Bis Imidazolium Salts Research Articles

A Convenient Approach for the Synthesis of Multidentate N-Heterocyclic Carbene Ligand Precursors.

Multidentate bis-NHCs ligands with various spacers are expected to combine the advantages of coordination chemistry and catalysis. These offer opportunities to construct various organometallic frameworks involving transition metals and main group elements. Therefore, developing a general procedure for synthesizing a variety of carbene salt precursors using a convenient technique is key in this context. The extended protocol of a solvent-free approach for synthesizing various bridged bis-imidazolium carbene salts, including tris and tetrakis-imidazolium precursors, is reported here. This method can be performed in the laboratory, leading to high yields (80-95 %) and isolated as analytically pure, multigram, bench-stable compounds.

Palladium(II)-Indenyl Complexes Bearing N-Heterocyclic Carbene (NHC) Ligands as Potent and Selective Metallodrugs toward High-Grade Serous Ovarian Cancer Models.

In this study, we synthesized novel Pd(II)-indenyl complexes using various N-heterocyclic carbene (NHC) ligands, including chelating NHC-picolyl, NHC-thioether, and diNHC ligands, and two monodentate NHCs. Transmetalation reactions between a Pd(II)-indenyl precursor and silver-NHC complexes were generally employed, except for chelating diNHC derivatives, which required direct reaction with bisimidazolium salts and potassium carbonate. Characterization included NMR, HRMS analysis, and single-crystal X-ray diffraction. In vitro on five ovarian cancer cell lines showed notable cytotoxicity, with IC50 values in the micro- and submicromolar range. Some compounds exhibited intriguing selectivity for cancer cells due to higher tumor cell uptake. Mechanistic studies revealed that monodentate NHCs induced mitochondrial damage while chelating ligands caused DNA damage. One chelating NHC-picolyl ligand showed promising cytotoxicity and selectivity in high-grade serous ovarian cancer models, supporting its consideration for preclinical study.

Perfluorinated Iridium Catalyst for Signal Amplification by Reversible Exchange Provides Metal-Free Aqueous Hyperpolarized [1-13C]-Pyruvate.

Hyperpolarized (HP) carbon-13 [13C] enables the specific investigation of dynamic metabolic and physiologic processes via in vivo MRI-based molecular imaging. As the leading HP metabolic agent, [1-13C]pyruvate plays a pivotal role due to its rapid tissue uptake and central role in cellular energetics. Dissolution dynamic nuclear polarization (d-DNP) is considered the gold standard method for the production of HP metabolic probes; however, development of a faster, less expensive technique could accelerate the translation of metabolic imaging via HP MRI to routine clinical use. Signal Amplification by Reversible Exchange in SHield Enabled Alignment Transfer (SABRE-SHEATH) achieves rapid hyperpolarization by using parahydrogen (p-H2) as the source of nuclear spin order. Currently, SABRE is clinically limited due to the toxicity of the iridium catalyst, which is crucial to the SABRE process. To mitigate Ir contamination, we introduce a novel iteration of the SABRE catalyst, incorporating bis(polyfluoroalkylated) imidazolium salts. This novel perfluorinated SABRE catalyst retained polarization properties while exhibiting an enhanced hydrophobicity. This modification allows the easy removal of the perfluorinated SABRE catalyst from HP [1-13C]-pyruvate after polarization in an aqueous solution, using the ReD-SABRE protocol. The residual Ir content after removal was measured via ICP-MS at 177 ppb, which is the lowest reported to date for pyruvate and is sufficiently safe for use in clinical investigations. Further improvement is anticipated once automated processes for delivery and recovery are initiated. SABRE-SHEATH using the perfluorinated SABRE catalyst can become an attractive low-cost alternative to d-DNP to prepare biocompatible HP [1-13C]-pyruvate formulations for in vivo applications in next-generation molecular imaging modalities.

Synthesis, and study biological activity of CuI complexes involving imidazole-2-selones as ligands

A series of imidazole-2-selone (IMSe) ligands were synthesized by reacting of bis-imidazolium salts with selenium in the presence of mild base. These lignads were treated with Cu2Cl2 to form IMSe-CuI complexes. All ligands and their complexes were characterized by FTIR, NMR spectroscopy and mass spectrometry. 1H NMR spectra suggested that the structures of the IMSe-CuI complexes are dinuclear complexes in form [Cu2(diIMSe)2]2+ existed in equilibrium. The complexes had limited stability, with the complexes exhibiting slow decomposition in the solid state and solution. All imidazol-2-selones and their Cu(I) complexes were investigated against E. coli as a Gram-negative bacteria and S. aureus as a Gram-positive bacteria. The ligands and their complexes had promising results against these types of bacterial activity, for example the Cu(I) complexes (C2 and C5) exhibited significantly low MIC values against E. coli (12.5 and 6.25 respectively) as well as S. aureus (6.25 and 3.12 respectively).

Theoretical and experimental investigation of N-alkyl substituted bis-imidazolium salts and their binuclear N-heterocyclic carbene silver acetate complexes

Our research centers on structural, biological, and electronic properties of N-heterocyclic carbene salts and their silver acetate-based complexes. After theoretical calculations, compounds were synthesized. In the DFT studies, functional of B3LYP was used with the basis set of 6-31++G and LanL2DZ for salts and complexes, respectively. The most stable structures were calculated and non-covalent interactions evaluated. Electronic parameters were checked while calculating their HOMO and LUMO energies so that their biological potential can be evaluated. Density of states were studied to check the electronic densities. Among all compounds, 3 was considered the best with energy gap of 0.121 eV. As all eight compounds have very reasonable HOMO-LUMO energy gaps they were considered feasible to synthesize and have strong biological potentials. Compounds were characterized by FT-IR and NMR spectroscopy.

Selective Oxidation of Glycerol via Acceptorless Dehydrogenation Driven by Ir(I)-NHC Catalysts.

Iridium(I) compounds featuring bridge-functionalized bis-NHC ligands (NHC = N-heterocyclic carbene), [Ir(cod)(bis-NHC)] and [Ir(CO)2(bis-NHC)], have been prepared from the appropriate carboxylate- or hydroxy-functionalized bis-imidazolium salts. The related complexes [Ir(cod)(NHC)2]+ and [IrCl(cod)(NHC)(cod)] have been synthesized from a 3-hydroxypropyl functionalized imidazolium salt. These complexes have been shown to be robust catalysts in the oxidative dehydrogenation of glycerol to lactate (LA) with dihydrogen release. High activity and selectivity to LA were achieved in an open system under low catalyst loadings using KOH as a base. The hydroxy-functionalized bis-NHC catalysts are much more active than both the carboxylate-functionalized ones and the unbridged bis-NHC iridium(I) catalyst with hydroxyalkyl-functionalized NHC ligands. In general, carbonyl complexes are more active than the related 1,5-cyclooctadiene ones. The catalyst [Ir(CO)2{(MeImCH2)2CHOH}]Br exhibits the highest productivity affording TONs to LA up to 15,000 at very low catalyst loadings.

Adsorption behavior and wettability alteration of bis-imidazolium salts on vermiculite: Experimental and theoretical studies

For further understanding the wettability alteration induced by organic salts, series of bis-imidazolium salts (EBMI, TBMI, HBMI, OBMI and DBMI) were employed for investigating their adsorption behavior and wettability alteration on vermiculite (Vt) by experimental and theoretical studies. The characterization results indicated that all bis-imidazolium salts had been loaded on Vts. The adsorption results showed that EBMI, TBMI, HBMI, OBMI and DBMI on Vt reached equilibrium of 0.159, 0.156, 0.145, 0.114 and 0.084 mmol g−1 around 30 min at 25 °C, respectively, which were sensitive to ionic strength and pH. Langmuir, statistical physical modelling and pseudo-second-order models could be well fitted with the adsorption data, and thermodynamic parameters suggested that the adsorption processes of bis-imidazolium salts were endothermic and spontaneous, indicating that the resultant bis-imidazolium salts could be self-assembled onto Vt in the form of the monolayer. Results of molecular dynamic simulation showed that bis-imidazolium salts were adsorbed on Vt with the lying-flat configuration, and the electrostatic interaction acted as the main interaction mechanism, which were consistent with that obtained experimentally. Changes of wettability of Vt induced by bis-imidazolium salts were verified by capillary rise experiments. Interestingly, the wettability of organo-Vts varied with the spacer length and the order was as follows: EBMI-Vt < TBMI-Vt < HBMI-Vt < OBMI-Vt < DBMI-Vt, which could be explained by their arrangements, hydrophobicity as well as the interaction energies. The longer the spacers of bis-imidazolium salts, the greater the absolute values of the interaction energy, the less the adsorbed bis-imidazolium salts, while the more hydrophobic of organo-Vt. This work aimed at revealing the adsorption behavior, mechanism as well as effect of bis-imidazolium salts on wettability alteration of negatively charged mineral surface, providing some information for the selection of flooding agent for enhanced oil recovery and wettability modifier.

Dicationic bis-imidazoliums as a platform for ionic liquids: Long tails and short spacers

A broad set of bis-imidazolium salts with long tails and short spacers (LTSS BIS) with odd and even number of carbons was synthesized and characterized with a number of experimental and computational methods, such as 1H and 13C NMR (2D techniques included), optical and electron microscopy, water content determinations, solubility in water assessments, melting points measurements, geometry and thermochemistry evaluation for model dications in PM6. Theoretically substantiated improvements for alkylimidazoles and bis-imidazolium dihalides synthesis have been proposed and experimentally verified. Good yields of LTSS BIS pure enough for physicochemical studies can be achieved in a fast and efficient manner, and factors essential for getting good results have been unveiled. The majority of LTSS BIS are prone to absorb water and retain it under usual conditions, but easily lose at heating. Large variety in crystal forms and thermal behavior of LTSS BIS subfamilies were found, depending mainly from spacer and anion. High thermal stability (more than 200°C) is typical for all LTSS BIS under study, but only a small part may be considered as a true ionic liquid. Fully stretched conformations were supposed for all alkyl fragments (tails and spacers) in solution, in accordance with experimental and computational results. Rotation around ordinary bonds is restricted only in 1,3-di(imidazolium-1-yl)-2-hydroxypropane dication, leading to unique four sorts of protons in three sp3-carbon chain. Due to specific structural features, bis-imidazolium salts cannot be represented as rod-like molecules. The concept of three principal structural motifs for LTSS BIS (U-shape, V-shape, and Z-shape) is proposed.

Bis-polyethylene glycol-functionalized imidazolium ionic liquids: A multi-method approach towards bulk and surface properties

Adding to the versatile class of ionic liquids, we report a new series of hydrophilic polyethylene glycol-functionalized room-temperature ionic liquids, offering interesting thermo- and electrochemical behavior as well as remarkable surface properties. A scalable and generally applicable synthetic procedure for the preparation of N,N’-bis(polyethylene glycol)imidazolium salts, generally abbreviated as [(mPEGn)2Im][A] (n = 2‒6, A = I‒, OMs‒, PF6‒, NTf2‒) was developed. These ionic liquids were studied concerning their thermo- and electrochemical properties, such as phase transition behavior, decomposition temperature, viscosity, and density, as well as electrical conductivity and electrochemical stability, using i.a. differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), electrochemical impedance spectroscopy (EIS) and linear sweep voltammetry (LSV). Additionally, the surface properties were investigated by angle-resolved X-ray photoelectron spectroscopy (ARXPS) and the pendant drop method. Molecular dynamics simulations complement the studies and provide insight into the molecular structure of the ionic liquids and their specific orientation at the liquid-vacuum interface.

Bisimidazolium Salt Glycosyltransferase Inhibitors Suppress Hepatocellular Carcinoma Progression In Vitro and In Vivo.

Hepatocellular carcinoma is a leading cause of cancer death, and the disease progression has been related to glycophenotype modifications. Previously synthesized bisimidazolium salts (C20 and C22) have been shown to selectively inhibit the activity of glycosyltransferases in cultured cancer cell homogenates. The current study investigated the anticancer effects of C20/C22 and the possible pathways through which these effects are achieved. The therapeutic value of C20/C22 in terms of inhibiting cancer cell proliferation, metastasis, and angiogenesis, as well as inducing apoptosis, were examined with hepatic cancer cell line HepG2 and a xenograft mouse model. C20/C22 treatment downregulated the synthesis of SLex and Ley sugar epitopes and suppressed selectin-mediated cancer cell metastasis. C20/C22 inhibited HepG2 proliferation, induced cell-cycle arrest, increased intracellular ROS level, led to ER stress, and eventually induced apoptosis through the intrinsic pathway. Furthermore, C20/C22 upregulated the expressions of death receptors DR4 and DR5, substantially increasing the sensitivity of HepG2 to TRAIL-triggered apoptosis. In vivo, C20/C22 effectively inhibited tumor growth and angiogenesis in the xenograft mouse model without adverse effects on major organs. In summary, C20 and C22 are new promising anti-hepatic cancer agents with multiple mechanisms in controlling cancer cell growth, metastasis, and apoptosis, and they merit further development into anticancer drugs.

Rigid chelating dicarbene ligands based on naphthyridine-fused bisimidazolium salts

Naphthyridine-fused bisimidazolium salts were designed and synthesized for the first time. The study of the Cu(II) and Pd(II) complexes demonstrated that the deprotonated dicarbene ligands are rigid chelating C,C-ligands with strong electron-donating ability in analogy with the classic phenanthroline N,N-ligands.

Azolium mediated N[sbnd]Heterocyclic carbene selenium adducts: Synthesis, cytotoxicity and molecular docking studies

Ionic liquids (ILs) are remarkable for biological activities in numerous medical fields. With the aim of enhancing biological potential of azolium based ILs, four new selenium-N-Heterocyclic Carbene (Se-NHC) adducts were synthesized from bis-imidazolium and bis-benzimidazolium molten salts. Synthesized ILs (L1-L4) and Se-NHC adducts (C1C4) were confirmed through elemental analysis, chromatographic and spectroscopic techniques including UHPLC-PDA, FTIR, 1H NMR & 13C NMR spectroscopy as well as mass spectrometry. The compounds were found stable in solution form for upto 96 h measured spectroscopically and showed partition coefficient with optimum lipophilicity measured through shake flask method. The simulation studies of these compounds for cancerous proteins indicated that there could be good to high anticancer potential due to their high affinity and less binding energies for COX-1, EGF, VEGF-A and HIF cancer protein targets. The In Vitro cytotoxicity study of compounds confirmed that these compounds were found highly active showeing IC50 against HCT-116 (1.074–1.116 µg mL−1), A549 (0.977–1.325 µg mL−1) and MCF-7 (0.869–1.378 µg mL−1) which is almost better than standard drug 5-Flourouracil but slightly lower than cisplatin and oxaliplatin. The interaction study of compounds with albumin proteins (BSA) and hemolysis assay assured their least toxicity.

Synthesis in combination with Biological and Computational evaluations of selenium-N-Heterocyclic Carbene compounds

Bis-imidazolium salts and their Se-NHC adducts were designed, synthesized, and characterized by various spectroscopic techniques. Density Functional Theory (DFT) was applied on designed molecules through the basis set of hybrid functional B3LYP/6-31 G level of theory. To estimate the structural properties of tested compounds and their influence on biological applications, the HOMO and LUMO energy levels and their energy gaps were calculated. Theoretical studies were used to elaborate on the optical properties of salts and respective selenium adducts. The synthesized salts and N-Heterocyclic carbenes adducts of selenium (Se-NHCs) were tested in vitro against the Breast Adenocarcinoma cell line (MCF-7) by cell viability measurements. It was found that the N-alkylated substitutions on imidazolium salts have more significant free radical scavenging property whereas the reverse case was observed in the selenium compounds. All the compounds except M1 were not showing prominent cytotoxicity against cancerous cell lines.

Synthesis, characterization, in vitro SAR study, and preliminary in vivo toxicity evaluation of naphthylmethyl substituted bis-imidazolium salts

A series of novel bis-imidazolium salts was synthesized, characterized, and evaluated in vitro against a panel of non-small cell lung cancer (NSCLC) cells. Two imidazolium cores were connected with alkyl chains of varying lengths to develop a structure activity relationship (SAR). Increasing the length of the connecting alkyl chain was shown to correlate to an increase in the anti-proliferative activity. The National Cancer Institute’s NCI-60 human tumor cell line screen confirmed this trend. The compound containing a decyl linker chain, 10, was chosen for further in vivo toxicity studies with C578BL/6 mice. The compound was well tolerated by the mice and all of the animals survived and gained weight over the course of the study.

Three anthracene-based bis-imidazolium salts: Synthesis, structure and recognition for 2,4-dinitrophenylhydrazine

Three anthracene-based bis-imidazolium salts 1,8-bis [2’-(N-R-imidazoliumyl) acetamido]anthracene 2× (1: R = nBu, X = Cl−; 2: R = nBu, X = PF6−; 3: R = Et, X = PF6−) were prepared. The structure of 1 was demonstrated by X-ray analysis. The selective recognition of 2 (or 3) for some aromatic compounds (toluene, chlorobenzene, phenylamine, phenol, anisole, benzaldehyde, acetophenone, nitrobenzene, m-dinitrobenzene, 2,4-dinitrotoluene, 2,4-dinitrophenylhydrazine (DNP), trinitrophenol, o-nitrophenol, p-nitrotoluene) was investigated through fluorescence, ultraviolet, 1H NMR, HRMS and IR spectra at 25 °C. Compounds 2 (or 3) showed good selective recognition ability for DNP, and they could effectively distinguish DNP from other aromatic compounds. The association constants and detection limits of 2 and 3 were similar, which displayed sizes of side chains (nBu for 2 and Et for 3) had no remarkable effect on the recognition of DNP.

Polynuclear Ag(I)-N-heterocyclic carbene complexes: synthesis, electrochemical and in vitro anticancer study against human breast cancer and colon cancer

Four new bis-imidazolium salts 3–6 and their di- and polynuclear silver(I)–N-heterocyclic carbene (Ag(I)–NHC) complexes 7–10 were synthesized and characterized by using various analytical techniques. Single-crystal studies of 8 revealed a dinuclear structure whereas that of 9 revealed an interesting polynuclear structure. The quasi-reversibility of redox events in electrochemical study of 9 indicated that reduction produces unstable decomposed species and oxidation may be ascribed to these decomposed species. All the compounds were studied for their in vitro anticancer study against human breast cancer (MDA-MB-231) and colon cancer (HCT-116) cells. The study revealed that Ag(I)–NHC complexes are comparatively more potent than NHC precursors (salts). MDA-MB-231 cells appeared more sensitive to complexes than HCT-116 cells while reverse is the case for NHC salts.

Linear tetraphenylethene-appended bis-imidazolium salts for sensing of ATP

Five tetraphenylethene (TPE) functionalized linear bis-imidazolium salts with different chain length spacers, i.e., methylene (BT-1), 1,2-ethanediyl (BT-2), 1,3-propanediyl (BT-3), 1,5-pentanediyl (BT-4) and 1,10-decanediyl (BT-5), have been designed and synthesized. The anion recognition ability of all of the probes to recognize anions was the investigated by emission spectra, 1H NMR titration and DLS experiments. All the bis-imidazolium salts show a very weak fluorescence in aqueous solution. However, the weak fluorescence of the free probes can be affected by ATP anion, with a significant fluorescence enhancement of the tetraphenylethene-based aggregation-induced emission at 471 nm. Importantly, the binding affinity of probes toward ATP can be modulated by adjusting the spacer length, with the binding constants being in the order of BT-1 > BT-2 >BT-3 > BT-4 > BT-5. The 1H NMR titration and the DLS experiments revealed the binding mechanisms between probes and ATP. For practical application, probe BT-3 was selected and successfully used for fluorescence imaging of intracellular ATP in live cells.

IrIII/AuI and RhIII/AuI Heterobimetallic Complexes as Catalysts for the Coupling of Nitrobenzene and Benzylic Alcohol

Two simple bisimidazolium salts derived from m- or p-bisimidazolebenzenes have been used as ligand precursors for the preparation of a series of heterobimetallic RhIII/AuI and IrIII/AuI complexes. All complexes have been fully characterized, and the molecular structures of selected derivatives have been determined by X-ray diffraction studies. These analyses showed that, regardless of the ligand used, the direct coordination environment of the metals is composed of identical donors (MIII: CNHC, Cbenzene, η5-Cp*, and I–; AuI: CNHC and I–) and is rather similar in the heterobimetallic complexes. The catalytic activity of the heterobimetallic complexes in the coupling of nitrobenzene with benzylic alcohol has been investigated. In all cases, the performance observed for the heterobimetallic complexes was superior to that shown by mixtures of homometallic MIII/AuI complexes, suggesting a cooperative effect between the two metal centers. In addition and in spite of the similarity of the donor groups of the two bis-NHC ligands used, the slightly different relative orientation of the two metals in the heterobimetallic complexes also plays a role in the catalytic conversion observed.

Preparation of Macrometallocycle and Selective Sensor for Copper Ion

Two bis-imidazolium salts 1,8-bis[2’-(N-R-imidazoliumyl)acetylamino]naphthalene chloride (L1H4·Cl2: R = Et; L2H4·Cl2: R = nBu), as well as their four NHC metal complexes [L1H2Ag]Cl (1), [L1Ni] (2), [L2Ni] (3) and [L1H2Hg(HgCl4)] (4) have been synthesized. In each of the cationic moieties of complexes 1 or 4, there is a groove-like 14-membered macrometallocycle, and each macrometallocycle is consisted of one biscarbene ligand L1H2 and one metal ion (silver(I) ion for 1 and mercury(II) ion for 4). Three 6-membered cycles are contained in each molecule of complexes 2 or 3. Additionally, the selective recognition of macrometallocycle 1 for Cu2+ was studied with the methods of fluorescence and ultraviolet spectroscopy, 1H NMR titrations, MS and IR spectra. The experimental results display macrometallocycle 1 can discriminate Cu2+ from other cations effectively.

Correlating morphology to thermal and electrical properties in imidazolium-poly(ethylene glycol) copolyesters

Ionic liquid-based copolyesters containing an imidazolium cation backbone and PF6− or Tf2N− counter-anion are synthesized from N,N′-bis(ω-hydroxyalkyl)imidazolium salts (PF6− or Tf2N−) (0.5 equiv.), poly(ethylene glycol) (PEG; number average molecular weight: 1000 or 2000) (0.5 equiv.), and sebacoyl chloride (1.0 equiv.). The imidazolium monomers are room-temperature ionic liquids. In the ionic copolymers, the 1:1 ratio between imidazolium and PEG, and number average molecular weights were confirmed using 1H NMR. Crystallization of the PEG segments was affected by the alkyl spacer length of the ionic units and by the anion type. Softer Tf2N− can prevent copolyester crystallization during cooling when the anions are close to the PEG segments; moreover, some Tf2N− copolymers show crystallization during a heating scan. The crystalline phase of the PEG-2000 segments gives distinct X-ray diffraction peaks at 2θ ≈ 19.0 and 23.1°, and the lateral chain packing of the C11-(imidazolium PF6)-C11 structures is shown at 2θ ≈ 21.5°. These crystalline domains are shown as Tc peaks during a cooling scan. The room-temperature ionic conductivities of the Tf2N− copolyesters are above 10−5 S cm−1; however, the ionic conductivity drops significantly below the melting temperatures of the PEG copolyesters. In contrast, the predominantly amorphous polymers that contain PF6− and Tf2N− counter-anions do not show a sudden conductivity drop over the entire temperature range. The imidazolium-PEG copolyesters, which have a low ion density, show a higher ionic conductivity than a reported poly(imidazolium-sebacate) without PEG segments because of the lower activation energy of the isolated conducting anions.