Cationic Bis Research Articles

Tris(benzhydryl) and Cationic Bis(benzhydryl) Ln(III) Complexes: Exceptional Thermostability and Catalytic Activity in Olefin Hydroarylation and Hydrobenzylation with Substituted Pyridines

AbstractA series of Ln(III) tris(benzhydryl) complexes [(p‐tBu‐C6H4)2CH]3Ln (Ln=La (1), Nd (2), Y (3)) were synthesized by the salt metathesis reactions of LnHal3(THF)3.5(Ln=La, Nd, Hal=Cl; Ln=Y, Hal=I) and [(p‐tBu‐C6H4)2CH]Na. In1–3the benzhydryl ligands are linked with the metal centres inη4‐coordination mode. For diamagnetic complexes1and3a fluxional behaviour was detected in solution. Complexes1–3proved to be thermally stable: no decomposition was observed even after heating their solutions in toluene‐d8at 140 °C during 72 h. The reactions of1and2with B(C6F5)3allowed for the synthesis of base‐free cationic complexes [(p‐tBu‐C6H4)2CH]2Ln[(p‐tBu‐C6H4)2CHB(C6F5)3] (Ln=La (4), Nd (5)) which adopt the structure of a contact ion pair. Combinations of1–3and borane ((B(C6F5)3, [Me2NHPh][B(C6F5)4], [Ph3C][B(C6F5)4]) as well as4and5were found to be highly efficient, regio‐ and chemoselective catalysts for hydroarylation and hydrobenzylation of C=C bonds of a variety of substrates with substituted pyridines. These catalysts enable highly challenging transformations such as hydrobenzylation of 1,1‐disubstituted and internal C=C bonds.magnified image

Selectivity and Mechanism of Iridium-Catalyzed Cyclohexyl Methyl Ether Cleavage

Cationic bis(phosphine)iridium complexes are found to catalyze the cleavage of cyclohexyl methyl ethers by triethylsilane. Selectivity for C−O cleavage is determined by the relative rates of SN2 de...

An Artemisinin‐Derivative–(NHC)Gold(I) Hybrid with Enhanced Cytotoxicity through Inhibition of NRF2 Transcriptional Activity

AbstractA family of hybrid complexes combining two biologically active motifs, an artemisinin derivative and a cationic bis(NHC)‐gold(I) unit, has been synthesized. One of these complexes, 2 a, has been analyzed by single‐crystal X‐ray diffraction. 2 a shows strong anticancer activities on a large panel of human cancer cell models (prostate, breast, lung, liver, bladder, bone, acute and chronic myeloid leukemias) with GI50 values in the nm range, together with a high selectivity. An original and distinctive mechanism of action, that is, through inhibition of the redox antioxidant NRF2 transcription factor (strongly associated with aggressiveness and resistance to cancer therapies) has been evidenced. 2 a could remarkably sensitize to sorafenib in HepG2 liver cells, in which dysregulated NRF2 signaling is linked to primary and acquired drug resistance. 2 a also inhibited NF‐κB and HIF transcriptional activities, which are also associated with progression and resistance in cancer. Our findings provide evidence that hybrid (NHC)gold(I) compounds represent a new class of organometallic hybrid molecules that may yield new therapeutic agents.

An Artemisinin-Derivative-(NHC)Gold(I) Hybrid with Enhanced Cytotoxicity through Inhibition of NRF2 Transcriptional Activity.

A family of hybrid complexes combining two biologically active motifs, an artemisinin derivative and a cationic bis(NHC)-gold(I) unit, has been synthesized. One of these complexes, 2 a, has been analyzed by single-crystal X-ray diffraction. 2 a shows strong anticancer activities on a large panel of human cancer cell models (prostate, breast, lung, liver, bladder, bone, acute and chronic myeloid leukemias) with GI50 values in the nm range, together with a high selectivity. An original and distinctive mechanism of action, that is, through inhibition of the redox antioxidant NRF2 transcription factor (strongly associated with aggressiveness and resistance to cancer therapies) has been evidenced. 2 a could remarkably sensitize to sorafenib in HepG2 liver cells, in which dysregulated NRF2 signaling is linked to primary and acquired drug resistance. 2 a also inhibited NF-κB and HIF transcriptional activities, which are also associated with progression and resistance in cancer. Our findings provide evidence that hybrid (NHC)gold(I) compounds represent a new class of organometallic hybrid molecules that may yield new therapeutic agents.

Efficient Z-Selective Semihydrogenation of Internal Alkynes Catalyzed by Cationic Iron(II) Hydride Complexes.

The bench-stable cationic bis(σ-B-H) aminoborane complex [Fe(PNPNMe-iPr)(H)(η2-H2B = NMe2)]+ (2) efficiently catalyzes the semihydrogenation of internal alkynes, 1,3-diynes and 1,3-enynes. Moreover, selective incorporation of deuterium was achieved in the case of 1,3-diynes and 1,3-enynes. The catalytic reaction takes place under mild conditions (25 °C, 4-5 bar H2 or D2) in 1 h, and alkenes were obtained with high Z-selectivity for a broad scope of substrates. Mechanistic insight into the catalytic reaction, explaining also the stereo- and chemoselectivity, is provided by means of DFT calculations. Intermediates featuring a bisdihydrogen moiety [Fe(PNPNMe-iPr)(η2-H2)2]+ are found to play a key role. Experimental support for such species was unequivocally provided by the fact that [Fe(PNPNMe-iPr)(H)(η2-H2)2]+ (3) exhibited the same catalytic activity as 2. The novel cationic bisdihydrogen complex 3 was obtained by protonolysis of [Fe(PNPNMe-iPr)(H)(η2-AlH4)]2 (1) with an excess of nonafluoro-tert-butyl alcohol.

Cover Picture: Syntheses and Catalytic Hydrogenation Performance of Cationic Bis(phosphine) Cobalt(I) Diene and Arene Compounds (Angew. Chem. Int. Ed. 27/2019)

Cover Picture: Syntheses and Catalytic Hydrogenation Performance of Cationic Bis(phosphine) Cobalt(I) Diene and Arene Compounds (Angew. Chem. Int. Ed. 27/2019)

Syntheses and Catalytic Hydrogenation Performance of Cationic Bis(phosphine) Cobalt(I) Diene and Arene Compounds

AbstractChloride abstraction from [(R,R)‐(iPrDuPhos)Co(μ‐Cl)]2 with NaBArF4 (BArF4=B[(3,5‐(CF3)2)C6H3]4) in the presence of dienes, such as 1,5‐cyclooctadiene (COD) or norbornadiene (NBD), yielded long sought‐after cationic bis(phosphine) cobalt complexes, [(R,R)‐(iPrDuPhos)Co(η2,η2‐diene)][BArF4]. The COD complex proved substitutionally labile undergoing diene substitution with tetrahydrofuran, NBD, or arenes. The resulting 18‐electron, cationic cobalt(I) arene complexes, as well as the [(R,R)‐(iPrDuPhos)Co(diene)][BArF4] derivatives, proved to be highly active and enantioselective precatalysts for asymmetric alkene hydrogenation. A cobalt–substrate complex, [(R,R)‐(iPrDuPhos)Co(MAA)][BArF4] (MAA=methyl 2‐acetamidoacrylate) was crystallographically characterized as the opposite diastereomer to that expected for productive hydrogenation demonstrating a Curtin–Hammett kinetic regime similar to rhodium catalysis.

Syntheses and Catalytic Hydrogenation Performance of Cationic Bis(phosphine) Cobalt(I) Diene and Arene Compounds.

Chloride abstraction from [(R,R)-(iPr DuPhos)Co(μ-Cl)]2 with NaBArF 4 (BArF 4 =B[(3,5-(CF3 )2 )C6 H3 ]4 ) in the presence of dienes, such as 1,5-cyclooctadiene (COD) or norbornadiene (NBD), yielded long sought-after cationic bis(phosphine) cobalt complexes, [(R,R)-(iPr DuPhos)Co(η2 ,η2 -diene)][BArF 4 ]. The COD complex proved substitutionally labile undergoing diene substitution with tetrahydrofuran, NBD, or arenes. The resulting 18-electron, cationic cobalt(I) arene complexes, as well as the [(R,R)-(iPr DuPhos)Co(diene)][BArF 4 ] derivatives, proved to be highly active and enantioselective precatalysts for asymmetric alkene hydrogenation. A cobalt-substrate complex, [(R,R)-(iPr DuPhos)Co(MAA)][BArF 4 ] (MAA=methyl 2-acetamidoacrylate) was crystallographically characterized as the opposite diastereomer to that expected for productive hydrogenation demonstrating a Curtin-Hammett kinetic regime similar to rhodium catalysis.

Novel cationic bis(acylhydrazones) as modulators of Epstein–Barr virus immune evasion acting through disruption of interaction between nucleolin and G-quadruplexes of EBNA1 mRNA

The oncogenic Epstein–Barr virus (EBV) evades the immune system through limiting the expression of its highly antigenic and essential genome maintenance protein, EBNA1, to the minimal level to ensure viral genome replication, thereby also minimizing the production of EBNA1-derived antigenic peptides. This regulation is based on inhibition of translation of the virally-encoded EBNA1 mRNA, and involves the interaction of host protein nucleolin (NCL) with G-quadruplex (G4) structures that form in the glycine–alanine repeat (GAr)-encoding sequence of the EBNA1 mRNA. Ligands that bind to these G4-RNA can prevent their interaction with NCL, leading to disinhibition of EBNA1 expression and antigen presentation, thereby interfering with the immune evasion of EBNA1 and therefore of EBV (M.J. Lista et al., Nature Commun., 2017, 8, 16043). In this work, we synthesized and studied a series of 20 cationic bis(acylhydrazone) derivatives designed as G4 ligands. The in vitro evaluation showed that most derivatives based on central pyridine (Py), naphthyridine (Naph) or phenanthroline (Phen) units were efficient G4 binders, in contrast to their pyrimidine (Pym) counterparts, which were poor G4 binders due to a significantly different molecular geometry. The influence of lateral heterocyclic units (N-substituted pyridinium or quinolinium residues) on G4-binding properties was also investigated. Two novel compounds, namely PyDH2 and PhenDH2, used at a 5 μM concentration, were able to significantly enhance EBNA1 expression in H1299 cells in a GAr-dependent manner, while being significantly less toxic than the prototype drug PhenDC3 (GI50 > 50 μM). Antigen presentation, RNA pull-down and proximity ligation assays confirmed that the effect of both drugs was related to the disruption of NCL–EBNA1 mRNA interaction and the subsequent promotion of GAr-restricted antigen presentation. Our work provides a novel modular scaffold for the development of G-quadruplex-targeting drugs acting through interference with G4–protein interaction.

Selective alkyl ether cleavage by cationic bis(phosphine)iridium complexes.

Catalysts capable of heterolytic silane activation have been successfully applied to the conversion of alkyl ethers to silyl ethers via C-O bond cleavage. The previously-reported cationic pincer-supported iridium complex for this transformation suffers from poor selectivity with regard to monodealkylation of substrate ethers. We demonstrate that a simple non-pincer iridium complex offers improved selectivity and is capable of benzylic ether cleavage in the presence of reductively-labile alkyl and aryl halide functionality. Preliminary mechanistic experiments suggest a neutral tetrahydridosilyliridium resting state which is consistent with previous mechanistic hypotheses. These experiments suggest that a pincer ligand framework is not required for activity in ether cleavage reactions and that simple cationic bis(phosphine)iridium complexes may offer improved selectivity profiles for applications to more-complex substrate molecules.

Spectroscopic Investigation of the Activation of a Chromium-Pyrrolyl Ethene Trimerization Catalyst.

1-Hexene is an important α-olefin for polyethylene production and is produced from ethene. Recent developments in the α-olefin industry have led to the successful commercialization of ethene trimerization catalysts. An important industrially applied ethene trimerization system uses a mixture of chromium 2-ethylhexanoate, AlEt3, AlEt2Cl, and 2,5-dimethylpyrrole (DMP). Here, we have studied the activation of this system using catalytic and spectroscopic experiments (XAS, EPR, and UV–vis) under conditions employed in industry. First, chromium 2-ethylhexanoate was prepared and characterized to be [Cr3O(RCO2)6(H2O)3]Cl. Next, the activation of chromium 2-ethylhexanoate with AlEt3, AlEt2Cl, and DMP was studied, showing immediate reduction (<5 ms) of the trinuclear Cr(III) carboxylate and formation of a neutral polynuclear Cr(II) carboxylate complex. Over time, this Cr(II) carboxylate complex is partially converted into a chloro-bridged dinuclear Cr(II) pyrrolyl complex. In cyclohexane, small quantities of an unknown Cr(I) complex (∼1% after 1 h) are observed, while in toluene, the quantity of Cr(I) is much higher (∼23% after 1 h). This is due to the formation of cationic bis(tolyl)Cr(I) complexes, which likely leads to the observed inferior performance using toluene as the reaction solvent. Catalytic studies allow us to exclude some of the observed Cr(I) and Cr(II) complexes as the active species in this catalytic system. Using this combination of techniques, we have been able to structurally characterize complexes of this selective Cr-catalyzed trimerization system under conditions which are employed in industry.

Photoluminescence of Cyclometalated Iridium Complexes in Poly(methyl methacrylate) Films

In this work, we describe the emission properties of 12 heteroleptic bis-cyclometalated iridium complexes immobilized in poly(methyl methacrylate) (PMMA) thin films. The compounds chosen for this study span a range of emission colors covering the visible spectrum and fall into three categories with electronically diverse ancillary ligands—four cationic bis(aryl isocyanide) complexes, four with chelating bis(acyclic diaminocarbene) (bis-ADC) ancillary ligands which can exist in two protonation states, and four neutral compounds with monoanionic, strongly π donating β-ketoiminate (acNac) and β-diketiminate (NacNac) ancillary ligands. Included in this suite of compounds are five new compounds, one with two aryl isocyanide ancillary ligands, two with bis-ADC ancillary ligands, and one each with acNac and NacNac; their syntheses are described, and crystal structures of three are presented. The bulk of the work presented here describes the emission spectra of all 12 compounds, comparing spectral features in sol...

Cationic and Neutral N-Heterocyclic Carbene Gold(I) Complexes: Cytotoxicity, NCI-60 Screening, Cellular Uptake, Inhibition of Mammalian Thioredoxin Reductase, and Reactive Oxygen Species Formation.

A structurally diverse library of 14 gold(I) cationic bis(NHC) and neutral mono(NHC) complexes (NHC: N-heterocyclic carbene) was synthesized and characterized in this work. Four of them were new cationic gold(I) complexes containing functionalized NHCs, and their X-ray crystal structures are presented herein. All of the complexes were investigated for their anticancer activities in four cancer cell lines, including a cisplatin-resistant variant, and a noncancerous cell line. Seven of the cationic gold(I) complexes were found to display high and specific cytotoxic activities toward cancer cells. Two of them were even able to overcome cisplatin resistance. Two highly potent cationic complexes (11 and 15) were also submitted to the NCI-60 cancer panel for further cytotoxicity evaluation. Complex 15 showed a surprisingly high potency toward leukemia among the nine examined cancer subtypes, particularly toward the CCRF-CEM leukemia cell line with a concentration for 50 % inhibition of growth down to 79.4 nm. In addition, cationic complex 13, which demonstrated a remarkable cytotoxicity against hepatocellular carcinoma, was selected to obtain insight into the mechanistic aspects in HepG2 cells. Cellular uptake measurements were indicative of good bioavailability. By various biochemical assays, this complex was found to effectively inhibit thioredoxin reductase and its cytotoxicity toward HepG2 cells was found to be reactive oxygen species dependent.

Cationic Bis(cyclometalated) Ir(III) Complexes with Pyridine-Carbene Ligands. Photophysical Properties and Photocatalytic Hydrogen Production from Water.

Precursors of chelate pyridine-N-heterocyclic carbene (N^C:) ligands with methyl- or benzyl-substituted imidazolylidene fragments were synthesized. They were used to obtain 12 iridium bis-cyclometalated complexes of the type [Ir(C^N)2(N^C:)]+ (C^N = 2-(phenyl)pyridinato-C2,N, ppy, 2-(4,6-difluorophenyl)pyridinato-C2,N, dfppy). The ancillary N^C: ligands contain different structural modifications. The aim of the work was to analyze the effect that changes in the two types of ligands have on the photophysical and electrochemical properties and also on the behavior of these materials as photosensitizers. The X-ray crystal structures of five complexes were determined. The complexes emitted in the blue-green region. It was expected that the frontier orbitals and thus the photophysical and electrochemical properties would be controlled by the main C^N ligands, and it was demonstrated that the effect of the modifications in the N^C: ligand, especially the presence of a nitro group in the pyridine ring or the interruption of conjugation between the two rings, also affected these properties. The quenching with O2 and photostability studies were also performed. Density functional theory calculations were used to explain the behavior of some derivatives. The complexes and other previously reported compounds were employed as photosensitizers (PS) in preliminary studies on the production of H2 from water using [Co(bpy)3]Cl2 (bpy = 2,2'-bipyridine) as catalyst and triethanolamine (TEOA) as the sacrificial reductant. The absence of quenching of the PS with TEOA allowed us to propose an oxidative quenching mechanism.

Orbital control over the metal vs. ligand reduction in a series of neutral and cationic bis(cyclopentadienyl) Ti(iv) complexes

LUMO of a complex reveals the extent of the electronic influence of ligand substituents on the reduction centre of the complex.

Structural resemblance and variation in transition metal complexes derived from dipicolinic acid and guanylhydrazine

New aminoguanidinium transition metal dipicolinates of the formula (AgunH)[MIII(dip)2]·xH2O, M = Cr, x = 1.5; Fe, x = 2, (AgunH)2[MII(dip)2]·nH2O, where M = Mn, n = 2; Co or Ni, n = 0 and Zn, n = 1, and [Cu(Agun)2][Cu3(dip)4(Agun)2]·4H2O have been prepared by the reaction of respective metal nitrates with aqueous mixture of dipicolinic acid (H2dip) and aminoguanidine bicarbonate (AgunH·HCO3) in appropriate mole ratios. These compounds have been characterized by various physico-chemical techniques. Among them Ni, Cu, Cr and Fe complexes have been structurally characterized. The asymmetric units of the Ni and Cr structures contain two independent molecules, whereas Fe has four. Unlike these, the copper compound has a unique structure with a tri-nuclear centrosymmetric anionic complex and cationic bis(aminoguanidine)copper(II). In all of these compounds, the dipicolinate dianion is acting as a tridentate (O,N,O) donor ligand, except copper in-which one of the dipicolinates is tetradentate (O,N,O,O). Cytotoxicity and DPPH scavenging activity studies reveal that the copper complex exhibits superior activity to that of cobalt and nickel.

Evidence for Reversible Cyclometalation in Alkane Dehydrogenation and C–O Bond Cleavage at Iridium Bis(phosphine) Complexes

Methyl tert-butyl ether is found to undergo C–O bond cleavage in the formation of an iridium(III) methallyl at a cationic bis(phosphine) iridium complex. An exploration of this transformation has revealed a cyclometalated complex which was previously postulated to form reversibly in the first example of alkane dehydrogenation by a homogeneous transition-metal complex. The competence of this cyclometalated species in alkane dehydrogenation is demonstrated in a stoichiometric example, giving an isolable olefin dihydride. Detection and assignment of this elusive species confirms a previous hypothesis that reversible intramolecular phosphine cyclometalation can precede intermolecular alkane dehydrogenation.

T-Shaped Gold→Stiborane Complexes as Carbophilic Catalysts: Influence of the Peripheral Substituents

As part of our efforts toward the discovery of new late transition metal catalysts, we synthesized [(o-(Ph2P)C6H4)2(o-C6Cl4O2)SbPh)Au]+ (3+) and [(o-(iPr2P)C6H4)2(o-C6Cl4O2)SbPh)Au]+ (4+), two cationic bis(phosphino)gold stiborane complexes, which were isolated as their hexafluorophosphate salts and fully characterized. Structural and computational studies indicate that the cores of these two complexes are almost structurally and electronically identical. Despite these similarities, these two complexes exhibit different catalytic activities in the hydroamination of phenylacetylene using anilines or in the cyclization of N-(prop-2-yn-1-yl)benzamide. Indeed, whereas 3+ catalyzes both reactions, we found that 4+ is inactive. The data collected on these two complexes suggest that the origin of this contrasting behavior is steric, rather than electronic, with the relatively bulky iPr2P ancillary ligands blocking access to the reactive gold center.

Synthesis and Catalytic Activity of PNP-Supported Iron Complexes with Ancillary Isonitrile Ligands

Pincer-supported iron complexes of the form [(iPrPNHP)Fe(H)(HBH3)(CO)] (iPrPNHP = HN(CH2CH2PiPr2)2), [(iPrPNHP)Fe(H){OC(O)H}(CO)], [(iPrPNP)Fe(H)(CO)]; iPrPNP = N(CH2CH2PiPr2)2–) have proven to be a privileged class of catalysts for hydrogenation and dehydrogenation reactions. Here, the synthesis, characterization, and reactivity of a family of complexes related to these species, in which the ancillary carbonyl ligand has been replaced with an aryl isonitrile ligand, is described. The complexes [(iPrPNHP)Fe(Cl)2(C≡NR)] (R = 2,6-dimethylphenyl (1a), 4-methoxyphenyl (1b)) were prepared in good yield through the dropwise addition of the aryl isonitrile to an in situ generated solution of [(iPrPNHP)Fe(Cl)2]. If the aryl isonitrile was added too quickly, significant amounts of the cationic bis(isonitrile) complexes [(iPrPNHP)Fe(Cl)(C≡NR)2][Cl] (R = 2,6-dimethylphenyl (2a); 4-methoxyphenyl (2b)) were also formed. Treatment of 1a with excess NaBH4 generated [(iPrPNHP)Fe(H)(HBH3)(C≡NR)] (3a), but the correspondin...

Oxidative Addition of Aryl Halides to Cationic Bis(phosphane)rhodium Complexes: Application in C–C Bond Formation

The oxidative addition of chloro‐, bromo‐ and iodobenzene to the cationic bis(phosphane)rhodium complex [Rh(DIPAMP)(MeOH)2]BF4 was investigated. The resulting complexes were characterized by X‐ray analysis and NMR spectroscopy and applied as catalysts in classical cross‐coupling reactions. Product inhibition was observed and quantified by UV/Vis and NMR spectroscopy.