Encapsulation Enhances the Catalytic Activity of C‐N Coupling: Reaction Mechanism of a Cu(I)/Calix[8]arene Supramolecular Catalyst

Development of C−N coupling methodologies based on Earth‐abundant metals is a promising strategy in homogeneous catalysis for sustainable processes. However, such systems suffer from deactivation and low catalytic activity. We here report that encapsulation of Cu(I) within the phenanthroyl‐containing calix[8]arene derivative 1,5‐(2,9‐dimethyl‐1,10‐phenanthroyl)‐2,3,4,6,7,8‐hexamethyl‐p‐tert‐butylcalix[8]arene (C(8)PhenMe(6) ) significantly enhances C−N coupling activity up to 92 % yield in the reaction of aryl halides and aryl amines, with low catalyst loadings (2.5 % mol). A tailored multiscale computational protocol based on Molecular Dynamics simulations and DFT investigations revealed an oxidative addition/reductive elimination process of the supramolecular catalyst [Cu(C(8)PhenMe(6))I]. The computational investigations uncovered the origins of the enhanced catalytic activity over its molecular analogues: Catalyst deactivation through dimerization is prevented, and product release facilitated. Capturing the dynamic profile of the macrocycle and the impact of non‐covalent interactions on reactivity allows for the rationalization of the behavior of the flexible supramolecular catalysts employed.