Single-face fluorinated carbon ring takes the strain

In a tour de force of synthetic chemistry, researchers in the UK have succeeded in taking a cyclohexane and bolting a fluorine atom onto each of the six carbons in such a way that the fluorines are all facing ‘upwards’. The all-cis 1,2,3,4,5,6-hexafluorocyclohexane represents a classic ‘molecule in distress’, with enormous internal steric strain given the proximity of the fluorines and their tendency to repel each other strongly. The extreme planar polarity of the molecule – with one face populated by highly electronegative fluorines and the other by protons – could make its derivatives potentially useful components in supramolecular architectures, the researchers suggest.

Neil Keddie and colleagues at the University St Andrews took as the starting point the cyclohexane derivative myo-inositol. To prepare for the addition of fluorines, oxygens were substituted onto each carbon in such a way that they were all sitting on the same face of the carbon ring, providing the desired stereochemical template.

‘The idea was to substitute the oxygens with fluorine with the hope that this would be accompanied by an inversion at each carbon, so that all the fluorines would end up on the same side of the structure, albeit on the opposite side to the oxygens of the precursor,’ says Keddie.

Over a period of more than three years, involving the testing of many deoxyfluorination reagents and a wide range of reaction environments, the synthesis was eventually successful.  It far more complicated than had been expected though, requiring a total of 12 steps and delivering a modest yield of around 10%. ‘For what looks like a relatively simple molecule, we did end up having to go round the houses,’ Keddie says.

The carbon ring retains its conventional ‘chair’ conformation, albeit one that is slightly splayed. Three alternating axial fluorines protrude vertically upwards, with the other three much flatter, in the equatorial plane. ‘It seems as though the equatorial fluorines are pushing against their axial neighbours, effectively holding them in position through a repulsive tension that stabilises the structure,’ Keddie suggests.

While the molecule is intriguing in its own right, it is probably the synthetic strategy which could be more useful in the long run. The approach could allow the substitution of four or five fluorines on the same face of a cyclohexane, leaving one or two bonds free for functionalisation. This would produce a highly facially polarised structure which could be useful as a building block for supramolecular constructs, Keddie says.

Duncan Browne, an organofluorine chemist at Cardiff University, UK, is impressed. ‘This work is particularly exciting both in terms of conquering the synthesis of a small yet complex target but also in the more fundamental concept of using strategically designed organofluorine compounds to open up new avenues for materials chemistry,’ he says.