Beyond Density: Unveiling the Trade‐Off in Catalytic Site Optimization Using Defect‐Engineered UiO‐66

A well‐designed experimental model reveals a trade‐off between intrinsic activity and catalytic site density in performance optimization, due to inherent diffusion resistance arising from substrate adsorption at catalytic sites. Abstract Enhancing intrinsic activity and increasing catalytic site density are two widely employed strategies to improve catalytic performance. Although typically considered independently, their interplay remains poorly understood. Here, two UiO‐66 metal–organic frameworks (MOFs) with distinct catalytic site densities—linker‐defective UiO‐66L and cluster‐defective UiO‐66C—are synthesized and systematically compared. Despite a higher density of open Zr catalytic sites, UiO‐66L exhibited lower catalytic activity than UiO‐66C across four model reactions, performing similarly to defect‐free UiO‐66. Although defect engineering is expected to enlarge pore connectivity, diffusion‐ordered spectroscopy (DOSY) and molecular dynamics (MD) simulations surprisingly reveal that UiO‐66C exhibits similar diffusion rates to defect‐free UiO‐66, while UiO‐66L shows significantly slower diffusion. This discrepancy is attributed to self‐adsorption of reactants at the high‐density catalytic sites, which induces local diffusion resistance even in the presence of expanded channels. These findings reveal a performance trade‐off between catalytic site density and intrinsic activity, establishing a critical threshold beyond which further increases in site density can hinder rather than enhance catalysis. A well-designed experimental model reveals a trade-off between intrinsic activity and catalytic site density in performance optimization, due to inherent diffusion resistance arising from substrate adsorption at catalytic sites. Abstract Enhancing intrinsic activity and increasing catalytic site density are two widely employed strategies to improve catalytic performance. Although typically considered independently, their interplay remains poorly understood. Here, two UiO-66 metal–organic frameworks (MOFs) with distinct catalytic site densities—linker-defective UiO-66L and cluster-defective UiO-66C—are synthesized and systematically compared. Despite a higher density of open Zr catalytic sites, UiO-66L exhibited lower catalytic activity than UiO-66C across four model reactions, performing similarly to defect-free UiO-66. Although defect engineering is expected to enlarge pore connectivity, diffusion-ordered spectroscopy (DOSY) and molecular dynamics (MD) simulations surprisingly reveal that UiO-66C exhibits similar diffusion rates to defect-free UiO-66, while UiO-66L shows significantly slower diffusion. This discrepancy is attributed to self-adsorption of reactants at the high-density catalytic sites, which induces local diffusion resistance even in the presence of expanded channels. These findings reveal a performance trade-off between catalytic site density and intrinsic activity, establishing a critical threshold beyond which further increases in site density can hinder rather than enhance catalysis. Advanced Science, Volume 12, Issue 43, November 20, 2025.