N-Heterocyclic Carbene Analogues of Wittig Hydrocarbon.

N-Heterocyclic carbene (NHC) analogues of Wittig hydrocarbon, [(NHC)(Stil)(NHC)] (3a-c) (NHC = SIPr (1a) = C[N(Dipp)CH2]2, Dipp = 2,6-iPr2C6H3; IPr (1b) = C[N(Dipp)CH]2; Me-IPr (1c) = C[N(Dipp)CMe]2 and Stil = C6H4CHCHC6H4) have been reported as crystalline solids. 3a-c are prepared by two-electron reductions of the corresponding bis-1,3-imidazoli(ni)um bromides [(NHC)(Stil)NHC)](Br)2 (2a-c) with KC8 in >94 % yields. 2a-c are accessible by the nickel catalyzed direct C-C coupling of NHCs (1a-c) with (E)-4,4'-dibromostilbene. One-electron oxidation of 3a,b yields the corresponding radical cations [(NHC)(Stil)NHC)]B(C6F5)4 4a,b. All compounds have been characterized by UV-Vis/NMR/EPR spectroscopy as well as 2a, 3a, and 3b by single crystal X-ray diffraction. The electronic structures of representative systems have been analyzed by quantum chemical calculations.

Recent Advances in NHC-Catalyzed Chemoselective Activation of Carbonyl Compounds.

N-Heterocyclic carbenes (NHCs) catalysts have been employed as effective tools in the development of various reactions, which have made notable contributions in developing diverse reaction modes and generating significant functionalized molecules. This review provides an overview of the recent advancements in the chemo- and regioselective activation of different aldehydes using NHCs, categorized into five parts based on the different activation modes. A brief conclusion and outlook is provided to stimulate the development of novel activation modes for accessing functional molecules.

How to Decarbonize N-Heterocyclic Carbenes (NHCs): The simple Alane Adducts (NHC) ⋠AlR3 (R=H, Me, Et).

The reaction of the amine-stabilized alane (NMe3) ⋅ AlH3 1 with the backbone-saturated N-heterocyclic carbene (NHC) SIDipp (SIDipp=1,3-bis-{2,6-di-iso-propyl-phenyl}-imidazolidin-2-ylidene) at 0 °C yielded the NHC alane adduct (SIDipp) ⋅ AlH3 2. Reaction at elevated temperatures or prolonged reaction at room temperature gave the product of a ring expansion reaction (RER) of the NHC, (NMe3) ⋅ AlH(RER-SIDippH2) 3 ⋅ (NMe3). Subsequent reaction of the latter with sterically less hindered NHCs (IMeMe {=1,3,4,5-tetramethyl-imidazolin-2-ylidene}, IiPrMe {=1,3-di-iso-propyl-4,5-dimethyl-imidazolin-2-ylidene}, and IiPr {=1,3-di-iso-propyl-imidazolin-2-ylidene}) afforded the NHC-stabilized RER-products (NHC) ⋅ AlH(RER-SIDippH2) 3 ⋅ (NHC) (NHC=IMeMe, IiPrMe, IiPr), while no reaction was observed with the sterically more demanding NHCs IDipp (=1,3-bis-{2,6-di-iso-propyl-phenyl}-imidazolin-2-ylidene), SIDipp and ItBu (=1,3-di-tert-butyl-imidazolin-2-ylidene). The compounds 3 ⋅ (NHC) were also obtained starting from (SIDipp) ⋅ AlH3 2 and NHC at room temperature. Heating solutions of (SIDipp) ⋅ AlH3 2 without additional base to 95 °C resulted in decarbonization of the NHC and substitution of the carbene carbon atom with aluminum hydride under loss of ethene. Subsequent dimerization afforded cis-[AlH{µ-N(Dipp)CH2CH2N(Dipp)}]2 4_dimer. Heating solutions of the NHC-ligated aluminum alkyls (SIDipp) ⋅ AlR3 2R (R=Me, Et) to 145 °C instead led to complete scission of the NHC backbone with evolution of ethene and isolation of the dialkylaluminium(III) amidinates {DippNC(R)NDipp}AlR2 5R (R=Me, Et).

Phosphaarsenes - Combining Phospha- and Arsa-Wittig-Reagents.

Dipnictenes of the type RPn=PnR (Pn=P, As, Sb, Bi) can be viewed as dimers of the corresponding pnictinidenes R-Pn. Phosphanylidene- and arsanylidenephosphoranes (R-Pn(PMe3); Pn=P, As) have been shown to be versatile synthetic surrogates for the delivery of pnictinidene fragments. We now report that thermal treatment of 1 : 1 mixtures of R-P(PMe3) and R'-As(PMe3) gives access to arsaphosphenes of the type RP=AsR'. Three examples are presented and the properties and reactivity of Mes*P=AsDipTer (1) (Mes*=2,4,6-tBu3-C6H2; DipTer=2,6-(2,6-iPr2C6H3)2-C6H3) were studied in detail. Solid state 31P NMR spectroscopy revealed a large 31P NMR chemical shift anisotropy with a span of ca. 920 ppm for 1 while computational methods were employed to investigate this pronounced magnetic deshielding of the P atom in 1. In the presence of the carbene IMe4 (IMe4=:C(MeNCMe)2) 1 is shown to be split into the corresponding NHC adducts Mes*P(IMe4) and DipTerAs(IMe4), which is additionally shown for diarsenes.

L→S Coordination Complexes Containing Benzothiazol-2-ylidene Ligand: Quantum Chemical Analysis and Synthesis.

(NHC)→E coordination interactions were known where NHC is an N-heterocyclic carbene, and E is a main group element (B, C, N, Si, P). Recently, it was suggested that compounds with (NHC)→S coordination chemistry are also possible. This work reports quantum chemical analysis and synthesis of (NHC)→S-R(+) complexes in which benzothiazol-2-ylidene acts as a ligand. A Density functional study established that (NHC)→S interaction can best be described as a coordination interaction. Synthetic efforts were made, initially, to generate divalent sulfur compounds containing benzothiazole substituents. N-alkylation of the heterocyclic ring in these sulfides using methyl triflate led to the generation of the desired products with (NHC)→S coordination chemistry, which involves the in situ generation of NHC ring ligands. The observed changes in the 13C NMR spectra, before and after methylation, confirmed the change in the electronic character of the C-S bond from a covalent character to a coordination character.

Mechanism of Action of Antitumor Au(I) N-Heterocyclic Carbene Complexes: A Computational Insight on the Targeting of TrxR Selenocysteine.

The targeting of human thioredoxin reductase is widely recognized to be crucially involved in the anticancer properties of several metallodrugs, including Au(I) complexes. In this study, the mechanism of reaction between a set of five N-heterocyclic carbene Au(I) complexes and models of the active Sec residue in human thioredoxin reductase was investigated by means of density functional theory approaches. The study was specifically addressed to the kinetics and thermodynamics of the tiled process by aiming at elucidating and explaining the differential inhibitory potency in this set of analogous Au(I) bis-carbene complexes. While the calculated free energy profile showed a substantially similar reactivity, we found that the binding of these Au(I) bis-carbene at the active CysSec dyad in the TrxR enzyme could be subjected to steric and orientational restraints, underlining both the approach of the bis-carbene scaffold and the attack of the selenol group at the metal center. A new and detailed mechanistic insight to the anticancer activity of these Au(I) organometallic complexes was thus provided by consolidating the TrxR targeting paradigm.

Platinum(0)-η2-1,2-(E)ditosylethene Complexes Bearing Phosphine, Isocyanide and N-Heterocyclic Carbene Ligands: Synthesis and Cytotoxicity towards Ovarian and Breast Cancer Cells.

A wide range of platinum(0)-η2-(E)-1,2-ditosylethene complexes bearing isocyanide, phosphine and N-heterocyclic carbene ancillary ligands have been prepared with high yields and selectivity. All the novel products underwent thorough characterization using spectroscopic techniques, including NMR and FT-IR analyses. Additionally, for some compounds, the solid-state structures were elucidated through X-ray diffractometry. The synthesized complexes were successively evaluated for their potential as anticancer agents against two ovarian cancer cell lines (A2780 and A2780cis) and one breast cancer cell line (MDA-MB-231). The majority of the compounds displayed promising cytotoxicity within the micromolar range against A2780 and MDA-MB-231 cells, with IC50 values comparable to or even surpassing those of cisplatin. However, only a subset of compounds was cytotoxic against cisplatin-resistant cancer cells (A2780cis). Furthermore, the assessment of antiproliferative activity on MRC-5 normal cells revealed certain compounds to exhibit in vitro selectivity. Notably, complexes 3d, 6a and 6b showed low cytotoxicity towards normal cells (IC50 > 100 µM) while concurrently displaying potent cytotoxicity against cancer cells.

Impact of the Methylene Bridge Substitution in Chelating NHC-Phosphine Mn(I) Catalyst for Ketone Hydrogenation.

Systematic modification of the chelating NHC-phosphine ligand (NHC = N-heterocyclic carbene) in highly efficient ketone hydrogenation Mn(I) catalyst fac-[(Ph2PCH2NHC)Mn(CO)3Br] has been performed and the catalytic activity of the resulting complexes was evaluated using acetophenone as a benchmark substrate. While the variation of phosphine and NHC moieties led to inferior results than for a parent system, the incorporation of a phenyl substituent into the ligand methylene bridge improved catalytic performance by ca. 3 times providing maximal TON values in the range of 15000-20000. Mechanistic investigation combining experimental and computational studies allowed to rationalize this beneficial effect as an enhanced stabilization of reaction intermediates including anionic hydride species fac-[(Ph2PC(Ph)NHC)Mn(CO)3H]- playing a crucial role in the hydrogenation process. These results highlight the interest of such carbon bridge substitution strategy being rarely employed in the design of chemically non-innocent ligands.

(4-Butyl-1-ethyl-1,2,4-triazol-5-yl-idene)[(1,2,5,6-η)-cyclo-octa-1,5-diene](tri-phenyl-phosphane)rhodium(I) tetra-fluorido-borate.

In the title triazole-based N-heterocyclic carbene rhodium(I) cationic complex with a tetra-fluorido-borate counter-anion, [Rh(C8H12)(C8H15N3)(C18H15P)]BF4, which crystallizes with two cations and two anions in the asymmetric unit, the Rh center has a distorted square-planar coordination geometry with expected bond distances. Several nonclassical C-H⋯F hydrogen-bonding inter-actions help to consolidate the packing. Two of the F atoms of one of the anions are disordered over adjacent sites in a 0.814 (4):0.186 (4) ratio.

NHC-Supported 2-Sila and 2-Germavinylidenes: Synthesis, Dynamics, First Reactivity and Theoretical Studies.

2-tetrelavinylidenes (C=EH2 ; E=Si, Ge) are according to quantum chemical studies the least stable isomers on the [E,C,2H] potential energy hypersurface isomerizing easily via the trans-bent tetrelaacetylenes HE≡CH to the thermodynamically most stable 1-tetrelavinylidenes (E=CH2 ). Consequently, experimental studies on 2-tetrelavinylidenes (C=ER2 ) and their derivatives are lacking. Herein we report experimental and theoretical studies of the first N-heterocyclic carbene (NHC) supported 2-silavinylidene (NHC)C=SiBr(Tbb) (1-Si: NHC=C[N(Dipp)CH]2 , Dipp=2,6-diisopropylphenyl, Tbb=2,6-bis[bis(trimethylsilyl)methyl]-4-tert-butylphenyl) and the isovalent 2-germavinylidenes (NHC)C=GeBr(R) (1-Ge, 1-GeMind: R=Tbb, Mind (1,1,3,3,5,5,7,7-octamethyl-s-hydrindacene-4-yl)). The NHC-supported 2-tetrelavinylidenes were obtained selectively from the 1,2-dibromoditetrelenes (E)-(R)BrE=EBr(R) using the diazoolefin (NHC)CN2 as vinylidene transfer reagent. 1-E (E=Si, Ge) have a planar vinylidene core, a bent-dicoordinated vinylidene carbon atom (CVNL ), a very short E=CVNL bond and an almost orthogonal orientation of the NHC five-membered ring to the vinylidene core. Quantum chemical analysis of the electronic structures of 1-E suggest a significantly bent 1-tetrelaallene and tetrelyne character. NMR studies shed light into the dynamics of 1-E involving NHC-rotation around the CVNL -CNHC bond with a low activation barrier. Furthermore, the synthetic potential of 1-E is demonstrated by the synthesis and full characterization of the unprecedented NHC-supported bromogermynes BrGe=C(EBr2 Tbb)(NHC) (2-SiGe: E=Si; 2-GeGe: E=Ge).

N-heterocyclic-carbene vs diphosphine auxiliary ligands in thioamidato Cu(I) and Ag(I) complexes towards the development of potent and dual-activity antibacterial and apoptosis-inducing anticancer agents.

Group 11 metal complexes exhibit promising antibacterial and anticancer properties which can be further enhanced by appropriate ligands. Herein, a series of mononuclear thioamidato Cu(I) and Ag(I) complexes bearing either a diphosphine (P^P) or a N-heterocyclic carbene (NHC) auxiliary ligand (L) was synthesized, and the impact of the co-ligand L on the in vitro antibacterial and anticancer properties of their complexes was assessed. All complexes effectively inhibited the growth of various bacterial strains, with the NHC-Cu(I) complex found to be particularly effective against the Gram (+) bacteria (IC50 = 1-4 µg mL-1). Cytotoxicity studies against various human cancer cells revealed their high anticancer potency and the superior activity of the NHC-Ag(I) complex (IC50 = 0.95-4.5 µΜ). Flow cytometric analysis on lung and breast cancer cells treated with the NHC-Ag(I) complex suggested an apoptotic cell-death pathway; molecular docking calculations provided mechanistic insights, proving the capacity of the complex to bind on apoptosis-regulating proteins and affect their functionalities.

Guest-Shuttling in a Nanosized Metallobox.

An iridium-conjoined long and narrow metallorectangle was obtained by combining a quinoxalinophenanthrophenazine-connected Janus-di-imidazolylidene ligand and pyrazine. The size and shape of this assembly together with the fused polyaromatic nature of its panels provides it with properties that are uncommon for other metallosupramolecular assemblies. For example, this nanosized 'slit-like' metallobox is able show very large binding affinities with planar organic molecules in such a way, that the cavity is asymmetrically occupied by the guest molecule. This unsymmetrical conformation leads to the existence of a large amplitude motion of these guests, which slide between the two sides of the cavity of the host, thus constituting rare examples of molecular shuttles.

Tailored Monolayers of N-Heterocyclic Carbenes by Kinetic Control.

Despite the substantial success of N-heterocyclic carbenes (NHCs) as stable and versatile surface modification ligands, their use in nanoscale applications beyond chemistry is still hampered by the failure to control the carbene binding mode, which complicates the fabrication of monolayers with the desired physicochemical properties. Here, we applied vibrational sum-frequency generation spectroscopy to conduct a pseudokinetic surface analysis of NHC monolayers on Au thin films under ambient conditions. We observe for two frequently used carbene structures that their binding mode is highly dynamic and changes with the adsorption time. In addition, we demonstrate that this transition can be accelerated or decelerated to adjust the binding mode of NHCs, which allows fabrication of tailored monolayers of NHCs simply by kinetic control.

Heteroditopic NHC Ligand Supported Manganese(I) Complexes: Synthesis, Characterization, and Activity as Non-bifunctional Phosphine-Free Catalyst for the α-Alkylation of Nitriles.

In the present work, several manganese(I) complexes of chelating heteroditopic ligands Mn1-3, featuring ImNHC (imidazol-2-ylidene) connected to a 1,2,3-triazole-N or tzNHC (1,2,3-triazol-5-ylidene) donors via a methylene spacer, with possible modifications at the triazole backbone have been synthesized and completely characterized. Notably, the CO stretching frequencies, electrochemical analysis, and frontier orbital analysis certainly suggest that the chelating ImNHC-tzNHC ligands have stronger donation capabilities than the related ImNHC-Ntz ligand in the synthesized complexes. Moreover, these well-defined phosphine-free Mn(I)-NHC complexes have been found to be effective non-bifunctional catalysts for the α-alkylation of nitriles using alcohols and importantly, the catalyst Mn1 containing ImNHC connected to a weaker triazole-N donor displayed higher activity compared to Mn2/Mn3 containing an unsymmetrical bis-carbene donors (ImNHC and tzNHC). A wide range of aryl nitriles were coupled with diverse (hetero)aromatic as well as aliphatic alcohols to get the corresponding products in good to excellent yields (32 examples, up to 95 % yield). The detailed mechanistic studies including deuterium labelling experiments reveal that the reaction follows a Borrowing Hydrogen pathway.

Alkylation and Arylation at Boron in NHC-Stabilized Phosphaborenes.

Phosphaborenes, featuring a phosphorus-boron multiple bond, remain a relatively untapped area in chemical research due to the limited synthetic methods. Introducing leaving groups as substituents to the phosphorus or boron can pave the way for enhanced functionalization and modification. In this study, we present the synthesis of phosphaborenes featuring an N-heterocyclic boryl group on phosphorus and halogen substituent on boron, with stabilization provided by an N-heterocyclic carbene. Straightforward alkylation/arylation of these phosphaborenes is achieved by substituting the halogen with benzyl and aryl groups at the boron terminus. Our approach offers an efficient route to produce a diverse array of phosphaborene structures.

Selective Deposition of N-Heterocyclic Carbene Monolayers on Designated Au Microelectrodes within an Electrode Array.

The incorporation of organic self-assembled monolayers (SAMs) in microelectronic devices requires precise spatial control over the self-assembly process. In this work, selective deposition of N-heterocyclic carbenes (NHCs) on specific electrodes within a two-microelectrode array is achieved by using pulsed electrodeposition. Spectroscopic analysis of the NHC-coated electrode arrays reveals that each electrode is selectively coated with a designated NHC. The impact of NHC monolayers on the electrodes' work function is quantified using Kelvin probe force microscopy. These measurements demonstrate that the work function values of each electrode can be independently tuned by the adsorption of a specific NHC. The presented deposition method enables to selectively coat designated microelectrodes in an electrode array with chosen NHC monolayers for tuning their chemical and electronic functionality.

A Facile Preparation of N-Heterocyclic Olefins: Ring-Opening Polymerization of ß-Butyrolactone and Frustrated Lewis Pair Reactivity.

A direct synthesis of N-heterocyclic olefins (NHOs) and their mesoionic congeners (mNHOs) from N-heterocyclic carbenes and N-aziridinylimines is reported. The reaction provided diverse functionalized (m)NHOs and π-extended analogues. The prepared NHOs initiated the ring-opening polymerization of ß-butyrolactone, and insertion of aldehyde and nitrile into an NHO-B(C6 F5 )3 adduct was demonstrated.

Wingtip-Flexible N-Heterocyclic Carbenes: Unsymmetrical Connection between IMes and IPr.

IMes (IMes=1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene) and IPr (IPr=1,3- bis(2,6-diisopropylphenyl)imidazol-2-ylidene) represent by far the most frequently used N-heterocyclic carbene ligands in homogeneous catalysis, however, despite numerous advantages, these ligands are limited by the lack of steric flexibility of catalytic pockets. We report a new class of unique unsymmetrical N-heterocyclic carbene ligands that are characterized by freely-rotatable N-aromatic wingtips in the imidazol-2-ylidene architecture. The combination of rotatable N-CH2 Ar bond with conformationally-fixed N-Ar linkage results in a highly modular ligand topology, entering the range of geometries inaccessible to IMes and IPr. These ligands are highly reactive in Cu(I)-catalyzed ß-hydroboration, an archetypal borylcupration process that has had a transformative impact on the synthesis of boron-containing compounds. The most reactive Cu(I)-NHC in this class has been commercialized in collaboration with MilliporeSigma to enable broad access of the synthetic chemistry community. The ligands gradually cover %Vbur geometries ranging from 37.3 % to 52.7 %, with the latter representing the largest %Vbur described for an IPr analogue, while retaining full flexibility of N-wingtip. Considering the modular access to novel geometrical space in N-heterocyclic carbene catalysis, we anticipate that this concept will enable new opportunities in organic synthesis, drug discovery and stabilization of reactive metal centers.

Synthesis and Reactivity of an Aluminium N-heterocyclic Aminal.

Tethered N-heterocyclic carbenes (NHCs) are an emerging class of ligand, as they feature all the desirable aspects of NHCs (ease of synthesis, high tunabilty) but also enable metal-ligand cooperativity when combined with Lewis acidic metal centres due to the donor-acceptor nature of the complexes formed. Herein we report a simple ethoxy-tethered NHC for the stabilisation of Al(III) hydrides, resulting in the unexpected formation of a bicyclic N-heterocyclic aminal (1). Compound 1 behaves as a metal hydride, capable of reducing benzophenone and carbodiimide to yield compounds 2 and 3, respectively. Furthermore, we show that 1 behaves as an efficient catalyst in the dehydrocoupling of amine-boranes due to the hemi-labile nature of the supporting ligand.

Divergent Acyl and Decarbonylative Liebeskind-Srogl Cross-Coupling of Thioesters by Cu-Cofactor and Pd-NHC (NHC = N-Heterocyclic Carbene) Catalysis.

Transition-metal-catalyzed cross-coupling reactions of thioesters by selective acyl C(O)-S cleavage have emerged as a powerful platform for the preparation of complex molecules. Herein, we report divergent Liebeskind-Srogl cross-coupling of thioesters by Pd-NHC (NHC = N-heterocyclic carbene) catalysis. The reaction provides straightforward access to functionalized ketones by highly selective C(acyl)-S cleavage under mild conditions. Most crucially, the conditions enable direct functionalization of a range of complex pharmaceuticals decorated with a palette of sensitive functional groups, providing attractive products for medicinal chemistry programs. Furthermore, decarbonylative Liebeskind-Srogl cross-coupling by C(acyl)-S/C(aryl)-C(O) cleavage is reported. Cu metal cofactor directs the reaction pathway to acyl or decarbonylative pathway. This reactivity is applicable to complex pharmaceuticals. The reaction represents the mildest decarbonylative Suzuki cross-coupling discovered to date. The Cu-directed divergent acyl and decarbonylative cross-coupling of thioesters opens up chemical space in complex molecule synthesis.