The role of intra and intermolecular interactions on the conformational dynamics of 2-halo-1-phenylpropanols: Structure and solvent effects

Experimental and theoretical ³J_HH scalar coupling constants allowed the identification of the conformational landscape of erythro (eX) and threo (tX) 2-halo-1-phenylpropanols (halo = F, Cl, and Br). NMR scalar coupling constants captured dynamics of the OC-C-X dihedral and OH rotameric states, in a dynamic and solvent-dependent equilibrium. The erythro series revealed a particular halogen-dependent equilibrium, which showed different sensitivity to the media, especially in acetone, where the eF populations were completely shifted. At the same time, threo showed a highly solvent-sensitive equilibrium. NBO calculations showed the importance of electron delocalization over steric and electrostatic effects to stabilize the preferred synclinal conformer in both diastereomers. A Principal Component Analysis (PCA) on the NBO stabilization energies pointed to a complex mixture of electronic delocalization happening simultaneously. Hyperconjugative interactions are significant, but they are not the only important effect. Non-covalent interactions were also identified through NCI surfaces. Hydrogen bonds and intramolecular C-X···π and CH···π interactions were proved to act differently in the two diastereomers, affecting their equilibria in different ways. Nuclear Overhauser (NOE) NMR experiments point to an intramolecular CH···π contact, while ¹H NMR of the aromatic hydrogens evidence an intermolecular effect of acetone and DMSO on the phenyl ring. DFT with explicit solvation shows a solvent shell favoring intermolecular CH···π contacts, in agreement with the experiments. This thorough analysis revealed that intra- and intermolecular factors contribute to the preference for the synclinal conformer in the studied compounds.