Proefschrift Rijksuniversiteit Groningen. / Met lit.opg. - Met samenvatting in het Nederlands.

Thesis (Ph. D.)--University of Texas at Austin, 2008. / Vita. Includes bibliographical references.

This thesis comprises three chapters united by a single theme: development of alkali metal cation sensors based on ion complexing macrocycles. In part 1, benzo-18-crown-6 and cryptand 2.2.2B were immobilised on polyacrylic acid backbone through an amide linkage. The benzo-18-crown-6 and 2.2.2B were functionalised using the Friedal-Crafts acylation reaction with ω-amino acids. The spacer between the polymer backbone and the crown ether was varied by using co-amino acids with varying numbers of methylene groups [special characters omitted]. Attempts to use co-amino acids with an intermediate spacer length [special characters omitted] failed due to formation of a cyclic imine. The amino crown ethers were immobilised on a poly(acryloyl chloride). Polymers 2a, 5ad and 6a failed to give self supporting membranes but a polymer blend with PVC/Plasticizer was employed for membrane fabrication. Ion Selective Electrodes (ISEs) and Coated Wire Electrodes (CWEs) were made from polymer blend membranes and their response to alkali metal cations was tested. The ISEs made with mobile carriers were active, while those prepared from immobilised carriers were inactive. The reverse was the case with CWEs. This dichotomy existed in all cases. The selectivity of the ionophores among the alkali metals was unaffected by linkage to the polymer backbone. However, the alkali metal/alkaline earth metal selectivity was enhanced. The effect of plasticizer and hydrophilic additives on electrode response was insignificant. The spacer length had considerable influence: the longer the spacer, the better the electrode response of the CWEs. In part 2, the mass transport of ions across the polymer blend membrane under a temperature gradient was investigated. The immobilised polymers prepared in part 1 were used here to fabricate membranes from polymer blends with NOMEX. In thermodialysis experiments, a low level of ion transport was detected. These preliminary experiments led to a rediscovery of membrane distillation. The scope of this latter process with hydrophobic membranes was explored in detail. Part 3 was devoted to the design and synthesis of water soluble photoionophores. Three series of molecules were synthesised: captands, bis crown ether compounds and phenol derivatives of tartaro crown ether carboxylic adds. Captand molecules were synthesised by a capping reaction of crown ether tetraacid chloride 14 with 1,3-bis(aminomwthyl) benzene, 1,4- bis(aminomethyl) benzene and 2,2’-bis(aminomethyl) biphenyl. Crystals of meta- and para xylene capped molecules were grown and their structures solved to establish the conformation of the molecules. Fluorescence quenching studies of these molecules were done in 0.3% methanol:water (v/v). Quenching due to alkali metal ions was insignificant ( < 20%) while copper and mercury cations quenched the emission significantly ( > 90%). Stern-Volmer analysis showed an upward curvature indicating association between the ligand and the cations [special characters omitted] cations, but dynamic and static components of the quenching could not be separated. Potentiometric titration with a potassium selective electrodes was carried out to obtain the stability constants for these ligands with potassium ion. The bis crown ethers 28 and 29, designed to increase water solubility, were prepared by the reaction of anhydride 27 with 9,10-bis(ammomethyl) anthracene and 1,2-bis(aminomethyl) benzene. The pKa values of the ligands and their stability constants with alkali and alkaline earth metal ions were determined by potentiometric titration. Fluorescence quenching studies were done in aqueous buffer at pH 10. These compounds also failed to give an emission quenching in the presence of alkali or alkaline earth metal cations, but both copper and mercury cations showed a significant amount of quenching. Stability constants were derived from emission quenching studies for [special characters omitted]. Chromoionophores, phenol derivatives of tartaro crown ethers, were synthesised from the reaction of crown ether anhydrides and 2-aminophenol. The structure of the compound 31 was assigned as the syn isomer based on nmr data in comparison to literature reports. Absorption studies were carried out in water. The absorption spectra of compound 30 were perturbed by alkali metal as well as alkaline earth metal ions, while the absorption spectrum of compound 31 showed no response to varying cation concentration. The lack of response from compound 31 was attributed to the competitive binding of cations among syn carboxylic groups away from the syn phenolic groups. / Graduate

Brominated flame retardants have been widely used in industry. There is a rapidly growing public concern about their ubiquity in the environment. This project investigated the possible removal treatments of polybrominated diphenyl ethers (PBDEs) using two treatment methods: (I) photocatalysis by TiO2 and (II) phytoremediation by Oryza sativa and Phragmites australis, and a combined system involving these two technologies. Advanced oxidation process (AOP) is a promising technology for removing emerging chemicals. In this case, nano-scaled titanium (IV) oxide was applied to evaluate its capability in the degradation of BDE-209 under visible light. The residual PBDE congeners after reaction were analyzed by gas chromatography-mass spectrometry (GC-MS). The half-life for removing BDE-209 by TiO2 was 3.05 days under visible light. Tetra- and penta-BDEs were the major degraded products of BDE-209. Optimum conditions for photocatalytical degradation of BDE-209 was found to be pH 12 (93% ± 1%), at least 5 mg/L (93 ± 1.70%) of humic acid and in the form of anatase/rutile TiO2 (82% ± 3%). Incomplete removal of PBDEs by water treatment plants and point-source contamination may lead to their discharge into water bodies and ultimately into soils. Consequently, the second part of the project was phytoremediation of PBDEs. Uptake of BDE-209 by rice cultivars, namely Fengmeizhan, Hefengzhan and Guangyinzhan, and common reed were examined by 60-day cultivation in sterilized BDE-209 spiked soil. Hefengzhan possessed the greatest ability in the removal and accumulation of BDE-209 among the three cultivars, especially when associated with Glomus intraradices, at pH 7. A series of plant-contamination sorption analyses were also employed for pathway studies of PBDEs uptake by rice. A partition-limited model was applied for describing and estimating the uptake of BDE-209 by rice roots. The average quasi-equilibrium factors (apt) of BDE-47, -99 and -209 in root uptake were 1.44 × 10-3 , 0.966 × 10 -3 and 0.115 × 10-3 in sand (< 1), implying a non-equilibrium state of the movement of molecules and a dominant passive transport uptake. From the result of sorption analysis of dead and fresh roots, the apoplastic pathway likely dominated the transport of PBDEs into root cells. These results provide essential information on the uptake mechanism of PBDEs into plants. Based on the results from photocatalysis and phytoremediation, a combined photocatalysis (TiO2 and visible light) and constructed wetland system (Oryza sativa (Hefengzhan) and Phragmites australis (common reed) was set up for comparing PBDEs removal efficiencies. The removal percentages of BDE-209 in the combined system were found to be promoted when compared to the individual systems, which could be explained by enhanced biodegradability of PBDEs in photocatalysis. Therefore, the proposed advanced wastewater treatment technology (combined photocatalysis and constructed wetland systems) might help to degrade and eliminate BDE-209 in the wastewater, and thus reduce the risks of marine contamination by discharging these incompletely or partially treated wastewaters containing PBDEs.

M.Sc. (Chemistry) / The work in this thesis describes some catalytic reactions of aluminium triflate. This Lewis acid has been shown to be of great value in the catalysis of several types of organic transformations. These include but are not limited to the alcoholysis and aminolysis of epoxides, uses in methoxycarbonylation catalysis and in esterification reactions. Therefore, aluminium triflate holds promise for application in both the bulk and fine chemistry industries. Aluminium triflate has received little interest compared to some other, more costly triflates such the lanthanide triflates. Oxetanes were used in various catalysis experiments during this study, yet few are commercially available. Therefore, various synthetic approaches to the synthesis of 2-phenyl-oxetane were explored. There were many failed attempts, but the preparation was eventually successful using a sulfur ylide route with good yield. The next part of this thesis explores the boundaries of ring-opening reactions of oxetanes. Lewis acid ring-opening of oxetanes has been neglected compared to that of epoxides, likely because it is a more difficult undertaking. Yet, alcoholysis reactions showed good yields with a variety of different alcohol substrates. Some of the alcohols contained functionality which could provide access to further modification. Furthermore, the aminolysis and thiolysis of oxetanes were explored, essentially without success. However, with an activated oxetane it was shown that oxetanes could be opened with good yield under mild conditions with amines and thiols...

Three cage-functionalized polyoxacrown ethers (9, 10 and 12) and four novel cage-functionalized polyoxamonoazacrown ethers (18, 20, 25 and 29) that contain 3,5-disubstituted-4-oxahexacyclo[5.4.0.02,6.03,10.05,9.08,11]dodecane ("oxahexacyclic") moiety have been synthesized and their respective alkali metal picrate extraction profiles along with that of three analogues 13, 14 and 21 have been obtained. The observed avidities and selectivities of the host molecules toward complexation and transport of alkali metal picrates can be related to the size and shape of their respective macrocyclic cavity and the number of donor atoms. The effect of N-alkyl substitution on the complexation properties of azacrown ethers has been studied. The avidity of N-Et azacrown ethers toward complexation with alkali metal cations is generally higher than that of the corresponding non-N-alkylated hosts. However, the presence of an N-Et group appears to have a negligible effect upon their relative selectivities in their regards. The effect of pH on extraction process was studied; it was thereby determined that the alkali metal picrate extraction experiments are best performed at high pH (ca. 11-12).

Based on the findings from breast cancer cells and nude mouse assays, we noticed that fatty acid metabolism was influenced by BDE-47 exposure. To have a comprehensive understanding of the impact, we performed targeted metabolomics analysis of fatty acids. Short-chain fatty acids (SCFAs) and hydroxylated short-chain fatty acids (OH-SCFAs) are crucial intermediates related to a variety of diseases, such as bowel disease, cardiovascular disease, renal disease and cancer. We developed a global profiling method to screen SCFAs and OH-SCFAs by tagging these analytes with d0/d6-N, N-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-d] pyrimidine-2-amine (d0/d6-DHPP) and UHPLC-MS/MS in parallel reaction monitoring (PRM) mode. The derivatization procedure was simple and rapid. The targeted compounds could be derivatized within three minutes under mild condition and analyzed without the need of further purification. The derivatization significantly improved the chromatographic performance and mass spectrometry response. The d6-DHPP tagged standards were used as internal standards, which remarkably reduced the matrix effects. The use of high resolution PRM mode made it possible to identify unknown SCFA and OH-SCFA species. The developed method was successfully applied to the analysis of mouse feces, serum, and liver tissue samples harvested from the breast cancer nude mice that had been exposed to BDE-47. By using the developed method, 40 analytes (10 SCFAs and 30 OH-SCFAs) were characterized. Semi-quantitative analysis indicated that the exposure of BDE-47 to the mice altered the SCFA and OH-SCFA metabolism, especially in the high dose group. In addition, medium- and long-chain fatty acids (MLFAs) are essential energy sources in cells and possess vital biological functions. Characteristics of MLFAs in biosamples can contribute to the understanding of biological process and the discovery of potential biomarkers for relevant diseases. However, there are obstacles of the MLFAs determination because of the poor ionization efficiency in mass spectrometry and structural similarity. Herein, a derivatization strategy was developed by labeling with d0-DHPP and detecting with UHPLC-MS/MS in multiple reaction monitoring (MRM) mode. The parallel isotope labeled internal standards were generated by tagging d6-DHPP to MLFAs. The simple and rapid derivatization procedure and mild reaction conditions greatly reduced the potential of MLFA degradation. With the methodology, the chromatography performance was greatly improved, and the mass spectrum response was enhanced up to 1, 600 folds. Finally, the developed derivatization method was applied to serum samples to analyze the alteration of MLFAs induced by BDE-47 exposure in breast cancer nude mice. The semi-quantitative results demonstrated that the BDE-47 exposure significantly influenced the MLFA metabolism. Together, mass spectrometry-based targeted and nontargeted metabolomics of in vitro and in vivo studies suggested that BDE-47 impacted multiple metabolic pathways and was positively associated with breast tumor growth in mice. This study might further our understanding of the health risks of BDE-47 to breast cancer.;Polybrominated diphenyl ethers (PBDEs) are commonly used to prevent the development of fire in various factory products. Due to the adverse effects on human health and bio-accumulation capacity, PBDEs are considered as one kind of persistent organic pollutants. 2,2',4,4'-Tetrabromodiphenyl ether (BDE-47) is one of the most frequently detected PBDE congeners in humans. Although numerous studies have shown the close connection between BDE-47 and human health, few reports were related to breast carcinoma. In vivo study of the association between BDE-47 and breast cancer was also scarce. In this study, both in vitro and in vivo experiments were conducted to explore the influence of BDE-47 to breast cancer. Firstly, we performed the in vitro study by exposing different concentrations of BDE-47 (5, 10 µM) to MCF-7 breast cancer cells. Nontargeted metabolomics analysis was conducted by using ultra-high performance liquid chromatography coupled with mass spectrometry (UHPLC-MS). Results showed that the toxicity to MCF-7 cells gradually increased when the concentration of BDE-47 exceeded 1 µM in the medium. Pyrimidine metabolism, purine metabolism and pentose phosphate pathway (PPP) were the most influenced metabolic pathways, and the metabolites in the three metabolic pathways were significantly downregulated. Moreover, the increase of reactive oxygen species was detected by using the 2',7'-dichlorodihydrofluorescein diacetate staining assay. Results suggested that the BDE-47 induced oxidative stress by downregulating the NADPH generation in PPP. The pyrimidine metabolism and purine metabolism might be downregulated by the downregulation of mRNA transcripts. Therefore, BDE-47 could induce oxidative stress in breast cancer cells by inhibiting PPP and disordering the metabolism of the entire cell subsequently. Secondly, we constructed a breast cancer nude mouse model, performed in vivo exposure of BDE-47 to the mice, and conducted mass spectrometry-based metabolomics and lipidomics analysis to investigate the metabolic changes in mice. Results showed that the tumor sizes were positively associated with the dosage of BDE-47. Metabolomics and lipidomics profiling analysis indicated that BDE-47 induced significant alterations of metabolic pathways in livers, including glutathione metabolism, ascorbate and aldarate metabolism, and lipids metabolism, etc. The upregulations of phosphatidylcholines and phosphatidylethanolamines suggested the membrane remodeling, and the downregulations of Lyso-phosphatidylcholines and Lyso-phosphatidylethanolamines might be associated with the tumor growth. Targeted metabolomics analysis revealed that BDE-47 inhibited fatty acid β-oxidation (FAO) and induced incomplete FAO. The inhibition of FAO and downregulation of PPARγ would contribute to inflammation, which could promote tumor growth. In addition, BDE-47 elevated the expression of the cytokines TNFRSF12A, TNF-α, IL-1β and IL-6, and lowered the cytokines SOCS3 and the nuclear receptor PPARα. The changes of cytokines and receptor may contribute to the tumor growth of mice.

Syntheses of diaryl ethers were approached by use of a Diels-Alder reaction employing a new type of diene attached with an aryloxy group. Thus, 2-methyl-3-phenoxybutadiene (90b ), 2- methoxy-3-phenoxybutadiene (92b) and (4S)-3-(t- butyloxycarbony1)-2 ,2-dimethyl-4-( 4-(3-methoxy-1,3 -butadienyl-2- oxy )phenylmethyl]oxazolidine (93b) were synthesized in ~65% yields by methylenation of the carbonyl function in the corresponding 2- substituted acrylate aryl ester using Tebbe's reagent. The 1,3- bis[(trimethylsilyl)oxy ]-2-phenoxybutadiene (105) was made from 1-phenoxy-2-propanone (101) by a sequence of formylation and enolsilylation. Methyl propiolate (107) and dimethyl acetylenedicarboxylate (113) were heated at reflux with diene 9 0 b and 92b in toluene to provide the cyclohexadiene adducts, which were easily oxidized to the corresponding diaryl ethers using DDQ in ~90% yields. Alkyne 107 was also reacted with diene 105 to provide 3-hydroxy-4-phenoxybenzoic acid methyl ester (116) m 49% yield. The diaryl ethers were characterized by IR, 1^ H NMR, l 3^C NMR and elemental analyses. N-Cbz-O-methyl-L-tyrosinol (129a) and (1R,2R)-N-Cbz-O-methyl- B-hydroxytyrosinol (136b) were synthesized by the condensation of Danishefsky's diene (124) with an acetylenic ketone, benzyl (R)-4-( 1-oxo-2-propynyl)-2,2-dimethyl-3- oxazolidinecarboxylate (120), which was derived from D-serine. Reduction of the ketone function in the adduct using NaBH_4 at 0°C provided 136b. Deoxygenation of the alcohol function in 136b via Barton's procedure gave the optically pure tyrosinol 129a. The synthesis of the fully differentiated (L,L)-isodityrosinol, ( 4R)-3-benzyloxycarbonyl-2,2-dimethyl-4- [3-[ 4-[ (2S)-2-( t-butyloxycarbonyl)amino-3-hydroxypropyl]phenoxy ]-4- methoxyphenylmethyl] oxazolidine (169) was also approached by a sequence of cycloaddition, aromatization and reduction. The cycloaddition between ketone 120 and diene 93b resulted in formation, in 91% yield, of an equal mixture of two regioisomers that were separated by flash chromatography on silica gel. The aromatization of the required cyclohexadiene adduct using DDQ gave (4R)-3-benzy loxycarbonyl-2,2-dimethyl-4-[3-[ 4-( 4S )-(3-t-butyloxycarbony 1-2,2-dimethy loxazolidin-4-yl)methyl phenoxy ]-4- methoxyphenyloxo] oxazolidine (145a), which was a precursor to isodityrosinol 169. The fortuitous selective methanolysis of one of the oxazolidine rings in 145a and reduction of the ketone function in the resulting monoalcohol via Barton's procedure gave isodityrosinol 169 in good overall yield (37%). The structure of isodityrosinol 169 was confirmed by l^H NMR, 13^C NMR, IR and elemental analyses. The diastereomeric purity of isodityrosinol 169 was proved by use of Mosher's acid. A new synthetic approach to K-13 was also described. Isodityrosinol 169 was oxidized by RuCl_3 + NalO_4, followed by coupling with tyrosine methyl ester to provide, in 56% overall yield, N-[N-( t-butyloxy )carbonyl]-O-[ (R)-5-(3-benzyloxy carbonyl-2,2- dimethyloxazolidin-4-y1-methy 1)-2-methoxypheny l]-L-tyrosyl]-O- methyl-L-tyrosine a-methyl ester (174 ), which was a precursor to K- 13. Cyclization of the resulting amino acid derived from the tripeptide 174 was unsuccessful, and more research on the cyclization is needed.

No description available.

Macrocyclic polyether sulfides have been prepared by reacting an oligoethylene glycol dichloride with a dithiol or sodium sulfide in ethanol. The following new compounds were prepared: 1-thia-(9-crown-3), 1,4-dithia-(9-crown-3), 1,4-dithia-(12-crown-4), 1,4,7-trithia-(12-crown-4), 1-thia-(18-crown-6), I,4-dithia-(18-crown-6), 1,7-dithia-(18-crown-6), 1,4,7-trithia-(18-crown-6), 1,7-dithia-(21-crown-7), 1,4,7-trithia-(21-crown-7). Four other previously reported macrocyclic polyether sulfides were also prepared. The symmetry of the nmr spectra of these compounds give added evidence for the proposed ring structures. The following subjects were presented and discussed: studies of cyclization by-products, dependence of cyclization yield on the size of the rings, high dilution principle and its application, medium-sized rings, effect of hetero-atoms on cyclization and melting point correlations. Also included in the dissertation is a detailed review of the syntheses of macrocyclic sulfides.