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Fluorocyclohexane Makes History

Fluorine Chemistry: Synthesis yields first confirmed stereoisomer of elusive molecule

by Stephen K. Ritter
September 19, 2012

Chemists have finally found a way to make a stereo­isomer of 1,2,3,4,5,6-hexafluorocyclohexane, a molecule with one fluorine and one hydrogen on each carbon of a six-membered ring. Their route to the long-sought molecule could open the way to the design of new pharmaceuticals and materials, including selectively fluorinated sugars.

To make the molecule, David O’Hagan, Alastair J. Durie, and coworkers of the University of St. Andrews, in Scotland, devised a five-step strategy that combines known fluorination, oxidation, and deoxyfluorination steps. Starting with benzene, the reaction selectively places one fluorine on each carbon atom in the ring, ending up with a single isomer out of the nine possible stereoisomers of 1,2,3,4,5,6-hexafluorocyclohexane. The team characterized the white crystalline solid by multinuclear magnetic resonance spectroscopy and X-ray crystallography (Angew. Chem. Int. Ed., DOI: 10.1002/anie201205577).

Benzene halogenations were among the first reactions carried out by modern chemists, O’Hagan notes. In 1825, Englishman Michael Faraday reported the preparation and isolation of hexachlorocyclohexane isomers from chlorine gas and benzene. In the 1940s, hexachlorocyclohexane was first marketed as lindane, which became widely used as an insecticide as well as a treatment for lice and scabies. In 1835, German Eilhard Mitscherlich reported the hexabromo­cyclohexane analog.

An iodo version of the molecule still hasn’t been reported, O’Hagan says. And although Englishman J. Colin Tatlow and coworkers reported in 1969 that they might have made a fluoro version as a minor by-product, they were not able to confirm the structure of the compound, he says.

“This novel class of polyfluorinated molecules, situated halfway between hydrocarbons and perfluorocarbons, remains relatively unexplored,” comments Graham Sandford of the University of Durham, in England. “The synthetic strategies developed by O’Hagan’s group open up further possibilities to probe the stereoelectronic effects of fluorine atoms on the molecular structure and function of cyclohexanes. Given the always growing number of applications for perfluorocarbons in everyday use as nonstick coatings, water-repelling fabrics, and ionic polymer membranes, these new partially fluorinated hydrocarbons may offer similarly exciting applications.”


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