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The University of Southampton

Research project: Linclau:Intramolecular hydrogen bonding between organofluorine and alcohols

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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 since extended our investigations to fluorohydrins with increasing conformational flexibility (published in Chem. Eur. J. 2015, 21, 17808)

We have done so by careful NMR analysis, in particular we determine the 1JOH•••F value. Because fluorine is a worse hydrogen bond acceptor than oxygen (water), solutions typically need to be rigorously dried.

For syn-4-fluoropentan-2-ol, J-value analysis by 1H and 1H{19F} experiments showed a large coupling constant between the alcohol hydrogen and the fluorine atoms (6.6 Hz). This is a significant value, and compares to 12 Hz for a conformationally fixed cis-3-fluorocyclohexanol system.



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For the anti-diastereomer, this J value was reduced to 1.9 Hz. This was attributed to the much lower population of this hydrogen bonded structure (due to a methyl group being axial).

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Interestingly, for 3-fluoropropanol, we also observed a J-value, despite various literature reports indicating there was no such coupling constant in this molecule.

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We were delighted to observe two different OH•••F J-values in 4,4-difluoropentan-2-ol. Indeed these fluorines are diastereotopic, and the population of these respective intramolecular hydrogen bonded structures is different.

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We are now extending this work into investigating other acyclic structures for which we predict a high population of intramolecular OH•••F hydrogen bonding. We also want to correlate this with the alcohol hydrogen bond donating capacity properties. Results of this type of work are important as they give insight in how fluorination can modify properties including conformation in non-aqueous media (eg in a protein binding site).

Related research groups

Organic Chemistry: Synthesis, Catalysis and Flow
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