41 research outputs found
Large-scale assessment of organic contaminant emissions from chemical and pharmaceutical manufacturing into Swiss surface waters
This study presents a nation-wide assessment of the influence of chemical and pharmaceutical manufacturing (CPM) wastewaters on synthetic organic contaminant (SOC) emissions to Swiss surface waters. Geographic Information System (GIS) based analysis of the presence of CPM in wastewater treatment plant (WWTP) catchments revealed wide distribution of this industrial sector across Switzerland, suggesting that one-third of the 718 Swiss WWTPs may be influenced by CPM wastewaters. To reflect the diversity of this type of wastewaters, we investigated the effluents of 11 WWTPs of diverse sizes and technologies, which treated 0-100% wastewater from a variety of CPM activities. In an extensive sampling campaign, we collected temporally high resolved (i.e., daily) samples for 2-3 months to capture the dynamics of CPM discharges. The > 850 samples were then measured with liquid chromatography high-resolution mass spectrometry (LC-HRMS). Non-target characterization of the LC-HRMS time series datasets revealed that CPM wastewaters left a highly variable and site-specific signature in the effluents of the WWTPs. Particularly, compared to WWTPs with purely domestic input, a larger variety of substances (up to 15 times more compounds) with higher maximum concentrations (1-2 orders of magnitude) and more uncommon substances were found in CPM-influenced effluents. Moreover, in the latter, highly fluctuating discharges often contributed to a substantial fraction of the overall emissions. The largely varying characteristics of CPM discharges between different facilities were primarily related to the type of activities at the industries (i.e., production versus processing of chemicals) as well as to the pre-treatment and storage of CPM wastewaters. Eventually, for one WWTP, LC-HRMS time series were correlated with ecotoxicity time series obtained from bioassays and major toxic components could be identified. Overall, in view of their potential relevance to water quality, a strong focus on SOC discharges from CPM is essential, including the design of situation-specific monitoring, as well as risk assessment and mitigation strategies that consider the variability of industrial emissions.
Keywords: Chemical and pharmaceutical industry; High-resolution mass spectrometry; Industrial wastewater; Micropollutants; Non-target analysis; Temporal data
Nitrogen-centered radicals in functionalization of sp2Â systems : generation, reactivity, and applications in synthesis
The chemistry of nitrogen-centered radicals (NCRs) has plentiful applications in organic synthesis, and they continue to expand as our understanding of these reactive species increases. The utility of these reactive intermediates is demonstrated in the recent advances in C-H amination and the (di)amination of alkenes. Synthesis of previously challenging structures can be achieved by efficient functionalization of sp2 moieties without prefunctionalization, allowing for faster and more streamlined synthesis. This Review addresses the generation, reactivity, and application of NCRs, including, but not limited to, iminyl, aminyl, amidyl, and aminium species. Contributions from early discovery up to the most recent examples have been highlighted, covering radical initiation, thermolysis, photolysis, and, more recently, photoredox catalysis. Radical-mediated intermolecular amination of (hetero)arenes can occur with a variety of complex amine precursors, generating aniline derivatives, an important class of structures for drug discovery and development. Functionalization of olefins is achievable in high anti-Markovnikov regioselectivity and allows access to difunctionalized structures when the intermediate carbon radicals are trapped. Additionally, the reactivity of NCRs can be harnessed for the rapid construction of N-heterocycles such as pyrrolidines, phenanthridines, quinoxalines, and quinazolinones
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The rapid synthesis of oxazolines and their heterogeneous oxidation to oxazoles under flow conditions.
A rapid flow synthesis of oxazolines and their oxidation to the corresponding oxazoles is reported. The oxazolines are prepared at room temperature in a stereospecific manner, with inversion of stereochemistry, from ÎČ-hydroxy amides using Deoxo-FluorÂź. The corresponding oxazoles can then be obtained via a packed reactor containing commercial manganese dioxide.We are grateful to the Swiss National Science Foundation (DNT), the Ralph Raphael fellowship (RJI), the German Academic Exchange Service DAAD (SF), the Royal Society Newton International Fellowship (ZEW), Pfizer Worldwide Research and Development (CB) and the EPSRC (SVL, SF and ZEW, grant nÂș EP/K0099494/1) for financial support. The Labtrix Start was kindly loaned by Chemtrix BV and the liquid-liquid phase separator by Zaiput Flow Technologies (we are grateful to Dr Andrea Adamo for technical support with this device).This is the final version. It was first published by the Royal Society of Chemistry at http://dx.doi.org/10.1039/C4OB02105
Coupling the core of the anticancer drug etoposide to an oligonucleotide induces topoisomerase II-mediated cleavage at specific DNA sequences
Etoposide and other topoisomerase II-targeted drugs are important anticancer therapeutics. Unfortunately, the safe usage of these agents is limited by their indiscriminate induction of topoisomerase II-mediated DNA cleavage throughout the genome and by a lack of specificity toward cancer cells. Therefore, as a first step toward constraining the distribution of etoposide-induced DNA cleavage sites and developing sequence-specific topoisomerase II-targeted anticancer agents, we covalently coupled the core of etoposide to oligonucleotides centered on a topoisomerase II cleavage site in the PML gene. The initial sequence used for this âoligonucleotide-linked topoisomerase inhibitorâ (OTI) was identified as part of the translocation breakpoint of a patient with acute promyelocytic leukemia (APL). Subsequent OTI sequences were derived from the observed APL breakpoint between PML and RARA. Results indicate that OTIs can be used to direct the sites of etoposide-induced DNA cleavage mediated by topoisomerase IIα and topoisomerase IIÎČ. OTIs increased levels of enzyme-mediated cleavage by inhibiting DNA ligation, and cleavage complexes induced by OTIs were as stable as those induced by free etoposide. Finally, OTIs directed against the PML-RARA breakpoint displayed cleavage specificity for oligonucleotides with the translocation sequence over those with sequences matching either parental gene. These studies demonstrate the feasibility of using oligonucleotides to direct topoisomerase II-mediated DNA cleavage to specific sites in the genome
Modular,step-efficient palladium-catalyzed cross-coupling strategy to access C6-heteroaryl 2-aminopurine ribonucleosides
This work was supported by an EPSRC-GSK industrial CASE studentship for H.B., a University studentship for T.D.K., and postdoctoral funding for S.P. by the Leverhulme Trust (RPG-2014-313).Two Pd-catalyzed methods to access 6-heteroaryl 2-aminopurine ribonucleosides from 6-chloroguanosine are described. First, Pd-132-catalyzed SuzukiâMiyaura cross-coupling using a series of boron substrates and 6-chloroguanosine forms 6-heteroaryl-2-aminopurines in a single step. The versatility of 6-chloroguanosine is further demonstrated using a modified Sonogashira coupling employing potassium iodide as an additive. Finally, the utility of the 6-alkynyl-2-aminopurine ribonucleoside as a dipolarophile in [3 + 2] cycloadditions is presented, affording triazoles and isoxazoles when reacted with azide and isonitrile 1,3-dipoles, respectively.Publisher PDFPeer reviewe
Nachhaltige Strategien zur Selektiven CâVC BindungsknĂŒpfung durch CâH Bindungsfunktionalisierung
WĂ€hrend der letzten zwei Jahrzehnte haben sich Ăbergangsmetall-katalysierte direkte Arylierungen als praktikable Alternative zu traditionellen Kreuzkupplungen herausgestellt, insbesondere bezĂŒglich ökonomischer und nachhaltiger ReaktionsfĂŒhrung. Demnach wurde der Fokus der vorliegenden Arbeit auf die Entwicklung generell anwendbarer Methoden zur selektiven CâC BindungsknĂŒpfung durch direkte CâH Bindungsfunktionalisierung gelegt. Im ersten Teil wurde ein Protokoll zur palladium-katalysierten direkten CâH Bindungsarylierung elektronenarmer Heteroarene mit Aryl- und Alkenylslufonaten ausgearbeitet. Das optimierte Katalysatorsystem liefert die gewĂŒnschten Arylierungsprodukte mit exzellenter Chemo- und RegioselektivitĂ€t in hohen Ausbeuten. Sowohl verschiedene Tosylate, als auch atomökonomischere Mesylate, dienten als kostengĂŒnstige, luft- und feuchtigkeitsstabile Elektrophile und wurde erfolgreich zur CâH Bindungsfunktionalisierung eingesetzt. Das hoch-aktive Katalysator-System ermöglichte zusĂ€tzlich die Funktionalisierung elektronenarmer Fluorarene mit desaktivierten Tosylaten. Im zweiten Projekt der Arbeit wurden nachhaltige ruthenium-katalysierte Annelierungen interner Alkine mit BenzhydroxamsĂ€ureestern via CâH/NâO Bindungsfunktionalisierung unter umweltfreundlichen Bedingungen ausgearbeitet. Redoxneutrale Isochinolon-Synthesen mit groĂer Anwendungsbreite wurden erfolgreich in Wasser als Lösungsmedium durchgefĂŒhrt. DarĂŒber hinaus können freie BenzhydroxamsĂ€uren als Substrate zur Synthese annelierter Lactame eingesetzt werden. Weiterhin wurde eine effiziente Strategie zur selektiven Funktionalisierung von Indolen unter ĂŒbergangasmetallfreien Reaktionsbedingungen entwickelt. Regioselektive C3-Arylierungen N-Alkyl- und NH-freier Indole wurde unter Verwendung von Diaryliodoniumsalzen bewerkstelligt. ZusĂ€tzlich gelang die direkte Arylierung an Pyrrolen. Im letzten Projekt der vorliegenden Arbeit wurde ein direkter Zugang zu heteroarylischen CarbonsĂ€urederivaten durch Kohlenstoffdioxid- Fixierung ermöglicht. Zahlreiche CarbonsĂ€ureester unterschiedlicher Heteroarene wurden in Abwesenheit eines Ăbergangsmetall-Katalysators, unter Verwendung der kostengĂŒnstigen, anorganischen Base KOt-Bu, in guten Ausbeuten erhalten
Quantification of Active Ingredient Losses from Formulating Pharmaceutical Industries and Contribution to Wastewater Treatment Plant Emissions
In this work, emissions of active pharmaceutical ingredients (APIs) from formulating pharmaceutical industries (FPIs) were investigated for the first time based on detailed production information and compared to overall API emissions in wastewater treatment plant (WWTP) effluents. At two municipal WWTPs, both receiving wastewater from several FPIs, two monthsâ daily effluent samples were collected and measured using liquid chromatography high-resolution mass spectrometry (LC-HRMS). Thirty-three APIs formulated during the sampling period as well as >120 organic contaminants commonly present in WWTP effluents were quantified. On the basis of their time patterns and manufacturing data, industrial contributions were found for 22 of 26 APIs (85%) detected in the samples and processed by the FPIs. API emissions from FPIs led to daily concentration increases of up to 300-fold, despite pretreatment of the industrial wastewater. However, emissions from FPIs seemed to depend on the type of formulating activity, with granulation and mixing being most prone to API losses. Losses from FPIs were responsible for the highest concentrations and for up to 60% of the daily total API emissions measured. Furthermore, screening for suspects in LC-HRMS data resulted in the detection of unexpected emissions from FPIs, demonstrating the value of these data to comprehensively assess industrial API losses. Overall, this study showed that FPIs were relevant contributors of APIs emitted in the WWTP effluents, although only a minor fraction (<1%) of the total processed API quantity was lost to the wastewater, and despite the small percentage (<5%) of FPI wastewater compared to the total wastewater flow