Kaiserslautern - Fachbereich Chemie
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Nucleophilic substitution of [(η5-cyclopentadienyl)(η6-chlorobenzene)iron(II)] hexafluorophosphate with sodium imidazolate resulted in the formation of [(η5-cyclopentadienyl)(η6-phenyl)iron(II)]imidazole hexafluorophosphate. The corresponding dicationic imidazolium salt, which was obtained by treating this imidazole precursor with methyl iodide, underwent cyclometallation with bis[dichlorido(η5-1,2,3,4,5-pentamethylcyclopentadienyl]iridium(III) in the presence of triethyl amine. The resulting bimetallic iridium(III) complex is the first example of an NHC complex bearing a cationic and cyclometallated [(η5-cyclopentadienyl)(η6-phenyl)iron(II)]+ substituent. As its iron(II) precursors, the bimetallic iridium(III) complex was fully characterized by means of spectroscopy, elemental analysis and single crystal X-ray diffraction. In addition, it was investigated in a catalytic study, wherein it showed high activity in transfer hydrogenation compared to its neutral analogue having a simple phenyl instead of a cationic [(η5-cyclopentadienyl)(η6-phenyl)iron(II)]+ unit at the NHC ligand.
A stereoselective synthesis of isoindolo[2,1-a]quinolin-11(5H)-ones containing three contiguous stereogenic centers is described. This Lewis-acid mediated reaction of enamides with N-aryl-acylimines affords the desired fused heterocyclic isoindolinones in high yields and diastereoselectivities. Scope and limitations of this method are discussed. The stereochemical outcome of this transformation indicates a stepwise reaction pathway.
A highly water-dispersible heterogeneous Brønsted acid surfactant was prepared by synthesis of a bi-functional anisotropic Janus-type material. The catalyst comprises ionic functionalities on one side and propyl-SO3H groups on the other. The novel material was investigated as a green substitute of a homogeneous acidic phase transfer catalyst (PTC). The activity of the catalyst was investigated for the aqueous-phase oxidation of cyclohexene to adipic acid with 30 % hydrogen peroxide even in a decagram-scale. It can also be used for the synthesis of some other carboxylic acid derivatives as well as diethyl phthalate.
1,3-Diynes are frequently found as an important structural motif in natural products, pharmaceuticals and bioactive compounds, electronic and optical materials and supramolecular molecules. Copper and palladium complexes are widely used to prepare 1,3-diynes by homocoupling of terminal alkynes; albeit the potential of nickel complexes towards the same is essentially unexplored. Although a detailed study on the reported nickel-acetylene chemistry has not been carried out, a generalized mechanism featuring a nickel(II)/nickel(0) catalytic cycle has been proposed. In the present work, a detailed mechanistic aspect of the nickel-mediated homocoupling reaction of terminal alkynes is investigated through the isolation and/or characterization of key intermediates from both the stoichiometric and the catalytic reactions. A nickel(II) complex [Ni(L-N4Me2)(MeCN)2](ClO4)2 (1) containing a tetradentate N,N′-dimethyl-2,11-diaza[3.3](2,6)pyridinophane (L-N4Me2) as ligand was used as catalyst for homocoupling of terminal alkynes by employing oxygen as oxidant at room temperature. A series of dinuclear nickel(I) complexes bridged by a 1,3-diyne ligand have been isolated from stoichiometric reaction between [Ni(L-N4Me2)(MeCN)2](ClO4)2 (1) and lithium acetylides. The dinuclear nickel(I)-diyne complexes [{Ni(L-N4Me2)}2(RC4R)](ClO4)2 (2) were well characterized by X-ray crystal structures, various spectroscopic methods, SQUID and DFT calculation. The complexes not only represent as a key intermediate in aforesaid catalytic reaction, but also describe the first structurally characterized dinuclear nickel(I)-diyne complexes. In addition, radical trapping and low temperature UV-Vis-NIR experiments in the formation of the dinuclear nickel(I)-diyne confirm that the reactions occurring during the reduction of nickel(II) to nickel(I) and C-C bond formation of 1,3-diyne follow non-radical concerted mechanism. Furthermore, spectroscopic investigation on the reactivity of the dinuclear nickel(I)-diyne complex towards molecular oxygen confirmed the formation of a mononuclear nickel(I)-diyne species [Ni(L-N4Me2)(RC4R)]+ (4) and a mononuclear nickel(III)-peroxo species [Ni(L-N4Me2)(O2)]+ (5) which were converted to free 1,3-diyne and an unstable dinuclear nickel(II) species [{Ni(L-N4Me2)}2(O2)]2+ (6). A mononuclear nickel(I)-alkyne complex [Ni(L-N4Me2)(PhC2Ph)](ClO4).MeOH (3) and the mononuclear nickel(III)-peroxo species [Ni(L-N4Me2)(O2)]+ (5) were isolated/generated and characterized to confirm the formulation of aforementioned mononuclear nickel(I)-diyne and mononuclear nickel(III)-peroxo species. Spectroscopic experiments on the catalytic reaction mixture also confirm the presence of aforesaid intermediates. Results of both stoichiometric and catalytic reactions suggested an intriguing mechanism involving nickel(II)/nickel(I)/nickel(III) oxidation states in contrast to the reported nickel(II)/nickel(0) catalytic cycle. These findings are expected to open a new paradigm towards nickel-catalyzed organic transformations.
We have investigated urine samples after coffee consumption using targeted and untargeted
approaches to identify furan and 2-methylfuran metabolites in urine samples by UPLC-qToF.
The aim was to establish a fast, robust, and time-saving method involving ultra-performance
liquid chromatography-quantitative time-of-flight tandem mass spectrometry (UPLC-qToF-MS/MS).
The developed method detected previously reported metabolites, such as Lys-BDA, and others that
had not been previously identified, or only detected in animal or in vitro studies. The developed
UPLC-qToF method detected previously reported metabolites, such as lysine-cis-2-butene-1,4-dial
(Lys-BDA) adducts, and others that had not been previously identified, or only detected in animal
and in vitro studies. In sum, the UPLC-qToF approach provides additional information that may be
valuable in future human or animal intervention studies.
Toxicology, the study of the adverse effects of chemicals and physical agents on living organisms, is a critical process in chemical and drug development. The low throughput, high costs, limited predictivity and ethical concerns related to traditional animal-based toxicity studies render them impractical to assess the growing number and complexity of both existing and new compounds and their formulations. These factors together with the increasing implementation of more demanding regulations, evidence the current need to develop innovative, reliable, cost effective and high throughput toxicological methods.
The use of metabolomics in vitro presents the powerful combination of a human relevant system with a multiparametric approach that allows assessing multiple endpoints in a single biological sample. Applying metabolomics in a cell-based system offers an alternative to both, the ethical concerns and relevance of animal testing and the restraining nature of single endpoint evaluations characteristic of conventional toxicological in vitro assays. However, there are still challenges that hamper the expansion of metabolomics beyond a research tool to a feasible and implementable technology for toxicology assessment.
The aim of this dissertation is to advance the applications of in vitro metabolomics in toxicology by addressing three major challenges that have limited its widespread implementation in the field. In chapter 2 the restrictive high cost and low throughput of in vitro metabolomics was addressed through the development, standardization and proof of concept of a high throughput targeted LC-MS/MS in vitro metabolomics platform for the characterization of hepatotoxicity. In chapter 3, the use of the developed in vitro metabolomics system was expanded beyond hazard identification, to its implementation for deriving dose- and time response metrics that were shown useful for Point of departure (PoD) estimations for human risk assessment. Finally, in chapter 4 in order to increase the reliance and confidence of using in vitro metabolomics data for risk assessment, the human relevance of the metabolomics in vitro assays was attempted to be improved by the implementation and evaluation of in vitro metabolomics in a hiPSCs-derived 3D liver organoid system.
The work developed here demonstrates the suitable of in vitro metabolomics for mechanistic-based hazard identification and risk assessment. By advancing the applications of metabolomics in toxicology, this work has significantly contributed to the aim of toxicology of the 21st century for a human-relevant non-animal toxicological testing, supporting the toxicology task of protecting human health and the environment.
A novel method for the highly stereoselective synthesis of tetrahydropyrans is reported. This domino reaction is based on a twofold addition of enamides to aldehydes followed by a subsequent cyclization and furnishes fully substituted tetrahydropyrans in high yields. Three new σ-bonds and five continuous stereogenic centers are formed in this one-pot process with a remarkable degree of diastereoselectivity. In most cases, the formation of only one out of 16 possible diastereomers is observed. Two different stereoisomers can be accessed in a controlled fashion starting either from an E- or a Z-configured enamide.
Spin Hamiltonian parameters of a pentanuclear Os Ni cyanometallate complex are derived from ab initio wave function based calculations, namely valence-type configuration interaction calculations with a complete active space including spin-orbit interaction (CASOCI) in a single-step procedure. While fits of experimental data performed so far could reproduce the data but the resulting parameters were not satisfactory, the parameters derived in the present work reproduce experimental data and at the same time have a reasonable size. The one-centre parameters (local matrices and single-ion zero field splitting tensors) are within an expected range, the anisotropic exchange parameters obtained in this work for an Os−Ni pair are not exceedingly large but determine the low-T part of the experimental χT curve. Exchange interactions (both isotropic and anisotropic) obtained from CASOCI have to be scaled by a factor of 2.5 to obtain agreement with experiment, a known deficiency of such types of calculation. After scaling the parameters, the isotropic Os−Ni exchange coupling constant is cm−1 and the D parameter of the (nearly axial) anisotropic Os−Ni exchange is −1, so anisotropic exchange is larger in absolute size than isotropic exchange. The negative value of the isotropic J (indicating antiferromagnetic coupling) seemingly contradicts the large-temperature behaviour of the temperature dependent susceptibility curve, but this is caused by the negative g value of the Os centres. This negative g value is a universal feature of a pseudo-octahedral coordination with configuration and strong spin-orbit interaction. Knowing the size of these exchange interactions is important because Os(CN) is a versatile building block for the synthesis of / magnetic materials.
Purpose
We investigated the cytosolic and membrane-associated contents of polyphenols after 4 hours of incubation (50 μM of each polyphenol) in the colon carcinoma cell line T84 using a novel, rapid, and convenient method based on permeabilization of the cell membrane using digitonin. The colon carcinoma cell line was used to investigate the intestinal uptake of polyphenols present in apple products.
Recent Findings
The results showed that hydroxycinnamic acids (caffeic and 5-caffeoylquinic acid) were only detected in the cytosolic fractions. In contrast, 0.3 to 8.2% of the initial concentrations (50 μM) of the flavonoids phloretin, quercetin, phloretin 2′-O-glucoside, and quercetin 3-O-rhamnoside were found in the membrane-associated fractions. In the cytosolic fractions, 0.2–2.9% of these compounds were detected, corresponding to 25 to 40% of the total cell-associated (cytosolic plus membrane-associated fractions) polyphenol content.
Summary
Our results showed that after uptake, polyphenols were present in the cytosolic fraction of the cells as well as associated with the cell membrane. The presented method provides a useful in vitro tool for determining biologically active compounds in cellular fractions.
The direct regioselective C−H-functionalization of simple, unfunctionalized pyridines is considered a long-standing challenge in heterocyclic chemistry. Herein, we report a novel one-pot protocol for the C4-selective sulfonylation of pyridines via triflic anhydride (Tf2O) activation, base-mediated addition of a sulfinic acid salt, and subsequent elimination/re-aromatization. Contrary to previous approaches employing tailored blocking groups, positional selectivity can be controlled by using N-methylpiperidine as simple, readily available external base. This method offers a highly modular and streamlined access to C4-sulfonylated pyridines.