NHC Complexes Research Articles

Facile synthesis of Pd(ii) and Ni(ii) pincer carbene complexes by the double C-H bond activation of a new hexahydropyrimidine-based bis(phosphine): catalysis of C-N couplings.

Hexahydropyrimidine-based bis(phosphine), a pro-NHC ligand, was synthesized in one step and excellent yield. It underwent spontaneous double C-H bond activation to give cationic pincer NHC complexes of the type [(PCP)MCl]X (M = Pd, Ni and X = Cl, BF4) in the absence of any external reagents. Their structures were determined by X-ray diffraction methods and the mechanism of formation of palladium carbene complexes as analyzed by DFT calculations showed two transition states. The Pd(ii) carbene complex effectively catalyzes a few C-N cross coupling reactions.

Recent advances in gold-NHC complexes with biological properties.

This tutorial review covers the recent advances made in the study of gold complexes containing N-heterocyclic carbene ligands with biological properties. The great stability, ease of modulation of the electronic properties and excellent σ-donating capacity displayed by NHCs allow gold-NHC derivatives to reach high stability in biological media and relatively good internalization into cells and for that they have emerged as excellent potential chemotherapeutics. The new gold-NHC derivatives show superior anticancer activity compared to other standards such as Cisplatin or Auranofin. In addition, the application of gold-NHC complexes in the treatment of other human diseases as antibacterial, antioxidant and antiparasitic agents is reviewed for the first time.

Synthesis, characterization, and photoluminescent studies of three-coordinate Cu(i)–NHC complexes bearing unsymmetrically-substituted dipyridylamine ligands

A series of heteroleptic three-coordinate Cu(i) complexes bearing monodentate N-heterocyclic carbene (NHC) ligands of the type 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr) and 1,3-bis(2,6-diisopropylphenyl)imidazolidin-2-ylidene (SIPr), and bidentate N-donor ligands of the type unsymmetrically-substituted dimethyl dipyridylamine (Me2Hdpa) and bis(mesityl)biazanaphthenequinone (mesBIAN) have been synthesized. The complexes [Cu(IPr)(3,4′-Me2Hdpa)]PF6, 1; [Cu(IPr)(3,5′-Me2Hdpa)]PF6, 2; [Cu(IPr)(3,6′-Me2Hdpa)]PF6, 3; [Cu(IPr)(mesBIAN)]PF6, 6; [Cu(SIPr)(3,4′-Me2Hdpa)]PF6, 7; [Cu(SIPr)(3,5′-Me2Hdpa)]PF6, 8; and [Cu(SIPr)(3,3′-Me2Hdpa)]PF6, 11 have been characterized by 1H and 13C NMR spectroscopies, elemental analysis, cyclic voltammetry, and photophysical studies in solid and solution phase. Single crystal X-ray structures were obtained for all complexes except 11. The crystallographic data reveal a mononuclear structure for all complexes with the copper atom ligated by one C and two N atoms. The UV-Vis absorption spectra of all dipyridylamine complexes in CH2Cl2 show a strong ligand-centered absorption band around 250 nm and a strong metal-to-ligand charge transfer (MLCT) band around 300 nm. When irradiated with UV light, the complexes exhibit strong emission maxima at 453–482 nm with photoluminescence quantum yields (PLQY) ranging from 0.21 to 0.87 in solid state. While the PLQY values are comparable to those of the symmetrical [Cu(IPr)(Me2Hdpa)]PF6 complexes, a stabilizing CH–π interaction has been reduced in the current systems. In particular, complex 3 lacks any strong CH–π interaction, but emits more efficiently than 1 and 2 wherein the interactions exist. Structural data analysis was performed to clarify the role of ligands' plane angle and the NH/CH⋯F interactions to the observed light interaction of unsymmetrical [Cu(NHC)(Me2Hdpa)]PF6 complexes. DFT calculations were performed to assist in the assignment of the electronic structure and excited state behavior of the complexes.

Access to divalent lanthanide NHC complexes by redox-transmetallation from silver and CO2 insertion reactions.

Through a redox-transmetallation procedure, divalent NHC-LnII (NHC = N-heterocyclic carbene; Ln = Eu, Yb) complexes were obtained from the corresponding NHC-AgI. The lability of the NHC-LnII bond was investigated and treatment with CO2 led to insertion reactions without oxidation of the metal centre. The EuII complex [EuI2(IMes)(THF)3] (IMes = 1,3-dimesitylimidazol-2-ylidene) exhibits photoluminescence with a quantum yield reaching 53%.

Heterobimetallic ruthenium-zinc complexes with bulky N-heterocyclic carbenes: syntheses, structures and reactivity.

The ruthenium-zinc heterobimetallic complexes, [Ru(IPr)2(CO)ZnMe][BArF4] (7), [Ru(IBiox6)2(CO)(THF)ZnMe][BArF4] (12) and [Ru(IMes)'(PPh3)(CO)ZnMe] (15), have been prepared by reaction of ZnMe2 with the ruthenium N-heterocyclic carbene complexes [Ru(IPr)2(CO)H][BArF4] (1), [Ru(IBiox6)2(CO)(THF)H][BArF4] (11) and [Ru(IMes)(PPh3)(CO)HCl] respectively. 7 shows clean reactivity towards H2, yielding [Ru(IPr)2(CO)(η2-H2)(H)2ZnMe][BArF4] (8), which undergoes loss of the coordinated dihydrogen ligand upon application of vacuum to form [Ru(IPr)2(CO)(H)2ZnMe][BArF4] (9). In contrast, addition of H2 to 12 gave only a mixture of products. The tetramethyl IBiox complex [Ru(IBioxMe4)2(CO)(THF)H][BArF4] (14) failed to give any isolable Ru-Zn containing species upon reaction with ZnMe2. The cyclometallated NHC complex [Ru(IMes)'(PPh3)(CO)ZnMe] (15) added H2 across the Ru-Zn bond both in solution and in the solid-state to afford [Ru(IMes)'(PPh3)(CO)(H)2ZnMe] (17), with retention of the cyclometallation.

Dinuclear zwitterionic silver(i) and gold(i) complexes bearing 2,2-acetate-bridged bisimidazolylidene ligands.

Four novel dinuclear Ag(i) and Au(i) NHC complexes bearing two 2,2-acetate-bridged bisimidazolylidene ligands (R = Me and iPr) of zwitterionic and metallacyclic forms are reported. The functionalized methylene bridge of the ligands leads to water soluble complexes, which have been characterized by NMR and IR spectroscopy, elemental analysis and single crystal X-ray diffraction in the case of La-H2-PF6, Ag2(La)2, Ag2(Lb)2 and Au2(La)2. Dimerization processes caused by hydrogen bonding or Ag(i)-carboxylate interactions in the solid state were observed for La-H2-PF6 and Ag2(La)2. DOSY NMR experiments confirmed that both bisimidazolium salts appear as dimers in aqueous solutions, in contrast to the corresponding monomeric Ag(i) and Au(i) complexes. Both gold(i) complexes form syn- and anti-isomers analogous to the reference coinage metal-based complexes. Protonation studies of the syn-isomer gold(i) complex Au2(La)2 were successful, whereas post-modification esterification or amidation reactions were not feasible. Additionally, decarboxylation reactions (thermally induced Krapcho- or oxidative Hunsdiecker-type) of the bisimidazolium salts were observed. Thus, the proximity of the carboxyl moiety to imidazolium/imidazolylidene rings seems to negatively affect stability and reactivity.

Amine-fnctionalized silver and gold N-heterocyclic carbene complexes: Synthesis, characterization and antitumor properties

Diisopropilamine-tethered benzimidazolium salts have been prepared as precursors for Ag(I)NHC and Au(I)NHC complexes. These NHC ligands were metallated with Ag2O on moderate conditions to give novel silver-NHC complexes. Gold-NHC complexes have been obtained by transmetalation using the silver-NHC precursor. The structures of all compounds were characterized by 1H NMR, 13C NMR, IR and elemental analysis techniques. The cytotoxic properties of the silver(I) and gold(I) complexes have been assessed in various human cancer lines, including cisplatin-sensitive and resistant cell. IC50 values of these four complexes were determined by the MTS based assay on three human cancer cell lines (SHSY5Y, HTC116 and HEP3B) and human healthy cell line (HF). These silver and gold N-heterocyclic carbene complexes have been highlighted metal-based cancer therapeutic agent with unique structures and functions. These strategies provide exciting opportunities for discovering new type metalodrug.

The Quest for Stable Silaaldehydes: Synthesis and Reactivity of a Masked Silacarbonyl

The first donor-acceptor complex of a silaaldehyde, with the general formula (NHC)(Ar)Si(H)OGaCl3 (NHC=N-heterocyclic carbene), was synthesized using the reaction of silyliumylidene-NHC complex [(NHC)2 (Ar)Si]Cl with water in the presence of GaCl3 . Conversion of this complex to the corresponding silacarboxylate dimer [(NHC)(Ar)SiO2 GaCl2 ]2 , free silaacetal ArSi(H)(OR)2 , silaacyl chloride (NHC)(Ar)Si(Cl)OGaCl3 , and phosphasilene-NHC adduct (NHC)(Ar)Si(H)PTMS unveil its true potential as a synthon in silacarbonyl chemistry.

The first mesomorphic benzimidazolium-based silver(I)-N-heterocyclic dicarbene complexes: Synthesis, characterization and phase properties

The first mesomorphic benzimidazolium based mononuclear silver (I) N-heterocyclic dicarbene complexes, Ag(I)-NHC were prepared via in situ deprotonation of 1-octadecyl-3-alkyl/arylbenzimidazolium salts with silver oxide (Ag2O). Both series of Ag (I)-NHC complexes contained a C18 alkyl chain on one N atom and differed in term of the substituent (alkyl and substituted benzyl moiety) on the other N atom in the benzimidazolium ring. All the synthesized compounds were characterized by elemental analysis, Fourier-transform infrared, 1H and 13C NMR spectroscopy. Cation geometry, anion and alkyl chain length were found to be essential parameters for mesophase formation in the salts and Ag(I)-NHC complexes in this study. All dialkylated salts except the one with the shortest chain, n = 10 were smectogenic. On the other hand, a large width-to-length ratio of the cationic core in the benzyl analogues had a negative effect on the formation and stability of mesophase. No mesophases were observed for these compounds. Wider mesophase range was seen with decrease in anion size and elongation of alkyl chains. A metastable SmA phase was observed in two Ag(I)-NHC complexes. The minimum chain length required for compounds with different anions to exhibit liquid crystal (LC) properties was addressed. Mesophase was observed for bromide salts with C12 onwards while C14 is the minimum chain length required for the hexaflurophosphate containing Ag(I)-NHC complexes to display LC properties. All Ag(I)-NHC complexes except the one bearing a cyano group could be considered ionic liquids with melting/clearing temperatures below 100 °C.

Novel N-heterocyclic carbene silver(I) complexes: Synthesis, structural characterization, and anticancer activity

In this study, we synthesized four novel unsymmetrically substituted NHC ligands (1a-d) and their Ag(I) complexes (2a-d). All new compounds were characterized using elemental analysis, FT-IR, 1H NMR, and 13C NMR spectroscopy and X-ray crystallography. The molecular structure of complex 2d was elucidated through single crystal X-ray diffraction analyses. Single crystal structural studies for complex 2d show that the benzene rings (C9–C14) and the central benzimidazole ring system make dihedral angles of 85.65(11)°. The Ag–Cl and Ag–C single bond lengths are 2.3553(7) and 2.096(2) Å, respectively. The C–Ag–Cl bond angle is 168.27(7)°. Both salts and complexes were tested for their anti-cancer potential against three human cancer cell lines (DU-145, MCF-7, and MDA-MB-231) and non-cancer cells adipose from mouse (L-929) for 24 h, 48 h and 72 h using the MTT assays. However, the Ag(I)–NHC complexes (2a-d) showed a dose and time-dependent cytotoxic activity against all cell lines. MDA-MB-231 human breast carcinoma cells were the most sensitive to the Ag(I)–NHC complex displaying IC50 lower than 1 μM all time points. Further, the IC50s for Ag(I)–NHC were higher in non-cancer cells, suggesting that complexes possessed noteworthy selectivity for human cancer cells.

Bidentate Iminophosphorane-NHC Ligand Derived from the Imidazo[1,5-a]pyridin-3-ylidene Scaffold

The synthesis of the bifunctional iminophosphorane-NHC (1) based on the imidazo[1,5-a]pyridin-3-ylidene (IPy) platform is reported. Its imidazo[1,5-a]pyridinium salt precursor [1·H](X) was readily obtained by an efficient three-component coupling reaction between 5-bromoimidazo[1,5-a]pyridinium bromide, sodium azide, and triphenylphosphine according to a SNAr/Staudinger reaction sequence. The stable free carbene 1 was generated by deprotonation of [1·H](X) with potassium bis(trimethylsilyl)amide, and its coordination ability toward various transition-metals was evaluated, either upon direct metalation of the free carbene or by transmetalation from a silver(I) NHC complex. While the ligand 1 is singly bounded through the carbene carbon atom in the latter complex, it behaves as a chelating bidentate ligand in all other complexes that were prepared, including the cationic and neutral palladium(II) complexes [Pd(allyl)(κ2C,N -1)](OTf) ([5](OTf)) and [PdCl2(κ2C,N -1)] (7), and the cationic rhodium(I) complexes...

Synthesis and Structures of Arene Ruthenium (II)–NHC Complexes: Efficient Catalytic α‐alkylation of ketones via Hydrogen Auto Transfer Reaction

A panel of six new arene Ru (II)‐NHC complexes 2a‐f, (NHC = 1,3‐diethyl‐(5,6‐dimethyl)benzimidazolin‐2‐ylidene 1a, 1,3‐dicyclohexylmethyl‐(5,6‐dimethyl)benzimidazolin‐2‐ylidene 1b and 1,3‐dibenzyl‐(5,6‐dimethyl)benzimidazolin‐2‐ylidene 1c) were synthesized from the transmetallation reaction of Ag‐NHC with [(η6‐arene)RuCl2]2 and characterized. The ruthenium (II)‐NHC complexes 2a‐f were developed as effective catalysts for α‐alkylation of ketones and synthesis of bioactive quinoline using primary/amino alcohols as coupling partners respectively. The reactions were performed with 0.5 mol% catalyst load in 8 h under aerobic condition and the maximum yield was up to 96%. Besides, the different alkyl wingtips on NHC and arene moieties were studied to differentiate the catalytic robustness of the complexes in the transformations.

2-methyl-1,4-benzodioxan-substituted bis(NHC)PdX2 complexes: Synthesis, characterization and the catalytic activity in the direct arylation reaction of some 2-alkyl-heterocyclic compounds

Almost in all fields of chemistry, the C–C cross-coupling reactions such as the direct arylation reaction have attracted much attention and have advanced quickly in recent years due to the importance of environment-friendly properties. This study contains the synthesis of the 2-methyl-1,4-benzodioxan-substituted bis(NHC)PdX2 complexes and their catalytic activity in direct arylation reaction. The bis(NHC)PdX2 complexes have been prepared from the 2-methyl-1,4-benzodioxan-substituted Ag(I)NHC complexes via transmetallation method. The bis(NHC)PdX2 complexes have been characterized using 1H NMR, 13C NMR, FT-IR spectroscopy and elemental analysis techniques. The bis(NHC)PdX2 complexes have been examined as catalysts in the direct arylation reactions with 2-n-butylfuran, 2-n-butylthiophene and 2-isopropylthiazole, and have demonstrated excellent activity in these reactions.

Use of an Air-Stable Cu(I)-NHC Catalyst for the Synthesis of Peptidotriazoles.

We report the use of air-stable Cu(I)-NHC complex 4a as a catalyst for the efficient microwave-assisted synthesis of peptidotriazoles on solid phase. Compared with the usual conditions (CuI or CuSO4/NaAsc), catalyst 4a allowed the preparation of a series of peptidomimetic compounds containing a 1,2,3-triazole ring in their backbone without the oxidation of common side-chains. Overall, the peptidotriazoles were obtained in good yields (61-87%), in excellent purity (higher than 94%) and with low copper contamination.

Polly L. Arnold

Polly L. Arnold

Well-Defined Palladium(II)-NHC Precatalysts for Cross-Coupling Reactions of Amides and Esters by Selective N-C/O-C Cleavage.

Transition-metal-catalyzed cross-coupling reactions represent a most powerful tool for the rapid construction of C-C and C-X bonds available to synthetic chemists. Recently, tremendous progress has been made in the burgeoning area of cross-coupling reactions of amides and esters enabled by regio- and chemoselective acyl C-X (X = N, O) cleavage using well-defined Pd(II)-NHC complexes. The use of N-heterocyclic carbenes as ligands in palladium-catalyzed cross-couplings permits reactions of amides and esters that were previously impossible using palladium or could be achieved only under harsh conditions. These reactions provide an attractive method to synthetic chemists to manipulate the traditionally inert amide and ester bonds with the broad cross-coupling generality inherent to palladium catalysis. Research in the area of cross-coupling of stable acyl electrophiles can be broadly categorized by the type of electrophile undergoing the cross-coupling. Recent studies have shown that cross-coupling of amides by transition-metal catalysis represents one of the most straightforward and wide-ranging ways of manipulating the classically inert amide bonds into generic acyl-metal intermediates that can be systematically exploited in cross-coupling reactions as a new paradigm in organic synthesis. The key to achieving high chemoselectivity of the process is control of amidic resonance (nN to πC═O* conjugation, rotation of ca. 15-20 kcal/mol in planar amides), enabling oxidative addition of the N-C amide bond to a metal in a rational and predictable manner. This mode of catalysis has been extended to C(acyl)-O cross-coupling reactions of aryl esters, where selective C-O bond cleavage is accomplished through a rational match of aryl ester electrophiles and nucleophilic metal catalysts. These two types of transition-metal-catalyzed cross-coupling reactions represent an attractive concept in synthetic chemistry because of the ubiquity of esters and amides as precursors in organic synthesis. Furthermore, the high stability of amides and esters provides unprecedented opportunities for orthogonal cross-coupling strategies in the presence of other electrophiles. In this Account, we highlight advances that have taken place in the past few years in the field of cross-coupling of amides and esters, focusing on both (1) the stereoelectronic properties of well-defined Pd(II)-NHC complexes that have been critical to realize this challenging cross-coupling manifold and (2) the role of the isomerization barrier of the acyl electrophiles undergoing the cross-coupling. In a broader sense, the chemistry described here provides a practical approach to functionalize common amide and ester functional groups in organic synthesis and establishes straightforward access to acyl-metal intermediates that enable nonconventional cross-coupling strategies.

Iron and Cobalt Metallotropism in Remote‐Substituted NHC Ligands: Metalation to Abnormal NHC Complexes or NHC Ring Opening

AbstractMetallotropism of the M[N(SiMe3)2]2 metal fragment in the tautomeric system IAR⇌ACR involving imidazolium salts/N‐heterocyclic carbenes with remote aminide/amine substituents, respectively, is manifested by its CNHC carbophilicity (R=tBu, M=Co, Fe) or NRaminido nitrogenophilicity (R=Cy, M=Co, Fe; R=Mes, M=Fe) and has been rationalized on the basis of steric and electronic effects. The thermolysis products of the [M{N(SiMe3)2}2]/ IAR⇌ACR system are also substituent‐dependent, leading to a rearranged aminide‐functionalized aNHC Co2 complex of an unprecedented type or to ring‐opened metallaketenimines; they are postulated to originate from different metalloisomers. The results are interpreted on the basis of the X‐ray diffraction analysis of 11 new compounds.

Iron and Cobalt Metallotropism in Remote-Substituted NHC Ligands: Metalation to Abnormal NHC Complexes or NHC Ring Opening.

Metallotropism of the M[N(SiMe3 )2 ]2 metal fragment in the tautomeric system IAR ⇌ACR involving imidazolium salts/N-heterocyclic carbenes with remote aminide/amine substituents, respectively, is manifested by its CNHC carbophilicity (R=tBu, M=Co, Fe) or NRaminido nitrogenophilicity (R=Cy, M=Co, Fe; R=Mes, M=Fe) and has been rationalized on the basis of steric and electronic effects. The thermolysis products of the [M{N(SiMe3 )2 }2 ]/ IAR ⇌ACR system are also substituent-dependent, leading to a rearranged aminide-functionalized aNHC Co2 complex of an unprecedented type or to ring-opened metallaketenimines; they are postulated to originate from different metalloisomers. The results are interpreted on the basis of the X-ray diffraction analysis of 11 new compounds.

Palladium(II) N-heterocyclic carbene complexes: synthesis, structures and cytotoxicity potential studies against breast cancer cell line

Mononuclear trans-Pd(II)–NHC complexes (where NHC = N-heterocyclic carbene) bearing asymmetrically substituted NHC-ligand have been synthesized via transmetalation reaction between Ag(I)–NHC complexes and [Pd(NCCH3)2Cl2]. The NHC precursors are accessible in two steps by N-n-alkyl reactions of benzimidazole. The resultant benzimidazolium salts were deprotonated with Ag2O by in situ deprotonation to facilitate the formation of mononuclear Ag(I)–NHC complexes. Single-crystal structural study for Pd(II)–NHC shows that the palladium(II) ion exhibits a square-planar geometry of two NHC ligands and two chloride ions. The cytotoxicity study was investigated against breast cancer cell line (MCF-7). The Ag(I)–NHC complexes exhibit better activities than their corresponding Pd(II)–NHC complexes, whereas all benzimidazolium salts are inactive toward MCF-7 cancer cell line.

Syntheses, Structures, and Antimicrobial Activities of Gold(I)- and Copper(I)- N-Heterocyclic Carbene (NHC) Complexes Derived from Basket-Shaped Dinuclear Ag(I)-NHC Complex.

Novel dinuclear gold(I)- and copper(I)- N-heterocyclic carbene (NHC, L-1a) complexes [M2(L-1a)](PF6)2 (M = AuI (Au-1·PF6) and M = CuI (Cu-1·PF6)) were synthesized by transmetalation of the dinuclear silver(I)-NHC complex [Ag2(L-1a)](PF6)2 (Ag-1·PF6) with [AuCl(Me2S)] or CuI in over 70% yield. These NHC complexes were characterized by CHN elemental analysis, Fourier transform infrared spectroscopy, thermogravimetry/differential thermal analysis, and solution (1H and 13C) NMR spectroscopy. X-ray crystallography revealed that Au-1·PF6 and Cu-1·PF6 are dinuclear molecules consisting of two linear intramolecular C-M-C bonds (M = AuI and CuI), one M···M interaction, and two metal atoms arranged in a T-shaped geometry; their molecular structures are very similar to the basket-shaped cage structure of the parent complex Ag-1·PF6. Because of the smaller ionic radius of copper(I), Cu-1·PF6 has the smallest upper space of the basket among the three complexes. Au-1·PF6 and Cu-1·PF6 were very stable in the solid state and in solution. They did not undergo nucleophilic reaction with thiols 2-mercaptoethanol and 2-benzimidazolethiol (Hbmt) at least for several hours, whereas Ag-1·PF6 did react, forming precipitates of silver(I) thiolate and the free ligand L-1a·PF6. The minimum inhibitory concentration values toward a panel of bacteria, yeasts, and molds were examined in a water-suspension system and a solution system containing dimethyl sulfoxide. The antimicrobial spectra of the three compounds were metal-dependent, and Au-1·PF6 showed the greatest activity toward Gram-positive bacteria.