The impact of selective fluorination on the properties of aliphatic and bioactive molecules

Abstract

This thesis explores the role that selective fluorination can have on the behaviour and bioactivity of selected aliphatic organic compounds.

In Chapter 1, an introduction is given to the element fluorine and the effects it can produce in organic chemistry related to its electronegativity.

In Chapter 2, the conformational equilibria of selectively halogenated cyclohexanes were explored both experimentally and computationally and the role of nonclassical hydrogen bonding (NCHB) is highlighted in favouring the axial conformation in 1,1,4-tri-fluorocyclohexane. In Chapter 3, a series of compounds were prepared using methods of asymmetric synthesis to test the hypothesis of a hydrogen bonding interaction between (R)-citronellol and the human olfactory receptor (OR1A1). A series of fluorinated and methylated isomer analogues of (R)-citronellol were also prepared and assayed against native and mutant OR1A1 receptors. In Chapter 4, a series of all cis- fluorinated (Janus face) cyclohexanes with progressively increasing levels of fluorine were incorporated into an amino acid and introduced into the W-peptide for assay against the formylpeptide receptor FPR2, a G-protein coupled receptor. These amino acids were also incorporated into ketopiperazine architectures for assay against trypanosomatid parasites in order to explore the level of fluorination on their bioactivity, particularly as the rings become more polar.

In Chapter 5, an ‘‘Experimental’’ section is given which outlines in detail the experimental methods used throughout the research and describes synthesis protocols and the analyses of prepared compounds.

Date of Award	3 Jul 2025
Original language	English
Awarding Institution	University of St Andrews
Supervisor	David O'Hagan (Supervisor)