title: Structural and Conformational Aspects of Equatorial and Axial Trifluoromethyl, Difluoromethyl, and Monofluoromethyl Groups.
abstract: 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 CF3group. Surprisingly, although the axial CF3derivative 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.
authors.affiliation: ETH Zürich, Laboratorium für Organische Chemie, Vladimir-Prelog-Weg 3, 8093, Zürich, Switzerland.
authors.forename: Quentin A
authors.initials: QA
authors.lastname: Huchet
authors.affiliation: ETH Zürich, Laboratorium für Organische Chemie, Vladimir-Prelog-Weg 3, 8093, Zürich, Switzerland.
authors.forename: W Bernd
authors.initials: WB
authors.lastname: Schweizer
authors.affiliation: F. Hoffmann-La Roche AG, Pharmaceutical Research & Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland.
authors.forename: Bernd
authors.initials: B
authors.lastname: Kuhn
authors.affiliation: ETH Zürich, Laboratorium für Organische Chemie, Vladimir-Prelog-Weg 3, 8093, Zürich, Switzerland.
authors.forename: Erick M
authors.identifier: http://orcid.org/0000-0003-1472-490X
authors.initials: EM
authors.lastname: Carreira
authors.affiliation: ETH Zürich, Laboratorium für Organische Chemie, Vladimir-Prelog-Weg 3, 8093, Zürich, Switzerland.
authors.forename: Klaus
authors.initials: K
authors.lastname: Müller
keywords: X-ray diffraction; conformation analysis; equatorial-axial; fluorinated methyl groups; methylcyclohexane