Homogeneously catalyzed hydroformylation in supercritical carbon dioxide : kinetics, thermodynamics, and membrane reactor technology for continuous operation

The increased awareness for environmental issues and concomitant environmentally conscious governmental policies has prompted the chemical process industry to implement "greener" production and synthesis methods. In particular, the reduction of the emission of harmful, often organic, substances, reduction of the production of waste, and increasing the energy efficiency are three important aspects in the development of environmentally benign chemical production processes. For the chemical and chemical engineering academic community this has given rise to a new direction, where the concept of "green chemistry" is being explored. Supercritical fluids have been established as promising substitutes to organic solvents. Carbon dioxide is of particular interest as an alternative solvent as it has a low toxicity, is non-flammable and has an accessible critical temperature and pressure. In addition, catalysis is an important tool for the optimization of atom efficiency of a chemical conversion, and therefore for the reduction of waste production. Additionally, catalysis allows for reactions to take place under milder conditions, which can also contribute to an increase in energy efficiency. In particular, soluble molecular organometallic catalysts allow chemical conversions with a higher rate and a better selectivity than their heterogeneous counterparts. The difficult separation of a homogeneous catalyst from reaction products, without deactivating the catalyst, is one of the main obstacles for their application on an industrial scale. Nanofiltration using a microporous ceramic membrane has the potential to be a solution to this problem. A large enough catalyst molecule will be retained while reaction products and solvent can permeate across the membrane. In the field of separation technology membranes have emerged as an energy efficient alternative to conventional separation methods, like distillation and extraction. Ceramic membranes are seen as one of the most promising candidates to purify process streams under demanding conditions. The main objectives of this thesis are the evaluation of the possible advantages of using supercritical carbon dioxide as a solvent as an alternative for organic solvents, and the investigation into the potential of membrane technology for the retention of homogeneous catalysts. The hydroformylation of 1-octene, which is an example of a homogeneously catalyzed reaction on an industrial scale, is considered as a model reaction. To perform the hydroformylation in supercritical carbon dioxide an experimental procedure has been developed, which allows for catalyst preparation under hydroformylation conditions and for carrying out the hydroformylation reaction with a well-defined starting point. It has been demonstrated that with this experimental procedure it is possible to obtain highly reproducible results. Furthermore, a relationship between the change in pressure and the change in reaction mixture composition as a function of time has been established. Using this experimental procedure the effect of total pressure, temperature, concentration of reactants, and concentration of catalyst precursors on the reaction rate, chemoselectivity, and the regioselectivity of the hydroformylation of 1-octene has been studied. The concentration of carbon dioxide had an effect on the regioselectivity of the reaction. Therefore, the same density of solvent has been used for each experiment rather than the more common approach of applying the same total pressure for each experiment. Based on the results obtained by the variation of the reaction parameters a kinetic model has been developed. An optimization method has been applied to find the model parameter values that best describe the experimental data. The observed kinetics for the catalyst based on rhodium(I) dicarbonyl acetylacetonate and tris(3,5-bis(trifluoromethyl)phenyl)phosphine shows resemblance to that observed for the hydroformylation where bulky phosphites have been used as the ligand. For this catalyst a high activity in the order of 5×103 to 12×103 mol1-octene molRh-1 h-1 has been observed at 70 °C. Organometallic complexes based on rhodium with phosphine ligands with a varying number of trifluoromethyl groups have been screened for their activity and selectivity for the hydroformylation of 1-octene. Furthermore, the effect of the type of solvent: carbon dioxide, hexane, and toluene has been included in this study. An increase in the number of trifluoromethyl substituents on the triphenylphosphine ligand results in an increase in 1-octene conversion rate and a decrease in the overall selectivity towards aldehydes. This behaviour is observed in all three solvents. For supercritical carbon dioxide or hexane, as the solvent, the outcome of the hydroformylation reaction in terms of activity and selectivity shows great similarity. By following the hydroformylation of 1-octene in time, it was observed that during batch operation rhodium catalysts with trifluoromethyl-substituted triarylphosphines showed a higher differential regioselectivity than based on the overall regioselectivity at the end of the reaction. For the hydroformylation in carbon dioxide this effect was most pronounced. Both the mode of operation, batch or semi batch, and the type of solvent had a significant influence on this phenomenon. The transport of a supercritical fluid across a microporous alumina supported titania membrane has been investigated. The dependence of the permeation of carbon dioxide across the titania membrane on the feed pressure is similar to what has been previously observed for microporous alumina supported silica membranes. At high feed pressure viscous flow appears to be the main mechanism of mass transport across the membrane. Furthermore, the titania membrane shows a reasonable stability over a period of operation of about at least six months in varying conditions. Finally, the first continuously operated experiment has been performed, in which hydroformylation of 1-octene and separation of the catalyst have been integrated using a membrane reactor. During a 27.5 h of operation of the membrane reactor, spread over four consecutive days, a maximum conversion of 17 % and a maximum regioselectivity of 5 in terms of n:iso ratio has been observed. The conversion and the n:iso ratio, which is the ratio between the linear and branched aldehyde product, decrease as a function of the number of permeated reactor volumes indicating a loss of catalyst. Permeation of free ligand and the catalytic species through the membrane appear to be the main reasons for the decrease in activity and selectivity. A good match between membrane retention characteristics and the size of the catalyst and its precursors is not found yet. However, a number of feasible improvements can be made to improve the retention of the catalyst. Using a membrane for retention of a homogeneous catalyst in combination with the application of carbon dioxide as a solvent for the continuous hydroformylation of 1-octene has great potential. Successful application of the envisioned membrane reactor process can have implications for other homogeneously catalyzed reactions of which asymmetric hydrogenation is a commercially relevant example. As a result of the experimental methods used in this thesis the potential benefits of using carbon dioxide as an environmentally benign alternative to organic solvents could be further extended

Придністровський конфлікт: чинники існування напруги

Стаття присвячена аналізу та систематизації чинників, що обумовлюють збереження статус-кво у процесі придністровського врегулювання на глобальному, регіональному та локальному рівні.The article is devoted to the analysis and systematization of factors leading to the preservation of the status-quo in the Transnistrian settlement process on global, regional and local level

Multi-Omics Approaches in Immunological Research

The immune system plays a vital role in health and disease, and is regulated through a complex interactive network of many different immune cells and mediators. To understand the complexity of the immune system, we propose to apply a multi-omics approach in immunological research. This review provides a complete overview of available methodological approaches for the different omics data layers relevant for immunological research, including genetics, epigenetics, transcriptomics, proteomics, metabolomics, and cellomics. Thereafter, we describe the various methods for data analysis as well as how to integrate different layers of omics data. Finally, we discuss the possible applications of multi-omics studies and opportunities they provide for understanding the complex regulatory networks as well as immune variation in various immune-related diseases

Potts Shunt to Be Preferred Above Atrial Septostomy in Pediatric Pulmonary Arterial Hypertension Patients: A Modeling Study

Aims: To quantitatively evaluate the basic pathophysiological process involved in the creation of Eisenmenger syndrome in pediatric pulmonary arterial hypertension (PAH) patients by either atrial septostomy (AS) or Potts shunt (PS) as well as to predict the effects of AS or PS in future PAH patients.Methods: The multi-scale lumped parameter CircAdapt model of the cardiovascular system was used to investigate the effects of AS and PS on cardiovascular hemodynamics and mechanics, as well as on oxygen saturation in moderate to severe PAH. The reference simulation, with cardiac output set to 2.1 l/min and mean systemic pressure to 61 mmHg, was used to create a compensated moderate PAH simulation with mPAP 50 mmHg. Thereupon we created a range of decompensated PAH simulations in which mPAP was stepwise increased from 50 to 80 mmHg. Then we simulated for each level of mPAP the acute effects of either PS or AS with connection diameters ranging between 0–16 mm.Results: For any mPAP level, the effect on shunt flow size is much larger for the PS than for AS. Whereas right ventricular pump work in PS is mainly dependent on mPAP, in AS it depends on both mPAP and the size of the defect. The effects on total cardiac pump work were similar for PS and AS. As expected, PS resulted in a drastic decrease of lower body oxygen saturation, whereas in AS both the upper and lower body oxygen saturation decreased, though not as drastically as in PS.Conclusion: Our simulations support the opinion that a PS can transfer suprasystemic PAH to an Eisenmenger physiology associated with a right-to-left shunt at the arterial level. Contrary to the current opinion that PS in PAH will decompress and unload the right ventricle, we show that while a PS does lead to a decrease in mPAP toward mean systemic arterial pressure, it does not unload the right ventricle because it mainly diverts flow from the pulmonary arterial system toward the lower body systemic arteries

Development of a species-specific polymerase chain reaction assay for Gardnerella vaginalis

The nucleotide sequence of the region between the 16S and 23S rRNA genes of the facultative anaerobic bacteriumGardnerella vaginalishas been determined, together with the 5′ proximal 500 nucleotides of the 23S rRNA gene. Regions suited for the development of specific, probe-confirmable polymerase chain reaction (PCR) assays were selected. PCR assays were evaluated with respect to sensitivity and specificity, the latter in comparison with a number ofG. vaginalisreference strains and closely related species likeBifidobacteriumspp. In an initial diagnostic study it appeared that the PCR test detectedG. vaginalisin 40% of women irrespective of their clinical status. Ten out of 11 patients suffering from bacterial vaginosis as defined on the basis of clinical parameters were carryingG. vaginalis

Tissue metabolic changes drive cytokine responses to Mycobacterium tuberculosis

Cellular metabolism can influence host immune responses to Mycobacterium tuberculosis (Mtb). Using a systems biology approach, differential expression of 292 metabolic genes involved in glycolysis, glutathione, pyrimidine and inositol phosphate pathways was evident at the site of a human tuberculin skin test challenge in patients with active tuberculosis infection. For 28 metabolic genes, we identified single nucleotide polymorphisms (SNPs) that were trans-acting for in vitro cytokine responses to Mtb stimulation, including glutathione and pyrimidine metabolism genes that alter production of Th1 and Th17 cytokines. Our findings identify novel therapeutic targets in host metabolism that may shape protective immunity to tuberculosis

Transmissible Mycobacterium tuberculosis Strains Share Genetic Markers and Immune Phenotypes

Successful transmission of tuberculosis depends on the interplay of human behavior, host immune responses, and Mycobacterium tuberculosis virulence factors. Previous studies have been focused on identifying host risk factors associated with increased transmission, but the contribution of specific genetic variations in mycobacterial strains themselves are still unknown.This study was funded by the Portuguese Foundation for Science and Technology (FCT) (SFRH/BD/33902/2009 [H.N.-G.])

Metformin Alters Human Host Responses to Mycobacterium tuberculosis in Healthy Subjects.

BACKGROUND: Metformin, the most widely administered diabetes drug, has been proposed as a candidate adjunctive host-directed therapy for tuberculosis, but little is known about its effects on human host responses to Mycobacterium tuberculosis. METHODS: We investigated in vitro and in vivo effects of metformin in humans. RESULTS: Metformin added to peripheral blood mononuclear cells from healthy volunteers enhanced in vitro cellular metabolism while inhibiting the mammalian target of rapamycin targets p70S6K and 4EBP1, with decreased cytokine production and cellular proliferation and increased phagocytosis activity. Metformin administered to healthy human volunteers led to significant downregulation of genes involved in oxidative phosphorylation, mammalian target of rapamycin signaling, and type I interferon response pathways, particularly following stimulation with M. tuberculosis, and upregulation of genes involved in phagocytosis and reactive oxygen species production was increased. These in vivo effects were accompanied by a metformin-induced shift in myeloid cells from classical to nonclassical monocytes. At a functional level, metformin lowered ex vivo production of tumor necrosis factor α, interferon γ, and interleukin 1β but increased phagocytosis activity and reactive oxygen species production. CONCLUSION: Metformin has a range of potentially beneficial effects on cellular metabolism, immune function, and gene transcription involved in innate host responses to M. tuberculosis