Mechanistic and Performance Studies on the Ligand Promoted Ullmann Amination Reaction

Over the last two decades many different auxiliary ligand systems have been utilized in the copper-catalyzed Ullmann amination reaction. However, there has been little consensus on the relative merits of the varied ligands and the exact role they might play in the catalytic process. Accordingly, in this work some of the most commonly employed auxiliary ligands have been evaluated for C–N coupling using reaction progress kinetic analysis (RPKA) methodology. The results reveal not only the relative kinetic competencies of the different auxiliary ligands but also their markedly different influences on catalyst degradation rates. For the model Ullmann reaction between piperidine and iodobenzene using the soluble organic base bis(tetra-n-butylphosphonium) malonate (TBPM) at room temperature, N-methylglycine was shown to give the best performance in terms of high catalytic rate of reaction and comparatively low catalyst deactivation rates. Further experimental and rate data indicate a common catalytic cycle for all auxiliary ligands studied, although additional off-cycle processes are observed for some of the ligands (notably phenanthroline). The ability of the auxiliary ligand, base (malonate dianion), and substrate (amine) to all act competitively as ligands for the copper center is also demonstrated. On the basis of these results an improved protocol for room-temperature copper-catalyzed C–N couplings is presented with 27 different examples reported

Mechanistic studies on the copper-catalyzed N-arylation of alkylamines promoted by organic soluble ionic bases

Experimental studies on the mechanism of copper-catalyzed amination of aryl halides have been undertaken for the coupling of piperidine with iodobenzene using a Cu­(I) catalyst and the organic base tetrabutylphosphonium malonate (TBPM). The use of TBPM led to high reactivity and high conversion rates in the coupling reaction, as well as obviating any mass transfer effects. The often commonly employed O,O-chelating ligand 2-acetylcyclohexanone was surprisingly found to have a negligible effect on the reaction rate, and on the basis of NMR, calorimetric, and kinetic modeling studies, the malonate dianion in TBPM is instead postulated to act as an ancillary ligand in this system. Kinetic profiling using reaction progress kinetic analysis (RPKA) methods show the reaction rate to have a dependence on all of the reaction components in the concentration range studied, with first-order kinetics with respect to [amine], [aryl halide], and [Cu]_total. Unexpectedly, negative first-order kinetics in [TBPM] was observed. This negative rate dependence in [TBPM] can be explained by the formation of an off-cycle copper­(I) dimalonate species, which is also argued to undergo disproportionation and is thus responsible for catalyst deactivation. The key role of the amine in minimizing catalyst deactivation is also highlighted by the kinetic studies. An examination of the aryl halide activation mechanism using radical probes was undertaken, which is consistent with an oxidative addition pathway. On the basis of these findings, a more detailed mechanistic cycle for the C–N coupling is proposed, including catalyst deactivation pathways

Safety of benzodiazepines and opioids in interstitial lung disease: A national prospective study

Copyright ©ERS 2018 Safety concerns are a barrier to prescribing benzodiazepines (BDZs) and opioids in interstitial lung disease (ILD). We therefore examined the association of BDZs and opioids on risk of admission to hospital and death. We conducted a population-based longitudinal cohort study of fibrotic ILD patients starting long-term oxygen therapy in Sweden between October 2005 and December 2014. Effects of BDZs and opioids on rates of admission to hospital and mortality were analysed using Fine-Gray and Cox regression while adjusting for potential confounders. We included 1603 patients (61% females). BDZs were used by 196 (12%) patients and opioids were used by 254 (15%) patients. There was no association between BDZs and increased admission. Treatment with high- versus low-dose BDZs was associated with increased mortality (subdistribution hazard ratio (SHR) 1.46, 95% CI 1.08-1.98 versus 1.13, 95% CI 0.92-1.38). Opioids showed no association with increased admission. Neither low-dose opioids (30 mg·day −1 oral morphine equivalent) (SHR 1.18, 95% CI 0.96-1.45) nor high-dose opioids (>30 mg·day −1 oral morphine equivalent) (SHR 1.11, 95% CI 0.89-1.39) showed association with increased mortality. This first ever study to examine associations between BDZ and opioid use and harm in ILD supports the use of opioids and low-dose BDZs in severely ill patients with respiratory compromise

Cognition and the brain of brood parasitic cowbirds.

Cowbirds are brood parasites. Females lay their eggs in the nests of other species, which then incubate the cowbird eggs and raise the young cowbirds. Finding and returning to heterospecific nests presents cowbirds with several cognitive challenges. In some species, such as brown-headed cowbirds (Molothrus ater), females but not males search for and remember the locations of potential host nests. We describe recent research on sex differences in cognition and the hippocampus associated with this sex difference in search for host nests. Female brown-headed cowbirds perform better than males on some, but not all, tests of spatial memory and females show a pattern of adult hippocampal neurogenesis not found in males or in closely related non-parasitic birds. Because of the apparent specialization of the hippocampus, brown-headed cowbirds may be a good model in which to examine spatial information processing in the avian hippocampus and we also describe recent research on the spatial response properties of brown-headed cowbird hippocampal neurons

The X-ray source population of the globular cluster M15: Chandra high-resolution imaging

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.The globular cluster M15 was observed on three occasions with the High Resolution Camera on-board Chandra in 2001 in order to investigate the X-ray source population in the cluster centre. After subtraction of the two bright central sources, four faint sources were identified within 50 arcsec of the core. One of these sources is probably the planetary nebula K648, making this the first positive detection of X-rays from a planetary nebula inside a globular cluster. Another two are identified with UV variables (one previously known), which we suggest are cataclysmic variables (CVs). The nature of the fourth source is more difficult to ascertain, and we discuss whether it is possibly a quiescent soft X-ray transient or also a CV.DCH is grateful to the Academy of Finland and to PPARC for financial support. MBD gratefully acknowledges the support of a Swedish Royal Academy of Sciences (KVA) Research Fellowship. The authors thank Craig Heinke, Bruce Balick and Joel Kastner for valuable comments. The authors also wish to thank Jonathan C. McDowell for useful suggestions, Miriam Krauss at the Chandra HelpDesk, and the anonymous referee for useful comments. DCH is grateful to Panu Muhli for useful comments. This research has made use of NASA's Astrophysics Data System, SAOImage DS9, developed by Smithsonian Astrophysical Observatory, and of the SIMBAD database operated at CDS, Strasbourg, France. Part of this work was based on observations made with the NASA/ESA Hubble Space Telescope, obtained from the Data Archive at the Space Telescope Science Institute, which is operated by the Association of Universities for Research in Astronomy, Inc., under NASA contract NAS 5-26555

Neutralino dark matter vs galaxy formation

Neutralino dark matter may be incompatible with current cold dark matter models with cuspy dark halos, because excessive synchrotron radiation may originate from neutralino annihilations close to the black hole at the galactic center.Comment: 6 pages, 3 figures, talk given at "Sources and detection of dark matter in the Universe", Marina del Rey, CA, February 23-25, 200

Catalysis by hen egg-white lysozyme proceeds via a covalent intermediate

Hen egg-white lysozyme (HEWL) was the first enzyme to have its three-dimensional structure determined by X-ray diffraction techniques(1). A catalytic mechanism, featuring a long-lived oxo-carbenium-ion intermediate, was proposed on the basis of model-building studies(2). The `Phillips' mechanism is widely held as the paradigm for the catalytic mechanism of beta -glycosidases that cleave glycosidic linkages with net retention of configuration of the anomeric centre. Studies with other retaining beta -glycosidases, however, provide strong evidence pointing to a common mechanism for these enzymes that involves a covalent glycosyl-enzyme intermediate, as previously postulated(3). Here we show, in three different cases using electrospray ionization mass spectrometry, a catalytically competent covalent glycosyl-enzyme intermediate during the catalytic cycle of HEWL. We also show the three-dimensional structure of this intermediate as determined by Xray diffraction. We formulate a general catalytic mechanism for all retaining beta -glycosidases that includes substrate distortion, formation of a covalent intermediate, and the electrophilic migration of C1 along the reaction coordinate