Figure 2.

Stereoelectronic effects in 4-substituted prolines lead to a preference in the Cγ-CS bond for a gauche relationship between the amide and electron-withdrawing 4-substituents. (a) In 4R-fluoroproline (Flp) and 4S-fluoroproline (flp), two major hyperconjugative interactions stabilize the gauche conformation: orbital overlap between the electron-rich C-H_δ bond (σ) and the electron-deficient C-F bond (σ*) (left), and orbital overlap between the electron-rich C-H, bond and the electron-deficient C-N bond (middle). When N and F are anti, neither stabilizing interaction is possible (right). Additional hyperconjugative stabilization is provided by an anti arrangement between a beta proton and the fluorine when Flp is exo or when flp is endo. (b) Manifestation of gauche effects on ring pucker. With electron-withdrawing substituents, a gauche conformation with 4R-substitution leads to a strong preference for exo ring pucker, while a gauche conformation with 4S-substitution leads to a strong preference for endo ring pucker. The exo/endo preference thus depends on both the stereochemistry of the substitution and how electron-withdrawing the substituent is. For sterically demanding and/or non-electron-withdrawing substituents, the reverse preferences will be observed due to a steric preference for anti over gauche conformation. Newman projections are simplified to show idealized torsion angles.