Nucleophilic Carbene Research Articles

Photoinduced Copper-Catalyzed Cross-Coupling of Acylsilanes with Heteroarenes via Bimetallic Relay.

The transition metal-catalyzed direct coupling reactions involving electron-rich Fischer carbene species are largely underdeveloped and remain a big challenge. Here, a direct coupling reaction of azoles and azine N-oxides is reported with Fischer copper carbene species bearing an α-siloxy group i, which can be in situ generated from acylsilanes catalytically under photoirradiation and redox-neutral conditions. This coupling reaction between electron-rich α-siloxy Fischer Cu-carbene species with hard carbanion nucleophiles may undergo a bimetallic relay process, which is confirmed by the kinetic analysis and in situ NMR analysis. This reaction features mild conditions and remarkable heterocycle compatibility. Notably, this protocol tolerates a series of azole or azine N-oxide derivatives, including benzoxazole, benzothiazole, benzoimidazole, benzoisoxazole, oxazole, oxadiazole, triazolo[4,3-a]pyridine, purine, caffeine, pyridine N-oxide, quinoline N-oxide, pyrazine N-oxide, pyridazine N-oxide, etc. The synthetic value of this approach is demonstrated by the efficient synthesis of a histamine h4 receptor ligand and a marketed drug carbinoxamine.

Highly Efficient and Reversible Carbon Dioxide Capture by Carbanion-Functionalized Ionic Liquids.

Due to the active unstable nature of carbon anions, it is challenging to develop carbanion-functionalized ionic liquids (ILs) for efficient and reversible carbon dioxide (CO2) capture. Here, a series of carbanion-based ILs with large conjugated structures were designed and a promising system was achieved through tuning the nucleophilicity of carbanions and screening the cation. The ideal carbanion-functionalized IL trihexyl(tetradecyl)phosphonium N,N-diethycyanoacetoamide ([P66614][DECA]) showed equimolar chemisorption of CO2 ( up to 0.98 mol CO2/mol IL) under ambient pressure and excellent absorption rate. What's more, the combined CO2 can be released easily, leading to excellent reversibility due to high stability of anion conjugated structures. More importantly, the presence of water had negligible effect on the absorption capacity, which makes it potential to be applied to the CO2 capture in industrial flue gas. The chemisorption mechanism of the carbanion and CO2 was confirmed by spectroscopic investigations and DFT calculations, where carboxylic acid product was formed through proton transfer after the carbanions reacted with CO2. Considering that high capacity, quick rate as well as excellent reversibility, these carbanion-functionalized ILs should certainly represent competitive candidates for further scale up and practical application in CO2 capture.

Abstraction of Trifluoroborane from Tetrafluoroborate: Li+‐Assisted Borylation of Nucleophilic Carbenes

AbstractThe small, lipophilic tetrafluoroborate anion is ubiquitous in the imidazol(in)ium and iminium precursors to N‐heterocyclic carbenes (NHCs), including cyclic (alkyl)(amino)carbenes (CAACs). Its symmetrical distribution of charge over four highly electronegative fluorine atoms confers high stability, attenuating basicity while shielding the boron center. Here we report that this inertness does not withstand the nucleophilicity of free carbenes, when combined with a polarizing lithium cation. Reaction of CAAC ⋅ HBF4 salts with LiN(SiMe3)2, a protocol widely used to liberate free CAACs, generates zwitterionic CAAC‐BF3 adducts within minutes at 80 °C, or hours at room temperature, even for bulky N‐diisopropylphenyl (DIPP) CAACs. Imidazol(in)ium tetrafluoroborates likewise form NHC‐BF3 adducts in excellent yields.

Philicity indices of carbenes

New electronic philicity indices Ie, P for donor–acceptor interactions of a wide range of carbenes of both nucleophilic and electrophilic type were assessed using the DFT methods. For typical nucleophilic neutral carbenes and hydrogen ions PH are in the range of 1.4–2.8 eV, PH′ 1.5– 1.9, IeH 9.5–11.9 eV; for typical electrophilic carbenes pH 0–0.6 eV, PH′ 1.0– −0.3, IeH −2.0–3.6 eV. The electronegativities χ and global electrophilicities ω of the same carbenes for one-electron processes were also determined. It was established that the electronegativity is suitable criterium of philicity. For typical nucleophilic neutral carbenes ω are in the range of 0.1–1.1 eV, χ 1.5–3.9 eV, for typical electrophilic carbenes ω 1.4–4.9 eV, χ 4.7–7.1 eV. The data obtained can be used in the design of structures for synthetic and practical applications.

Reversible Dihydrogen Activation and Catalytic Transfer Hydrogenation with Iminophosphinoyl‐Tethered Ruthenium Carbene Complexes

AbstractIn the last decades, metal ligand cooperativity has intensively been used as tool in homogeneous catalysis for the development of potent catalysts for a variety of applications, above all hydrogenation and transfer hydrogenation reactions. Herein, we report on the synthesis of iminophosphinoyl‐tethered ruthenium carbene complexes and their use in the activation of dihydrogen and the catalytic transfer hydrogenation of p‐fluoroacetophenone. Variation of the N‐substituent to an electron‐withdrawing p‐nitrophenyl group enabled the reversible activation of elemental hydrogen via a 1,2‐addition across the metal carbon double bond both in solution and in solid state. In comparison to the thiophosphinoyl‐tethered carbene complex the presented iminophosphinoyl systems showed a considerably increased catalytic activity in transfer hydrogenation reactions, thus highlighting the tunability of the cooperative behavior of nucleophilic carbene complexes.

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.

Acylsilanes in Transition-Metal-Catalyzed and Photochemical Reactions: Clarifying Product Formation.

Acylsilanes are able to react as nucleophilic carbene precursors, electrophiles, and directing groups in C-H functionalization. To date, some of the products reportedly formed during transition-metal-catalyzed and photochemical reactions involving acylsilanes have been incorrectly assigned. To provide clarity, we herein address these structural misassignments and detail the revised structures. New insights into the reactivity of acylsilanes were also afforded via the discovery that light-induced siloxy carbenes participate in intramolecular 1,2-carbonyl addition to proximal esters.

Nucleophilic Carbenes Derived from Dichloromethane

AbstractNickel PyBox catalysts promote nucleophilic cyclopropanation reactions using CH2Cl2 as a methylene source and Mn as a stoichiometric reductant. The substrate scope includes a broad range of alkenes bearing electron‐withdrawing substituents, including esters, amides, ketones, nitriles, sulfones, phosphonate esters, trifluoromethyl groups, and electron‐deficient arenes. Enantioselective cyclopropanations of α,β‐unsaturated esters have been developed using chiral PyBox ligands. Mechanistic studies suggest the intermediacy of a (PyBox)Ni=CH2 species, which adds to the alkene by a stepwise [2+2]‐cycloaddition/C−C reductive elimination mechanism. DFT models provide a rationale for the nucleophilic character of the nickel carbene and the sense of enantioinduction.

Nucleophilic Carbenes Derived from Dichloromethane.

Nickel PyBox catalysts promote nucleophilic cyclopropanation reactions using CH2 Cl2 as a methylene source and Mn as a stoichiometric reductant. The substrate scope includes a broad range of alkenes bearing electron-withdrawing substituents, including esters, amides, ketones, nitriles, sulfones, phosphonate esters, trifluoromethyl groups, and electron-deficient arenes. Enantioselective cyclopropanations of α,β-unsaturated esters have been developed using chiral PyBox ligands. Mechanistic studies suggest the intermediacy of a (PyBox)Ni=CH2 species, which adds to the alkene by a stepwise [2+2]-cycloaddition/C-C reductive elimination mechanism. DFT models provide a rationale for the nucleophilic character of the nickel carbene and the sense of enantioinduction.

Generation of N-heterocyclic carbenes (NHC) in aqueous solutions of zwitterionic imidazolium surfactant micelles

N-heterocyclic carbenes (NHCs) are important compounds that are often prepared and used in water free environment. Herein we investigate transient formation of a NHC in the headgroup of zwitterionic imidazolium sulfonate surfactants of the type 3-(1-alkyl-1H-imidazol-3-ium-3-yl)propane-1-sulfonate (ImS3-n) in water. As demonstrated by a series of 1H NMR experiments, the formation of the NHC reactive species is accelerated above the critical micelle concentration of these surfactants due to an increased local concentration of the hydroxide or deuteroxide ions (OH−/OD−) responsible for deprotonation of C(2)-H. The rate of NHC formation can be modulated by the nature and concentration of the anions of added salts, reflecting the selectivity of anion binding to the zwitterionic micelle surface. Analogous anion binding affects are observe in the NMR chemical shifts of the C(2)-H signal of the imidazolium headgroup of the surfactants. The NHCs generated at the surface of ImS3-n micelles promote the selective oxidation of 4-nitrobenzaldehyde to 4-nitrobenzoic acid, a reaction known to be catalyzed by nucleophilic carbenes. Below the cmc or in the presence of a short-chain non-micelle-forming analogue, 3-(1-methyl-1H-imidazol-3-ium-3-yl)propane-1-sulfonate (ImS3-1), no selective oxidation of 4-nitrobenzaldehyde takes place. The results demonstrate the importance of the micellar microenvironment for controlling the reactivity and selectivity of chemical reactions involving NHC species in aqueous media and can ultimately lead to greener catalytic systems.

Latent Carbene in Diaminomethylation of Benzenes: Mechanism and Practical Application

Silylformamidine 1 exists in equilibrium with its carbenic form 1' due to an easy migration of the silyl group. The reaction of 1 with variously substituted fluorobenzenes proceeds as an insertion of the nucleophilic carbene 1' into the most acidic C-H bond upon mixing the reagents and does not require any catalyst. According to DFT calculations, the classical interpretation of the insertion reaction proceeding via a three-membered transition state structure requires high activation energy. Instead, low activation barriers are predicted for a transfer of the most acidic proton in the aromatic substrate to the carbene carbon. As the next step, a barrierless rearrangement of the formed ion pair toward the product completes the process. The reactivity of substituted benzenes in the reaction with silylformamidine can be roughly assessed by calculated pKa (DMSO) values for the C-H hydrogens. Benzene derivatives having pKa approx. less than 31 can undergo C-H insertion. The reaction provides aminals as the first products, which can easily be transformed into the corresponding aldehydes via acidic hydrolysis. As silylformamidine 1 is tolerant to many functional groups, the reaction can be applied to numerous benzene derivatives, making it a reliable strategy for application in organic synthesis.

Updating the Benzoin Condensation of Benzaldehyde Using Microwave-Assisted Organic Synthesis and N-Heterocyclic Carbene Catalysis

The benzoin condensation of benzaldehyde is a staple of the undergraduate organic chemistry laboratory, introducing the current topic of nucleophilic carbene organocatalysis. Our procedure makes notable improvements to current practice, including the elimination of solvent waste and an 18-fold reduction of reaction time. We have demonstrated that microwave heating provides yields comparable to current practice in 5 min, using significantly less power (70 W) than traditional heating methods. The highest yields were obtained with N,N′-(2,4,6-trimethylphenyl)imidazolium chloride (IMes·HCl) as the catalyst and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the base. Our procedure has been successfully executed by multiple cohorts of organic chemistry undergraduates, both with and without pandemic social distancing constraints.

Ultrasound-Assisted Rapid Synthesis of Functionalized 1,2-Teraryls by Ring Transformation Methodology

AbstractThe function of styryl acetate as a carbanion nucleophile source has been explored in the ring transformation reaction of 2H-pyranones. The ultrasound-assisted carbanion-induced ring transformation of 4-amino-6-aryl-3-cyano-2H-pyran-2-ones using (E)-styryl acetate in the presence of KOH and DMF at room temperature is presented as an alternative strategy for the synthesis of functionalized 1,2-teraryls in high yields. This metal-free methodology provides easy access to a series of 1,2-teraryls and features broad functional group tolerance and mild reaction condition. Single crystal X-ray diffraction analysis of 4-(piperidin-1-yl)-6-(thiophen-2-yl)-[1,1′-biphenyl]-3-carbonitrile indicated that the crystal belongs to monoclinic system with a P21 space group having twisted aryl rings.

Functionalized Cyclopentenes via the Formal [4+1] Cycloaddition of Photogenerated Siloxycarbenes from Acyl Silanes.

This work describes the first formal cycloaddition reaction of photogenerated nucleophilic carbenes derived from acylsilanes with electrophilic dienes. The resulting transient donor-acceptor cyclopropane rearranges to its stable and highly functionalized cyclopentene isomer in an unprecedented metal-free process. The cyclopropanation-vinyl cyclopropane rearrangement sequence was corroborated by computational calculations. The cyclopropane formation corresponds to a higher energetic barrier, and the vinylcyclopropane-cyclopentene rearrangement proceeds through different mechanisms, although of comparable energies, depending on the stereochemistry of the cyclopropane.

Bond Dissociation Energies of Carbene-Carbene and Carbene-Main Group Adducts.

A range of carbene structures and their adducts with one another and with a selection of small-molecule electrophiles and nucleophiles were examined at the composite correlated molecular orbital theory G3MP2 level to explore ground-state "carbenic" structures, their stabilities, and reactivities. Differences between carbene general classification as a singlet electrophilic carbene or singlet nucleophilic carbene and their given reactivity are discussed. A key quantity is the carbon-carbon bond dissociation energy for carbene dimers or the carbene-adduct dissociation energy for other species. The carbene dimer bond dissociation energies span a wide range from 10 to 170 kcal/mol. The hydrogenation energies and singlet-triplet splitting were found to correlate best with the carbene's self-dimerization energy, whereas other descriptors do not. The proton and fluoride affinities of the carbenes alone prove inadequate for classifying reactivity among classes of carbenes. The self-dimerization bond dissociation energy, hydrogenation energy, and singlet-triplet splitting of various carbenes, despite sometimes large differences in proton affinity and other indicators of reactivity, provide usable metrics to correlate substantial amounts of thermodynamic and kinetic (reactivity) information regarding these structures.

Recent Advances in the Domain of Cyclic (Alkyl)(Amino) Carbenes.

Isolation of cyclic (alkyl) amino carbenes (cAACs) in 2005 has been a major achievement in the field of stable carbenes due to their better electronic properties. cAACs and bicyclic(alkyl)(amino)carbene (BicAAC) in essence are the most electrophilic as well as nucleophilic carbenes are known till date. Due to their excellent electronic properties in terms of nucleophilic and electrophilic character, cAACs have been utilized in different areas of chemistry, including stabilization of low valent main group and transition metal species, activation of small molecules, and catalysis. The applications of cAACs in catalysis have opened up new avenues of research in the field of cAAC chemistry. This review summarizes the major results of cAAC chemistry published until August 2021.

Carbene Character in a Series of Neutral PCcarbeneP Cobalt(I) Complexes: Radical Carbenes versus Nucleophilic Carbenes

Carbene Character in a Series of Neutral PC_carbeneP Cobalt(I) Complexes: Radical Carbenes versus Nucleophilic Carbenes

N-Alkoxyimidazolylidines (NOHCs): nucleophilic carbenes based on an oxidized imidazolium core.

We report the first preparation of N-alkoxyimidazolylidene (NOHC), a nucleophilic carbene based on an oxidized imidazolium core. The Arduengo-type analogous carbene center shows the most upfield 13C NMR shift compared to common NHCs. The obtained gold(I) complex of the carbene follows the 13C NMR upfield trend and shows the marked influence the alkoxy substituents. Similarly, the 77Se and 15N NMR shifts of a range of NOHC-selenium adducts show increased σ-donation and decreased π-back donation in the bonding with the nucleophile. This extension of the NHC family provides altered electronic properties for the use of such carbenes as ligands or catalysts.

Intramolecular photochemical [2 + 1]-cycloadditions of nucleophilic siloxy carbenes

Visible light induced singlet nucleophilic carbenes undergo rapid [2 + 1]-cycloaddition with tethered olefins to afford unique bicyclo[3.1.0]hexane and bicyclo[4.1.0]heptane scaffolds. This cyclopropanation process requires only visible light irradiation to proceed, circumventing the use of exogenous (photo)catalysts, sensitisers or additives and showcases a vastly underexplored mode of reactivity for nucleophilic carbenes in chemical synthesis. The discovery of additional transformations including a cyclopropanation/retro-Michael/Michael cascade process to afford chromanones and a photochemical C–H insertion reaction are also described.

Latent Nucleophilic Carbenes.

Using DFT and ab initio calculations, we demonstrate that noncyclic formamidines can undergo thermal rearrangement into their isomeric aminocarbenes under rather mild conditions. We synthesized the silylformamidine, for which the lowest activation energy in this process was predicted. Experimental studies proved it to serve as a very reactive nucleophilic carbene. The reactions with acetylenes, benzenes, and trifluoromethane proceeded via insertion into sp, sp2, and sp3 CH bonds. The carbene also reacted with the functional groups, such as CHO, COR, and CN at double or triple bonds, displaying high mobility of the trimethylsilyl group. The obtained silylformamidine can be considered as a latent nucleophilic carbene. It can be prepared in bulk quantities, stored, and used when the need arises. Calculation results predict similar behavior for some other silylated formamidines and related compounds.