Post-translational modifications (PTMs) diversify the functions and control the stability of proteins by the covalent addition of chemical groups or proteins. These modifications include phosphorylation, acetylation, glycosylation, methylation, ubiquitination, etc. and affect all aspects of cellular activities. Dysregulation of PTMs is often linked to aging, oncogenesis, and various autoimmune diseases. Proteins involved in the PTM writing, removing, and reading process are very important biomarkers and hot therapeutic targets. Yet, current chemical methodologies to globally profiling PTM substrates rely on coppercatalyzed azide-alkyne cycloaddition (CuAAC) reaction in which bulky alkyne or azide groups in length and size are used. The intrinsic steric hinderance limits the general application of chemical reporters to metabolic incorporation by PTM writers possessing spacious active pockets.This dissertation will start with the demonstration that the alpha fluorine to amide bond was a steric free chemical reporter in protein acetylation. Fluorinated cofactors or precursors could be utilized by acetyltransferases to modify peptides and proteins both in vitro and in live cells. A novel bioorthogonal reaction named as fluorine thiol displacement reaction (FTDR) using thiophenol as the warhead was developed for converting a fluorine label in biomolecules to a fluorophore or biotin tag. This whole platform showed great potential to label, image, and enrich acetylation substrates. Another goal of this dissertation was the evolution of FTDR to fluorine selenol displacement reaction (FSeDR). Aliphatic selenol, aromatic selenol and thiol derivatives were compared in parallel in the labelling of fluorinated small molecules and proteins. Aliphatic selenol displayed the best reactivity under the mild physiological condition and exhibited a high degree of chemical stability. The updated platform was then used in the SILAC-based quantitative proteomics study of acetylation in the prostate cancer cell PC-3. The final goal of this dissertation focuses on the study of steric-free bioorthogonal labeling of glycosylation substrates based on FSeDR. The fluorine-tag labelled unnatural monosaccharides could be utilized by glycotransferases in live cells to modify sialylated glycoproteins, N-glycoproteins, and O-GlcNAcylated proteins. With the help of FSeDR, the fluorine reporter was further functionalized to fluorescent probes or affinity tags for imaging or enrichment studies. The steric-free fluorine reporter has the potential to become a powerful chemical reporter for glycan labelling. / Chemistry

<p> Fluorine-18 labelled F2, produced by the nuclear reaction, 18O(p,n)18F, and recovered from an oxygen-18 gas target, has been used to elucidate the mechanism for the formation of XeF+AsF6- from Xe, F2, and AsF5 under low temperature and dark conditions. Formation of XeF+AsF6- was confirmed by Raman spectroscopy. A method was designed to allow for the dilution of the 18F activity onto a pool of carrier 19F2 such that suitable quantities of low specific activity [18F]F2 could be produced for the mechanistic study of this reaction. Based on the 18F distributions within the products and unreacted [18F]F2 and AsF5, it was shown that an F2-AsF5 activated complex containing an electrophilic fluorine reacts with the weak electron donor, xenon gas, in a Lewis acid-base type reaction. The absence of random fluorine exchange within the activated complex indicated that a transient Fδ+ was responsible for the enhanced oxidizing ability of the F2-AsF5 complex, rather than the production of a formal "F+" or F· intermediate. Fluorine-18 investigations into the reaction of the F2-AsF5 activated complex with other possible electron donors have shown some 18F transfer with krypton gas. Attempts to establish the formation of KrF+ using 19F NMR spectroscopy have shown no evidence for the presence of the cation in the Kr/F2/AsF5 system. The systems Kr/F2/HF/SbF5 and OF2/F2/AsF5 were not seen to undergo a reaction.</p> <p> The results of such sensitive radiotracer experiments required a complete analysis of the composition of the target gas delivered from the 18O(p,n)18F oxygen gas target; the presence of reactive agents other than [18F]F2 could affect the distribution of activities in reaction mixtures. Oxygen difluoride, which was suspected as a possible side product of the double bombardment method, was identified as a constituent of the target gas by 19F NMR characterization. An analysis of the effect of the variation of irradiation parameters has concluded that the quantity of [18F]OF2 activity is independent of the production irradiation parameters and is most likely a consequence of the presence of small amounts of O2 within the target during the recovery irradiation.</p> <p> The application of CsSO4F as an electrophilic fluorinating agent has provided preliminary evidence for the flourination of biologically active aromatic amino acids. Cesium fluoroxysulphate was found to react with 3,4-dihydroxyphenylalanine (L-Dopa) in an CH3CN solution containing BF3 to produce a mixture 2-, 5-, and 6-fluoro-L-dopa. Fluorine-19 NMR spectroscopy was used to confirm the presence of the 2-, 5-, and 6-fluoro-isomers of fluorodopa in the reaction mixture.</p> / Thesis / Master of Science (MSc)

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Non-invasive techniques to measure bone fluorine levels in vivo are few and not well studied. These techniques would prove useful for longitudinal studies of fluorine accumulation and treatment optimization for patients with poor bone health. Two measurement techniques were analyzed and improvements to each technique attempted with bone samples and bone-mimicking phantoms. The first method analyzed was neutron activation analysis (NAA), a technique previously studied in our laboratory. A previous detector setup consisting of nine sodium iodide detectors was re-tested and a new detector setup consisting of two high-purity germanium detectors was also tested. The detection limit of the sodium iodide setup was found to be higher than previously reported by a factor of 4, and the new high-purity germanium detector setup was found to result in a higher detection limit by a factor of 5 compared to the sodium iodide setup. The second method analyzed was nuclear magnetic resonance (NMR). Magic angle spinning was performed on a human bone sample, and a novel probe was constructed for future in vivo measurements. MAS NMR measurement of the human bone sample showed it to have an appropriate chemical shift and shape consistent with previous research on substances similar to bone. The constructed probe successfully resonated at the appropriate frequency, however there were potential contamination problems which prevented a measurable fluorine signal from being obtained. Both the NAA and NMR techniques may be optimized further, though with the results obtained, NAA remains the more sensitive technique for measuring bone fluorine in vivo. / Thesis / Master of Science (MSc) / Fluorine is an element which accumulates in bones and teeth. High levels of fluorine have been shown to be unhealthy, causing both dental and skeletal fluorosis. Low levels of fluorine have been shown to reduce dental cavities, however, their effect on bone health is not well understood. Currently, fluorine can be measured in bone samples from either biopsies or cadavers. Having a non-invasive way to measure fluorine concentrations in living humans without the need for surgery would be invaluable. These measurements could be used to optimize treatment for osteoporosis patients or to determine if emergency measures are necessary in cases of high accidental doses to members of the public. Additionally, long-term studies examining fluorine metabolism and bone health could be performed on population groups of interest. For these reasons, two different non-invasive methods for determining fluorine content in bone were analyzed and enhancements to each measurement technique attempted.

The first chapter of this dissertation reports the synthesis of highly fluorinated Diels-Alder polyphenylenes. The first section of this chapter describes the three-pot synthesis of a perfluoroarylated bis(cyclopentadienone) monomer. The synthesis begins with the previously reported substitution reaction of decafluorobiphenyl and sodium cyclopentadienide. To the resulting 4,4'-octafluorobiphenylene-linked bis(cyclopentadiene), six perfluoro-4-tolyl groups (three on each of the two cyclopentadienyl moieties) are attached by nucleophilic aromatic substitution (SNAr) reactions. The remaining ring methylenes are subjected to a selenium dioxide-catalyzed oxidation to obtain the desired bis(cyclopentadienone) monomer. The next part of this chapter describes the polymerization of the perfluoroarylated bis-(cyclopentadienone) monomer and bis(4-ethynylphenyl) ether. The reaction affords an oligomer (Mn ~ 14,000 g/mol according to size-exclusion chromatographic analysis) that is soluble in several solvents and that decomposes above about 300°C according to thermogravimetric analysis. The second chapter of this dissertation describes a novel method to oxidize per-fluoroarylated cyclopentadiene compounds to the corresponding ketones using catalytic selenium dioxide and stoichiometric hydrogen peroxide. The first part of this chapter shows the synthesis of some perfluoroarylated cyclopentadiene substrates, while the second part of the chapter explores the oxidation of these compounds along with other perfluoroarylated cyclopentadienes already available within our research group. This chapter also explains how the reactivity of the perfluoroarylated cyclopentadienes under the oxidation conditions depends on their structure. Generally more electron-deficient cyclopentadienes react more readily, while sterically crowded cyclopentadienes react more reluctantly. This third chapter of this dissertation describes the synthesis and characterization of a reversible Diels-Alder polymer from an octafluorobiphenylene-linked bis(cyclopentadiene). In the first section, the synthesis of a reversible homopolymer of the bis(cyclopentadiene) monomer is described. The polymer reaches an optimized molecular weight of 11,000 g/mol (degree of polymerization is 20) under the reaction conditions because there is an equilibrium between polymerization and depolymerization even at the mild polymerization temperature (65°C). The TGA trace of the polymer shows that chain degradation takes place beyond 300°C. The thermal reversibility of the polymer was examined by bulk thermolysis, and flash-vacuum thermolysis. The second section describes the synthesis of a methylated bis(cyclopentadiene) that does not undergo self-polymerization at comparatively lower temperature but instead reacts with a second bis(maleimide) monomer. The resulting polymer typically shows a number-average molecular weight of 15,400 g/mol. This polymerization also is limited by the attainment of steady-state end group concentrations. The reversibility of the polymerization is demonstrated by solution thermolysis experiments in which unmasked cyclopentadiene groups are trapped by a monofunctional maleimide. / Ph. D.

The impacts of fluorine doping of ceria are studied by means of surface science experimental methods. Fluorine-doped and fluorine-free ceria layers are epitaxially grown on rhodium single crystals and their properties are compared in regular and inverse catalyst configurations. A procedure for epitaxial growth of CeO2(110) and CeOxFy(110) layers on Rh(110) single crystal is developed and described in detail. Shape alterations of Ce 3d spectrum brought about by fluorine doping are explained and a suitable deconvolution method is proposed. Special attention is focused towards stability of fluorine in ceria. Presented data show that fluorine incorporation in ceria lattice causes stable reduction of ceria, which withstands up to 200řC in near-ambient pressure conditions. Morphological changes are observed due to elongation of surface lattice constant of reduced ceria. Oxygen storage capacities and hydrogen oxidation reaction rates of four different studied systems are compared and discussed. The twofold nature of oxygen exposure of fluorinated ceria is discovered and explained. Oxygen repels fluorine from the surface, while the remaining part of fluorine is expelled to adsorbate positions, where its electronic state is altered. Moreover, such fluorine is prone to interact with atomic hydrogen. This reaction is...

abstract: Fluorine (F) is a volatile constituent of magmas and hydrous mantle minerals. Compared to other volatile species, F is highly soluble in silicate melts, allowing F to remain in the melt during magma differentiation and rendering F less subject to disturbance during degassing upon magma ascent. Hence, the association between fluorine in basalts and fluorine in the mantle source region is more robust than for other volatile species. The ionic radius of F- is similar to that of OH- and O2-, and F may substitute for hydroxyl and oxygen in silicate minerals and melt. Fluorine is also incorporated at trace levels within nominally anhydrous minerals (NAMs) such as olivine, clinopyroxene, and plagioclase. Investigating the geochemical behavior of F in NAMs provides a means to estimate the pre-eruptive F contents of degassed magmas and to better understand the degassing behavior of H. The partition coefficients of F were determined for clinopyroxene, olivine, plagioclase, and hornblende within melts of olivine-minette, augite-minette, basaltic andesite, and latite compositions. The samples analyzed were run products from previously-published phase-equilibria experiments. Fluorine was measured by secondary ion mass spectrometry (SIMS) using an 16O- primary beam and detection of negative secondary ions (19F-, 18O-, 28Si-). SIMS ion intensities are converted to concentrations by analyzing matrix-matched microanalytical reference materials and constructing calibration curves. For robust F calibration standards, five basaltic glasses (termed Fba glasses) were synthesized in-house using a natural tholeiite mixed with variable amounts of CaF2. The Fba glasses were characterized for F content and homogeneity, using both SIMS and electron-probe microanalysis (EPMA), and used as F standards. The partition coefficients for clinopyroxene (0.04-028) and olivine (0.01-0.16) varied with melt composition such that DF (olivine-minette) < DF (augite-minette) < DF (basaltic andesite) < DF (latite). Crystal chemical controls were found to influence the incorporation of F into clinopyroxene, but none were found that affected olivine. Fluorine partitioning was compared with that of OH within clinopyroxenes, and the alumina content of clinopyroxene was shown to be a strong influence on the incorporation of both anions. Fluorine substitution into both olivine and clinopyroxene was found to be strongly controlled by melt viscosity and degree of melt polymerization. / Dissertation/Thesis / Ph.D. Geological Sciences 2012

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