Carbene Chemistry Research Articles

Spin States Matter─from Fundamentals toward Synthetic Methodology Development and Drug Discovery.

ConspectusThe potent reactivity of carbenes and nitrenes has been traditionally harnessed by the employment of a transition-metal catalyst in which the reactivity of the metal carbene/nitrene intermediates can be controlled via the judicious tuning of the metal catalyst. In recent years, progress made in this research area has unveiled novel strategies to directly access free carbenes or nitrenes under visible-light-mediated conditions without the necessity of a metal catalyst for stabilization of the carbene/nitrene intermediate. Such photochemical approaches present new opportunities to leverage orthogonal reactions with classic metal-catalyzed transformations.In this Account, we describe the major contributions from our group over the past years pushing the boundaries of light-mediated carbene and nitrene transfer reactions. In the first section, the development from purely singlet carbene chemistry toward methods that allow access to triplet carbene intermediates will be dissected. We describe how the triplet spin state of reagents provides a rich array of novel synthetic methods that build on the fundamentals of spin conservation. We lay out the different strategies in accessing the triplet spin state of carbenes (i.e., via electronic stabilization, via triplet sensitization with suitable photocatalysts, or via exploitation of geometric features of these intermediates), followed by an analysis of how the triplet spin state can be employed to leverage reactions distinct to the classic singlet carbene chemistry.The second part focuses on free nitrene intermediates, whereby both photochemical and photocatalytic strategies are analyzed and compared. We initiate with a discussion of the reactivity of iminoiodinanes as nitrene precursors in the presence of a photocatalyst or under photochemical conditions and how these two approaches result in fundamentally distinct nitrogen-based intermediates. While a nitrene radical anion is formed under photocatalytic conditions, triplet nitrene is generated under photochemical conditions. We commence with an outline of the basic reactivity of nitrene transfer reactions under both conditions, with a focus on the reaction with substrates containing double bonds. Finally, the latest developments in advanced cycloaddition chemistry beyond classic aziridination reactions are examined, with a special emphasis on the relay of the triplet nitrene reactivity to enable a Pauson-Khand-like (2 + 2 + 1) cycloaddition reaction that offers convenient access to high value bioisosteres in drug discovery.The work from our group on spin-dependent reactivities offers insight into important fundamentals in synthesis, where the spin state of the reactive intermediate will dictate the reaction outcome. We hope this may inspire others to widen the scope of applications of light-mediated carbene and/or nitrene transfer reactions, and furthermore, we anticipate that these understandings may also enable the development of advanced catalytic systems featuring triplet metal carbene/nitrene intermediates.

Crystal Structure of the Monocarborane Magnesium(II) Acetylide and Its Use in the Synthesis of α,β-Unsaturated Ketones.

We report the first crystal structure of heteroleptic Grignard reagent 2 based on the carborane endo/exo dianion [CB11H11-12-C≡C]2-. Full characterization reveals a rare coordination pattern and affirms the bimetallic nature. Navigating the reactivity landscape, we unlock the potential of 2 in nucleophilic addition with ketones to afford propargylic alcohols 3, renowned for their synthetic versatility and potential biological activities, and unveil the Meyer-Schuster rearrangement, yielding α,β-unsaturated carbonyl compounds 4. This narrative of synthesis, characterization, and reactivity opens new horizons for carborane chemistry, offering avenues for innovation and facile functionalization of carborane scaffolds.

Triplet carbenes with transition-metal substituents.

The extraordinary advances in carbene (R1-C-R2) chemistry have been fuelled by strategies to stabilize the electronic singlet state via π interactions. In contrast, the lack of similarly efficient approaches to obtain authentic triplet carbenes with appreciable lifetimes beyond cryogenic temperatures hampers their exploitation in synthesis and catalysis. Transition-metal substitution represents a potential strategy, but metallocarbenes (M-C-R) usually represent high-lying excited electronic configurations of the well-established carbyne complexes (M≡C-R). Here we report the synthesis and characterization of triplet metallocarbenes (M-C-SiMe3, M = PdII, PtII) that are persistent beyond cryogenic conditions, and their selective reactivity towards carbene C-H insertion and carbonylation. Bond analysis reveals significant stabilization by spin-polarized push-pull interactions along both π-bonding planes, which fundamentally differs from bonding in push-pull singlet carbenes. This bonding model, thus, expands key strategies for stabilizing the open-shell carbene electromers and closes a conceptual gap towards carbyne complexes.

Enantioselective α-Boryl Carbene Transformations

α-Boryl carbenes, which are hybrid structures combining elements of carbenes and boryl groups, represent promising intermediates for constructing organoboron compounds. However, these carbenes are challenging to synthesize and exhibit limited structural diversity. Moreover, their applications in asymmetric transformations remain largely unexplored. In this study, we utilized boryl cyclopropenes as precursors to rapidly synthesize α-Bpin metal carbenes, a novel category of intermediates critical for the synthesis of chiral organoboron molecules. Facilitated by a copper complex modified by a chiral bisoxazoline ligand, these α-boryl carbenes participate in a range of highly enantioselective transfer reactions, including B–H and Si–H insertions, as well as cyclopropanation and cyclopropanation/Cope rearrangement processes. This methodology provides access to previously inaccessible, yet highly useful, chiral organoborons, thereby significantly advancing both carbene and organoboron chemistry.

Who is Who in the Carbene Chemistry of N‐Sulfonyl Hydrazones

Comprehensive SummaryOver the past few decades, N‐sulfonyl hydrazones have been recognized as alternative precursors for hazardous diazo compounds in organic synthesis, allowing for diverse innovative and original chemical transformations that were otherwise difficult to achieve. This critical review summarizes the major advancements in the carbene chemistry of N‐sulfonyl hydrazones. The contents of this review are organized based on research conducted by leading scientists who have made significant contributions to this field. The individual carbene transfer reactions and their mechanisms, as well as the potential applications in the synthesis of natural products and complex bioactive molecules, are thoroughly discussed.

Carbene-Assisted Arene Ring-Opening.

Despite the significant achievements in dearomatization and C-H functionalization of arenes, the arene ring-opening remains a largely unmet challenge and is underdeveloped due to the high bond dissociation energy and strong resonance stabilization energy inherent in aromatic compounds. Herein, we demonstrate a novel carbene assisted strategy for arene ring-opening. The understanding of the mechanism by our DFT calculations will stimulate wide application of bulk arene chemicals for the synthesis of value-added polyconjugated chain molecules. Various aryl azide derivatives now can be directly converted into valuable polyconjugated enynes, avoiding traditional synthesis including multistep unsaturated precursors, poor selectivity control, and subsequent transition-metal catalyzed cross-coupling reactions. The simple conditions required were demonstrated in the late-stage modification of complex molecules and fused ring compounds. This chemistry expands the horizons of carbene chemistry and provides a novel pathway for arene ring-opening.

Breaking the Base Barrier: Cu(II)-Mediated C-H Heteroarylation of o-Carboranes with Base-Sensitive Heteroaryl Halides.

While cage C-arylation reactions using strong bases are among the most frequently used transformations in carborane chemistry, there has been no general solution to allow for the use of weak bases in the reaction. Moreover, base-metal-promoted C-H heteroarylation with base-sensitive heteroaryl halides remained elusive. Herein, copper-mediated cage C-H (hetero)arylation has been achieved without the need for strong bases, leading to the facile synthesis of a wide range of C-(hetero)arylated carboranes in good to excellent yields with a broad substrate scope and good functional group compatibility.

Enantioselective α-Boryl Carbene Transformations.

Carbenes, recognized as potent intermediates, enable unique chemical transformations, and organoborons are pivotal in diverse chemical applications. As a hybrid of carbene and the boryl group, α-boryl carbenes are promising intermediates for the construction of organoborons; unfortunately, such carbenes are hard to access and have low structural diversity with their asymmetric transformations largely uncharted. In this research, we utilized boryl cyclopropenes as precursors for the swift synthesis of α-boryl metal carbenes, a powerful category of intermediates for chiral organoboron synthesis. These α-boryl carbenes undergo a series of highly enantioselective transfer reactions, including B-H and Si-H insertion, cyclopropanation, and cyclopropanation/Cope rearrangement, catalyzed by a singular chiral copper complex. This approach opens paths to previously unattainable but easily transformable chiral organoborons, expanding both carbene and organoboron chemistry.

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.

Construction of antithrombotic and antimicrobial ultra-thin structures on a polyethylene terephthalate implant via the surface grafting of heparin brushes.

It remains a challenge to endow a polymeric material with antithrombotic ability by surface grafting without disturbing the bulk properties of the substrate. Heparin-based functional structures of less than 80 nm were fabricated and covalently grafted on a polyethylene terephthalate surface via carbene chemistry (Hep-g-PET). Heparin was oxidized with the minimum antithrombrin sequence retained, creating an aldehyde group on the chain terminus. Oxidized heparin was then covalently attached to a poly(amidoamine) (PAMAM)-grafted PET substrate. The interface between blood and PET was improved by the surface functionality, and the amount of attached platelets decreased to 29 ± 12.1% of its initial value. The bulk properties of the functionalized film were hardly influenced, and the visible light transmittance remained more than 96%. The tethered structures also showed the ability to kill attached S. aureus and E. coli efficiently. The functionalized membrane showed negligible ex vivo cell cytotoxicity and a low hemolysis ratio. Hep-g-PET was implanted in between rat skin and muscle, and showed an outstanding histological response and antimicrobial ability. The influences of the graft thickness and the heparin chain length were explored. The strategies reported in this work may help to improve the design of polymeric implant bio-devices.

Recent advances in the chemistry of isolable carbene analogues with group 13-15 elements.

Carbenes (R2C:), compounds with a divalent carbon atom containing only six valence shell electrons, have evolved into a broader class with the replacement of the carbene carbon or the RC moiety with main group elements, leading to the creation of main group carbene analogues. These analogues, mirroring the electronic structure of carbenes (a lone pair of electrons and an empty orbital), demonstrate unique reactivity. Over the last three decades, this area has seen substantial advancements, paralleling the innovations in carbene chemistry. Recent studies have revealed a spectrum of unique carbene analogues, such as monocoordinate aluminylenes, nitrenes, and bismuthinidenes, notable for their extraordinary properties and diverse reactivity, offering promising applications in small molecule activation. This review delves into the isolable main group carbene analogues that are in the forefront from 2010 and beyond, spanning elements from group 13 (B, Al, Ga, In, and Tl), group 14 (Si, Ge, Sn, and Pb) and group 15 (N, P, As, Sb, and Bi). Specifically, this review focuses on the potential amphiphilic species that possess both lone pairs of electrons and vacant orbitals. We detail their comprehensive synthesis and stabilization strategies, outlining the reactivity arising from their distinct structural characteristics.

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.

Introducing N-Sulfinylamines into Visible-Light-Induced Carbene Chemistry for the Synthesis of Diverse Amides and α-Iminoesters.

A rare example of visible-light-mediated diverse reactivity of N-sulfinylamines with different types of carbene precursors has been disclosed. Acylsilanes and aryldiazoacetates have been utilized as nucleophilic and electrophilic carbene precursors into the N═S═O linchpin, to achieve valuable amides and α-iminoesters, respectively. Interestingly, diazocarbonyls can also participate in the amidation reaction with N-sulfinylamines via in situ generated ketenes. This operationally simple modular method offers a mild, transition-metal-free, and coupling-reagent-free protocol to fabricate structurally diverse amides and a promptly accessible technique to achieve α-iminoesters, where visible light remains as a key promoter.

Unveiling the Noncovalent Interaction of Thiazol-2-ylidene and Its Derivatives as N-heterocyclic Carbene with Different Proton Donor Molecules.

The importance of noncovalent interaction has gained attention in various domains covering drug and novel catalyst design. The present study mainly characterizes the role of hydrogen bond (H-bond) and other intermolecular interactions in different (1 : 1) complex analogues formed between the N-aryl-thiazol-2-ylidene (YR) and five proton donor (HX) molecules. The analysis of the singlet-triplet energy gap ( ) confirmed the stability of the singlet state for this class of N-aryl-thiazol-2-ylidenes than the triplet state. The interaction energy values of the YR-HX complexes follow the order: YR-NH3 <YR-HCN<YR-H2 O<YR-MeOH<YR-HF. In addition, substituting the H-atom of the N-H bond with bulky groups (-R) leads to an increase in the interaction energy of the YR-HX complexes. Hence, it was found that the replacement of N-atom in N-heterocyclic carbene (NHC) by S-atom forming N-aryl-thiazol-2-ylidene results in comparable intermolecular interactions with proton donor molecules similar to imidazole-2-ylidene (NHC). The current study enlightened the role of noncovalent interactions in carbene complexes with proton donor molecules. We hope that our work on carbene chemistry will pave the way for its application in the designing and synthesis of efficient catalysts.

Basic Organic and Inorganic Chemistry of Boron Clusters and Its Application to Drug Discovery

In the past, drug discovery using low-molecular-weight compounds was dominated by structural design based on combinations of non-metallic elements such as carbon, nitrogen, oxygen, and halogens. Recent drug discovery efforts have shown extraordinary progress, an example of which is the adoption of non-universal elements. The approval of boron neutron capture therapy (BNCT) using a neutron accelerator in Japan ahead of other countries is still fresh in our memory. Other small-molecule drugs containing boron atoms have also been developed, and boron is becoming widely recognized as a constituent element for drug discovery. It is known that borane (BH3) is unstable because of its electron-deficient bonds; nevertheless, its stability has been improved by the formation of clusters through multimerization. Carborane (C2B10H12), one of the borane clusters, has an icosahedral structure with two carbon atoms and ten boron atoms and exhibits properties that vastly differ from conventional boron compounds. In this symposium review, we will introduce the basic chemistry of carboranes and their application to drug discovery. Boron is an essential element in plant cell wall formation and has extremely low toxicity to humans. I hope that this symposium review will be an opportunity for us to free ourselves from existing prejudices and constraints in drug discovery, and that new modalities that skillfully utilize the characteristics of boron and boron clusters will be developed one after another.

Recent Advances in Asymmetric [1,2]-Stevens-Type Rearrangement via Metal Carbenes

AbstractThe [1,2]-Stevens rearrangement is a widely used transformation in synthetic organic chemistry. However, enantioselective versions are relatively limited and most of them rely on substrate-induced methodologies. In recent years, metal carbene chemistry has been extensively investigated, and the related asymmetric [1,2]-Stevens rearrangement has experienced rapid development by employing ylide intermediates generated from the reaction of metal carbenes with heteroatoms. This review summarizes recent advances in the asymmetric [1,2]-Stevens-type rearrangement via metal carbenes by presenting their product diversity, selectivity, and mechanistic rationale, which is organized based on the mode of chirality control.1 Introduction2 Substrate-Induced Asymmetric [1,2]-Stevens-Type Rearrangement3 Catalyst-Controlled Asymmetric [1,2]-Stevens-Type Rearrangement4 Conclusion and Outlook

An Air-Stable "Masked" Bis(imino)carbene: A Carbon-Based Dual Ambiphile.

Carbenes, once considered laboratory curiosities, now serve as powerful tools in the chemical and material sciences. To date, all stable singlet carbenes are single-site ambiphiles. Here we describe the synthesis of a carbene which is a carbon-based dual ambiphile (both single-site and dual-site). The key is to employ imino substituents derived from a cyclic (alkyl)(amino)carbene (CAAC), which imparts a 1,3-dipolar character to the carbene. Its dual ambiphilic nature is consistent with the ability to activate simple organic molecules in both 1,1- and 1,3-fashion. Furthermore, its 1,3-ambiphilicity facilitates an unprecedented reversible intramolecular dearomative [3 + 2] cycloaddition with a proximal arene substituent, giving the carbene the ability to "mask" itself as an air-stable cycloadduct. We perceive that the concept of dual ambiphilicity opens a new dimension for future carbene chemistry, expanding the repertoire of applications beyond that known for classical single-site ambiphilic carbenes.

Porous organic polycarbene nanotrap for efficient and selective gold stripping from electronic waste

The role of N-heterocyclic carbene, a well-known reactive site, in chemical catalysis has long been studied. However, its unique binding and electron-donating properties have barely been explored in other research areas, such as metal capture. Herein, we report the design and preparation of a poly(ionic liquid)-derived porous organic polycarbene adsorbent with superior gold-capturing capability. With carbene sites in the porous network as the “nanotrap”, it exhibits an ultrahigh gold recovery capacity of 2.09 g/g. In-depth exploration of a complex metal ion environment in an electronic waste-extraction solution indicates that the polycarbene adsorbent possesses a significant gold recovery efficiency of 99.8%. X-ray photoelectron spectroscopy along with nuclear magnetic resonance spectroscopy reveals that the high performance of the polycarbene adsorbent results from the formation of robust metal-carbene bonds plus the ability to reduce nearby gold ions into nanoparticles. Density functional theory calculations indicate that energetically favourable multinuclear Au binding enhances adsorption as clusters. Life cycle assessment and cost analysis indicate that the synthesis of polycarbene adsorbents has potential for application in industrial-scale productions. These results reveal the potential to apply carbene chemistry to materials science and highlight porous organic polycarbene as a promising new material for precious metal recovery.

Manganese(III) complexes stabilized with N-heterocyclic carbene ligands for alcohol oxidation catalysis.

The chemistry of N-heterocyclic carbenes with Earth-abundant manganese has largely focused on low-valent systems for reductive catalysis. Here, we have decorated imidazole- and triazole-derived carbenes with phenol substituents to access higher-valent Mn(III) complexes [Mn(O,C,O)(acac)], where acac = acetylacetonato, and O,C,O = bis(phenolate)imidazolylidene (1) or bis(phenolate)triazolylidene (2). Both complexes catalyze the oxidation of alcohols in the presence of tBuOOH as terminal oxidant. Complex 2 is slightly more active than 1 (TOF up to 540 h-1vs. 500 h-1), yet significantly more robust towards deactivation. Secondary and primary alcohols are oxidized, the latter with high selectivity and essentially no overoxidation of the aldehyde product to carboxylic acids unless the reaction time is substantially extended. Mechanistic investigations using Hammett parameters, IR spectroscopy, isotope labelling experiments, and specific substrates and oxidants as probes support the formation of a manganese(V) oxo system as the active species and subsequent turnover-limiting hydrogen atom abstraction.

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.