Electrophilic Reactions Research Articles

Oxidative Coupling of Hydroquinone Derivatives with Olefins to Dihydrobenzofurans.

Dihydrobenzofuran is an important skeleton for bioactive compounds and natural products. Hydroquinones can be easily modified into substituted hydroquinones, which effectively undergo oxidation to produce the corresponding benzoquinone derivatives. Benzoquinones are reactive electrophiles that are frequently utilized in coupling with olefins to dihydrobenzofurans. Herein, we report the one-pot oxidative coupling of hydroquinones bearing an electron-withdrawing group at the C2 position with olefins to dihydrobenzofurans in the presence of the Lewis acidic FeCl3 and 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) oxidant. Furthermore, this method was applied to the oxidative coupling of N-electron-withdrawing group-substituted 4-aminophenol.

Bifunctional Ligand Enables Gold-Catalyzed Propargyl C-H Functionalization via Reactive Gold Allenylidene Intermediate.

Gold allenylidene species have been seldom exploited as reactive intermediates in synthetically versatile catalytic reactions. By employing alkynylbenziodoxoles as the substrates and bifunctional WangPhos as the metal ligand, this work demonstrated ready catalytic access to these intermediates of general substitution patterns and their electrophilic reactivities at the γ-carbon center with a diverse range of nucleophiles. The reaction is driven by the reductive decomposition of the benziodoxole moiety and achieves the replacement of a propargylic proton with an N/O/C-based nucleophile, hence realizing reactivity umpolung. Corroborated by Density Functional Theory (DFT) calculations, the reaction mechanism involves a mild propargylic deprotonation. In contrast to prior works employing a tertiary amine functionality, a weakly BrØnsted-basic amide group in WangPhos is surprisingly effective in deprotonation at the propargylic position under a gold-ligand cooperation regime.

Bifunctional Ligand Enables Gold‐Catalyzed Propargyl C−H Functionalization via Reactive Gold Allenylidene Intermediate

AbstractGold allenylidene species have been seldom exploited as reactive intermediates in synthetically versatile catalytic reactions. By employing alkynylbenziodoxoles as the substrates and bifunctional WangPhos as the metal ligand, this work demonstrated ready catalytic access to these intermediates of general substitution patterns and their electrophilic reactivities at the γ‐carbon center with a diverse range of nucleophiles. The reaction is driven by the reductive decomposition of the benziodoxole moiety and achieves the replacement of a propargylic proton with an N/O/C‐based nucleophile, hence realizing reactivity umpolung. Corroborated by Density Functional Theory (DFT) calculations, the reaction mechanism involves a mild propargylic deprotonation. In contrast to prior works employing a tertiary amine functionality, a weakly BrØnsted‐basic amide group in WangPhos is surprisingly effective in deprotonation at the propargylic position under a gold‐ligand cooperation regime.

SYNTHESIS OF BENZO[B]THIOPHENE-BASED ORGANIC COMPOUNDS AND THEIR HYDRAZINE ELECTROOXIDATION PERFORMANCE AS AN ANODE CATALYST

In this study, 3-iodo-2-(p-tolyl)benzo[b]thiophene (4C) is synthesized by using Sonagashira coupling reactions and electrophilic cyclization reactions. Electrochemical measurements have been performed using electrochemical methods such as cyclic voltammetry (CV), chronoamperometry (CA) and electrochemical impedance spectroscopy (EIS) in the environment of 1 M KOH + 0.5M N2H4 solution. The CV results obtained showed that 4C catalyst promoted the generation of the best current (15.40 mA/cm2), and EIS results confirmed that electrode modifeed with the same derivative presented the lowest charge transfer resistance. Taken together, these results suggest that 4C organocatalyst could be used as an anode efficient catalyst in hydrazine (N2H4) fuel cells.

Nucleophiles Target the Tungsten Center Over Acetylene in Biomimetic Models.

Inspired by the first shell mechanism proposed for the tungstoenzyme acetylene hydratase, the electrophilic reactivity of tungsten-acetylene complexes [W(CO)(C2H2)(6-MePyS)2] (1) and [WO(C2H2)(6-MePyS)2] (2) was investigated. The biological nucleophile water/hydroxide and tert-butyl isocyanide were employed. Our findings consistently show that, regardless of the nucleophile used, both tungsten centers W(II) and W(IV), respectively, are the preferred targets over the coordinated acetylene. Treatment of 2 with aqueous NaOH led to protonation of coordinated acetylene to ethylene, pointing toward the Brønsted basic character of the coordinated alkyne instead of the anticipated electrophilic behavior. In cases involving isocyanides as nucleophiles, the attack on the W(II) center of 1 took place first, whereas the W(IV) complex 2 remained unchanged. These experiments indicate that the direct nucleophilic attack of W-coordinated acetylene by water, as some computational studies of acetylene hydratase propose, is unlikely to occur.

Be12B12: A core@cage structure beryllo-borospherene

A new class of beryllium-boron cluster, core@cage structure beryllo-borospherene, is described herein theoretically. The global minimum of Be12B12 cluster is a core@cage configuration with D3 symmetry, one Be atom is positioned at the center of cage, with the cage surface composed of η6-Be atom face-capping a hexagon (a Be atom occupies a Be3B3 hexagon in a face-capping η6 configuration) at both ends (top and bottom) and a jagged Be3B6 ring in the middle. Theoretical analyses reveal that in this system, the Be atom serves as donor for almost two electrons to the B atoms, forming typical electrostatic interactions, while the interaction between the B atoms is mainly covalent interaction. Further theoretical calculations indicate that the core@cage structure Be12B12 exhibits unique polarization properties, nucleophilic and electrophilic reaction site characteristics, and spectral properties. Similar to the magic-size (CdSe)13 and B12N12, Be12B12 is anticipated to yield more exotic properties and further widespread applications.

Controlling Redox Potential of a Manganese(III)-Bis(hydroxo) Complex through Protonation and the Hydrogen-Atom Transfer Reactivity.

A series of mononuclear manganese(III)-hydroxo and -aqua complexes, [MnIII(TBDAP)(OH)2]+ (1), [MnIII(TBDAP)(OH)(OH2)]2+ (2) and [MnIII(TBDAP)(OH2)2]3+ (3), were prepared from a manganese(II) precursor and confirmed using various methods including X-ray crystallography. Thermodynamic analysis showed that protonation from hydroxo to aqua species resulted in increased redox potentials (E1/2) in the order of 1 (-0.15 V) < 2 (0.56 V) < 3 (1.11 V), while pKa values exhibited a reverse trend in the order of 3 (3.87) < 2 (11.84). Employing the Bordwell Equation, the O-H bond dissociation free energies (BDFE) of [MnII(TBDAP)(OH)(OH2)]+ and [MnII(TBDAP)(OH2)2]2+, related to the driving force of 1 and 2 in hydrogen atom transfer (HAT), were determined as 75.3 and 77.3 kcal mol-1, respectively. It was found that the thermodynamic driving force of 2 in HAT becomes greater than that of 1 as the redox potential of 2 increases through protonation from 1 to 2. Kinetic studies on electrophilic reactions using a variety of substrates revealed that 1 is only weakly reactive with O-H bonds, whereas 2 can activate aliphatic C-H bonds in addition to O-H bonds. The reaction rates increased by 1.4 × 104-fold for the O-H bonds by 2 over 1, which was explained by the difference in BDFE and the tunneling effect. Furthermore, 3, possessing the highest redox potential value, was found to undergo an aromatic C-H bond activation reaction under mild conditions. These results provide valuable insights into enhancing electrophilic reactivity by modulating the redox potential of manganese(III)-hydroxo and -aqua complexes through protonation.

Electrophilic aryl spiroannulation induced by diaryliodonium salts: efficient synthesis of [5,5]-spiro lactone-lactam scaffolds from α-cyanocarboxylates

Spirocyclic architectures represent one of the privileged three-dimensional scaffolds in pharmaceutical chemistry and drug discovery, while the new-skeletal synthesis of spiromolecules from simple starting materials remains a challenging task. Here, we report a first diaryliodonium salts mediated electrophilic aryl spiroannulation reaction from simple substrates α-cyanocarboxylate. With this strategy, a broad spectrum of new [5,5] spiro-fused skeletons could be efficiently constructed in one step via Cu-catalyzed cascaded N-arylation-acylation and etheral skeleton rearrangement reaction. The key point of this transformation was the intramolecular electrophilic cyclization due to the nucleophilicity of O-atom and electrophilicity of α-C induced by diaryliodonium salts. With this protocol, the more challenging activation of ether bonds was achieved via diaryliodonium salts-mediated. This method has the major advantages of a broad substrate scope and excellent functional group compatibility. Further synthesis elaboration was performed using substrate with steric hindrance to showcase the versatility of this methodology.

In situ activation of peroxymonosulfate with bioelectricity for sulfamethoxazole sustainable removal

Conventional electrochemical activation of peroxymonosulfate (PMS) is not very cost-effective and practical by the excessive input of energy. The electricity generated by photosynthetic microalgae fuel cells (MFCs) is utilized to activate PMS, which would achieve the combination of green bioelectricity and advanced oxidation processes for sustainable pollutants degradation. In this study, a novel dual-chamber of MFCs was constructed by using microalgae as anode electron donor and PMS as cathode electron acceptor, which was operating under both close-circuit and open-circuit conditions. Under close-circuit condition, 1–12 mM PMS in cathode was successfully in situ activated, where 32.00%–99.83% of SMX was removed within 24 h, which was about 1.21–1.78 times of that in the open-circuit of MFCs. Meanwhile, a significant increase in bioelectricity generation in MFCs was observed after the accumulation of microalgae biomass (4.65–5.37 mg/L), which was attributed to the efficient electron separation and transfer. Furthermore, the electrochemical analysis demonstrated that SMX or its products were functioned as electronic shuttles, facilitating the electrochemical reaction and altering the electrical capacitance. The quenching experiments and voltage output results reflected that complex active radical (SO4⋅-, ⋅OH, and 1O2) were involved in SMX removal. Seven degradation products of SMX were detected and S–N bond cleavage was the main degradation pathway. Predicted toxicity values calculated by ECOSAR program showed that all the products were less toxic or nontoxic. Finally, the density functional theory (DFT) calculations revealed that the O and N atoms on SMX were more susceptible to electrophilic reactions, which were more vulnerable to be attacked by reactive species. This study provided new insights into the activation of PMS by bioelectricity for SMX degradation, proposing the mechanisms for PMS activation and degradation sites of SMX.

Kinetic Behavior of Glutathione Transferases: Understanding Cellular Protection from Reactive Intermediates.

Glutathione transferases (GSTs) are the primary catalysts protecting from reactive electrophile attack. In this review, the quantitative levels and distribution of glutathione transferases in relation to physiological function are discussed. The catalytic properties (random sequential) tell us that these enzymes have evolved to intercept reactive intermediates. High concentrations of enzymes (up to several hundred micromolar) ensure efficient protection. Individual enzyme molecules, however, turn over only rarely (estimated as low as once daily). The protection of intracellular protein and DNA targets is linearly proportional to enzyme levels. Any lowering of enzyme concentration, or inhibition, would thus result in diminished protection. It is well established that GSTs also function as binding proteins, potentially resulting in enzyme inhibition. Here the relevance of ligand inhibition and catalytic mechanisms, such as negative co-operativity, is discussed. There is a lack of knowledge pertaining to relevant ligand levels in vivo, be they exogenous or endogenous (e.g., bile acids and bilirubin). The stoichiometry of active sites in GSTs is well established, cytosolic enzyme dimers have two sites. It is puzzling that a third of the site's reactivity is observed in trimeric microsomal glutathione transferases (MGSTs). From a physiological point of view, such sub-stoichiometric behavior would appear to be wasteful. Over the years, a substantial amount of detailed knowledge on the structure, distribution, and mechanism of purified GSTs has been gathered. We still lack knowledge on exact cell type distribution and levels in vivo however, especially in relation to ligand levels, which need to be determined. Such knowledge must be gathered in order to allow mathematical modeling to be employed in the future, to generate a holistic understanding of reactive intermediate protection.

Crystalline Olefin-Linked Chiral Covalent Organic Frameworks as a Platform for Asymmetric Catalysis.

The construction of olefin-linked chiral covalent organic frameworks (COFs) with high crystallinity is highly desirable while remains great challenge due to the poor reversibility of the formation reaction for the olefin linkages during the in situ structural self-healing process. Herein, we successfully synthesized two sets of enantiomeric olefin-linked COFs. The chiral catalytic groups are uniformly distributed on the pore walls of COFs, resulting in the full exposure of catalytic sites to the reactants in asymmetric catalysis. The as-prepared (R)/(S)-CCOF8 exhibits excellent catalytic performance with exceeding 99 % enantiomeric excess in the enantioselective electrophilic amination reaction. Moreover, the heterogeneous chiral catalysts are conveniently recycled and could maintain the performance after ten catalytic cycles. Our findings expand the scope to construct stable and crystalline chiral COFs for the asymmetric catalysis.

Crystalline Olefin‐Linked Chiral Covalent Organic Frameworks as a Platform for Asymmetric Catalysis

AbstractThe construction of olefin‐linked chiral covalent organic frameworks (COFs) with high crystallinity is highly desirable while remains great challenge due to the poor reversibility of the formation reaction for the olefin linkages during the in situ structural self‐healing process. Herein, we successfully synthesized two sets of enantiomeric olefin‐linked COFs. The chiral catalytic groups are uniformly distributed on the pore walls of COFs, resulting in the full exposure of catalytic sites to the reactants in asymmetric catalysis. The as‐prepared (R)/(S)‐CCOF8 exhibits excellent catalytic performance with exceeding 99 % enantiomeric excess in the enantioselective electrophilic amination reaction. Moreover, the heterogeneous chiral catalysts are conveniently recycled and could maintain the performance after ten catalytic cycles. Our findings expand the scope to construct stable and crystalline chiral COFs for the asymmetric catalysis.

Modification of extracellular matrix proteins by oxidants and electrophiles.

The extracellular matrix (ECM) is critical to biological architecture and determines cellular properties, function and activity. In many situations it is highly abundant, with collagens and elastin being some of the most abundant proteins in mammals. The ECM comprises of multiple different protein species and sugar polymers, with both different isoforms and post-translational modifications (PTMs) providing a large variety of microenvironments that play a key role in determining tissue structure and health. A number of the PTMs (e.g. cross-links) present in the ECM are critical to integrity and function, whereas others are deleterious to both ECM structure and associated cells. Modifications induced by reactive oxidants and electrophiles have been reported to accumulate in some ECM with increasing age. This accumulation can be exacerbated by disease, and in particular those associated with acute or chronic inflammation, obesity and diabetes. This is likely to be due to higher fluxes of modifying agents in these conditions. In this focused review, the role and effects of oxidants and other electrophiles on ECM are discussed, with a particular focus on the artery wall and atherosclerotic cardiovascular disease. Modifications generated on ECM components are reviewed, together with the effects of these species on cellular properties including adhesion, proliferation, migration, viability, metabolic activity, gene expression and phenotype. Increasing data indicates that ECM modifications are both prevalent in human and mammalian tissues and play an important role in disease development and progression.

Investigating the Potential Pharmacological Applications of 5-Hydroxy-2 (hydroxymethyl)-4H pyran-4 one through Electronic Characterization and MM-GBSA Studies for Oxidative Stress and Tyrosinase Inhibition: A Quantum Chemical Approach

The study thoroughly examines the possible applications of 5 Hydroxy – 2 (hydroxymethyl) – 4 H pyran – 4 one. Through Quantum chemical analysis, the research rigorously evaluates the compound's properties, including its optoelectronics, geometrical structure, and intermolecular interactions. The geometrical structure parameters were optimized using a 6–311++G(d,p) basis set in the DFT/B3LYP method, and the resulting geometrical factors were then scaled to calculate probable vibrational wavenumbers. The Mulliken charges and MEP map were used to locate electrophilic, nucleophilic regions, and chemical reactivity was described using FMOs and Fukui function assessments. The multiwfn was employed to investigate topological analysis (surface distance projection and Hirshfeld maps). The UV-visible spectrum was used to estimate the absorption of maximum wavelengths, which was then correlated with the TD-DFT, DOS, and band structure investigations. The study also calculated parameters, including Total Energies, ZPE, Entropy, Dipole moment, and Heat Capacity for monomeric and dimeric units. Pharmacokinetics were used to determine the biological characteristics of the compound. The MM-GBSA simulation was performed, and the results suggest that this compound has the potential to be an enhancing anti-oxidant protection agent due to its high binding affinity and intermolecular interactions. These findings are crucial in developing therapeutic agents with pharmacological effects and potential toxicities.

Molecular structure, optical, first-order hyper polarizability, electronic properties, reactivity (ELF and LOL) − computational analysis using DFT and Multiwfn for 2, 3-diaminopyridinium selenate

A detailed study on the first principle calculations of 2,3-diaminopyridinium selenite (2,3-DAPS) – an organometallic salt has been performed using B3LYP/6–311++G(d,p). Single crystal X-ray diffraction (XRD) analysis confirms that the crystal formed exhibits a monoclinic crystal structure, specifically belonging to the centrosymmetric space group P21/c. The obtained primitives and interfacial angles are as follows: a = 7.4978(15)Å, b = 7.6681(15) Å, c = 14.314(3) Å, α = γ = 90°, β = 93.75(3)°, and the volume of the unit cell V = 821.2(3) (Å)3. The structure was optimized with a global minimum. The natural bonding orbital charge transfer studies between the cation and anion was performed to gain insights into their electronic interactions. Energy gap and other global chemical reactivity descriptors have been computed with the aid of molecular orbital studies. The influence of solvent on the absorption spectra provided the evidence of solvent–solute interactions and their impact on the electronic transitions within the molecule. The presence of electrophilic and nucleophilic reactivity in the chemical is indicated by the molecular electrostatic potential (MEP) map. From the nonlinear optical (NLO) studies, it has been found that the first-order hyperpolarizability value is 30.771 × 10−31 esu, which is 8.252 times that of urea. This suggests that the compound may be a better non-linear optical material and suitable for laser applications. To calculate the proportion of intermolecular interactions and examine the distribution compound's electrostatic potential, a Hirshfeld surface analysis was conducted. The analysis provided insights into the spatial arrangement of molecules and their interactions. Additionally, topology path calculations elucidated the intrinsic connectivity between critical points, shedding light on the bonding characteristics within the compound. The likelihood of electron density at bonding and anti-bonding sites was also determined using the Electron Localization Function (ELF) and Localised Orbital Locator (LOL) plots. These analyses aided in understanding the electron distribution and the nature of chemical bonding within the compound, providing valuable information about its electronic structure and reactivity.

DFT investigation for the mechanisms of γ-butyrolactones from styrene and acrylic acid, catalyzed by NMA*BF4 and PhSSPh

The reaction mechanisms of γ-butyrolactones through electrophilic addition reactions between styrene and acrylic acid, catalyzed by the 9-mesityl-10-methylacridinium ion (NMA*BF4) and diphenyl disulfide (PhSSPh) under 450 nm visible-light, were investigated by employing M06-2X-D3/ma-def2SVP method and basis set. In this study, the SMD model was taken to simulate the solvent effect of dichloromethane. The photocatalyst NMA absorbs the energy of photons and becomes an excited state, capturing an electron from styrene; this leads to an electrophilic addition reaction happened between the obtained styrene cationic radical and acrylic acid anion (or acrylic acid molecule); finally, an intramolecular ring-closure process and H-shift process result in the formation of the final product. The computational results point out that the electrophilic reaction is an exothermic process; and the optimal path for ring-closure reaction and H-shift reaction has Gibbs free energy barriers of 11.10 and 9.94 kcal/mol, respectively. In particular, the recycling of the photo-catalyst NMA and cocatalyst PhSSPh has also been discussed. The ρhole and ρele can reveal the charge transfer process during the photo-catalytic reaction. Results would provide valuable insights into these types of interaction and related processes.

Catalytic Enantioselective Electrophilic Difunctionalization of Unsaturated Sulfones.

An efficient protocol of enantioselective thiolative azidation of sulfone-tethered alkenes via a chiral chalcogenide catalyzed electrophilic reaction is disclosed. A series of enantioenriched sulfones bearing remote stereogenic centers was achieved with good yields and high enantioselectivities with linear unsaturated sulfones and cyclic unsaturated sulfones. Mechanistic studies revealed the importance of the sulfone group in the improvement of the reactivity and enantioselectivity of the reaction.

Engineering of Halide Methyltransferase BxHMT through Dynamic Cross-Correlation Network Analysis.

Halide methyltransferases (HMTs) provide an effective way to regenerate S-adenosyl methionine (SAM) from S-adenosyl homocysteine and reactive electrophiles, such as methyl iodide (MeI) and methyl toluene sulfonate (MeOTs). As compared with MeI, the cost-effective unnatural substrate MeOTs can be accessed directly from cheap and abundant alcohols, but shows only limited reactivity in SAM production. In this study, we developed a dynamic cross-correlation network analysis (DCCNA) strategy for quickly identifying hot spots influencing the catalytic efficiency of the enzyme, and applied it to the evolution of HMT from Paraburkholderia xenovorans. Finally, the optimal mutant, M4 (V55T/C125S/L127T/L129P), exhibited remarkable improvement, with a specific activity of 4.08 U/mg towards MeOTs, representing an 82-fold increase as compared to the wild-type (WT) enzyme. Notably, M4 also demonstrated a positive impact on the catalytic ability with other methyl donors. The structural mechanism behind the enhanced enzyme activity was uncovered by molecular dynamics simulations. Our work not only contributes a promising biocatalyst for the regeneration of SAM, but also offers a strategy for efficient enzyme engineering.

Engineering of Halide Methyltransferase BxHMT through Dynamic Cross‐Correlation Network Analysis

AbstractHalide methyltransferases (HMTs) provide an effective way to regenerate S‐adenosyl methionine (SAM) from S‐adenosyl homocysteine and reactive electrophiles, such as methyl iodide (MeI) and methyl toluene sulfonate (MeOTs). As compared with MeI, the cost‐effective unnatural substrate MeOTs can be accessed directly from cheap and abundant alcohols, but shows only limited reactivity in SAM production. In this study, we developed a dynamic cross‐correlation network analysis (DCCNA) strategy for quickly identifying hot spots influencing the catalytic efficiency of the enzyme, and applied it to the evolution of HMT from Paraburkholderia xenovorans. Finally, the optimal mutant, M4 (V55T/C125S/L127T/L129P), exhibited remarkable improvement, with a specific activity of 4.08 U/mg towards MeOTs, representing an 82‐fold increase as compared to the wild‐type (WT) enzyme. Notably, M4 also demonstrated a positive impact on the catalytic ability with other methyl donors. The structural mechanism behind the enhanced enzyme activity was uncovered by molecular dynamics simulations. Our work not only contributes a promising biocatalyst for the regeneration of SAM, but also offers a strategy for efficient enzyme engineering.

Transition Metal‐Free Catalytic C−H Zincation and Alumination

AbstractC−H metalation is the most efficient method to prepare aryl–zinc and –aluminium complexes that are ubiquitous nucleophiles. Virtually all C−H metalation routes to form Al/Zn organometallics require stoichiometric, strong Brønsted bases with no base‐catalyzed reactions reported. Herein we present a catalytic in amine/ammonium salt (Et3N/[(Et3N)H]+) C−H metalation process to form aryl‐zinc and aryl‐aluminium complexes. Key to this approach is coupling an endergonic C−H metalation step with a sufficiently exergonic dehydrocoupling step between the ammonium salt by‐product of C−H metalation ([(Et3N)H]+) and a Zn−H or Al−Me containing complex. This step, forming H2/MeH, makes the overall cycle exergonic while generating more of the reactive metal electrophile. Mechanistic studies supported by DFT calculations revealed metal‐specific dehydrocoupling pathways, with the divergent reactivity due to the different metal valency (which impacts the accessibility of amine‐free cationic metal complexes) and steric environment. Notably, dehydrocoupling in the zinc system proceeds through a ligand‐mediated pathway involving protonation of the β‐diketiminate Cγ position. Given this process is applicable to two disparate metals (Zn and Al), other main group metals and ligand sets are expected to be amenable to this transition metal‐free, catalytic C−H metalation.