Asthma: an inflammatory mediator soup

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldReversible or partially reversible airway obstruction, inflammation, and bronchial hyperresponsiveness to various stimuli are the defining characteristics of asthma. Airway obstruction in asthma is a complex event that is due to bronchospasm, inflammation, and mucus formation. Inflammation has assumed a more central role in the pathogenesis of the disease, as it contributes not only to airflow obstruction, but also to bronchial hyperresponsiveness. The inciting trigger, or inhaled allergen, in asthma induces the activation of mast cells and macrophages with the subsequent release of several proinflammatory mediators, including leukotrienes, chemotactic factors, and cytokines. Antigen processed by macrophages is presented to undifferentiated T helper cells, inducing differentiation to the Th2 phenotype, with the subsequent release of IL-4 and IL-5, causing IgE synthesis and eosinophil infiltration, respectively. Macrophage-derived cytokines, such as IL-1, TNF-alpha, and IFN-gamma, activate endothelial cells, upregulating the expression of adhesion molecules such as ICAM-1 and VCAM-1, which permit egression of leukocytes from the vasculature to the airway mucosa. Several inflammatory cells, such as eosinophils, mast cells, and macrophages, not only cause airway damage, but also synthesize cytokines that perpetuate the inflammatory process. This complex interplay of inflammatory cells and mediators causes the classic histopathophysiologic features in the airways of both symptomatic and asymptomatic individuals with asthma, emphasizing the importance of early recognition and antiinflammatory treatment

Thermochemical Studies of Nickel Hydride Complexes with Cationic Ligands in Aqueous and Organic Solvents

Transition metal hydride complexes are key intermediates in a variety of catalytic processes. Transfer of a hydride, hydrogen atom, or proton is defined by the thermochemical parameters of hydricity, bond dissociation free energy (BDFE), and pKa, respectively. These values have been studied primarily in organic solvents to predict or understand reactivity. Despite growing interest in the development of aqueous metal hydride catalysis, BDFE measurements of transition metal hydrides in water are rare. Herein, we report two nickel hydride complexes with one or two cationic ligands that enable the measurement of BDFE values in both aqueous and organic solvents using their reduction potential and pKa values. The Ni(I/0) reduction potentials increase anodically as more charged groups are introduced into the ligand framework and are among the most positive values measured for Ni complexes. The complex with two cationic ligands, 2-Ni(II)–H, displays exceptional stability in water with no evidence of decomposition at pH 1 for at least 2 weeks. The BDFE of the nickel hydride bond in 2-Ni(II)–H was measured to be 53.6 kcal/mol in water and between 50.9 and 56.2 kcal/mol in acetonitrile, consistent with prior work that indicates minimal solvent dependence for BDFEs of O–H and N–H bonds. These results indicate that transition metal hydride BDFEs do not change drastically in water and inform future studies on highly cationic transition metal hydride complexes

C(sp³)–H Fluorination with a Copper(II)/(III) Redox Couple

Despite the growing interest in the synthesis of fluorinated organic compounds, few reactions are able to incorporate fluoride ions directly into alkyl C–H bonds. Here, we report the C­(sp3)–H fluorination reactivity of a formally copper­(III) fluoride complex. The C–H fluorination intermediate, LCuF, along with its chloride and bromide analogues, LCuCl and LCuBr, were prepared directly from halide sources with a chemical oxidant and fully characterized with single-crystal X-ray diffraction, X-ray absorption spectroscopy, UV–vis spectroscopy, and 1H nuclear magnetic resonance spectroscopy. Quantum chemical calculations reveal significant halide radical character for all complexes, suggesting their ability to initiate and terminate a C­(sp3)–H halogenation sequence by sequential hydrogen atom abstraction (HAA) and radical capture. The capability of HAA by the formally copper­(III) halide complexes was explored with 9,10-dihydroanthracene, revealing that LCuF exhibits rates 2 orders of magnitude higher than LCuCl and LCuBr. In contrast, all three complexes efficiently capture carbon radicals to afford C­(sp3)–halogen bonds. Mechanistic investigation of radical capture with a triphenylmethyl radical revealed that LCuF proceeds through a concerted mechanism, while LCuCl and LCuBr follow a stepwise electron transfer–halide transfer pathway. The capability of LCuF to perform both hydrogen atom abstraction and radical capture was leveraged to enable fluorination of allylic and benzylic C–H bonds and α-C–H bonds of ethers at room temperature

C(sp³)–H Fluorination with a Copper(II)/(III) Redox Couple

Despite the growing interest in the synthesis of fluorinated organic compounds, few reactions are able to incorporate fluoride ions directly into alkyl C–H bonds. Here, we report the C­(sp3)–H fluorination reactivity of a formally copper­(III) fluoride complex. The C–H fluorination intermediate, LCuF, along with its chloride and bromide analogues, LCuCl and LCuBr, were prepared directly from halide sources with a chemical oxidant and fully characterized with single-crystal X-ray diffraction, X-ray absorption spectroscopy, UV–vis spectroscopy, and 1H nuclear magnetic resonance spectroscopy. Quantum chemical calculations reveal significant halide radical character for all complexes, suggesting their ability to initiate and terminate a C­(sp3)–H halogenation sequence by sequential hydrogen atom abstraction (HAA) and radical capture. The capability of HAA by the formally copper­(III) halide complexes was explored with 9,10-dihydroanthracene, revealing that LCuF exhibits rates 2 orders of magnitude higher than LCuCl and LCuBr. In contrast, all three complexes efficiently capture carbon radicals to afford C­(sp3)–halogen bonds. Mechanistic investigation of radical capture with a triphenylmethyl radical revealed that LCuF proceeds through a concerted mechanism, while LCuCl and LCuBr follow a stepwise electron transfer–halide transfer pathway. The capability of LCuF to perform both hydrogen atom abstraction and radical capture was leveraged to enable fluorination of allylic and benzylic C–H bonds and α-C–H bonds of ethers at room temperature

C(sp³)–H Fluorination with a Copper(II)/(III) Redox Couple

Despite the growing interest in the synthesis of fluorinated organic compounds, few reactions are able to incorporate fluoride ions directly into alkyl C–H bonds. Here, we report the C­(sp3)–H fluorination reactivity of a formally copper­(III) fluoride complex. The C–H fluorination intermediate, LCuF, along with its chloride and bromide analogues, LCuCl and LCuBr, were prepared directly from halide sources with a chemical oxidant and fully characterized with single-crystal X-ray diffraction, X-ray absorption spectroscopy, UV–vis spectroscopy, and 1H nuclear magnetic resonance spectroscopy. Quantum chemical calculations reveal significant halide radical character for all complexes, suggesting their ability to initiate and terminate a C­(sp3)–H halogenation sequence by sequential hydrogen atom abstraction (HAA) and radical capture. The capability of HAA by the formally copper­(III) halide complexes was explored with 9,10-dihydroanthracene, revealing that LCuF exhibits rates 2 orders of magnitude higher than LCuCl and LCuBr. In contrast, all three complexes efficiently capture carbon radicals to afford C­(sp3)–halogen bonds. Mechanistic investigation of radical capture with a triphenylmethyl radical revealed that LCuF proceeds through a concerted mechanism, while LCuCl and LCuBr follow a stepwise electron transfer–halide transfer pathway. The capability of LCuF to perform both hydrogen atom abstraction and radical capture was leveraged to enable fluorination of allylic and benzylic C–H bonds and α-C–H bonds of ethers at room temperature