Supramolecular Host‐Guest Complexation Dynamics by Cost‐Efficient Electronic Structure Methods

Multilevel computational approaches based on electronic structure methods currently enable the accurate structural and thermodynamic characterization of medium to large-sized host-guest systems, but have been scarcely used to systematically study their kinetics. Here, we show how this type of protocol can be easily applied for the task, using the well-known complexation reaction between the cucurbit[6]uril host and alkylammonium cations as a test case. To this end, the recently reported aISS docking workflow is used for the fast exploration of the coconformational space of a set of nine host-guest aggregates, at the robust and fast semiempirical GFN2-xTB(ALPB) level of theory. After identification of appropriate intermediates and reaction products, those can be in turn efficiently connected by the Nudged Elastic Band method, enabling fast screening of different potential reaction mechanisms, and the identification of the corresponding transition states. Further refinement of the equilibrium geometries and a better energetic description of the stationary points is nevertheless mandatory, for instance with the state of the art and efficient ωB97X-3c(COSMO-RS)//r²SCAN-3c(CPCM) density functional-based protocol, which not only accurately reproduces the experimental reference values of the free energy of association (MAE = 1.4 kcal/mol), but also the kinetic in/out barriers reported for the processes (MAE = 2.0 and 2.9 kcal/mol, respectively). Overall, this work presents a robust and cost-effective multilevel workflow for the routine kinetic profiling of supramolecular association processes.