A three-phase heterogeneous model was developed to simulate the performance of pilot-plant
and industrial trickle-bed reactors applied to the hydrodesulfurization of diesel fractions. The
model is based on two-film theory and incorporates mass-transfer phenomena at the gas−liquid
and liquid−solid interfaces. The major hydrotreating reactions, namely, hydrodesulfurization,
hydrodenitrogenation, hydrodearomatization, saturation of olefins, and hydrocracking, were
modeled. Detailed pilot-plant experiments were carried out in a continuous-flow trickle-bed
reactor using feedstock and catalyst samples collected from an industrial reactor to determine
kinetic parameters and to validate the model under various operating conditions. The reactor
temperature was varied from 320 to 360 °C and the liquid hourly space velocity from 1.0 to 2.5
h-1 at a constant operating pressure of 4.0 MPa and a H2/oil ratio of 200 L/L. The three-phase
heterogeneous model was solved to estimate kinetic parameters for various hydrotreating
reactions using the data generated in pilot-plant experiments. A partial wetting model was
proposed to account for incomplete wetting of the catalyst particles in pilot-plant reactors. The
model simulations were found to agree well with the experimental data in the range of operating
conditions studied. A three-phase nonisothermal heterogeneous model with complete catalyst
wetting was applied to simulate the performance of an industrial reactor under various operating
conditions using the kinetic parameters estimated from pilot-plant experiments. Temperature
profiles in the industrial reactor were generated. The model was found to simulate the
performance of the industrial reactor adequately. The model was also applied to study the
influence of operating conditions such as reactor temperature and feed rate on product quality.
Synthetically versatile 3,3-disubstituted fluorooxindoles exhibiting vicinal
chirality centers were obtained in high yields and with excellent enantio-, diastereo- and regioselectivity by catalytic asymmetric fluoroenolate alkylation with allylic acetates. The reaction proceeds under mild conditions and can be upscaled without compromising the asymmetric induction. The unique synthetic usefulness of the products is highlighted with the incorporation of additional functionalities and the formation of 3-fluorinated oxindoles exhibiting an array of four adjacent chirality centers. A new C-F bond functionalization path that provides unprecedented means for stereoselective generation of a chiral quaternary carbon center in the alkaloid scaffold is introduced.
The role of Discoidin Domain Receptors (DDRs) is poorly understood in neurodegeneration. DDRs are upregulated in Alzheimer’s and Parkinson’s disease, and DDRs knockdown reduces neurotoxic protein levels. Here we show that potent and preferential DDR1 inhibitors reduce neurotoxic protein levels in vitro and in vivo. Partial or complete deletion or inhibition of DDR1 in a mouse model challenged with alpha-synuclein increases autophagy and reduces inflammation and neurotoxic proteins. Significant changes of cerebrospinal fluid miRNAs that control inflammation, neuronal injury, autophagy and vesicular transport genes are observed in Parkinson’s disease with and without dementia and Lewy body dementia, but these changes are attenuated or reversed after treatment with the DDR1 inhibitor, nilotinib. Collectively, these data demonstrate that DDR1 regulates autophagy and reduces neurotoxic proteins and inflammation and is a therapeutic target in neurodegeneration.
Click reactions have become powerful synthetic tools with unique applications in the health and materials sciences. Despite the progress with optical sensors that exploit the principles of dynamic covalent chemistry, metal coordination or supramolecular assemblies, quantitative analysis of complex mixtures remains challenging. Herein, we report the use of a readily available coumarin conjugate acceptor for chiroptical click chirality sensing of the absolute configuration, concentration and enantiomeric excess of several compound classes. This method has several attractive features, including wide scope, fast substrate fixation without by-product formation or complicate equilibria often encountered in reversible substrate binding, excellent solvent compatibility, and tolerance of air and water. The ruggedness and practicality of this approach are demonstrated by comprehensive analysis of nonracemic monoamine samples and crude asymmetric imine hydrogenation mixtures without work-up. Click chemosensing addresses increasingly important time efficiency, cost, labor and chemical sustainability aspects and streamlines asymmetric reaction development at the mg scale.
Ubiquitin Specific Protease-13 (USP13) promotes protein de-ubiquitination and is poorly understood in neurodegeneration. USP13 is upregulated in Alzheimer’s disease (AD) and Parkinson’s disease (PD), and USP13 knockdown via shRNA reduces neurotoxic proteins and increases proteasome activity in models of neurodegeneration. We synthesized novel analogues of spautin-1 which is a non-specific USP13 inhibitor but unable to penetrate the brain. Our synthesized small molecule compounds are able to enter the brain, more potently inhibit USP13, and significantly reduce alpha-synuclein levels in vivo and in vitro. USP13 inhibition in transgenic mutant alpha-synuclein (A53T) mice increased the ubiquitination of alpha-synuclein and reduced its protein levels. The data suggest that novel USP13 inhibitors improve neurodegenerative pathology via antagonism of de-ubiquitination, thus alleviating neurotoxic protein burden in neurodegenerative diseases.
Suzuki cross-coupling of benzylic
and unactivated aliphatic fluorides
with aryl- and alkenylboronic acids has been achieved via mechanistically
distinct Pd and Ni catalyzed pathways that outperform competing protodeboronation,
β-hydride elimination, and homocoupling processes. The utility
is demonstrated with more than 20 examples including heterocyclic
structures, 1,1-disubstituted and trans-1,2-disubstituted
alkenes, and by the incorporation of acetonitrile into functionalized
(hetero)arenes.
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