Synthese von Triafulven-Vorstufen aus trisubstituierten Cyclopropanen

Synthesis of Triafulvene-Precursors from Trisubstituted Cyclopropanes Trisubstituted cyclopropanes 5a–f are prepared by carbene addition to the appropriate olefins. While 5a (Y = OAc) and 5c (Y = Cl) rearrange in the presence of BuLi, 5d (Y = SPh) is stable enough to allow the envisaged sequence for triafulvene (Scheme 2) : halogen-Li exchange, followed by methylation of 6d , gives 7d in a 93% yield; after base-induced elimination of HB r from 7d , the key precursor 1-methylene-2-(phenylthio)cyclopropane ( 9 , 70% yield) is isolated. Compound 9 is transformed into the corresponding sulfoxide 10 (83%), sulfone 11 (80%), and sulfonium fluoroborate 12 (95% yield) by subsequent oxidation and methylation, respectively. Some ¹H-NMR results of cyclopropanes 5a–f and 7d as well as of methylidene-cyclopropanes 9–11 are discussed.     

Progress in the Understanding of the Key Pharmacophoric Features of the Antimalarial Drug Dihydroartemisinin: An Experimental and Theoretical Charge Density Study

The accurate, experimental charge density distribution, ρ( r ), of the potent antimalarial drug dihydroartemisinin (DHA) has been derived for the first time from single‐crystal X‐ray diffraction data at T=100(2) K. Gas‐phase and solid‐state DFT simulations have also been performed to provide a firm basis of comparison with experimental results. The quantum theory of atoms in molecules (QTAIM) has been employed to analyse the ρ( r ) scalar field, with the aim of classifying and quantifying the key real‐space elements responsible for the known pharmacophoric features of DHA. From the conformational perspective, the bicyclo[3.2.2]nonane system fixes the three‐dimensional arrangement of the 1,2,4‐trioxane bearing the active O? O redox centre. This is the most nucleophilic function in DHA and acts as an important CH???O acceptor. On the contrary, the rest of the molecular backbone is almost neutral, in accordance with the lipophilic character of the compound. Another remarkable feature is the C? O bond length alternation along the O‐C‐O‐C polyether chain, due to correlations between pairs of adjacent C? O bonds. These bonding features have been related with possible reactivity routes of the α‐ and β‐DHA epimers, namely 1) the base‐catalysed hemiacetal breakdown and 2) the peroxide reduction. As a general conclusion, the base‐driven proton transfer has significant non‐local effects on the whole polyether chain, whereas DHA reduction is thermodynamically favourable and invariably leads to a significant weakening (or even breaking) of the O? O bond. The influence of the hemiacetal stereochemistry on the electronic properties of the system has also been considered. Such findings are discussed in the context of the known chemical reactivity of this class of important antimalarial drugs.     

Targeted Metabolomics of Dried Blood Spot Extracts

Dried blood spot (DBS) samples are already successfully used in newborn screening and pharmacological analyses. The application of DBS matrix to further metabolomic methods will considerably extend the analytical options for the diagnostics of metabolic diseases. We present an MS/MS based method for the simultaneous extraction and quantification of 188 metabolites from dried blood spots. We provide a sensitive and reproducible method that adapts the AbsoluteIDQ? p180 kit of Biocrates to the DBS matrix for the quantification of metabolites of different substance classes including amino acids, biogenic amines, free carnitine, acylcarnitines, hexoses, glycerophospholipids, lysophosphatidylcholines, phosphatidylcholines, and sphingolipids.     

Analytical determination of specific 4,4′-methylene diphenyl diisocyanate hemoglobin adducts in human blood

4,4′-Methylene diphenyl diisocyanate (MDI) is one of the most important isocyanates in the industrial production of polyurethane and other MDI-based synthetics. Because of its high reactivity, it is known as a sensitizing agent, caused by protein adducts. Analysis of MDI is routinely done by determination of the nonspecific 4,4′-methylenedianiline as a marker for MDI exposure in urine and blood. Since several publications have reported specific adducts of MDI and albumin or hemoglobin, more information about their existence in humans is necessary. Specific adducts of MDI and hemoglobin were only reported in rats after high-dose MDI inhalation. The aim of this investigation was to detect the hemoglobin adduct 5-isopropyl-3-[4-(4-aminobenzyl)phenyl]hydantoin (ABP-Val-Hyd) in human blood for the first time. We found values up to 5.2 ng ABP-Val-Hyd/g globin (16 pmol/g) in blood samples of workers exposed to MDI. Because there was no information available about possible amounts of this specific MDI marker, the analytical method focused on optimal sensitivity and selectivity. Using gas chromatography–high-resolution mass spectrometry with negative chemical ionization, we achieved a detection limit of 0.02 ng ABP-Val-Hyd/g globin (0.062 pmol/g). The robustness of the method was confirmed by relative standard deviations between 3.0 and 9.8 %. Combined with a linear detection range up to 10 ng ABP-Val-Hyd/g globin (31 pmol/g), the enhanced precision parameter demonstrates that the method described is optimized for screening studies of the human population.     

Modified dispersive liquid-liquid microextraction for pre-concentration of benzene, toluene, ethylbenzene and xylenes prior to their determination by GC

We have developed a modified method for the extraction and preconcentration of benzene, toluene, ethylbenzene and xylenes (BTEX) in aqueous samples. It based on dispersive liquid-liquid microextraction along with solidification of floating organic microdrops. The dispersion of microvolumes of an extracting solvent into the aqueous occurs without dispersive solvent. Various parameters have been optimized. BTEX were quantified via GC with FID detection. Under optimized conditions, the preconcentration factors range from 301 to 514, extraction efficiencies from 60 to 103 %, repeatabilities from 2.2 to 4.1 %, and intermediate precisions from 3.5 to 7.0 %. The relative recovery for each analyte in water samples at three spiking levels is >85.6 %, with a relative standard deviation of <7.4 %.

Determination of organochlorine pesticides in river water using dispersive liquid–liquid microextraction and gas chromatography–electron capture detection

Dispersive liquid–liquid microextraction (DLLME) coupled with gas chromatography–electron capture detection (GC–ECD), has been developed for the extraction and determination of 14 organochlorine pesticides (hexachlorocyclohexanes (α-HCH, β-HCH and δ-HCH), Lindane (γ-HCH), Aldrin, Dieldrin, Endrin, Heptachlor, Heptachlor epoxide, α-Chlordane, β-Chlordane and p,p′-DDT, p,p′-DDD, p,p′-DDE) in river water samples. Factors relevant to the microextraction efficiency, such as the kind of extraction and disperser solvent, their volume and the salt effect was investigated and optimised. In this method the appropriate mixture of extraction solvent (13.5 µL carbon disulphide) and disperser solvent (0.50 mL acetone) were rapidly injected into the aqueous sample by syringe. The values of the detection limit of the method were in the range of 0.05–0.001 µg L^?1, while the relative standard deviations for five replicates varied from 2.7 to 9.3%. A good linearity (0.9894 ≤ r ² ≤ 0.9998) and a broad linear range (0.01–200 µg L^?1) were obtained. The method exhibited enrichment factors ranging from 647 to 923, at room temperature. The relative standard deviations varied from 2.7 to 9.3% (n = 5). The relative recoveries of each pesticide from water samples at spiking levels of 2.00 and 10.0 µg L^?1 were 88.0–111.0% and 95.8–104.1%, respectively. Finally, the proposed method was successfully utilised for the preconcentration and determination of the organochlorine pesticides in the Jajrood River water samples.     

Aggregation induced colour change for phosphorescent iridium(III) complex-based anionic surfactants

We describe a new class of water soluble metallosurfactant molecules based on luminescent neutral iridium(III) complexes. The compounds possess an alkyl chain terminated with a negatively charged group, a sulphate. Due to their amphiphilic nature they assemble in aggregates in water and their photophysical properties, as well as the morphological characterization of the assemblies are presented. In particular, UV-Vis absorption, steady-state and time-resolved emission spectroscopy, dynamic light scattering and scanning electron microscopy techniques have been employed towards the analysis of the assemblies in different media. Comparison with the single components shows that the aggregates have very different photophysical properties. Importantly, the change in colour upon self-assembly is a remarkable feature which could be used for the design of probes which can change properties in different environments.     

Optical, morphological and structural characterization of Langmuir-Schaefer films of a functionalized copper phthalocyanine

Langmuir-Schaefer (LS) films of copper(II) tetrakis-(isoprpoxy-carbonyl)-phthalocyanine (TiPCuPc) have been deposited onto various solid supports. Its floating film have been characterized at the air-water interface by means of Brewster Angle Microscopy and Langmuir curves. Vibrational modes of multilayer transferred LS film have been studied by Raman spectroscopy and the optical parameters (refractive index n and extinction coefficient k) have been determined in the visible range of the electromagnetic spectrum. Linearly polarized light absorbance measurements have been performed at room temperature in the 400-800 nm spectral range and the average orientation of the phthalocyanine rings have been estimated. Transmission electron microscopy has been also used to characterize the morphological properties of the LS film and a close packed arrangement of the deposited molecules has been observed.