Informing Molecular Design by Stereoelectronic Theory: The Fluorine Gauche Effect in Catalysis.

The axioms of stereoelectronic theory constitute an atlas to navigate the contours of molecular space. All too rarely lauded, the advent and development of stereoelectronic theory has been one of organic chemistry's greatest triumphs. Inevitably, however, in the absence of a comprehensive treatise, many of the field's pioneers do not receive the veneration that they merit. Rather their legacies are the stereoelectronic pillars that persist in teaching and research. This ubiquity continues to afford practitioners of organic chemistry with an abundance of opportunities for creative endeavor in reaction design, in conceiving novel activation modes, in preorganizing intermediates, or in stabilizing productive transition states and products. Antipodal to steric governance, which mitigates destabilizing nonbonding interactions, stereoelectronic control allows well-defined, often complementary, conformations to be populated. Indeed, the prevalence of stabilizing hyperconjugative interactions in biosynthetic processes renders this approach to molecular preorganization decidedly biomimetic and, by extension, expansive. In this Account, the evolution and application of a simple donor-acceptor model based on the fluorine gauche effect is delineated. Founded on reinforcing hyperconjugative interactions involving C(sp3 )-H bonding orbitals and C(sp3 )-X antibonding orbitals [σC-H → σC-X *], this general stratagem has been used in conjunction with an array of secondary noncovalent interactions to achieve acyclic conformational control (ACC) in structures of interest. These secondary effects range from 1,3-allylic strain (A1,3 ) through to electrostatic charge-dipole and cation-π interactions. Synergy between these interactions ensures that rotation about strategic C(sp3 )-C(sp3 ) bonds is subject to the stereoelectronic requirement for antiperiplanarity (180°). Logically, in a generic [X-CH2 -CH2 -Y] system (X, Y = electron withdrawing groups) conformations in which the two C(sp3 )-X bonds are synclinal (i.e., gauche) are significantly populated. As such, simple donor-acceptor models are didactically and predictively powerful in achieving topological preorganization. In the case of the gauche effect, the low steric demand of fluorine ensures that the remaining substituents at the C(sp3 ) hybridized center are placed in a predictable area of molecular space: An exit vector analogy is thus appropriate. Furthermore, the intrinsic chemical stability of the C-F bond is advantageous, thus it may be considered as an inert conformational steering group: This juxtaposition of size and electronegativity renders fluorinated organic molecules unique among the organo-halogen series. Cognizant that the replacement of one fluorine atom in the difluoroethylene motif by another electron withdrawing group preserves the gauche conformation, it was reasoned that β-fluoroamines would be intriguing candidates for investigation. The burgeoning field of Lewis base catalysis, particularly via iminium ion activation, provided a timely platform from which to explore a postulated fluorine-iminium ion gauche effect. Necessarily, activation of this stereoelectronic effect requires a process of intramolecularization to generate the electron deficient neighboring group: Examples include protonation, condensation to generate iminium salts, or acylation. This process, akin to substrate binding, has obvious parallels with enzymatic catalysis, since it perturbs the conformational dynamics of the system [ synclinal-endo, antiperiplanar, synclinal-exo]. This Account details the development of conformationally predictable small molecules based on the [X-Cα -Cβ -F] motif through a logical process of molecular design and illustrates their synthetic value in enantioselective catalysis.