Understanding the Conformational Behavior of Fluorinated Piperidines: The Origin of the Axial‐F Preference

Abstract

Scheme2.The conformational preferences of 3-fluoropiperidine (1)and 3,5-difluoropiperidine (2)a nd their TFA-(A), HCl-(B), and NH-(C)-analogues.T he free enthalpydifferences between the equatorial conformer to the axial conformer (DG)are presenteda sf ollows: DG Solvent( DG Gas Phase). The DG valuesfor TFA-, and for both HCl-, and NH-analoguesa re given in chloroform andwater,r espectively. All values are given in kcal mol À1 .Experimentally,a ll analogues of 1 and 2 showed high axialpreference. In NH-analogues 1C and 2C,wew ere unable to determine the orientation of the NÀHb ond becauseofafast H/D exchange in solution.[a] Both computationala nalysis and experimental observation were carriedo ut in toluene.

Accessing (Multi)Fluorinated Piperidines Using Heterogeneous Hydrogenation

“… 21 A recent, detailed study investigated the fundamental interactions of fluorinated piperidines. 22 NMR analysis of the free NH piperidines synthesized in this study proved the gauche conformation of the products in CDCl 3 .…”

Fluorinated Rings: Conformation and Application

“…[9] Therefore, it is more reasonable to consider the stabilization forces for the axial preference in 3-fluoropiperidinium analogues as chargedipole interactions. [77,78] This has been further demonstrated while investigating the conformational behavior of N-methyl-3fluoropiperidinium derivatives 48 and 51. [76d] Calculated values in the gas phase show that the axial preference in 48 and 51 is favored by 4.5 and 3.7 kcal mol À1 , respectively, over the equatorial conformers (Figure 11).…”

“…[76a,d] The latter is favored in gas phase and aqueous solution by 4.8 and 1.8 kcal mol À1 , respectively (Figure 11). [77] This unexpected axial preference is even more shocking in 3,5-difluoropiperidinium cation 49, which contains two diaxial CÀF bonds that typically lead to destabilizing electrostatic interactions and hence to equatorial conformation (compare 49 to 26 Figure 9. A) Conformational preference and crystal packing of aryl-all-cis-2,3,5,6-tetrafluorocyclohexane 34.…”

“…[76b] Computational models in the gas phase show a strong gauche preference in fluoropiperidinium cations 46 and 49 which is attributed to electrostatic interactions, particularly charge-dipole (CÀF•••HN + ) interactions (Figure 11). [77,78] In aqueous solution, these interactions are strongly attenuated and hyperconjugation, through s CÀH !s* CÀN and s CÀH !s* CÀF orbital interactions, become more relevant. [77,78] It should be noted that the gauche conformation in 3-fluoropiperidinium analogues results in short contacts of CÀF•••HN + , indicative of hy-drogen bonding interactions.…”

“…[77,78] In aqueous solution, these interactions are strongly attenuated and hyperconjugation, through s CÀH !s* CÀN and s CÀH !s* CÀF orbital interactions, become more relevant. [77,78] It should be noted that the gauche conformation in 3-fluoropiperidinium analogues results in short contacts of CÀF•••HN + , indicative of hy-drogen bonding interactions. However, these interactions in organofluorine compounds are typically weak.…”