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

Area of Science:

• Computational chemistry
• Supramolecular chemistry
• Chemical kinetics

Background:

• Electronic structure methods accurately characterize host-guest systems but are rarely used for kinetics.
• Systematic kinetic studies of host-guest complexation are needed.

Purpose of the Study:

• To present a robust and cost-effective multilevel computational workflow for kinetic profiling of supramolecular association processes.
• To demonstrate the workflow's applicability using the cucurbit[6]uril and alkylammonium cation system.

Main Methods:

• Utilized the aISS docking workflow for conformational space exploration at the GFN2-xTB(ALPB) level.
• Employed the Nudged Elastic Band method to connect intermediates and identify transition states.
• Refined geometries and energies using the ωB97X-3c(COSMO-RS)//r2SCAN-3c(CPCM) density functional protocol.

Main Results:

• Accurately reproduced experimental free energies of association (MAE = 1.4 kcal/mol).
• Successfully predicted kinetic in/out barriers (MAE = 2.0 and 2.9 kcal/mol).
• Demonstrated efficient screening of reaction mechanisms and identification of transition states.

Conclusions:

• The developed multilevel workflow enables routine kinetic profiling of supramolecular association.
• This approach provides accurate predictions for both thermodynamics and kinetics of host-guest systems.