Investigating the influence of fluorination on hydrogen bonding properties of functional groups

Fluorination of organic molecules is a widespread tactic to improve molecular properties in many areas, and hydrogen bonding is the most important non-covalent intermolecular interaction. This project aims to undertake a thorough investigation of the effects of fluorination on hydrogen-bonding properties of alcohol and amine (ammonium) functional groups, with as ultimate aim the provision of predictive tools in which these properties can be calculated for functional groups as part of a multifunctional substrate. This is important as the influence of fluorination on hydrogen bonding properties of functional groups is not straightforward: our first results have shown that fluorine introduction next to alcohols can lead to an increase as well as a decrease of the alcohol hydrogen bond donating capacity, clearly demonstrating a crucial importance of the relative configuration and position.
For each functional group, a set of specifically designed model compounds is proposed that allows the investigation of particular effects of fluorination on the hydrogen bonding properties. For this purpose, conformationally constrained compounds that allow for singling out a particular effect will be investigated first. In a second stage, conformationally flexible model compounds containing different relative stereochemistries will be evaluated as well. These compounds will be synthesised, followed by experimental determination of hydrogen bonding properties.
The prediction of H-bond properties of functional groups will be achieved by theoretical calculation of a suitable molecular descriptor, which will then be correlated with the experimentally obtained values to create a set of Linear Free Energy Relationships (one for each hydrogen bond property). Part of the model compounds aim to evaluate subtle substituent effects, which, if successfully predicted, will be viewed as important test cases for the accuracy of our predictive tool for polyfunctional substrates.
Thorough conformational, NBO and AIM analyses will be employed to aid the rationalisation of the observed effects. This will lead to the establishment of a set of rules or guidelines describing how fluorination influences H-bond properties of the abovementioned functional groups, which will further increase our understanding of the effects of fluorination.
Where feasible, the hydrogen bonding characteristics will be compared with experimental lipophilicity and pKa (pKa(H)) values, both of which are important molecular properties.

The introduction of the small and electronegative fluorine atom in organic compounds can lead to significant alterations in a wide range of properties, including acid-base strength, conformation, lipophilicity, and chemical stabilisation. This has perhaps been most expensively exploited by the pharma and agro industries. Some statistics are very impressive: up to 20% of the pharmaceuticals prescribed or administered in the clinic and a third of the leading 30 blockbuster drugs contain at least one fluorine atom, and 30-40% of currently marketed agrochemicals contain fluorine. More recent applications involve investigating fluorination in materials chemistry (especially liquid crystals), crystal engineering and organocatalysis.
A large research effort has been devoted, especially in the last 20 years, to the understanding of the effects of fluorination.

Hydrogen bonding (H-bonding) is the most important specific non-covalent intermolecular interaction, and is at the heart of many different disciplines including pharmaceuticals, agrochemicals, materials and catalyst design, and underpins research in biological sciences. Crucial functional roles include the binding of ligands to protein receptors, and the promotion of enzyme catalysis. In the design of bioactive compounds, H-bonding impacts on a wide range of molecular properties such as potency, selectivity, permeability and solubility. Despite this, the influence of fluorination on H-bonding properties has not been studied yet in detail, except for some polyfluorinated solvents. So far it has been assumed that, due to the fluorine electronegativity effect, fluorination always increases H-bond donating capacity of H-bond donors (and vice versa for acceptors).

Our first results involving fluorinated alcohols show that this is not the case, with the H-bond donating capacity of some F-alcohols decreased compared to the parent alcohol. We also have shown significant effects can be achieved by introducing a single fluorine (in both directions). Furthermore, we found that there is an excellent correlation between a (calculated) molecular descriptor, and the experimental H-bond donating capacity, which can be used in H-bond property prediction.

Given the importance of both fluorination and H-bonding, increased understanding of how fluorination influences H-bond properties of functional groups (FG) will be of great relevance to the abovementioned fields and industries. The knowledge from the proposed research will allow scientists to better understand the consequences of fluorine introduction (leading to improved accuracy in data-interpretation, and also provide a new strategy to increase or attenuate H-bond properties of the molecule in question, not by changing a particular FG, but by judicious fluorination.
In addition, the proposed research involving a wider range of model compounds and FGs will validate the correlation between molecular descriptor and experimental H-bond properties, with as ultimate aim to provide a predictive tool for the calculation of H-bond properties of polyfunctional molecules.

Clearly, this work will accelerate drug discovery through improved compound design, and open new avenues in supramolecular chemistry, materials and organocatalysis, through the ability for finetuning of H-bond properties. This will lead to improved healthcare, improved agrochemicals, better catalysts, higher performing liquid crystals etc, all of which will directly impact upon our lives.

Hence, there will be an impact in several research areas within the EPSRC portfolio, such as Synthetic Supramolecular Chemistry, Catalysis, Chemical Biology and Biological Chemistry, Computational and Theoretical Chemistry and Chemical Structure. Also, there is a potential impact in the "Systems Chemistry:understanding interactions" EPSRC Grand Challenge, especially in Theme 3: "Controlling molecular self-assembly in biological and biomimetic systems".