Reaction dynamics of C-N coupling mediated by a supramolecular Cu(I)/calix[8]arene catalyst

Abstract

Encapsulation of molecular complexes is an attractive strategy to develop highly efficient catalysts based on Earth abundant metals that otherwise suffer from deactivation. One such example is the Cu-calix[8]arene catalyst facilitating C-N coupling reactions. However, the rational design of such systems has been hampered by a lack of adequate computational protocols. To investigate such a large supramolecular catalyst, studying only the catalytic centre is not enough to obtain all the information about the complex. The inherent flexibility of the calixarene cage needs to be taken into account, as it can have a significant influence on the way the reaction proceeds.

Thus, we developed a multistep protocol to model this class of homogeneous, supramolecular catalysts. The first steps comprised the investigation of the reaction mechanism with quantum chemistry. Here, the conformational diversity and flexibility of the calixarene macrocycle was approximately described by classical MD simulations of the educts, products, and reaction intermediates in explicit solvent. While this static picture already revealed some features that explain the high catalytic activity, we next turned to developing a full QM/MM MD scheme to study the dynamic nature of the bond formations in solution. The main downside of such a strategy is the large number of computational resources needed for an evaluation of the reaction pathway. By utilizing semi-empirical quantum mechanical methods (GFN2-xTB) to describe the QM zone, the computational costs were reduced by orders of magnitudes, while the results were remarkably similar to full DFT. Hence, massive sampling of the reaction pathway was possible. It allowed us to perform statistical analyses of the reaction energetics, of the response of the macrocyclic ligand during bond formation, and of the dynamic nature of the transition states in explicit solvent. By providing a detailed molecular picture of the reaction dynamics new design strategies to supramolecular catalysts emerge.