Accuracy in determining interproton distances using Nuclear Overhauser Effect data from a flexible molecule

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 ((3)J(CH) and (3)J(HH)). 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.

Keywords: NMR spectroscopy; NOE; conformation; internuclear distances.

Figure 1

Four low energy conformations of 4-propylaniline obtained from B3LYP/6-31G* conformational search and labelled 2D structure (1a/2a differ from 1b/2b in the pyramidalization at the amine nitrogen, see main text for details).

Figure 2

Plot of the mean calculated error arising from fitting the population distribution of conformers 1a/b (x) and 2a/b (1−x) to the experimental NOE-derived interproton distances. Exemplar error thresholds are represented at 3% (black line) and 10% (red line).