Biomimetic Oxidation Research Articles

Two‐Phase Perchlorate Activation Enabled by a Dinuclear Fe‐NHC (N‐Heterocyclic Carbene) Complex

AbstractPerchlorate, initially regarded as a weakly coordinating counterion rather than a reactive oxidizing reagent due to its kinetic stability, has garnered attention for its potential in microbial systems. Under anaerobic conditions, microbes utilize perchlorate as a terminal oxidant for methane oxidation, involving two distinct stages: extraction and release of oxidizing ability. This two‐phase activation process necessitates the collaborative action of multiple enzymes, a phenomenon not extensively explored in artificial systems. To address this issue, a dinuclear Fe‐NHC (N‐heterocyclic carbene) complex 1 was designed to enable the two‐phase activation of perchlorate. Initially, complex 1 extracts the oxidative potential of perchlorate, leading to the formation of Fe(III)‐O−Fe(III) complex 2 as the oxidation product. Subsequently, the extracted oxidative potential can be released by photolyzing a mixture of complex 2 and 9,10‐dihydroanthracene. In contrast to the commonly observed selectivity, the homocoupling product 5 was identified as the major product in this C−H activation reaction. Further, a catalytic C−H activation reaction is initiated under anaerobic conditions to selectively form the C−C coupling product, achieving the complete two‐phase activation of perchlorate using a single artificial catalyst. This work provides a new paradigm for constructing biomimetic anaerobic oxidation using kinetically inert high‐valent oxygenated acid anions as oxidants.

Two-Phase Perchlorate Activation Enabled by a Dinuclear Fe-NHC (N-Heterocyclic Carbene) Complex.

Perchlorate, initially regarded as a weakly coordinating counterion rather than a reactive oxidizing reagent due to its kinetic stability, has garnered attention for its potential in microbial systems. Under anaerobic conditions, microbes utilize perchlorate as a terminal oxidant for methane oxidation, involving two distinct stages: extraction and release of oxidizing ability. This two-phase activation process necessitates the collaborative action of multiple enzymes, a phenomenon not extensively explored in artificial systems. To address this issue, a dinuclear Fe-NHC (N-heterocyclic carbene) complex 1 was designed to enable the two-phase activation of perchlorate. Initially, complex 1 extracts the oxidative potential of perchlorate, leading to the formation of Fe(III)-O-Fe(III) complex 2 as the oxidation product. Subsequently, the extracted oxidative potential can be released by photolyzing a mixture of complex 2 and 9,10-dihydroanthracene. In contrast to the commonly observed selectivity, the homocoupling product 5 was identified as the major product in this C-H activation reaction. Further, a catalytic C-H activation reaction is initiated under anaerobic conditions to selectively form the C-C coupling product, achieving the complete two-phase activation of perchlorate using a single artificial catalyst. This work provides a new paradigm for constructing biomimetic anaerobic oxidation using kinetically inert high-valent oxygenated acid anions as oxidants.

Biomimetic oxidation of tetracycline and derivatives at C11a

Tetracycline destructases (TDases), a type of TC-inactivating enzymes, inactivate all known TC antibiotics by C11a oxidation, which is considered as a clinical threat. To provide more information on this enzymatic inactivation and oxygenated TCs, we report here a chemical oxidation of Tetracycline and its derivatives at the C11a position using m-CPBA with additives via biomimetic pathways. The structures of the oxygen-containing TCs (2h, 2i) were confirmed by X-ray analysis, and further transformations were performed with oxygen-containing TCs (2e, 2i).

Copper nitrate as a powerful and eco-friendly natural catalyst for mediator-free aerobic oxidation of 2,3-dihydroquinazolinones and 1,4-dihydropyridines under mild conditions

For the first time, copper (II) nitrate trihydrate was used as an efficient, eco-friendly, operational ease, inexpensive, and commercially available catalyst for the biomimetic aerobic oxidation synthesis of quinazolinones and Hantzsch pyridines from their corresponding 2,3-dihydroquinazolinones and 1,4-dihydropyridines, respectively. The products were achieved in satisfactory to excellent yields using acetonitrile as the solvent. These methods are considered to be more eco-friendly, efficient, uncomplicated, and useful compared to existing ones as they align with various principles of green chemistry. Hence, these techniques can be utilized in pharmaceuticals and other delicate synthesis processes.

Electrochemically driven nonheme iron complex-catalyzed oxidation reactions using water as an oxygen source

High-valent metal-oxo species have been invoked as key intermediates in enzymatic and biomimetic oxidation reactions. The generation of high-valent metal-oxo species using water (H2O) as an oxygen source represents one of the most environmentally friendly approaches in developing biologically inspired oxidation catalysis. Herein, we report the electrochemical oxidation of benzylic C−H bonds and alcohols utilizing a mononuclear nonheme iron(III)-monoamidate complex [FeIII(dpaq)(H2O)]2+ (dpaq = 2-[bis(pyridin-2-ylmethyl)]amino-N-quinolin-8-yl-acetamidate) as a catalyst and H2O as an oxygen source. Selective benzylic C−H bond oxidation of alkanes to ketones was achieved in 43–85 % yields, and primary and secondary alcohols were converted to the corresponding aldehydes and ketones, respectively, in 46–95 % yields. The generation of an iron(V)-oxo species [FeV(O)(dpaq)]2+ from proton-coupled electron-transfer (PCET) oxidation of the iron(III) aqua complex [FeIII(dpaq)(H2O)]2+ was evidenced by cyclic voltammetry analysis; the iron(V)-oxo species [FeV(O)(dpaq)]2+ was recently detected using transient absorption spectroscopy in water oxidation reactions. Mechanistic studies revealed that electrochemical oxidation of alcohols catalyzed by FeIII(dpaq) is a two-electron oxidation process, hydrogen-atom transfer (HAT) from the α-C−H bond of alcohols by iron(V)-oxo species is the rate-determining step, and there is a remarkable charge transfer from the highly electrophilic iron(V)-oxo species to the alcohols in the HAT step. This research paves a significant groundwork aimed at developing electrochemically driven biomimetic asymmetric oxidation reactions catalyzed by nonheme metal complexes supported by chiral ligands.

Enhanced Reactivities of Iron(IV)-Oxo Porphyrin Species in Oxidation Reactions Promoted by Intramolecular Hydrogen-Bonding.

High-valent iron-oxo species are one of the common intermediates in both biological and biomimetic catalytic oxidation reactions. Recently, hydrogen-bonding (H-bonding) has been proved to be critical in determining the selectivity and reactivity. However, few examples have been established for mechanistic insights into the H-bonding effect. Moreover, intramolecular H-bonding effect on both C-H activation and oxygen atom transfer (OAT) reactions in synthetic porphyrin model system has not been investigated yet. In this study, a series of heme-containing iron(IV)-oxo porphyrin species with or without intramolecular H-bonding are synthesized and characterized. Kinetic studies revealed that intramolecular H-bonding can significantly enhance the reactivity of iron(IV)-oxo species in OAT, C-H activation, and electron-transfer reactions. This unprecedented unified H-bonding effect is elucidated by theoretical calculations, which showed that intramolecular H-bonding interactions lower the energy of the anti-bonding orbital of iron(IV)-oxo porphyrin species, resulting in the enhanced reactivities in oxidation reactions irrespective of the reaction type. To the best of the knowledge, this is the first extensive investigation on the intramolecular H-bonding effect in heme system. The results show that H-bonding interactions have a unified effect with iron(IV)-oxo porphyrin species in all three investigated reactions.

Mild and selective transformations of amines and alcohols through bioinspired oxidation with nitrous oxide or oxygen

Herein we report on the biomimetic catalytic oxidation of amines to nitriles and alcohols to aldehydes.

Curbing chlorine disinfection byproduct formation with a biomimetic FeTAML oxidation catalyst

An [Fe(TAML)]− catalyst boosts the oxidising power of chlorine disinfectants to clear a model organic pollutant and inhibits formation of trihalomethane disinfection byproducts.

Synthesis and characterization of novel uranyl clusters supported by bis(pyrazolyl) methane ligands: biomimetic catalytic oxidation, BSA protein interaction and cytotoxicity studies.

Two novel uranyl complexes were synthesized using bis-pyrazolyl methane ligands. The complexes were characterized by several spectroscopic techniques, including UV-Vis, IR, NMR, mass spectrometry, fluorescence, electrochemical, and thermogravimetric analysis. The solid-state structure of the complex C1 was determined with the help of single-crystal X-ray diffraction studies. The complexes C1 and C2 efficiently catalyse the oxidation of 3,5-di-tert-butyl catechol and 2-aminophenol in the atmospheric air, imitating the catalytic activity of the catechol oxidase and phenoxazinone synthase enzymes. The kinetic parameters and the catalytic efficiency (K cat/K M) of the reactions were calculated. Formation of organic free radicals in the catalytic reactions was confirmed by EPR spectroscopy. The interaction of these complexes with the protein, bovine serum albumin, was investigated by using UV-Vis and fluorescence spectral analysis. The cytotoxicity of the complexes against MDAMB-231 and A549 cell lines was investigated, and IC50 values were determined.

Efficient synthesis of carbon-14 labeled metabolites of the strobilurin fungicide mandestrobin using biomimetic iron-porphyrin catalyzed oxidation.

Biomimetic oxidation using synthetic iron-porphyrin (F20 TPPFeCl) as a catalyst eliminated a xylene moiety of the fungicide mandestrobin, uniformly labeled with carbon-14 at the benzyl ring, to produce the corresponding radiolabeled metabolite 1. This reaction mechanism was investigated by identifying chemical structures of intermediate 5 and p-xyloquinone derivatives 6 and 7, as by-products. Optimization of reaction factors based on the mechanism improved the yield of 1 from mandestrobin up to 87%. Finally, various carbon-14 labeled metabolites of mandestrobin were prepared from 1.

Synthesis, characterization and application of a highly dispersed and reactive hypervalent iodine(V)/polyvinylpyrrolidone dendrimer nanocomposite: Hetero- vs. homo-intermolecular secondary O---I bonds

Polyvinylpyrrolidone (PVP) assisted aerobic oxidation of bulk iodosylbenzene or hydrolysis/oxidation of iodobenzene diacetate under mild conditions leading to the formation of nanostructured iodylbenzene is reported. AFM and FESEM-EDX analyses confirmed the formation of dendrimer iodylbenzene-polyvinylpyrrolidone nanocomposite (PhIO2-PVP) through the two top-down approaches. The formation of PhIO2 was confirmed by 1H NMR spectroscopy. Strong interactions between iodylbenzene molecules and the polymer through secondary intermolecular O---I bonds was evident from the large difference between the morphology of PVP (cubic) and PhIO2-PVP (dendrimer) nanoparticles. FESEM images showed a maximum width and length of 70 and 1000 nm for the dendrimers, respectively. The dual role played by PVP, i.e., facilitating the oxidation of I(III) to I(V) and stabilization the hypervalent I(V) compound was attributed to the formation of strong secondary hetero-intermolecular O---I bonds, between the polymer and iodine centre. The very fine aqueous and dichloromethane suspensions of PhIO2-PVP were indistinguishable to the naked eye. Efficient direct oxidation of cyclohexene and methylene blue with PhIO2-PVP at room temperature and a short reaction time provided evidence of significantly increased reactivity of PhIO2-PVP compared to that of the bulk oxidant. PhIO2-PVP was also used in the oxidation of methyl phenyl sulfide and styrene in water and dichloroethane, using water soluble and insoluble metalloporphyrins, respectively. The former led to the formation of the corresponding sulfoxide as the sole product in the two solvents. In addition to styrene oxide formed in both solvents, benzaldehyde was also formed with a selectivity of 24% in water. Almost complete oxidation of the organic substrates was observed in dichloroethane. The results of this study show that the nanostructured iodine(V) compound can be used as an efficient terminal oxidant in biomimetic oxidations.

Synthesis of biphenyl-type and diarylether-type oligostilbenes from the biomimetic oxidation of cyano-resveratrol derivatives

Two trans-cyanostilbene derivatives were prepared, and their oxidative dimerizations promoted by horseradish peroxidase-H2O2 were investigated. An M5–M5-coupled biphenyl-type dimer was first synthesized from the biomimetic oxidative coupling reaction of 8-cyano-resveratrol. A novel M5–MO-4-coupled diarylether-type dimer was obtained through the oxidation of 3,5-dibromo-8-cyano-resveratrol and the following debromination reaction. The cyano group at the C-8 of two cyano-stilbenes had obvious influences on the regioselectivity of their coupling reactions.

Oxidation Products from the Neolignan Licarin A by Biomimetic Reactions and Assessment of in vivo Acute Toxicity.

Licarin A, a dihydrobenzofuranic neolignan presents in several medicinal plants and seeds of nutmeg, exhibits strong activity against protozoans responsible for Chagas disease and leishmaniasis. From biomimetic reactions by metalloporphyrin and Jacobsen catalysts, seven products were determined: four isomeric products yielded by epoxidation from licarin A, besides a new product yielded by a vicinal diol, a benzylic aldehyde, and an unsaturated aldehyde in the structure of the licarin A. The incubation with rat and human liver microsomes partially reproduced the biomimetic reactions by the production of the same epoxidized product of m/z 343 [M + H]+. In vivo acute toxicity assays of licarin A suggested liver toxicity based on biomarker enzymatic changes. However, microscopic analysis of tissues sections did not show any tissue damage as indicative of toxicity after 14 days of exposure. New metabolic pathways of the licarin A were identified after in vitro biomimetic oxidation reaction and in vitro metabolism by rat or human liver microsomes.

Regeneration and Degradation in a Biomimetic Polyoxometalate Water Oxidation Catalyst.

Complete understanding of catalytic cycles is required to advance the design of water oxidation catalysts, but it is difficult to attain, due to the complex factors governing their reactivity and stability. In this study, we investigate the regeneration and degradation pathways of the highly active biomimetic water oxidation catalyst [Mn3+ 2Mn4+ 2V4O17(OAc)3]3-, thereby completing its catalytic cycle. Beginning with the deactivated species [Mn3+ 4V4O17(OAc)2]4- left over after O2 evolution, we scrutinize a network of reaction intermediates belonging to two alternative water oxidation cycles. We find that catalyst regeneration to the activated species [Mn4+ 4V4O17(OAc)2(OH)(H2O)]- proceeds via oxidation of each Mn center, with one water ligand being bound during the first oxidation step and a second water ligand being bound and deprotonated during the final oxidation step. ΔΔG values for this last oxidation are consistent with previous experimental results, while regeneration within an alternative catalytic cycle was found to be thermodynamically unfavorable. Extensive in silico sampling of catalyst structures also revealed two degradation processes: cubane opening and ligand dissociation, both of which have low barriers at highly reduced states of the catalyst due to the presence of Jahn-Teller effects. These mechanistic insights are expected to spur the development of more efficient and stable Mn cubane water oxidation catalysts.

Scavengome of an antioxidant.

The term "scavengome" refers to the chemical space of all the metabolites that may be formed from an antioxidant upon scavenging reactive oxygen or nitrogen species (ROS/RNS). This chemical space covers a wide variety of free radical metabolites with drug discovery potential. It is very rich in structures representing an increased chemical complexity as compared to the parent antioxidant: a wide range of unusual heterocyclic structures, new CC bonds, etc. may be formed. Further, in a biological environment, this increased chemical complexity is directly translated from the localized conditions of oxidative stress that determines the amounts and types of ROS/RNS present. Biomimetic oxidative chemistry provides an excellent tool to model chemical reactions between antioxidants and ROS/RNS. In this chapter, we provide an overview on the known metabolites obtained by biomimetic oxidation of a few selected natural antioxidants, i.e., a stilbene (resveratrol), a pair of hydroxycinnamates (caffeic acid and methyl caffeate), and a flavonol (quercetin), and discuss the drug discovery perspectives of the related chemical space.

The elusive reaction mechanism of Mn(II)-mediated benzylic oxidation of alkylarene by H2O2: a gem-diol mechanism or a dual hydrogen abstraction mechanism?

The direct oxygenation of alkylarenes at the benzylic position employing bioinspired nonheme catalysts has emerged as a promising strategy for the production of bioactive arene ketone scaffolds in drugs. However, the structure-activity relationship of the active species and the mechanism of these reactions remain elusive. Herein, the reaction mechanism of the Mn(II)-mediated benzylic oxygenation of phenylbutanoic acid (PBA) to 4-oxo-4-phenylbutyric acid (4-oxo-PBA) by H2O2 was investigated using density functional theory calculations. The calculated results demonstrated that the MnIII-OOH species (1) is a sluggish oxidant and needs to be converted to a high-valent manganese-oxo species (2). The conversion of PBA to 4-oxo-PBA by 2 occurs via the consecutive hydroxylation of PBA to 4-hydroxyl-4-phenylbutyric acid (4-OH-PBA) and the alcohol oxidation of 4-OH-PBA to 4-oxo-PBA. The hydroxylation of PBA proceeds via a novel hydride transfer/hydroxyl-rebound mechanism and the alcohol oxidation of 4-OH-PBA occurs via three pathways (gem-diol, dual hydrogen abstraction (DHA), and reversed-DHA pathways). The regio-selectivity of benzylic oxidations was caused by a strong π-π stacking interaction between the pyridine ring of the nonheme ligand and the phenyl ring of the substrate. These mechanistic findings enrich the knowledge of biomimetic alcohol oxidations and play a positive role in the rational design of new non-heme catalysts.

NEW METHOD OF KINETIC MODELING OF ETHYLENE OXIDATION REACTION TO ETHYL ALCOHOL AND ACETALDEHYDE BY HYDROGEN PEROXIDE ON THE PER-FTPhPFe3+OH/Al2O3

The process of biomimetic monooxidation of ethylene into ethyl alcohol and acetaldehyde by hydrogen peroxide on the per-FTPhPFe3+OH/Al2O3 bioimitator, which showed high activity and unique resistance to the action of high-active intermediate reaction products was investigated. As a result of studying the kinetic regularities of the selective biomimetic oxidation of ethylene by hydrogen peroxide, a coherent-synchronized nature of the reaction was observed, consisting of two reactions: 1) primary (catalase) and 2) secondary (monooxygenase and peroxidase) reactions. A new approach to the kinetic modeling based on the determinant equation and coherence correlation of catalase-monooxygenase and catalase-peroxidase reactions coherently synchronized with each other was developed. The kinetic model of the process was developed on the basis of the determinant equation, which allows assessing the coherent nature of synchronously flowing reactions both qualitatively and quantitatively. Effective rate constants of catalase, monooxygenase and peroxidase reactions were determined based on this model as well as their effective activation energies were calculated.

Concise synthesis of moracin M using Appel mediated dehydration of a bioinspired endoperoxide

A synthesis of moracin M using Appel dehydration of a biomimetic inspired endoperoxide and subsequent late stage aromatization, is described. A key 1,3-diene, obtained from a base-free Suzuki-Miyaura coupling, can undergo biomimetic oxidation to its endoperoxide, followed by dehydration under Appel conditions and aromatization to give a benzofuran, with subsequent deprotection then providing moracin M in only 4-steps. Alternatively, this 1,3‑diene can undergo aromatization and subsequent deprotection providing a synthetic route to resveratrol.

KINETICS OF COHERENT-SYNCHRONIZED PEROXIDASE OXIDATION OF ETHYL ALCOHOL TO ACETALDEHYDE ON HETEROGENIZED BIOMIMETIC CATALYSTS

The peroxidase activity of the synthesized heterogeneous biomimetic catalysts, PPFe3+OH/Al2O3, TPhPFe3+OH/Al2O3 and per-FTPhPFe3+OH/Al2O3 in the reaction of ethyl alcohol oxidation to acetaldehyde with hydrogen peroxide has been studied, which showed high catalase activity and unique resistance to the action of highly active intermediate reaction products. As a result of studying the kinetic regularities of the selective biomimetic oxidation of ethyl alcohol with hydrogen peroxide, a coherent-synchronized nature of the reaction was established, consisting of two: 1) catalase and 2) peroxidase reactions. The kinetics of coherent-synchronized peroxidase oxidation of ethyl alcohol to acetaldehyde on heterogenized biomimetic catalysts, PPFe3+OH/Al2O3, TPhPFe3+OH/Al2O3 and per-FTPhPFe3+OH/Al2O3 has been studied. Based on the determinant equation, which makes it possible to qualitatively and quantitatively evaluate the coherent nature of synchronously occurring reactions and the reaction coherence ratio, a kinetic model of the process has been compiled. On the basis of the compiled kinetic model, the effective rate constants of the catalase and peroxidase reactions were derived, respectively. The derived kinetic model of the process is characterized by a high adequate description of the experimental data

Progress in the application of metalloporphyrins compounds in catalytic oxidation reactions

<p indent="0mm"><b/>Metalloporphyrins, as model compounds of P-450 enzyme, have been widely used in biomimetic catalytic oxidation reactions. The biomimetic catalytic oxidation system developed by metalloporphyrins has been gathering much attention due to the characteristics of high efficiency, good selectivity and mild conditions. In this paper, the application of metalloporphyrins as catalysts for the catalytic oxidation were reviewed, mainly including the oxidation of alkanes, olefins, alcohols, ketones and other substrates. The possible reaction mechanism and active species were summarized. Last, the challenges and prospects of metalloporphyrins complexes in catalytic oxidation were discussed.