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.

A method for the synthesis of a symmetrical fluorous tagged benzodithiol support has been developed through a seven-step synthetic pathway. The Wittig olefination and catalytic hydrogenation reactions were employed to attach two perfluoroalkyl chains in the o-positions of phthalaldehyde. These fluorous tags were used as soluble supports which facilitated the purification of the crude reaction mixtures using fluorous solid phase extraction (FSPE). A selective and high yielding dibromination reaction was developed to synthesize a fluorous tagged 1,2-dibromo aryl compound. A thorough study was carried out to demonstrate the ease of an aryl-sulfur bond formation with the 1,2-dibromo compound varying palladium catalysts and ligands. A new palladium catalyzed dithiolation reaction is reported to synthesize a surrogated dithiol, which was exploited as a precursor for the synthesis of hitherto inaccessible symmetrical fluorous tagged benzodithiol support. The utility of the benzodithiol was explored by the synthesis of benzodithianes with two aldehydes. The lithiated dithiane generated was further used to form a C-C bond employing the umpolung reaction. The ring-closing metathesis reaction using Grubbs II catalyst was performed to construct 5-membered and 6-membered spiro-ring systems. Several approaches were made to form a C-C bond with lithiated dithianes using various nitrogen containing electrophiles leading to N-heterocycles. / October 2008

A method for the synthesis of a symmetrical fluorous tagged benzodithiol support has been developed through a seven-step synthetic pathway. The Wittig olefination and catalytic hydrogenation reactions were employed to attach two perfluoroalkyl chains in the o-positions of phthalaldehyde. These fluorous tags were used as soluble supports which facilitated the purification of the crude reaction mixtures using fluorous solid phase extraction (FSPE). A selective and high yielding dibromination reaction was developed to synthesize a fluorous tagged 1,2-dibromo aryl compound. A thorough study was carried out to demonstrate the ease of an aryl-sulfur bond formation with the 1,2-dibromo compound varying palladium catalysts and ligands. A new palladium catalyzed dithiolation reaction is reported to synthesize a surrogated dithiol, which was exploited as a precursor for the synthesis of hitherto inaccessible symmetrical fluorous tagged benzodithiol support. The utility of the benzodithiol was explored by the synthesis of benzodithianes with two aldehydes. The lithiated dithiane generated was further used to form a C-C bond employing the umpolung reaction. The ring-closing metathesis reaction using Grubbs II catalyst was performed to construct 5-membered and 6-membered spiro-ring systems. Several approaches were made to form a C-C bond with lithiated dithianes using various nitrogen containing electrophiles leading to N-heterocycles.

A method for the synthesis of a symmetrical fluorous tagged benzodithiol support has been developed through a seven-step synthetic pathway. The Wittig olefination and catalytic hydrogenation reactions were employed to attach two perfluoroalkyl chains in the o-positions of phthalaldehyde. These fluorous tags were used as soluble supports which facilitated the purification of the crude reaction mixtures using fluorous solid phase extraction (FSPE). A selective and high yielding dibromination reaction was developed to synthesize a fluorous tagged 1,2-dibromo aryl compound. A thorough study was carried out to demonstrate the ease of an aryl-sulfur bond formation with the 1,2-dibromo compound varying palladium catalysts and ligands. A new palladium catalyzed dithiolation reaction is reported to synthesize a surrogated dithiol, which was exploited as a precursor for the synthesis of hitherto inaccessible symmetrical fluorous tagged benzodithiol support. The utility of the benzodithiol was explored by the synthesis of benzodithianes with two aldehydes. The lithiated dithiane generated was further used to form a C-C bond employing the umpolung reaction. The ring-closing metathesis reaction using Grubbs II catalyst was performed to construct 5-membered and 6-membered spiro-ring systems. Several approaches were made to form a C-C bond with lithiated dithianes using various nitrogen containing electrophiles leading to N-heterocycles.

A new class of fluorous materials was developed to create a hybrid solid-solution phase strategy for the expedient preparation of 125I-labelled compounds, without the need of HPLC purification. The system is referred to as a hybrid platform in that it combines solution phase labelling and fluorous solid-phase purification in one step as opposed to two separate individual processes. Initial success was achieved by treating fluorous stannanes, coated on fluorous silica, with [125I]NaI and chloramine-T (CAT) as the oxidant, where the desired nonfluorous radiolabelled products were isolated in minutes in biocompatible solutions in high purity (>98%) free from excess starting material and unreacted radioiodine. This platform was initially developed through a model system based on a fluorous benzoic acid derivative. The platform was then validated with simple aryl and heterocyclic derivatives, known radiopharmaceuticals including meta-iodobenzylguanidine (MIBG) and iododeoxyuridine (IUdR), and a new agent with high affinity for prostate-specific membrane antigen (PSMA). The limitation of the platform was the presence of non-radioactive UV impurities which came from the oxidants employed. To resolve this issue a new class of fluorous oxidants based on chloramine-T (CAT, F-CAT) were prepared. F-CAT, was prepared in 87% overall synthesis yield from commercially available starting materials and found to be effective in labelling arylstannanes and proteins with [125I]NaI. The utility of the oxidant was further demonstrated in successfully preparing a radioiodinated tetrazine (125I-Tz) through a concomitant oxidation-halodemetallation reaction. 125I-Tz can be used to label biomolecules through bioorthogonal coupling reactions with prosthetic groups containing strained alkenes including norbornene and trans-cyclooctene (TCO). The reported hybrid platform labelling approach is readily accessible and requires minimal radiochemistry expertise and should therefore find widespread use. It is also noteworthy that a second generation of the fluorous oxidant, F-CAT2, was also prepared with the aim of obtaining an oxidant which has a higher solubility in perfluorinated solvents. Application of F-CAT2 for oxidation of hydrogen sulfide to elemental sulphur in a fluorous-aqueous biphasic system was demonstrated. This approach offers a new metal-free approach to scrubbing sour gas wells and demonstrates that the fluorous oxidants developed here have utility beyond radiochemistry. / Thesis / Doctor of Philosophy (PhD)

<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

Hydrophobicity is the generalized characteristic of non-polar substances that brings about their exclusion from aqueous phases. This property, entropic in its nature, drives key self-assembly and phase separation processes in water. Protein folding, the formation of DNA double helix, the existence of lipid bilayers and the wetting properties of leaf surfaces are all due to hydrophobic interactions. Inspired by Nature, we aimed to use hydrophobicity for creating novel and improved catalytic systems. (I) A number of fluorous amphiphilic star block-copolymers containing a tris(benzyltriazolylmethyl)amine motif have been prepared. These polymers assembled into well-defined nanostructures in water, and their mode of assembly could be controlled by changing the composition of the polymer. The polymers were used for enzyme-inspired catalysis of alcohol oxidation. (II) An enzyme-inspired catalytic system based on a rationally designed multifunctional surfactant was developed. The resulting micelles feature metal-binding sites and stable free radical moieties as well as fluorous pockets that attract and preconcentrate molecular oxygen. In the presence of copper ions, the micelles effect chemoselective aerobic alcohol oxidation under ambient conditions in water, a transformation that is challenging to achieve nonenzymatically. (III) Development of a facile means of photo/electrocatalytic water splitting is one of the main barriers to establishing of a solar hydrogen economy. Of the two half-reactions involved in splitting water into O2 and H2, water oxidation presents the most challenge due to its mechanistic complexity. A practical water oxidation catalyst must be highly active, yet inexpensive and indefinitely stable under harsh oxidative conditions. Here, I shall describe the synthesis of a library of molecular water oxidation catalysts based on the Co complex of tris(2-benzimidazolylmethyl)amine, (BimH)3. A wide range of catalysts differing in their electronic properties, surface affinity, and steric bulk was explored. We identified hydrophobicity as the key variable in mediating the catalytic competence of Co-(BimH)3 complexes. The change in this parameter correlates both with the conformational mobility of the ligand core and the structural changes in the local solvent environment around the catalytic metal site. The optimal ligand identified is superhydrophobic due to three fluorinated side chains. The corresponding Co complex catalyzes water electrooxidation efficiently, with an onset potential equal to that for the well-established CoPi heterogeneous system, albeit with a dramatically higher turnover frequency (TOF) and in the absence of soluble Co salts. As an added benefit, the hydrophobic catalyst can be immobilized through physisorption, and remains stable after prolonged controlled-potential electrolysis. A DFT calculation was also performed to understand the catalytic pathway.

Supporting Information attached / <p> The development of a convenient route for the preparation of fluorous-tagged compounds for use with the fluorous labeling strategy (FLS) is described in this thesis. The FLS is a new and convenient method for the preparation of radiotracers and therapeutics in high effective specific activity (HESA) without the use of preparative HPLC. The objective of this thesis was to expand the general utility of the FLS by enabling the introduction of fluorous tags into molecules using a palladium-catalyzed cross-coupling reaction. To this end, a fluorous distannane, hexa(1H,1H,2H,2Hperfluorooctyl) distannane, was prepared from the corresponding fluorous tin hydride and used to produce trialkylarylstannanes from aryl and vinyl halides. Using the developed methodology, fluorous precursors for two radiopharmaceuticals, fialuridine (FIAU) and idoxuridine (IUdR), were prepared. The fluorous-tagged products were radiolabeled with iodine-125 to afford the desired compounds in high effective specific activity and in good radiochemical yield. </p> <p> Hexa(1H,1H,2H,2H perfluorooctyl)distannane was prepared from the corresponding tin hydride in nearly quantitative yield in the presence of Pd(PPh3)4. The distannane was combined with a series of seventeen aryl bromides and iodides and the appropriate palladium catalyst to afford trialkylarylstannanes in 15-59% isolated yield. </p> <p> The use of a phosphaadamantane ligand reported by Capretta et al. in the cross-coupling was also investigated, and the yields for the model compounds ranged from 13-67% Although no substantial change in yields was observed for aryl halides compared to the traditional catalyst Pd(PPh3)4, the phosphaadamantane ligands were more effective for the synthesis of precursors to [125I]fialuridine (FIAU) and [125I]idoxuridine (IUdR). Using this ligand system, the FIAU precursor was prepared in 38% overall yield from a dibenzoyl-protected vinyl bromide, and the IUdR precursor was prepared in 21% yield from a vinyl iodide. </p> <p> Following preparation of the FIAU and IUdR precursors, direct iodinolysis using a sub-stoichiometric amount of iodine was performed and the products isolated in excellent yield and purity using fluorous solid-phase extraction (FSPE). Following these experiments, the precursors were radiolabeled with [125I]NaI (50 – 500 μCi, 1.9 – 19 MBq) in the presence of Iodo-Gen® as an oxidant. Average radiochemical yields for three trials were 88% for FIAU and 94% for IUdR. The precursor was not observed in the FSPE-purified reaction mixture by UV-HPLC within the instrument’s detection limit. </p> <p> The fluorous labeling strategy allows molecular imaging and associated therapy agents to be produced in high effective specific activity in a rapid and convenient manner. With the development of the fluorous distannane and the associated coupling reactions reported here, the general utility of the fluorous labeling strategy has been greatly expanded. </p> / Thesis / Master of Science (MSc)

The origin of fluorous interaction was explored and experimentally examined based on both HPLC and CEC data in this project. It was found that the selective fluorous interaction is a kind of reduced instantaneous or induced dipole interaction compared to the hydrophobic interaction. A series of FPPM preparation parameters were optimized. The optimized FPPM column can resolve the components in a manner that was otherwise not possible with its non-fluorous (hydrocarbon) counterpart. Following, the CEC separation of fluorous analytes on FPPM stationary phase based upon fluorous-fluorous interaction was realized for the first time. It was also found that, quantitatively, hydrophobic stationary phases have better methylene selectivity (〖 α〗_(-CH_2-)), while fluorous stationary phases have better perfluoromethylene selectivity (〖 α〗_(-CF_2-)). Thermodynamically, ∆G_(-CF_2- → -CF_2-)^° : ∆G_(-CH_2- → -CH_2-)^° (Gibbs free energy change of transferring a –CF2– unit to pure fluorous stationary phase versus Gibbs free energy change of transferring a –CH2– unit to pure hydrophobic stationary phase) is approximately equal to 8:1. A new concept, hypothetical water percentage (HWP) based on the comparison of 〖 α〗_(-CH_2-) and〖 α〗_(-CF_2-) was proposed for the first time to quantitatively evaluate the hydrophobicity/fluorophilicity of a stationary phase. A stationary phase can be classified as fluorous stationary phase when the HWP is less than 0 (more negative indicates more fluorous), or as a hydrophobic stationary phase when the HWP is larger than 100. For the range between 0 and 100, the stationary phase can be treated as either fluorous or hydrophobic due to the similar values of〖 α〗_(-CH_2-) and〖 α〗_(-CF_2-). Fluorous tagged peptides and proteins (up to 5800 Da) were effectively separated from their non-fluorous counterparts on the FPPM stationary phase in capillary-based columns and detected both on-line with ESI-MS and off-line with MALDI-MS. Finally, the FPPM solid-phase extraction (SPE) stationary phase was transplanted from the capillary to a microchip format. This microchip exhibits the merits of both selective fluorous interaction and micro total analysis system (µTAS). / Thesis (Ph.D, Chemistry) -- Queen's University, 2013-11-19 23:11:16.636