New methods and reagents for carbon-fluorine bond formation

After a general introduction about the properties and preparation of organofluorine compounds (Chapter 1), this thesis is divided into two parts focussing on the development of new methods for C–F bond formation (Part A) as well as studies towards the development of novel fluorinating reagents (Part B).
Part A: New Methods for Carbon–Fluorine Bond Formation
Part A consists of two chapters outlining the development of a Pd-catalysed hydrofluorination of alkenylarenes (Chapter 2) as well as a halofluorination of alkynes (Chapter 3).
Chapter 2
This chapter describes the development of a novel, regioselective, syn-specific hydrofluorination of alkenylarenes under Pd-catalysis leading to the formation of benzylic fluorides. An extensive substrate scope is presented together with a model of the catalytic cycle, based on observations during the development of this reaction, deuterium labelling experiments as well as mechanistic control experiments starting from isolated palladacycles.
Chapter 3
In this chapter the development of a novel iodo- as well as bromofluorination of internal and terminal alkynes, leading to the formation of (E)-halofluoroalkenes, is presented. For the former substrate class, the effects of steric as well as electronic bias on regioselectivity are discussed. For the latter substrate class, this methodology could be extended to the corresponding double iodofluorination, and for both transformations it was found to exclusively lead to the fluorination of the internal carbon. An extensive substrate scope as well as different iodofluorination-cross-coupling sequences including Suzuki, Sonogashira and Ullmann couplings, are illustrated. A representative reaction was successfully carried out on gram-scale and an iodofluorination-Suzuki-coupling sequence was used to prepare a fluorinated tamoxifen derivative.
Part B: Hydrogen-Bonded Fluoride Complexes as Novel Reagents for Carbon–Fluorine Bond Formation
Part B consists of two chapters describing structural as well as reactivity studies of fluoride–alcohol (Chapter 4) and fluoride–urea complexes (Chapter 5).
Chapter 4
In this chapter the synthesis of 19 novel hydrogen-bonded tetraalkylammonium fluoride–alcohol complexes is described. For a subset of 15, the solid-state structures as determined by single-crystal X-ray diffraction experiments are presented. Trends of reactivity and selectivity were determined using these complexes as sources of fluoride anion in a model SN2 reaction. Preliminary results from in silico modelling of the fluoride–alcohol system provide a basis for explaining the results.
Chapter 5
This chapter summarises the synthesis and solid-state structures of 20 hydrogen-bonded fluoride complexes using the urea and related squaramide and amide motifs. Also, the size of the tetraalkylammonium counter-cation was varied to study the influence on the solid-state structure. The reactivity and selectivity of a series of complexes was studied using the same model SN2 reaction as in Chapter 4 and results were compared accordingly. Different UV-vis and NMR spectroscopic techniques were used to study the behaviour of the fluoride–urea system in solution. Preliminary results demonstrate the use of 1,3-diarylureas as organocatalysts for nucleophilic fluorination.

Keywords: Nucleophilic Fluorination
Electrophilic Fluorination
Hydrogen Bonding
Transition Metal Catalysis
Advisor: Gouverneur, V