1H NMR and conformational analysis of diastereotopic methylene protons in achiral flexible molecules

Abstract

Unlike diastereotopic -CH2- protons from chiral compounds, the diastereotopic protons from achiral compounds may not be easily predictable. For molecules with flexible chain this task is even more problematic. Additionally, the assignment from the experimental 1H NMR spectrum of chemical shifts and coupling constants is very frequently uncertain. Nevertheless, computationally, for both chiral and achiral molecules the -CH2- protons diastereotopic nature is evident as well as NMR parameters assignments. In the present paper we examine the NMR parameters calculated as a sum of Boltzmann weighted average of the lowest conformations that fits a window less than 10 kJ/mole. A Spartan20 six steps protocol was chosen to select the lower energy conformations. The NMR conformationally averaged parameters obtained for 2-ethyl-2-hyroxybutanoic acid (EHB) and citric acid (CA), both achiral molecules, and the chiral malic acid (MA) fit acceptable well with the experimental data, although the calculation is done for gas phase (conformations dominated by intermolecular hydrogen bonding) and the experiment was carried out in D2O (conformations controlled by intermolecular hydrogen bonding of highly decorated molecules with OH and COOH that can interact with the solvent). In addition, in the present paper we have examined EHB, CA and MA the lowest energy conformer geometry, Atom in Molecules (AIM) and Natural Bond Orbital protocols to identify the intramolecular hydrogen bonds.