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

Abstract

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 CDCl3 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 (ΔGs) 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 (δH, δC and some (n)JHH data) were in close agreement with those measured experimentally; binuclear (δH,C 1 : 1) correlations, rH,C(2) = 0.9998. The associated individual ΔG 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 ΔGs. 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.

Shortfall of B3LYP in Reproducing NMR JCH Couplings in Some Isomeric Epoxy Structures with Strong Stereoelectronic Effects: A Benchmark Study on DFT Functionals

“…The greater value of the Pearson correlation coefficient r or its square r 2 was considered as a very simple indication of better adjustment of the compared J data (vide infra). In addition, the four standard statistical metrics for errors, namely, the root‐mean‐square deviation (RMSD), mean absolute deviation (MAD=(1/ n )∑ i | − |, where n is the total number of J CH values), corrected RMSD, that is, CRMSD=[(1/ n )∑ i ( − ) 2 ] 1/2 , and corrected MAD (CMAD=(1/ n )∑ i | − |), were used as much more reliable estimates of the uncertainties of calculation results. Moreover, maximum positive or negative deviations between the (or ) and data, that is, max(+/−), were evaluated.…”

“…All molecular structures of flexible systems 1 – 6 were computed starting from their MMX (1986) geometries created with PCMODEL . Specifically, an extensive conformational search for preferred forms was carried out with an internal GMMX randomize subroutine of the above program, in a similar manner to that described elsewhere . Further cascade geometry refinement of low‐energy candidate conformers was done with the Gaussian 09 package .…”

“…Equilibrium structures optimized at this level of theory were also used in a critical test of some computational methods for prediction of δ H and δ C values . The “Tight” SCF and Opt convergence criteria were applied to ascertain accuracy ,. A fine‐pruned (150,590) numerical integration grid was used, owing to soft modes arising from the dynamic phenomena of methyl‐group rotations .…”

“…The Gaussian 09 default parameters (including the UFF atomic radii) were applied when constructing solute cavities, whereby a cavity is understood as a free space inside a bulk solvent. A few calculations were also performed with nonstandard IDSCRF atomic radii, which were found beneficial in recently reported structure optimizations and calculations of NMR chemical shifts . The UA0 model and unscaled ( α =1) van der Waals surfaces were used in this case, and related input files were produced with the SCRF‐RADII program .…”

What is the form of muscimol from fly agaric mushroom (Amanita muscaria) in water? An insight from NMR experiment supported by molecular modeling

“…Such works start with full structure optimization, followed by vibrational analysis . In many cases, gauge‐independent atomic orbital approach allows reasonable prediction of isotropic nuclear magnetic shieldings and the corresponding theoretical chemical shifts . Somehow more difficult calculations provide theoretical indirect spin–spin coupling constants (SSCCs) .…”