The Design and Synthesis of Fluorinated Model Compounds to Investigate the Influence of Fluorination on Lipophilicity and Hydrogen Bonding

Abstract

The properties of fluorine make it an attractive tool within medicinal chemistry to modulate the lipophilicity of a compound. The effects of aromatic fluorination on lipophilicity have been widely researched, but the study of fluorinated aliphatic compounds is limited by the need for UV chromophores in most logP determination methods. However, using a quantitative ¹⁹F NMR logP determination method previously developed within this research group, the effects of aliphatic fluorination on lipophilicity can be examined. This thesis explored the effect of fluorination motifs containing heteroatoms on the lipophilicity of aliphatic alkanols and a drug scaffold, where the choice of heteroatom and its proximity to the fluorine atoms led to large changes in lipophilicity. The effects on lipophilicity of carbohydrate fluorination were investigated, where pronounced effects were observed depending on the relative stereochemical configurations of polar atoms. Fluorine is known to participate in weak O/NH···F intramolecular hydrogen bonds (IMHB). This interaction can alter molecular polarity through shielding of hydrogen bond donors (HBD) and acceptors (HBA), increasing the solubility of the compound in apolar media. Conversely, in polar media, the HBD and HBA are solvated by water. This thesis aimed to investigate how the ability of fluorine to act as a weak HBA could be exploited for physiochemical property modulation, by evaluating the propensity of intramolecular hydrogen bonds involving fluorine. This was investigated by measurement of A_NMR and ∆logP_oct-tol values, to evaluate differences in HBD properties as a surrogate for IMHB propensity. For fluorohydrins, the weak OH···F IMHB interaction led to only small A_NMR and ∆logP_oct-tol value differences between compounds. Exploration of benzamide NH···F IMHB propensity identified that the ∆logP_oct-tol descriptor is unsuitable when compounds possess a static IMHB. Generally, the importance of understanding the solute conformation and competitive intermolecular interactions in each specific solvent was established. To understand how the A_NMR and ∆logP_oct-tol descriptors can evaluate IMHB propensity of F-containing IMHB, considerations for future study using these descriptors are proposed.

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ORCID for Bruno Linclau: orcid.org/0000-0001-8762-0170

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