Fluorine Conformational Effects in Organocatalysis: An Emerging Strategy for Molecular Design

Abstract

Molecular design strategies that profit from the intrinsic stereoelectronic and electrostatic effects of fluorinated organic molecules have mainly been restricted to bio-organic chemistry. Indeed, many fluorine conformational effects remain academic curiosities with no immediate application. However, the renaissance of organocatalysis offers the possibility to exploit many of these well-described phenomena for molecular preorganization. In this minireview, we highlight examples of catalyst refinement by introduction of an aliphatic C-F bond which functions as a chemically inert steering group for conformational control.

Dekonstruktion kovalenter Organokatalyse

“…[84] Die grundlegende Idee war, dass das durch Kondensation des Katalysators und des a,b-ungesättigten Aldehyds gebildete,i ntermediäre b-Fluor-Iminium-Salz 32 von stabilisierenden hyperkonjugativen (s C-H !s C-F *) und elektrostatischen Wechselwirkungen (N + ···F dÀ )p rofitieren würde und dadurch die synklinale endo-Anordnung bevorzugt würde. [85] Die Folge des Fluor-Iminiumionen-gauche-Effekts ist, dass eine der abschirmenden Phenylgruppen des Fluor-tragenden Kohlenstoffatoms über die anhängende Iminiumkette positioniert wird, wodurch die Molekülanordnung bereits vor dem Angriff des externen Nukleophils (z. B. H 2 O 2 )gesteuert wird.…”

Intramolecular interactions contributing for the conformational preference of bioactive diphenhydramine: Manifestation of the gauche effect

“…Organofluorine compounds, e.g. the milestone 1,2-difluoroethane, are known to exhibit the gauche effect, because they have low-lying r ⁄ C-F orbitals and, therefore, antiperiplanar hyperconjugative electron donation from relatively good donor orbitals (r CH for 1,2-difluoroethane) to the electron acceptor r ⁄ C-F orbital stabilize the gauche conformation, overriding steric or electrostatic repulsions between the adjacent electronegative substituents in an ethane fragment [2][3][4] of the gauche effect in fluorinated compounds can also be due to electrostatic interactions [5][6][7], in which the negatively charged fluorine interacts with the positive nitrogen in b-fluoro-N-ethylpyridinium/ammonium salts [8][9][10], or due to hydrogen bonding, in which the proximity of gauche fluorine and hydroxyl groups allows the establishment of hydrogen bonds [11]. However, the gauche effect in non-fluorinated compounds has been less explored, despite the prospective framework of some relevant molecules to exhibit this effect, i.e.…”

Synthesis of 1-Tetrasubstituted 2,2,2-Trifluoroethylamine Derivatives <i>via</i> Palladium-Catalyzed Allylation of <i>sp</i>³ C–H Bonds

“…2,2,2-Trifluoroethylamines are important structures in organic molecules 1) and pharmaceuticals because they improve bioactivities compared with the corresponding ethylamine derivatives. 2,3) Thus, the development of synthetic methods for 1-tetrasubstituted-2,2,2-trifluoroethylamines that cannot be accessed by hydrogenation of imines and reductive amination of ketones is an important challenge.…”