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Cyclic ketene acetals (CKAs) possess unique features in two aspects. On one hand, after the addition of a radical on the alkene, CKAs can undergo ring‐opening via radical rearrangement, enabling polyester preparation based on chain‐growth polymerization. On the other hand, the alkene connected with two electron‐donating oxygens in a strained form exhibit unique reactivities, resulting in complex reactions in the presence of electron deficient compounds. In this investigation, fundamental studies on CKA radical ring‐opening polymerization and charge‐mediated reactions were performed. Alternating copolymers of CKA and maleimides, or maleates, were prepared and characterized. Quantum chemistry modeling from the perspectives of reaction kinetics and thermodynamics enabled an in‐depth mechanistic study on the side reactions between CKA and maleic anhydride or itaconic anhydride, inspiring the techniques to minimize those side reactions in competition with radical copolymerization. After purifying the anhydride monomers with sublimation, the copolymerization with CKA successfully occurred. The anhydride containing polyester structures with an alternating sequence were confirmed with comprehensive characterizations. Facile post‐functionalization with an alcohol was performed, resulting in carboxylate containing polyesters.

The catalytic construction of well-defined materials from mixtures of building blocks is an important challenge in sustainable catalysis. In this regard, we have recently reported a new type of selective ring-opening terpolymerisation (ROTERP), in which three monomers (A, B, C) are selectively enchained into a (ABA′C)nsequence, but the reasons behind this unusual selectivity remained unanswered. In this study, we present a detailed investigation into the full ROTERP mechanism based on the reactivity of model intermediates, computational studies investigating >100 possible intermediates and transition states and reaction kinetics. Experimental verification of the intermediate speciation, the primary insertion steps and the side-reactions lets us show that although most insertions and side-reactions are thermodynamically viable, kinetic selection processes at the propagating chain end determine the sequence selectivity. Computational studies elucidate the special role and speciation of the lithium catalyst which during the catalytic cycle involves mono-metallic, bi-metallic and charge separated transition states comprising both coordinative activation of incoming monomers and functional groups of the polymer backbone adjacent to the propagating chain. Our study not only deciphers the mechanism of a rare selective terpolymerisation but also helps answering open questions relevant to ring-opening copolymerisation (ROCOP) and alkali-metal catalysis in general, thus guiding the design of future polymerisation catalysis for degradable materials.

Combinations of dienes and dienophiles were examined in order to elicit possible combinations for thermoreversible crosslinking units. Comparison of experimental results and quantum calculations indicated that reaction kinetics and activation energy were much better prediction factors than change in enthalpy for the prediction of successful cycloaddition. Further testing on diene–dienophile pairs that underwent successful cycloaddition determined the feasibility of thermoreversibility/retro-reaction of each of the Diels–Alder compounds. Heating and testing of the compounds in the presence of a trapping agent allowed for experimental determination of reverse kinetics and activation energy for the retro-reaction. The experimental values were in good agreement with quantum calculations. The combination of chemical calculations with experimental results provided a strong insight into the structure–property relationships and how quantum calculations can be used to examine the feasibility of the thermoreversibility of new Diels–Alder complexes in potential polymer systems or to fine-tune thermoreversible Diels–Alder systems already in use.

One of the most important application areas of molecular quantum chemistry is the study and prediction of chemical reactivity. Large-scale, fully error-tolerant quantum computers could provide exact or near-exact solutions to the underlying electronic structure problem with exponentially less effort than a classical computer thus enabling highly accurate predictions for comparably large molecular systems. In the nearer future, however, only “noisy” devices with a limited number of qubits that are subject to decoherence will be available. For such near-term quantum computers the hybrid quantum-classical variational quantum eigensolver algorithm in combination with the unitary coupled-cluster ansatz(UCCSD-VQE) [Peruzzo et al. Nat. Commun.2014, 5, 4213and McClean et al. New J. Phys.2016, 18, 023023] has become an intensively discussed approach that could provide accurate results before the dawn of error-tolerant quantum computing. In this work we present an implementation of UCCSD-VQE that allows for the first time to treat both open- and closed-shell molecules. We study the accuracy of the obtained energies for nine small molecular systems as well as for four exemplary chemical reactions by comparing to well-established electronic structure methods like (nonunitary) coupled-cluster and density functional theory. Finally, we roughly estimate the required quantum hardware resources to obtain “useful” results for practical purposes.

We investigate ligand-exchange reactions of a biomimetic Co(II)-based heterocubane complex in aqueous solution by means of various approaches for consideration of solvent effects. Static calculations based on geometry optimizations carried out in vacuum, with solvent continuum models, or with several explicit solvent molecules have been carried out as well as density functional theory (DFT)-based molecular dynamics simulations. In addition, reaction pathways and barriers have been elucidated via nudged elastic band calculations and metadynamics. The results show that static approaches with approximate consideration of the solvent environment lead to reaction energies, which may change drastically depending on the method employed. A more sophisticated approach is DFT-molecular dynamics at ambient conditions with full solvation, i.e. enough solvent molecules to retain bulk water properties far from the solute, which, however, comes with a much higher computational cost. The investigated example of the exchange of an acetate ligand by a hydroxide demonstrates that entropic contributions can be vital and consideration of electronic energies alone may be a rather rough approximation.

The homogeneous dinuclear zinc catalyst going back to the work of Williams et al. is to date the most active catalyst for the copolymerisation of cyclohexene oxide and CO2at one atmosphere of carbon dioxide. However, this catalyst shows no copolymer formation in the copolymerisation reaction of propylene oxide and carbon dioxide, instead only cyclic carbonate is found. This behaviour is known for many zinc‐based catalysts, although the reasons are still unidentified. Within our studies, we focus on the parameters that are responsible for this typical behaviour. A deactivation of the catalyst due to a reaction with propylene oxide turns out to be negligible. Furthermore, the catalyst still shows poly(cyclohexene carbonate) formation in the presence of cyclic propylene carbonate, but the catalyst activity is dramatically reduced. In terpolymerisation reactions of CO2with different ratios of cyclohexene oxide to propylene oxide, no incorporation of propylene oxide can be detected, which can only be explained by a very fast back‐biting reaction. Kinetic investigations indicate a complex reaction network, which can be manifested by theoretical investigations. DFT calculations show that the ring strains of both epoxides are comparable and the kinetic barriers for the chain propagation even favour the poly(propylene carbonate) over the poly(cyclohexene carbonate) formation. Therefore, the crucial step in the copolymerisation of propylene oxide and carbon dioxide is the back‐biting reaction in the case of the studied zinc catalyst. The depolymerisation is several orders of magnitude faster for poly(propylene carbonate) than for poly(cyclohexene carbonate).

Summary:A non‐exhaustive and somehow arbitrary review on actual trends and remaining challenges for a model based process development is given. An example how state of the art molecular modeling methods help to provide kinetic information is explained in some detail. A brief sketch of various methods providing thermodynamic information for engineering is given, and finally, recent concurrent coupling schemes of particle based simulation and computational fluid dynamics are highlighted.

Ruthenium complexes, mer‐[RuX3(MeCN)3] and cis/trans‐[RuX2(MeCN)4] with X=Br, Cl, were investigated as precatalysts in homogeneously catalyzed hydrosilylation of CO2. The oxidation state of ruthenium and nature of the halide in the precatalysts were found to influence the catalytic activity in the conversion of Me2PhSiH to the formoxysilane Me2PhSiOCHO, with RuIIIhaving chloride ligands being most active. Monitoring the reactions by in‐situ IR spectroscopy in MeCN as the solvent indicates an interaction of the precatalyst with the silane prior to activation of CO2. In the absence of CO2, hydrosilylation of the MeCN solvent occurs. Catalytic activity in CO2hydrosilylation is enhanced by Me2PhSiCl, generated during reduction of RuIIIin mer‐[RuX3(MeCN)3] to RuIIor, when added as promoter to RuIIprecatalysts. The reaction mechanism for the catalytic cycle has been calculated by DFT methods for the reaction of Me3SiH. The key steps are: Transfer of the Me3Si moiety to a coordinated halide ligand, resulting in an LnRuH(XSiMe3) intermediate → CO2coordination → Me3Si transfer to CO2→ reductive elimination of formoxysilane product. This reaction sequence is more favorable energetically for chloride complexes than for the analogous bromide complexes, which accounts for their differences in catalytic activity. Calculations also explain the rate increase observed experimentally in the presence of Me2PhSiCl. A parallel reaction pathway leads to (Me3Si)2O as a minor byproduct which arises from the condensation of two initially formed Me3SiOH molecules.

T cells constitute a large population of cellular infiltrate in atopic/allergic inflammation and a dysregulated, Th2‐biased peripheral immune response appears to be an important pathogenetic factor. In atopic dermatitis, circulating cutaneous lymphocyte‐associated antigen‐bearing (CLA+) CD45RO+T cells with skin‐specific homing property represent an activated memory/effector T cell subset. They express high levels of Fas and Fas ligand and undergo activation‐induced apoptosis. The freshly purified CLA+CD45RO+T cells of atopic individuals display distinct features of in vivo‐triggered apoptosis such as pro‐caspase degradation and active caspase‐8 formation. In particular, the Th1 compartment of activated memory/effector T cells selectively undergoes activation‐induced cell death, skewing the immune response toward surviving Th2 cells in atopic dermatitis patients. The apoptosis of circulating memory/effector T cells was confined to atopic individuals whereas non‐atopic patients such as psoriasis, intrinsic‐type asthma, contact dermatitis, intrinsic type of atopic dermatitis, bee venom allergic patients, and healthy controls showed no evidence for enhanced T cell apoptosis in vivo. These results define a novel mechanism for peripheral Th2 response in atopic diseases. —Akdis, M., Trautmann, A., Klunker, S., Daigle, I., Küçüksezer, U. C., Deglmann, W., Disch, R., Blaser, K., Akdis, C. A. T helper (Th) 2 predominance in atopic dermatitis is due to preferential apoptosis of circulating memory/effector Th1 cells. FASEB J.17, 1026–1035 (2003)

New approaches for in vitro testing of hepato-mediated toxicity are undertaken to offer alternatives to in vivo animal testing. The described bioassay for hepato-mediated toxicity testing is based on a small scale hepatocyte-bioreactor with pig hepatocytes connected to a silicon sensor based microphysiometer system for monitoring of the extracellular acidification rate (EAR) of cells and the microphysiometer alone. EAR represents the metabolic activity of tested cells (hepatocytes and ZR 751 cells) under the influence of perfused media, compared to controls, which were set to 100%. Cyclophosphamide (CYCL), whose cytostatic effect is dependent on CYP 450 biotransformation was used as a model substrate. CYCL showed decrease of EAR in hepatocytes, but not in ZR 751 cells. Bioreactor supernatant including CYCL was pumped into the microphysiometer and EARs of the target ZR 751 cell line were recorded. After 7 h of bioreactor supernatant perfusion the ZR 751 cell line showed an EAR decrease of 18.68% ± 10.18, as compared to controls (bioreactor supernatant from the identical set-up without CYCL). Thus the presented model of hepato-activated toxicity showed an EAR decrease in the ZR 751 cell line that reflected the toxic activation of CYCL by the bioreactor. This new bioassay serves as an example of future applications for hepatocyte bioreactors in automated toxicity testing devices, e.g. in preclinical drug studies or evaluation of hepato-mediated toxicity, not depending on cell destruction or further assays.

Kohn–Sham orbital energy patterns were used to rationalize valence electron counts for stable face‐capped octahedral clusters [M6E8L6] (E=S, Se, Te, Cl; L=CO, PMe3, Cl−). When L is a π acceptor such as CO or PMe3, stable closed‐shell clusters are found for 80, 84, and 98 electrons. For L=Cl−(i.e. a π‐electron donor), only a count of 84 electrons appears favorable, as is found in [Mo6Cl14]2−. These counting rules apply to fivefold coordination of M, which becomes unstable if the electron count exceeds 98, for example, for M=Ni. In this case structures with tetrahedrally coordinated M are energetically favored, and this leads to different cluster structures.

Proteins encoded by the human CYP3Agenes metabolize every second drug currently in use. The activity of CYP3Agene products in the general population is highly variable and may affect the efficacy and safety of drugs metabolized by these enzymes. The mechanisms underlying this variability are poorly understood, but they include gene induction, protein inhibition and unknown genetic polymorphisms. To better understand the regulation of CYP3Aexpression and to provide a basis for a screen of genetic polymorphisms, we determined and analysed the sequence of the human CYP3Alocus. The 231 kb locus sequence contains the three CYP3Agenes described previously (CYP3A4, CYP3A5and CYP3A7), three pseudogenes as well as a novel CYP3Agene termed CYP3A43. The gene encodes a putative protein with between 71.5 and 75.8 identity to the other CYP3A proteins. The highest expression level of CYP3A43mRNA is observed in the prostate, an organ with extensive steroid metabolism. CYP3A43is also expressed in several other tissues including liver, where it can be induced by rifampicin. CYP3A43transcripts undergo extensive splicing. The identification of a new member of the CYP3Afamily and the characterization of the full CYP3Alocus will aid efforts to identify the genetic variants underlying its variable expression. This, in turn, will lead to a better optimization of therapies involving the numerous substrates of CYP3A proteins.