Difluorination is an attractive chemical modification to achieve conformational control of hydrocarbon chains. In this work, density functional theory calculations have been used to examine fluorine gauche conformational effects. This was done via decomposition of the electronic energy into electrostatic and steric contributions and hyperconjugation contributions, calculating free energy corrections to the electronic energy, and accounting for solvation effects using solvents with increasing dielectric constants. For hydrocarbon chains larger than ethane, our results show that a 1,2 vicinal difluorination pattern only adopts a fluorine gauche conformation due to stabilisation of the molecular dipole moment by polar solvents. Combined with energy differences between conformations being less than 1 kcal/mol,[1] this results in a 1,2 difluorination pattern having a limited amount of stereoselective conformational control. In contrast, a 1,3 difluorination results in considerably larger energy differences between conformations, of around 3 kcal/mol between syn and anti conformations.[2] The polarity of the solvent has very little effect on the conformation populations, with fluorine gauche effects being dominant in the conformational landscape. The results of this study suggest that a 1,3 difluorination pattern shows great promise for use in stereoselective conformational control of hydrocarbon chains.[1] Goodman, L.; Pophristic, V. J., J. Phys. Chem. A, 2005 , 109, 1223-1229[2] Wu, D.; Tian, A., J. Phys. Chem. A, 1998  , 102, 9901-9905: Hunter, L.; Slawin, A. M. Z.; Krisch, P.; O'Hagan, D., Angew. Chem. Int. Ed., 2007 , 46, 7887-7890

How much conformational control can fluorine really give you?

248th National Meeting (2014)

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