On the use OF H-NMR chemical shifts and thermodynamic data for the prediction of the predominant conformation of organic molecules in solution: the example of the flavonoid rutin.

Conformational analyses of organic compounds in solution still represent a challenge to be overcome. The traditional methodology uses the relative energies of the conformations to decide which one is most likely to exist in the experimental sample. The goal of this work was to deepen the approach of conformational analysis of flavonoid rutin (a well-known antioxidant agent) in DMSO solution. The methodology we used in this paper involves expanding the sample configuration space to a total of 44 possible geometries, using Molecular Dynamics (MD) simulations, which accesses structures that would hardly be considered with our chemical perception, followed by DFT geometry optimizations using the B97X-D/6-31G(d,p) - PCM level of theory. Spectroscopic and thermodynamic analyses were done, by calculating the relative energies and nuclear magnetic resonance (H-NMR) chemical shifts, comparing the theoretical and experimental H-NMR spectra (DMSO- ) and evaluating Mean Absolute Error (MAE). The essence of this procedure lies in searching for patterns, like those found in traditional DNA tests common in healthcare. Here, the theoretical spectrum plays the role of the analyzed human sample, while the experimental spectrum acts as the reference standard. In solution, it is natural for the solute to dynamically alter its geometry, going through various conformations (simulated here by MD). However, our DFT/PCM results show that a structure named 32 with torsion angles and manually rotated by approx. 20° showed the best theoretical-experimental agreement of H-NMR spectra (in DMSO- ). Relative energies benchmarking involving 16 DFT functionals revealed that the B97X-D is very adequate for estimating energies of organic compounds with dispersion of charge (MAE < 1.0 kcal mol, using post-Hartree-Fock MP2 method as reference). To describe the stability of the conformations, calculations of Natural Bonding Orbitals (NBO) were made, aiming to reveal possible intramolecular hydrogen bonds that stabilize the structures. Since van der Waals (vdW) interactions are difficult to be identified by NBO donations, the Reduced Density Gradient (RDG) were calculated, which provides 2D plots and 3D surfaces that describe Non-Covalent Interactions (NCI). These data allowed us to analyze the effect of dispersion interactions on the relative stability of the rutin conformations. Our results strongly indicate that a combination of DFT (B97X-D)-PCM relative energies and NMR spectroscopic criterion is a more efficient strategy in conformational analysis of organic compounds in solution.