Phenol Coupling Reaction Research Articles

Solvent-dependent reaction mechanisms in the electrooxidative coupling of phenols: insights by operando Raman spectroelectrochemistry.

The electrochemical oxidative phenol coupling reaction is a sustainable method for accessing biphenolic compounds. Using the dimerization of sesamol as a model reaction, insights into the reaction mechanism were gained via operando Raman spectroscopy. By varying the solvent and electrodes, different reaction mechanisms were identified and correlated with the respective product yields.

Advances in Exploring Mechanisms of Oxidative Phenolic Coupling Reactions

Biphenolic compounds serve as important scaffolds for the development of biologically active molecules. Among the methods for the synthesis of biarenols, oxidative coupling, which directly forms a C–C bond, has been extensively explored in various metal‐catalyzed (V, Cr, Co, Fe, Cu, etc.) reactions, electrochemical reactions, and photochemical reactions over the decades. While the exact mechanisms remain elusive in many cases, numerous mechanistic studies have provided valuable insights. This review focuses on the mechanistic details of the oxidative coupling of phenols or naphthols, involving at least one radical at least one radical intermediate. Additionally, the factors governing chemoselectivity (homo‐ and cross‐coupling), regioselectivity (ortho‐, meta‐ and para‐), and enantioselectivity (R and S configuration) are discussed, with a particular emphasis on intermediates and transition states, encompassing various oxidation sites for phenols and potential coupling sites.

Cell-free hemoglobin and hemin catalyzing triclosan oxidative coupling in plasma: A novel exogenous phenolic pollutants coupling pathway

Previous studies reported that hemoprotein CYP450 catalyzed triclosan coupling is an “uncommon” metabolic pathway that may enhance toxicity, raising concerns about its environmental and health impacts. Hemoglobin, a notable hemoprotein, can catalyze endogenous phenolic amino acid tyrosine coupling reactions. Our study explored the feasibility of these coupling reactions for exogenous phenolic pollutants in plasma. Both hemoglobin and hemin were found to catalyze triclosan coupling in the presence of H₂O₂. This resulted in the formation of five diTCS-2 H, two diTCS-Cl-3 H, and twelve triTCS-4 H in phosphate buffer, with a total of nineteen triclosan coupling products monitored using LC-QTOF. In plasma, five diTCS-2 H, two diTCS-Cl-3 H, and two triTCS-4 H were detected in hemoglobin-catalyzed reactions. Hemin showed a weaker catalytic effect on triclosan transformation compared to hemoglobin, likely due to hemin dimerization and oxidative degradation by H₂O₂, which limits its catalytic efficiency. Triclosan transformation in the human plasma-like medium still occurs with high H₂O₂, despite the presence of antioxidant proteins that typically inhibit such transformations. In plasma, free H₂O₂ was depleted within 40 minutes when 800 µM H₂O₂ was added, suggesting a rapid consumption of H₂O₂ in these reactions. Antioxidative species, or hemoglobin/hemin scavengers such as bovine serum albumin, may inhibit but not completely terminate the triclosan coupling reactions. Previous studies reported that diTCS-2 H showed higher hydrophobicity and greater endocrine-disrupting effects compared to triclosan, which further underscores the potential health risks. This study indicates that hemoglobin and heme in human plasma might significantly contribute to phenolic coupling reactions, potentially increasing health risks.

Discovery and Biosynthesis of Cihanmycins Reveal Cytochrome P450-Catalyzed Intramolecular C–O Phenol Coupling Reactions

Discovery and Biosynthesis of Cihanmycins Reveal Cytochrome P450-Catalyzed Intramolecular C–O Phenol Coupling Reactions

Solar‐Light‐Driven Photocatalytic Oxidative Coupling of Phenol Derivatives over Bismuth‐Based Porous Metal Halide Perovskites

AbstractThe selective oxidative coupling of phenol derivatives, involving carbon‐carbon (C−C) and carbon‐oxygen (C−O) bond formation, has emerged as a critical approach in the synthesis of natural products. However, achieving precise control over the selectivity in coupling reactions of unsubstituted phenols utilizing solar light as the driving force remains a big challenge. In this study, we report a series of porous Cs3Bi2X9 (X=Cl, Br, I) photocatalysts with tailored band gaps and compositions engineered for efficient solar‐light‐driven oxidative phenol coupling. Notably, p‐Cs3Bi2Br9 exhibited about 73 % selectivity for C−C coupling, displaying a high formation rate of 47.3 μmol gcat−1 h−1 under solar radiation. Furthermore, this approach enables control of the site‐selectivity for phenol derivatives on Cs3Bi2X9, enhancing C−C coupling. The distinctive porous structure and appropriate band‐edge positions of Cs3Bi2Br9 facilitated efficient charge separation, and surface interaction/activation of phenolic hydroxyl groups, resulting in the kinetically preferred formation of C−C over C−O bond. Mechanistic insights into the reaction pathway, supported by comprehensive control experiments, unveiled the crucial role of interfacial charge transfers and Lewis acid Bi sites in stabilizing phenolic intermediates, thereby directing the regioselectivity of diradical couplings and resulting in the formation of unsymmetrical biphenols.

Solar-Light-Driven Photocatalytic Oxidative Coupling of Phenol Derivatives over Bismuth-Based Porous Metal Halide Perovskites.

The selective oxidative coupling of phenol derivatives, involving carbon-carbon (C-C) and carbon-oxygen (C-O) bond formation, has emerged as a critical approach in the synthesis of natural products. However, achieving precise control over the selectivity in coupling reactions of unsubstituted phenols utilizing solar light as the driving force remains a big challenge. In this study, we report a series of porous Cs3Bi2X9 (X=Cl, Br, I) photocatalysts with tailored band gaps and compositions engineered for efficient solar-light-driven oxidative phenol coupling. Notably, p-Cs3Bi2Br9 exhibited about 73 % selectivity for C-C coupling, displaying a high formation rate of 47.3 μmol gcat -1 h-1 under solar radiation. Furthermore, this approach enables control of the site-selectivity for phenol derivatives on Cs3Bi2X9, enhancing C-C coupling. The distinctive porous structure and appropriate band-edge positions of Cs3Bi2Br9 facilitated efficient charge separation, and surface interaction/activation of phenolic hydroxyl groups, resulting in the kinetically preferred formation of C-C over C-O bond. Mechanistic insights into the reaction pathway, supported by comprehensive control experiments, unveiled the crucial role of interfacial charge transfers and Lewis acid Bi sites in stabilizing phenolic intermediates, thereby directing the regioselectivity of diradical couplings and resulting in the formation of unsymmetrical biphenols.

Racemic total synthesis of oxomaritidine by iodobenzene-catalyzed oxidative phenolic coupling under mild reaction conditions

A hypervalent iodine-catalyzed phenolic coupling reaction of norbelladine derivatives was examined with a catalytic amount of iodobenzene and meta-chloroperbenzoic acid as the terminal oxidant. The addition of acetic acid dramatically accelerated the reaction rate even at room temperature, and the cyclized products were successfully obtained under mild reaction conditions. The methods were applicable to the racemic total synthesis of oxomaritidine.

Characterization of two CYP80 enzymes provides insights into aporphine alkaloid skeleton formation in Aristolochia contorta.

Aporphine alkaloids are a large group of natural compounds with extensive pharmaceutical application prospects. The biosynthesis of aporphine alkaloids has been paid attentions in the past decades. Here, we determined the contents of four 1-benzylisoquinoline alkaloids and five aporphine alkaloids in root, stem, leaf, and flower of Aristolochia contorta Bunge, which belongs to magnoliids. Two CYP80 enzymes were identified and characterized from A. contorta. Both of them catalyze the unusual C-C phenol coupling reactions and directly form the aporphine alkaloid skeleton. AcCYP80G7 catalyzed the formation of hexacyclic aporphine corytuberine. AcCYP80Q8 catalyzed the formation of pentacyclic proaporphine glaziovine. Kingdom-wide phylogenetic analysis of the CYP80 family suggested that CYP80 first appeared in Nymphaeales. The functional divergence of hydroxylation and C-C (or C-O) phenol coupling preceded the divergence of magnoliids and eudicots. Probable crucial residues of AcCYP80Q8 were selected through sequence alignment and molecular docking. Site-directed mutagenesis revealed two crucial residues E284 and Y106 for the catalytic reaction. Identification and characterization of two aporphine skeleton-forming enzymes provide insights into the biosynthesis of aporphine alkaloids.

Synthetic Studies of Hasubanan Alkaloids Based on Oxidative Phenolic Coupling and Intramolecular Aza-Michael Reaction

Synthetic Studies of Hasubanan Alkaloids Based on Oxidative Phenolic Coupling and Intramolecular Aza-Michael Reaction

Proposal for the classification of sinomenine alkaloids

The chemical structure of sinoacutine is formed by a phenanthrene nucleus and an ethylamine bridge. Because it has a similar parent structure to morphine, it is subdivided into morphinane. At present, all reports have pointed out that the basic skeleton of morphine alkaloids is salutaridine (the isomer of sinoacutine), which is generated by the phenol coupling reaction of (R)-reticuline. This study shows that the biosynthetic precursors of sinoacutine and salutaridine are different. In this paper, the sinoacutine synthetase (SinSyn) gene was cloned from Sinomenium acutum and expressed SinSyn protein. Sinoacutine was produced by SinSyn catalyzed (S)-reticuline, according to the results of enzyme-catalyzed experiments. The optical activity, nuclear magnetic resonance, and mass spectrum of sinoacutine and salutaridine were analyzed. The classification and pharmacological action of isoquinoline alkaloids were discussed. It was suggested that sinoacutine should be separated from morphinane and classified as sinomenine alkaloids.

Unravelling the C-C and C-N coupling mechanism for the CYP96T1-catalyzed biosynthesis of Amaryllidaceae alkaloids

Plant cytochrome P450s (CYPs) comprise a vast family of enzymes intricately involved in the biosynthesis of natural products. However, the mechanistic understanding of the plant P450s’ catalysis is rather limited before. In this study, comprehensive simulations were performed to elucidate the C-C and C-N coupling mechanism involved in the biosynthesis of Amaryllidaceae alkaloids catalyzed by CYP96T1. Our simulations propose that the C-C coupling process follows a diradical mechanism. Especially, the proximal phenol OH group can be H-bonded to the active species of Cpd I, allowing the facile hydrogen atom transfer (HAT) from the phenol OH to Cpd I. In addition, the initial HAT disrupts the H-bond interaction between the proximal phenol group and the Cpd II species, enabling the approach of the distal phenol group for the second HAT, en route to the diradical species. The following para-para' C-C phenolic coupling reaction was observed to take place within the active site. In the context of the C-N coupling reaction, our calculations indicate that the reactions proceed via an Aza-Michael addition mechanism, facilitated by the acid-base catalysis provided by phosphate ions from the pH buffer. Notably, both the C1-N and C5-N coupling exhibit comparable energy barriers, resulting in the formation of the experimentally observed products 3 ((6R, 1S)-noroxomaritidine) and 4 ((6R, 5S)-noroxomaritidine). Our investigation has not only elucidated the mechanistic aspects of the C-C and C-N formation mechanism underlying the biosynthesis of Amaryllidaceae alkaloids, but also underscored the synergy between enzymatic transformations within P450 and non-enzymatic transformations within an aqueous solution during the biosynthesis of natural products.

Co(II)-Based Metal-Organic Framework Derived CA-CoNiMn-CLDHs with Peroxidase-like Activity for Colorimetric Detection of Phenol.

Given the serious harm of toxic phenol to human health and the ecological environment, it is urgent to develop an efficient, low-cost and sensitive nanoenzyme-based method to monitor phenol. MOF-derived nanozyme has attracted wide interest due to its hollow polyhedra structure and porous micro-nano frameworks. However, it is still a great challenge to synthesize MOF-derived multimetal synergistic catalytic nanoenzymes in large quantities with low cost. Herein, we reported the synthetic strategy of porous hollow CA-CoNiMn-CLDHs with ZIF-67 as templates through a facile solvothermal reaction. The prepared trimetallic catalyst exhibits excellent peroxidase-like activity to trigger the oxidative coupling reaction of 4-AAP and phenol in the presence of H2O2. The visual detection platform for phenol based on CA-CoNiMn-CLDHs is constructed, and satisfactory results are obtained. The Km value for CA-CoNiMn-CLDHs (0.21 mM) is lower than that of HRP (0.43 mM) with TMB as the chromogenic substrate. Because of the synergistic effect of peroxidase-like activity and citric acid functionalization, the built colorimetric sensor displayed a good linear response to phenol from 1 to 100 μM with a detection limit of 0.163 μM (3σ/slope). Additionally, the CA-CoNiMn-CLDHs-based visual detection platform possesses high-chemical stability and excellent reusability, which can greatly improve economic benefits in practical applications.

Tyrosine glucosylation of collagen films exploiting Horseradish Peroxidase (HRP)

The development of human tissue models for regenerative medicine and animal-free drug screening requires glycosylated biomaterials such as collagen. An easy and fast biomaterial glycosylation method exploiting Horseradish Peroxidase (HRP) phenol coupling reaction is proposed. The protocol is adaptable to any polymer functionalized with phenol residues or tyrosine containing proteins. As a model the tyrosine residues on collagen films were functionalized with salidroside, a natural β-glucoside with a phenol in the aglycone. Scanning Electron Microscope (SEM) and contact angle analysis revealed the influence of glycosylation on the sample's morphology and wettability. Preliminary biological evaluation showed the cytocompatibility of the glucosylated collagen films.

Preparation and catalytic degradation of phenol achieved by utilizing pH and Upper Critical Solution Temperature dual responsive intelligent enzyme catalysts

Phenolic compounds are toxic substances that exert harmful effects on all living organisms. Irrigation farmland with phenolic wastewater can result in reduced crop yields or even crop failure, while consuming phenolic wastewater has a strong carcinogenic effect. Horseradish peroxidase (HRP), a heme-containing peroxidase, is capable of catalyzing the oxidative conversion and coupling reaction of phenols in sewage to form polymerization products in the presence of hydrogen peroxide (H2O2). However, free HRP can only function within a relatively narrow range of temperature and pH conditions, and its excellent water solubility makes it difficult to recover, thereby significantly increasing the cost of enzyme utilization. The immobilized enzyme was prepared by incorporating HRP and self-synthesized UCST (Upper Critical Solution Temperature) and pH dual responsive polymer P(NAGA-b-AA-b-VBA). The loading capacity of HRP reached 295 mg/g while maintaining the UCST performance. Compared to the free enzyme, the immobilized enzyme exhibited enhanced pH stability, thermal stability and storage stability. In laboratory experiments as well as actual water samples, the immobilized enzyme achieved phenol degradation rates of 90.4% and 88.4% respectively, within 1 h. After five cycles, the immobilized enzyme retained 80.1% catalytic activity with a recovery rate of 84.5%. Furthermore, it was demonstrated that the biological toxicity of the reaction product was significantly lower than that of simulated pollutant phenol.

Scope and Mechanistic Studies on the Ruthenium-Catalyzed Multicomponent Deaminative C–H Coupling Reaction of Phenols with Aldehydes and Enamines for the Formation of Xanthene and Dioxacyclic Derivatives

The in situ generated catalytic system from the tetranuclear Ru–H complex [(PCy3)(CO)RuH]4(O)(OH)2 (1) with 3,4,5,6-tetrachloro-1,2-benzoquinone (L1) has been found to mediate a multicomponent deaminative coupling reaction of phenols with aldehydes and enamines to form xanthene products. The multicomponent C–H coupling reaction of phenols with 2-hydroxybenzaldehydes and cyclic enamines efficiently installed the tricyclic 1,3-dioxacin derivatives, while the analogous coupling reaction of phenols with 2-hydroxybenzaldehydes and triethylamine selectively formed bicyclic 1,5-dioxacyclic derivatives. The density functional theory (DFT) calculations established two energetically viable mechanistic pathways for the formation of xanthene products, in which both pathways identified the C–O bond cleavage step as the turnover limiting step. A Hammett plot from the coupling reaction of 3,5-dimethoxyphenol with an enamine and para-substituted benzaldehydes p-X-C6H4CHO (X = OMe, Me, H, Cl, CF3) showed a negative slope (ρ = −0.98). The calculated energy analysis showed a similar trend (ρ = −0.59) for the mechanism via the C–O cleavage rate-limiting step. The combined experimental and DFT computational results support a mechanistic path that involves the dehydrative C–H coupling of phenol with aldehyde, followed by the deaminative coupling reaction with an enamine in forming the xanthene product.

One-Pot Synthesis of Diverse 1,4-[60]Fullerephenols via Three-Component Umpolung Cascade Coupling of Phenols, C60 , and Nucleophiles.

A three-component umpolung cascade coupling reaction of phenols, C60 , and different nucleophiles which includes H2 O, alcohols, triphenylamines and carbazoles was developed. Furthermore, one-pot 1,4-bisphenol coupling on C60 has been realized by this method. This practical protocol features high chemo- and regioselectivity, wide substrate range, easy operation and low cost, thus providing a robust method for the one-pot synthesis of various unsymmetrical 1,4-[60]fullerephenols.

Customizable Low-Friction Tough Hydrogels for Potential Cartilage Tissue Engineering by a Rapid Orthogonal Photoreactive 3D-Printing Design.

Hydrogels have demonstrated wide applications in tissue engineering, but it is still challenging to develop strong, customizable, low-friction artificial scaffolds. Here, we report a rapid orthogonal photoreactive 3D-printing (ROP3P) strategy to achieve the design of high-performance hydrogels in tens of minutes. The orthogonal ruthenium chemistry enables the formation of multinetworks in hydrogels via phenol-coupling reaction and traditional radical polymerization. Further Ca2+-cross-linking treatment greatly improves their mechanical properties (6.4 MPa at a critical strain of 300%) and toughness (10.85 MJ m-3). The tribological investigation reveals that the high elastic moduli of the as-prepared hydrogels improve their lubrication (∼0.02) and wear-resistance performances. These hydrogels are biocompatible and nontoxic and promote bone marrow mesenchymal stem cell adhesion and propagation. The introduction of 1-hydroxy-3-(acryloylamino)-1,1-propanediylbisphosphonic acid units can greatly enhance their antibacterial property to kill typical Escherichia coli and Staphylococcus aureus. Moreover, the rapid ROP3P can achieve hydrogel preparation in several seconds and is readily compatible with making artificial meniscus scaffolds. The printed meniscus-like materials are mechanically stable and can maintain their shape under long-term gliding tests. It is anticipated that these high-performance customizable low-friction tough hydrogels and the highly efficient ROP3P strategy could promote further development and practical applications of hydrogels in biomimetic tissue engineering, materials chemistry, bioelectronics, and so on.

Spectrophotometric Determination of Some Phenolic Compounds Via Oxidative Coupling Reaction Using 4-Aminoantipyrine

A spectrophotometric method has been developed for the determination of some phenolic compounds (Catechol, Resorcinol and Quinol). The method is based on oxidative coupling reaction of these compounds with 4-aminoantipyrine (4-AAP) in the presence of cupper sulphate as oxidizing agent in alkaine medium forming a brown colour. The products show maximum absorption at 404 nm, 474 nm and 392 nm for Catechol, Resorcinol and Quinol respectively. The molar absorptivities are 12133, 7695 and 16570 l/mol.cm for concentrations obeyed Beer’s law in the range 0.2 - 14, 0.04 - 18 and 0.2 - 4 μg.ml-1 for the above compounds respectively. The average recovery was ranged between 97.72% and 100.05% with relative standard deviation less than 3.4 for all the studied compounds, The 4-AAP products were formed in the ratio of 1:2 phenolic compound: 4-AAP With the exception of the complex catechol:4-amino antipyrine, it is in a 1:1 ratio. The stability constant of the products was 1.8369 × 104 (l.mol-1) , 2.82 × 1010 and 1.285 × 1010 (l2.mol-2) for Catechol, Resorcinol and Quinol products respectively indicating the good stability of these products, The effect of a number of interfering substances represented by primary and secondary aliphatic alcohols, aliphatic amines and other organic compounds was also studied. Finally, the results obtained indicate the selectivity of the method as there was no interference from the additives.

19F‐NMR shows that active site aromatic residues in CYP121 of Mycobacterial tuberculosisplay a dual role in substrate interaction and protein structure

CYP121 is an essential cytochrome P450 enzyme (CYP) from Mycobacterium tuberculosis.CYP121 mediates an atypical phenol‐coupling reaction that converts cyclodityrosine (cYY) into mycocylosin. Our lab has previously employed a 19F nuclear magnetic resonance (NMR) label, 3‐bromo‐1,1,1‐trifluoroacetone (BTFA), to study dynamics of the FG‐loop, a region connecting the F and G‐helices. In other CYPs, the FG‐loop region has been implicated in active site access and substrate recognition. The 19F‐NMR spectrum for the FG‐loop in CYP121 is heterogeneous, suggesting that in solution there are multiple conformations. Upon titration of cYY, the signal converges to a single peak representing a bound state. Interestingly, this labeling site exists approximately 20 angstroms away from the active site heme, where ligand binding is typically measured in CYPs by UV‐visible spectroscopy. Crystal structures show an invariable protein structure with ligands clustered near the FG‐helices, away from the heme.Here we investigate the specificity of this interaction site by expanding our use of 19F labeling. Supplementing cells with 5‐fluoroindole (5‐FI) during recombinant protein expression, 19F was incorporated into each tryptophan residue of CYP121. This method of labeling allowed for four tryptophan residues to be monitored, which span the entire protein structure. Notably, two residues, Trp‐182 and Trp‐380, are located adjacent to the CYP121 homodimer interface. The 19F‐NMR spectrum contains three distinct signals, two of which are equal in intensity, and a third which has been determined to be two overlapping resonances. Addition of cYY causes a shift of equilibrium in the spectra, with the overlapped resonances resolving and resulting in four peaks of roughly equal area and intensity. These results suggest that only the active site residue Trp‐182 is affected by the addition of cYY. Using this labeling scheme, we also tested alanine substitutions of Trp‐182 and another active site aromatic residue, Phe‐168. 19F‐NMR spectra from these mutants indicate a general perturbation of the structure, with only one Trp residue left unaffected. Since Trp‐182 extends into a hydrophobic pocket of CYP121 (suggesting a structural role), additional substitutions were made using tyrosine and leucine side chains. The conservative W182Y mutant yielded similar disorder as seen when replaced with alanine, while W182L results a partially restored spectrum. Interestingly, both mutants bind substrate in a similar manner as wild‐type when measured by UV‐visible spectroscopy, although with weakened affinity.These findings indicate that while Phe‐168 and Trp‐182 are involved in substrate interaction, they also play a role in the fold of the protein, with mutagenesis causing long range changes in structure.

Computational Investigation of the Bisphenolic Drug Metabolism by Cytochrome P450: What Factors Favor Intramolecular Phenol Coupling.

Intramolecular phenol coupling reactions of alkaloids can lead to active metabolites catalyzed by the mammalian cytochrome P450 enzyme (P450); however, the mechanistic knowledge of such an "unusual" process is lacking. This work performs density functional theory computations to reveal the P450-mediated metabolic pathway leading from R-reticuline to the morphine precursor salutaridine by exploring possible intramolecular phenol coupling mechanisms involving diradical coupling, radical addition, and electron transfer. The computed results show that the outer-sphere electron transfer with a high barrier (>20.0 kcal/mol) is unlikely to happen. However, for inter-sphere intramolecular phenol coupling, it reveals that intramolecular phenol coupling of R-reticuline proceeds via the diradical mechanism consecutively by compound I and protonated compound II of P450 rather than the radical addition mechanism. The existence of a much higher radical rebound barrier than that of H-abstraction in the quartet high-spin state can endow the R-reticuline phenoxy radical with a sufficient lifetime to enable intramolecular phenol coupling, while the H-abstraction/radical rebound mode with a negligible rebound barrier leading to phenol hydroxylation can only happen in the doublet low-spin state. Therefore, the ratio [coupling]/[hydroxylation] can be approximately reflected by the relative yield of the high-spin and low-spin H-abstraction by P450, which thus can provide a theoretical ratio of 16:1 for R-reticuline, which is in accordance with previous experimental results. Especially, the high rebound barrier of the phenoxy radical derived from the weak electron-donating ability of the phenoxy radical is revealed as an intrinsic nature. Therefore, the revealed intramolecular phenol coupling mechanism can be potentially extended to several other bisphenolic drugs to infer groups of unexpected metabolites in organisms.