Liquid Dynamics Determine Transition Metal-N-Heterocyclic Carbene Complex Formation.

Invited for the cover of this issue are Oldamur Hollóczki and co-workers at the Universities of Bonn, Ghent and Debrecen. The image depicts the search of an ionic base for the acidic proton of an imidazolium cation in order to form a carbene complex. Read the full text of the article at 10.1002/chem.202203636.

Liquid Dynamics Determine Transition Metal-N-Heterocyclic Carbene Complex Formation.

The mechanism of metal-N-heterocyclic carbene (NHC) complex formation from imidazolium salts in the presence of weak bases was investigated through theoretical methods. Quantum chemical calculations revealed that the two bases considered here, sodium acetate and trimethylamine, both facilitate complex formation. In contrast to previous experiments, these calculations indicated a slightly lower barrier with the amine. Molecular dynamics simulations showed that the ionic nature of the [AuCl2 ]- and imidazolium ions, as well as the sodium acetate base keep these species associated in the reaction mixture through ion pairing. This pre-association of the components produces those clusters that are essential for the metal complex formation reaction. The neutral amine, however, remains mostly separated from the other reaction partners, making it a significantly less effective base.

Correlation of Experimental and Calculated Reaction Enthalpies with Ligand Donor Strengths.

Ylide-functionalized phosphines (YPhos) have recently proven to be strongly donating ligands that enable high catalyst activities in gold(I)-mediated transformations. We now report on a calorimetric study dealing with the [Au(YPhos)Cl] system and assess YPhos-Au bond dissociation enthalpies (BDE). Comparison with other commonly used phosphines confirmed the high binding strengths of the YPhos ligands. Furthermore, the values of the reaction enthalpies were shown to correlate with the electronic properties of the ligands measured via the Tolman electronic parameter or the calculated molecular electrostatic potential at phosphorus. Notably, the reaction enthalpies can conveniently be derived by computational methods, thus making these easy-to-obtain descriptors for ligand donor property quantification.

Gold(I)-N-Heterocyclic Carbene Synthons in Organometallic Synthesis.

The prominent role of gold-N-heterocyclic carbene (NHC) complexes in numerous research areas such as homogeneous (photo)catalysis, medicinal chemistry and materials science has prompted organometallic chemists to design gold-based synthons that permit access to target complexes through simple synthetic steps under mild conditions. In this review, the main gold-NHC synthons employed in organometallic synthesis are discussed. Mechanistic aspects involved in their synthesis and reactivity as well as applications of gold-NHC synthons as efficient pre-catalysts, antitumor agents and/or photo-emissive materials are presented.

PtII -N-Heterocyclic Carbene Complexes in Solvent-Free Alkene Hydrosilylation.

Herein, we report the catalytic activity of a series of platinum(II) pre-catalysts, bearing N-heterocyclic carbene (NHC) ligands, in the alkene hydrosilylation reaction. Their structural and electronic properties are fully investigated using X-ray diffraction analysis and nuclear magnetic resonance spectroscopy (NMR). Next, our study presents a structure-activity relationship within this group of pre-catalysts and gives mechanistic insights into the catalyst activation step. An exceptional catalytic performance of one of the complexes is observed, reaching a turnover number (TON) of 970 000 and a turnover frequency (TOF) of 40 417 h-1 at 1 ppm catalyst loading. Finally, an attractive solvent-free and open-to-air alkene hydrosilylation protocol, featuring efficient platinum removal (reduction of residual Pt from 582 ppm to 5.8 ppm), is disclosed.

Suzuki-Miyaura Cross-Coupling of Amides by N-C Cleavage Mediated by Air-Stable, Well-Defined [Pd(NHC)(sulfide)Cl2] Catalysts: Reaction Development, Scope, and Mechanism.

The Suzuki-Miyaura cross-coupling of amides by selective N-C acyl bond cleavage represents a powerful tool for constructing biaryl ketones from historically inert amide bonds. These amide bond activation reactions hinge upon efficient oxidative addition of the N-C acyl bond to Pd(0). However, in contrast to the well-researched activation of aryl halides by C(sp2)-X oxidative addition, very few studies on the mechanism of C(acyl)-N bond oxidative addition and catalyst effect have been reported. Herein, we report a study on [Pd(NHC)(sulfide)Cl2] catalysts in amide N-C bond activation. These readily prepared, well-defined, air- and moisture-stable Pd(II)-NHC catalysts feature SMe2 (DMS = dimethylsulfide) or S(CH2CH2)2 (THT = tetrahydrothiophene) as ancillary ligands. The reaction development, kinetic studies, and reaction scope are presented. Extensive DFT studies were conducted to gain insight into the mechanism of C(acyl)-N bond oxidative addition and catalyst activation. We expect that [Pd(NHC)(sulfide)Cl2] precatalysts featuring sulfides as well-defined, readily accessible ancillary ligands will find application in C(acyl)-X bond activation in organic synthesis and catalysis.

Optimizing Catalyst and Reaction Conditions in Gold(I) Catalysis-Ligand Development.

This review considers phosphine and N-heterocyclic carbene complexes of gold(I) that are used as (pre)catalysts for a range of reactions in organic synthesis. These are divided according to the structure of the ligand, with the narrative focusing on studies that offer a quantitative comparison between the ligands and readily available or widely used existing systems.

Unveiling the Potential of Innovative Gold(I) and Silver(I) Selenourea Complexes as Anticancer Agents Targeting TrxR and Cellular Redox Homeostasis.

A series of NHC-based selenourea Ag(I) and Au(I) complexes were evaluated for their anticancer potential in vitro, on 2D and 3D human cancer cell systems. All NHC-based selenourea complexes possess an outstanding cytotoxic potency, which was comparable or even better than that of the reference metallodrug auranofin, and were also able to overcome both platinum-based and multi-drug resistances. Intriguingly, their cytotoxic potency did not correlate with solution stability, partition coefficient or cellular uptake. On the other hand, mechanistic studies in cancer cells revealed their ability to strongly and selectively inhibit the redox-regulating enzyme Thioredoxin Reductase (TrxR), being even more effective than auranofin, a well-known TrxR inhibitor, without affecting other redox enzymes such as Glutathione Reductase (GR). The inhibition of TrxR in H157 human cancer cells caused, in turn, the disruption of cellular thiol-redox homeostasis and of mitochondria pathophysiology, ultimately leading to cancer cell death through apoptosis.

Synthesis of Carbene-Metal-Amido (CMA) Complexes and Their Use as Precatalysts for the Activator-Free, Gold-Catalyzed Addition of Carboxylic Acids to Alkynes.

A straightforward synthetic protocol leading to carbene-metal-amido (CMA) complexes (metal=Au, Cu) using a mild base and an environmentally desirable solvent (EtOH) has been explored, with a focus on complexes bearing backbone-substituted N-heterocyclic carbene (NHC) ligands, including BIAN-NHCs (BIAN=bis(imino)acenaphthene). The novel CMAs were structurally characterized, and gold-based CMAs bearing diverse NHCs were screened as simple, Brønsted-basic precatalysts. The readily accessible complexes display high catalytic activity in the intermolecular and intramolecular hydrocarboxylation of internal alkynes and alkynoic acids respectively, while the screening reveals the ancillary ligand effect of NHCs in these catalytic systems.

Gold N-Heterocyclic Carbene Catalysts for the Hydrofluorination of Alkynes Using Hydrofluoric Acid: Reaction Scope, Mechanistic Studies and the Tracking of Elusive Intermediates.

An efficient and chemoselective methodology deploying gold-N-heterocyclic carbene (NHC) complexes as catalysts in the hydrofluorination of terminal alkynes using aqueous HF has been developed. Mechanistic studies shed light on an in situ generated catalyst, formed by the reaction of Brønsted basic gold pre-catalysts with HF in water, which exhibits the highest reactivity and chemoselectivity. The catalytic system has a wide alkyl substituted-substrate scope, and stoichiometric as well as catalytic reactions with tailor-designed gold pre-catalysts enable the identification of various gold species involved along the catalytic cycle. Computational studies aid in understanding the chemoselectivity observed through examination of key mechanistic steps for phosphine- and NHC-coordinated gold species bearing the triflate counterion and the elusive key complex bearing a bifluoride counterion.

Azolium Aurates as Pre-Catalysts for the Oxidative Coupling of Terminal Alkynes under Mild Conditions.

A simple and efficient method for the oxidative coupling of terminal alkynes is reported for the first time, making use of imidazol(in)ium aurates as pre-catalysts. This approach displays high functional group tolerance and leads to a broad range of 1,3-diyne compounds in moderate to excellent yields using low catalyst loading and is performed in air under mild and sustainable conditions.

N-Heterocyclic Carbene Gold Complexes in a Photocatalytic CO2 Reduction Reaction.

Molecular catalysts that are durable and highly selective in the photocatalytic CO2 reduction reaction (PCO2RR) are in high demand. Molecular gold complexes are underexplored in the CO2RR manifold despite heterogeneous gold-CO2 reduction catalyst counterparts being frequently studied. In this report, a series of N-heterocyclic carbene (NHC)-ligated Au complexes are evaluated in the PCO2RR with an added photosensitizer (tris(2-phenylpyridine)iridium, Ir(ppy)3). The complexes were each studied with and without an added activator used to open a coordination site on the Au complexes. Results show an example of an exceptionally durable PCO2RR catalyst lasting >100 h with high product selectivity for CO. Heterogeneity tests reveal no evidence of a nonhomogeneous active catalyst, and structure-activity relationships of the molecular complexes are discussed.

N-Heterocyclic Carbene Complexes in C-H Activation Reactions.

In this contribution, we provide a comprehensive overview of C-H activation methods promoted by NHC-transition metal complexes, covering the literature since 2002 (the year of the first report on metal-NHC-catalyzed C-H activation) through June 2019, focusing on both NHC ligands and C-H activation methods. This review covers C-H activation reactions catalyzed by group 8 to 11 NHC-metal complexes. Through discussing the role of NHC ligands in promoting challenging C-H activation methods, the reader is provided with an overview of this important area and its crucial role in forging carbon-carbon and carbon-heteroatom bonds by directly engaging ubiquitous C-H bonds.

Mechanistic Aspects of the Palladium-Catalyzed Suzuki-Miyaura Cross-Coupling Reaction.

The story of C-C bond formation includes several reactions, and surely Suzuki-Miyaura is among the most outstanding ones. Herein, a brief historical overview of insights regarding the reaction mechanism is provided. In particular, the formation of the catalytically active species is probably the main concern, thus the preactivation is in competition with, or even assumes the role of the rate determining step (rds) of the overall reaction. Computational chemistry is key in identifying the rds and thus leading to milder conditions on an experimental level by means of predictive catalysis.

Continuous Flow Synthesis of [Au(NHC)(Aryl)] (NHC=N-Heterocyclic Carbene) Complexes.

The use of weak and inexpensive bases has recently opened promising perspectives towards the simpler and more sustainable synthesis of Au(I)-aryl complexes with valuable applications in catalysis, medicinal chemistry, and materials science. In recent years, continuous manufacturing has shown to be a reliable partner in establishing sustainable and controlled process scalability. Herein, the first continuous flow synthesis of a range of Au(I)-aryl starting from widely available boronic acids and various [Au(NHC)Cl] (NHC=N-heterocyclic carbene) complexes in unprecedentedly short reaction times and high yields is reported. Successful synthesis of previously non- or poorly accessible complexes exposed fascinating reactivity patterns. Via a gram-scale synthesis, convenient process scalability of the developed protocol was showcased.

Continuous Flow Synthesis of Metal-NHC Complexes*.

The use of weak bases and mild conditions is currently the most sustainable and attractive synthetic approach for the preparation of late-transition metal complexes, some of which are widely used in catalysis, medicinal chemistry and materials science. Herein, the use of cuprate, aurate or palladate species for a continuous flow preparation of CuI , AuI and PdII -NHC complexes is reported. All reactions examined proceed under extremely mild conditions and make use of technical grade acetone as solvent. The scalability of the process was exemplified in a multigram-scale synthesis of [Cu(IPr)Cl].

Synthesis of Gold(I)-Trifluoromethyl Complexes and their Role in Generating Spectroscopic Evidence for a Gold(I)-Difluorocarbene Species.

Readily prepared and bench-stable [Au(CF3 )(NHC)] compounds were synthesized by using new methods, starting from [Au(OH)(NHC)], [Au(Cl)(NHC)] or [Au(L)(NHC)]HF2 precursors (NHC=N-heterocyclic carbene). The mechanism of formation of these species was investigated. Consequently, a new and straightforward strategy for the mild and selective cleavage of a single carbon/fluorine bond from [Au(CF3 )(NHC)] complexes was attempted and found to be reversible in the presence of an additional nucleophilic fluoride source. This straightforward technique has led to the unprecedented spectroscopic observation of a gold(I)-NHC difluorocarbene species.

Simple Synthetic Routes to Carbene-M-Amido (M=Cu, Ag, Au) Complexes for Luminescence and Photocatalysis Applications.

The development of novel and operationally simple synthetic routes to carbene-metal-amido (CMA) complexes of copper, silver and gold relevant for photonic applications are reported. A mild base and sustainable solvents allow all reactions to be conducted in air and at room temperature, leading to high yields of the targeted compounds even on multigram scales. The effect of various mild bases on the N-H metallation was studied in silico and experimentally, while a mechanochemical, solvent-free synthetic approach was also developed. Our photophysical studies on [M(NHC)(Cbz)] (Cbz=carbazolyl) indicate that the occurrence of fluorescent or phosphorescent states is determined primarily by the metal, providing control over the excited state properties. Consequently, we demonstrate the potential of the new CMAs beyond luminescence applications by employing a selected CMA as a photocatalyst. The exemplified synthetic ease is expected to accelerate the applications of CMAs in photocatalysis and materials chemistry.

Dinuclear gold(i) complexes: from bonding to applications.

The last two decades have seen a veritable explosion in the use of gold(i) complexes bearing N-heterocyclic carbene (NHC) and phosphine (PR3) ligands. Both ligand families have significantly contributed to the stability and design of a plethora of gold complexes. Design is oftentimes associated with application. Here, we wish to present an overview of the synthesis and structural properties of dinuclear gold(i) complexes reported to date with their applications across numerous research areas.

Au⋠⋠⋠H-C Hydrogen Bonds as Design Principle in Gold(I) Catalysis.

Secondary ligand-metal interactions are decisive in many catalytic transformations. While arene-gold interactions have repeatedly been reported as critical structural feature in many high-performance gold catalysts, we herein report that these interactions can also be replaced by Au⋅⋅⋅H-C hydrogen bonds without suffering any reduction in catalytic performance. Systematic experimental and computational studies on a series of ylide-substituted phosphines featuring either a PPh3 (Ph YPhos) or PCy3 (Cy YPhos) moiety showed that the arene-gold interaction in the aryl-substituted compounds is efficiently compensated by the formation of Au⋅⋅⋅H-C hydrogen bonds. The strongest interaction is found with the C-H moiety next to the onium center, which due to the polarization results in remarkably strong interactions with the shortest Au⋅⋅⋅H-C hydrogen bonds reported to date. Calorimetric studies on the formation of the gold complexes further confirmed that the Ph YPhos and Cy YPhos ligands form similarly stable complexes. Consequently, both ligands showed the same catalytic performance in the hydroamination, hydrophenoxylation and hydrocarboxylation of alkynes, thus demonstrating that Au⋅⋅⋅H-C hydrogen bonds are equally suited for the generation of highly effective gold catalysts than gold-arene interactions. The generality of this observation was confirmed by a comparative study between a biaryl phosphine ligand and its cyclohexyl-substituted derivative, which again showed identical catalytic performance. These observations clearly support Au⋅⋅⋅H-C hydrogen bonds as fundamental secondary interactions in gold catalysts, thus further increasing the number of design elements that can be used for future catalyst construction.