Anomeric and Perlin Effect Ladders for 2-Substituted 2-Fluorotetrahydro-2H-pyrans Using Sensitive Structural, Energetic, and NMR Probes

Abstract

A comprehensive exploration of the anomeric and Perlin effects in a series of 2-substituted-2-fluorotetrahydro-2H-pyrans employing sensitive structural, energetic, and NMR probes calculated by density functional theory (DFT) and natural bond orbital (NBO) approaches is undertaken. We used a wide variety of X substituents exhibiting diverse electronic features (σ-donors, σ-donors/π-donors, and σ-donors/π-acceptors). It is noteworthy that a group of 8 substituents (NHMe, SCN, OBr, NO3, OCl, Cl, OF, and Br) favor the axial conformations, while a group of 13 substituents (NO2, NF2, NH2, CN, SH, H, N3, B(OH)2, OMe, BH2, OH, Me, and Ph) favor the equatorial conformations. Interestingly, a group of 6 substituents (NH2, NHMe, NF2, OF, OCl, and OBr) are responsible for the observed normal Perlin effect while the remaining 16 substituents induce the reverse Perlin effect. An exhaustive investigation of possible correlations of anomeric and Perlin effect descriptors with structural, energetic, one-bond 1JC-F couplings and the nucleophilicity of X descriptors demonstrated the general relationship of the Perlin and anomeric effects and manifested their common stereoelectronic origin.