Multi-conformer molecules in solutions: an NMR-based DFT/MP2 conformational study of two glucopyranosides of a vitamin E model compound

Overall conformations of both anomeric per- O -acetylated glucosyl derivatives of 2,2,5,7,8-pentamethylchroman-6-ol were studied in the context of their high flexibility, on the basis of NMR spectra in CDCl 3 solution and related DFT calculation results. A few computational protocols were used, including diverse density functional/basis set combinations with a special emphasis on accounting (at various steps of the study) for the impact of intramolecular London-dispersion (LD) effects on geometries and relative Gibbs free energies (Δ G s) of different conformers coexisting in solution. The solvent effect was simulated by an IEF-PCM approach with the UFF radii; its other variants, including the use of the recently introduced IDSCRF radii, were employed for a few compact B3LYP-GD3BJ optimized structures showing one small imaginary vibrational frequency. The advantage of using IDSCRF radii for such purposes was shown. Of the four tested DFT methods, only the application of the B3LYP/6-31+G(d,p) approximation afforded ensembles of 7-8 single forms for which population-average values of computed NMR parameters ( δ H , δ C and some n J HH data) were in close agreement with those measured experimentally; binuclear ( δ H,C 1 : 1) correlations, r H,C 2 = 0.9998. The associated individual Δ G values, corrected for LD interactions by applying Grimme's DFT-D3 terms, afforded relative contents of different contributors to the analyzed conformational families in much better agreement with pertinent DFT/NMR-derived populations ( i.e. , both data sets were found to be practically equal within the limits of estimated errors) than those calculated from dispersion uncorrected Δ G s. All these main findings were confirmed by additional results obtained at the MP2 level of theory. Various other aspects of the study such as the crystal vs. solution structure, gg / gt rotamer ratio, diagnostic (de)shielding effects, dihydrogen C-H H-C contacts, and doubtful applicability of some specialized DFT functionals (M06-2X, ωB97X-D and B3LYP-GD3BJ) for the description of highly flexible molecules are also discussed in detail. Overall geometries of both glucosyl derivatives of PMC were found on the basis of their NMR spectra in CDCl 3 and related δ H,C / n J HH IEF-PCM(UFF,CHCl 3 )/DFT calculational results.