Interactions affecting 1JC–F SSCCs in neutral and ionic 2-, 3- and 4-fluoro-substituted piperidines: normal and reverse fluorine Perlin-like effect

Abstract

The fluorine Perlin-like effect is an NMR phenomenon characterized by |¹J_C–Fax| < |¹J_C–Feq| in fluorinated six-membered rings and can be useful to determine the stereochemistry of such organofluorine compounds. The reverse fluorine Perlin-like effect is the opposite, that is |¹J_C–Fax| > |¹J_C–Feq|. The origin of the traditional Perlin effect in tetrahydropyran (¹J_C–Hax < ¹J_C–Heq) has long been explained in terms of hyperconjugation, that elongates the C–Hax bond, then reduces ¹J_C–Hax relative to ¹J_C–Heq. However, dipolar interactions have recently been invoked as the dominant contribution for the Perlin effect. The effects ruling the ¹J_C–F coupling constant in 2-, 3- and 4-fluoro-substituted piperidines and respective cations and anions are reported in this work, because of the important role of fluorine and nitrogen (either neutral or charged) in pharmaceutical and material sciences. The proximity (either scalar or spatial) of nitrogen to fluorine affects the ¹J_C–F coupling constant, but the nitrogen electron lone pair and the charge on nitrogen interacting with the C–F bond or fluorine lone pairs play a major role in describing the ¹J_C–F transmission mechanism, rather than hyperconjugation. This is made clear upon analysis of the axial 3-fluoropiperidinium cation, which experiences the electrostatic gauche effect F⋯N⁺, decreasing the |¹J_C–Fax| relative to |¹J_C–Feq|, and also by investigating non-covalent interactions (NCI), canonical molecular orbitals (CMOs) and the angular dependence of ¹J_C–F with molecular dipole moments and interactions for the title compounds and 1-(fluoromethyl)aziridine.