Conformational exploitation of polyfunctional organic compounds using spectroscopic and theoretical methods

Abstract

Comprehension of the conformational preferences in organic molecules plays a fundamental role in several fields of science, such as in agrochemistry, medicinal chemistry, material science, organic synthesis and spectroscopy. Accordingly, the conformational analysis of model compounds in this study is divided in two parts: i) the first part aims at elucidating the conformational isomerism of 1-chloro-1,1-difluoro-2-pentanol (CDP) in solution, by means of nuclear magnetic resonance (NMR) and infrared (IR) spectroscopies, with the aid of theoretical calculations. CDP was chosen as model compound because it contains some structural features of last generation inhalational anesthetics; ii) the second part aims to analyze, theoretically, the counterclockwise effect (name given to the effect that rules the counterclockwise orientation of the hydroxyl groups in D-glucose), whose origin is still controversial. To achieve this finding, a series of -halogen derivatives of D-glucose is proposed to confront the possible intramolecular interactions controlling the conformational equilibrium of this molecule. The 1 H, 13 C and 19 F NMR spectra in cyclohexane, chloroform and acetonitrile solution, through the analysis of ³JH,H, ³JH,F and 1 JC,H coupling constants, allowed to determine the main conformers of CDP in the equilibrium, as well as to evaluate how the conformational populations varied by changing the solvent polarity. The quantitative results obtained through NMR were consistent with the infrared data obtained in cyclohexane solution, as well as with the computational estimations, which were determined at the ωB97X-D and CCSD(T) levels, using the 6-311++g(d,p) basis set. It is worth mentioning that calculations using an implicit solvation model (PCM) did not reproduce the experimental results appropriately, mainly for the polar solvent acetonitrile, probably due to specific solute-solvent interactions. Surprisingly, the most stable conformer in nonpolar solvent was not the one that maximizes the gauche orientation between the fluorine atoms and the vicinal electronegative group (OH), in disagreement with the well-known gauche effect. Instead, the main conformer exhibits the chlorine substituent with gauche relationship with the OH group, in such a way that an electronic delocalization from the electron donor orbital σC-H to the good electron acceptor orbital σ*C-Cl is effective. NBO (Natural Bond Orbital) calculations confirmed that the hyperconjugative interaction σC-H → σ*C-Cl is highly stabilizing. To evaluate the counterclockwise effect, some structural modifications at D-glucose were carried out, thus allowing to obtain the relevant intramolecular interactions (electrostatic and stereoeletronic interactions) that rule the tridimensional shape of D-glucose. This work was theoretically carried out at the B3LYP/aug-cc-pVDZ level, from which the compound energies and conformer populations could be achieved. On the contrary of earlier statements, the origin for the counterclockwise effect is not related to intramolecular hydrogen bonds, but it is rather governed by repulsive dipolar and steric effects in the clockwise conformation.