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- Item3,3-Difluoroallyl ammonium salts: highly versatile, stable and selective gem-difluoroallylation reagents([London] : Nature Publishing Group UK, 2021) Ye, Fei; Ge, Yao; Spannenberg, Anke; Neumann, Helfried; Xu, Li-Wen; Beller, MatthiasThe selective synthesis of fluorinated organic molecules continues to be of major importance for the development of bioactive compounds (agrochemicals and pharmaceuticals) as well as unique materials. Among the established synthetic toolbox for incorporation of fluorine-containing units, efficient and general reagents for introducing -CF2- groups have been largely neglected. Here, we present the synthesis of 3,3-difluoropropen-1-yl ammonium salts (DFPAs) as stable, and scalable gem-difluoromethylation reagents, which allow for the direct reaction with a wide range of fascinating nucleophiles. DFPAs smoothly react with N-, O-, S-, Se-, and C-nucleophiles under mild conditions without necessity of metal catalysts with exclusive regioselectivity. In this way, the presented reagents also permit the straightforward preparation of many analogues of existing pharmaceuticals.
- ItemEffect on healthcare utilization and costs of spinal manual therapy for acute low back pain in routine care: A propensity score matched cohort study(San Francisco, California, US : PLOS, 2017) Walker, Jochen; Mertens, Ulf Kai; Schmidt, Carsten Oliver; Chenot, Jean-FrançoisSpinal manual therapy (SMT) is a popular treatment option for low back pain (LBP). The aim of our analysis was to evaluate the effects of manual therapy delivered by general practitioners and ambulatory orthopedic surgeons in routine care on follow up consultations, sick leave, health service utilization and costs for acute LBP compared to matched patients not receiving manual therapy. This is a propensity score matched cohort study based on health claims data. We identified a total of 113.652 adult patients with acute LBP and no coded red flags of whom 21.021 (18%) received SMT by physicians. In the final analysis 17.965 patients in each group could be matched. Balance on patients' coded characteristics, comorbidity and prior health service utilization was achieved. The provision of SMT for acute LBP had no relevant impact on follow up visits and days of sick leave for LBP in the index billing period and the following year. SMT was associated with a higher proportion of imaging studies for LBP (30.6% vs. 23%, SMD: 0.164 [95% CI 0.143-0.185]). SMT did not lead to meaningful savings by replacing other health services for LBP. SMT for acute non-specific LBP in routine care was not clinically meaningful effective to reduce sick leave and reconsultation rates compared to no SMT and did not lead to meaningful savings by replacing other health services from the perspective of health insurance. This does not imply that SMT is ineffective but might reflect a problem with selection of suitable patients and the quality and quantity of SMT in routine care. National Manual Medicine societies should state clearly that imaging is not routinely needed prior to SMT in patients with low suspicion of presence of red flags and monitor the quality of provided services.
- ItemHomogeneous cobalt-catalyzed reductive amination for synthesis of functionalized primary amines([London] : Nature Publishing Group UK, 2019) Murugesan, Kathiravan; Wei, Zhihong; Chandrashekhar, Vishwas G.; Neumann, Helfried; Spannenberg, Anke; Jiao, Haijun; Beller, Matthias; Jagadeesh, Rajenahally V.The development of earth abundant 3d metal-based catalysts continues to be an important goal of chemical research. In particular, the design of base metal complexes for reductive amination to produce primary amines remains as challenging. Here, we report the combination of cobalt and linear-triphos (bis(2-diphenylphosphinoethyl)phenylphosphine) as the molecularly-defined non-noble metal catalyst for the synthesis of linear and branched benzylic, heterocyclic and aliphatic primary amines from carbonyl compounds, gaseous ammonia and hydrogen in good to excellent yields. Noteworthy, this cobalt catalyst exhibits high selectivity and as a result the -NH2 moiety is introduced in functionalized and structurally diverse molecules. An inner-sphere mechanism on the basis of the mono-cationic [triphos-CoH]+ complex as active catalyst is proposed and supported with density functional theory computation on the doublet state potential free energy surface and H2 metathesis is found as the rate-determining step.
- ItemSimple ruthenium-catalyzed reductive amination enables the synthesis of a broad range of primary amines([London] : Nature Publishing Group UK, 2018) Senthamarai, Thirusangumurugan; Murugesan, Kathiravan; Schneidewind, Jacob; Kalevaru, Narayana V.; Baumann, Wolfgang; Neumann, Helfried; Kamer, Paul C. J.; Beller, Matthias; Jagadeesh, Rajenahally V.The production of primary benzylic and aliphatic amines, which represent essential feedstocks and key intermediates for valuable chemicals, life science molecules and materials, is of central importance. Here, we report the synthesis of this class of amines starting from carbonyl compounds and ammonia by Ru-catalyzed reductive amination using H2. Key to success for this synthesis is the use of a simple RuCl2(PPh3)3 catalyst that empowers the synthesis of >90 various linear and branched benzylic, heterocyclic, and aliphatic amines under industrially viable and scalable conditions. Applying this catalyst, −NH2 moiety has been introduced in functionalized and structurally diverse compounds, steroid derivatives and pharmaceuticals. Noteworthy, the synthetic utility of this Ru-catalyzed amination protocol has been demonstrated by upscaling the reactions up to 10 gram-scale syntheses. Furthermore, in situ NMR studies were performed for the identification of active catalytic species. Based on these studies a mechanism for Ru-catalyzed reductive amination is proposed.
- ItemA meta-analysis of catalytic literature data reveals property-performance correlations for the OCM reaction([London] : Nature Publishing Group UK, 2019) Schmack, Roman; Friedrich, Alexandra; Kondratenko, Evgenii V.; Polte, Jörg; Werwatz, Axel; Kraehnert, RalphDecades of catalysis research have created vast amounts of experimental data. Within these data, new insights into property-performance correlations are hidden. However, the incomplete nature and undefined structure of the data has so far prevented comprehensive knowledge extraction. We propose a meta-analysis method that identifies correlations between a catalyst’s physico-chemical properties and its performance in a particular reaction. The method unites literature data with textbook knowledge and statistical tools. Starting from a researcher’s chemical intuition, a hypothesis is formulated and tested against the data for statistical significance. Iterative hypothesis refinement yields simple, robust and interpretable chemical models. The derived insights can guide new fundamental research and the discovery of improved catalysts. We demonstrate and validate the method for the oxidative coupling of methane (OCM). The final model indicates that only well-performing catalysts provide under reaction conditions two independent functionalities, i.e. a thermodynamically stable carbonate and a thermally stable oxide support.
- ItemCation-cation clusters in ionic liquids: Cooperative hydrogen bonding overcomes like-charge repulsion([London] : Macmillan Publishers Limited, part of Springer Nature, 2015) Knorr, Anne; Ludwig, RalfDirect spectroscopic evidence for H-bonding between like-charged ions is reported for the ionic liquid, 1-(2-hydroxyethyl)-3-methylimidazolium tetrafluoroborate. New infrared bands in the OH frequency range appear at low temperatures indicating the formation of H-bonded cation-cation clusters similar to those known for water and alcohols. Supported by DFT calculations, these vibrational bands can be assigned to attractive interaction between the hydroxyl groups of the cations. The repulsive Coulomb interaction is overcome by cooperative hydrogen bonding between ions of like charge. The transition energy from purely cation-anion interacting configurations to those including cation-cation H-bonds is determined to be 3–4 kJmol−1. The experimental findings and DFT calculations strongly support the concept of anti-electrostatic hydrogen bonds (AEHBs) as recently suggested by Weinhold and Klein. The like-charge configurations are kinetically stabilized with decreasing temperatures.
- ItemThe role of allyl ammonium salts in palladium-catalyzed cascade reactions towards the synthesis of spiro-fused heterocycles([London] : Nature Publishing Group UK, 2020) Ye, Fei; Ge, Yao; Spannenberg, Anke; Neumann, Helfried; Beller, MatthiasThere is a continuous need for designing new and improved synthetic methods aiming at minimizing reaction steps while increasing molecular complexity. In this respect, catalytic, one-pot cascade methodologies constitute an ideal tool for the construction of complex molecules with high chemo-, regio-, and stereoselectivity. Herein, we describe two general and efficient cascade procedures for the synthesis of spiro-fused heterocylces. This transformation combines selective nucleophilic substitution (SN2′), palladium-catalyzed Heck and C–H activation reactions in a cascade manner. The use of allylic ammonium salts and specific Pd catalysts are key to the success of the transformations. The synthetic utility of these methodologies is showcased by the preparation of 48 spiro-fused dihydrobenzofuranes and indolines including a variety of fluorinated derivatives.
- ItemCationic clustering influences the phase behaviour of ionic liquids(London : Nature Publishing Group, 2018) Niemann, Thomas; Zaitsau, Dimitri; Strate, Anne; Villinger, Alexander; Ludwig, Ralf“Unlike charges attract, but like charges repel”. This conventional wisdom has been recently challenged for ionic liquids. It could be shown that like-charged ions attract each other despite the powerful opposing electrostatic forces. In principle, cooperative hydrogen bonding between ions of like-charge can overcome the repulsive Coulomb interaction while pushing the limits of chemical bonding. The key challenge of this solvation phenomenon is to establish design principles for the efficient formation of clusters of like-charged ions in ionic liquids. This is realised here for a set of well-suited ionic liquids including the same hydrophobic anion but different cations all equipped with hydroxyethyl groups for possible H-bonding. The formation of H-bonded cationic clusters can be controlled by the delocalization of the positive charge on the cations. Strongly localized charge results in cation-anion interaction, delocalized charge leads to the formation of cationic clusters. For the first time we can show, that the cationic clusters influence the properties of ILs. ILs comprising these clusters can be supercooled and form glasses. Crystalline structures are obtained only, if the ILs are dominantly characterized by the attraction between opposite-charged ions resulting in conventional ion pairs. That may open a new path for controlling glass formation and crystallization. The glass temperatures and the phase transitions of the ILs are observed by differential scanning calorimetry (DSC) and infrared (IR) spectroscopy.
- ItemHomo- and heterodehydrocoupling of phosphines mediated by alkali metal catalysts([London] : Nature Publishing Group UK, 2019) Wu, Lipeng; Annibale, Vincent T.; Jiao, Haijun; Brookfield, Adam; Collison, David; Manners, IanCatalytic chemistry that involves the activation and transformation of main group substrates is relatively undeveloped and current examples are generally mediated by expensive transition metal species. Herein, we describe the use of inexpensive and readily available tBuOK as a catalyst for P–P and P–E (E = O, S, or N) bond formation. Catalytic quantities of tBuOK in the presence of imine, azobenzene hydrogen acceptors, or a stoichiometric amount of tBuOK with hydrazobenzene, allow efficient homodehydrocoupling of phosphines under mild conditions (e.g. 25 °C and < 5 min). Further studies demonstrate that the hydrogen acceptors play an intimate mechanistic role. We also show that our tBuOK catalysed methodology is general for the heterodehydrocoupling of phosphines with alcohols, thiols and amines to generate a range of potentially useful products containing P–O, P–S, or P–N bonds.
- ItemSteering carbon dioxide reduction toward C–C coupling using copper electrodes modified with porous molecular films([London] : Nature Publishing Group UK, 2023) Zhao, Siqi; Christensen, Oliver; Sun, Zhaozong; Liang, Hongqing; Bagger, Alexander; Torbensen, Kristian; Nazari, Pegah; Lauritsen, Jeppe Vang; Pedersen, Steen Uttrup; Rossmeisl, Jan; Daasbjerg, KimCopper offers unique capability as catalyst for multicarbon compounds production in the electrochemical carbon dioxide reduction reaction. In lieu of conventional catalysis alloying with other elements, copper can be modified with organic molecules to regulate product distribution. Here, we systematically study to which extent the carbon dioxide reduction is affected by film thickness and porosity. On a polycrystalline copper electrode, immobilization of porous bipyridine-based films of varying thicknesses is shown to result in almost an order of magnitude enhancement of the intrinsic current density pertaining to ethylene formation while multicarbon products selectivity increases from 9.7 to 61.9%. In contrast, the total current density remains mostly unaffected by the modification once it is normalized with respect to the electrochemical active surface area. Supported by a microkinetic model, we propose that porous and thick films increase both local carbon monoxide partial pressure and the carbon monoxide surface coverage by retaining in situ generated carbon monoxide. This reroutes the reaction pathway toward multicarbon products by enhancing carbon–carbon coupling. Our study highlights the significance of customizing the molecular film structure to improve the selectivity of copper catalysts for carbon dioxide reduction reaction.