Mechanistic Investigations into Diastereodivergent Synthesis of 1,2-Chlorofluoroalkanes and their SN2 Reactivity

Abstract

The properties of fluorine in organic molecules, the type of bonding between carbon and fluorine, and the impact of fluorine on molecular conformation is discussed in Chapter 1. Hypervalent iodine chemistry is broadly introduced with a view to the electronic structure of hypervalent iodine compounds and their reactivity. Hypervalent iodine-mediated and -catalysed fluorination methodologies are focussed on, with a summary of the latest developments in mechanistic inquiry of such fluorination reactions.
The diastereodivergent chlorofluorination of alkenes with an electrochemically generated hypervalent iodine reagent was developed by Lennox and co-workers. Anti-chlorofluorination of alkenes as well as the syn-chlorofluorination of homoallylic amines were demonstrated in moderate to excellent yields. A combined computational and experimental mechanistic study of this reaction is presented in Chapter 2, with a view to understanding the active hypervalent iodine species that mediate the anti- and syn-chlorofluorination pathways. Also, through the use of DFT, VT-NMR and control experiments probing various aspects of the reaction system, the mechanistic steps that give rise to the diastereodivergence phenomenon towards anti- and syn-chlorofluoride products are laid out in two mechanistic proposals.
Often an elementary reaction in the chlorofluorination reaction and ubiquitous in organic chemistry in general, Chapter 3 discusses the aliphatic nucleophilic substitution (SN2) mechanism and its history in the context of substituent effects on the rate of SN2 reactions, through to the latest theoretical developments. Especial focus is placed on the effects of α-, β- and γ-halogenation on the SN2 activation barrier, and how these effects relate to another hypervalent iodine-mediated fluorination reaction developed by Lennox and co-workers: the 1,3-difluorination of homoallylic ethers. An in-depth theoretical study into the effect of β-fluorination follows, and uses energy decomposition analysis to uncover the causal mechanisms that are at play in the SN2 rate-slowing effect upon successive β-halogenation in alkyl chlorides.

Date of Award	10 Dec 2024
Original language	English
Awarding Institution	University of Bristol
Supervisor	Alastair J J Lennox (Supervisor)