Azolium-derived metallates are well-established intermediates in metal–N-heterocyclic carbene chemistry; however, their potential as standalone therapeutic agents remains largely unexplored. Herein, we report the first systematic biological investigation of a diverse family of Au(I), Cu(I), Pt(II), Pd(II), and Ru(II) metallates paired with functionalized azolium cations. The complexes were synthesized quantitatively through a simple, atom-economical, and purification-free protocol under aerobic conditions in technical-grade green solvents. Structural characterization by multinuclear NMR spectroscopy and single-crystal X-ray diffraction confirmed metallate formation and enabled the first isolation and crystallographic characterization of unprecedented azolium-derived ruthenates. The antiproliferative activity of the complexes was evaluated against cisplatin-sensitive (A2780) and cisplatin-resistant (A2780cis) ovarian cancer cell lines, alongside non-cancerous MRC-5 fibroblasts. Backbone-functionalized derivatives emerged as the most potent compounds, displaying activities comparable or superior to cisplatin in A2780 cells and up to 1000-fold higher potency in the resistant A2780cis model. Notably, unlike cisplatin, the metallates retained nearly unchanged IC50 values across both ovarian cancer lines, strongly suggesting resistance-evasive mechanisms of action. While benzylazido- and methyl guanosine-derived complexes generally exhibited lower overall potency, several members retained significant activity in resistant cells while showing markedly reduced toxicity toward normal fibroblasts, highlighting promising selectivity profiles. Ethoxide-functionalized derivatives and platinum-based metallates combined pronounced anticancer activity with favourable therapeutic windows. Overall, this work establishes azolium-derived metallates as a previously overlooked class of metal-based anticancer agents combining exceptional synthetic accessibility, broad structural tunability, and remarkable activity against platinum-resistant ovarian cancer.

Development of novel metallotherapeutics poses both significant potential and numerous challenges due to their complex reactivity in physiological systems and the ambiguity of molecular targets. Advances in target-agnostic and phenotypic-based drug profiling approaches have yielded success in anticancer therapeutic development, but their application to the development and discovery of metal-based drug candidates has been limited. This study demonstrates the use of morphological profiling on a diverse library of metal-containing compounds to elucidate mechanisms of action, providing new insights into the activities of established chemotherapeutics and guiding downstream studies of select novel compounds in the absence of predefined molecular targets. The validity of this strategy was established using a subset of clinically approved anticancer therapeutics, where morphological profiling discerned the mechanistic differences among oxaliplatin, cisplatin, carboplatin, and the clinical-stage ruthenium-based compound BOLD-100. Subsequently, a combination of cytotoxicity and selectivity assessments in conjunction with an analysis of morphological profiles of the compound library identified a novel ruthenium 2-(2-pyridyl)-benzimidazole-based compound series, which induced changes in the mitochondrial morphology of cancer cells. This association was investigated further, revealing an accompanying increase in levels of mitochondrial reactive oxygen species and a corresponding depolarization of the mitochondrial membrane. This application of morphological profiling will enable the rapid identification of promising metal-containing therapeutics, aiding in rational development strategies and mitigating persistent challenges in metallotherapeutic development.

Herein we describe our findings dealing with the activation of the Au–Cl bond in [Au(L)Cl] complexes with several additives. We have probed several additives for their ability to promote the activation of the Au–Cl bond, in a prototypical cationic Au(I)‐mediated reaction, namely the cyclization/cycloisomerization of propargylamides. Phenol was found to be an efficient additive, successfully promoting the activation of the gold precatalysts, and the progression of the reaction, under mild conditions. Further studies on the reactivity of several substrates and the kinetic profile of the reaction provide valuable insight to the phenol‐mediated activation of Au–Cl bond and its catalytic competence. Density functional theory calculations provided additional details regarding the effect of the studied additives.

We present a comprehensive mechanistic investigation of the well-defined precatalyst [Pd(IMesMe)(cin)Cl], which has exhibited high catalytic efficiency in the Miyaura borylation of various aryl chlorides. Despite its proven catalytic performance, key aspects of the mechanism, particularly the transmetalation step, remained elusive. In this study, we addressed these mechanistic aspects through detailed density functional theory (DFT) calculations. Our results elucidate the role of the second equivalent of base, pinpointing its specific involvement within the catalytic cycle. Furthermore, we unraveled the activation pathway of bis(pinacolato)diboron (B2Pin2), determining whether base-mediated cleavage occurs independently or requires direct coordination to the palladium center. The mechanism reveals a surprising concerted fusion of the oxidative addition and transmetalation steps, paving the way not only for a new avenue in the Miyaura reaction, but potentially for other cross-coupling processes. This synergy may prompt a re-evaluation of previous studies, suggesting that similar pathways could enable milder reaction conditions.

Abstract A series of gold(I) complexes featuring a novel ligand–gold–ynaminyl architecture was synthesized and characterized. The incorporation of a (carbazolyl)ethynide (C≡C-Cbz) ligand connects the photonic functionality of the carbazolyl with the N-heterocyclic carbene (NHC) through a long ethynide-Au bridge, showing shorter radiative lifetimes and higher ET values in solution in comparison to their carbene–metal–amido (CMA) congeners. The photophysical properties of the NHC complexes reveal a broad UV emission band when measured at room temperature and a hidden phosphorescence band with high quantum yield (up to 94%) at 77 K. This new photonic functional group based on polar ynamines is presented as a versatile platform for the design of high-energy gold-based luminophores with applications in photocatalysis.

A combination of mechanical synthesis, solid-state analytical techniques (ssNMR, powder XRD, ATR-FTIR) and DFT calculations sheds light on the mechanisms operating in two organometallic solid-state syntheses and highlight the importance of workup protocols in mechanochemical syntheses. The data clearly indicate that product formation can occur during or post grinding.

Ovarian cancer therapy relies heavily on platinum-based drugs, yet clinical efficacy is limited by toxicity and the rapid emergence of resistance. Herein, we report a systematic study of trans-configured Pt(II)-NHC and less conventional Pt(0)-NHC complexes as alternative platinum architectures for the treatment of ovarian cancer, including cisplatin-resistant disease. A sustainable and operationally simple synthetic platform enabled the preparation of a structurally coherent library of trans-[Pt(NHC)Cl2(L)] and [Pt(NHC)(dvtms)] derivatives. In the Pt(II) series, L comprises dimethyl sulfide, pyridine, imidazole, benzimidazole, benzotriazole, 2-aminopyridine, 2-aminoquinoline, and phenazine, allowing systematic modulation of steric and electronic properties. The Pt(0) complexes incorporate dvtms (1,3-divinyltetramethyldisiloxane) as an olefin-stabilizing ligand. Both classical and backbone-functionalized N-heterocyclic carbenes (NHCs) were investigated, the latter accessed through recently developed mild one-pot methodologies, thereby enabling direct evaluation of backbone modification as a medicinal design element. Biological assessment in A2780 and A2780cis ovarian cancer cells reveals that many trans-Pt(II)-NHC complexes display cytotoxicity comparable to or exceeding that of cisplatin and, crucially, retain activity in the resistant model. Clear structure-activity relationships emerge: the nature of the NHC ligand predominates over variation of the neutral co-ligand. In addition, most of the newly synthesized Pt(0) complexes combine high antiproliferative activity with no detectable toxicity toward non-cancerous fibroblasts, highlighting an unprecedented in vitro selectivity within this family.

Development of novel metallotherapeutics poses both significant potential and numerous challenges due to their complex reactivity in physiological systems and the ambiguity of molecular targets. Advances in target-agnostic and phenotypic-based drug profiling approaches have yielded success in anticancer therapeutic development, but their application to the development and discovery of metal-based drug candidates has been limited. This study demonstrates the use of morphological profiling on a diverse library of metal-containing compounds to elucidate mechanisms of action, providing new insights into the activities of established chemotherapeutics and guiding downstream studies of select novel compounds in the absence of predefined molecular targets. The validity of this strategy was established using a subset of clinically approved anticancer therapeutics, where morphological profiling discerned the mechanistic differences among oxaliplatin, cisplatin, carboplatin, and the clinical-stage ruthenium-based compound BOLD-100. Subsequently, a combination of cytotoxicity and selectivity assessments in conjunction with an analysis of morphological profiles of the compound library identified a novel ruthenium 2-(2-pyridyl)benzimidazole-based compound series, which induced changes in the mitochondrial morphology of cancer cells. This association was investigated further, revealing an accompanying increase in levels of mitochondrial reactive oxygen species and a corresponding depolarization of the mitochondrial membrane. This application of morphological profiling will enable the rapid identification of promising metal-containing therapeutics, aiding in rational development strategies and mitigating persistent challenges in metallotherapeutic development.

The quinoline/tetrahydroquinoline scaffold is ubiquitous in natural products and commercial drugs; therefore, several synthetic methods have been developed to provide access to such structures. However, many of these established protocols rely on external activators or additives, relatively high catalyst loadings, and experimentally demanding setups, limiting their practicality and scalability. In this study, a user-friendly, gold-catalyzed, silver-, and additive- free protocol is reported for the cycloisomerization of aromatic propargylamines towards quinoline and tetrahydroquinoline derivatives, by employing hexafluoroisopropanol (HFIP) as both solvent and activator. HFIP can activate the catalytically inert Au(I)-Cl complexes through hydrogen bonding, obviating the use of silver salts or other external additives, while also acting as a recyclable solvent. This simple activation mode, combined with a robust N-heterocyclic carbene (NHC) gold catalyst, enables high catalytic efficiency at low catalyst loadings and with a broad substrate scope under mild conditions. The methodology provides access to, among others, complex phenanthrolines and biquinolines, enhancing the toolbox for N-heterocycle synthesis. This method further allows selective access to either quinolines or tetrahydroquinolines, through the controlled addition of a Hantzsch ester as hydride donor. Mechanistic studies permit the observation of a key intermediate, shedding light on the reaction mechanism and the crucial role of HFIP in the catalyst activation and proton transfer steps.

Guanidine-based azines combine two functional groups in their structure, both of which are widely encountered in medicinal chemistry. Such molecules are accessible, among others, via the versatile reaction of N-heterocyclic carbene (NHC)-derived selenoureas with diazo compounds. Our present work introduces a highly efficient version of this transformation, simultaneously expanding its structural scope beyond the currently known ester-containing analogues. By utilizing a broad scope of diazo compounds, bearing amide, ketone, or heteroatom rich functionalities, we access various azine derivatives of biological significance. Key innovations of this new synthetic protocol include the use of polystyrene-supported triphenylphosphine as a recyclable reagent, enabling a streamlined purification process, eliminating the need for column chromatography, and allowing its repeated use under ambient conditions. Post-synthetic functionalization strategies further expand the structural diversity of the azine scaffold, and preliminary biological evaluation identifies several compounds with in vitro anti-cancer activity. The findings highlight guanidine-based azines as a promising scaffold for further chemical and biological exploration.

The mechanochemical synthesis of well-defined [Rh(L)(acac)(CO)] (L = NHC or phosphine) complexes via planetary milling and manual grinding with a mortar and pestle is reported. This solventless protocol, which proceeds via a ligand displacement from [Rh(acac)(CO)2], was successfully applied to various NHC·HCl salts (NHC = IPr, SIPr, IMes, SIMes, IPr*), neat phosphines (PPh3 and PCy3), and the PtBu3·HBF4 salt. This method offers rapid access, using readily available tools, to the electronic characterization of ligands in organometallic chemistry.

We report a gold-mediated energy transfer strategy for the sequential double [2 + 2] photocycloaddition of coumarins with dienes, providing access to polymethylene-linked bis(cyclobutane-fused chromanones). The reaction proceeds under mild conditions and affords structurally complex products in moderate to good yields. Optimization studies, control experiments, triplet-energy analysis, and DFT calculations support a triplet energy transfer pathway involving diradical intermediates.

High‐throughput experimentation (HTE) was employed to optimize the Suzuki–Miyaura coupling of electronically challenging substrates using a series of N‐heterocyclic carbene–palladium precatalysts. The screening of 768 conditions revealed that sulfide‐based and PEPPSI‐type Pd‐NHC complexes showed highest activity, with cesium carbonate identified as the most effective base. Further optimization showed that careful adjustment of base and boronic acid loading was essential to minimize side‐product formation, while the addition of water accelerated the process and enabled efficient catalysis at 1 mol % Pd loading. The resulting conditions delivered >98% yield within 1 h, demonstrating how the integration of HTE and targeted optimization can permit the rapid identification of robust and sustainable protocols for cross‐coupling chemistry.

We report the first uses of a copper carbene-metal-amido complex, [Cu(IPr)(Cbz)] (1), as an efficient photosensitizer for a broad range of triplet-triplet energy transfer (TTEnT) catalytic processes. Mechanistic studies confirm a triplet-triplet energy-transfer pathway. These findings establish 1 as the first copper-based photosensitizer competent in intermolecular [2+2] cycloaddition involving substrates with ET > 62 kcal/mol and hydrogen atom transfer via EnT, offering a cost-effective, sustainable alternative to noble-metal photocatalysts.

The gold-catalyzed addition of phenols, alcohols, and carboxylic acids to 2,2,2-trifluoroethyl-substituted alkynes is reported. The reaction is highly regioselective, once again illustrating the strong directing effect of the trifluoromethyl group in gold-catalyzed additions to alkynes through its inductive influence.

We report the synthesis and catalytic evaluation of hydrogen‐bond‐stabilized palladium–N‐heterocyclic carbene (NHC) fluoroalkoxide adducts of the type [Pd(NHC)(acac)Cl]·(HFIP), (HFIP = 1,1,1,3,3,3‐hexafluoroisopropanol). These air‐stable complexes were readily obtained under ambient conditions and fully characterized, including by single‐crystal X‐ray diffraction analysis. Their catalytic performance was investigated in the α‐arylation of ketones. The HFIP‐stabilized adducts displayed significantly enhanced catalytic activity compared with the corresponding non‐HFIP containing analogs. Mechanistic investigations indicated that this effect originates from an alternative activation pathway that leads to the formation of the catalytically active [(NHC)Pd(0)] species. Furthermore, extensive optimization studies demonstrated that catalyst loadings as low as 1 ppm are sufficient to achieve high conversions under mild reaction conditions.

The utility of molecular organoplatinum complexes in catalytic transformations has long driven major industrial advancements, most notably in the hydrosilylation reaction, a process that is critical to the global, multibillion-dollar silicones industry. One of the most important breakthroughs in this field was the introduction of platinum- N -heterocyclic carbene (NHC) pre-catalysts. Apart from their significance in hydrosilylation processes, these unique complexes have also contributed to developments in other research areas, including cancer therapy and photophysics. This two-part review highlights the evolving role of platinum in homogeneous catalysis, with an emphasis on NHC complexes, providing both historical context and the latest findings. Part I introduces platinum-NHC complexes, covering their synthetic accessibility, properties and role in homogeneous catalysis, along with other notable applications. Part II () will discuss the fundamentals and recent developments in the catalytic hydrosilylation of alkenes and alkynes, centred around platinum-NHC pre-catalysts.

Olefin metathesis has become a cornerstone in modern synthetic chemistry, enabling diverse applications across organic synthesis, polymer science, and industrial processes. Despite its transformative impact, significant challenges persist, including catalyst stability, functional group tolerance, selectivity, and scalability. Ruthenium-based catalysts dominate the field, yet their sensitivity to oxygen, moisture, and harsh conditions limits industrial applicability. Functional group incompatibility and the difficulty in achieving precise product selectivity further hinder its versatility, particularly in cross-metathesis (CM) and ring-closing metathesis (RCM). Advances in catalyst recycling, green chemistry practices, and alternative systems using earth-abundant metals like iron are promising but remain underdeveloped. Expanding substrate scope, improving mechanistic understanding, and integrating metathesis with other catalytic processes offer opportunities for innovation. Addressing these issues through predictive catalysis, novel ligand design, and artificial intelligence-driven insights will enhance the sustainability and efficiency of metathesis, cementing its role as a pivotal reaction in future chemical synthesis.

We present a comprehensive overview of the Buchwald-Hartwig amination, one of the most useful methods for C-N bond formation, mediated by NHC-transition-metal-complexes, covering the literature since 1999 (the first report on Buchwald-Hartwig amination by Nolan et al.) through December 2024. Palladium- and nickel-N-heterocyclic carbene (NHC) complexes are key contributors to Buchwald-Hartwig amination and are thoroughly discussed in this review, along with examples of cobalt and rhodium-NHC complexes. Apart from the conventional aryl/alkyl amines and aryl halides coupling, participation of versatile and challenging functional groups like pseudohalides, amides, ester, sulfoxides, unactivated aryl sulfamates, carbamates, pivalates, as well as novel electrophiles, such as aryl fluorides, methyl ethers, and silyloxyarenes, are also presented. The Reader is provided with an overview of the key role of metal-NHC complexes, their crucial role in constructing carbon-nitrogen bonds, and their importance in medicinal and materials chemistries as well as in drug discovery.

This study explores a novel N-heterocyclic carbene-mediated siloxane exchange mechanism, laying the foundation for designing covalent adaptable networks (CANs) with high temperature stability (>200 °C) for dynamic covalent chemistry. Small molecule siloxane compounds, obtained by hydrosilylation reactions, are used to demonstrate siloxane-exchange via a mechanism supported by density functional theory. The proposed mechanism presents an equilibrium, at elevated temperatures, between an imidazolium salt and its free carbene form, which is the catalytically active species. Following this mechanistic insight, a tetra-substituted ester-terminated siloxane cross-linker was synthesized and cured with a commercial amine hardener. The ensuing ester-amine reaction yields thermally stable, non-dynamic amide bonds, thereby enhancing material stability. The resulting CANs exhibit rapid stress relaxation at elevated temperatures and demonstrate successful recycling through compression molding without any significant loss of material properties. Remarkably, the synthesized material showcases high creep resistance, even up to 150 °C, indicating the benefits of having a thermally reversible catalyst system for siloxane activation. This ground-up design of dynamic chemistry and material synthesis not only presents innovative material design but also suggests avenues for exploring thermally stable, fast-exchanging and yet creep-resistant CANs.