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The University of Southampton
Chemistry

Research project: Linclau: The influence of fluorination on hydrogen bonding properties of functional groups

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The hydrogen bond is the most important specific interaction between a molecule and its local environment, and is hence of utmost relevance in ligand-protein binding, supramolecular chemistry, catalysis etc. Optimisation of ligand binding is often achieved by changing particular hydrogen bond donating or –accepting groups. However, the hydrogen bond properties of a given functional group can also be changed by the introduction of the highly electronegative fluorine atom in the vicinity of the functional group.

While fluorination usually increases the H-bond donating capacity of typical donors, our work with fluorohydrins has shown that this is not always the case, in part due to the occurrence of F•••HO intramolecular hydrogen bonds (IMHBs). We have synthesized a series of conformationally restricted fluorohydrins, and investigated the influence of the relative stereochemistry on the alcohol hydrogen bond donating capacity. To our surprise, we found that in some cases, the alcohol group had a reduced hydrogen bond donating capacity. We are still investigating the reasons for this, but intramolecular hydrogen bonding is likely to be a major factor, next to a variety of stereoelectronic effects.

Table with hydrogen bond donating capacities of conformationally fixed fluorohydrins

A communication of these first results has been published in Angew. Chem. Int. Ed. 2012, 51, 6176

We have since extended our investigations to fluorohydrins with increasing conformational flexibility, and results will be published soon.

In studying fluorinated benzyl alcohols, we were surprised to find that o-monofluorination led to an increase in alcohol hydrogen bond donating capacity, as the OH•••F 6-membered ring would have been expected to compete with NMP for hydrogen bonding. Then, equally surprising, o,o’-difluorination led to a reduction in OH hydrogen bond donating capacity (as the inductive effect of the two fluorine atoms was expected to lead to an increase.

Table with hydrogen bond donating capacities of analogous series of o-fluorinated benzyl alcohols

These results were shown to have their origin in comformational effects, as explained in Chem. Eur. J. 2015, 21, 11462.

This work has been funded by EPSRC, and is a collaboration with Dr Jerome Graton and Prof Jean-Yves Le Questel from the University of Nantes, France.

Related research groups

Organic Chemistry: Synthesis, Catalysis and Flow
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