This thesis covers work investigating the effects of fluorine incorporation on the structure, biological activity, and NMR properties of anticancer chalcones as well as novel methods for the inclusion of fluorinated moieties into organic compounds. The first chapter looks at the use of silanes as carriers of small fluorinated nucleophiles which can be activated by fluoride anion catalysis to deliver such nucleophiles to organic electrophiles such as aldehydes. The synthesis of a group of such silanes and an assessment of their reactivity towards aromatic aldehydes is described. The second and third chapters describe the synthesis and compare the structures and biological activities of four series of chalcones; chapter two looks at chalcones which have non fluorinated groups (a nitrile group and an ethyl ester group) on the alpha position and chapter three looks at chalcones which have F and CF3 groups on that position. A comparison of the effects of substitution, at both the alpha position and on the B ring, on structure and cytotoxicity of these compounds is given. Several of the fluorinated chalcones were found to be highly cytotoxic and further assessment of their tubulin-binding properties was carried out. Chapter four looks at some unusual, long range fluorine-hydrogen coupling interactions which have been observed in the NMR spectra of certain types of chalcones. The effects of various substitutions and structural changes on these coupling patterns are examined. In addition a brief study into the dimerisation of chalcones is described. The final chapter looks at the use of FAR type reagents to generate asymmetric fluorinated amides using secondary chiral amines. Synthesis of a number of chiral amines praline and their addition, with limited success, to trifluorovinyl styrenes is discussed.

A series of novel fluorinated lanthanide complexes has been synthesised for use as responsive probes for 19F MRS and MRI. The careful positioning of the CF3 group within 6.5 Å from the metal ion caused the fluorine longitudinal and transversal relaxation rates to be strongly enhanced. This allows faster MR signal acquisition, reducing the sample concentration and acquisition time required to obtain the desired signal intensity. The lanthanide ion also enhanced the chemical shift sensitivity of the fluorine nucleus to changes in the chemical environment. These characteristics have been exploited to develop responsive probes. A series of pH reporters containing an aromatic mono-amide arm has been prepared and their pH sensitivity assessed. Deprotonation of the amide proton caused a large variation of the 19F chemical shift. The pKa of the probe was modulated by varying the substituents on the aromatic group and an optimal value of 7.1 was obtained with an ortho cyano substituent. The introduction of phosphinate pendant arms allowed narrower linewidths and faster longitudinal relaxation rates to be achieved. The spectroscopic properties and the conformational isomerism of the same series of complexes have been analysed. In particular, their 19F NMR chemical shift, relaxation properties and 1H relaxivity characteristics were studied. A series of complexes bearing different ester functional groups was prepared and their ability as reporters for enzymatic activity assessed. PLE and -chymotripsin recognised the substrate and catalysed its transformation. Modification of the probe structure was revealed by variation of the relative signal intensity of the substrate and product fluorine resonances in the 19F NMR spectrum. Glycol chitosan conjugates with paramagnetic fluorinated complexes were prepared and their NMR properties assessed. In vivo MRI studies in animal models were undertaken and a selective uptake of the contrast agent in the tumour was observed with the Gd analogue.

Use of the carbon hydrogen bond as a functional group in free radical addition reactions to fluoro - alkenes has been studied. Reactions involving additions of cyclic alcohols and cyclic as well as acyclic diols to hexafluoropropene, yielded selective hydroxyl group directed products in high yield. The subsequent alcohol or diol - hexafluoropropyl adducts were easily dehydrated using thionyl chloride and pyridine, forming alkenes and dienes containing a polyfluoroalkyl moety, in good yield. The resultant alkenes following bromination and epoxidation, were found to be electrophilic in nature. Furthermore, these alkenes were dehydrogenated using sulphur, yielding aromatic compounds containing the hexafluoropropyl moiety, in high yield. Additions of hydrocarbons to hexafluoropropene gave complex final mixtures, illustrating the poor selectivity of such reactions.

Novel CF3-labelled lanthanide(III) complexes have been synthesised for use as probes for 19-F and 1-H magnetic resonance spectroscopy and imaging. The syntheses and evaluation of two classes of fluorinated paramagnetic complexes are defined. Notably, the 19-F magnetic resonance relaxation processes for the complexes have been assessed, allowing for the analysis of the interplay between applied field, Ln(III) ion and rotational correlation time on relaxation properties. Strategies employed to enhance signal intensity are discussed, examining a number of different of fluorinated mono- and di-amide cyclen ligands. Systems incorporating phosphinate pendant arms are of particular interest, resulting in complexes with favourable isomer distributions, faster longitudinal relaxation rates and narrower linewidths. Finally, the synthesis of high molecular weight conjugates with paramagnetic fluorinated complexes is described. Three different classes of medium to high molecular adducts were considered, with the merits and limitations of each assessed. The desirable formation of one species in solution, ease of solubility and attractive 19F and 1H relaxometric properties render the chitosan conjugates promising candidates for future use as imaging probes.

Chapter 1. An introduction to the principles of two different types of LC cell and the design of new fluorinated materials for modem LCD applications is presented here. Discussion includes reasons why fluorinated molecules have become the compounds of choice for display devices, and a history of organo-fluorine chemistry from early discovery of the element, through nucleophilic substitution and debromolithiation reactions of bromoperfluorobenzenes, to very recent developments in synthesis.Chapter 2. This chapter presents a brief overview of some of our early ideas as to how new fluorinated LCs might be made synthetically, exploiting advances in the field of organo-fluorine chemistry, utilising perfluorobenzene and bromoperfluorobenzene "scaffolds."Chapter 3. A discussion of how new "model" fluorinated LC materials were obtained via nucleophilic aromatic substitution in bromoperfluorobenzenes is presented in this chapter. The flexibility of the methodology is demonstrated through use of different substrate isomers to afford different aromatic fluorination patterns, and of different nucleophiles to create "families" of homologous materials.Chapter 4. The versatility of bromoperfluorobenzenes as substrates is exemplified in this chapter, whereby a number of isomers of these "scaffold" molecules were built upon via debromolithiation followed by reaction with electrophiles. This methodology was also applied to functionalised bromofluorobenzenes from chapter 3, and a small library of related compounds was synthesised as in the previous chapter.Chapter 5. Recent advances in metal C-F bond activation have assisted with ourdevelopment of a new synthetic route to fluorobiphenyl moieties, based on Suzuki- Miyaura chemistry and presented in this chapter.Chapter 6. Many of the novel fluorinated materials synthesised in chapters 3 to 4 were sent to SONY MSL, Stuttgart, and their properties determined by tests including electro- optical, DSC, and VHR analysis. The results are discussed and compared, and their potential for application in current LC display devices assessed.

Current approaches to drug discovery tends to involve the rapid analogue synthesis and testing of small, focused libraries of low molecular weight, structurally similar "drug-like" molecules, often based around heterocyclic core scaffolds. If some desired activity is shown by a compound, elaboration can give higher activity and more favourable pharmiokinetic properties. As this "lead generation" stage of drug development has been identified as a major bottleneck in the drug pipeline process, there is a great demand for methodology detailing the synthesis of highly functionalised heterocyclic compounds. Our approach involves the sequential nucleophilic aromatic substitution of highly fluorinated pyridines, in an efficient and flexible manner, to furnish a range of novel, functionalised polycyclic systems.

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The research described within this thesis may be divided into four areas: 1) Unsaturated perfluorinated systems have been reduced, or defluorinated, using alkali metal amalgams to give products with a higher degree of unsaturation. For example, perfluoro-3,4-dimethylhex-3-ene (105) can be reduced to perfluoro-3,4- dimethylhex-2,4-diene (106). Remarkably, these reductions have also been performed, with equal success, using an electron rich amine, tetrakis(dimethylamino)ethene (107), which avoids the difficult, and potentially hazardous, use of amalgams. A difluoride salt, of amine (107), is produced as a by-product, which has potential as a soluble fluoride ion source.2) Diene (105) is highly electron deficient and, therefore, is susceptible to nucleophilic attack, which occurs at the vinylic positions. This compound was reacted with difunctional oxygen nucleophiles, forming potential polymer precursors, which remain reactive towards nucleophiles, suggesting the possibility of their use in block co-polymer syntheses to give highly fluorinated products.3) Calcium hypochlorite has been utilised to oxidise perfluorinated alkenes and dienes to yield the corresponding epoxide(s). An alternative methodology, using t-butyl hydroperoxide and butyl lithium, has been successfully applied to perfluorinated systems, for the first time, to give previously inaccessible compounds. The diepoxide (162) has been shown to undergo an unusual thermal ring opening, and expansion, to form a perfluorinated dioxin (179).4) An efficient route to hexakis(trifluoromethyl)cyclopentadiene (181) has been developed via an unusual cyclisation process, which is induced by fluoride ion. This diene displays an interesting chemistry, including its reduction by tetraalkylammonium iodides to form the pentakis(trifluoromethyl)cyclopentadienyl anion, as crystalline ammonium salts (tetraethyl show below), in good yields. When these salts are combined with concentrated sulphuric acid, 5H-pentakis(trifluoromethyl)cyclopentadiene (188) is produced, which is the strongest non-conjugated carbon acid known.

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