Synthesis of Imidazolium Cations Linked to Para-t-Butylcalix[4]arene Frameworks and Their Use as Synthons for Nickel-NHC Complexes Tethered to Calix[4]arenes.

A series of cationic p-tert-butylcalix[4]arenes, with side-arms that are functionalized with imidazolium groups, have been synthesized in good yields. The parent tetrahydroxy para-t-butyl-calix[4]arene was dialkylated at the phenolic hydrogen atoms using α,ω-dibromo-alkanes to yield bis(mono-brominated) alkoxy-chains of variable length. The brominated side-arms in these compounds were then further alkylated with substituted imidazoles (N-methylimidazole, N-(2,4,6-trimethyl-phenyl)imidazole, or N-(2,6-di-isopropylphenyl)imidazole) to yield a series of dicationic calixarenes with two imidazolium groups tethered, via different numbers of methylene spacers (n = 2-4), to the calixarene moiety. Related tetracationic compounds, which contain four imidazolium units linked to the calix[4]arene backbone, were also prepared. In all of these compounds, the NMR data show that the calixarenes adopted a cone configuration. All molecules were characterized by NMR spectroscopy and by MS studies. Single crystal X-ray diffraction studies were attempted on many mono-crystals of these cations, but significant disorder problems, partly caused by occluded solvent in the lattice, and lack of crystallinity resulting from partial solvent loss, precluded the good resolution of most X-ray structures. Eventually, good structural data were obtained from an unusually disordered single crystal of 5a, (1,3)-Cone-5,11,17,23-tetra-t-butyl-25,27-di-hydroxy-26,28-di-[2-(N-2,6-diisopropylphenyl-imidazolium)ethoxy]calix[4]arene dibromide and its presumed structure was confirmed. The structure revealed the presence of H-bonded interactions and some evidence of π-stacking. Some of these imidazolium salts were reacted with nickelocene to form the nickel N-heterocyclic carbene (NHC) complexes 7a-7d. A bis-carbene nickel complex 8 was also isolated and its structure was established by single crystal X-ray diffraction studies. The structure was disordered and not of high quality, but the structural data corroborated the spectroscopic data.

Nickel-Imidazolium Low Transition Temperature Mixtures with Lewis-Acidic Character.

Low transition temperature mixtures (LTTMs) are a new generation of solvents that have found extensive application in organic synthesis. The interactions between the components often generate highly activated, catalytically active species, thus opening the possibility of using LTTMs as catalysts, rather than solvents. In this work, we introduce a nickel-based imidazolium LTTM, study its thermal behavior and explore its catalytic activity in the solvent-free allylation of heterocycles with allylic alcohols. This system is effective in this reaction, affording the corresponding products in excellent yield without the need for additional purifications, thus resulting in a very environmentally friendly protocol.

Synthesis and antitumor activity of novel hybrid compounds between 1,4-benzodioxane and imidazolium salts.

A series of novel hybrid compounds between 1,4-benzodioxane and imidazolium salts was designed and prepared. The compounds were evaluated in vitro against a panel of human tumor cell lines (K562, SMMC-7721, and A-549). The structure-activity relationship results demonstrated that the 2-methyl-benzimidazole or 5,6-dimethyl-benzimidazole ring and substitution of the imidazolyl-3-position with a 4-phenylphenacyl substituent were critical for promoting cytotoxic activity. Particularly, compound 25 was found to be the most potent compound with IC50 values of 1.06-8.31 µM against the three human tumor cell lines and exhibited higher selectivity to K562 and SMMC-7721 cells with IC50 values 4.5- and 4.7-fold lower than cisplatin. Moreover, compound 25 inhibited cell proliferation by inducing the G0/G1 cell cycle arrest and apoptosis in SMMC-7721 cells.

Phthalimide-tethered imidazolium salts: Synthesis, characterization, enzyme inhibitory properties, and in silico studies.

A series of new imidazolium salts were prepared in good yield by the reaction between 1-alkylimidazole and a variety of alkyl halides. The structures of the compounds were identified by FT-IR, 1 H NMR, and 13 C NMR spectroscopy, elemental analysis, and mass spectrometry. The crystal structure of 1b was determined by the single-crystal X-ray diffraction method. The phthalimide-tethered imidazolium salts exhibited inhibition abilities toward acetylcholinesterase (AChE) and human carbonic anhydrases (hCAs) I and II, with Ki values in the range of 24.63 ± 3.45 to 305.51 ± 35.98 nM for AChE, 33.56 ± 3.71 to 218.01 ± 25.21 nM for hCA I and 17.75 ± 0.96 to 308.67 ± 13.73 nM for hCA II. The results showed that the new imidazolium salts can play a key role in the treatment of Alzheimer's disease, epilepsy, glaucoma, and leukemia, which is related to their inhibition abilities of hCA I, hCA II, and AChE. Molecular docking and in silico absorption, distribution, metabolism, excretion and toxicity studies were used to look into how the imidazolium salts interacted with the specific protein targets. To better visualize and understand the binding positions and the influence of the imidazolium salts on hCA I, hCA II, and AChE conformations, each one was subjected to molecular docking simulations.

Establishment of In Vitro and In Vivo Anticolorectal Cancer Efficacy of Lithocholic Acid-Based Imidazolium Salts.

Imidazolium salts (IMSs) are the subject of many studies showing their anticancer activities. In this research, a series of novel imidazolium salts substituted with lithocholic acid (LCA) and alkyl chains of various lengths (S1-S10) were evaluated against colon cancer cells. A significant reduction in the viability and metabolic activity was obtained in vitro for DLD-1 and HT-29 cell lines when treated with tested salts. The results showed that the activities of tested agents are directly related to the alkyl chain length, where S6-S8 compounds were the most cytotoxic against the DLD-1 line and S4-S10 against HT-29. The research performed on the xenograft model of mice demonstrated a lower tendency of tumor growth in the group receiving compound S6, compared with the group receiving 5-fluorouracil (5-FU). Obtained results indicate the activity of S6 in the induction of apoptosis and necrosis in induced colorectal cancer. LCA-based imidazolium salts may be candidates for chemotherapeutic agents against colorectal cancer.

Fluorinated Analogues of Lepidilines A and C: Synthesis and Screening of Their Anticancer and Antiviral Activity.

Starting with fluorinated benzylamines, a series of 2-unsubstituted imidazole N-oxides was prepared and subsequently deoxygenated in order to prepare the corresponding imidazoles. The latter were treated with benzyl halides yielding imidazolium salts, which are considered fluorinated analogues of naturally occurring imidazolium alkaloids known as lepidilines A and C. A second series of oxa-lepidiline analogues was obtained by O-benzylation of the initially synthetized imidazole N-oxides. Both series of imidazolium salts were tested as anticancer and antiviral agents. The obtained results demonstrated that the introduction of a fluorine atom, fluoroalkyl or fluoroalkoxy substituents (F, CF3 or OCF3) amplifies cytotoxic properties, whereas the cytotoxicity of some fluorinated lepidilines is promising in the context of drug discovery. All studied compounds revealed a lack of antiviral activity against the investigated viruses in the nontoxic concentrations.

One-Step Access to Heteroatom-Functionalized Imidazol(in)ium Salts.

Imidazolium salts have ubiquitous applications in energy research, catalysis, materials and medicinal sciences. Here, we report a new strategy for the synthesis of diverse heteroatom-functionalized imidazolium and imidazolinium salts from easily available 1,4-diaza-1,3-butadienes in one step. The strategy relies on a discovered family of unprecedented nucleophilic addition/cyclization reactions with trialkyl orthoformates and heteroatomic nucleophiles. To probe general areas of application, synthesized N-heterocyclic carbene (NHC) precursors were feasible for direct metallation to give functionalized M/carbene complexes (M=Pd, Ni, Cu, Ag, Au), which were isolated in individual form. The utility of the chloromethyl function for the postmodification of the synthesized salts and Pd/carbene complexes was demonstrated. The obtained complexes and imidazolium salts demonstrated good activities in Pd- or Ni-catalyzed model cross-coupling and C-H activation reactions.

Tetrakis(pentafluoroethyl)gallate, [Ga(C2 F5 )4 ]- , Ionic Liquids.

We synthesized new imidazolium-based tunable aryl alkyl ionic liquids (TAAILs) with the weakly coordinating tetrakis(pentafluoroethyl)gallate anion, [Ga(C2 F5 )4 ]- . Phenyl and phenyl derivatives (2-Me, 4-OMe, 2,4-F) were combined with varying alkyl chain lengths at the imidazolium core leading to TAAILs, which were investigated with regard to their viscosity, conductivity, and electrochemical window and compared to EMIM and BMIM standard cations. Remarkable low viscosities of 29 cP at 25 °C for [BMIM][Ga(C2 F5 )4 ] were achieved. However, the EMIM and BMIM gallates show electrochemical instability, releasing pentafluoroethane at a voltage of 1.5 V. The 2-Me-substituted gallate-TAAILs slowly decompose over several weeks, whereas all other gallate-TAAILs showed no decomposition at all. With electrochemical windows of up to 5.15 V and low viscosities in a range of 66-162 cP, the gallate-TAAILs are promising candidates as electrolytes in electrochemical applications.

Steroid-Functionalized Imidazolium Salts with an Extended Spectrum of Antifungal and Antibacterial Activity.

It is established that high rates of morbidity and mortality caused by fungal infections are related to the current limited number of antifungal drugs and the toxicity of these agents. Imidazolium salts as azole derivatives can be successfully used in the treatment of fungal infections in humans. Steroid-functionalized imidazolium salts were synthesized using a new, more efficient method. As a result, 20 salts were obtained with high yields, 12 of which were synthesized and characterized for the first time. They were derivatives of lithocholic acid and 3-oxo-23,24-dinorchol-4-ene-22-al and were fully characterized by 1H and 13C nuclear magnetic resonance (NMR), infrared spectroscopy (IR), and high resolution mass spectrometry (HRMS). Due to the excellent activity against bacteria and Candida albicans, new research was extended to include tests on five species of pathogenic fungi and molds: Aspergillus niger ATCC 16888, Aspergillus fumigatus ATCC 204305, Trichophyton mentagrophytes ATCC 9533, Cryptococcus neoformans ATCC 14116, and Microsporum canis ATCC 11621. The results showed that the new salts are almost universal antifungal agents and have a broad spectrum of activity against other human pathogens. To initially assess the safety of the synthesized salts, hemocompatibility with host cells and cytotoxicity were also examined. No toxicity was observed at the concentration at which the compounds were active against pathogens.

Chiral Imidazolium Prolinate Salts as Efficient Synzymatic Organocatalysts for the Asymmetric Aldol Reaction.

Chiral imidazolium l-prolinate salts, providing a complex network of supramolecular interaction in a chiral environment, have been studied as synzymatic catalytic systems. They are demonstrated to be green and efficient chiral organocatalysts for direct asymmetric aldol reactions at room temperature. The corresponding aldol products were obtained with moderate to good enantioselectivities. The influence of the presence of chirality in both the imidazolium cation and the prolinate anion on the transfer of chirality from the organocatalyst to the aldol product has been studied. Moreover, interesting match/mismatch situations have been observed regarding configuration of chirality of the two components through the analysis of results for organocatalysts derived from both enantiomers of prolinate (R/S) and the trans/cis isomers for the chiral fragment of the cation. This is associated with differences in the corresponding reaction rates but also to the different tendencies for the formation of aggregates, as evidenced by nonlinear effects studies (NLE). Excellent activities, selectivities, and enantioselectivities could be achieved by an appropriate selection of the structural elements at the cation and anion.

Synthesis and biological activity of new bisbenzofuran-imidazolium salts.

A series of novel bisbenzofuran-imidazolium salts were designed and prepared. The in vitro antitumor activity of these derivatives was evaluated against a panel of human tumor cell lines (A549, HL-60, MCF-7, SMMC-7721 and SW480). Results demonstrated that 2-methyl-benzimidazole ring and substitution of the imidazolyl-3-position with a 4-methoxyphenacyl or 2-naphthylacyl substituent were important for promoting cytotoxic activity. Notably, compound 23 was found to be the most potent compound with IC50 values of 0.64-1.47 µM against five human tumor cell lines, and exhibited higher selectivity to MCF-7 and SW-480 cell lines with IC50 values 15.3-fold and 9.1-fold lower than DDP.

Synthesis and biological evaluation of novel 3-benzylcoumarin-imidazolium salts.

A series of novel 3-benzylcoumarin-imidazolium salts were prepared and evaluated in vitro against a panel of human tumor cell lines. The results showed that the existence of 5,6-dimethyl-benzimidazole ring and substitution of the imidazolyl-3-position with a naphthylacyl group were vital for modulating cytotoxic activity. Notably, compound 38 was found to be the most potent derivative with IC50 values of 2.04-4.51 µM against five human tumor cell lines, while compound 34 were more selective to SW-480 cell lines with IC50 value 40.0-fold lower than DDP. Mechanism of action studies indicated that compound 38 can cause the G0/G1 phase cell cycle arrest and apoptosis in SMMC-7721 cell lines.

Inhibition of bacterial growth and galactosyltransferase activity of WbwC by α, ω-bis(3-alkyl-1H-imidazolium)alkane salts: Effect of varying carbon content.

A series of compounds was designed and synthesized having two imidazolium rings separated by a polymethylene spacer and having alkyl substituents on each of the imidazolium rings. The compounds were assayed for their effects on the activity of galactosyltransferase WbwC, and also on the growth of Gram-negative and Gram-positive bacteria, as well as human cells. The inhibition observed on enzyme activities and cell growth was dependent on the total number of carbons in the spacer and the alkyl substituents on the imidazolium rings. These readily synthesized, achiral compounds have potential as antimicrobial and antiseptic agents.

Chiral Ionic Liquids: Structural Diversity, Properties and Applications in Selected Separation Techniques.

Ionic liquids (ILs) are chemical compounds composed of ions with melting points below 100 °C exhibiting a design feature. ILs are commonly used as the so-called green solvents, reagents or highly efficient catalysts in varied chemical processes. The huge application potential of ionic liquids (IL) justifies the growing interest in these compounds. In the last decade, increasing attention has been devoted to the development of new methods in the synthesis of stable chiral ionic liquids (CILs) and their application in various separation techniques. The beginnings of the successful use of CILs to separate enantiomers date back to the 1990 s. Most chiral ILs are based on chiral cations or chiral anions. There is also a limited number of CILs possessing both a chiral cation and a chiral anion. Due to the high molecular diversity of both ions, of which at least one has a chiral center, we have the possibility to design a large variety of optically active structures, thus expanding the range of CIL applications. Research utilizing chiral ionic liquids only recently has become more popular. However, it is the area that still has great potential for future development. This review aimed to describe the diversity of structures, properties and examples of applications of chiral ionic liquids as new chiral solid materials and chiral components of the anisotropic environment, providing chiral recognition of enantiomeric analytes, which is useful in liquid chromatography, countercurrent chromatography and other various CIL-based extraction techniques including aqueous biphasic (ABS) extraction systems, solid-liquid two-phase systems, liquid-liquid extraction systems with hydrophilic CILs, liquid-liquid extraction systems with hydrophobic CILs, solid-phase extraction and induced-precipitation techniques developed in the recent years. The growing demand for pure enantiomers in the pharmaceutical and food industries sparks further development in the field of extraction and separation systems modified with CILs highlighting them as affordable and environmentally friendly both chiral selectors and solvents.

Tailored Palladate Tunable Aryl Alkyl Ionic Liquids (TAAILs).

We present a new class of tunable aryl alkyl ionic liquids (TAAILs) containing different palladate counter ions. Solid-state structures for representative compounds have been obtained. Their properties are presented in comparison to those of newly synthesized and reported palladate ionic liquids with conventional counter ions. It was found that the aryl substitution pattern and the type of anion have a profound influence on the melting point. The speciation of the different anions in solution has been rationalized by DFT calculations.

Synthesis and selected transformations of 2-unsubstituted 1-(adamantyloxy)imidazole 3-oxides: straightforward access to non-symmetric 1,3-dialkoxyimidazolium salts.

Adamantyloxyamine reacts with formaldehyde to give N-(adamantyloxy)formaldimine as a room-temperature-stable compound that exists in solution in monomeric form. This product was used for reactions with α-hydroxyiminoketones leading to a new class of 2-unsubstituted imidazole 3-oxides bearing the adamantyloxy substituent at N(1). Their reactions with 2,2,4,4-tetramethylcyclobutane-1,3-dithione or with acetic acid anhydride occurred analogously to those of 1-alkylimidazole 3-oxides to give imidazol-2-thiones and imidazol-2-ones, respectively. Treatment of 1-(adamantyloxy)imidazole 3-oxides with Raney-Ni afforded the corresponding imidazole derivatives without cleavage of the N(1)-O bond. Finally, the O-alkylation reactions of the new imidazole N-oxides with 1-bromopentane or 1-bromododecane open access to diversely substituted, non-symmetric 1,3-dialkoxyimidazolium salts. Adamantyloxyamine reacts with glyoxal and formaldehyde in the presence of hydrobromic acid yielding symmetric 1,3-di(adamantyloxy)-1H-imidazolium bromide in good yield. Deprotonation of the latter with triethylamine in the presence of elemental sulfur allows the in situ generation of the corresponding imidazol-2-ylidene, which traps elemental sulfur yielding a 1,3-dihydro-2H-imidazole-2-thione as the final product.

Tetrasubstituted Imidazolium Salts as Potent Antiparasitic Agents against African and American Trypanosomiases.

Imidazolium salts are privileged compounds in organic chemistry, and have valuable biological properties. Recent studies show that symmetric imidazolium salts with bulky moieties can display antiparasitic activity against T. cruzi. After developing a facile methodology for the synthesis of tetrasubstituted imidazolium salts from propargylamines and isocyanides, we screened a small library of these adducts against the causative agents of African and American trypanosomiases. These compounds display nanomolar activity against T. brucei and low (or sub) micromolar activity against T. cruzi, with excellent selectivity indexes and favorable molecular properties, thereby emerging as promising hits for the treatment of Chagas disease and sleeping sickness.

Novel Imidazole Aldoximes with Broad-Spectrum Antimicrobial Potency against Multidrug Resistant Gram-Negative Bacteria.

In the search for a new class of potential antimicrobial agents, five novel N-substituted imidazole 2-aldoximes and their six quaternary salts were evaluated. The antimicrobial activity was assessed against a panel of representative Gram-positive and Gram-negative bacteria, including multidrug resistant bacteria. All compounds demonstrated potent in vitro activity against the tested microorganisms, with MIC values ranging from 6.25 to 50.0 µg/mL. Among the tested compounds, two quaternary compounds (N-but-3-enyl- and meta- (10) or para- N-chlorobenzyl (11) imidazolium 2-aldoximes) displayed the most potent and broad-spectrum activity against both Gram-positive and Gram-negative bacterial strains. The broth microdilution assay was also used to investigate the antiresistance efficacy of the both most active compounds against a set of Enterobacteriaceae isolates carried a multiple extended-spectrum ß-lactamases (ESBLs) in comparison to eight clinically relevant antibiotics. N-but-3-enyl-N-meta-chlorobenzyl imidazolium 2-aldoxime was found to possess promising antiresistance efficacy against a wide range of ß-lactamases producing strains (MIC 2.0 to 16.0 µg/mL). Best results for that compound were obtained against Escherichia coli and Enterobacter cloacae producing multiple ß-lactamases form A and C molecular classes, which were 32- and 128-fold more potent than ceftazidime and cefotaxime, respectively. To visualize the results, principal component analysis was used as an additional classification tool. The mixture of ceftazidime and compound 10 (3 µg:2 µg) showed a strong activity and lower the necessary amount (up to 40-fold) of 10 against five of ESBL-producing isolates (MIC ≤ 1 µg/mL).

Halogen-Bonding-Mediated and Controlled Cationic Polymerization of Isobutyl Vinyl Ether: Expanding the Catalytic Scope of 2-Iodoimidazolium Salts.

Metal-free initiating systems for living cationic polymerizations are desirable from the viewpoint of environmentally benign polymer synthesis. We describe here the development of a halogen-bonding-mediated and controlled cationic polymerization of isobutyl vinyl ether (IBVE) using 2-iodoimidazolium salts as an organocatalyst. Due to the ionic nature of the catalysts, the polymerization should be performed in CH2 Cl2 . The HCl-adduct of IBVE was the most suitable initiator, and the polymerization was carried out at -10 °C under the catalyst concentration of 10 mm to suppress alcohol elimination from the polymer chain. The addition of a small amount of nBu4 NCl (0.02 equivalent) was effective to accomplish the controlled cationic polymerization and obtain polyIBVE, having the molecular weight distribution below 1.3.

Fluorinated Unsymmetrical N,N'-Diaryl Imidazolium Salts-New Functionalized NHC-Ligand Precursors.

An efficient and scaled-up synthesis of the imidazol-2-ylidene-based unsymmetrical NHC precursors bearing the sterically demanding hexafluoroisopropylalkoxy group [(CF3 )2 (OR)C-] at the ortho position of the N-aryl substituent was developed. The key step of the method involved the transformation of a Mes-substituted oxazolinium tetrafluoroborate salt through the reaction with the corresponding binucleophilic fluoroalkyl-substituted aniline. The subsequent post-modification of the resulting hydroxyl-containing salt through a simple one-step O-alkylation protocol provided access to a new family of unsymmetrical fluorinated NHC precursors. These compounds were successfully utilized for the preparation of several novel metal complexes. The molecular structures of some NHC precursors and their metal complexes have been unambiguously characterized by single-crystal X-ray diffraction analysis. A preliminary evaluation of the catalytic activity of the palladium complexes was performed on a Buchwald-Hartwig amination reaction. As a result, two PEPPSI-type (PEPPSI=pyridine-enhanced pre-catalyst preparation stabilization and initiation) Pd complexes have demonstrated promising activity in alkane solvents.