N-heterocyclic Carbene Precursors Research Articles

4-Halomethyl-Substituted Imidazolium Salts: A Versatile Platform for the Synthesis of Functionalized NHC Precursors.

N,N'-Diarylimidazolium salts containing haloalkyl functional groups that are reactive with various nucleophiles are considered to be promising reagents for the preparation of functionalized N-heterocyclic carbene (NHC) ligands, which are in demand in catalysis, materials science, and biomedical research. Recently, 4-chloromethyl-functionalized N,N'-diarylimidazolium salts became readily available via the condensation of N,N'-diaryl-2-methyl-1,4-diaza-1,3-butadienes with ethyl orthoformate and Me3SiCl, but these compounds were found to have insufficient reactivity in reactions with many nucleophiles. These chloromethyl salts were studied as precursors in the synthesis of bromo- and iodomethyl-functionalized imidazolium salts by halide anion exchange. The 4-ICH2-functionalized products were found to be unstable, whereas a series of novel 4-bromomethyl functionalized N,N'-diarylimidazolium salts were obtained in good yields. These bromomethyl-functionalized imidazolium salts were found to be significantly more reactive towards various N, O and S nucleophiles than the chloromethyl counterparts and enabled the preparation of previously inaccessible heteroatom-functionalized imidazolium salts, some of which were successfully used as NHC proligands in the preparation of Pd/NHC and Au/NHC complexes.

Recent advances in the synthesis of highly substituted imidazolidines.

Imidazolidine is a saturated heterocycle with a cyclic aminal core that can be found in natural products and biologically active molecules. Additionally, these heterocyclic compounds have been utilized as chiral ligands, N-heterocyclic carbene precursors, and catalysts in organic synthesis. This review is an attempt to compile the literature of various synthetic procedures of highly substituted imidazolidines, chiral imidazolidines with high diastereoselectivities and enantioselectivities, bis-imidazolidines, and spiro-imidazolidines, as well as their pharmacological properties during the period from 1949 to 2023.

Novel nonsymmetrically benzimidazolium salts and their silver(I)-N-heterocyclic carbene complexes: Synthesis, DFT study and Anticancer activities

A series of unsymmetrically substituted N-heterocyclic carbene (NHC) precursors were synthesized from the action of 5,6-dimethylbenzimidazole or benzimidazole with various alkyl halides in DMF at 80 °C for 72 h . These compounds were used to synthesize NHC–silver(I) complexes (3) by reacting these NHC precursors with Ag2O in DMC.The prepared compounds were structurally verified by several spectroscopic techniques including 1H NMR, 13C NMR, FT-IR, LC-MS, and C, H, N analysis. The structures of the NHC precursors and their corresponding silver(I) complexes were also investigated theoretically using density functional theory (DFT) at the BLYP/TZ2P level to optimize geometries and assess electronic properties via Voronoi Deformation Density (VDD) charge analysis. Additionally, the newly synthesized ligands and silver(I) complexes were evaluated for their in vitro anticancer activity against three human cancer cell lines including hepatocellular carcinoma (HePG2), lung adenocarcinoma (A549) and breast adenocarcinoma (MCF7). Most of the newly synthesized silver(I) complexes exhibited better activity than the ligands, and the results have been compared with Cisplatin as a reference drug.

Mechanochemical Synthesis of Corannulene Flanked N-heterocyclic Carbene (NHC) Precursors and Preparation of Their Metal Complexes.

The synthesis of new compounds is an important pillar for the advancement of the field of chemistry and adjacent fields. In this regard, over the last decades huge efforts have been made to not only develop new molecular entities but also more efficient sustainable synthetic methodologies due to the increasing concerns over environmental sustainability. In this context, we have developed synthetic routes to novel corannulene flanked imidazolium bromide NHC precursors both in the solid-state and solution phases. Our work presents a comprehensive comparative study of mechanochemical routes and conventional solution-based methods. Green metrics and energy consumption comparison were performed for both routes revealing ball-milling generation of these compounds to be an environmentally greener technique to produce such precursors compared to conventional solvent-based methods. In addition, we have demonstrated proof-of-concept of the herein reported corannulene flanked NHCs to be robust ligands for transition metals and their ligand substitution reactions.

Exploiting the Reversible Dimerization of N-Heterocyclic Carbenes to Access Dynamic Polymer Networks with an Organocatalytic Activity.

The capability of some N-heterocyclic carbenes (NHCs) to reversibly dimerize is exploited to access dynamic polymer networks. Benzimidazolium motifs serving as NHC precursors have thus been supported onto copolymer chains by reversible addition-fragmentation chain transfer (RAFT) copolymerization of styrene and up to 20 mol % of 4-vinylbenzyl-ethyl-benzimidazolium chloride. Molecular versions of 1,3-dialkyl benzimidazolium salts have been synthesized as models, the deprotonation of which with a strong base yields the NHC dimers in the form of tetraaminoalkenes. The crossover reaction between two distinct NHC homodimers, forming heterodimers, is then evidenced. Applying this deprotonation method to the RAFT-derived copolymers leads to polymer networks with cross-links consisting of labile dimerized NHC motifs. These networks can be subsequently decross-linked using two distinct triggers, namely, a monofunctional NHC precursor as competitor and carbon dioxide (CO2). In the latter case, regeneration of the network occurs by chemically fueling the linear copolymer bearing benzimidazolium motifs with tBuOK in the presence of trace amounts of water. The same networks can also be used as latent precursors of transient polyNHCs to catalyze the benzoin condensation upon heating. The polymer-supported organocatalysts can thus be used in successive catalytic cycles.

Synthesis and Systematic Investigation of Lepidiline A and Its Gold(I), Silver(I), and Copper(I) Complexes Using In Vitro Cancer Models and Multipotent Stem Cells.

The imidazole alkaloid lepidiline A from the root of Lepidium meyenii has a moderate to low in vitro anticancer effect. Our aim was to extend cytotoxicity investigations against a panel of cancer cells, including multidrug-resistant cancer cells, and multipotent stem cells. Lepidiline A is a N-heterocyclic carbene precursor, therefore a suitable ligand source for metal complexes. Thus, we synthesized lepidiline A and its copper(I), gold(I), and silver(I) complexes and tested them against ovarian, gastrointestinal, breast, and uterine cancer cells and bone marrow-derived and adipose-derived mesenchymal stem cells. Lepidiline A and its copper complex demonstrated moderate cytotoxicity, while silver and gold complexes exhibited significantly enhanced and consistent cytotoxicity against both cancer and stem cell lines. ABCB1 in the multidrug-resistant uterine sarcoma line conferred significant resistance against lepidiline A and the copper-lepidiline A complex, but not against the silver and gold complexes. Our results indicate that only the copper complex induced a significant and universal increase in the production of reactive oxygen species within cells. In summary, binding of metal ions to lepidiline A results in enhanced cytotoxicity with the nature of the metal ion playing a critical role in determining its properties.

Synthesis and Medicinal Applications of N-Heterocyclic Carbene Complexes Based on Caffeine and Other Xanthines.

Xanthines are purine derivatives predominantly found in plants. These include compounds such as caffeine, theophylline, and theobromine and exhibit a variety of pharmacological properties, demonstrating efficacy in treating neurodegenerative disorders, respiratory dysfunctions, and also cancer. The versatile attributes of these materials render them privileged scaffolds for the development of compounds for various biological applications. Xanthines are N-heterocyclic carbene precursors that combine a pyrimidine and an imidazole ring. Owing to their biological relevance, xanthines have been employed as N-heterocyclic carbenes in the development of metallodrugs for anticancer and antimicrobial purposes. In this conceptual review, we examine key examples of N-heterocyclic carbene complexes derived from caffeine and other xanthines, elucidating their synthetic methods and describing their pertinent medicinal applications.

Synthesis of 4-amino-1,3-diarylimidazolium chlorides

The first representatives of 4-amino-1,3-diarylimidazolium chlorides have been synthesized by heating chloroacetonitrile with N,Nʹ-diarylformamidines containing alkyl substituents at positions 2 and 6 of the N-aryl groups. The possibility of postfunctionalization of the obtained aminoimidazolium salts by acylation of the amino group was demonstrated, as well as their applicability as precursors of N-heterocyclic carbenes in the synthesis of Cu/NHC complexes after preliminary protection of the amino group.

A 12-Vertex Metallacarborane of Silver(I).

The discovery of ferrocene in 1951 was a significant landmark in the field of organometallic chemistry, and since then, numerous sandwich- or half-sandwich metallic complexes have been reported. However, silver stands as an intriguing exception in this regard, and knowledge of its bonding situation has remained undisclosed. Herein, unprecedented 12-vertex metallacarboranes of Ag(I) (2a and 2b) were synthesized through the reaction of sodium hexamethyldisilazide (NaHMDS) with the mixture of nido-C2B9 carborane anion-supported N-heterocyclic carbene precursors (1a and 1b) and [Ag(PPh3)Cl]4. The X-ray structural analysis of the resulting metallacarboranes revealed a unique "slipped" half-sandwich structure, which is a rarity among cyclopentadienyl analogues. DFT calculations provided insights into the asymmetric π-interactions between the pentagonal C2B3 face and the silver ion.

Tuning N-heterocyclic carbene wingtips to form electrochemically stable adlayers on metals.

Self-assembled monolayers (SAMs) are employed in electrochemical biosensors to passivate and functionalize electrode surfaces. These monolayers prevent the occurrence of undesired electrochemical reactions and act as scaffolds for coupling bioaffinity reagents. Thiols are the most common adlayer used for this application; however, the thiol-gold bond is susceptible to competitive displacement by naturally occurring solvated thiols in biological fluids, as well as to desorption under continuous voltage interrogation. To overcome these issues, N-heterocyclic carbene (NHC) monolayers have been proposed as an alternative for electrochemical biosensor applications due to the strong carbon-gold bond. To maximize the effectiveness of NHCs for SAMs, a thorough understanding of both the steric effects of wingtip substituents and NHC precursor type to the passivation of electrode surfaces is required. In this study, five different NHC wingtips as well as two kinds of NHC precursors were evaluated. The best performing NHC adlayers can be cycled continuously for four days (over 30 000 voltammetric cycles) without appreciably desorbing from the electrode surface. Benchmark thiol monolayers, in contrast, rapidly desorb after only twelve hours. Investigations also show NHC adlayer formation on other biosensor-relevant electrodes such as platinum and palladium.

Synthesis of imidazole-fused pentacyclic pyrrolo[3,4-c]coumarins via base-promoted rearrangement of coumarin-substituted N-heterocyclic carbene precursors

The stoichiometric reaction between coumarin-substituted N-heterocyclic carbene (NHC) precursors and Pd(OAc)2, in the presence of an external base, yielded imidazole-fused pentacyclic pyrrolo[3,4-c]coumarin derivatives.

Fabrication of azido-PEG-NHC stabilized gold nanoparticles as a functionalizable platform.

Rapid and precise detection of biochemical markers is vital for accurate medical diagnosis. Gold nanoparticles (AuNPs) have emerged as promising candidates for diagnostic sensing due to their biocompatibility and distinctive physical properties. However, AuNPs functionalized with selective targeting vectors often suffer from reduced stability in complex biological environments. To address this, (N)-heterocyclic carbene (NHC) ligands have been investigated for their robust binding affinity to AuNP surfaces, enhancing stability. This study outlines an optimized top-down synthesis route for highly stable, azide-terminal PEGylated NHC (PEG-NHC) functionalized AuNPs. This process employs well-defined oleylamine-protected AuNPs and masked PEGylated NHC precursors. The activation and attachment mechanisms of the masked NHCs were elucidated through the identification of intermediate AuNPs formed during incomplete ligand exchange. The resulting PEG-NHC@AuNPs exhibit exceptional colloidal stability across various biologically relevant media, showing no significant aggregation or ripening over extended periods. These particles demonstrate superior stability compared to those synthesized via a bottom-up approach. Further functionalization of azide-terminal PEG-NHC@AuNPs was achieved through copper-catalyzed click- and bioorthogonal strain-promoted azide-alkyne cycloaddition reactions. The maintained colloidal stability and successful conjugation highlight the potential of azide-functionalized PEG-NHC@AuNPs as a versatile platform for a wide range of biomedical applications.

Synthesis of Six-Membered N-Heterocyclic Carbene Precursors Based on Camphor.

The endo- and exo-N-heterocyclic carbene precursors based on camphor were prepared diastereoselectively in five synthetic steps starting from (1S)-(+)-ketopinic acid. The obtained N-heterocyclic carbene precursors were investigated in an asymmetric benzoin reaction. All new compounds were fully characterized, and the absolute configurations were determined via X-ray diffraction and NOESY measurements.

New sugar-incorporated N-heterocyclic carbene precursors and their Ag(I) and Pd(II) complexes: Synthesis, characterization, and cytotoxicity studies

In the present work, a new series of sugar-incorporated N-heterocyclic carbene precursors namely 1-(3,4,5-trimethoxybenzyl)-3-[2-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-ethyl]imidazolium bromide (7a), 4-methyl-1-(3,4,5-trimethoxybenzyl)-3-[2-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-ethyl]imidazolium bromide (7b), 4,5-diphenyl-1-(3,4,5-trimethoxybenzyl)-3-[2-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-ethyl]imidazolium bromide (7c), and 1-(3,4,5-trimethoxybenzyl)-3-[2-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-ethyl]benzimidazolium bromide (8) were synthesized by the direct reaction of the N-alkylated benzimidazoles with 2-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-ethyl bromide. Ag(I)–NHC complexes (9a-c, 10) of the abovementioned precursors were synthesized by in-situ reaction with Ag2O in light-excluded conditions. The transmetallation reaction technique was used to synthesize Pd(II)–NHC complexes (11a-c, 12) by the reaction of [PdCl2(MeCN)2] with corresponding Ag(I)–NHC complexes. All NHC precursors and their corresponding Ag(I) and Pd(II) complexes were spectrally characterized using 1H &13C NMR, and mass spectrometry. Further, Pd(II) complexes were evaluated for their anticancer activity against eight diverse cancer cell lines, namely; Pancreatic Adenocarcinoma (Capan-1), Colorectal Carcinoma (HCT-116), Glioblastoma (LN229), Lung Carcinoma (NCI-H1975), Acute Lymphoblastic Leukemia (DND-41), Acute Myeloid Leukemia (HL-60), Chronic Myeloid Leukemia (K562), and non-Hodgkin Lymphoma (Z138). Standard antineoplastic drugs docetaxel and etoposide were included as reference compounds. Among the tested complexes, complex 11c displayed broad activity against all tested cancer types, albeit at higher concentrations when compared to the reference drugs.

Interaction analysis of a new NHC precursor and its Ag-NHC complex with bovine serum albumin by spectrophotometric and molecular docking methods

Potential bioactive molecules must reach the target tissue safely and serum albumin, which is a well-known major component in human blood, is an efficient transporter. Therefore, the interactions of possible bioactive species with serum albumin must be determined. In the current study, an N-heterocyclic carbene precursor and its silver complex were synthesized, characterized, and analyzed for interactions with bovine serum albumin. Stern-Volmer constant was recorded as 4.50 × 105 for Ag-NHC with a 1.255 binding number at 298 K. Also, the molecules have spontaneously interacted with bovine serum albumin with a negative ΔG value (−32.93 kJ mol−1) for the complex at 298 K. Additionally, the effects of Ca2+, Mg2+, and Zn2+ on binding properties were evaluated by fluorescence spectroscopy. The binding constant of the complex was recorded as 6.76 × 103 in the presence of Zn2+ and 5.93 × 105 without the metals. The molecules were optimized by DFT-based calculations and the details of the bindings were investigated by molecular docking methods. Ag-NHC has interacted with the IIA subdomain region of bovine serum albumin with −8.46 kcal/mol.

Surface Modification of ITO with N-Heterocyclic Carbene Precursors Results in Electron Selective Contacts in Organic Photovoltaic Devices.

Surface modification of indium tin oxide (ITO) electrodes with organic molecules is known to tune their work function which results in higher charge carrier selectivity in corresponding organic electronic devices and hence influences the performance of organic solar cells. In recent years, N-heterocyclic carbenes (NHCs) have also been proven to be capable to modify the work function of metals and semimetals compared to the unfunctionalized surface via the formation of strong covalent bonds. In this report, we have designed and performed the modification of the ITO surface with NHC by using the zwitterionic bench stable IPr-CO2 as the NHC precursor, applied via spin coating. Upon modification, the work function of ITO electrodes was reduced significantly which resulted in electron selective contacts in corresponding organic photovoltaic devices. In addition, various characterization techniques and analytical methods are used to elucidate the nature of the bound species and the corresponding binding mechanism of the material to the ITO surface.

Cu−NHC Complex for Chan‐Evans‐Lam Cross‐Coupling Reactions of N‐Heterocyclic Compounds and Arylboronic Acids

AbstractAn efficient copper(II) N‐heterocyclic carbene (NHC) complex with an NCN coordination mode was optimized to catalyze the Chan–Evans‐Lam (CEL) cross‐coupling reaction of imidazole and other N‐heterocyclic nucleophiles with arylboronic acid. This air‐stable copper catalyst shows robust catalytic performance and tolerates a diverse array of functional groups on both the N‐nucleophile and arylboronic acid coupling partners in C−N bond forming reactions with up to 95 % yield. Formation of the Cu−NHC complex in situ generated similar catalytic performance for CEL coupling. Alternative metal ions (Mn2+, Fe2+, Co2+, Ni2+, Zn2+, Ru2+, and Pd2+) were also screened in the presence of the NHC precursor as CEL catalysts.

Cu(I)–N-heterocyclic carbene complexes bearing a naphthyl substituent: synthesis, characterization, and antimicrobial activities

A series of 1-(alkyl)-3-(1-naphthyl)imidazolinium bromides (2a–d) as N-heterocyclic carbene (NHC) precursors were synthesized from 3-(1-naphthyl)-1H-imidazolinium chloride (1). By reacting these NHC precursors with fresh CuCl, Cu(I)–NHC complexes (3a–d) were synthesized. The structures of the compounds were elucidated using 1H, 13C-NMR, FT-IR, ESI-MS, X-ray diffraction, scanning electron microscopy with energy-dispersive X-ray spectroscopy analysis, and elemental analysis techniques. The thermal properties of selected complexes were determined. Salts (1, 2a–d) and Cu(I)–NHC complexes (3a–d) were investigated against test microorganisms to determine their antimicrobial potency. The imidazolinium salts 2b and 2d displayed remarkable antibacterial efficacy, particularly against gram-positive bacteria; however, the corresponding Cu(I)–NHC derivatives (3a–d) did not exhibit a similar level of potency probably due to limited solubility. Overall, it can be concluded that incorporation of N-substituent species with O-heteroatoms, instead of benzyl, allyl, or hexyl groups on NHC, can enhance the activity against microbial derivatives.

Synthesis of Tetrahydrobenzo[b]pyrans Catalyzed by 1,3-Dibenzyl-1H-benzo[d] imidazole-3-ium Chloride

Abstract: Tetrahydrobenzo[b]pyrans are fused oxygen-containing heterocycles that are found in many biologically active compounds. Therefore, researchers in organic synthesis are searching for suitable, efficient, and useful methods for their synthesis. In this contribution, a series of tetrahydrobenzo[b]pyran derivatives was synthesized using aryl aldehydes, malononitrile, and cyclohexane-1,3-dione or dimedone as the available starting materials. The three-component reactions were catalyzed by 1,3-dibenzyl-1H-benzo[d]imidazol-3-ium chloride as the N-heterocyclic carbene precursor. The heterocyclic oxygen-containing products were obtained in good to excellent isolated yields within relatively shorter reaction times. Optimizing the reaction conditions was performed from the point of view of various parameters of the reaction. The results of these experiments showed that the best solvent system includes water-ethanol, the most suitable reaction temperature is 60ºC, and the optimal amount of the imidazolium catalyst loading is 5 mol%. Operational simplicity, no need for chromatographic methods for purification, simple work-up for pure products, and avoiding hazardous solvents are remarkable features of this three-component reaction. Moreover, in these multicomponent cyclo-condensations, no by-products were observed.

Hydrodehalogenation of aryl halides by the mixture of palladium(II) and a newly synthesized chiral macrocyclic bis(N-heterocyclic carbene) ligand

A novel macrocyclic bis(N-heterocyclic carbene) precursor was designed and prepared, which manifested high catalytic efficiency when combining Pd(OAc)2 in hydrodehalogenation of aryl halides. The generation of a little amount of the intermediate product chlorobenzene is closely related with the synergistic effect of two imidazoline protons lying on the two opposite sides of the macrocycle.