Interrogating the Configurational Stability of Atropisomers

Atropisomers are molecules whose stereogenicity arises from restricted
rotation about a single bond and are of current importance due to their applications in catalysis, medicine, and materials science. The defining feature of atropisomeric molecules is that their stereoisomers may interconvert by bond rotation: as a result, evaluating their configurational stability (i.e., the rate at which their stereoisomers interconvert) is central to any work in this area. Important atropisometric scaffolds include C–C linked biaryls (such as the ligand BINAP and the drug vancomycin) and C– N linked amine derivatives such as the drug telenzepine. This article focusses upon the three most widely used experimental methods that are available to measure the rate of racemization in atropisomers, namely: (i) kinetic analysis of the racemization of an enantioenriched sample: (ii) dynamic HPLC; and (iii) variable temperature NMR. For each technique, an explanation of the theory is set out, followed by a detailed experimental procedure. A discussion is also included of which technique to try when confronted with a new molecular structure whose properties are not yet known. None of the three procedures require complex experimental techniques, and all can be performed using standard analytical equipment (NMR and HPLC). The time taken to determine a racemization rate depends on which experimental method is required, but for a new compound it is generally possible to measure a racemization rate in <1 day.