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.