N-heterocyclic Carbene Ligands Research Articles

Ultrafast 3MLCT quenching and vibrational coherence: excited-state dynamics of the first-discovered Fe(ii)–carbene sensitiser resolved

Full-dimensional trajectory surface hopping dynamics simulations reveal the intricate details of the photorelaxation mechanism in [Fe(bmip)2]2+, the first-discovered Fe–carbene photosensitiser (bmip = 2,6-bis(3-methyl-imidazole-1-ylidine)-pyridine).

Cyclometalated Ru(II)-NHC complexes with phenanthroline ligands induce apoptosis mediated by mitochondria and endoplasmic reticulum stress in cancer cells.

The exploration of ruthenium complexes as anticancer drugs has been the focus of intense investigation. In this study, we synthesized and characterized four C,N-cyclometalated ruthenium(II) complexes (Ru1-Ru4) coordinated with pyridine-functionalized N-heterocyclic carbene (NHC) and auxiliary ligands (e.g., acetonitrile, 1,10-phenanthroline, 3,4,7,8-tetramethyl-1,10-phenanthroline, and 4,7-diphenyl-1,10-phenanthroline). X-ray diffraction analysis showed that all of the four cycloruthenated complexes are hexa-coordinated in a typical octahedral geometry. In vitro cytotoxic studies revealed that cyclometalated Ru-NHC complexes Ru3 and Ru4 had stronger anticancer activity than their corresponding Ru-NHC precursor Ru1 and the clinically used cisplatin. For HeLa cells, Ru3 and Ru4 exhibited potent cytotoxicity with the IC50 value of 4.31 ± 0.42 μM and 3.14 ± 0.23 μM, respectively, which was approximately three times lower than that of cisplatin. More interestingly, Ru3 and Ru4 not only effectively inhibited the proliferation of HeLa cells, but also exhibited potential anti-migration activity. In the scratch wound healing assay, Ru3 and Ru4 treatment significantly reduced the wound healing rate of HUVEC cells. Mechanistic studies showed that Ru3 and Ru4 caused a dual action mode of mitochondrial membrane depolarization and endoplasmic reticulum stress and finally induced apoptosis of HeLa cells.

Unsymmetric N-heterocyclic carbene ligand enabled nickel-catalysed arylation of bulky primary and secondary amines.

The arylation of sterically hindered amines represents one of the long-standing challenges in synthetic chemistry. Herein, we report a highly efficient Ni-catalysed arylation of sterically hindered primary and secondary amines with aryl chlorides or phenol derivatives enabled by an unsymmetric N-heterocyclic carbene (NHC) ligand. The protocol provides general, efficient, and scalable access to various sterically demanding anilines in excellent yields under mild conditions. A wide range of functional groups and heterocycles are compatible (>50 examples), including those present in biologically relevant molecules. Computational studies suggest that the unsymmetric bulky and flexible NHC ligand was critical to balance the oxidative addition and reductive elimination elementary steps, thus promoting this challenging transformation.

Chiral Benzimidazolium N-Heterocyclic Carbene Ligands with Hydroxyamide- or Hydroxyalkyl-Functionalized Wingtip for Cu-Catalyzed Asymmetric Allylic Alkylation

Chiral Benzimidazolium N-Heterocyclic Carbene Ligands with Hydroxyamide- or Hydroxyalkyl-Functionalized Wingtip for Cu-Catalyzed Asymmetric Allylic Alkylation

Ferrous and ferric complexes with cyclometalating N-heterocyclic carbene ligands: a case of dual emission revisited.

Iron N-heterocyclic carbene (FeNHC) complexes with long-lived charge transfer states are emerging as a promising class of photoactive materials. We have synthesized [FeII(ImP)2] (ImP = bis(2,6-bis(3-methylimidazol-2-ylidene-1-yl)phenylene)) that combines carbene ligands with cyclometalation for additionally improved ligand field strength. The 9 ps lifetime of its 3MLCT (metal-to-ligand charge transfer) state however reveals no benefit from cyclometalation compared to Fe(ii) complexes with NHC/pyridine or pure NHC ligand sets. In acetonitrile solution, the Fe(ii) complex forms a photoproduct that features emission characteristics (450 nm, 5.1 ns) that were previously attributed to a higher (2MLCT) state of its Fe(iii) analogue [FeIII(ImP)2]+, which led to a claim of dual (MLCT and LMCT) emission. Revisiting the photophysics of [FeIII(ImP)2]+, we confirmed however that higher (2MLCT) states of [FeIII(ImP)2]+ are short-lived (<10 ps) and therefore, in contrast to the previous interpretation, cannot give rise to emission on the nanosecond timescale. Accordingly, pristine [FeIII(ImP)2]+ prepared by us only shows red emission from its lower 2LMCT state (740 nm, 240 ps). The long-lived, higher energy emission previously reported for [FeIII(ImP)2]+ is instead attributed to an impurity, most probably a photoproduct of the Fe(ii) precursor. The previously reported emission quenching on the nanosecond time scale hence does not support any excited state reactivity of [FeIII(ImP)2]+ itself.

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.

N-Heterocyclic carbenes as privileged ligands for nickel-catalysed alkene functionalisation.

Alkene functionalisation is a powerful strategy that has enabled access to a wide array of compounds including valuable pharmaceuticals and agrochemicals. The reactivity of the alkene π-bond has allowed incorporation of a diverse range of atoms and functional groups through a wide variety of reaction pathways. N-Heterocyclic carbenes (NHCs) are a class of persistent carbenes that are widely employed as ancillary ligands due to their ability to act as strong σ-donors compared to widely-applied conventional phosphine-based ligands. NHCs are also unique as their molecular bulk provides steric influence for regio- and stereo-control in many alkene functionalisation reactions, illustrated by the examples covered in this review. A combination of the unique reactivity of NHC ligands and nickel's characteristics has facilitated the design of reaction pathways that show distinct selectivity and reactivity, including the activation of bonds previously considered "inert", such as C-H bonds, the C-O bond of ethers and esters, and the C-N bonds of amides. This review summarises the advancements in Ni(NHC) catalysed alkene functionalisation up to 2022, covering the following major reaction classes: Heck-type reactions, hydrofunctionalisation and dicarbofunctionalisation.

Synthesis, crystallographic structure, theoretical analysis, molecular docking studies, electronic properties and biological activity evaluation of ruthenium-complex bearing N-heterocyclic carbene ligand

The development of new classes of antimicrobials is urgently needed due to the widespread occurrence of multi-resistant pathogens.

C 2-Symmetric atropisomeric N-heterocyclic carbene-palladium(II) complexes: synthesis, chiral resolution, and application in the enantioselective α-arylation of amides.

The concept of atropisomeric N-heterocyclic carbene (NHC)-metal complexes was extended to NHCs possessing a C2-symmetry and implemented to prepare palladium-based complexes. An in-depth study of the NHC precursors and the screening of various NHC ligands enabled us to circumvent the issue associated with the formation of meso complexes. A set of 8 atropisomeric NHC-palladium complexes were prepared and then obtained with high enantiopurities, thanks to an efficient resolution by chiral HPLC at the preparative scale. These complexes displayed good activity in the intramolecular α-arylation of amides and various cyclic products were isolated with excellent enantioselectivities (up to 98% ee).

Why surface hydrophobicity promotes CO2 electroreduction: a case study of hydrophobic polymer N-heterocyclic carbenes.

We report the use of polymer N-heterocyclic carbenes (NHCs) to control the microenvironment surrounding metal nanocatalysts, thereby enhancing their catalytic performance in CO2 electroreduction. Three polymer NHC ligands were designed with different hydrophobicity: hydrophilic poly(ethylene oxide) (PEO-NHC), hydrophobic polystyrene (PS-NHC), and amphiphilic block copolymer (BCP) (PEO-b-PS-NHC). All three polymer NHCs exhibited enhanced reactivity of gold nanoparticles (AuNPs) during CO2 electroreduction by suppressing proton reduction. Notably, the incorporation of hydrophobic PS segments in both PS-NHC and PEO-b-PS-NHC led to a twofold increase in the partial current density for CO formation, as compared to the hydrophilic PEO-NHC. While polymer ligands did not hinder ion diffusion, their hydrophobicity altered the localized hydrogen bonding structures of water. This was confirmed experimentally and theoretically through attenuated total reflectance surface-enhanced infrared absorption spectroscopy and molecular dynamics simulation, demonstrating improved CO2 diffusion and subsequent reduction in the presence of hydrophobic polymers. Furthermore, NHCs exhibited reasonable stability under reductive conditions, preserving the structural integrity of AuNPs, unlike thiol-ended polymers. The combination of NHC binding motifs with hydrophobic polymers provides valuable insights into controlling the microenvironment of metal nanocatalysts, offering a bioinspired strategy for the design of artificial metalloenzymes.

Synthesis of Indolo[2,1-a]isoquinolines by Nickel-Catalyzed Mizoroki-Heck/Amination Cascade Reaction.

An efficient Mizoroki-Heck/amination cascade reaction of o-dihaloarenes with cyclic imines was realized by combining nickel and a sterically bulky N-heterocyclic carbene ligand. This protocol provides access to a variety of indole[2,1-a]isoquinolines from readily available starting materials. This cascade approach could be applied to produce straightforward synthesis of the natural product cryptowoline.

Alternating Ring-Opening Metathesis Polymerization Promoted by Ruthenium Catalysts Bearing Unsymmetrical NHC Ligands

In this paper, Grubbs- and Hoveyda–Grubbs-type olefin metathesis catalysts featuring N-cyclopentyl/N’-mesityl backbone-substituted N-heterocyclic carbene (NHC) ligands were synthesized. Their propensity to promote the alternating ring-opening metathesis copolymerization (ROMP) of norbornene (NBE) with cyclooctene (COE) or cyclopentene (CPE) was evaluated and compared to that shown by analogous N-cyclohexyl complexes. High degrees of chemoselectivity were achieved in both copolymerizations. The presence of the N-cyclopentyl substituent allowed for the achievement of up to 98% and 97% of alternating diads for NBE-COE and NBE-CPE copolymers, respectively, at low comonomer ratios. Density functional theory (DFT) studies showed that both the sterical and electronic effects of NHC ligands influence catalyst selectivity.

Understanding the Reaction Mechanism of Nickel-Catalyzed Enantioselective Arylative Activation of the Aromatic C–O Bond

Mild synthetic methods to transform aromatic carbon–oxygen (C–O) bonds into useful molecules have great potential in renewable biomass conversion. Recently, a Ni–NHC (N-heterocyclic carbene) complex catalyzing an asymmetric ring-opening reaction of dinaphthofuran with PhMgCl at room temperature was reported. In this work, we carried out density functional theory (DFT) calculations to investigate the detailed mechanism. The DFT results reveal a novel mechanism that involves Mg(II)–O coordination followed by migration of the phenyl nucleophile to the Ni(0) metal center prior to oxidative addition of a C–O bond to Ni(0). Insights into how the chiral NHC ligand helps induce the enantioselectivity have been obtained.

Finding Design Principles of OLED Emitters through Theoretical Investigations of Zn(II) Carbene Complexes.

In this work, Zn(II) carbene complexes carrying a dianionic 1,2-dithiolbenzene (dtb) or 1,2-diolbenzene (dob) ligand were investigated regarding their suitability as organic light-emitting diode (OLED) emitter. For the optimization of the complexes, density functional-based methods were used and frequency analyses verified the obtained structures as minima. All calculations were carried out including a polarizable continuum model to mimic solvent-solute interactions. Multireference configuration interaction methods were used to determine excitation energies, spin-orbit couplings, and luminescence properties. Rate constants of spin-allowed and spin-forbidden transitions were calculated according to a Fermi golden rule expression. Using carbene ligands with varying σ-donor and π-acceptor strengths, the luminescence is found to be tunable from yellow to orange/red to deep red/near-infrared. The calculated intersystem crossing (ISC) time constants indicate thermally activated delayed fluorescence (TADF) to be the main decay channel. In contrast to many d10 coinage metal complexes, a parallel orientation of dtb or dob and the carbene ligand is found to be highly favorable. For the complexes with a cyclic (alkyl)(amino) carbene (CAAC) or cyclic (amino)(aryl) carbene (CAArC) ligand, the S1 and T1 states have ligand-to-ligand charge-transfer (LLCT) character and are energetically close. The complex with a classical N-heterocyclic carbene (NHC) ligand has S1 and T1 states with mixed ligand-to-metal charge-transfer (LMCT)/LLCT character and is a very rare example in which the zinc ion contributes to the excitation.

Synthesis and Investigation of Antimicrobial, Antioxidant, Enzymatic Inhibitory, and Antiproliferative Activities of Ruthenium (II) Complexes Bearing Benzimidazole-Based N-Heterocyclic Carbene (NHC) Ligands

The benzimidazolium salts 2a-d were synthesized by quaternization of 1-(4-tet-buthylbenzyl) benzimidazole, with the corresponding benzysl bromide. The reactions were carried out in dimethylformamide at 70 °C for 48 h. Therefore, Ag2O and benzimidazolium salts 2a-d were reacted in dichloromethane at room temperature under dark and Ag(I)-NHC complex 3 was obtained in very good yields. The Ru(II)-NHC complexes (4a-d) were synthesized via transmetalation reaction from 3a-d. The structures of the obtained compounds were characterized by different spectroscopic techniques such as 1H and 13C NMR, elemental analysis, and melting point detection. The lowest MICs values were obtained with the two complexes 4b and 4d. Enzymatic inhibitory investigation against acetylcholinesterase (AChE) and tyrosinase (TyrE), showed that the two complexes 4b and 4d are the most potent inhibitors against (AchE) with an IC50 of 2.52 and 5.06 µg mL–1 respectively, and against (TyrE) with an IC50 of 19.88 and 24.95 µg mL–1 respectively. Screening of the selected N-Heterocyclic carbene (NHC) ligands (2a-2d) and their respective ruthenium (II) complexes (4a-4d) against colon carcinoma cells lines (HCT-116) and hepatocellular carcinoma cells lines (HepG-2). Furthermore, compounds 2c, 2d, 4b were showed weak cytotoxic action with IC50 ranging from 13.38 to 18.33 µg in human colon carcinoma cancer cell lines and from 14.36 to 18.45 µg in hepatocellular carcinoma cells lines.

Copper(I)–Thiazol-2-ylidenes: Highly Reactive N-Heterocyclic Carbenes for the Hydroboration of Terminal and Internal Alkynes. Ligand Development, Synthetic Utility, and Mechanistic Studies

In the last 15 years, copper-catalyzed borylative transformations utilizing boryl–copper have been established as a powerful activation mode in organic synthesis and catalysis, enabling direct transformations of various π-systems. Although many of these transformations use NHC (N-heterocyclic carbene) ligands, these studies have been almost exclusively limited to the derivatives of imidazol-2-ylidenes. However, the molecular properties of N-aryl-imidazol-2-ylidenes, such as IPr (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene), are limited by (1) the high degree of heteroatom stabilization and (2) symmetrical substitution of the nitrogen atoms. Herein, we report a study on Cu(I)–thiazol-2-ylidenes, thiazole analogues of imidazol-2-ylidenes, which (1) feature a distinct half-umbrella shape of the coordinating ligand and (2) exhibit lower heteroatom stabilization of the ancillary ligand through reduced π-donation from sulfur. We present the development of a family of stable Cu(I)–thiazol-2-ylidenes, where the combined sterics of thiazol-2-ylidenes lead to monomers [Cu(NHC)X] or bridged-halo dimers [Cu(NHC) (μ-X)]2, their crystallographic characteristics, and application to the hydroboration of alkynes to afford trisubstituted vinylboronates by β-hydroboration of internal alkynes or terminal vinylboronates by β-hydroboration of terminal alkynes. Application to the late-stage modification and detailed mechanistic studies on the catalyst structure and activation are presented. Most crucially, Cu(I)–thiazol-2-ylidenes show a much higher β-selectivity in the hydroboration of alkynes than that of classical imidazol-2-ylidenes, affording vinylborons in excellent yields at ambient conditions. The unique “half-umbrella” shape of thiazol-2-ylidenes reverses the α/β regioselectivity observed with imidazol-2-ylidenes in the hydroboration of terminal alkynes. Kinetic studies demonstrate that Cu(I)–thiazol-2-ylidenes supersede imidazol-2-ylidenes. Considering the significant utility of borylative transformations of π-systems, we anticipate that Cu(I)–thiazol-2-ylidenes will advance the synthetic transformations of boryl–copper in organic synthesis and catalysis.

Methanol-Mediated Formation of an Iridium(III) NHC/Azolato Chelate Complex: An Experimental and Theoretical Study

One equivalent of methanol-d4 reacts with the iridium(III)-carbonato-NHC complex [Ir(Cp*)(NHC-theo)(O2CO)] [1] containing an N-heterocyclic carbene ligand with an N-tethered C8-iodotheophylline group (NHC-theo) to form the iridium(III) chelate complex [Ir(Cp*)(theophyllinato^NHC)I] [2] that bears a theophyllinato^NHC chelate ligand, an iodo ligand, and the pentamethylcyclopentadienyl ligand (Cp*). The methanol-d4 solvent is oxidized to formaldehyde-d2 that was identified by a detailed LC–MS study using the 2,4-dinitrophenylhydrazine (DNPH) method. A plausible rearrangement involving the unusual oxidative addition of the C8–I bond of the theophylline group to an iridium(III) center to give a seven-coordinate iridium(V) intermediate is supported by density functional theory calculations.

N-heterocyclic carbene ligands with a bicyclic framework fused with either naphthalene or anthracene

N-heterocyclic carbene (NHC) ligands equipped with a bicyclic framework fused with either naphthalene or anthracene (NCPSI and ACPSI, respectively) were synthesized, and their silver and iridium complexes were obtained. Tolman's electronic parameter (TEP) values for these NHC ligands were calculated by using the Ir complexes, which indicated that the electron-donating ability of these NHCs was almost identical to that of the structurally related NHCs, DHASI and BCPSI, that we had previously reported. The structures of [(NHC)AgCl] and [Ir(COD)Cl(NHC)] were analyzed via XRD study, which showed structural changes that depended on the bound metals. Although the NHCs analyzed in this study involve the same bicyclo[2.2.1]heptene core, three aromatic rings, benzene, naphthalene, and anthracene, caused different interplanar angles between the aromatic rings and the NHC's five-membered rings. The regio-selectivities during copper-catalyzed allylic arylation were found to be related to the interplanar angles of the [(NHC)AgCl] complexes, indicating that the interplanar angles would be a useful factor in tuning the steric properties of these NHC ligands.

Steric and Electronic Effects in N-Heterocyclic Carbene Gold(III) Complexes: An Experimental and Computational Study

A series of neutral acridine-based gold(III)-NHC complexes containing the pentafluorophenyl (-C6F5) group were synthesized. All of the complexes were fully characterized by analytical techniques. The square planar geometry around the gold center was confirmed by X-ray diffraction analysis for complexes 1 (Trichloro [1-methyl-3-(9-acridine)imidazol-2-ylidene]gold(III)) and 2 (Chloro-bis(pentafluorophenyl)[1-methyl-3-(9-acridine)imidazol-2-ylidene]gold(III)). In both cases, the acridine rings play a key role in the crystal packing of the solid structures by mean of π-π stacking interactions, with centroid-centroid and interplanar distances being similar to those found in other previously reported acridine-based Au(I)-NHC complexes. A different reactivity when using a bulkier N-heterocyclic carbene ligand such as 1,3-bis-(2,6-diisopropylphenyl)-2-imidazolidinylidene (SIPr) was observed. While the use of the acridine-based NHC ligand led to the expected organometallic gold(III) species, the steric hindrance of the bulky SIPr ligand led to the formation of the corresponding imidazolinium cation stabilized by the tetrakis(pentafluorophenyl)aurate(III) [Au(C6F5)4]- anion. Computational experiments were carried out in order to figure out the ground state electronic structure and the binding formation energy of the complexes and, therefore, to explain the observed reactivity.

Improving the Configurational Stability of Chiral-at-Iron Catalysts Containing Two N-(2-Pyridyl)-Substituted N-Heterocyclic Carbene Ligands.

Recently, we introduced the first example of chiral-at-iron catalysts in which two achiral N-(2-pyridyl)-substituted N-heterocyclic carbene (NHC) ligands in addition to two labile acetonitriles are coordinated around a central iron, to generate a stereogenic metal center [Hong Y.Chiral-at-Iron Catalyst: Expanding the Chemical Space for Asymmetric Earth-Abundant Metal Catalysis. J. Am. Chem. Soc.2019, 141, 4569-4572]. A more facile synthesis of such chiral-at-iron catalysts was developed, which omits the use of expensive silver salts and an elaborate electrochemical setup. Configurational robustness was improved by replacing the imidazol-2-ylidene carbene moieties with benzimidazol-2-ylidenes. The π-acceptor properties of the altered NHCs were investigated by Ganter's 77Se NMR method. The obtained benzimidazol-2-ylidene chiral-at-iron complex is an excellent catalyst for an asymmetric hetero-Diels-Alder reaction under open-flask conditions.