School of Chemistry, University of Bristol, Bristol, UK.
Chemistry Research Laboratory, University of Oxford, Oxford, UK.
Nat Protoc. 2023 Sep;18(9):2745-2771. doi: 10.1038/s41596-023-00859-y. Epub 2023 Aug 4.
Atropisomers are molecules whose stereogenicity arises from restricted rotation about a single bond. They are of current importance because of their applications in catalysis, medicine and materials science. The defining feature of atropisomeric molecules is that their stereoisomers are related to one another 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 atropisomeric 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 focuses on 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 by 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 d.
手性异构体是指由于单键旋转受限而产生手性的分子。它们目前具有重要意义，因为它们在催化、医学和材料科学方面的应用。手性异构体分子的定义特征是，它们的立体异构体通过键旋转相互关联：因此，评估它们的构型稳定性（即它们的立体异构体相互转化的速率）是该领域任何工作的核心。重要的手性异构体支架包括 C-C 键联的联芳基，如配体 BINAP 和药物万古霉素，以及 C-N 键联的胺衍生物，如药物替仑西平。本文重点介绍了三种最广泛使用的实验方法，可用于测量手性异构体的外消旋化速率，即：（i）对富集对映异构体的样品的外消旋化进行动力学分析，（ii）动态 HPLC 和（iii）变温 NMR。对于每种技术，都解释了其理论原理，然后详细介绍了实验步骤。还讨论了在遇到新的分子结构且其性质尚不清楚的情况下，应尝试哪种技术。这三种方法都不需要复杂的实验技术，并且都可以使用标准分析设备（NMR 和 HPLC）来进行。确定外消旋化速率所需的时间取决于所使用的实验方法，但对于新化合物，通常可以在 <1 天内测量其外消旋化速率。
