Abstract
The determination of accurate NOE-derived interproton distances and confirmation/prediction of relative populations in multi-conformer, flexible small molecules was investigated with the model compound 4-propylaniline. The low accuracy assumed for semi-quantitative NOE distance restraints is typically taken to suggest that large numbers of constraints need to be used in the dynamical analysis of flexible molecules, and this requires, for example, the measurement and Karplus-type analysis of scalar coupling constants (3JCH and 3JHH). Herein we demonstrate that, contrary to this common perception, NOE measurements alone are accurate enough to establish interproton distances, and hence conformational detail, in flexible molecules to within a few percent of their ensemble-averaged values, hence reducing the demand for additional restraints in such dynamic analyses.
Highlights
Information obtained from Nuclear Overhauser Effect (NOE) experiments in NMR spectroscopy is widely employed in the determination of stereochemical and conformational details [1]
The quantitative use of NOEs is often discounted or at least considered to be only approximately accurate. This perceived inaccuracy in NOE-distance relationships arises because many factors may perturb NOE intensities, including spin diffusion, selective polarisation transfer, variation in τc between spins, accuracy of signal integration and conformational flexibility [1]
We have recently shown that surprisingly accurate NOE-derived distances can be obtained in small organic molecules, and that many of the perturbing factors do not contribute significantly to NOE intensities when the molecule of interest is in the fast tumbling regime and measurements are made within the Initial Rate Approximation limits [2]
Summary
Information obtained from Nuclear Overhauser Effect (NOE) experiments in NMR spectroscopy is widely employed in the determination of stereochemical and conformational details [1]. The ensemble-averaged NOE-determined distances can be used, along with computations of conformer geometries, to confirm the structures and energies/populations of contributing conformers.
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