N-heterocyclic Carbene Complexes Research Articles

Effect of bromine substitution on blue phosphorescent trans-(N-heterocyclic carbene)Pt(II) acetylide complexes.

N-heterocyclic carbene complexes of the type trans-(NHC)2PtII(CC-Ar)2 (where Ar = phenyl or substituted phenyl) are of interest as violet and blue phosphors. These complexes emit efficient phosphorescence in solution and in the solid state, and they have been applied as phosphors in organic light emitting diodes. This study explores the effect of bromine substitution on the trans-(NHC)2PtII(CC-Ar)2 chromophore through photophysical studies of a pair of complexes in which the phenyl groups feature either 3,5-dibromo- or 4-monobromo-substituents (IPt-DB and IPt-MB, respectively). The Br atoms were introduced as heavy atom(s) with the aim to enhance spin-orbit coupling and increase the radiative and non-radiative decay rates of the phosphorescent triplet state. Both IPt-MB and IPt-DB exhibit sky-blue phosphorescence in solution and in PMMA matrix. Interestingly, the emission quantum yield and lifetime of IPt-MB are substantially lower compared to IPt-DB in solution. This effect is attributed to a substantially larger non-radiative decay rate in the mono-bromo complex. Analysis of the photophysical data, combined with DFT and TD-DFT calculations, suggest that the difference in photophysical properties of the two complexes is related to the position of the Br-substituents on the phenyl acetylide rings. In short, in IPt-MB, the Br-substituents are located para-to the Pt-CC-unit, and this gives rise to stronger electron-vibrational coupling in the excited state, enhancing the rate of non-radiative decay.

Silver N-heterocyclic carbene complexes are potent uncompetitive inhibitors of the papain-like protease with antiviral activity against SARS-CoV-2.

The ongoing SARS-CoV-2 pandemic has caused a high demand for novel innovative antiviral drug candidates. Despite promising results, metal complexes have been relatively unexplored as antiviral agents in general and in particular against SARS-CoV-2. Here we report on silver NHC complexes with chloride or iodide counter ligands that are potent inhibitors of the SARS-CoV-2 papain-like protease (PLpro) but inactive against 3C-like protease (3CLpro) as another SARS-CoV-2 protease. Mechanistic studies on a selected complex confirmed zinc removal from a zinc binding domain of PLpro as relevant factor of their activity. In addition, enzyme kinetic experiments revealed that the complex is an uncompetitive inhibitor and with this rare type of inhibition it offers great pharmacological advantages in terms selectivity. The silver NHC complexes with iodide ligands showed very low or absent host cell toxicity and triggered strong effects on viral replication in cells infected with SARS-CoV-2, making them promising future antiviral drug candidates.

Chemoselective reduction of imines and azobenzenes catalyzed by silver N-heterocyclic carbene complexes

The first example of NHC (N-heterocyclic carbene) ligand-promoted reduction of imines and azobenzenes with a homogeneous silver catalyst is reported.

C-H activation in bimetallic rhodium complexes to afford N-heterocyclic carbene pincer complexes.

The pro-ligands 1,8-bis(di-R-phosphinomethyl)-2,3-dihydroperimidine (RH2Pm, R = phenyl, cyclohexyl) react with [RhCl(CE)(PPh3)2] (E = O, S) to afford the bimetallic complexes [RhCl(CE)(μ-RH2Pm)]2 (E = O, S). Upon heating, these species undergo double C-H activation to afford the N-heterocyclic carbene (NHC) pincer complexes [RhCl(RPm)]. Reduction of [RhCl(CO)(μ-PhH2Pm)]2 with KC8 results in the bimetallic rhodium(0) complex, [Rh(μ-CO)(PhH2Pm)]2, with a formal Rh-Rh bond and a hydrogen-bonding interaction between rhodium and the central methylene group (C-H⋯Rh = 2.802 Å). Upon treatment with tritylium, ferrocenium or triphenylcyclopropenium tetrafluoroborates this species undergoes double C-H activation to afford a mononuclear NHC pincer complex salt, [Rh(CO)(PhPm)]BF4. Treatment of [RhCl(CO)(PhH2Pm)]2 with lithium (trimethylsilyl)acetylide provides another bimetallic species, [Rh(CCSiMe3)(CO)(PhH2Pm)]2, however heating this species does not proceed cleanly to the monomeric NHC complex, [Rh(CCSiMe3)(CO)(PhPm)] which may however be obtained from [RhCl(RPm)] and LiCCSiMe3.

Synthesis, Characterization and Larvicidal Activity of Nitrile-functionalized Dinuclear Silver(I)-N-heterocyclic Carbene Complexes

Synthesis, Characterization and Larvicidal Activity of Nitrile-functionalized Dinuclear Silver(I)-N-heterocyclic Carbene Complexes

Novel benzimidazolium salts and their silver(I)-N-heterocyclic carbene complexes: synthesis, characterization and their biological properties

This study was conducted to synthesize and characterize 1,3-dialkyl-5,6-dimethyl-benzimidazolium salts and their silver complexes. Four novel silver(I)-N-heterocyclic carbene complexes were synthesized and characterized by mass analyses, FT-IR and NMR spectroscopy. The biological capacity of the synthesized compounds was evaluated in vitro for their antimicrobial and antitumor activities. The minimum inhibitory concentration (MIC) of the 1,3-dialkyl-5,6-dimethyl-benzimidazolium salts and their complexes was determined for E. coli, P. aeruginosa, S. aureus, C. glabrata and C. albicans in vitro through BMD (Broth Microdilution). The results indicated that silver(I)-NHC complexes exhibit antimicrobial activity. In particular, complex 3c presented a significant broad-spectrum antimicrobial activity. The anticancer properties of the synthesized compounds were evaluated against MCF-7, HCT116, SH-SY5Y and BEAS-2B cell lines. Anticancer activity measurements were carried out according to the Alamar Blue assay. Efficacy was established by comparison of the salts and silver compounds with cisplatin.

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.

"Dynamical Docking" of Cyclic Dinuclear Au(I) Bis-N-heterocyclic Complexes Facilitates Their Binding to G-Quadruplexes.

With the aim to improve the design of metal complexes as stabilizers of noncanonical DNA secondary structures, namely, G-quadruplexes (G4s), a series of cyclic dinuclear Au(I) N-heterocyclic carbene complexes based on xanthine and benzimidazole ligands has been synthesized and characterized by various methods, including X-ray diffraction. Fluorescence resonance energy transfer (FRET) and CD DNA melting assays unraveled the compounds' stabilization properties toward G4s of different topologies of physiological relevance. Initial structure-activity relationships have been identified and recognize the family of xanthine derivatives as those more selective toward G4s versus duplex DNA. The binding modes and free-energy landscape of the most active xanthine derivative (featuring a propyl linker) with the promoter sequence cKIT1 have been studied by metadynamics. The atomistic simulations evidenced that the Au(I) compound interacts noncovalently with the top G4 tetrad. The theoretical results on the Au(I) complex/DNA Gibbs free energy of binding were experimentally validated by FRET DNA melting assays. The compounds have also been tested for their antiproliferative properties in human cancer cells in vitro, showing generally moderate activity. This study provides further insights into the biological activity of Au(I) organometallics acting via noncovalent interactions and underlines their promise for tunable targeted applications by appropriate chemical modifications.

Stereoselective Ring‐Opening Metathesis Polymerization with Tungsten Sulfido Alkylidene N‐Heterocyclic Carbene Complexes

AbstractA series of cationic tungsten sulfido alkylidene N‐heterocyclic carbene (NHC) complexes (W01 – W09) of the general formula [W(S)(CHCMe3)(X)(NHC)(CMe3CN)+B(ArF)4−] (NHC = 1,3‐dimesitylimidazol‐2‐ylidene, IMes; 1,3‐dimesityl‐4,5‐dichloroimidazol‐2‐ylidene, IMesCl2; 1,3‐bis(2,6‐xdiisopropyl)phenyl)imidazol‐2‐ylidene, IDipp; X = Cl, C6F5O, 2,6‐Ph2‐C6H3; B(ArF)4− = tetrakis(3,5‐bis(trifluoromethyl)phenyl)borate) are used as initiators in the stereoselective ring‐opening metathesis polymerization (ROMP) of (+) 2,3‐endo, exo‐dicarbomethoxynorborn‐5‐ene ((+)DCMNBE, M1). Trans‐isospecifity up to 84% is achieved along with varying percentages of cis‐syndiospecifity. The different extent of trans‐isospecifity is compared to the one of related benchmark cationic molybdenum and tungsten imido and tungsten oxo alkylidene NHC complexes. Mechanistic investigations suggest that the syn‐isomer of a nitrile‐free initiator reacts with M1 presumably in an eneanti fashion to yield a syn‐first insertion product via turnstile rearrangement, which accounts for the predominant trans‐isospecifity of the polymerization. The cis‐syndiotactic sequences are proposed to stem from the competing enesyn addition of M1 to a nitrile‐containing syn‐isomer of the initiator.

Silyl-functionalised silver rhodium and iridium N-heterocyclic carbene complexes with promising cytotoxicity and antimicrobial potential

In the present study, we have synthesized Ag, Rh, and Ir complexes of a silyl-substituted NHC ligand in order to investigate their biological properties. Firstly, Ag-NHC ( 2 ) complex was synthesized by the interaction of Ag 2 O with benzimidazolium iodide ( 1 ). Rh- ( 3 ) and Ir-NHC ( 4 ) complexes were synthesized by the transmetalation reaction between Ag-NHC and [M(cod)Cl] 2 (M = Rh or Ir) dimers. The complexes were characterised by NMR spectroscopy and elemental analyses, and crystal structures of Rh- and Ir-NHC ( 3 and 4 ) were also reported. The cytotoxic effects of the complexes were tested on four human cancer cell lines and the antimicrobial activities of the complexes were tested against a panel of nine pathogenic microorganisms. The complexes performed comparable or better activity than standards, cisplatin and AgNO 3 .

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.

Ring opening polymerization of lactide promoted by Zinc and Magnesium complexes with a N-heterocyclic carbene-phenoxy-imine hybrid non-innocent ligand

Zinc and magnesium complexes of N-heterocyclic carbene (NHC)-phenoxy-imine ligands derived from chiral (S,S)-trans-1,2-diaminocyclohexane have been synthetized. Either monomeric or dimeric species have been obtained depending on the reaction conditions. All complexes were tested as catalysts for the ring opening polymerization (ROP) of lactide showing moderate activity and control degree. MALDI-ToF-MS spectra of PLA highlighted that magnesium complex promoted the formation of cyclic PLA, whereas zinc analogous and its monomeric species gave linear PLA, suggesting that different polymerization mechanisms occur depending on the metal center. Moreover, according to MALDI-ToF-MS spectra, in the absence of additional initiators, polymers arising from zinc catalysts would bear the NHC-phenoxy-imine hybrid ligand as terminal unit. Computational studies were performed in order to shed light on catalyst behaviors and on the mechanisms involved in the ROP of lactide. Free energy profiles of the initiation step suggest that microstructural differences lie in the ligand role. Indeed, in the absence of additional initiators, the ligand participates to the initiation involving its NHC moiety when wrapped around magnesium and its phenoxy-imine moiety when bound to zinc.

Convenient preparation of copper(I) N-heterocyclic carbene complexes under mild conditions

This work describes a new method for the preparation of copper N-heterocyclic carbene (NHC) complexes, which is conducted under air with mild conditions, using bench-stable precursors and a weak base (NEt3). Under optimized conditions, the complexes were prepared in short reaction times of 1 h, giving moderate to good yields after purification by column chromatography. Commonly utilized NHC–HCl salts were found to be applicable reacting with CuCl or CuI giving [(NHC)CuX]-type complexes (X = Cl, I). This study adds to the growing literature in the preparation of catalytically relevant transition metal NHC complexes under mild and operationally simple conditions.

Antioxidant activity, enzyme inhibition, electrochemical and theoretical evaluation of novel PEPPSI type N-heterocyclic carbene complexes

N-Heterocyclic carbenes have attracted attention due to their strong sigma-donor and weak pi-acceptor properties since they were first isolated. Pyridine is also found in many natural products and is included in the content of many pharmaceutical molecules. Palladium complexes containing two halogens, a pyridine and an N-heterocyclic carbene have been identified as PEPPSI (Pyridine-Enhanced Precatalyst Preparation Stabilization and Initiation). Although Alzheimer Disease is thought to be affected by environmental and genetic factors, it has not been fully elucidated. There are various mechanisms used to explain the pathogenesis of this disease which guide the design of new drugs. In Alzheimer Disease cases, acetylcholinesterase activity decreases while butyrylcholinesterase increases and disproportionate reactive oxygen species is also recorded. So, the drug used in Alzheimer Disease treatment must have more than one function, that is, the molecule is expected to be effective in both acetylcholinesterase/butyrylcholinesterase balance and antioxidant activity. In this study, PEPPSI type complexes were synthesized and characterized. The structural, electronic, and reactivity properties of the molecules were analyzed by DFT-based calculation methods and Koopman’s Theory. The inhibition activities against acetylcholinesterase, butyrylcholinesterase and tyrosinase were also analyzed, and the antioxidant activity of the molecules were investigated. The inhibition and the activity details of the molecules were also evaluated by molecular docking methods.

Luminescent Complexes of Platinum, Iridium, and Coinage Metals Containing N-Heterocyclic Carbene Ligands: Design, Structural Diversity, and Photophysical Properties.

The employment of N-heterocyclic carbenes (NHCs) to design luminescent metal compounds has been the focus of recent intense investigations because of the strong σ-donor properties, which bring stability to the whole system and tend to push the d-d dark states so high in energy that they are rendered thermally inaccessible, thereby generating highly emissive complexes for useful applications such as organic light-emitting diodes (OLEDs), or featuring chiroptical properties, a field that is still in its infancy. Among the NHC complexes, those containing organic chromophores such as naphthalimide, pyrene, and carbazole exhibit rich emission behavior and thus have attracted extensive interest in the past five years, especially carbene coinage metal complexes with carbazolate ligands. In this review, the design strategies of NHC-based luminescent platinum and iridium complexes with large spin-orbit-coupling (SOC) are described first. Subsequent paragraphs illustrate the recent advances of luminescent coinage metal complexes with nucleophilic- and electrophilic-based carbenes based on silver, gold, and copper metal complexes that have the ability to display rich excited state emissions in particular via thermally activated delayed fluorescence (TADF). The luminescence mechanism and excited state dynamics are also described. We then summarize the advance of NHC-metal complexes in the aforementioned fields in recent years. Finally, we propose the development trend of this fast-growing field of luminescent NHC-metal complexes.

Design, Synthesis, and Preclinical Activity in Ovarian Cancer Models of New Phosphanegold(I)-N-heterocyclic Carbene Complexes.

A new series of seven gold(I) complexes (1-7) containing 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr) and phosphane ligands (L1-L7) were synthesized and evaluated for antitumor activity in ovarian cancer (OvCa) models. The synthesized complexes were characterized by IR, mass spectrometry and NMR spectroscopy, and complex 6 was characterized by XRD crystallography. The antiproliferative effect of the new complexes (1-7) was found to be higher than cisplatin and auranofin in OvCa cells sensitive and resistant to cisplatin. The anticancer activity of the most active complex 6 was investigated using OvCa in vitro models, including three-dimensional (3D) multicellular tumor spheroids and in vivo tumor xenografts. Both cisplatin and auranofin were used for comparative purposes. Complex 6 induced apoptosis, mitochondrial reactive oxygen species, and DNA damage; caused a G1 phase cell cycle arrest, inhibited proteasome activity, and cell migration; modified actin polymerization; and significantly inhibited OvCa murine xenografts. These promising results suggest further preclinical testing of these complexes for future applications.

Photophysical Integrity of the Iron(III) Scorpionate Framework in Iron(III)-NHC Complexes with Long-Lived 2LMCT Excited States.

Fe(III) complexes with N-heterocyclic carbene (NHC) ligands belong to the rare examples of Earth-abundant transition metal complexes with long-lived luminescent charge-transfer excited states that enable applications as photosensitizers for charge separation reactions. We report three new hexa-NHC complexes of this class: [Fe(brphtmeimb)2]PF6 (brphtmeimb = [(4-bromophenyl)tris(3-methylimidazol-2-ylidene)borate]-, [Fe(meophtmeimb)2]PF6 (meophtmeimb = [(4-methoxyphenyl)tris(3-methylimidazol-2-ylidene)borate]-, and [Fe(coohphtmeimb)2]PF6 (coohphtmeimb = [(4-carboxyphenyl)tris(3-methylimidazol-2-ylidene)borate]-. These were derived from the parent complex [Fe(phtmeimb)2]PF6 (phtmeimb = [phenyltris(3-methylimidazol-2-ylidene)borate]- by modification with electron-withdrawing and electron-donating substituents, respectively, at the 4-phenyl position of the ligand framework. All three Fe(III) hexa-NHC complexes were characterized by NMR spectroscopy, high-resolution mass spectroscopy, elemental analysis, single crystal X-ray diffraction analysis, electrochemistry, Mößbauer spectroscopy, electronic spectroscopy, magnetic susceptibility measurements, and quantum chemical calculations. Their ligand-to-metal charge-transfer (2LMCT) excited states feature nanosecond lifetimes (1.6-1.7 ns) and sizable emission quantum yields (1.7-1.9%) through spin-allowed transition to the doublet ground state (2GS), completely in line with the parent complex [Fe(phtmeimb)2]PF6 (2.0 ns and 2.1%). The integrity of the favorable excited state characteristics upon substitution of the ligand framework demonstrates the robustness of the scorpionate motif that tolerates modifications in the 4-phenyl position for applications such as the attachment in molecular or hybrid assemblies.

Preparation of Mixed Bis-N-Heterocyclic Carbene Rhodium(I) Complexes.

A series of mixed bis-NHC rhodium(I) complexes of type RhCl(η2-olefin)(NHC)(NHC’) have been synthesized by a stepwise reaction of [Rh(μ-Cl)(η2-olefin)2]2 with two different NHCs (NHC = N-heterocyclic carbene), in which the steric hindrance of both NHC ligands and the η2-olefin is critical. Similarly, new mixed coumarin-functionalized bis-NHC rhodium complexes have been prepared by a reaction of mono NHC complexes of type RhCl(NHC-coumarin)(η2,η2-cod) with the corresponding azolium salt in the presence of an external base. Both synthetic procedures proceed selectively and allow the preparation of mixed bis-NHC rhodium complexes in good yields.

Impact of Coordination Mode and Ferrocene Functionalization on the Anticancer Activity of N-Heterocyclic Carbene Half-Sandwich Complexes.

The substitution of phenyl rings in established drugs with ferrocenyl moieties has been reported to yield compounds with improved biological activity and alternative modes of action, often involving the formation of reactive oxygen species (ROS). Translating this concept to N-heterocyclic carbene (NHC) complexes, we report here organometallics with a piano-stool structure that feature di- or tridentate ligand systems. The ligands impacted the cytotoxic activity of the NHC complexes, but the coordination modes seemed to have a limited influence, which may be related to the propensity of forming the same species in solution. In general, the stability of the complexes in an aqueous environment and their reactivity to selected biomolecules were largely dominated by the nature of the metal center. While the complexes promoted the formation of ROS, the levels did not correlate with their cytotoxic activity. However, the introduction of ferrocenyl moieties had a significant impact on the antiproliferative potency of the complexes and, in particular, some of the ferrocenyl-functionalized compounds yielded IC50 values in the low μM range.

Synthesis, characterization, in vitro antibacterial, and anticancer studies of Ag(I)-N-heterocyclic carbene (NHC) complexes

Synthesis, characterization, in vitro antibacterial, and anticancer studies of Ag(I)-N-heterocyclic carbene (NHC) complexes