Reactions Of Carbanions Research Articles

Discovery of drug targets based on traditional Chinese medicine microspheres (TCM-MPs) fishing strategy combined with bio-layer interferometry (BLI) technology

Target discovery of natural products is a key step in the development of new drugs, and it is also a difficult speed-limiting step. In this study, a traditional Chinese medicine microspheres (TCM-MPs) target fishing strategy was developed to discover the key drug targets from complex system. The microspheres are composed of Fe3O4 magnetic nanolayer, oleic acid modified layer, the photoaffinity group (4- [3-(Trifluoromethyl)-3H-diazirin-3-yl] benzoic acid, TAD) layer and active small molecule layer from inside to outside. TAD produces highly reactive carbene under ultraviolet light, which can realize the self-assembly and fixation of drug active small molecules with non-selective properties. Here, taking Shenqi Jiangtang Granules (SJG) as an example, the constructed TCM-MPs was used to fish the related proteins of human glomerular mesangial cells (HMCs) lysate. 28 differential proteins were screened. According to the target analysis based on bioinformatics, GNAS was selected as the key target, which participated in insulin secretion and cAMP signaling pathway. To further verify the interaction effect of GNAS and small molecules, a reverse fishing technique was established based on bio-layer interferometry (BLI) coupled with UHPLC-Q/TOF-MS/MS. The results displayed that 26 small molecules may potentially interact with GNAS, and 7 of them were found to have strong binding activity. In vitro experiments for HMCs have shown that 7 active compounds can significantly activate the cAMP pathway by binding to GNAS. The developed TCM-MPs target fishing strategy combined with BLI reverse fishing technology to screen out key proteins that directly interact with active ingredients from complex target protein systems is significant for the discovery of drug targets for complex systems of TCM.

Polymer Mechanochemistry on Reactive Species Generated from Mechanochemical Reactions†

Comprehensive SummaryPolymer mechanochemistry on reactive species has attracted more and more attentions over the past 20 years, as the mechanochemical generation of reactive species has a great potential in developing different polymeric materials for various purposes, such as stress detection, self‐healing, self‐strengthening, controllable degradation and release of small molecules. In this review, we first discuss the recent progress on polymer mechanochemistry of the reactive species that are generated from the mechanochemical reactions of mechanophores. Five types of reactive species, including radical, zwitterion, ionic, carbene and neutral intermediates, and their applications were reviewed in detail. Since mechanochemical reactions are sensitive to the mechanophore structure and polymer framework, we then discuss how mechanophore isomerism, polymer structure, polymer attachment point, and polymer architecture influence the mechanophore activation. At last, we provide our perspectives on the polymer mechanochemistry of reactive species. Key ScientistsIn the 1930s, a seminal work by Staudinger showed that the molecular weight of poly(styrene) reduced after mastication. However, polymer mechanochemistry mainly focused on the destructive effects of mechanical force, until Moore reported that the azo‐mechanophore was cleaved selectively upon sonication in 2005. Afterwards, his group also found that mechanical force changed the reaction pathway of benzocyclobutene and made spiropyran display purple color under stress. In 2009, Sijbesma revealed that metal–NHC could be used as a latent catalyst to catalyze transesterification and polymerization. Subsequently, the Craig group disclosed the special mechanical reactivity of perfluorocyclobutane in 2011 and examined the influence of polymer backbone on the reactivity of epoxides in 2012. Later, they also reported that the lever‐arm effect enhanced gDBC or gDCC mechanochemistry. Since 2015, Otsuka's group has developed a series of mechanophores that generated various carbon radicals and showed different colors under mechanical force. De Bo subsequently investigated the effect of regio‐ and stereochemistry on the reactivity of furan–maleimide adduct in 2017, and he examined the different mechanisms of the mechanical activation of tetrafluorobenzene–NHC (N‐heterocyclic carbene) adduct in 2020. During that time, the Choi group explored the influence of polymer architecture on the mechanophore activation, and Robb's group utilized a furan‐maleimide adduct to achieve the release of different small molecules. In 2020, Göstl and Herrmann employed the scission of the disulfide within polymers to release drugs and reporting molecules by ultrasound, and the Chen group also investigated the mechanochemistry of diselenides which afforded selenium radicals. In 2021, Boydston's group realized the “flex‐activation” of NHC‐carbodiimide to release NHC small molecules. Recently, the Chen group achieved multistate mechanochromism by combining two Rh structures together through a conjugated connector. In addition, Robb designed a furan‐maleimide adduct to mechanically give a donor–acceptor Stenhouse adduct that reacted with different amines to display various colors. This review has focused on the chemistry of reactive species that are generated from mechanochemical reactions.

Photoelectrothermocatalytic reduction of CO2 to glycol via Cu2S/MoS2-Vs octahedral heterostructure with synergistic mechanism

The defects and interface engineering are efficient approaches to adjust the physical and chemical properties of nanomaterials to enhance catalytic performance. In this study, we report a new MOFs-driven porous Cu2S/MoS2-Vs octahedral semiconductor with heterostructure and photothermal effect. The introduction of sulfur vacancies directly improves the adsorption performance of CO2, and the formation of heterostructure significantly increases the charge transfer rate. The C-penetrating material obtained from MOFs not only acts as an octahedral skeleton support, but also gives photothermal effects under photoelectric conditions. The formation rate of sole C2 products in photoelectrocatalytic CO2 reduction by using Cu2S/MoS2-Vs heterostructure is up to 52 μM·h−1·cm−2 equal to the total electron transfer rate of 541 μM·h−1·cm−2. The carbene mechanism and reaction pathways were proposed and verified by 13CO2 isotopic labelling and operando Fourier transform infrared (FT-IR) spectra. The important intermediates of *CO2−, *CO, *CHO and *CHO-CHO were identified by operando FT-IR spectra. In the comparative experiments, the photothermal electrons are beneficial to C2 products. DFT calculations indicate that the presence of S vacancies (Vs) reduces the energy barrier for product generation.

Reactivities and Bohmian perspectives on pnictogen N-heterocyclic carbene analogues reactions with methane and ethene

The chemical reactions of monocationic pnictogen N-heterocyclic carbene (NHC) analogues [(tBu2DAB)M+, M = N, P, As, Sb, and Bi, and tBu2DAB =1,4-tert-butyl-1,4-diaza-1,3-butadiene] with methane and ethene are studied by the density functional theory. The activation energies and reaction enthalpies are analyzed by the natural energy decomposition analysis (NEDA) to understand the reactivities of the reactions. The activation energies and reaction enthalpies of the ethene reactions, and the activation energies of the methane reactions decrease with the atomic numbers of the pnictogen elements M. However, the reaction enthalpies of the methane reactions do not follow a monotonic trend because the size and geometry of the methane structure are better accommodated by the product states of (tBu2DAB)P+ than (tBu2DAB)N+. The NEDA also suggests that the carbene and hydrocarbon fragments are subject to singlet–singlet interactions for all reactions of this work. The electronic and energetic structures of the reactions involving the N-centered NHC reactant, (tBu2DAB)N+ characteristically differ from all other carbenic reactants, which is in agreement with the well-known fact that the 2s and 2p orbitals of the N atom are more amenable to hybridization than the higher s and p orbitals of other pnictogen elements. The Bohmian perspectives on the stationary states of the pnictogen NHC reactions are also explored. It is found that the Bohmian potentials may reveal some bonding informations of the complexes, but further investigations are still required for deeper understanding.

Reactivity of Superbasic Carbanions Generated via Reductive Radical-Polar Crossover in the Context of Photoredox Catalysis.

Photocatalytic reactions involving a reductive radical-polar crossover (RRPCO) generate intermediates with carbanionic reactivity. Many of these proposed intermediates resemble highly reactive organometallic compounds. However, conditions of their formation are generally not tolerated by their isolated organometallic versions and often a different reactivity is observed. Our investigations on their nature and reactivity under commonly used photocatalytic conditions demonstrate that these intermediates are indeed best described as free, superbasic carbanions capable of deprotonating common polar solvents usually assumed to be inert such as acetonitrile, dimethylformamide, and dimethylsulfoxide. Their basicity not only towards solvents but also towards electrophiles, such as aldehydes, ketones, and esters, is comparable to the reactivity of isolated carbanions in the gas-phase. Previously unsuccessful transformations thought to result from a lack of reactivity are explained by their high reactivity towards the solvent and weakly acidic protons of reaction partners. An intuitive explanation for the mode of action of photocatalytically generated carbanions is provided, which enables methods to verify reaction mechanisms proposed to involve an RRPCO step and to identify the reasons for the limitations of current methods.

Asymmetric Carbene Transformations for the Construction of All-Carbon Quaternary Centers.

Asymmetric catalytic carbene reactions have been well documented in the last few decades for the expeditious assembly of chiral molecules with structural diversity. However, the enantioselective construction of all-carbon quaternary centers remains a challenge in this area. In this review article, two types of asymmetric carbene reactions that beyond cyclopropanation, cyclopropenation, and Büchner reaction, have been summarized for the construction of all-carbon quaternary centers: 1) using carbene species as a 1C synthon that reacts with a trisubstituted prochiral center; 2) sequential installation of two different C-C bonds on the carbene position, which features a gem-difunctionalization reaction. Especially, the asymmetric metal carbene gem-dialkylation process, which has emerged as a practical and versatile method for the expeditious assembly of complex architectures from readily available chemical resources, is a complementary approach for the expeditious assembly of all-carbon quaternary centers.

Reactivity of Nickel Complexes Bearing P(C=X)P Ligands (X = O, N) Toward Diazoalkanes: Evidence for Phosphorus Ylide Intermediates.

Nickel carbenes are attracting attention for the development of more sustainable catalysts, among others, for cyclopropanation. Intramolecular trapping of a nickel carbene intermediate with an olefin incorporated in a P(C=C)P Ni pincer complex had previously allowed the isolation of a nickelacyclobutane intermediate and a detailed characterization of its reactivity. Herein, we report the reactivity of related nickel pincer complexes bearing a ketone P(C=O)P or an imine P(C=N)P with diazoalkanes as the carbene precursor. The observed reactivity suggests, in both cases, the reaction of the transient nickel carbene with one of the phosphine arms to form phosphorus ylides that subsequently react with the unsaturated backbone. Density functional theory (DFT) calculations are used to shed light on the mechanisms of these reactions.

Dechlorination Helps Defluorination: Insights into the Defluorination Mechanism of Florfenicol by S-nZVI and DFT Calculations on the Reaction Pathways.

Defluorination is essential to eliminate the antibiotic resistance and detrimental effects of florfenicol (C12H14Cl2FNO4S, FF), which is achievable by sulfidated nanoscale zerovalent iron (S-nZVI), yet a comprehensive understanding of the mechanism is lacking. Herein, we used experimental data and density functional theory calculations to demonstrate four dechlorination-promoted defluorination pathways of FF, depending on S-nZVI or not. FF was defluorinated in a rapid and then slow but continuous manner, accompanying a consecutive dechlorination to deschloro (dFF) and dideschloro FF (ddFF). Unexpectedly, the predominant defluorination occurs by spontaneous hydrolysis of ddFF to form the hydrolyzed byproduct (HO-ddFF), i.e., independent of S-nZVI, which is initiated by intramolecular attack from carbonyl O to alkyl F and is thus limited for FF and dFF owing to the diminished nucleophilicity by electron-withdrawing Cl. The removal of Cl also makes the reductive defluorination of ddFF by S-nZVI amenable. The other two minor but more rapid defluorination pathways occur in synergy with the dechlorination of FF and dFF, which are mediated by the reactive carbanion intermediates and generate HO-dFF and HO-ddFF, respectively. The reliability of these dechlorination-facilitated defluorination pathways was verified by the consistency of theoretical calculations with experimental data, providing valuable insights into the degradation of fluorinated contaminants.

Synergistic enhancement of interfacial adhesion for CF/PEEK composites through carbene chemistry and water‐based self‐catalyzed cross‐linkable PENK‐NH2 sizing agent

AbstractTo address the issue of inadequate interfacial adhesion in carbon fiber/poly ether ether ketone (CF/PEEK) composites, an innovative approach that combines carbene chemistry and sizing treatment was meticulously designed to achieve remarkable synergistic enhancement. Specifically, cyano groups were chemical‐grafted on CF surface via carbene reaction. Meanwhile, a water‐based self‐catalyzed cross‐linkable PENK‐NH2 sizing agent with good storage stability was prepared. Noteworthy, the presence of amino groups as blocking agents of sizing agent significantly accelerated the rate of cyano‐crosslinking, thus effectively avoiding the adverse effects of excessively prolonged cross‐linking period during composites preparation. As a result, robust interaction between cyano‐modified CF and PEEK was established by cross‐linking reaction, along with chemical bonds generated between amino groups of sizing agent and ketone groups in PEEK. The maximum interlaminar shear strength (ILSS) of CF‐CN‐1.5/PEEK composites was 22.0% and 57.0% higher than CF‐1.5/PEEK and CF/PEEK composites. Furthermore, the presence of cyano‐cross‐linked structure endowed interphase with outstanding solvent‐resistance, the mechanical properties of CF composites after solvent treatment were well‐preserved. The strong synergistic interfacial interactions facilitated by chemical bonds in different components provide an effective and fascinating methodology for producing high‐performance CF/composites.Highlights Water‐based self‐catalyzed cross‐linkable PENK‐NH2 sizing agents for CF/PEEK were prepared. NH2 was introduced to avoid the adverse effects of prolonged cyano‐crosslinking. Designed carbenoid motif with cyano group was grafted on CF via carbene chemistry. The interaction between sizing agent and CF was boosted by the cyano‐crosslinking. Mechanical properties of sized composites corroded by solvent were well‐preserved.

Accessing Functionalized Furans from Reacting Enynones and Enynals through Furyl Metal Carbenes

AbstractEnynones and enynals represent donor‐type carbene precursors that efficiently form furyl metal carbenes via a catalytic intramolecular 5‐exo‐dig cyclization and rearrangement cascade, in a 100 % atom‐economical manner, using various metals. These furyl metal carbenes have been successfully utilized in numerous carbene reactions, including metal carbene X−H insertion, cyclopropanations, metathesis, and cross‐coupling, demonstrating a broad reaction scope and efficiency in constructing highly functionalized furans. Recent years have witnessed significant advancements in transformations involving furyl metal carbenes, especially in asymmetric carbene insertion reactions, domino reactions involving zwitterionic intermediates, various rearrangement strategies, and their application in synthesizing functional materials and drug candidates. In this review, we summarize recent progress in furyl metal carbene reactions generated from enynones and enynals, focusing on the synthesis of highly functionalized furans.

Low coordinate Zn(II) organocations bearing extremely bulky NHC ligands: structural features, air-/water-tolerance and use in hydrosilylation and hydrogenation catalysis.

This work details the synthesis and characterization of low-coordinate Zn(II)-based organocations [(NHC)Zn(R)]+ incorporating extremely bulky NHCs [ITr] and [IAd] ([ITr] = ([ITr] = [(HCNCPh3)2C:]; [IAd] = [(HCNAd)2C:], Ad = adamantyl)). Their structural features and particularities are thoroughly assessed as well as their air and water tolerance. Neutral ITr and IAd adducts [(ITr)Zn(R)2] (1, R = Me; 2, R = Et) and [(IAd)Zn(R)2] (3, R = Me; 4, R = Et) were synthesized by reaction of carbene [ITr] or [IAd] with a stoichiometric amount of [ZnR2] and isolated in good yields. Despite the steric bulk of [ITr] and [IAd], neutral compounds 1-4 are robust and the solid state structure of adduct 3 was established through X-ray crystallographic studies as a trigonal monomer Zn(II) species. Adducts 1-4 may readily be ionized by [Ph3C][B(C6F5)4] to afford two-coordinate Zn(II) alkyl cations [(ITr)Zn(Me)]+ ([5]+) and [(ITr)Zn(Et)]+ ([6]+), [(IAd)Zn(Me)]+ ([7]+) and [(IAd)Zn(Me)]+ ([8]+), all isolated in high yields (>80%) as [B(C6F5)4]- salts, which were fully characterized. Remarkably, cation [(ITr)Zn(C6F5)]+ ([9]+), prepared by reaction of [5][B(C6F5)4] with [B(C6F5)3], features π-arene interactions with the electrophilic Zn(II), as deduced from solid state data and further completed by DFT-estimated non-covalent interactions (NCI), indicating that [ITr] may provide substantial steric and electrostatic stabilization. The latter certainly explains the remarkable stability of [(ITr)Zn(C6F5)]+ ([9]+) towards hydrolysis at RT, as it only coordinates H2O to afford an unprecedented stable Zn-OH2 organocation [10]+. Also noteworthy, H2O coordination is reversible allowing recovery of [(ITr)Zn(C6F5)]+ cation, even after prolonged air exposure. Yet, controlled hydrolysis of [(ITr)Zn(C6F5)]+ may occur upon heating with selective protonolysis of the Zn-C6F5 bond to afford structurally characterized dication [(ITr)Zn(OH)]22+ [11]2+. Interestingly, despite steric hindrance, the air-/water-tolerant cation [(ITr)Zn(C6F5)]+ is an effective CO2 hydrosilylation catalyst, and was also shown to mediate imine hydrogenation catalysis.

Silicon-aryl cooperative activation of ammonia.

Herein, we report the reactivity of N-heterocyclic carbene stabilized silylene-phosphinidene IDippPSi(TMS)2SiTol3 (IDipp = 1,3-bis(2,6-diisopropylphenyl)-imidazolin-2-ylidene) with ammonia, which results in an intermolecular 1,5-hydroamination and dearomatization of the NHC wingtip. DFT calculations reveal an unprecedented mechanism involving ammonia coordination to the silicon center, Meisenheimer-type complex formation, and a proton abstraction by the dearomatized aryl moiety.

Directed C–H activation with iron carbene complexes

The reactivity of PCcarbeneP iron carbenes, was investigated toward imines, ketones, diazenes, 2-vinylpyridine, and 8-methylquinoline, revealing the directed activation of aryl, vinyl, or benzyl C–H bonds by 1,2-addition across the iron-carbene bond.

Synthesis and reactivity of N-heterocyclic carbene (NHC)-supported heavier nitrile ylides.

The synthesis and isolation of stable heavier analogues of nitrile ylide as N-heterocyclic carbene (NHC) adducts of phosphasilenyl-tetrylene [(NHC)(TerAr)Si(H)PE14(TerAr)] (E14 = Ge 1, Sn 2; TerAr = 2,6-Mes2C6H3, NHC = IMe4) are reported. The delocalized Si-P-E14 π-conjugation was examined experimentally and computationally. Interestingly, the germanium derivative 1 exhibits a 1,3-dipolar nature, leading to an unprecedented [3 + 2] cycloaddition with benzaldehyde, resulting in unique heterocycles containing four heteroatoms from group 14, 15, and 16. Further exploiting the nucleophilicity of germanium, activation of the P-P bond of P4 was achieved, leading to a [(NHC)(phosphasilenyl germapolyphide)] complex. Moreover, the [3 + 2] cycloaddition and the σ-bond activation by 1 resemble the characteristics of the classic nitrile ylide.

Synthesis and reactivity of N-heterocyclic carbene (NHC) gold-fluoroalkoxide complexes.

We disclose a novel series of N-heterocyclic carbene (NHC) gold complexes with varied steric and electronic properties, bearing fluorinated alkoxide anions. Early reactivity studies involving these synthons, lead to the synthesis of various complexes of relevance to gold chemistry and catalysis.

Copper-catalyzed crosscoupling of vinyl nitrenes and CF3-carbenes to synthesize CF3-2-azadienes

A unique and efficient copper catalytic system has been established for the synthesis of fluorinated 2-azadienes from isoxazoles and CF3-N-tosylhydrazones via crosscoupling reactions of vinyl nitrenes with fluoroalkyl carbenes.

Photoinduced cerium-catalyzed C-H acylation of unactivated alkanes.

Ketones are ubiquitous motifs in the realm of pharmaceuticals and natural products. Traditional approaches to accessing these species involve the addition of metal reagents to carboxyl compounds under harsh conditions. Herein, we report a cerium-catalyzed acylation of unactivated C(sp3)-H bonds using bench-stable acyl azolium reagents under mild and operationally-friendly conditions. This reaction exhibits excellent generality, accommodating a wide range of feedstock chemicals such as cycloalkanes and acyclic compounds as well as facilitating the late-stage functionalization of pharmaceuticals. We demonstrate further applications of our strategy with a three-component radical relay reaction and an enantioselective N-heterocyclic carbene (NHC) and cerium dual-catalyzed reaction.

Mechanistic differences between linear vs. spirocyclic dialkyldiazirine probes for photoaffinity labeling.

Dialkyldiazirines have emerged as a photo-reactive group of choice for interactome mapping in live cell experiments. Upon irradiation, 'linear' dialkyldiazirines produce dialkylcarbenes which are susceptible to both intramolecular reactions and unimolecular elimination processes, as well as diazoalkanes, which also participate in intermolecular labeling. Cyclobutylidene has a nonclassical bonding structure and is stable enough to be captured in bimolecular reactions. Cyclobutanediazirines have more recently been studied as photoaffinity probes based on cyclobutylidene, but the mechanism, especially with respect to the role of putative diazo intermediates, was not fully understood. Here, we show that photolysis (365 nm) of cyclobutanediazirines can produce cyclobutylidene intermediates as evidenced by formation of their expected bimolecular and unimolecular products, including methylenecyclopropane derivatives. Unlike linear diazirines, cyclobutanediazirine photolysis in the presence of tetramethylethylene produces a [2 + 1] cycloaddition adduct. By contrast, linear diazirines produce diazo compounds upon low temperature photolysis in THF, whereas diazo compounds are not detected in similar photolyses of cyclobutanediazirines. Diazocyclobutane, prepared by independent synthesis, is labile, reactive toward water and capable of protein alkylation. The rate of diazocyclobutane decomposition is not affected by 365 nm light, suggesting that the photochemical conversion of diazocyclobutane to cyclobutylidene is not an important pathway. Finally, chemical proteomic studies revealed that a likely consequence of this primary conversion to a highly reactive carbene is a marked decrease in labeling by cyclobutanediazirine-based probes relative to linear diazirine counterparts both at the individual protein and proteome-wide levels. Collectively, these observations are consistent with a mechanistic picture for cyclobutanediazirine photolysis that involves carbene chemistry with minimal formation of diazo intermediates, and contrasts with the photolyses of linear diazirines where alkylation by diazo intermediates plays a more significant role.

Synthesis and Reactivity of N-Heterocyclic Carbene Coordinated Formal Germanimidoyl-Phosphinidenes.

Treatment of N-heterocyclic carbene (NHC) ligated germylidenylphosphinidene MsFluidtBu-GeP(NHCiPr) (where MsFluidtBu is a bulky hydrindacene substituent, and NHCiPr is 1,3-diisopropyl-4,5-dimethyl-imidazolin-2-ylidene) with mesityl azide and 4-tertbutylphenyl azide afforded NHC coordinated formal germanimidoyl-phosphinidenes, which represent the first compounds bearing both Ge═N double bond and phosphinidene functionalities. Studies of the chemical properties revealed that the reactions preferred to occur at the Ge═N double bond, which underwent [2 + 2] cycloadditions with CO2 and ethyl isocyanate, and coordinated with coinage metals through the nitrogen atom.

Recent Update on Alkylation of Indole and Its Derivatives Using N‐Tosylhydrazone

AbstractN‐Tosylhydrazones are valuable synthons in various organic transformations to achieve potent bioactive heterocycles. N‐tosylhydrazones largely serve as 1,3‐dipolar species for cycloaddition reactions, diazo precursors for carbene or carbenoid reactions, and alternatives to parent carbonyl compounds. On the other hand, indole derivatives exhibit wide range of pharmacological and therapeutic activities including anticancer, antiviral, antimalarial, antiasthmatic, antibacterial and anti‐inflammatory. This review mainly highlights the recent developments in the synthetic usefulness of N‐tosylhydrazones derived from indole‐carboxaldehydes and other carbonyl compounds. Moreover, the synthetic potential, scope, limitations, and mechanism of these transformations have also been discussed.