An Aza-Enolate Strategy Enables Iridium-Catalyzed Enantioselective Hydroalkenylations of Minimally Polarized Alkenes en Route to Complex N-Aryl ß2-Amino Acids.

Cationic Ir(I)-complexes modified with homochiral diphosphines promote the hydroalkenylative cross-coupling of ß-(arylamino)acrylates with monosubstituted styrenes and α-olefins. The processes are dependent on the presence of an NH unit, and it is postulated that metalation of this generates an iridium aza-enolate that engages the alkene during the C-C bond forming event. The method offers high branched selectivity and enantioselectivity and occurs with complete atom economy. Diastereocontrolled reduction of the products provides ß2-amino acids that possess contiguous stereocenters.

In Vitro and In Vivo Studies on a Mononuclear Ruthenium Complex Reveals It is a Highly Effective, Fast-Acting, Broad-Spectrum Antimicrobial in Physiologically Relevant Conditions.

The crystal structure of a previously reported antimicrobial RuII complex that targets bacterial DNA is presented. Studies utilizing clinical isolates of Gram-negative bacteria that cause catheter-associated urinary tract infection, (CA)UTI, in media that model urine and plasma reveal that good antimicrobial activity is maintained in all conditions tested. Experiments with a series of Staphylococcus aureus clinical isolates show that, unlike the majority of previously reported RuII-based antimicrobial leads, the compound retains its potent activity even in MRSA strains. Furthermore, experiments using bacteria in early exponential growth and at different pHs reveal that the compound also retains its activity across a range of conditions that are relevant to those encountered in clinical settings. Combinatorial studies involving cotreatment with conventional antibiotics or a previously reported analogous dinuclear RuII complex showed no antagonistic effects. In fact, although all combinations show distinct additive antibacterial activity, in one case, this effect approaches synergy. It was found that the Galleria Mellonella model organism infected with a multidrug resistant strain of the ESKAPE pathogen Acinetobacter baumannii could be successfully treated and totally cleared within 48 h after a single dose of the lead complex with no detectable deleterious effect to the host.

Zero-Bias Anti-Ohmic Behaviour in Diradicaloid Molecular Wires.

Open-shell materials bearing multiple spin centres provide a key route to efficient charge transport in single-molecule electronic devices. They have narrow energy gaps, and their molecular orbitals align closely to the Fermi level of the metallic electrodes, thus allowing efficient electronic transport and higher conductance. Maintaining and stabilising multiple open-shell states - especially in contact with metallic electrodes - is however very challenging, generally requiring a continuous chemical or electrochemical potential to avoid self-immolation of the open-shell character. To overcome this issue, we designed, synthesised, and measured the conductance of a series of bis(indeno) fused acenes, where stability is imparted by a close-shell quinoidal conformation in resonance with the diradical electronic configuration. We show here that these compounds have anti-ohmic behaviour, with conductance increasing with increasing molecular length, at an unprecedented rate and across the entire bias window ([[EQUATION]]). Density Functional Theory (DFT) calculations support our findings, showing the rapidly narrowing HOMO-LUMO gap, unique to these diradicaloid structures, is responsible for the observed behaviour. Our results provide a framework for achieving efficient transport in neutral compounds and demonstrate the promise that diradicaloid materials have in single-molecule electronics, owing to their great stability and unique electronic structure.

Stereoselective Asymmetric Syntheses of Molecules with a 4,5-Dihydro-1H-[1,2,4]-Triazoline Core Possessing an Acetylated Carbohydrate Appendage: Crystal Structure, Spectroscopy, and Pharmacology.

A new series of chiral 4,5-dihydro-1H-[1,2,4]-triazoline molecules, featuring a ß-ᴅ-glucopyranoside appendage, were synthesized via a 1,3-dipolar cycloaddition reaction between various hydrazonyl chlorides and carbohydrate Schiff bases. The isolated enantiopure triazolines (8a-j) were identified through high-resolution mass spectrometry (HRMS) and vibrational spectroscopy. Subsequently, their solution structures were elucidated through NMR spectroscopic techniques. Single-crystal X-ray analysis of derivative 8b provided definitive evidence for the 3-D structure of this compound and revealed important intermolecular forces in the crystal lattice. Moreover, it confirmed the (S)-configuration at the newly generated stereo-center. Selected target compounds were investigated for anti-tumor activity in 60 cancer cell lines, with derivative 8c showing the highest potency, particularly against leukemia. Additionally, substituent-dependent anti-fungal and anti-bacterial behavior was observed.

Reductive Transamination of Pyridinium Salts to N-Aryl Piperidines.

Saturated N-heterocycles are found in numerous bioactive natural products and are prevalent in pharmaceuticals and agrochemicals. While there are many methods for their synthesis, each has its limitations, such as scope and functional group tolerance. Herein, we describe a rhodium-catalyzed transfer hydrogenation of pyridinium salts to access N-(hetero)aryl piperidines. The reaction proceeds via a reductive transamination process, involving the initial formation of a dihydropyridine intermediate via reduction of the pyridinium ion with HCOOH, which is intercepted by water and then hydrolyzed. Subsequent reductive amination with an exogenous (hetero)aryl amine affords an N-(hetero)aryl piperidine. This reductive transamination method thus allows for access of N-(hetero)aryl piperidines from readily available pyridine derivatives, expanding the toolbox of dearomatization and skeletal editing.

A Systematic Study of Methyl Carbodithioate Esters as Effective Gold Contact Groups for Single-Molecule Electronics.

There are several binding groups used within molecular electronics for anchoring molecules to metal electrodes (e.g., R-SMe, R-NH2, R-CS2 -, R-S-). However, some anchoring groups that bind strongly to electrodes have poor/unknown stability, some have weak electrode coupling, while for some their binding motifs are not well defined. Further binding groups are required to aid molecular design and to achieve a suitable balance in performance across a range of properties. We present an in-depth investigation into the use of carbodithioate esters as contact groups for single-molecule conductance measurements, using scanning tunnelling microscopy break junction measurements (STM-BJ) and detailed surface spectroscopic analysis. We demonstrate that the methyl carbodithioate ester acts as an effective contact for gold electrodes in STM-BJ measurements. Surface enhanced Raman measurements demonstrate that the C=S functionality remains intact when adsorbed on to gold nanoparticles. A gold(I) complex was also synthesised showing a stable C=S→AuI interaction from the ester. Comparison with a benzyl thiomethyl ether demonstrates that the C=S moiety significantly contributes to charge transport in single-molecule junctions. The overall performance of the CS2Me group demonstrates it should be used more extensively and has strong potential for the fabrication of larger area devices with long-term stability.

Phenazine Cations as Anticancer Theranostics†.

The biological properties of two water-soluble organic cations based on polypyridyl structures commonly used as ligands for photoactive transition metal complexes designed to interact with biomolecules are investigated. A cytotoxicity screen employing a small panel of cell lines reveals that both cations show cytotoxicity toward cancer cells but show reduced cytotoxicity to noncancerous HEK293 cells with the more extended system being notably more active. Although it is not a singlet oxygen sensitizer, the more active cation also displayed enhanced potency on irradiation with visible light, making it active at nanomolar concentrations. Using the intrinsic luminescence of the cations, their cellular uptake was investigated in more detail, revealing that the active compound is more readily internalized than its less lipophilic analogue. Colocalization studies with established cell probes reveal that the active cation predominantly localizes within lysosomes and that irradiation leads to the disruption of mitochondrial structure and function. Stimulated emission depletion (STED) nanoscopy and transmission electron microscopy (TEM) imaging reveal that treatment results in distinct lysosomal swelling and extensive cellular vacuolization. Further imaging-based studies confirm that treatment with the active cation induces lysosomal membrane permeabilization, which triggers lysosome-dependent cell-death due to both necrosis and caspase-dependent apoptosis. A preliminary toxicity screen in the Galleria melonella animal model was carried out on both cations and revealed no detectable toxicity up to concentrations of 80 mg/kg. Taken together, these studies indicate that this class of synthetically easy-to-access photoactive compounds offers potential as novel therapeutic leads.

Control of Polarity in Kagome-NiAs Bismuthides.

A 2×2×1 superstructure of the P63/mmc NiAs structure is reported in which kagome nets are stabilized in the octahedral transition metal layers of the compounds Ni0.7Pd0.2Bi, Ni0.6Pt0.4Bi, and Mn0.99Pd0.01Bi. The ordered vacancies that yield the true hexagonal kagome motif lead to filling of trigonal bipyramidal interstitial sites with the transition metal in this family of "kagome-NiAs" type materials. Further ordering of vacancies within these interstitial layers can be compositionally driven to simultaneously yield kagome-connected layers and a net polarization along the c axes in Ni0.9Bi and Ni0.79Pd0.08Bi, which adopt Fmm2 symmetry. The polar and non-polar materials exhibit different electronic transport behaviour, reflecting the tuneability of both structure and properties within the NiAs-type bismuthide materials family.

Superionic lithium transport via multiple coordination environments defined by two-anion packing.

Fast cation transport in solids underpins energy storage. Materials design has focused on structures that can define transport pathways with minimal cation coordination change, restricting attention to a small part of chemical space. Motivated by the greater structural diversity of binary intermetallics than that of the metallic elements, we used two anions to build a pathway for three-dimensional superionic lithium ion conductivity that exploits multiple cation coordination environments. Li7Si2S7I is a pure lithium ion conductor created by an ordering of sulphide and iodide that combines elements of hexagonal and cubic close-packing analogously to the structure of NiZr. The resulting diverse network of lithium positions with distinct geometries and anion coordination chemistries affords low barriers to transport, opening a large structural space for high cation conductivity.

Radical coupling of aryl halides to arenes facilitated by Ni(COD)(DQ) and other nickel sources.

The air-stable complex Ni(COD)(DQ) (COD = 1,5-cyclooctadiene, DQ = duroquinone) promotes the coupling of aryl halides to arenes in the presence of KOtBu. This complex has recently been shown to perform coupling reactions based on organonickel intermediates, but in this case the coupling reactions proceed via aryl radicals as shown by our newly developed assay for aryl radicals. Coupling with this nickel source is more efficient than with Ni(COD)2, Ni(PPh3)4 and Ni(acac)2, all of which we also show to operate through aryl radical pathways.

An assay for aryl radicals using BHAS coupling.

Aryl radicals are intermediates in many reactions, but determining their presence unambiguously is often challenging. As we recently reported, reaction of 2-iodo-1,3-dimethylbenzene (7) in benzene with KOtBu and a suitable organic additive, leads to a base-induced homolytic aromatic substitution (BHAS) coupling reaction giving 2,6-dimethylbiphenyl (12) and biphenyl (3) as coupled products, together with xylene (13). In this case, biphenyl arises from a radical translocation and is the major coupling product. This paper now quantitatively investigates that reaction, which shows a very similar ratio for 3 : 12 [ca. 4 : 1] when using different sources of radical initiation. Deuterium isotope studies provide detailed mechanistic support for the proposed mechanism; when carried out in C6D6vs. C6H6, the reaction is characterised by a strong isotope effect for formation of 3-d10vs. 3, but not for formation of 12-d5vs. 12. These distinctive properties mean that the transformation can act as an assay for aryl radicals. An advantage of such a BHAS process is its sensitivity, since it involves a chain reaction that can amplify radical activity.

Mechanical Manipulation of Quantum Interference in Single-Molecule Junctions.

Mechanosensitive molecular junctions, where conductance is sensitive to an applied stress such as force or displacement, are a class of nanoelectromechanical systems unique for their ability to exploit quantum mechanical phenomena. Most studies so far relied on reconfiguration of the molecule-electrode interface to impart mechanosensitivity, but this approach is limited and, generally, poorly reproducible. Alternatively, devices that exploit conformational flexibility of molecular wires have been recently proposed. The mechanosensitive properties of molecular wires containing the 1,1'-dinaphthyl moiety are presented here. Rotation along the chemical bond between the two naphthyl units is possible, giving rise to two conformers (transoid and cisoid) that have distinctive transport properties. When assembled as single-molecule junctions, it is possible to mechanically trigger the transoid to cisoid transition, resulting in an exquisitely sensitive mechanical switch with high switching ratio (> 102). Theoretical modeling shows that charge reconfiguration upon transoid to cisoid transition is responsible for the observed behavior, with generation and subsequent lifting of quantum interference features. These findings expand the experimental toolbox of molecular electronics with a novel chemical structure with outstanding electromechanical properties, further demonstrating the importance of subtle changes in charge delocalization on the transport properties of single-molecule devices.