Nucleophilic fluorination under synergistic hydrogen bonding phase-transfer catalysis

Thesis

Chapter 1 – Introduction

Chapter 1 aims to highlight the importance of fluorination in modern life science with emphasis to its presence in the pharmaceutical, agrochemical and materials industry. Fluorine’s unique properties and the effect of its substitution within molecules is described, as well as the origins of the fluorinating reagents which are prevalent in organic synthesis. Finally, the chapter provides a concise overview of asymmetric fluorination methodologies, covering both electrophilic and nucleophilic fluorine sources.

Chapter 2 - Development of an Enantioconvergent Nucleophilic Substitution under Synergistic Hydrogen Bonding Phase Transfer Catalysis with Potassium Fluoride

Chapter 2 outlines the discovery and development of a nucleophilic fluorination strategy for neutral electrophiles, benzylic bromides, using potassium fluoride (KF). Motivated by the Gouverneur group’s interest in Hydrogen Bonding Phase-Transfer Catalysis (HBPTC) led to the development of a synergistic approach employing two-phase transfer agents, an onium halide salt and chiral bis-urea hydrogen bond donor catalysts. This combination of catalysts was critical for the solubilisation and subsequent reactivity of KF for the fluorination of a scope of benzylic halides providing fluorinated products in high yields and enantioselectivities. Furthermore, this method was demonstrated to be applicable towards a second class of neutral electrophiles – α-bromoketones.

Chapter 3 - Mechanistic Investigations into Fluorination under Synergistic HBPTC

Chapter 3 describes the mechanistic investigations that were undertaken on the novel catalytic manifold entitled Synergistic HBPTC (S-HBPTC). A detailed spectroscopic NMR investigation highlighted the synergistic role of the urea and onium catalysts for the solubilisation of KF. The preparation of the resultant urea-onium-fluoride complexes allowed for their evaluation as reactive fluorinating species. A kinetic isotope effect study deciphered the mode of substitution on the benzylic substrate class and key control experiments were performed to gain understanding of the mechanisms at play which allowed for enantioconvergence to be achieved within the system.

Authors: Dooley, C

• DOI: 10.5287/ora-pdgzyp6a7
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: fluorination; organocatalysis; hydrogen bonding; organic chemistry
• Subjects: Organic Chemistry