O₂ through the methanol‐driven reductive activation of ambient oxygen in amounts that ensure that the enzyme remains highly active and stable. Using this approach, the stereoselective hydroxylation of ethylbenzene to (R )‐1‐phenylethanol was achieved with high enantioselectivity (>98 % ee ) and excellent turnover numbers for the biocatalyst (>71 000).     

Enhanced formation of quercetin by combined use of gamma ray and H2O2 from cyanidin-3-O-xylosylrutinoside

Cyanidin-3-O-xylosylrutinoside (cya-3-O-xylrut), a major pigment in Schizandra chinensis Baillon, was effectively removed by gamma irradiation of greater than 2 kGy, whereas quercetin, the most abundant of the flavonoids and has anti-inflammatory and anti-allergic effects, could be generated by degradation of cya-3-O-xylrut. In the present study, we investigated the effect of combination treatment of gamma irradiation and hydrogen peroxide (H₂O₂) on the formation of quercetin through the degradation of cya-3-O-xylrut. Cya-3-O-xylrut was significantly degraded (～93%) by gamma irradiation at 2 kGy and it was completely removed by a combination treatment (0.2% H₂O₂ and 2 kGy gamma ray). The formation of quercetin was significantly appeared at 2 kGy of gamma ray, together with disappearance of cya-3-O-xylrut. The quercetin formation by gamma ray is 3.2 μg/ml and combination treatment is 7.7 μg/ml. Therefore, the combination treatment of H₂O₂ and gamma ray is more effective to convert cya-3-O-xylrut into quercetin than gamma irradiation only. In conclusion, gamma ray combined with H₂O₂ would be a promising tool for bio-conversion of organic compounds.     

Hydroxylation of phenol over ts-2, a titanium silicate molecular sieve

The influence of different process parameters on the hydroxylation of phenol with H₂O₂ over the titanium silicate molecular sieve TS-2 has been investigated. Apart from the primary products vis., p- and o-dihydroxybenzenes, the corresponding quinones are also formed. Higher Ti contents in the catalyst (TS-2) and higher catalyst concentrations lower the formation of the secondary oxidation products. Solvents have an influence on the relative amounts of the two dihydroxybenzenes in the product. H₂O₂ efficiency of up to 74% is obtainable at ∼ 28% phenol conversion to dihydroxybenzenes.     

Unusual efficiency of a non-heme iron complex as catalyst for the hydroxylation of aromatic compounds by hydrogen peroxide: comparison with iron porphyrins

The non-heme iron complex, Fe(TPAA = tris-〚N-(2-pyridylmethyl)-2-aminoethyl〛amine)(ClO₄)₂, is a bad catalyst for the epoxidation of alkenes such as cyclooctene, cyclohexene and cis-stilbene and for the hydroxylation of alkanes such as adamantane by H₂O₂, when compared to the iron porphyrin Fe〚TDCPN₅P = meso-tetra-(2,6-dichlorophenyl)-β-pentanitroporphyrin〛Cl. At the opposite, Fe(TPAA)(ClO₄)₂ is a much better catalyst for the hydroxylation of arenes by H₂O₂; in its presence, anisole, toluene, ethylbenzene, benzene and chlorobenzene are transformed into the corresponding phenols, with respective yields of 53, 17, 24, 22 and 13% based on H₂O₂. Interestingly, in Fe(TPAA)-catalysed oxidations of anisole, toluene and ethylbenzene by H₂O₂, hydroxylation of the aromatic ring is by far the major reaction, even when compared to usually favoured reactions such as benzylic oxidation and oxidative demethylation.     

Direct hydroxylation of aromatics with a mixture of H2 and O2 gases over Fe- and Pd-incorporated zeolites

The hydroxylation of benzene and phenol with in-situ-generated oxidant was performed under mild reaction conditions over the bicatalytic system which has dual abilities of direct H₂O₂ generation and the hydroxylation activity by combining Pd-zeolite with redox zeolites such as TS-1, Ti-MCM-41, V-MCM-41 and Fe-zeolite. The amount of H₂O₂ formed directly from H₂ and O₂ increases with increasing Pd loading over zeolite up to 0.6% and subsequently decreases slightly as the Pd loading increases. The optimum amount of H₂O₂ produced is 6.4 mmol. Over Pd/HBEA + Fe/Y, when H₂ : O₂ = 40 : 40 ml/min is supplied, phenol conversion increases from 4.6% at 2 h to 13.6% at 8 h with high catechol selectivity in the range of 65–79%. The hydroxylation activities over redox catalyst with H₂O₂ are compared. Hydroxylation activity is improved by encapsulating FePc onto Y zeolite. In terms of TON, FePc/Y exhibits 3.5 times higher capacity than Fe/Y.     

Iron Incorporated Mesoporous Molecular Sieves Synthesized by a Microwave-Hydrothermal Process and Their Application in Catalytic Oxidation

Fe-FSM-16 and Fe-containing mesoporous materials (Fe-JLU-15) prepared by using semifluorinated surfactant as a template, have been synthesized by microwave-hydrothermal (M-H) process and characterized by several spectroscopic techniques. The catalytic activity of these materials was tested for the phenol hydroxylation and wet phenol oxidation with H₂O₂ under mild reaction conditions. The effect of pH, H₂O₂/PhOH molar ratio and stability of the catalyst on the oxidation process was also investigated. Phenol oxidation and H₂O₂ decomposition show that the Fe-JLU-15 is more active than Fe-FSM-16 and more stable in aqueous solution. The total amount of dissolved iron is less than 5 wt% of the iron initially contained in the catalyst. In phenol hydroxylation, these two solids can effectively catalyze the phenol hydroxylation. Catechol and hydroquinone were observed as the major products, with a difference in the product distribution for these solids. The Fe-JLU-15 has a high selectivity for catechol (63.5 % phenol conversion, CAT/HQ = 2.7) while the Fe-FSM-16 shows a high selectivity for hydroquinone (56.8 % phenol conversion, CAT/HQ < 1) under the same reaction conditions.     

Efficient hydroxylation of aromatic compounds catalyzed by an iron(II) complex with H2O2

A mononuclear iron(II) complex, Et₄N[Fe(C₁₀H₆NO₂)₃], coordinated by three 1‐nitroso‐2‐naphtholate ligands in a fac‐N₃O₃ geometry, was initiated to catalyze the direct hydroxylation of aromatic compounds to phenols in the presence of H₂O₂ under mild conditions. Various reaction parameters, including the catalyst dosage, temperature, mole ratio of H₂O₂ to benzene, reaction time and solvents which could affect the hydroxylation activity of the catalyst, were investigated systematically for benzene hydroxylation to obtain ideal benzene conversion and high phenol distribution. Under the optimum conditions, the benzene conversion was 10.2% and only phenol was detected. The catalyst was also found to be active towards hydroxylation of other aromatic compounds with high substrate conversions. The hydroxyl radical formed due to the reaction of the catalyst and H₂O₂ was determined to be the crucial active intermediate in the hydroxylation. A rational pathway for the formation of the hydroxyl radical was proposed and justified by the density functional theory calculations. Copyright © 2014 John Wiley & Sons, Ltd.     

One-Step Hydroxylation of Benzene to Phenol Over Layered Double Hydroxides and their Derived Forms

Phenol, an important bulk organic compound, has diverse applications encompassing both industry and society. Commercially, it is produced through energy intensive three-step cumene process operating at relatively low yield with the co-production of acetone. Several attempts were made for producing phenol through challenging one-step direct hydroxylation of benzene using different oxidants like O₂, N₂O and H₂O₂. Liquid phase hydroxylation of benzene using H₂O₂ found to be more attractive due to its low reaction temperature and environmentally friendly nature (as water is only formed as by-product). The hydroxylation reaction occurs through Fenton’s mechanism; however along with phenol several other products are also formed due to higher reactivity of phenol compared to benzene. Our research group has been working on this reaction for nearly a decade using layered double hydroxides (LDHs) and their derived forms as heterogeneous selective oxidation catalyst. Screening of different LDHs having different metal ions in the layers revealed the necessity of copper for hydroxylation in pyridine. Addition of co-bivalent metal ion along with copper was made in an endeavour to improve the activity that revealed the promising results for CuZnAl LDHs. Efforts were then made to shift from pyridine to environmentally benign solvent, water, for this reaction that showed reasonably good yields with very high selectivity of phenol. Addition of small amount of sulfolane as a co-solvent increased the selectivity for phenol further. The reusability difficulty faced while using as-synthesized LDHs was overcome when calcined LDHs were used. Structure–property-activity relationships were deduced to understand the results observed. The present review besides covering our work also provides the state-of-art on this reaction using different oxidants with emphasis on H₂O₂.     

Selective Oxidations Using a Cytochrome P450 Enzyme Variant Driven with Surrogate Oxygen Donors and Light

Cytochrome P450 monooxygenase enzymes are versatile catalysts, which have been adapted for multiple applications in chemical synthesis. Mutation of a highly conserved active site threonine to a glutamate can convert these enzymes into peroxygenases that utilise hydrogen peroxide (H₂O₂). Here, we use the T252E-CYP199A4 variant to study peroxide-driven oxidation activity by using H₂O₂ and urea-hydrogen peroxide (UHP). We demonstrate that the T252E variant has a higher stability to H₂O₂ in the presence of substrate that can undergo carbon-hydrogen abstraction. This peroxygenase variant could efficiently catalyse O-demethylation and an enantioselective epoxidation reaction (94 % ee). Neither the monooxygenase nor peroxygenase pathways of the P450 demonstrated a significant kinetic isotope effect (KIE) for the oxidation of deuterated substrates. These new peroxygenase variants offer the possibility of simpler cytochrome P450 systems for selective oxidations. To demonstrate this, a light driven H₂O₂ generating system was used to support efficient product formation with this peroxygenase enzyme.     

Direct hydroxylation of benzene to phenol by supported vanadium substitution polyoxometalates using H<Subscript>2</Subscript>O<Subscript>2</Subscript> as oxidant

A practical method for the direct hydroxylation of benzene to phenol catalyzed by supported vanadium-substituted polyoxometalates using H₂O₂ as an oxidant is described. Three vanadium-doped polyoxometalate Na₂H₃PMo₁₀V₂O₄₀·xH₂O catalysts were designed and prepared through support on graphitic carbon nitride (g-C₃N₄), montmorillonite, and activated carbon and named as CN-PMoV₂, M-PMoV₂, and C-PMoV₂, respectively. Their characterization was elucidated through the Fourier transform infrared spectroscopy (FT-IR), thermogravimetric analysis (TGA), inductively coupled plasma-atomic emission spectrometry (ICP-AES) and scanning electron microscopy (SEM). This heterogeneous catalyst demonstrated promising activity in the hydroxylation of benzene to phenol with H₂O₂. Especially, CN-PMoV₂ catalyst was highly active and selective even under mild conditions. Moreover, CN-PMoV₂ catalyst still has a certain catalytic effect even after three instances of repeated use.     

From Alkanes to Carboxylic Acids: Terminal Oxygenation by a Fungal Peroxygenase

A new heme–thiolate peroxidase catalyzes the hydroxylation of n‐alkanes at the terminal position—a challenging reaction in organic chemistry—with H₂O₂ as the only cosubstrate. Besides the primary product, 1‐dodecanol, the conversion of dodecane yielded dodecanoic, 12‐hydroxydodecanoic, and 1,12‐dodecanedioic acids, as identified by GC–MS. Dodecanal could be detected only in trace amounts, and 1,12‐dodecanediol was not observed, thus suggesting that dodecanoic acid is the branch point between mono‐ and diterminal hydroxylation. Simultaneously, oxygenation was observed at other hydrocarbon chain positions (preferentially C2 and C11). Similar results were observed in reactions of tetradecane. The pattern of products formed, together with data on the incorporation of ¹⁸O from the cosubstrate H₂¹⁸O₂, demonstrate that the enzyme acts as a peroxygenase that is able to catalyze a cascade of mono‐ and diterminal oxidation reactions of long‐chain n‐alkanes to give carboxylic acids.     

Kinetics and reaction mechanism of phenol hydroxylation catalyzed by La-Cu<Subscript>4</Subscript>FeAlCO<Subscript>3</Subscript>

The present work synthesizes La-Cu₄FeAICO₃ catalyst under microwave irradiation and characterizes its structure using XRD and IR techniques. The results show that the obtained La-Cu₄FeAICO₃ has a hydrotalcite structure. In the phenol hydroxylation with H₂O₂ catalyzed by La-Cu₄FeAICO₃, the effects of reaction time and phenol/H₂O₂ molar ratio on the phenol hydroxylation, and relationships between the initial hydroxylation rate with concentration of the catalyst, phenol, H₂O₂ and reaction temperature are also investigated in details. It is shown the phenol conversion can reach 50.09% (mol percent) in the phenol hydroxylation catalyzed by La-Cu₄FeAICO₃, under the reaction conditions of the molar ratio of phenol/H₂O₂1/2, the amount ratio of phenol/catalyst 20, reaction temperature 343 K, reaction time 120 min, 10 ml_ distilled water as solvent. Moreover, a kinetic equation of v = k[La-Cu₄FeAlCO₃][C₆H₅OH][H₂O₂]. and the activation energy of E _a=58.37 kJ/mol are obtained according to the kinetic studies. Due to the fact that the HO-Cu⁺-OH species are detected in La-Cu₄FeAICO₃/H₂O₂ system by XPS, the new mechanism about the generation of hydroxyl free radicals in the phenol hydroxylation is proposed, which is supposed that HO-Cu⁺-OH species are transition state in this reaction.     

Transformation of 2,4-dichlorophenol by H2O2/UV-C, Fenton and photo-Fenton processes: Oxidation products and toxicity evolution

In the present study, H₂O₂/UV-C, Fenton and photo-Fenton treatment of 2,4-dichlorophenol was compared in terms of oxidation products and acute toxicity. The oxidation products were identified by gas chromatography-mass spectroscopy, high performance liquid chromatography and ion chromatography, whereas changes in acute toxicity were evaluated by the Vibrio fischeri luminescence inhibition assay. H₂O₂/UV-C and photo-Fenton processes ensured complete 2,4-dichlorophenolremoval, detoxification and significant mineralization. Hydroquinone and formic acid were identified as the common oxidation products of the studied advanced oxidation processes investigated. 3,5-dichloro-2-hydroxybenzaldehyde, phenol, 4-chlorophenol and 2,5-dichlorohydroquinone were identified as the additional H₂O₂/UV-C oxidation products of 2,4-dichlorophenol. Acute toxicity decreased with decreasing 2,4-dichlorophenol and increasing chloride release.     

Specific Enhancement of Catalytic Activity by a Dicopper Core: Selective Hydroxylation of Benzene to Phenol with Hydrogen Peroxide

A dicopper(II) complex, stabilized by the bis(tpa) ligand 1,2‐bis[2‐[bis(2‐pyridylmethyl)aminomethyl]‐6‐pyridyl]ethane (6‐hpa), [Cu₂(μ‐OH)(6‐hpa)]³⁺, was synthesized and structurally characterized. This complex catalyzed selective hydroxylation of benzene to phenol using H₂O₂, thus attaining large turnover numbers (TONs) and high H₂O₂ efficiency. The TON after 40 hours for the phenol production exceeded 12000 in MeCN at 50 °C under N₂, the highest value reported for benzene hydroxylation with H₂O₂ catalyzed by homogeneous complexes. At 22 % benzene conversion, phenol (95.2 %) and p ‐benzoquinone (4.8 %) were produced. The mechanism of H₂O₂ activation and benzene hydroxylation is proposed.     

Preparation, Characterization And Catalytic Properties OF α -Fe2O3/SiO2 Catalyst in Phenol Hydroxylation with Hydrogen Peroxide

7KH .H₂ O₃ /SiO₂ catalyst was synthesized by simple impregnation. The catalyst was characterized by means of X-ray diffraction (XRD), transmission electron microscopy (TEM) and Mössbauer spectroscopy. The results showed that the size RI .H₂ O₃ particles on silica was very small. This kind of catalyst exhibited very good catalytic performance in phenol hydroxylation by H₂ O₂ to dihydroxy-benzene.     

Effect of bulky substitution on catalytic activity of a manganese salen complex used in biomimetic alkene epoxidation and alkane hydroxylation with sodium periodate

The catalytic activity of Mn(salen)Cl containing tert-pentyl groups at the 3,5-positions of the salen ligand in the epoxidation of alkenes and hydroxylation of alkanes was studied at room temperature, using sodium periodate as an oxygen source. The effects of various axial ligands were investigated in the epoxidation of cyclooctene. Imidazole, as a strong π-donor ligand, was the best axial ligand. The effect of different solvents was studied in the epoxidation of cyclooctene in CH₃CN/H₂O solvent mixture. The epoxidation reactions of cyclooctene by different oxygen donors including NaIO₄, Bu₄NIO₄, KHSO₅, H₂O₂, H₂O₂/urea, NaOCl and tert-BuOOH were also studied and NaIO₄ was selected as oxygen source. The presence of bulky substituents in the 3,5-positions of the salen ligand was found to increase the catalytic activity of this complex.     

Elucidation of methyl tert-butyl ether degradation with Fe/H2O2 by purge-and-trap gas chromatography-mass spectrometry

Degradation of methyl tert-butyl ether (MTBE) with Fe²⁺/H₂O₂ was studied by purge-and-trap gas chromatography-mass spectrometry. MTBE was degraded 99% within 120 min under optimum conditions. MTBE was firstly degraded rapidly based on a Fe²⁺/H₂O₂ reaction and then relatively slower based on a Fe³⁺/H₂O₂ reaction. The dissolved oxygen decreased rapidly in the Fe²⁺/H₂O₂ reaction stage, but showed a slow increase in the Fe³⁺/H₂O₂ reaction stage. tert-Butyl formate, tert-butyl alcohol, methyl acetate and acetone were identified as primary degradation products by mass spectrometry. A preliminary reaction mechanism involving two different pathways for the degradation of MTBE with Fe²⁺/H₂O₂ was proposed. This study suggests that degradation of MTBE can be achieved using the Fe²⁺/H₂O₂ process.     

Microsensor in vivo monitoring of oxidative burst in oilseed rape (Brassica napus L.) leaves infected by Sclerotinia sclerotiorum

Oxidative burst is the rapid and transient production of large amounts of reactive oxygen species, including superoxide anion, hydrogen peroxide (H₂O₂), and hydroxyl radical. A rapid and simple technique was employed for in vivo detection of oxidative burst in oilseed rape (Brassica napus L.) leaves, using a modified electrode. Platinum (Pt) micro-particles were dispersed on a Pt electrode, coated with a poly (o-phenylenediamine) film. This exhibited high sensitivity, selectivity and stability in H₂O₂ detection. Amperometry was used to obtain satisfactory linear relationships between reductive current intensities and H₂O₂ concentrations at −0.1 V potential in different electrolytes. This electrode was used in vivo to detect oxidative burst in oilseed rape following fungal infection. Oxidative bursts induced by infection of the fungal pathogen Sclerotinia sclerotiorum (Lib.) de Bary exhibited notably different mechanisms between a susceptible and a resistant glucose oxidase-transgenic genotype.     

An expeditious synthesis of quercetin 3-O-β-d-glucuronide from rutin

We report the synthesis of the major human metabolite of quercetin, quercetin 3-O-β-d-glucuronide, from rutin (quercetin-3-rutinoside), which is commercially available at low cost. This straightforward synthesis is based on the key intermediate 3′,4′,5,7-tetra-O-benzyl-quercetin which is obtained in only two steps by the total benzylation of rutin followed by acid hydrolysis of the rutinoside residue. Glycosylation of the free 3 hydroxyl group by 1-bromo-3,4,6-tetra-O-acetyl-α-d-glucopyranoside yields the protected glucoside. TEMPO-mediated oxidation of primary alcohol on the deprotected glucoside gives access to the benzylated glucuronide. Removal of the benzyl groups which protect the quercetin hydroxyl groups by H₂ (10% Pd/C) yields quercetin 3-O-β-d-glucuronide.