Engineering Hierarchy to Porous Organic Cages for Biomimetic Catalytic Applications

Conspectus In nature, hierarchy is a core organizational principle intricately woven into biological systems, facilitating the compartmentalization of enzymes within living cells. This spatial arrangement enables multistep metabolic reactions to occur simultaneously with remarkable efficiency and precision. Inspired by this, significant progress has been made in artificial biomimetic heterogeneous catalytic systems using porous materials like metal-organic frameworks, porous organic polymers, and zeolites. Among these, molecular cages, with their well-defined cavities, stand out as synthetic models for enzyme-mimic catalysis. They not only provide biomimetic microenvironments for substrate binding, mimicking the highly specific and efficient interactions observed in natural enzymatic systems, but also integrate active centers within confined nanoscale spaces, enabling synergistic functionality. However, research in cage-based biomimetic catalysts has largely focused on tailoring the cavity environment─such as optimizing cavity size, pore geometry, and functional groups on the pore walls─to regulate catalytic processes, while comparatively less attention has been given to the catalytic role of metal centers, akin to the critical function in natural metalloenzymes. While metal nodes in metal-organic cages can act as active sites, their catalytic efficiency may be hindered by coordination saturation. Moreover, the restricted (sub)nanoscale space of molecular cage reactors limits their capacity to host larger active sites or accommodate bulky substrates. Thus, rationally engineering the confined spaces and optimizing the spatial arrangement of active sites within molecular cage-based catalytic systems is essential for advancing the field and unlocking their full potential. This Account leverages recent advancements in molecular cage materials, particularly porous organic cages (POCs), to design hierarchical POCs as versatile platforms for biomimetic catalytic systems. It begins by defining hierarchical POCs, outlining their structural and compositional hierarchies, and highlighting the significant potential they hold for biomimetic catalysis. We then explore the approaches for introducing hierarchy into POCs, discussing how insights from both serendipitous experimental data (shear flow assisted crystallization) and deliberate design lead to the development of specific strategies. These include noncovalent and covalent/coordination-driven assembly approaches for creating architectural hierarchies with micro-, meso-, and/or macropores. By integrating diverse active sites, such as metal clusters (MCs), metal complexes, and enzymes, within these (hierarchical) pores, we establish component hierarchies. The focus then shifts to biomimetic catalysis, where we emphasize the precise optimization of active site size, location, and the surrounding microenvironment to enhance catalytic performance. Additionally, we highlight the importance of communication and cooperative interactions among multiple active sites compartmentalized within hierarchical POCs to achieve precise control over activity and selectivity. This Account hopefully can provide the innovative avenue by engineering hierarchy to molecular cages for advanced biomimetic heterogeneous catalysis, offering new insights and opportunities in the field.