Primary vs. secondary alkylpyridinium salts: a comparison under electrochemical and chemical reduction conditions.

This report details a systematic comparison of the scope of aryl bromides in nickel-catalyzed, reductive cross-electrophile couplings of primary vs. secondary alkylpyridinium salts using both electrochemical and chemical reductants. Facilitated by the use of high-throughput experimentation (HTE) techniques, 37 aryl bromides, including 13 complex, drug-like examples, were investigated. By using primary and secondary substrates differing only by one methylene, we observed that the trends in ArBr scope are similar between the primary and secondary alkylpyridinium salts, although distinctions were observed in isolated cases. In addition, the electrochemical conditions compared favorably to those using chemical reductants, especially among the more complex, drug-like aryl halides.

Nickel-Catalyzed Electroreductive Coupling of Alkylpyridinium Salts and Aryl Halides.

An electrochemical, nickel-catalyzed reductive coupling of alkylpyridinium salts and aryl halides is reported. High-throughput experimentation (HTE) was employed for rapid reaction optimization and evaluation of a broad scope of pharmaceutically relevant structurally diverse aryl halides, including complex drug-like substrates. In addition, the transformation is compatible with both primary and secondary alkylpyridinium salts with distinct conditions. Mechanistic insights were critical to enhance the efficiency of coupling using secondary alkylpyridinium salts. Systematic comparisons of the electrochemical and non-electrochemical methods revealed the complementary scope and efficiency of the two approaches.

Selected Ion Monitoring Using Low-Cost Mass Spectrum Detectors Provides a Rapid, General, and Accurate Method for Enantiomeric Excess Determination in High-Throughput Experimentation.

High-Throughput Experimentation (HTE) workflows are efficient means of surveying a broad array of chiral catalysts in the development of catalytic asymmetric reactions. However, use of traditional HPLC-UV/vis methodology to determine enantiomeric excess (ee) from the resulting reactions is often hampered by co-elution of other reaction components, resulting in erroneous ee determination when crude samples are used, and ultimately requiring product isolation prior to ee analysis. In this study, using four published reactions selected as model systems, we demonstrate that the use of LC-MS, SFC-MS, and selected ion monitoring (SIM) mass chromatography provides a highly accurate means to determine ee of products in crude reaction samples using commonplace, low-cost MS detectors. By using ion selection, co-eluting signals can be deconvoluted to provide accurate integrations of the target analytes. We also show that this method is effective for samples lacking UV/vis chromophores, making it ideal for HTE workflows in asymmetric catalysis.

Ligand switchable site selectivity in C-H alkenylation of thiophenes by turnover-limiting step control.

The origin of switchable site selectivity during Pd-catalysed C-H alkenylation of heteroarenes has been examined through More O'Ferrall-Jencks, isotope effect, and DFT computational analyses, which indicate substitution of ionic thioether for pyridine dative ligands induces a change from selectivity-determining C-H cleavage to C-C bond formation, respectively.

Base-Assisted C-H Bond Cleavage in Cross-Coupling: Recent Insights into Mechanism, Speciation, and Cooperativity.

This review analyzes recent mechanistic studies that have provided new insights into how the structure of a metal complex influences the rate and selectivity of base-assisted C-H cleavage. Partitioning a broader mechanistic continuum into classes delimited by the polarization between catalyst and substrate during C-H cleavage is postulated as a method to identify catalysts favoring electrophilic or nucleophilic reactivity patterns, which may be predictive based on structural features of the metal complex (i.e., oxidation state, d-electron count, charge). Multi-metallic cooperativity and polynuclear speciation also provide new avenues to affect energy barriers for C-H cleavage and site selectivity beyond the limitations of single metal catalysts. An improved understanding of mechanistic nuances and structure-activity relationships on this important bond activation step carries important implications for efficiency and controllable site selectivity in non-directed C-H functionalization.

Early Metal Di(pyridyl) Pyrrolide Complexes with Second Coordination Sphere Arene-π Interactions: Ligand Binding and Ethylene Polymerization.

Early metal complexes supported by hemilabile, monoanionic di(pyridyl) pyrrolide ligands substituted with mesityl and anthracenyl groups were synthesized to probe the possibility of second coordination sphere arene-π interactions with ligands with potential for allosteric control in coordination chemistry, substrate activation, and olefin polymerization. Yttrium alkyl, indolide, and amide complexes were prepared and structurally characterized; close contacts between the anthracenyl substituents and Y-bound ligands are observed in the solid state. Titanium, zirconium, and hafnium tris(dimethylamido) complexes were synthesized, and their ethylene polymerization activity was tested. In the solid state structure of one of the Ti tris(dimethylamido) complexes, coordination of Ti to only one of the pyridine donors is observed pointing to the hemilabile character of the di(pyridyl) pyrrolide ligands.

Factors Related to Linguistic Content in Video Narrative of Adolescents with Cancer and Healthy Controls.

A long history exists of the utilization of narratives to help young people cope with stress and illness. Research is beginning to focus on video based story-telling for the purpose of intervention, however little research has been conducted to look at factors that influence the narrative content of these films. As a pilot, and within the context of a larger study, the current research was conducted with n = 10 adolescents with cancer and n = 10 healthy peers exploring participant characteristics (e.g. personality, quality of life, etc.) and their relationship with linguistic consent of the film. Despite little to no differences identified in demographic characteristics, results identified distinct differences between each group, suggesting that linguistic aspects of film narratives differ in adolescents with and without cancer. This research can serve to motivate future directions of exploration surrounding the content of film narratives and their relationship to patient well-being.

A-Disintegrin and Metalloprotease (ADAM) 10 and 17 promote self-renewal of brain tumor sphere forming cells.

It has been proposed that gliomas contain a subpopulation of 'Brain Tumor Stem Cells' (BTSCs), which demonstrate resistance to conventional therapies. A potential component of the environment governing the behavior of these BTSCs is a class of transmembrane proteins with structural and signaling functions, the A-Disintegrin And Metalloproteases (ADAMs). In this study we confirm overexpression of ADAM10 and 17 in human glioma tissue compared to human controls, and especially in tumor sphere cultures thought to enrich for BTSCs. Inhibition of ADAM10/17 function impairs the growth of tumor spheres with evidence of depletion of the sphere forming cell population. This results from a combination of reduced proliferation, cell death and a switch of sphere-forming cells away from symmetric self-renewal division towards neuronal differentiation. A developing appreciation of the role of ADAMs in BTSC promises insights into pathophysiology and potential therapeutic avenues in this intractable group of tumors.

Salmon olfaction is impaired by an environmentally realistic pesticide mixture.

Many of the salmon-producing waterways of the world contain pesticides known to harm olfactory sensory neurons (OSNs) that are critically important throughout the salmon lifecycle. The ability of OSNs to retain functionality after exposure to complex pesticide mixtures remains unknown. Here we show that a 96-h exposure to an environmentally realistic concentration of a mixture made from the ten most frequently occurring pesticides in British Columbia's Nicomekl River reduced the OSN responses of rainbow troutto a behaviorally relevant odorant. Odor-evoked responses were not altered by exposure to one-fifth of the realistic concentration, and this may have been due an upregulation in detoxification enzymes, since glutathione-S-transferase activity reached a maximum (> 32% above control) at this concentration. Mixture exposure did not help to prevent OSN impairment from a second, brief (5 min) exposure to a higher (20 x) concentration of the mixture, suggesting longer-term, low-concentration exposures may not prevent damage from brief, high-concentration pulse exposures. This study demonstrates that environmentally observed pesticide mixtures can injure salmon olfactory tissue, and by extension, contribute to the threatened and endangered status of many salmon stocks.