Trifluoromethyl groups tug on cyclohexane

Researchers in David O’Hagan’s lab at the University of St. Andrews delighted chemists back in 2015 by making a cyclohexane with 6 all-cis fluorine substituents. Thanks to the molecule’s two sides—one with polar fluorines and the other with milquetoast hydrogens—it displayed surprising polarity, making it a “Janus face” molecule, a nod to the two-faced Roman god. Now O’Hagan’s lab and collaborators are at it again. This time, they’ve traded the relatively sleek fluorines for bulky trifluoromethyl groups (Angew. Chem., Int. Ed. 2020, DOI: 10.1002/anie.202008662). By hydrogenating hexa­trifluoromethylbenzene, O’Hagan’s graduate student Cihang Yu made all-cis 1,2,3,4,5,6-hexakis(trifluoromethyl)cyclohexane. The reaction was tough. It required 14 days to make the desired material in just 13% yield, even with elevated temperature and pressure. A crystal structure of the material reveals that the classic chair conformation of cyclohexane gets flattened somewhat as the three axial trifluoromethyl groups splay because of their bulk. In the small family of all-cis hexakis substituted cyclohexanes that have been prepared to date, this molecule has the highest barrier to cyclohexane ring inversion, thanks to dramatic steric clashes between its trifluoromethyl groups. And while the molecule isn’t as polar as the all-cis hexafluorinated cyclohexane, its trifluoromethyl groups have enough pull to give it a mild affinity for chloride ions.