Construction of supramolecular structures with internal functionalities is a promising approach to build enzyme‐like cavities. The endo‐functionalized [Pd12L24] and [Pd2L4] coordination cages represent the most successful systems in this regard. However, these systems mainly contain one type of endo‐moiety. We herein provide a solution for the controlled endo‐functionalization of [Pd2L4] cages. Site‐selective introduction of the endo‐functional group was achieved through the formation of heteroleptic [Pd2(LA)2(LB)(LC)] cages. Using two orthogonal steric control elements is the key for the selective formation of the hetero‐assemblies. We demonstrated the construction of two hetero‐cages with a single internal functional group as well as a hetero‐cage with two distinct endohedral functionalities. The endo‐functionalized hetero‐cages bound sulfonate guests with fast‐exchange dynamics. This strategy provides a new solution for the controlled endo‐functionalization of supramolecular cavities.

Construction of supramolecular structures with internal functionalities is a promising approach to build enzyme‐like cavities. The endo‐functionalized [Pd12L24] and [Pd2L4] coordination cages represent the most successful systems in this regard. However, these systems mainly contain one type of endo‐moiety. We herein provide a solution for the controlled endo‐functionalization of [Pd2L4] cages. Site‐selective introduction of the endo‐functional group was achieved through the formation of heteroleptic [Pd2(LA)2(LB)(LC)] cages. Using two orthogonal steric control elements is the key for the selective formation of the hetero‐assemblies. We demonstrated the construction of two hetero‐cages with a single internal functional group as well as a hetero‐cage with two distinct endohedral functionalities. The endo‐functionalized hetero‐cages bound sulfonate guests with fast‐exchange dynamics. This strategy provides a new solution for the controlled endo‐functionalization of supramolecular cavities.