Fluorous chemistry has seen a number of advances since its birth in the early 1990s. One of the most attractive characteristics of fluorous solvents is their unique solubility properties depending on temperature. This phenomenon has led to the development of a wide range of catalysts that are modified with fluorous tags and are used in biphasic catalysis and easily recovered. Many fluorous phase transfer catalysts are confined to bringing small ions into fluorous media by using fluorous onium or crown ether vehicles. The most popular method to bring transition metal complexes into fluorous media is quite limited, usually resulting in ligand tuning and thus a change in reactivity at the metal center. This can be circumvented by pairing a cationic transition metal with a highly fluorous anion rendering the neutral species highly fluorophilic. To achieve this goal, we chose to use fluorous BArf₆, [B(3,5-C₆H₃(Rf₆)₂)₄]⁻, as the mode of transport and pair it with classic Werner-type complexes that recently have been shown act as organocatalysts in enantioselective Michael additions. The literature synthesis of Na[B(3,5-C₆H₃(Rf₆)₂)₄] (3) was improved and through salt metathesis two new fluorophilic salts were made. The Werner-type trication [Co(en)₃]³⁺ was solubilized in PFMC (perfluoromethylcyclohexane) to generate [Co(en)₃][B(3,5-C₆H₃(Rf₆)₂)₄]₃ (4). This fluorophilic salt was found to be preferentially soluble in fluorous media with a partition coefficient in PFMC/H₂O of 99.0:1.0 and in PFMC/CH₃C₆H₅ of >99.3:<0.7. Another Werner-type trication, [Co(R,R-chxn)₃]³⁺, was also paired with [B(3,5-C₆H₃(Rf₆)₂)₄]⁻ to afford [Co(R,R-chxn)₃][B(3,5-C₆H₃(Rf₆)₂)₄]₃ (5), whose partition coefficients in PFMC/H₂O and PFMC/CH₃C₆H₅ were the same as 4. Within the scope of Werner-type complexes, this work constitutes a significant stride toward developing a series of compounds that bring the concept of organocatalysis into fluorous media. The new compounds 3-5 show high preferences for the fluorous phase and provide a baseline for future Werner-type salt metathesis with fluorous BArf₆.

<p> Nuclear medicine requires the use of radio labelled pharmaceuticals in order to carry out imaging and therapeutic protocols.1 Unfortunately, traditional radiolabelling approaches used in radiopharmaceutical synthesis often generate multiple products, which require exhaustive HPLC purification prior to use.2 Chromatographic purification reduces radiochemical yields, increases exposure, and can, in certain cases, preclude the use of shorter-lived isotopes.</p> <p> In light of the limitations of current radio labelling methods, we endeavored to develop a versatile and efficient radiolabelling strategy that would avoid the need for HPLC purification. To this end, the compounds to be labelled were first bound to a highly fluorinated stannylated precursor, which, when reacted with a radiohalogen, generated the corresponding radiolabelled compound. Unlike other halodestannylation reactions, however, the radiolabelled compound could be isolated from the stannylated precursor by elution through a fluorous Sep-Pak.</p> <p> As a model system, tris(perfluorohexylethyl)tin-3-benzoic acid (1), was synthesised and labelled. Compound 1 was prepared through a novel reaction which involved treatment of bromotris[(2-perfluorohexyl)ethyl]tin with the organozinc reagent 3-(ethoxycarbonyl)phenylzinc. Reaction of compound 1 with [18F]F2, followed by fluorous Sep-Pak purification, generated the corresponding labelled 3-[18F]fluorobenzoic acid in 27 min, in 30% radiochemical yield, and having a specific activity of 1966 mCi/mol. Alternatively, reaction of compound 1 with Na125I provided the corresponding product, 3-[125I[iodobenzoic acid, in <1 hr, in 75% radiochemical yield, and greater than 99% radiochemical purity. Prior tests clearly showed that any excess or unreacted substrate was fully removed from the product using a fluorous Sep-Pak.</p> <p> In addition to the initial validation studies, new synthetic methods were developed as a means of preparing more complex "fluorous" substrates. A coupling methodology was developed which permitted synthesis of a fluorous "tagged" benzamide, through reaction of 1 in the presence of HBTU with N,N-dimethylethylenendiamine. Subsequent labelling using F2 and I2 has been shown to generate the corresponding labelled benzamides, which are important agents for imaging melanoma and dopamine receptors.3 Another relevant radiopharmaceutical precursor, tris[(2-perfluorohexyl)ethyl]tin-3-benzylamine (2), was synthesized though reaction of bromotris[(2-perfluorohexyl)ethyl]tin with 1-(3-bromobenzyl)-2,2,5,5-tetramethyl-1,2,5-azadisilolidine. Compound 2 was successfully coupled to the chemotactic peptide, GFLM(f), and the product subsequently labelled with iodine. Compound 2 was also used to prepare the corresponding benzylguanidine (3), an important precursor to m-iodobenzylguanidine, which is used for imaging and therapy of neural crest tumors.4 Initial labelling results show that reaction of 3 with NaI and an oxidant generates the corresponding labelled m-iodobenzylguanidine.</p><p> Results suggest that the fluorous synthesis method will offer several advantages over traditional radiolabelling strategies. The radiolabelled products are generated in high yield, through rapid and facile reactions that avoid the need for HPLC purification.</p> / Thesis / Master of Science (MSc)

Applications taking advantage of fluorine-fluorine interactions for separations are a recent analytical trend, with benefits in terms of cost, ease of use and specificity cited as advantages of these so-called “fluorous” techniques. While most current fluorous separations employ columns packed with microspheres, columns based on entrapped microspheres, porous polymer monoliths (PPMs) and open tubes all represent viable alternatives to conventional packed capillaries. In this thesis, the design, optimization and implementation of fluorous stationary phases based on all three of these new technologies are explored. Development of methods and techniques using these systems are presented, with factors affecting their performance being examined. Doing this, the specificity of the fluorous interaction can also be explored, and potential applications for these new materials can be discussed. For the work with entrapped microspheres, the columns that were formed did not prove to have an advantage over those that were unentrapped. Although affixing spheres within a matrix is known to have benefits in terms of bed stability over repeated use, the inclusion of a polymer coating proved to represent a greater concern for the availability of the bead-based stationary phases. Layers of polymer forming over the surface were shown to limit the access of analytes to the entrapped microspheres, restricting the usefulness of these materials. The work with fluorous monoliths proved the most successful, providing clear evidence of improved selectivity when compared to analogs made without fluorination. Fluorous retention specificity was also effectively examined, with secondary effects probed and compared to those that had been discussed for commercially-available fluorous microspheres. Results showed that the monoliths were very much in-line with what had already been seen for sphere-based systems, with residual substrate character providing only a slight contribution to the observed separations. Finally, development of open-tubular columns based on microstructured optical fibers was the most speculative of the projects discussed here. The introduction of a fluorous stationary phase through silanization was demonstrated to be an effective method for imparting chromatographic selectivity into these columns, and controllable factors such as treatment protocol and silane character were shown to affect the performance of the resulting materials. / Thesis (Ph.D, Chemistry) -- Queen's University, 2011-05-06 17:03:14.803