Theoretical volume profiles for conformational changes: Application to internal rotation of benzene ring in 1,12-dimethoxy-[12]-paracyclophane

Identification of the transition state is an important step in the study of reaction kinetics and mechanisms. However, for non-rigid chemical systems where multiple viable reaction pathways may exist, enumeration of all possible transition states quickly becomes computationally expensive, if at all feasible. As an alternative approach, we recently proposed a methodology where the volumetric properties of a flexible reaction system are used to locate its transition state ensemble through a comparison of its theoretically determined volume profile and experimental activation volumes derived from high pressure kinetic data. In this work, we apply this method to internal rotation of the benzene ring in 1,12-dimethoxy-[12]-paracyclophane. For this system, the transition state ensemble was found to be the state with the lowest volume, where the benzene ring and the flexible methylene tether are coplanar. This result was verified by comparison with a Gibbs free energy profile obtained via umbrella sampling.