Robust fluorine effects on molecular conformations of 2-amino-2-fluorotetrahydro-2H-pyrans: fluorine-Perlin-like vs. Perlin effects

Abstract

The conformational behavior of a wide variety of amino substituents (totally 13) in 2-amino-2-fluorotetrahydro-2H-pyrans and 2-amino-tetrahydro-2H-pyrans is thoroughly explored employing density functional theory and natural bond orbital methods. Calculations demonstrated the robust fluorine effect on the anomer equilibria of the tetrahydropyran conformers. Anomeric effect ladders for the amino substituents are built based on sensitive energetic, structural and NMR probes. In the anomeric effect ladders based on the ΔG_ax→eq energetic parameters the majority of the amino substituents favor the equatorial conformation (reverse anomeric effect). The electronic (natural atomic charge q_N, s-character of the n_N(spⁿ) hybrids, polarity μ), steric (molecular volume) and stereoelectronic (hyperconjugative interactions) features of the amino substituents in conjunction with the fluorine effect constitute the driving force for the conformational preferences inducing normal or reverse anomeric, fluorine-Perlin-like (F-Perlin-like) and Perlin effects in 2-amino-2-fluorotetrahydro-2H-pyrans and 2-amino-tetrahydro-2H-pyrans. The stereoelectronic features of the amino substituents are associated with the predominant n_O → σ*(C–E) (E = H, N, F), n_N → σ*(C–E), (E = H, O, F) and n_F → σ*(C–E) (E = N, O) hyperconjugative interactions in the tetrahydro-2H-pyran conformers. The acceptor capacity of the σ*(C–E) (E = N, O, C, F, H) NBOs expressed by their occupancies (occupation numbers) was related to the relevant hyperconjugative interactions. In this context the anomeric effect is associated with the predominant electron density transmissions (EDTs) either through the σ- or the σ- and π-subspaces of the tetrahedral coordination sphere of the anomeric carbon atom. Along this line we introduced the concept of anomerphore for the electronic profile of the –C(Y)(X)(E) group in analogy with the well established terms of chromophore and pharmacophore.