Three-component conformational equilibria of some flexible pyrrolidin-2-(thi)ones in solution by NMR data (δC, δH, and nJHH) and their DFT predictions: a confrontation of different approaches

Three standard gas-phase B3LYP/6-31G(d) methods of the analysis of δC, δH, and JHH NMR data for solutions initially used for the title γ-lactams 1a–c led to conflicting findings on fractional populations ηs of their fast interconverting conformers A–C, which were also inconsistent with energy data. In order to find the source(s) of these discrepancies, several additional DFT computations were carried out at the double- and triple-zeta theory level with simultaneous modeling of the solutions in explicit solvents with the COSMO or IEF-PCM technique. The WC04/WP04 functionals and IGLO-II (or IGLO-III) basis set were applied for predicting δC/δH, and JHH data, respectively. The limits of efficiency and accuracy of a few current NMR-oriented computational protocols were determined by their specific use to the main forms of 1a–c treated as test cases. Thus, an unreliability of the modified Karplus-type equation for this purpose was shown. In turn, only the use of DFT-D3 corrections for the attractive van der Waals dispersion interactions (London forces) not present in conventional DFT, to Gibbs free energies (ΔG) estimated for the forms A–C of 1a–c in solution, yielded energetics and so populations (ηGs) compatible within ±15% (only ±2%, for 1a) with the best results found by considering the 1H NMR data. These ηHs were found by a linear regression of GIAO-predicted δH sets reproducing experiment in the best way (r2>0.9996, for 1a and 1b, r2=0.9970, for 1c with strongly degenerated δHs). As for ηJs, they permitted only for evaluations of the ratios (A+B)/C, excepting sufficiently differentiated JHHs (1b in acetone). In contrast, an application of δCs for assessing ηCs was unsuccessful. Selected findings were finally compared with the DP4-probability results (ηDP4s) and fairly good agreement was found. The greatest divergence in ηs exists for the Cdouble bond; length as m-dashS bond-containing object 1b, what suggests a large effect of the intramolecular London forces on its structure and properties. The present results should be useful guidelines for NMR studies on the other multi-conformer systems in rapid equilibrium between more than two energetically feasible forms.