Reactions Of Carbanions Research Articles

Formation of Breslow Intermediates from N‐Heterocyclic Carbenes and Aldehydes Involves Autocatalysis by the Breslow Intermediate, and a Hemiacetal

Under aprotic conditions, the stoichiometric reaction of N‐heterocyclic carbenes (NHCs) such as imidazolidin‐2‐ylidenes with aldehydes affords Breslow Intermediates (BIs), involving a formal 1,2‐C‐to‐O proton shift. We herein report kinetic studies (NMR), complemented by DFT calculations, on the mechanism of this kinetically disfavored H‐translocation. Variable time normalization analysis (VTNA) revealed that the kinetic orders of the reactants vary for different NHC‐to‐aldehyde ratios, indicating different and ratio‐dependent mechanistic regimes. We propose that for high NHC‐to‐aldehyde ratios, the H‐shift takes place in the primary, zwitterionic NHC‐aldehyde adduct. With excess aldehyde, the zwitterion is in equilibrium with a hemiacetal, in which the H‐shift occurs. In both regimes, the critical H‐shift is auto‐catalyzed by the BI. Kinetic isotope effects observed for R‐CDO are in line with our proposal. Furthermore, we detected an H‐bonded complex of the BI with excess NHC (NMR).

Die Bildung von Breslow‐Intermediaten aus N‐heterocyclischen Carbenen und Aldehyden verläuft autokatalytisch und mit einem Halbacetal als Intermediat

AbstractUnter aprotischen Bedingungen liefert die Reaktion von N‐heterocyclischen Carbenen (NHCs) wie bspw. Imidazolidin‐2‐ylidenen mit Aldehyden Breslow‐Intermediate (BIs) und beinhaltet einen formalen 1,2‐C‐zu‐O H‐shift. Wir berichten hier über kinetische Studien (NMR) und ergänzende DFT‐Berechnungen zum Mechanismus dieser kritischen H‐Verschiebung. Mittels der zeitvarianten Normalisierungsanalyse (VTNA) wurde nachgewiesen, dass die kinetische Ordnung der Reaktanden bei verschiedenen NHC‐zu‐Aldehyd‐Verhältnissen variiert, was auf verschiedene und Verhältnis‐abhängige Mechanismen hindeutet. Wir postulieren für NHC‐Überschuss, dass der H‐Transfer im primären, zwitterionischen NHC‐Aldehyd‐Addukt erfolgt. Bei einem Überschuss Aldehyd ist das Zwitterion im Gleichgewicht mit einem Halbacetal, in welchem der H‐Transfer stattfindet. In beiden Mechanismen wird die H‐Übertragung durch das Breslow‐Intermediat autokatalysiert. Die beobachteten kinetischen Isotopeneffekte für R‐CDO sind im Einklang mit diesem Vorschlag. Zudem wurde ein Komplex des BI mit einem Überschuss an NHC (NMR) detektiert, welcher durch H‐Brückenbildung zustande kommt.

Capturing Reactive Carbanions by Microdroplets.

Carbanions appear in many organic or biological reactions as fleeting intermediates, prohibiting direct observation or spectroscopic measurement. An aqueous environment is known to rapidly annihilate a carbanion species, reducing its lifetime to as short as picoseconds. We report that aqueous microdroplets can capture and stabilize reactive carbanion intermediates isolated from four classic organic reactions, aldol and Knoevenagel condensations, alkyne alkylation, and the Reimer-Tiemann reaction, enabling the detection of their carbanion intermediates by desorption electrospray ionization mass spectrometry. This is accomplished in real time of the reaction, allowing new insights into reaction mechanisms to be obtained. The efficacy of microdroplets in capturing such elusive species was examined by varying the solvent and the microdroplet negative charge density. We observed that microdroplets composed of water-methanol outperform other solvents, such as pure water, in capturing carbanions, which is in contrast to the earlier report that presented the highest performance of pure water microdroplets in capturing carbocations. We offer some mechanistic insights to explain the discriminatory behavior of these two oppositely charged species in microdroplets.

Cobalt(II)-tetraphenylporphyrin-catalysed carbene transfer from acceptor-acceptor iodonium ylides via N-enolate-carbene radicals.

Square-planar cobalt(II) systems have emerged as powerful carbene transfer catalysts for the synthesis of numerous (hetero)cyclic compounds via cobalt(III)-carbene radical intermediates. Spectroscopic detection and characterization of reactive carbene radical intermediates is limited to a few scattered experiments, centered around monosubstituted carbenes. Here, we reveal the formation of disubstituted cobalt(III)-carbene radicals derived from a cobalt(II)-tetraphenylporphyrin complex and acceptor-acceptor λ3-iodaneylidenes (iodonium ylides) as carbene precursors and their catalytic application. Iodonium ylides generate biscarbenoid species via reversible ligand modification of the paramagnetic cobalt(II)-tetraphenylporphyrin complex catalyst. Two interconnected catalytic cycles are involved in the overall mechanism, with a monocarbene radical and an N-enolate-carbene radical intermediate at the heart of each respective cycle. Notably, N-enolate formation is not a deactivation pathway but a reversible process, enabling transfer of two carbene moieties from a single N-enolate-carbene radical intermediate. The findings are supported by extensive experimental and computational studies.

Gold Nanoparticle-Based Photo-Cross-Linking Strategy for Cellular Target Identification of Supercomplex Molecular Systems.

Cellular target identification plays an essential role in innovative drug development and pharmacological mechanism elucidation. However, very few practical experimental methodologies have been developed for identifying target proteins for supercomplex molecular systems such as biologically active phytochemicals or pharmaceutical compositions. To overcome this limitation, we synthesized gold nanoparticles (AuNPs) as solid scaffolds, which were bound with 4,4'-dihydroxybenzophenone (DHBP) as a photo-cross-linking group on the surface. Then, DHBP-modified AuNPs cross-linked various organic compounds from phytochemicals under ultraviolet radiation via carbene reactions, H-C bond insertion, for catalytic C-C bond formation. We next used the phytochemical-cross-linked AuNPs (phytoAuNPs) to pull down potential binding proteins from brain tissue lysate and identified 13 neuroprotective targets by mass spectrometry analysis. As an exemplary study, we selected Hsp60 as a crucial cellular target to further screen 14 target-binding compounds from phytochemicals through surface plasmon resonance (SPR) analysis, followed by Hsp60 activity detection and neuroprotective effect assay in cells. Collectively, this gold nanoparticle-based photo-cross-linking strategy can serve as a useful platform for discovering novel cellular targets for supercomplex molecular systems and help to explore pharmacological mechanisms and active substances.

Hydrogenative Cycloisomerization and Sigmatropic Rearrangement Reactions of Cationic Ruthenium Carbenes Formed by Catalytic Alkyne gem‐Hydrogenation

Abstractgem‐Hydrogenation of propargyl alcohol derivatives with [CpXRu(MeCN)3]PF6 (CpX=substituted cyclopentadienyl) as catalysts affords cationic pianostool ruthenium carbene complexes which are so electrophilic that they attack a tethered olefin to furnish cyclopentene products; cyclopropanation or metathesis do not compete with this novel transformation. If the transient carbenes carry appropriate propargylic substituents, however, they engage in ([2,3]‐sigmatropic) rearrangements to give enol esters (carbonates, carbamates, sulfonates) or alkenyl halides. Both pathways are unprecedented in the vast hydrogenation literature. The proposed mechanistic scenarios are in line with labeling experiments and spectroscopic data; most notably, PHIP NMR spectroscopy (PHIP=parahydrogen induced polarization) provides compelling evidence that the reactions are indeed triggered by highly unorthodox gem‐hydrogenation events.

Hydrogenative Cycloisomerization and Sigmatropic Rearrangement Reactions of Cationic Ruthenium Carbenes Formed by Catalytic Alkyne gem-Hydrogenation.

gem‐Hydrogenation of propargyl alcohol derivatives with [CpXRu(MeCN)3]PF6 (CpX=substituted cyclopentadienyl) as catalysts affords cationic pianostool ruthenium carbene complexes which are so electrophilic that they attack a tethered olefin to furnish cyclopentene products; cyclopropanation or metathesis do not compete with this novel transformation. If the transient carbenes carry appropriate propargylic substituents, however, they engage in ([2,3]‐sigmatropic) rearrangements to give enol esters (carbonates, carbamates, sulfonates) or alkenyl halides. Both pathways are unprecedented in the vast hydrogenation literature. The proposed mechanistic scenarios are in line with labeling experiments and spectroscopic data; most notably, PHIP NMR spectroscopy (PHIP=parahydrogen induced polarization) provides compelling evidence that the reactions are indeed triggered by highly unorthodox gem‐hydrogenation events.

Titanium complexes with unsymmetrically substituted imidazolin-2-iminato ligands.

The reaction of the unsymmetrical N-heterocyclic carbenes 1-(2,4,6-trimethylphenyl)-3-(adamantyl)imidazolin-2-ylidene (IAdMes, 1a) and 1-(2,6-diisopropylphenyl)-3-(adamantyl)imidazolin-2-ylidene (IAdDipp, 1b) with trimethylsilyl azide furnished the 2-(trimethylsilylimino)imidazolines 2a (ImAdMesNSiMe3) and 2b (ImAdDippNSiMe3). Desilylation by stirring in methanol gave the corresponding imidazolin-2-imines 3a (ImAdMesNH) and 3b (ImAdDippNH). 2a and 2b were treated with [TiCl4(THF)2] (THF = tetrahydrofuran) and [CpTiCl3] (Cp = η5-C5H5) to form the mono- and bis(imidazolin-2-iminato) titanium(IV) complexes [(ImAdRN)TiCl3] (4, R = Mes, Dipp), [Cp(ImAdRN)TiCl2] (5, R = Mes, Dipp), and [(ImAdRN)2TiCl2] (6, R = Mes, Dipp). The crystal structures of all compounds except 2b were determined by X-ray diffraction analysis.

Computational insights into different regioselectivities in the Ir-porphyrin-catalyzed C–H insertion reaction of quinoid carbene

Carbene insertion into the secondary C–H bond of 1-methyl-1,3-cyclohexadiene and the primary C–H bond of 1-methylcyclohexene follows the HAA-O and HAA-C pathway, respectively.

Divergent stereochemical outcomes in the insertion of donor/donor carbenes into the C-H bonds of stereogenic centers.

Intramolecular C–H insertions with donor/donor dirhodium carbenes provide a concise and highly stereoselective method to set two contiguous stereocenters in a single step. Herein, we report the insertion of donor/donor carbenes into stereogenic carbon centers allowing access to trisubstituted benzodihydrofurans in a single step. This study illuminates, for the first time, the stereochemical impact on the carbene center and delineates the structural factors that enable control over both stereogenic centers. Sterically bulky, highly activated C–H insertion centers exhibit high substrate control yielding a single diastereomer and a single enantiomer of product regardless of the catalyst used. Less bulky, less activated C–H insertion centers exhibit catalyst control over the diastereomeric ratio (dr), where a single enantiomer of each diastereomer is observed with high selectivity. A combination of experimental studies and DFT calculations was used to elucidate the origin of these results. First, hydride transfer from the stereogenic insertion site proceeds with high stereoselectivity to the carbene center, thus determining the absolute configuration of the product. Second, the short lived zwitterionic intermediate can diaster-eoselectively ring-close by a hitherto unreported SE2 mechanism that is either controlled by the substrate or the catalyst. These results demonstrate that donor/donor carbenes undergo uniquely stereoselective reactions that originate from a stepwise reaction mechanism, in contrast to the analogous concerted reactions of carbenes with one or more electron-withdrawing groups attached.

Photocatalytic 1,2-oxo-alkylation reaction of styrenes with diazoacetates.

We report on the photocatalytic 1,2-difunctionalization reaction of styrenes with acceptor-only diazoalkanes. In the presence of DABCO and tBuOOH, the carbene reactivity of diazoalkanes can be suppressed and a 1,2 oxo-alkylation reaction can be achieved (32 examples, up to 94% yield) without the formation of cyclopropane by-products via the formation of radical intermediates from ethyl diazoacetate.

Theoretical study on the mechanism, chemo- and enantioselectivity of the Ag- vs. Rh-catalyzed intramolecular carbene transfer reaction of diazoacetamides.

To explore the mechanism of silver and rhodium catalysis and reveal the origin of the chemo- and enantioselectivity of the reaction, density functional theory calculations were performed on the first silver-catalyzed highly enantioselective carbene transfer reaction. The calculation results reveal that when silver is used as a catalyst, due to the participation of the phosphate anion in the transition state, the enhanced nucleophilicity of the α-diazoacetamide unit promotes smooth dearomatization before generation of the silver carbene. Because the generated rhodium carbene has stronger electrophilicity, typical carbene reactions (C–H insertion and the Büchner reaction) are favored. In addition, in the process of silver catalyzed dearomatization, the formation of an R-type transition state is determined by the small torsion energy and strong interaction energy.

Triarylborane Catalyzed Carbene Transfer Reactions Using Diazo Precursors.

Reactive carbenes generated from diazo compounds are key intermediates for a range of organic reactions to afford synthetically useful organic compounds. The majority of these reactions have been carried out using transition metal catalysts. However, the formation of carbene intermediates using main group elements has not been widely investigated for synthetic purposes. Recent studies have demonstrated that triarylboranes can be used for the in situ generation of reactive carbene intermediates in both stoichiometric and catalytic reactions. These new reactivities of triarylboranes have gained significant attention in synthetic chemistry particularly in catalytic studies. The range of organic compounds that have been synthesized through these reactions are important as pharmaceuticals or agrochemicals. In this perspective, we highlight the recent progress and ongoing challenges of carbene transfer reactions generated from their corresponding diazo precursors using triarylboranes as catalysts. We also highlight the stoichiometric use of triarylboranes in which the boranes not only activate the diazo functionality to afford a carbene intermediate but also actively participate in the reactions as a reagent. The different mechanisms for activation and carbene transfer are described along with the mechanistic and computational studies that have aided the elucidation of these reaction pathways. Potential opportunities for the use of boranes as a catalyst toward different carbene transfer reactions and their future prospects are discussed.

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.

Borane Catalyzed Selective Diazo Cross‐Coupling Towards Pyrazoles

AbstractDecomposition of donor‐acceptor diazo compounds leads to the formation of reactive carbene intermediates. These can undergo a wide variety of carbene transfer reactions to yield synthetically useful products. Herein, we report a selective borane catalyzed cyclization reaction from the combination of two different diazo compounds to afford N‐substituted pyrazoles. The selective decomposition of the more reactive α‐aryl α‐diazoester and subsequent reaction with a vinyl diazoacetate produces N‐alkylated pyrazoles in a regioselective manner. Catalytic amounts of tris(pentafluorophenyl)borane (10 mol%) were employed to afford the pyrazole products (36 examples) in yields from 59 to 80%. Extensive DFT studies have been undertaken to interpret the mechanism for this reaction which was found to go through two tandem catalytic cycles, both catalyzed by B(C6F5)3.magnified image

Divergent Reactivity of an Isolable Nickelacyclobutane

AbstractNickelacyclobutanes are mostly invoked as reactive intermediates in the reaction of nickel carbenes and olefins to yield cyclopropanes. Nevertheless, early work suggested that other decomposition routes such as β‐hydride elimination and even metathesis could be accessible. Herein, we report the isolation and characterization of a stable pentacoordinated nickelacyclobutane incorporated in a pincer complex. The coordination of different coligands to the nickelacyclobutane determines its selective decomposition along cyclopropanation, metathesis or apparent β‐hydride elimination pathways. DFT calculations shed light on the mechanism of these different pathways.

Divergent Reactivity of an Isolable Nickelacyclobutane.

Nickelacyclobutanes are mostly invoked as reactive intermediates in the reaction of nickel carbenes and olefins to yield cyclopropanes. Nevertheless, early work suggested that other decomposition routes such as β‐hydride elimination and even metathesis could be accessible. Herein, we report the isolation and characterization of a stable pentacoordinated nickelacyclobutane incorporated in a pincer complex. The coordination of different coligands to the nickelacyclobutane determines its selective decomposition along cyclopropanation, metathesis or apparent β‐hydride elimination pathways. DFT calculations shed light on the mechanism of these different pathways.

Dimethylcarbene versus Direct Propene Formation in Dimethylketene Photodissociation.

Highly reactive carbenes are usually produced by photolysis of ketenes, diazoalkanes, or diazirines. Sequential kinetic pathways for deactivation of nascent carbenes usually involve bimolecular reactions in competition with isomerization producing stable products such as alkenes. However, the direct photolytic production of stable products, effectively bypassing formation of free carbenes, has been postulated for over 50 years but remains very poorly understood. Often termed "rearrangement in the excited state" (RIES), examples include 1,2-hydrogen migration within photoexcited carbene precursors yielding alkenes and the Wolff rearrangement in photogenerated carbonyl-substituted carbenes producing ketenes. In this study, the two competing CO elimination channels from photoexcited gaseous dimethylketene, producing dimethylcarbene and propene, were studied as a function of electronic excitation energy, under collision-free conditions, by using photofragment translational energy spectroscopy with vacuum ultraviolet photoionization of the products. A significant fraction of the dimethylcarbene → propene isomerization exothermicity (∼300 kJ/mol) was released as propene + CO translational energy, indicating that propene is formed prior to or concurrent with CO elimination. An increase in the propene yield with increasing excitation energy suggests that the effective potential energy barrier for this channel lies ∼24 kJ/mol above the energetic threshold for dimethylcarbene formation via C═C bond fission. Possible mechanisms for direct propene elimination are discussed in light of the observed energy dependence for the competing pathways.

Harnessing the reactivity of borenium for methane activation

Methane (CH₄) functionalization is an important field that is traditionally dominated by transition-metal catalysis. In this issue of <i>Chem</i>, Wang and colleagues report the exceptional reactivity of an N-heterocyclic carbene (NHC)-stabilized hydroborenium cation that allows for the selective C−H activation of CH₄, affording value-added borylated products in a transition-metal-free fashion.

Competitive Reactivity of SO2 and NO2 with N-Heterocyclic Carbene: A Mechanistic Study.

Recent DFT based molecular engineering to obtain stable oxathiirane S-oxide derivatives evokes the recommencement of the use of carbenes for the sequestering of SO2, which has been kept separate so far. Carbene is one of the key chemicals for the sequestering of various premier greenhouse gases like CO2, CO, N2O, etc. In this respect, a comparative study of the reactivity of carbenes with variant greenhouse gases is highly demanding. The present investigation is engrossed in the comparative reactivity of SO2 and NO2 with carbenes. All three selected carbenes are highly susceptible to SO2 and NO2. Through an immaculate mechanistic study, we are able to corroborate that the end product of the carbene-SO2 reaction is an adduct which has a preferable structure having a six-membered ring with hydrogen bonding instead of ketone and SO with higher thermodynamic stability than the corresponding oxathiirane S-oxide derivative. Carbene reacts with NO2 to form a stable carbene N, N-dioxide derivative which forms vibrationally excited oxaziridine N-oxide which rapidly dissociates to form a ketone derivative. The formation of carbene S, S-dioxide and carbene N, N-dioxide is a barrierless process. The dissociation of oxaziridene N-oxide is also a barrierless process.