Carbene Chemistry Research Articles

Carbenes from cyclopropanated aromatics.

Although a ripe old discipline by now, carbene chemistry continues to flourish as both theorists and experimentalists have shown sustained interest in this area of research. While there are numerous ways of generating carbenes, the thermal and/or photochemical decomposition of diazo compounds and diazirines remains, by far, the most commonly used method of producing these intermediates. There is no disputing the fact that these nitrogenous precursors have served carbene researchers well, but their use is not without problems. They are often sensitive and hazardous to handle and, sometimes, the desired nitrogenous precursor simply may not be available, e.g., for synthetic reasons, to study the particular carbene of interest. Furthermore, there is a legitimate concern that the photochemical generation of carbenes in solution from diazo compounds and diazirines may be contaminated by reactions in the excited states (RIES) of the precursors themselves. As an alternative, several laboratories, including ours, have used cyclopropanated aromatic systems to generate a wide range of carbenes. In each case, the cheleotropic extrusion of carbenes is accompanied by the formation of stable aromatic by-products such as phenanthrene, indane, naphthalene, and 1,4-dihydronaphthalene. The emergence of these "non-traditional" carbene sources, their versatility, and promise are reviewed in this work.

Cu(OTf)2/NBS Promoted Cyclization of 1‐Cinnamyl Alcohol‐o‐Carboranes: An Efficient Approach for Synthesis ofo‐Carboranes Substituted Oxetanes

AbstractThe Cu(OTf)2/NBS promoted cyclization of 1‐cinnamyl alcohol‐o‐carboranes for synthesis ofo‐carborane substituted oxetanes has been developed. A series of substituted oxetanes has been synthesized with moderate to good yields, which would be an important synthon for design novel reactions in oxetane chemistry as well as carborane chemistry.

How to Stabilize Carbenes in Enzyme Active Sites without Metal Ions.

Carbenes are highly reactive compounds with unique value to synthetic chemistry. However, a small number of natural enzymes have been shown to utilize carbene chemistry, and artificial enzymes engineered with directed evolution required transition metal ions to stabilize the carbene intermediates. To facilitate the design of broader classes of enzymes that can take advantage of the rich carbene chemistry, it is thus important to better understand how to stabilize carbene species in enzyme active sites without metal ions. Motivated by our recent studies of the anaerobic ergothioneine biosynthesis enzyme EanB, we examine carbene-protein interaction with both cluster models and QM/MM simulations. The cluster calculations find that an N-heterocyclic carbene interacts strongly with polar and positively charged protein motifs. In particular, the interaction between a guanidinium group and carbene is as strong as ∼30 kcal/mol, making arginine a great choice for the preferential stabilization of carbenes. We also compare the WT EanB and its mutant in which the key tyrosine was replaced by a non-natural analogue (F2Tyr) using DFTB3/MM simulations. The calculations suggest that the carbene intermediate in the F2Tyr mutant is more stable than that in the WT enzyme by ∼3.5 kcal/mol, due to active site rearrangements that enable a nearby arginine to better stabilize the carbene in the mutant. Overall, the current work lays the foundation for the pursuit of enzyme designs that can take advantage of the unique chemistry offered by carbenes without the requirement of metal ions.

Ambiphilic singlet carbenes: Electron donors and acceptors

AbstractThe isolation of cyclic(alkyl)(amino)carbenes (CAACs) and N,N′‐diamidocarbenes (DACs) has opened up new avenues in the field of carbene chemistry due to their unique properties. CAACs are strong σ‐donors and π‐acceptors, whereas DACs are extremely strong π‐acceptors. The ambiphilicity of carbenes can facilitate new applications such as small molecule activation and catalysis. Since the isolation of CAACs and DACs, several new ambiphilic carbenes have been synthesized, thereby advancing the development of carbene chemistry. This review summarizes the most relevant findings on ambiphilic carbene chemistry until 2022.

On the Coexistence of the Carbene⋯H-D Hydrogen Bond and Other Accompanying Interactions in Forty Dimers of N-Heterocyclic-Carbenes (I, IMe2, IiPr2, ItBu2, IMes2, IDipp2, IAd2; I = imidazol-2-ylidene) and Some Fundamental Proton Donors (HF, HCN, H2O, MeOH, NH3).

The subject of research is forty dimers formed by imidazol-2-ylidene (I) or its derivative (IR) obtained by replacing the hydrogen atoms in both N-H bonds with larger important and popular substituents of increasing complexity (methyl = Me, iso-propyl = Pr, tert-butyl = Bu, phenyl = Ph, mesityl = Mes, 2,6-diisopropylphenyl = Dipp, 1-adamantyl = Ad) and fundamental proton donor (HD) molecules (HF, HCN, HO, MeOH, NH). While the main goal is to characterize the generally dominant C⋯H-D hydrogen bond engaging a carbene carbon atom, an equally important issue is the often omitted analysis of the role of accompanying secondary interactions. Despite the often completely different binding possibilities of the considered carbenes, and especially HD molecules, several general trends are found. Namely, for a given carbene, the dissociation energy values of the IRHD dimers increase in the following order: NH< HO < HCN ≤ MeOH ≪ HF. Importantly, it is found that, for a given HD molecule, IDipp forms the strongest dimers. This is attributed to the multiplicity of various interactions accompanying the dominant C⋯H-D hydrogen bond. It is shown that substitution of hydrogen atoms in both N-H bonds of the imidazol-2-ylidene molecule by the investigated groups leads to stronger dimers with HF, HCN, HO or MeOH. The presented results should contribute to increasing the knowledge about the carbene chemistry and the role of intermolecular interactions, including secondary ones.

Unraveling the carbene chemistry of oxymethylene ethers: Experimental investigation and kinetic modeling of the high-temperature pyrolysis of OME-2

Oxymethylene ethers (OMEs) form an interesting family of synthetic compounds to replace fossil fuels. This alternative liquid energy carrier can contribute to a circular carbon economy when produced via carbon capture and utilization technology using renewable electricity. Despite the potential to reduce greenhouse gas and particulate matter emissions and their ideal ignition characteristics, little is known about the thermal decomposition behavior of OMEs. In this work, new insights are obtained in the pyrolysis chemistry of oxymethylene ether-2 (OME-2) and the role of carbenes by performing experiments at high temperatures (> 850 K) in a tubular quartz reactor. The used continuous bench-scale pyrolysis unit has a dedicated on-line analysis section including comprehensive two-dimensional gas chromatography (GC × GC) coupled with flame ionization detection (FID) and mass spectroscopy (MS) to identify and quantify the full product spectrum over the complete temperature range. The reactor temperature was varied between 850 and 1150 K at a fixed pressure of 0.15 MPa and residence times of 400 to 850 ms. The major products are dimethoxymethane, formaldehyde, methyl formate, methane, CO2, CO and H2. Minor intermediate compounds comprise dimethyl ether, formic anhydride, formic acid, methoxymethyl formate and methoxymethanol. The yields of compounds with carbon-carbon bonds are low since no such bonds originally occur in OME-2. Precursors of aromatic compounds and soot particles are absent in the reactor effluent. The experimental results are simulated with a new first principles-based kinetic model for pyrolysis and combustion of OME-2. This model can predict the experimental trends of major products on average within the experimental uncertainty margin of ± 10% relative for major product species. A reaction pathway and sensitivity analysis are presented to highlight the importance of the carbenes for initiation of the radical chemistry under pyrolysis conditions.

N-Triftosylhydrazones: A New Chapter for Diazo-Based Carbene Chemistry.

Over recent decades, N-sulfonylhydrazones have attracted significant attention in academic and industrial contexts owing to their ease of preparation, versatile reactivity, high stability, and practicality. In particular, the use of N-sulfonylhydrazones as precursors for diazo compounds has paved the way for innovative and original organic reactions that are otherwise difficult to achieve. Three key developments are noteworthy in the history of N-sulfonylhydrazone chemistry: (1) Bamford and Stevens initially disclosed the application of N-tosylhydrazones as a diazo source in 1952; (2) Aggarwal and co-workers investigated N-tosylhydrazone salts as diazo precursors for sulfur ylide-mediated asymmetric epoxidation and aziridination in 2001; and (3) Barluenga, Valdés and co-workers first reported Pd-catalyzed cross-coupling reactions with N-tosylhydrazones in 2007, thus introducing the direct use of N-tosylhydrazones in carbene transfer reactions. In the past 2 decades, the synthetic exploration of N-sulfonylhydrazones in carbene chemistry has increased remarkably. N-Tosylhydrazones are the most commonly used N-sulfonylhydrazones, but they are not easy to decompose and normally need relatively high temperatures (e.g., 90-110 °C). Temperature, as a key reaction parameter, has a significant influence on the selectivity and scope of organic reactions, especially the enantioselectivity. Aggarwal and co-workers have addressed this issue by using N-tosylhydrazone salts and achieved a limited number of asymmetric organic reactions, but the method is greatly limited because the salts must be freshly prepared or stored in the dark at -20 °C prior to use. Hence, easily decomposable N-sulfonylhydrazones, especially those capable of decomposing at low temperature, should open up new opportunities for the development of N-sulfonylhydrazone chemistry. Since 2014, our group has worked toward this goal and eventually identified N-2-(trifluoromethyl)benzenesulfonylhydrazone (i.e., N-triftosylhydrazone) as an efficient diazo surrogate that can decompose at temperatures as low as -40 °C. This allowed us to carry out a range of challenging synthetic transformations and to broaden the applications of some known reactions of great relevance.In this Account, we report our achievements in the application of N-triftosylhydrazones in carbene chemistry. On the basis of the reaction types, such applications can be categorized as (i) C(sp3)-H insertion reactions, (ii) defluorinative reactions of fluoroalkyl N-triftosylhydrazones, (iii) cycloaddition reactions with alkenes and alkynes, and (iv) asymmetric reactions. Additional applications in Doyle-Kirmse rearrangements and cross-coupling with isocyanides (ours) and benzyl chlorides (from the group of Xia) are also summarized in this Account concerning miscellaneous reactions. In terms of reaction efficiency, selectivity, and functional group tolerance, N-triftosylhydrazones are generally superior to traditional N-tosylhydrazones because of their easy decomposition. Mechanistic investigations by theoretical calculations provide insights into both the reaction mechanisms and the origin of selectivity. We hope that this Account will inspire broad interest and promote new progress in the synthetic exploration of easily decomposable N-sulfonylhydrazones.

Computationally Probing the Mechanism of the Blue-Light-Driven O-H Functionalization of Alcohols by Aryldiazoacetates: Photobasicity or Carbene Chemistry.

Photochemistry provides green alternatives to traditional reaction conditions and opens up routes toward products that are otherwise difficult to make. Recent work by Koenigs and co-workers demonstrated the blue-light-driven O-H functionalization of alcohols by aryldiazoacetates. Based on spectroscopic and computational analyses, Koenigs and co-workers demonstrated that the alcohols form a hydrogen-bonding complex with aryldiazoacetates prior to the light absorption, with the strength of hydrogen bonding correlated with the product yield. Because methyl phenyldiazoacetate (MPDA) was observed to preferentially react with alcohols over cyclopropanation with styrene, the reaction was speculated to occur via excited-state proton transfer, with MPDA acting as a photobase. In this paper, we use time-dependent density functional theory to show that the electronic excited state of aryldiazoacetates is inconsistent with photobasicity. Instead, we argue that the reaction proceeds via a carbene intermediate generated through the photolysis of the aryldiazoacetate. Using density functional theory, we demonstrate that the reaction between the singlet state of the carbene intermediate and the alcohol is thermodynamically favorable and very fast. Moreover, we provide a rationalization for the experimentally observed preference for O-H functionalization with alcohols over cyclopropanation with alkenes. Overall, this work provides a refined mechanistic understanding of an interesting photochemical transformation.

18F]Difluorocarbene for positron emission tomography.

The advent of total-body positron emission tomography (PET) has vastly broadened the range of research and clinical applications of this powerful molecular imaging technology1. Such possibilities have accelerated progress in fluorine-18 (18F) radiochemistry with numerous methods available to 18F-label (hetero)arenes and alkanes2. However, access to 18F-difluoromethylated molecules in high molar activity is mostly an unsolved problem, despite the indispensability of the difluoromethyl group for pharmaceutical drug discovery3. Here we report a general solution by introducing carbene chemistry to the field of nuclear imaging with a [18F]difluorocarbene reagent capable of a myriad of 18F-difluoromethylation processes. In contrast to the tens of known difluorocarbene reagents, this 18F-reagent is carefully designed for facile accessibility, high molar activity and versatility. The issue of molar activity is solved using an assay examining the likelihood of isotopic dilution on variation of the electronics of the difluorocarbene precursor. Versatility is demonstrated with multiple [18F]difluorocarbene-based reactions including O-H, S-H and N-H insertions, and cross-couplings that harness the reactivity of ubiquitous functional groups such as (thio)phenols, N-heteroarenes and aryl boronic acids that are easy to install. The impact is illustrated with the labelling of highly complex and functionalized biologically relevant molecules and radiotracers.

Chemistry of Carbanions Stabilised by (Trifluoromethyl) sulfonyl Group: Synthesis, Structure and Applications

Chemistry of Carbanions Stabilised by (Trifluoromethyl) sulfonyl Group: Synthesis, Structure and Applications

Dual Catalysis in Rhodium(II) Carbenoid Chemistry

AbstractDual catalysis represents an alternative archetype in carbene chemistry that surpasses traditional single catalyst systems. By employing dual catalyst systems, one can improve the efficiency of existing reactions and enable new chemical transformations. Reactions involving dual synergistic catalysis are increasingly valuable as they offer convenient strategies for synthesizing challenging quaternary carbon centers and bioactive core structures. This review article focuses on trapping diazo‐derived, rhodium (II) zwitterionic intermediates with varying electrophiles such as Michael acceptors, alkynes, π‐allyl Pd(II) complexes, and the Nicholas intermediate.

The merger of vinyl-N-triftosylhydrazones and silver catalysis to enable stereoselective vinylcyclopropanation of alkenes

Despite extensive synthetic efforts, the application of vinyl- N -sulfonylhydrazones as a vinylcarbene precursor remains a persistent challenge in carbene chemistry, owing to the competitive formation of pyrazoles through [1,5] self-cyclization. Here, we report a strategy to address this long-term issue by combining vinyl- N -triftosylhydrazones and silver catalysis. This strategy inhibited the formation of pyrazoles and offered a highly electrophilic silver vinylcarbenoid species, thereby establishing a powerful silver-catalyzed stereoselective vinylcyclopropanation of alkenes. We found that diverse alkenes and vinyl- N -triftosylhydrazones are well suited for this protocol, affording a variety of vinylcyclopropanes in high yield with excellent stereoselectivity. The usefulness of this method was further showcased in gram-scale synthesis, late-stage modification, and total synthesis of bioactive molecules. DFT calculations disclosed that both the easy decomposition of vinyl- N -triftosylhydrazones and the weak coordination of silver play a crucial role during the vinylcyclopropanation of alkenes. • Electrophilic silver vinylcarbenes generated in situ from vinyl- N -sulfonylhydrazones • Highly cis -stereoselective vinylcyclopropanation of alkenes • Detailed mechanistic investigations Vinyl- N -sulfonylhydrazones are the most ideal and highly desirable vinylcarbene precursors due to their ready availability, great stability, and operational safety. However, their application in organic synthesis remains a long-standing challenge because they easily undergo the self-cyclization to form pyrazoles as the main side reaction. Here, we report a strategy to address this long-term issue by combining easily decomposable vinyl- N -triftosylhydrazones and silver catalysis. This strategy offered a highly electrophilic silver vinylcarbenoid species, thereby establishing a powerful stereoselective vinylcyclopropanation of alkenes. The usefulness of this method was further showcased in gram-scale synthesis, late-stage modification, and total synthesis of bioactive molecules. More important, the undesired reactivity of vinyl- N -sulfonylhydrazones was completely bypassed, which should seed the creation of new catalytic transforms based on metal vinylcarbenes. A powerful stereoselective vinylcyclopropanation of alkenes was achieved by the merger of easily decomposable vinyl- N -triftosylhydrazones and weakly coordinated silver catalysis, in which the inherent propensity of vinyl- N -sulfonylhydrazones to undergo intramolecular cyclization to form pyrazoles was totally suppressed. The usefulness of this methodology has been demonstrated by broad substrate scope, high product yields, and excellent cis -diastereoselectivity, as well as the successful applications in the late-stage modification and the total synthesis of bioactive molecules.

Carbene chemistry of arsenic, antimony, and bismuth: origin, evolution and future prospects.

The discovery of the first isolable N-heterocyclic carbene in 1991 ushered in a new era in coordination chemistry. The remarkable bonding properties of carbenes have led to their rapid proliferation as auxiliary ligands for a wide range of transition metals and main group elements. In the case of group 15, while carbene-stabilized nitrogen and phosphorus compounds are extensively studied, the scope of research has shrunk significantly from arsenic to bismuth. This is essentially attributed to the decrease in stability of the C-E bond upon descending the group. Even so, modulating the carbene backbone or introducing alternative synthetic strategies not only alleviates the stability issues but also offers promising results in terms of the bonding and reactivities of these compounds. The purpose of the present perspective is to provide a comprehensive overview of the origins and development of carbene chemistry of arsenic, antimony, and bismuth, as well as to highlight the future prospects of this field.

Organometallic catalysis in aqueous and biological environments: harnessing the power of metal carbenes.

Translating the power of transition metal catalysis to the native habitats of enzymes can significantly expand the possibilities of interrogating or manipulating natural biological systems, including living cells and organisms. This is especially relevant for organometallic reactions that have shown great potential in the field of organic synthesis, like the metal-catalyzed transfer of carbenes. While, at first sight, performing metal carbene chemistry in aqueous solvents, and especially in biologically relevant mixtures, does not seem obvious, in recent years there has been a growing number of reports demonstrating the feasibility of the task. Either using small molecule metal catalysts or artificial metalloenzymes, a number of carbene transfer reactions that tolerate aqueous and biorelevant media are being developed. This review intends to summarize the most relevant contributions, and establish the state of the art in this emerging research field.

Transformation of the sp2 Carbanion to Carbene with Subsequent 1,1-Migratory Insertion and Nucleophilic Substitution in Rare-Earth Metal Chemistry.

The development of Fischer-type electrophilic carbene chemistry with early transition metals has been a great challenge due to the fact that such metals in their high oxidation states lack the d electrons to stabilize the electrophilic carbene. Herein, we disclose the first experimental and theoretical findings of in situ transformation of an sp2 carbanion to a Fischer-type electrophilic carbene with rare-earth metals in their high oxidation state with a d0 electron via electron transfer. The carbene may undergo 1,1-migratory insertion into an adjacent RE-C(sp3) bond, and an unprecedented ring opening of the indole ring of the ligand occurs when the carbenes undergo nucleophilic substitution with a special organolithium reagent o-Me2NC6H4CH2Li. The key to success is the uniquely tailored novel ligand systems featuring a suitable conjugate building block (-C═C-C═N) bearing an sp2 carbanion connected to the rare-earth metal center.

Recent advances in the chemistry and applications of N-heterocyclic carbenes.

N-Heterocyclic carbenes, despite being isolated and characterized three decades ago, still capture scientists' interest as versatile, modular and strongly coordinating moieties. In the last decade, driven by the increasingly refined fundamental understanding of their behaviour, the emergence of new carbene frameworks and cogent sustainability issues, N-heterocyclic carbenes have experienced a tremendous increase in utilization across several disparate fields. In this Review, a concise overview of N-heterocyclic carbenes encompassing their history, properties and applications in transition metal catalysis, on-surface chemistry, main group chemistry and organocatalysis is provided. Emphasis is placed on developments emerging in the last seven years and on envisaging future directions.

Triple Resonance Experiments for the Rapid Detection of 103Rh NMR Shifts: A Combined Experimental and Theoretical Study into Dirhodium and Bismuth-Rhodium Paddlewheel Complexes.

A H(C)Rh triple resonance NMR experiment makes the rapid detection of 103Rh chemical shifts possible, which were previously beyond reach. It served to analyze a series of dirhodium and bismuth–rhodium paddlewheel complexes of the utmost importance for metal–carbene chemistry. The excellent match between the experimental and computed 103Rh shifts in combination with a detailed analysis of the pertinent shielding tensors forms a sound basis for a qualitative and quantitative interpretation of these otherwise (basically) inaccessible data. The observed trends clearly reflect the influence exerted by the equatorial ligands (carboxylate versus carboxamidate), the axial ligands (solvents), and the internal “metalloligand” (Rh versus Bi) on the electronic estate of the reactive Rh(II) center.

Access to Indole-Fused Benzannulated Medium-Sized Rings through a Gold(I)-Catalyzed Cascade Cyclization of Azido-Alkynes.

Because benzannulated and indole-fused medium-sized rings are found in many bioactive compounds, combining these fragments might lead to unexplored areas of biologically relevant and uncovered chemical space. Herein is shown that α-imino gold carbene chemistry can play an important role in solving the difficulty in the formation of medium-sized rings. Namely, phenylene-tethered azido-alkynes undergo arylative cyclization through the formation of a gold carbene intermediate to afford benzannulated indole-fused medium-sized tetracycles. The reactions allow a range of different aryl substitution patterns and efficient access to these otherwise difficult-to-obtain medium-sized rings. This study also demonstrates the feasibility of the semihollow-shaped C-dtbm ligand for the construction of a nine-membered ring.

Recent Advances in Theoretical Studies on Transition-Metal-Catalyzed Carbene Transformations.

Metal carbene plays a vital role in modern organic synthesis. The neutral divalent carbon of metal carbene renders it an active intermediate throughout a range of reactions. In experiments, diverse metal carbene-related transformation reactions have been established, including transition-metal-catalyzed cross-coupling reactions using N-heterocyclic carbenes as ligands, metal carbene insertion into σ bonds, cyclopropanations, ylide formation, and so forth. The remarkable progress achieved in synthetic chemistry, in turn, has increased the demand for mechanistic studies of carbene chemistry. A thorough understanding of reaction mechanisms can extend the application scope of metal carbene compounds and inspire the rational design of new carbene transformation reactions.Density functional theory (DFT) calculations have been performed in our group to gain more mechanistic insights into metal carbene-related reactions. This account focuses on computational studies of transition-metal-catalyzed carbene transformation reactions with nucleophiles. The generation of metal carbene or metal-ligated free carbene and subsequent carbene transformation pathways is discussed. According to our mechanistic studies of carbene transformation with nucleophiles, three generalized reaction models are summarized, including the intramolecular migratory insertion of metal carbene, intermolecular nucleophilic addition toward metal carbene, and outer-sphere nucleophilic addition to the metal-ligated free carbene.In general, the intermolecular nucleophilic addition mechanism is commonly proposed since metal carbene has an electrophilic carbene carbon. From a mechanistic point of view, the intramolecular migratory insertion mechanism is also widely used because metal carbene insertion into σ bonds formally occurs through this mechanism. An outer-sphere nucleophilic addition mechanism is proposed for reactions that form a metal-ligated free carbene complex instead of the commonly proposed metal carbene. The metal-ligated free carbene complex contains a naked carbene carbon that is not coordinated with the metal center. In this case, a transition-metal catalyst is used only as a Lewis acid, and nucleophilic addition occurs directly at the free carbene carbon. Our computational results suggested that outer-sphere nucleophilic addition is a facile step because metal ligation could stabilize the transition state as well as the generated intermediate. The intramolecular migratory insertion mechanism also has a low energy barrier due to the lack of an entropy penalty. Carbene formation from carbene precursors is usually the rate-determining step, except in intermolecular nucleophilic addition, and the reactivity of nucleophiles has a significant influence on the overall reaction rate. We can also envision that the weak nucleophilicity of nucleophiles would suppress outer-sphere nucleophilic addition. These computational studies showcase the characteristics of three carbene transformation models, and we hope that it will spur the development of mechanistic studies of carbene chemistry.

Isolation and reactivity of an elusive diazoalkene.

Most functional groups, especially those consisting of the abundant elements of organic matter-carbon, nitrogen and oxygen-have been extensively studied and only very few remain speculative due to their high intrinsic reactivity. In contrast to the well-explored chemistry of diazoalkanes (R2C=N2), diazoalkenes (R2C=C=N2) have been postulated in several organic transformations, but remain elusive long-sought intermediates. Here, we present a room-temperature stable diazoalkene, utilizing a dinitrogen transfer from nitrous oxide. This functional group shows dual-site nucleophilicity (C and N atoms) and features a bent C-C-N entity (124°) and a long N-N bond together with a remarkable low infrared absorption (1,944 cm-1). Substitution of N2 by an isocyanide leads to a vinylidene ketenimine. Furthermore, photochemically triggered loss of dinitrogen might proceed through a transient triplet vinylidene. We anticipate the existence of a stable diazoalkene functional group to pave an exciting avenue into the chemistry of low-valent carbon and unsaturated carbenes.