Fluorinated alkyl substances, which can be persistent, toxic, and bioaccumulative, have been quantitated in many densely populated and remote regions, including in air, surface waters, groundwater, and biota; however, little is known about their transport or behavior in the environment. Wastewater effluent is one of the principal routes for introducing environmental contaminants into aquatic environments. The partitioning behavior of fluorinated alkyl substances between aqueous and particulate phases is not well characterized; thus, sorption onto sludge can be a removal mechanism of fluorinated alkyl substances from the wastewater stream. This is another route into the environment if the biosolids are land-applied. In an attempt to analyze for the fluorinated alkyl substances in wastewater, known aqueous-film-forming-foam (AFFF)-laden groundwater sampled from 3 military bases was used to develop an assay using liquid chromatography (LC), electrospray ionization (ESI) tandem mass spectrometry (MS/MS). While working on the method development, fluorotelomer sulfonates were detected at Wurtsmith AFB, MI, and Tyndall AFB, FL, where total fluoroatkyl sulfonates ranged respectively from below quantitation (���0.60 ��g/L) to 182 ��g/L and from 1100 ��g/L to 14,600 ��g/L. The LC ESI-MS/MS method was modified to quantitate fluorinated alkyl sulfonates in wastewater by incorporating a htgh volume sample loop (500 ��L), which lowered detection and quantitation limits by at least a factor of 50. This method was applied to 24 h composites of influents and effluents collected from treatment plants distributed nationwide. Fluorinated alkyl substances were observed at all 10 plants sampled, and each wastewater treatment plant was found to have a unique distribution of fluorinated alkyl substances, despite similar treatment processes. In 9 out of the 10 plants sampled, at least one class of fluorinated alkyl substance exhibited significant increases in the effluent as compared to the influent levels. The high-volume-injection LC ESI-MS/MS method was also used to monitor the mass flows of perfluoroalkyl sulfonates and carboxylates through a municipal wastewater treatment plant for 10 d. The perfluoroalkyl carboxylates were overall removed by the wastewater treatment process (25-40% removal). Perfluoroalkyl sulfonates were found to increase significantly (~200%) in the final effluent, and the fluoroalkyl sulfonamide acetic acids were found to increase by approximately 500% throughout the sludge process. From this plant, significant quantities of fluorochemicals are discharged with treated wastewater and biosolids, indicating that wastewater treatment plants are point sources of fluorinated alkyl substances and must be considered when determining origins and behavior of fluorinated alkyl substances in the environment. / Graduation date: 2005

No description available.

Thesis (Ph. D.)--Rutgers University, 2010. / "Graduate Program in Chemistry and Chemical Biology." Includes bibliographical references.

Thesis (M.S.)--Rochester Institute of Technology, 1994. / Typescript. Includes bibliographical references (leaves 62-65).

Thesis (doctoral)--University of Stockholm, 1983. / Bibliography: p. 36-39.

Fluorinated arenes are considered valuable in organic chemistry. They display different types of reactivity and physicochemical properties compared to their hydrogen analogues. In this project, our medicinal chemistry programme focused on developing rapidly accessible and modifiable heterocyclic scaffolds. Different classes of fluorinated heteroatom-containing organic compounds including benzothiophenes, (aza)phenoxazines and benzaldehyde phenylhydrazones were synthesised from highly fluorinated aromatic compounds with a diverse range of functional groups appropriate for medicinal chemistry development. Mechanistic studies for heterocyclic scaffold synthesis were discussed in the project. The mechanisms of the ring-forming reactions were elaborated in detail in each chapter. A range of substituents were introduced flexibly into the aromatic heterocycles, which were designed to meet the requirements for biological screening programmes. New compounds were characterized by 1H, 19F and 13C NMR spectroscopy, mass spectrometry and elemental analysis. The X-ray crystal structures of a fluorinated benzothiophene and two benzopyridooxazine derivatives were obtained confirming the structure and substitution pattern. From the heterocyclic scaffolds prepared, 6-benzimidazol-1-yl-benzothiophene derivatives (91), 3-imidazol-1-yl-pyridobenzoxazine derivatives (130) and 4-1-methylpiperazinyl-benzaldehyde phenylhydrazone derivatives (195) acted as hit compounds and demonstrated significant trypanocidal activities. SAR studies were employed in structural modifications on these samples to search for the best activities with highest selectivity.

Chapter 1 gives an introduction on the physical and electronic properties of fluorine and the C-F bond. The application of fluorine in organic chemistry, which is mainly attributed to the electronic properties of fluorine is described. The role of fluorine in neuropsychiatric drug development and for influencing the conformational study of bioactive amines is also illustrated. Chapter 2 of the thesis describes the synthesis of the two fluorinated stereoisomers (2R, 3S) and (2S, 3S) 3-fluoro N-methyl–D-aspartate (NMDA). These were prepared as analogues to study the binding conformation of NMDA on the glutameric NMDA receptor. The (2S, 3S)-3-fluoro NMDA D-72 was successfully prepared from diethyl D-tartrate. The (2S,3R)- stereoisomer was prepared by separation of diastereoisomers generated by reaction of a meso- epoxide with an enantiomerically pure amine, followed by fluorination. Both the (2S,3R)- and (2R,3S)- enantiomers were prepared separately, however assignment of the absolute configuration to each enantiomer could not be unambiguously proven. The fluorinated 3F-NMDA stereoisomers were assessed by dose response analysis and TEVC analysis in the rat glutamate receptor. The biological results show that the (2S, 3S)-3F NMDA D-72 is a good agonist, whereas (2R, 3S)- and (2S, 3R)-3-fluoro NMDA are inactive stereoisomers. The result of this study indicates that (2S, 3S)-3F NMDA D-72 is the only relevant agonist that can access a conformation for binding to NMDA receptor. Chapter 3 describes the preparation of fluorinated analogues of the calcium receptor agonist Cinacalcet. The (2R,1’R)-123 and (2S,1’R)-124 fluoro Cinacalcet diastereoisomers were prepared from 3’-(trifluoromethyl)cinnamic acid and 3’’-SF₅-137 Cinacalcet was synthesized from pentafluorosulfanyl benzyl alcohol. The biological assessment in the calcium receptor (CaR) revealed that both (2R,1’R)-123 and (2S,1’R)-124 fluoro Cinacalcet is slightly lower in potency compared to the non-fluorinated Cinacalcet 117. This suggests that the Cinacalcet 117 adopts an extended conformation when bound to the receptor. The 3’’-SF₅-137 Cinacalcet possesses equipotent activity with Cinacalcet 117.

Chapter 1 provides a general introduction to organofluorine chemistry and focuses on recent developments in fluorination techniques. It also details how the C–F bond influences conformational and physiochemical properties of organic molecules. Chapter 2 highlights the biological role of the telomere, telomerase and quadruplex DNA in cells. It discusses the inhibition of telomerase with small molecules that stabilise quadruplex DNA as a treatment for cancer. An overview of the development of structurally related telomerase inhibitors and recent X-ray crystallographic structural data with BSU6039 and BRACO-19 telomeric DNA is presented. Chapter 3 discusses the synthesis of fluorinated BSU6039 analogues for the investigation of the conformational effects of fluorine in 5-membered rings and its influence on binding with quadruplex DNA. These compounds have been successfully co-crystallised with telomeric DNA and their relative stabilisation of telomeric DNA has been assessed. The latter half of this chapter focuses on the co-crystal structures between (S,S)- and (R,R)-144 with Oxytricha nova telomeric DNA, discussing the key differences between the two stereoisomers. Chapter 4 details the synthesis of fluorinated BRACO-19 analogues. The syntheses of such fluorinated analogues were achieved through a base mediated coupling between 3,6-diaminoacridone and an α-fluorinated-β-amino ester. The α-fluorinated-β-amino ester was synthesised through a deoxyfluorination-mediated approach, using the stereochemistry of natural amino acids. Chapter 5 describes the stereo- and regio- selectivity of deoxyfluorination reactions with dipeptides bearing the β-amino alcohol functionality. Understanding this selectivity enabled the development of a method towards α-fluorination of tertiary amides. The application of this fluorination method with an orthogonally protected tertiary amide is described.

*Please refer to dissertation for diagrams. / Part I describes the silicon-hydrogen bond activation (SiHA) of silanes with both electron-deficient iridium porphyrin carbonyl chloride (Ir(ttp)Cl(CO)) and electron-rich iridium porphyrin methyl (Ir(ttp)Me) to give iridium(III) porphyrin silyls (Ir(ttp)SiR3). Firstly, Ir(ttp)SiR3 were synthesized in moderate to good yields conveniently from the reactions of Ir(ttp)Cl(CO) and Ir(ttp)Me with silanes, via SiHA in solvent-free conditions and non-polar solvents at 200°C. Base facilitated the SiHA reaction even at lower temperature of 140°C. Specifically, K3PO4 accelerated the SiHA with Ir(ttp)Cl(CO), while KOAc promoted the SiHA by Ir(ttp)Me. Mechanistic experiments suggest that Ir(ttp)Cl(CO) initially forms iridium porphyin cation (Ir(ttp)+), which then reacts with silanes likely via heterolysis to give iridium porphyrin hydride (Ir(ttp)H). Ir(ttp)H further reacts with silanes to yield Ir(ttp)SiR3. On the other hand, Ir(ttp)Me and Ir(ttp)SiR3 undergo either oxidative addition (OA) or sigma-bond metathesis (SBM) to form the products. In the presence of base, a penta-coordinated silicon hydride species likely forms and reacts with Ir(ttp)Me to form iridium porphyrin anion (Ir(ttp) -) that can further react with silane to yield Ir(ttp)H after protonation. Ir(ttp)H finally reacts with excess silane to give Ir(ttp)SiR 3.* / Part II describes successful base promoted aromatic carbon-fluorine (C-F) and carbon-hydrogen (C-H) bond activation of fluorobenzenes in neat conditions to give the corresponding iridium(III) porphyrin aryls (Ir(ttp)Ar) at 200°C in up to 95% yield. Mechanistic studies suggested that Ir(ttp)SiEt3 is firstly converted to Ir(ttp)- in the presence of KOH. Ir(ttp)- cleaves the aromatic C-F bond via an S NAr process. As the reaction proceeds, a hydroxide anion can coordinate to the iridium center of Ir(ttp)Ar to form an iridium porphyrin trans aryl hydroxyl anion (trans-[ArIr(ttp)OH]-). In the presence of water, trans-[ArIr(ttp)OH]- can give Ir(ttp)OH and ArH. Ir(ttp)OH then undergoes aromatic C-H bond activation reaction to give Ir(ttp)Ar'. Furthermore, the aromatic C-F bond activation products were found as the kinetic products, and aromatic C-H bond activation products were the thermodynamic ones.* / Part III describes the successful C(C=O)-C(alpha) bond activation of acetophenones by high-valent iridium porphyrin complexes (Ir(ttp)X, X = Cl(CO), (BF4)(CO), Me) in solvent-free conditions at 200°C to give the corresponding iridium porphyrin benzoyls (Ir(ttp)COAr) in up to 92% yield. Mechanistic studies suggest that Ir(ttp)X reacts with acetophenones to give alpha-CHA product as the primary product, which can re-convert back to the active intermediate Ir(ttp)OH or Ir(ttp)H in the presence of water formed from the concurrent iridium-catalyzed aldol condensation of acetophenones. Then Ir(ttp)OH cleaves the aromatic C-H bonds to produce the aromatic CHA products, which are more thermally stable than the alpha-CHA product. Both Ir(ttp)H and Ir(ttp)OH were the possible intermediates to cleave the C(C=O)-C(alpha) bond to give thermodynamic products of Ir(ttp)COAr. On the other hand, only Ir(ttp)(BF 4)(CO) can react with the aliphatic ketones, likely due to the stronger Lewis acidity and the HBF4 generated in catalyzing the aldol condensation of aliphatic ketones to facilitate the formation of Ir(ttp)OH and Ir(ttp)H.* / The objectives of the research focus on the bond activation chemistry by iridium porphyrin complexes with three organic substrates, (1) hydrosilanes (HSiR3), (2) fluorobenzenes (C6HnF6-n , n = 0--6), and (3) aromatic or aliphatic ketones (RCOR, R = alkyl or aryl). / Li, Baozhu. / Adviser: Kin Shing Chan. / Source: Dissertation Abstracts International, Volume: 72-01, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references. / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese.

The fluorinase enzyme, originally isolated from Streptomyces cattleya, has the unique ability to generate a C–F bond from aqueous fluoride ion and S-adenosylmethionine, making the fluorinase an attractive biochemical tool for radiolabelling biomolecules with fluorine-18 for application to positron emission tomography (PET). The inherent substrate specificity of the enzyme is, however, limiting, as only small modifications to the natural nucleoside substrate were known to be tolerated. This thesis describes an exploration and expansion of the substrate scope of the fluorinase enzyme, and its application to radiolabelling biomolecules for PET. The design and synthesis of a novel acetylene bearing substrate for the fluorinase, 5'-chloro-5'-deoxy-2-ethynyladenosine (ClDEA) is described. ClDEA proved an excellent substrate for the fluorinase, and the kinetics of the transformation and binding affinities of the new substrate and product were investigated. The fluorinated acetylenic product was demonstrated to undergo a copper-catalysed azide-alkyne cycloaddition (CuAAC) reaction with an azide bearing RGD peptide, and this methodology was investigated for the synthesis of a novel fluorine-18-bearing prosthetic group for the synthesis of a radiolabelled RGD peptide, which was assessed in vivo in a rat. After the demonstration that the fluorinase can be used for “last step” radiolabelling of bioactive peptides, the synthesis of dimeric and tetrameric RGD-bearing substrates for the fluorinase was investigated. These large constructs underwent efficient enzymatic fluorination, and the fluorinated products showed increased binding affinity to their targets, compared to monomeric analogues. The challenges encountered during radiolabelling of these multimers with fluorine-18 using the fluorinase are discussed. A difluoromethyl-bearing nucleoside substrate (F₂DA) was synthesised as a potential substrate in the reverse direction for the fluorinase, to further probe the substrate specificity if the fluorinase. Upon incubation with the enzyme, F₂DA did not appear to undergo reaction, despite the demonstration that F₂DA binds to the enzyme. Finally, the optimisation of a fluorinase-based protocol for the synthesis of the PET radiotracer [¹⁸F]fluoroacetate is described. The enzymatic method proved unsuitable for a small animal study due to contamination of the final product, and a chemical method was investigated and optimised as an alternative approach. [¹⁸F]Fluoroacetate synthesised using the developed chemical method was employed in an in vivo evaluation of acetyl CoA synthetase (ACSS2) activity in healthy and tumour-bearing mouse models, in an study to assess the activity of ACSS2 in breast and colon cancer models in mice.