A crystalline doubly oxidized carbene.

The chemistry of carbon is governed by the octet rule, which refers to its tendency to have eight electrons in its valence shell. However, a few exceptions do exist, for example, the trityl radical (Ph3C∙) (ref. 1) and carbocation (Ph3C+) (ref. 2) with seven and six valence electrons, respectively, and carbenes (R2C:)-two-coordinate octet-defying species with formally six valence electrons3. Carbenes are now powerful tools in chemistry, and have even found applications in material and medicinal sciences4. Can we undress the carbene further by removing its non-bonding electrons? Here we describe the synthesis of a crystalline doubly oxidized carbene (R2C2+), through a two-electron oxidation/oxide-ion abstraction sequence from an electron-rich carbene5. Despite a cumulenic structure and strong delocalization of the positive charges, the dicoordinate carbon centre maintains significant electrophilicity, and possesses two accessible vacant orbitals. A two-electron reduction/deprotonation sequence regenerates the parent carbene, fully consistent with its description as a doubly oxidized carbene. This work demonstrates that the use of bulky strong electron-donor substituents can simultaneously impart electronic stabilization and steric protection to both vacant orbitals on the central carbon atom, paving the way for the isolation of a variety of doubly oxidized carbenes.

1H-1,2,3-Triazol-5-ylidenes as Catalytic Organic Single-Electron Reductants.

Most of the known single-electron reductants are either metal based reagents, used in a stoichiometric amount, or a combination of an organic species and a photocatalyst. Here we report that 1H-1,2,3-triazol-5-ylidenes act not only as stoichiometric one-electron donors but also as catalytic organic reducing agents, without the need of a photocatalyst. As a proof of concept, we studied the reduction of quinones, which are well-known electron conveyors that are involved in various biological and industrial processes. This work also provides experimental evidence for the formation of a bis(triazolium)carbonate adduct, which acts as the resting state of the catalytic cycle and as the carbene reservoir.

Genuine carbene versus carbene-like reactivity.

Singlet carbenes are not always isolable and often even elude direct detection. When they escape observation, their formation can sometimes be evidenced by in situ trapping experiments. However, is carbene-like reactivity genuine evidence of carbene formation? Herein, using the first example of a spectroscopically characterized cyclic (amino)(aryl)carbene (CAArC), we cast doubt on the most common carbene trapping reactions as sufficient proof of carbene formation.

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.

Enhancing Substrate-Metal Catalyst Affinity via Hydrogen Bonding: Pd(II)-Catalyzed ß-C(sp3)-H Bromination of Free Carboxylic Acids.

The achievement of sufficient substrate-metal catalyst affinity is a fundamental challenge for the development of synthetically useful C-H activation reactions of weakly coordinating native substrates. While hydrogen bonding has been harnessed to bias site selectivity in existing C(sp2)-H activation reactions, the potential for designing catalysts with hydrogen bond donors (HBDs) to enhance catalyst-substrate affinity and, thereby, facilitate otherwise unreactive C(sp3)-H activation remains to be demonstrated. Herein, we report the discovery of a ligand scaffold containing a remote amide motif that can form a favorable meta-macrocyclic hydrogen bonding interaction with the aliphatic acid substrate. The utility of this ligand scaffold is demonstrated through the development of an unprecedented C(sp3)-H bromination of α-tertiary and α-quaternary free carboxylic acids, which proceeds in exceedingly high mono-selectivity. The geometric relationship between the NHAc hydrogen bond donor and the coordinating quinoline ligand is crucial for forming the meta-macrocyclophane-like hydrogen bonding interaction, which provides a guideline for the future design of catalysts employing secondary interactions.

Reactivity of Yellow Arsenic towards Cyclic (Alkyl)(Amino) Carbenes (CAACs).

Different cyclic (alkyl)(amino)carbenes (CAACs) were reacted with yellow arsenic. Several products [(CAAC-n)2 (µ,η1:1 -As2 )] (n=1 (1), 4 (2)), [(CAAC-2)3 (µ3 ,η1:1:1 -As4 )] (3) and [(CAAC-3)4 (µ4 ,η1:1:1:1 - As8 )] (6) were isolated due to the differing steric properties of CAAC-1-4. The products contain As2 , As4 or As8 units and represent the first examples of CAACs-substituted products of yellow arsenic. The reactivity of As4 was compared with the reactivities of P4 and the interpnictogen compound AsP3 , which led to a series of phosphorus-containing derivatives such as ([(CAAC-3)3 (µ3 ,η1:1:1 -P4 )] (4) and [(CAAC-3)4 (µ4 ,η1:1:1:1 -P8 )] (7)) and [(CAAC-3)3 (µ3 ,η1:1:1 -AsP3 )] (5). The products were characterized by spectroscopic and crystallographic methods and DFT computations were performed to clarify their formation pathway.

How To Enhance the Efficiency of Breslow Intermediates for SET Catalysis.

Oxidative carbene organocatalysis, which proceeds via single electron transfer (SET) pathways, has been limited by the moderately reducing properties of deprotonated Breslow intermediates BI-s derived from thiazol-2-ylidene 1 and 1,2,4-triazolylidene 2. Using computational methods, we assess the redox potentials of BI-s based on ten different types of known stable carbenes and report our findings concerning the key parameters influencing the steps of the catalytic cycle. From the calculated values of the first oxidation potential of BI-s derived from carbenes 1 to 10, it appears that, apart from the diamidocarbene 7, all the others are more reducing than thiazol-2-ylidene 1 and the 1,2,4-triazolylidene 2. We observed that while the reducing power of BI-s significantly decreases with increasing solvent polarity, the redox potential of the oxidant can increase at a greater rate, thus facilitating the reaction. The cation, associated with the base, also plays an important role when a nonpolar solvent is used; large and weakly coordinating cations such as Cs+ are beneficial. The radical-radical coupling step is probably the most challenging step due to both electronic and steric constraints. Based on our results, we predict that mesoionic carbene 3 and abnormal NHC 4 are the most promising candidates for oxidative carbene organocatalysis.

Mesoionic Carbene-Catalyzed Formyl Alkylation of Aldehydes.

Ketones are among the most useful functional groups in organic synthesis, and they are commonly encountered in a broad range of compounds with various applications. Herein, we describe the mesoionic carbene-catalyzed coupling reaction of aldehydes with non-activated secondary and even primary alkyl halides. This metal-free method utilizes deprotonated Breslow intermediates derived from mesoionic carbenes (MICs), which act as super electron donors and induce the single-electron reduction of alkyl halides. This mild coupling reaction has a broad substrate scope and tolerates many functional groups, which allows to prepare a diversity of simple ketones as well as bio-active molecules by late-stage functionalization.

Circularly Polarized Luminescence from Cyclic (Alkyl)(Amino) Carbene Derived Propellers.

Organic circularly polarized luminescence (CPL)-active molecular emitters featuring dynamic propeller-like luminophores were prepared in one step from cyclic(alkyl)(amino) carbenes (CAACs). These molecules exhibit through-space arene-arene π-delocalization and rapid intramolecular inter-system crossing (ISC) in line with their helical character.

Cyclic (Alkyl)(amino)carbenes: Synthesis of Iminium Precursors and Structural Properties.

Using readily available preallylated aldehydes, we report a simple and divergent synthesis of cyclic (alkyl)(amino)carbene (CAAC) iminium precursors. Using a combination of crystallographic data and steric maps, we further elaborate on the specific steric properties of CAAC ligands with respect to state-of-the-art phosphine and carbene ligands.

Cyclic (Alkyl)- and (Aryl)-(amino)carbene Coinage Metal Complexes and Their Applications.

Cyclic (alkyl)- and (aryl)-(amino)carbenes (CAACs and CAArCs) are stronger σ-donors and π-acceptors than imidazol-2-ylidenes and imidazolidin-2-ylidenes, the well-known N-heterocyclic carbenes (NHCs). Consequently, they form strong bonds with coinage metals and stabilize both low and high oxidation states. This Review shows that CAACs and CAArCs have allowed for the isolation of copper and gold complexes that were believed to be only transient intermediates. This has not only allowed for a better understanding of the mechanism of known processes but has also led to the development of novel coinage metal-catalyzed reactions. In addition to their role in homogeneous catalysis, CAAC and CAArC coinage metal complexes have recently found applications in medicinal chemistry, as well as in materials science. When possible, the performance of CAAC and CAArC ligands are compared with those of classical NHCs.

Cyclic (Alkyl)(Amino)Carbene (CAAC) Gold(I) Complexes as Chemotherapeutic Agents.

Cyclic (Alkyl)(Amino)Carbenes (CAACs) have become forceful ligands for gold due to their ability to form very strong ligand-metal bonds. Inspired by the success of Auranofin and other gold complexes as antitumor agents, we have studied the cytotoxicity of bis- and mono-CAAC-gold complexes on different cancer cell lines: HeLa (cervical cancer), A549 (lung cancer), HT1080 (fibrosarcoma) and Caov-3 (ovarian cancer). Further investigations aimed at elucidating their mechanism of action are described. This includes quantification of affinities for TrxR, evaluation of their bioavailability and determination of associated cell death process. Moreover, Transmission Electron Microscopy (TEM) was used to study morphological changes upon exposure. Noticeably, a significant reduction in non-specific binding to serum proteins was observed with CAAC complexes when compared to Auranofin. These results confirm the potential of CAAC-gold complexes in biological environments, which may result in more specific drug-target interactions and decreased side effects.

Stable abnormal N-heterocyclic carbenes and their applications.

Although N-heterocyclic carbenes (NHCs) have been known as ligands for organometallic complexes since the 1960s, these carbenes did not attract considerable attention until Arduengo et al. reported the isolation of a metal-free imidazol-2-ylidene in 1991. In 2001 Crabtree et al. reported a few complexes featuring an NHC isomer, namely an imidazol-5-ylidene, also termed abnormal NHC (aNHCs). In 2009, it was shown that providing to protect the C-2 position of an imidazolium salt, the deprotonation occurred at the C-5 position, affording imidazol-5-ylidenes that could be isolated. Over the last ten years, stable aNHCs have been used for designing a range of catalysts employing Pd(ii), Cu(i), Ni(ii), Fe(0), Zn(ii), Ag(i), and Au(i/iii) metal based precursors. These catalysts were utilized for different organic transformations such as the Suzuki-Miyaura cross-coupling reaction, C-H bond activation, dehydrogenative coupling, Huisgen 1,3-dipolar cycloaddition (click reaction), hydroheteroarylation, hydrosilylation reaction and migratory insertion of carbenes. Main-group metal complexes were also synthesized, including K(i), Al(iii), Zn(ii), Sn(ii), Ge(ii), and Si(ii/iv). Among them, K(i), Al(iii), and Zn(ii) complexes were used for the polymerization of caprolactone and rac-lactide at room temperature. In addition, based on the superior nucleophilicity of aNHCs, relative to that of their nNHCs isomers, they were used for small molecules activation, such as carbon dioxide (CO2), nitrous oxide (N2O), tetrahydrofuran (THF), tetrahydrothiophene and 9-borabicyclo[3.3.1]nonane (9BBN). aNHCs have also been shown to be efficient metal-free catalysts for ring opening polymerization of different cyclic esters at room temperature; they are among the most active metal-free catalysts for ε-caprolactone polymerization. Recently, aNHCs successfully accomplished the metal-free catalytic formylation of amides using CO2 and the catalytic reduction of carbon dioxide, including atmospheric CO2, into methanol, under ambient conditions. Although other transition metal complexes featuring aNHCs as ligand have been prepared and used in catalysis, this review article summarize the results obtained with the isolated aNHCs.

Stable Singlet Carbenes as Organic Superbases.

A simple experimental procedure for scaling carbene Brønsted basicity is described. The results highlight the strong basicity of pyrazol-4-ylidenes, a type of mesoionic carbene, also named cyclic-bentallenes (CBA). They are more basic (pKaH >42.7 in acetonitrile) than the popular proazaphosphatrane Verkade bases, and even the Schwesinger phosphazene superbase P4 (t Bu). The basicity of these compounds can readily be tuned, and they are accessible in multigram quantities. These results open new avenues for carbon centered superbases.

Cyclic (Alkyl)(amino)carbene Ligands Enable Cu-Catalyzed Markovnikov Protoboration and Protosilylation of Terminal Alkynes: A Versatile Portal to Functionalized Alkenes*.

Regioselective hydrofunctionalization of alkynes represents a straightforward route to access alkenyl boronate and silane building blocks. In previously reported catalytic systems, high selectivity is achieved with a limited scope of substrates and/or reagents, with general solutions lacking. Herein, we describe a selective copper-catalyzed Markovnikov hydrofunctionalization of terminal alkynes that is facilitated by strongly donating cyclic (alkyl)(amino)carbene (CAAC) ligands. Using this method, both alkyl- and aryl-substituted alkynes are coupled with a variety of boryl and silyl reagents with high α-selectivity. The reaction is scalable, and the products are versatile intermediates that can participate in various downstream transformations. Preliminary mechanistic experiments shed light on the role of CAAC ligands in this process.

Absolute Templating of M(111) Cluster Surrogates by Galvanic Exchange.

The precise preparation of monodisperse nanomaterials is among the most fundamental tasks in inorganic synthesis and materials science. Achieving this goal by galvanic exchange is hardly predictable and often results in major structural changes and polydisperse mixtures. Taking advantage of the enhanced stability imparted by ambiphilic carbenes, we report and rationalize the absolute templating, the complete exchange of metals in a template, of group 11 clusters across the entire coinage metal family by means of galvanic exchange. We further delineate that these species provide a molecular model for better understanding the reduction of CO2 at M(111) coinage metal surfaces.

Realizing Metal-Free Carbene-Catalyzed Carbonylation Reactions with CO.

Many organic and main-group compounds, usually acids or bases, can accelerate chemical reactions when used in substoichiometric quantities, a process known as organocatalysis. In marked contrast, very few of these compounds are able to activate carbon monoxide, and until now, none of them could catalyze its chemical transformation, a classical task for transition metals. Herein we report that a stable singlet ambiphilic carbene activates CO and catalytically promotes the carbonylation of an o-quinone into a cyclic carbonate. These findings pave the way for the discovery of metal-free catalyzed carbonylation reactions.

Optically Pure C1-Symmetric Cyclic(alkyl)(amino)carbene Ruthenium Complexes for Asymmetric Olefin Metathesis.

An expedient access to the first optically pure ruthenium complexes containing C1-symmetric cyclic (alkyl)(amino)carbene ligands is reported. They demonstrate excellent catalytic performances in asymmetric olefin metathesis with high enantioselectivities (up to 92% ee). Preliminary mechanistic insights provided by density functional theory models highlight the origin of the enantioselectivity.

The Influence of C(sp3 )H-Selenium Interactions on the 77 Se†NMR Quantification of the π-Accepting Properties of Carbenes.

Selenium NMR has become a standard tool for scaling the π-accepting character of carbenes. Herein, we highlight that non-classical hydrogen bonding (NCHB), likely resulting from hyperconjugation, can play a significant role in the carbene-selenium 77 Se NMR chemical shift, thus triggering a non-linear behavior of the Se-Scale.

Understanding the Activity and Enantioselectivity of Acetyl-Protected Aminoethyl Quinoline Ligands in Palladium-Catalyzed ß-C(sp3)-H Bond Arylation Reactions.

Chiral acetyl-protected aminoalkyl quinoline (APAQ) ligands were recently discovered to afford highly active and enantioselective palladium catalysts for the arylation of methylene C(sp3)-H bonds, and herein, we investigate the origins of these heightened properties. Unprecedented amide-bridged APAQ-Pd dimers were predicted by density functional theory (DFT) calculations and were confirmed by single-crystal X-ray diffraction studies. Comparison of structural features between APAQ-Pd complexes and an acetyl-protected aminoethylpyridine APAPy-Pd complex strongly suggests that the high activity of the former originates from the presence of the quinoline ring, which slows the formation of the off-cycle palladium dimer. Furthermore, steric topographic maps for a representative subset of monomeric, monoligated palladium complexes allowed us to draw a unique parallel between the three-dimensional structures of these catalysts and their reported asymmetric induction in ß-C(sp3)-H bond arylation reactions. Finally, cooperative noncovalent interactions present between the APAQ ligand and the substrate were identified as a crucial factor for imparting selectivity between chemically equivalent methylenic C(sp3)-H bonds prior to concerted metalation deprotonation activation.