Improving the Prediction of Antioxidant Activity by Identifying High-Probability Conformations with NMR.

Abstract

A single-experiment NMR methodology was recently proposed for characterizing chemical structures in solution. This approach employs measured and computed one-bond carbon-carbon J-couplings to establish atomic connectivity, molecular conformation, heteroatom identity, intramolecular hydrogen bonding, and tautomeric form with high confidence. This methodology also identifies mixtures of conformers and assigns relative amounts. The present study applies this approach to establish conformations in the antioxidants trolox and 3-hydroxythiophene-2-carboxylic acid. The ability to accurately assign conformations in antioxidants is a key step needed before computational mechanistic studies can be successfully performed. In the case of antioxidants, this is especially important because at least four mechanisms of activity are feasible, and an incorrect assignment of conformation can alter mechanistic conclusions. Herein, the NMR methodology is shown to clearly select a single most probable conformation for trolox and two highly probable conformations of 3-hydroxythiophene-2-carboxylic acid. The NMR analysis also identified a possible conformational error in prior computational studies involving trolox.