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Structural and Conformational Aspects of Equatorial and Axial Trifluoromethyl, Difluoromethyl, and Monofluoromethyl Groups.
Journal article

Structural and Conformational Aspects of Equatorial and Axial Trifluoromethyl, Difluoromethyl, and Monofluoromethyl Groups.

  • Huchet QA ETH Zürich, Laboratorium für Organische Chemie, Vladimir-Prelog-Weg 3, 8093, Zürich, Switzerland.
  • Schweizer WB ETH Zürich, Laboratorium für Organische Chemie, Vladimir-Prelog-Weg 3, 8093, Zürich, Switzerland.
  • Kuhn B F. Hoffmann-La Roche AG, Pharmaceutical Research & Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland.
  • Carreira EM ETH Zürich, Laboratorium für Organische Chemie, Vladimir-Prelog-Weg 3, 8093, Zürich, Switzerland.
  • Müller K ETH Zürich, Laboratorium für Organische Chemie, Vladimir-Prelog-Weg 3, 8093, Zürich, Switzerland.
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  • 2016-10-13
Published in:
  • Chemistry (Weinheim an der Bergstrasse, Germany). - 2016
X-ray diffraction
conformation analysis
equatorial-axial
fluorinated methyl groups
methylcyclohexane
English The X-ray crystal structures of cis- and trans-1-(indol-3-yl)-4-methyl cyclohexane and its congeners with stepwise fluorination of the methyl group are reported. The trans-configured compounds adopted diequatorial conformations, whereas the cis analogues adopted regular cyclohexane chair conformations with the methyl group preferentially assuming the axial position, even in the case of the CF3 group. Surprisingly, although the axial CF3 derivative displayed distinct valence deformations in the cyclohexane moiety, the observed structural changes were relatively modest. The cis derivatives with axial mono- and difluorinated methyl groups exhibited conformational disorder in the crystals with significant population levels for the staggered conformations that had one fluorine atom in the endo position; their respective trans counterparts adopted unique conformations, but again with one fluorine atom in the endo position. Theoretical calculations for a series of cis- and trans-1,4-dimethyl cyclohexane model compounds with stepwise fluorination of one equatorial or axial methyl group reproduced the experimentally observed structural response patterns very well, reproduced the experimentally determined nonlinear correlation of the axial-equatorial energy difference with the degree of methyl fluorination in a satisfactory manner, and provided further insights into important conformational aspects of partially fluorinated methyl groups.
Language
  • English
Open access status
closed
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Persistent URL
https://sonar.rero.ch/global/documents/231453
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