Redox-neutral decarboxylative coupling reactions have emerged as a powerful strategy for C-C bond formation. However, the existing reaction conditions possess limitations, such as the coupling of aryl halides restricted to ortho-substituted benzoic acids; alkenyl halides were not applicable in decarboxylative coupling reaction. Within this thesis, the developments of Pd/Cu bimetallic catalyst systems are presented to overcome the limitations.
In the first part of the PhD work, a customized bimetallic PdII/CuI catalyst system was successfully developed to facilitate the decarboxylative cross-coupling of non-ortho-substituted aromatic carboxylates with aryl chlorides. The restriction of decarboxylative cross-coupling reactions to ortho-substituted or heterocyclic carboxylate substrates was overcome by holistic optimization of this bimetallic Cu/Pd catalyst system. All kinds of benzoic acids regardless of their substitution pattern now can be applied in decarboxylative cross-coupling reaction. This confirms prediction by DFT studies that the previously observed limitation to certain activated carboxylates is not intrinsic. The catalyst system also presents higher performance in the coupling of ortho-substituted benzoates, giving much higher yields than those previously reported. ortho-Methyl benzoate and ortho-phenyl benzoate which have never before been converted in decarboxylative coupling reactions, gave reasonable yields. These together further confirm the superiority of the new protocol.
In the second part of the PhD work, arylalkenes syntheses via two different Pd/Cu bimetallic-catalyzed decarboxylative couplings have been developed. This part consists of two projects: 2a) decarboxylative coupling of alkenyl halides; 2b) decarboxylative Mizoroki-Heck coupling of aryl halides with α,β-unsaturated carboxylic acids.
In project 2a, widely available, inexpensive, bench-stable aromatic carboxylic acids are used as nucleophile precursors instead of expensive and sensitive organometallic reagents that are commonly used in previously reported transition-metal catalyzed cross-couplings of alkenyl halides. With this protocol, alkenyl halides for the first time are used in decarboxylative coupling reaction, allowing regiospecific synthesis of a broad range of (hetero)arylalkenes in high yields. Unwanted double bond isomerization, a common side reaction in the alternative Heck reactions especially in the coupling of cycloalkenes or aliphatic alkenes, did not take place in this decarboxylative coupling reaction. Polysubstituted alkenes that hard to access with Heck reaction are also produced in good yields. The reaction can easily be scaled up to gram scale. The synthetic utility of this reaction was also demonstrated by synthesizing an important intermediate of fungicidal compound in high yield within 2 steps.
In project 2b, a Cu/Pd bimetallic catalyzed decarboxylative Mizoroki-Heck coupling of aryl halides with α, β-unsaturated carboxylic acids was successfully developed in which the carboxylate group directs the arylation into its β-position before being tracelessly removed via protodecarboxylation. It opens up a convenient synthesis of unsymmetrical 1,1-disubstituted alkenes from widely available precursors. This reaction features good regioselectivity, which is complementary to that of traditional Heck reactions, and also presents excellent functional group tolerance. Moreover, a one-pot 3-step 1,1-diarylethylene synthesis from methyl acrylate was achieved, where solvent changes or isolation of intermediates are not required. This subproject presents an example of carboxylic acids utility in synthesizing valuable compounds which are hard to access via conventional methodologies.
This work introduces a promising concept for the preparation of new nano-sized receptors. Mixed monolayer protected gold nanoparticles (AuNPs) for low molecular weight compounds were prepared featuring functional groups on their surfaces. It has been shown that these AuNPs can engage in interactions with peptides in aqueous media. Quantitative binding information was obtained from DOSY-NMR titrations indicating that nanoparticles containing a combination of three orthogonal functional groups are more efficient in binding to dipeptides than mono or difunctionalised analogues. The strategy is highly modular and easily allows adapting the receptor selectivity to a
given substrate by varying the type, number, and ratio of binding sites on the nanoparticle
C-H activations(C-H bond weakening effects) under impact of transition metal atoms
are theoretically investigated,
two model systems are used, one is CH3MX, the other is
n-ButMX, (X=F,Cl,Br,I,H,CN, M include all transition metal
atoms from group 4 to group 10).
In this thesis, collision-induced dissociation (CID) studies serve to elucidate relative stabilities and to determine bond strengths within a given structure type of transition metal complexes. The infrared multi photon dissociation (IRMPD) spectroscopy combined with density functional theory (DFT) allow for structural analysis and provide insights into the coordination sphere of transition metal centers. The used combination of CID and IRMPD experiments is a powerful tool to obtain a detailed and comprehensive characterization and understanding of interactions between transition metals and organic ligands. The compounds’ spectrum comprises mono- or oligonuclear transition metal complexes containing iron, palladium, and ruthenium as well as lanthanide containing single molecule magnets (SMM). The presented investigations on the different transition metal complexes reveal manifold effects for each species leading to valuable results. A fundamental understanding of metal to ligand interactions is mandatory for the development of new and better organometallic complexes with catalytic, optical or magnetic properties.
In the present work, magnetic moments of isolated Single Molecule Magnets (SMMs) and transition
metal clusters were investigated. Gas phase X‐ray Magnetic Circular Dichroism (XMCD) in
combination with sum rule analysis served to separate the total magnetic moments of the
investigated species into their spin and orbital contributions. Two different mass spectrometry based
setups were used for the presented investigations on transition metal clusters (GAMBIT‐setup) and
on single molecule magnets (NanoClusterTrap). Both experiments were coupled to the UE52‐PGM
beamline at the BESSY II synchrotron facility (Helmholtz Zentrum Berlin) which provided the
necessary polarized X‐ray photons. The investigation of the given compounds as isolated molecules
in the gas phase enabled a determination of their intrinsic magnetic properties void of any influences
of e.g. a surrounding bulk or supporting surface
The aim of this work was to synthesize and characterize new bidentate N,N,P-ligands and their corresponding heterobimetallic complexes. These bidentate pyridylpyrimidine aminophosphine ligands were synthesized by ring closure of two different enaminones ( 3-(dimethylamino)-1-(pyridine-2-yl)-prop-2-en-1-one or 3-(dimethylamino)-1-(pyridine-2-yl)-but-2-en-1-one) with excess amount of guanidinium salts in the presence of base. The novel phosphine functionalized guanidinium salts were prepared from 2-(diphenylphosphinyl)ethylamine or 3-(diphenyl-phosphinyl)propylamine. These bidentate N,N,P-ligands contain hard and soft donor sites which allows the coordination of two different metal centers and bimetallic complexes. These bimetallic complexes can exhibit a unique behavior as a result of a cooperation between the two metal atoms. First, the gold(I) complexes of all these four different ligands were synthesized. The gold metal coordinates only to the phosphorus atom. It was proved by X-Ray crystallography technique and 31P NMR spectroscopy. Addition to the gold(I)-monometallic complexes, trans- coordinated rhodium complex of (2-amino)pyridylpyrimidine aminophosphine ligand was successfully prepared. The characterization of this complex was achieved by NMR and IR spectroscopy. Reacting the mono gold(I) complexes with the different metal salts like Pd(PhCN)2Cl2, ZnCl2, [Ru(p-cymene)Cl2] dimer gave the target heterobimetallic complexes. The second metal centers coordinated to the N,N donor site which was proved by the help of NMR spectroscopy and ESI-MS measurements. The Au(I) and Au-Zn complexes of N,N,P-ligands were examined as catalysts for the hydroamidation reaction of cyclohexene with p-toluenesulfonamide. They did not show activities under the tested conditions. Further studies are necessary to understand the catalytic activities and cooperativity between the two metal atoms. In addition, bi-and trimetallic complexes with the rhodium compound could be synthesized and tested in different organic transformations. Furthermore, the chiral hydroxyl[2.2]paracyclophane substituted with five different aminopyrimidines were accomplished. These aminopyrimidine ligands were synthesized by a cyclization reaction with hydroxyl[2.2]paracyclophane substituted enaminone and excess amount of corresponding guanidinium salts under basic conditions. In the last part of this work, kinetic studies of cyclopalladation reaction of the 2-(arylaminopyrimidin-4-yl)pyridine ligands with Pd(PhCN)2 These measurements were carried out by using UV-Vis spectroscopy. The spectral studies of cyclometallation step showed that the reaction fits a second order kinetics. In addition to this, a full kinetic investigation was performed at different temperatures and the activation parameters of complex formation were calculated.
Nitrogen element is preponderant in Nature. Found in its simplest form as diatomic gas in the air, as well as in elaborated molecules such as the double helix of DNA, this element is indisputably essential for life. Indeed, nitrogen is omnipresent in all metabolic pathways.
With the advent of green chemistry, researchers attempt to functionalize arenes without pre-functionalization of the later for the establishment of C-C bond formation. Why not C-N bond formation?
We investigated new oxidative amination reactions by cross-dehydrogenative-coupling. Concerned by atom economy and green processes, our objectives were: 1) to obviate pre-activation or pre-oxidation of both C-H coupling partner and N-aminating agent. 2) to avoid the use of chelating directing group.
We achieved C-N bond formation for some classes of amines. Thus, we will describe the reactivity of cyclic secondary amines: carbazole, in presence of catalytic amount of ruthenium (II) and copper (II) to build the challenging C-N bond between two carbazoles. The initial mechanistic experiments will be present and discuss.
Then, we will describe more challenging hetero-coupling formation between diarylamines and carbazoles. The new ruthenium (II)/ copper (II) catalytic system allowed forming the ortho-N-carbazolation of diarylamines. This reaction performed under mild conditions (O2 as terminal oxidant) displays an unusual intramolecular N-H••N interaction in the novel class of compounds.
Finally, we will present a surprising metal free C-N bond formation between the ubiquitous phenols and the phenothiazines. Initially conducted in the presence of transition metals (RuII/CuII), this reaction proved to be efficient with the only effect of cumene and O2. Those components suggest a mechanism initiated by a Hock process. An initial infra-red analysis might point out a strong intramolecular O-H••N interaction in the resulting products.
These first elements of reactivity, developed within the laboratory for “modern dehydrogenative amination reactions”, will be presented and discussed.
‘Dioxin-like’ (DL) compounds occur ubiquitously in the environment. Toxic responses associated with specific dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs), and polychlorinated biphenyls (PCBs) include dermal toxicity, immunotoxicity, liver toxicity, carcinogenicity, as well as adverse effects on reproduction, development, and endocrine functions. Most, if not all of these effects are believed to be due to interaction of these compounds with the aryl hydrocarbon receptor (AhR).
With tetrachlorodibenzo-p-dioxin (TCDD) as representatively most potent congener, a toxic equivalency factor (TEF) concept was employed, in which respective congeners were assigned to a certain TEF-value reflecting the compound’s toxicity relative to TCDD’s.
The EU-project ‘SYSTEQ’ aimed to develop, validate, and implement human systemic TEFs as indicators of toxicity for DL-congeners. Hence, the identification of novel quantifiable biomarkers of exposure was a major objective of the SYSTEQ project.
In order to approach to this objective, a mouse whole genome microarray analysis was applied using a set of seven individual congeners, termed the ‘core congeners’. These core congeners (TCDD, 1-PeCDD, 4-PeCDF, PCB 126, PCB 118, PCB 156, and the non dioxin-like PCB 153), which contribute to approximately 90% of toxic equivalents (TEQs) in the human food chain, were further tested in vivo as well as in vitro. The mouse whole genome microarray revealed a conserved list of differentially regulated genes and pathways associated with ‘dioxin-like’ effects.
A definite data-set of in vitro studies was supposed to function as a fundament for a probable establishment of novel TEFs. Thus, CYP1A induction measured by EROD activity, which represents a sensitive and yet best known marker for dioxin-like effects, was used to estimate potency and efficacy of selected congeners. For this study, primary rat hepatocytes and the rat hepatoma cell line H4IIE were used as well as the core congeners and an additional group of compounds of comparable relevance for the environment: 1,6-HxCDD, 1,4,6-HpCDD, TCDF, 1,4-HxCDF, 1,4,6-HpCDF, PCB 77, and PCB 105.
Besides, a human whole genome microarray experiment was applied in order to gain knowledge with respect to TCDD’s impact towards cells of the immune system. Hence, human primary blood mononuclear cells (PBMCs) were isolated from individuals and exposed to TCDD or to TCDD in combination with a stimulus (lipopolysaccharide (LPS), or phytohemagglutinin (PHA)). A few members of the AhR-gene batterie were found to be regulated, and minor data with respect to potential TCDD-mediated immunomodulatory effects were given. Still, obtained data in this regard was limited due to great inter-individual differences.
A positive affection of human health by nutrition is of high interest, especially for bioactive compounds which are consumed daily in high amounts. This is the case for chlorogenic acids (CGA) ingested by coffee. This molecule class is associated with several possible beneficial health effects observed in vitro that strongly depend on their bioavailability. So far factors influencing bioavailability of CGA such as dose, molecule structure and site of absorption haven´t been investigated sufficiently.
Therefore we performed an in vivo dose-response study with ileostomists, who consumed three different nutritional doses of CGA ingested as instant coffee (4,525 (HIGH); 2,219 (MEDIUM); 1,053 (LOW) μmol CGA). CGA concentrations were determined in ileal fluid, urine and plasma. Furthermore, we conducted an ex vivo study with pig jejunal mucosa using the Ussing chamber model to confirm the in vivo observations. Individual transfer rates of CGA from coffee were investigated, namely: caffeoylquinic acid (CQA), feruloylquinic acid (FQA), caffeic acid (CA), dicaffeoylquinic acid (diCQA) and QA at physiological concentrations (0.2–3.5 mM). Samples were analyzed by HPLC-DAD, -ESI-MS and -ESI-MS/MS.
About ⅔ of the ingested CGA by coffee consumption were available in the colon dose independent. Nevertheless, the results showed that the consumption of higher CGA doses leads to a faster ileal excretion. This corresponds to a plasma AUC0-8h for CGA and metabolites of 4,412 ± 751 nM*h0-8-1 (HIGH), 2,394 ± 637 nM*h0-8-1 (MEDIUM) and 1,782 ± 731 nM*h0-8-1 (LOW) respectively, and a renal excretion of 8.0 ± 4.9% (HIGH), 12.1 ± 6.7% (MEDIUM) and 14.6 ± 6.8% (LOW). Moreover interindividual differences in gastrointestinal transit times were related to differences in total CGA absorption. Thus the variety of patient´s physiology is a decisive bioavailability factor for CGA uptake. This is corroborated ex vivo by a direct proportional relationship of incubation time with absorbed CGA amount.
The consumption of high CGA doses influences the metabolism pattern as an increasing glucuronidation was observed with consumption of increasing CGA doses. However, the different CGA doses have only minor effects on the overall bioavailability which was confirmed ex vivo by a non-saturable passive diffusion of 5-CQA. Furthermore, we identified in the Ussing chamber an active efflux secretion for 5-CQA that decreases its bioavailability and the physicochemical properties of the CGA subgroups as an important bioavailability factor. Transferred amount in increasing order: diCQA, trace amounts; CQA ≈ 1%; CA ≈ 1.5%; FQA ≈ 2%; and QA ≈ 4%.
Altogether, the consumption of increasing CGA doses by coffee had a minor effect on oral bioavailability in ileostomists, such as a slightly increased glucuronidation. Thus, the consumption of high amounts of CGA from coffee in the daily diet is not limiting the CGA concentrations at the site of possible health effects in the human body. However, according to the patient´s physiology the interindividual gastrointestinal transit time which is possibly influenced by dose is influencing CGA bioavailability. Moreover, ex vivo CGA absorption is governed by diffusion as an absorption mechanism corroborating an unsaturable uptake in vivo and by the individual physicochemical properties of CGA.