Probing Proximal Intramolecular Hydrogen Bonding Interactions on a Norbornane Scaffold

A systematic computational study was conducted on 12 unique 2,6-disubstituted norbornane derivatives to assess the ability of various acceptor groups (A = F, Cl, Br, OH, OCH₃, SH, SCH₃, NHCH₃, N(CH₃)₂, PH₂, PHCH₃, and P(CH₃)₂) to engage in intramolecular hydrogen bonding with a proximal OH donor. 32 unique minima have been characterized with M06-2X and df-MP2 geometry optimizations as well as PNO-LCCSD(T)-F12 single point energy computations. Conformations with the OH donor oriented toward the acceptor to form an OH···A contact (+HB) consistently had lower electronic energies (by approximately 2 to 8 kcal mol^-1) than their counterparts with the OH directed away from the acceptor (-HB). Additional M06-2X computations revealed that these intramolecular contacts also induce significant shifts to lower energy in the OH stretching frequencies (usually by -50 to -100 cm^-1, but more than -200 cm^-1 for OH···N interactions) and notable deshielding of the hydrogen atom (with shifts in the isotropic nuclear magnetic resonance (NMR) chemical shielding constants ranging from -1 to -5 ppm). Quantum theory of atoms in molecules (QTAIM) analysis confirms the presence of bond critical points with electron densities (ca. 0.02 to 0.03 e bohr^-3) that are within the typical range of values for hydrogen bonds. These findings demonstrate the capacity of not only N and O, but also P and S, acceptor groups, to establish appreciable attractive intramolecular interactions with a proximal OH group on a rather rigid molecular scaffold.