NHC-gold Complexes Research Articles

Insight into the nature of carbon-metal bonding for N-heterocyclic carbenes in gold/silver complexes and nanoparticles using DFT-correlated Raman spectroscopy: strong evidence for π-backbonding.

N-Heterocyclic carbenes (NHCs) have emerged as promising ligands for stabilizing metallic complexes, nanoclusters, nanoparticles (NPs) and surfaces. The carbon-metal bond between NHCs and metal atoms plays a crucial role in determining the resulting material's stability, reactivity, function, and electronic properties. Using Raman spectroscopy coupled with density functional theory calculations, we investigate the nature of carbon-metal bonding in NHC-silver and NHC-gold complexes as well as their corresponding NPs. While low wavenumbers are inaccessible to standard infrared spectroscopy, Raman detection reveals previously unreported NHC-Au/Ag bond-stretching vibrations between 154-196 cm-1. The computationally efficient r2SCAN-3c method allows an excellent correlation between experimental and predicted Raman spectra which helps calibrate an accurate description of NHC-metal bonding. While π-backbonding should stabilize the NHC-metal bond, conflicting reports for the presence and absence of π-backbonding are seen in the literature. This debate led us to further investigate experimental and theoretical results to ultimately confirm and quantify the presence of π-backbonding in these systems. Experimentally, an observed decrease in the NHC's CN stretching due to the population of the π* orbital is a good indication for the presence of π-backbonding. Using energy decomposition analysis - natural orbitals for chemical valence (EDA-NOCV), our calculations concur and quantify π-backbonding in these NHC-bound complexes and NPs. Surprisingly, we observe that NPs are less stabilized by π-backbonding compared to their respective complexes-a result that partially explains the weaker NHC-NP bond. The protocol described herein will help optimize metal-carbon bonding in NHC-stabilized metal complexes, nanoparticles and surfaces.

Hydroamination of alkynes catalyzed by NHC-Gold(I) complexes: the non-monotonic effect of substituted arylamines on the catalyst activity.

Imines are valuable key compounds for synthesizing several nitrogen-containing molecules used in biological and industrial fields. They have been obtained, as highly regioselective Markovnikov products, by reacting several alkynes with arylamines in the presence of three new N-Heterocyclic carbene gold(I) complexes (3b, 4b, and 6b) together with the known 1-2b and 7b gold complexes as well as silver complexes 1-2a. Gold(I) complexes were investigated by means of NMR, mass spectroscopy, elemental analysis, and X-ray crystallographic studies. Accurate screening of co-catalysts and solvents led to identifying the best reaction conditions and the most active catalyst (2b) in the model hydroamination of phenylacetylene with aniline. Complex 2b was then tested in the hydroamination of alkynes with a wide variety of arylamines yielding a lower percentage of product when arylamines with both electron-withdrawing and electron-donating substituents were involved. Computational studies on the rate-determining step of hydroamination were conducted to shed light on the significantly different yields observed when reacting arylamines with different substituents.

Anti-Tumoural [NHC(thiolato)] Gold(I) Complexes Derived from HIF-1α Inhibitor AC1-004 Target the Mitochondrial Redox System and Show Antiangiogenic Effects in vivo.

AC1-004 is a potent inhibitor of the hypoxia-inducible factor alpha (HIF-1α) pathway, essential for tumour growth, angiogenesis and metastasis. We modelled a series of gold(I) complexes on AC1-004, retaining its 5-carboalkoxybenzimidazole as an NHC ligand while replacing its 2-aryloxymethyl residue with modified thiolato gold(I) fragments. The intention was to augment a potential HIF-1α inhibition by conducive effects typical of NHC gold complexes, such as an inhibition of tumoural thioredoxin reductase (TrxR), an increase in reactive oxygen species (ROS), and cytotoxic and antiangiogenic effects. We report on the synthesis and biological effects of twelve such N,N'-dialkylbenzimidazol-2-ylidene gold(I) complexes, obtained in average yields of 65 % for the thiophenolato and 45 % for the novel 4-(adamant-2-yl)benzenethiol complexes. The structure of one complex was validated via single-crystal X-ray diffraction. Structure-activity relationships (SAR) were derived by variation of the N-substituents (Me, Et, iPr, pentyl, Bn) and the thiolato ligand. Their cytotoxicity against various human cancer cell lines of different entities reached IC50 values in the single-digit micromolar range. The complexes were also assayed for the induction of tumour cell apoptosis (activation of caspase-3/7), TrxR inhibition and antiangiogenic effects in zebrafish. Cyclopropene-bearing congeners were employed in click reactions to examine the subcellular accumulation of the complexes.

New Insights into the Behavior of NHC-Gold Complexes in Cancer Cells

Among the non-platinum antitumor agents, gold complexes have received increased attention owing to their strong antiproliferative effects, which generally occur through non-cisplatin-like mechanisms of action. Several studies have revealed that many cytotoxic gold compounds, such as N-heterocyclic carbene (NHC)-gold(I) complexes, are potent thioredoxin reductase (TrxR) inhibitors. Many other pathways have been supposed to be altered by gold coordination to protein targets. Within this frame, we have selected two gold(I) complexes based on aromatic ligands to be tested on cancer cells. Differently from bis [1,3-diethyl-4,5-bis(4-methoxyphenyl)imidazol-2-ylidene]gold(I) bromide (Au4BC), bis [1-methyl-3-acridineimidazolin-2-ylidene]gold(I) tetrafluoroborate (Au3BC) inhibited TrxR1 activity in vitro. Treatment of Huh7 hepatocellular carcinoma (HCC) cells, and MDA-MB-231 triple-negative breast cancer (TNBC) cells, with Au4BC inhibited cell viability, increased reactive oxygen species (ROS) levels, caused DNA damage, and induced autophagy and apoptosis. Notably, we found that, although Au3BC inhibited TrxR1 activity, no effect on the cell viabilities of HCC and BC cells was observed. At the molecular level, Au3BC induced a protective response mechanism in Huh7 and MDA-MB-231 cells, by inducing up-regulation of RAD51 and p62 protein expression, two proteins involved in DNA damage repair and autophagy, respectively. RAD51 gene knock-down in HCC cells increased cell sensitivity to Au3BC by significant reduction of cell viability, induction of DNA damage, and induction of apoptosis and autophagy. All together, these results suggest that the tested NHC-Gold complexes, Au3BC and Au4BC, showed different mechanisms of action, either dependent or independent of TrxR1 inhibition. As a result, Au3BC and Au4BC were found to be promising candidates as anticancer drugs for the treatment of HCC and BC.

Helical Chiral N-Heterocyclic Carbene Ligands in Enantioselective Gold Catalysis.

The first chiral helicene-NHC gold(I) complexes efficient in enantioselective catalysis were prepared. The L-shaped chiral ligand is composed of an imidazo[1,5-a]pyridin-3-ylidene (IPy) scaffold laterally substituted by a configurationally stable [5]-helicenoid unit. The chiral information was introduced in a key post-functionalization step of a NHC-gold(I) complex bearing a symmetrical anionic fluoreno[5]helicene substituent, leading to a racemic mixture of complexes featuring three correlated elements of chirality, namely central, axial and helical chirality. After HPLC enantiomeric resolution, X-ray crystallography and theoretical calculations enabled structural and stereochemical characterization of these configurationally stable NHC-gold(I) complexes. The high potential in asymmetric catalysis is demonstrated in the benchmark cycloisomerization of N-tethered 1,6-enynes with up to 95 : 5 er.

N-Heterocyclic Carbene-Gold(I) Complexes Targeting Actin Polymerization

Transition metal complexes are attracting attention because of their various chemical and biological properties. In particular, the NHC-gold complexes represent a productive field of research in medicinal chemistry, mostly as anticancer tools, displaying a broad range of targets. In addition to the already known biological targets, recently, an important activity in the organization of the cell cytoskeleton was discovered. In this paper, we demonstrated that two NHC-gold complexes (namely AuL4 and AuL7) possessing good anticancer activity and multi-target properties, as stated in our previous studies, play a major role in regulating the actin polymerization, by the means of in silico and in vitro assays. Using immunofluorescence and direct enzymatic assays, we proved that both the complexes inhibited the actin polymerization reaction without promoting the depolymerization of actin filaments. Our outcomes may contribute toward deepening the knowledge of NHC-gold complexes, with the objective of producing more effective and safer drugs for treating cancer diseases.

Ring size and nothing else matters: unusual regioselectivity of alkyne hydration by NHC gold(I) complexes.

We have investigated the role of ring sizes and substituents in NHC ligands in some (NHC)Au(i) complexes in the hydration of internal alkynes. Despite the fact that using (NHC)Au(i) complexes in the hydration of diarylacetylenes leads to Markovnikov-type products, the precise tuning of ligands allows changing the regioselectivity in arylalkylacetylene hydration to the anti-Markovnikov-type.

Gold(I) Complexes with Eight‐Membered NHC Ligands: Synthesis, Structures and Catalytic Activity

AbstractA series of expanded‐ring NHC gold complexes of the formula (NaphtDHD−Ar)Au−X (NaphtDHD=4,5‐dihydro‐1H‐naphtho[1,8‐ef][1,3]diazocin‐3(2H)‐ylidene; Ar: Mes=2,4,6‐trimethylphenyl, Dipp=2,6‐diisopropylphenyl or Xyl=2,6‐dimethylphenyl; X=Cl, NCCH3, NTf2) have been synthesized, including the first gold(I) triflimidate complex (5) stabilized by an eight‐membered NHC ligand. The new organogold compounds have been characterized by mass spectrometry, IR spectroscopy, and 1H and 13C NMR spectroscopy. The structural geometries of 3 b–c and 5 have been unequivocally established by crystallographic analysis revealing broad N‐C‐N angles (>121°) and high buried volume values (46–54%). The first catalytic studies were carried out on the cycloisomerization of 1,6‐enynes, obtaining full conversions (0.5 mol% catalyst loading) and excellent endo/exo selectivity (up to 99:1), and on the gold‐catalyzed phenol synthesis. Lastly, the (NaphtDHD‐Dipp)Au+ NTf2− species was subjected to a kinetic experiment in the cyclization of a N‐propargyl carboxamide to evaluate the efficiency of the pre‐formed catalyst (5) and the in situ activated gold complex (3 b+AgNTf2).magnified image

Robust gold nanorods stabilized by bidentate N-heterocyclic-carbene-thiolate ligands.

Although N-heterocyclic carbenes (NHCs) have demonstrated outstanding potential for use as surface anchors, synthetic challenges have limited their application to either large planar substrates or very small spherical nanoparticles. The development of a strategy to graft NHCs onto non-spherical nanomaterials, such as gold nanorods, would greatly expand their utility as surface ligands. Here, we use a bidentate thiolate-NHC-gold(I) complex that is easily grafted onto commercial cetyl trimethylammonium bromide-stabilized gold nanorods through ligand exchange. On mild reduction of the resulting surface-tethered NHC-gold(I) complexes, the gold atom attached to the NHC complex is added to the surface as an adatom, thereby precluding the need for reorganization of the underlying surface lattice upon NHC binding. The resulting thiolate-NHC-stabilized gold nanorods are stable towards excess glutathione for up to six days, and under conditions with large variations in pH, high and low temperatures, high salt concentrations, or in biological media and cell culture. We also demonstrate the utility of these nanorods for in vitro photothermal therapy.

Steric hindrance and electronic effects of sulfonatepropyl chain on gold center. An experimental and DFT study

Density Functional Theories (DFT) methods were applied to describe the catalytic effect of a series of sulfonated NHC gold(I) complexes In order to explain the experimental results obtained in the hydration of phenylacetylene in aqueous media. The complexes [1,3-bis(2,6-diisopropyl-4-sodiumsulfonatophenyl)imidazol-2-ylidene]gold(I) chloride (C1) and [(3-sulfonatepropyl)imidazol-2-ylidene]gold(I) chloride (C5) were considered representative compounds based on their structure and reactivity. In accordance to the experimental results, the DFT studies show that the alkyl chain folds generate a strong steric hindrance and electronic effects on the metal center causing a decrease of the catalytic activity.

Silica-Immobilized NHC-Gold(I) Complexes: Versatile Catalysts for the Functionalization of Alkynes under Batch and Continuous Flow Conditions

Immobilized sterically demanding NHC-Au(I) complexes silica-[(IPrR)Au]Cl and silica-[(IAdPrR)Au]Cl are synthesized and characterized. These complexes are suitable catalysts in typical homogeneous Au(I)-catalyzed alkyne reactions such as hydration, hydroamination, hydroarylation, or cycloisomerization. The results obtained with the immobilized catalysts in reactions in batch are comparable to those obtained with their homogeneous counterparts with the advantage of easily recovered and recycled in successive reactions. Their catalytic activity decreases when reused in batch reactions, probably because of crushing that is associated with magnetic stirring. In contrast, these immobilized catalysts are very effective when used under continuous flow conditions in which the same cartridge can be used to catalyze different types of reaction successively for a long period without any noticeable loss of activity.

Some insights into the gold-catalysed A3-coupling reaction

A series of cyclometallated and functionalised NHC gold(I) and gold(III) complexes, many of which feature chiral ligands, and their application to A3-coupling reactions is presented. Gold(III) complexes were found to be particularly effective catalysts for the coupling in a range of solvents, however no asymmetric induction was obtained when using chiral gold complexes and the rate of product formation was found to be similar even when using different ligand systems. In-situ NMR analysis of these reactions indicates that decomposition of the catalyst occurs during the course of the reaction while TEM studies revealed the presence of gold nanoparticles in crude reaction mixtures. Taken together these data suggest that the gold nanoparticles, rather than the intact gold complexes, could be the catalytically active species, and if so this may have significant implications for other gold-catalysed systems.

Metal Confinement through N-(9-Alkyl)fluorenyl-Substituted N-Heterocyclic Carbenes and Its Consequences in Gold-Catalysed Reactions Involving Enynes.

A series of gold(I) and gold(III) complexes containing bulky bis-N,N'-(9-alkylfluorenyl) heterocyclic carbene (R F-NHC) ligands have been prepared in high yields from appropriate imidazolinium, imidazolium and benzimidazolium salts. In all complexes, the carbene ligand provides high steric protection of the Au-X bond trans to the carbenic C atom. Irrespective of the metal oxidation state, the complexes showed high efficiency in a tandem 3,3-rearrangement/Nazarov reaction of an enynyl acetate. One of the AuIII complexes, [AuCl3 (R F-NHC)], was further found to be suitable for the efficient cyclisation of a propargylcarboxamide. Furthermore, unlike related NHC-gold(I) complexes based on conventional bulky N-heterocyclic carbenes (notably, 1,3-bis-(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr), 1,3-bis-(2,4,6-trimethylphenyl)imidazol-2-ylidene (IMes) and 1,3-(bis-tert-butyl)imidazol-2-ylidene (ItBu)), the studied [AuI Cl(R F-NHC)] complexes catalysed the conversion of a 1,6-enyne in the presence of indole into a single product; this arises from the embracing character of the ligand, which prevents indole addition on one of the catalytic intermediates. A structure/selectivity relationship was established for all carbenes tested that took into account percent buried volumes and topographic steric maps. The results illustrate the high potential of confining NHCs in organic synthesis.

Synthesis of Propargyl-Functionalized NHC Gold Complexes

A series of propargyl functionalized N-heterocyclic carbene gold(I) complexes have been synthesized from the corresponding imidazolium salts with tetrabutylammonium acetylacetonate in the presence of a gold(I) precursor in a one-pot reaction. Several complexes of different stoichiometries are described: [AuBr(NHC)], [Au(NHC)2]Br and [Au(C6F5) (NHC)], and many of these have been characterized by X-ray diffraction studies. Aurophilic interactions are present in the compounds bearing less sterically hindered carbenes, and secondary interactions such as hydrogen bonds, π–π stacking, or weak contacts of the gold center with the carbon of the propargyl unit have also been found. These complexes possess a high degree of water solubility, which makes them potentially useful for the synthesis of biologically active compounds or as gold catalysts in water. Activation of the propargyl unit in [AuBr(NHC)] complexes leads to the formation of interesting trimers with bridging bidentate C∧C alkynyl-carbene ligands.

Catalytic domino amination and oxidative coupling of gold acetylides and isolation of key vinylene digold intermediates as a new class of ditopic N-heterocyclic carbene complexes.

A catalytic domino amination and oxidative coupling of in situ prepared gold acetylides has been developed for the synthesis of abnormal NHC (aNHC) gold complexes, and key vinylene digold intermediates are isolated and structurally characterized.

Fluorescence resonance energy transfer (FRET) for the verification of dual gold catalysis.

Fluorescence resonance energy transfer (FRET) in appropriately tagged NHC-gold complexes can be utilized to in situ observe the formation of digold species, which are known to be catalytically relevant intermediates in various gold catalyzed reactions.

An efficient and sustainable synthesis of NHC gold complexes.

A simple, efficient and sustainable method for the general synthesis of NHC gold(i) complexes is described. The reaction of imidazolium salts, of different electronic and steric requirements, with [AuX(tht)] (tht = tetrahydrothiophene) derivatives, in the presence of NBu4(acac), in air and at room temperature leads to the NHC gold species in good yields and with very short reaction times.

Simple and Mild Synthesis of Indoles via Hydroamination Reaction Catalysed by NHC–Gold Complexes: Looking for Optimized Conditions

An efficient heterocyclization of 2-alkynylanilines to indole derivatives has been developed. The reaction proceeds under very mild conditions using small amounts of a gold precatalyst. A range of substrates possessing various functional groups were employed, and the substituted indoles were obtained in very good yields.

Mechanistic Insight into the Gold-Catalyzed Carboxylative Cyclization of Propargylamines

DFT calculations have been carried out to study the detailed mechanisms for the carboxylative cyclization of propargylamine using CO2 catalyzed by NHC-gold(I) complexes. The calculation results indicate that the reaction starts with an N-coordinated species, [(NHC)Au(propargylamine)]Cl, which undergoes isomerization to an alkyne-coordinated species. An amine–carbon dioxide interaction gives a carbamate ion species, from which a nucleophilic attack of the in-plane lone pair of electrons in the carbamate anion moiety on one of two coordinated alkyne carbons leads to formation of a five-membered-ring intermediate. The final product is generated through deprotonation and protonation processes. Through a detailed mechanistic study, we found that the substrate propargylamine assists (catalyzes) the deprotonation and protonation processes. Careful study of the solvent effect indicates that solvents, which are polar and capable of hydrogen bonding, promote the catalytic reactions through stabilizing the carbamate ion intermediate species.

Chiral [2.2]paracyclophane-based NAC- and NHC-gold(I) complexes

From enantiomerically pure, planar chiral [2.2]paracyclophane amines a series of nitrogen acyclic carbenegold(I) complexes and nitrogen heterocyclic carbenegold(I) complexes are prepared by a modular template synthesis using isonitriles and amines. These chiral catalysts are tested in two reactions, the enantiotopos-selective furanyne cyclization and the enantioselective enyne cyclization. While excellent conversions could be achieved with these new catalysts, the enantioselectivities in only some cases are in the range of best known catalysts for these conversion.