title: Determination of absolute configuration in chiral solvents with nuclear magnetic resonance. A combined molecular dynamics/quantum chemical study.
abstract: Nuclear magnetic resonance (NMR) spectroscopy is omnipresent in chemical analysis. However, chirality of a molecule can only be detected indirectly by NMR, e.g., by monitoring its interaction with another chiral object. In the present study, we investigate the spectroscopic behavior of chiral molecules placed into a chiral solvent. In this case, the solvent-solute interaction is much weaker, but the application range of such NMR analysis is wider than for a specific chemical shift agent. Two alcohols and an amine were used as model systems, and differences in NMR chemical shifts dependent on the solute-solvent chirality combination were experimentally detected. Combined quantum mechanic/molecular mechanic (QM/MM) computations were applied to reveal the underlying solute-solvent interactions. NMR shielding was calculated using the density functional theory (DFT). While the experimental observations could not be reproduced quantitatively, the modeling provided a qualitative agreement and detailed insight into the essence of solvent-solute chiral interactions. The potentials of mean force (PMF) obtained using molecular dynamics (MD) and the weighted histogram analysis method (WHAM) indicate that the chiral interaction brings about differences in conformer ratios, which are to a large extent responsible for the NMR shifts. The MD results also predicted slight changes in the solvent structure, including the radial distribution function (RDF), to depend on the solvent/solute chirality combination. Apart from the conformer distribution, an effective average solvent electrostatic field was tested as another major factor contributing to the chiral NMR effect. The possibility to simulate spectral effects of chiral solvents from the first-principles opens up the way to NMR spectroscopic determination of the absolute configuration for a larger scale of compounds, including those not forming specific complexes.
authors.affiliation: †Institute of Organic Chemistry and Biochemistry, Academy of Sciences, Flemingovo náměstí 2, 166 10 Prague, Czech Republic.|‡Department of Physical and Macromolecular Chemistry, Faculty of Science, Charles University, Hlavova 8, 128 40 Prague, Czech Republic.
authors.forename: Jiří
authors.initials: J
authors.lastname: Kessler
authors.affiliation: †Institute of Organic Chemistry and Biochemistry, Academy of Sciences, Flemingovo náměstí 2, 166 10 Prague, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Dračínský
authors.affiliation: †Institute of Organic Chemistry and Biochemistry, Academy of Sciences, Flemingovo náměstí 2, 166 10 Prague, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Bouř