Easy chairs: the conformational preferences of polyfluorocyclohexanes

Abstract

Polyfluorocyclohexanes present an interesting challenge to our current understanding of fundamental organic chemistry. In part to improve molecular mechanics methods and facilitate drug design, a systematic survey of cyclohexanes with up to six fluorine substituents has been carried out, using theoretical methods. The preferred conformers are determined by delocalization effects, such as hyperconjugation, and do not necessarily follow the common assumption that substituents prefer the equatorial position. Thus, accurate ab intio results, which can capture electronic effects, are required. The lowest energy conformations of fluorocyclohexane, difluorocyclohexanes (six structural isomers), trifluorocyclohexanes (nine structural isomers), tetrafluorocyclohexanes (seventeen structural isomers), pentafluorocyclohexane (ten structural isomers), and hexafluorocyclohexanes (seven structural isomers) have been determined; relative energies, geometries, dipole moments, and population distributions are reported. We present a model for predicting the relative energies of polyfluorocyclohexane conformers based on the number of 1,2; 1,3; and 1,4 interactions present. The model is based on the energies from the difluorocyclohexanes; the correlation coefficient (R2) between computed relative energies and model relative energies is 0.967