Spatial Configuration‐Directed Design of Artificial Carbonic Anhydrases with Self‐Modulating Zr‐OH Sites for Carbon Dioxide Hydration Reactions

Carbonic anhydrase (CA) mimics hold significant promise for diverse applications, particularly in CO 2 capture, catalysis, and storage, while creating efficient CA mimics has rarely been achieved. Here, by emulating the Zn‐OH active centers of natural CA, the spatial configuration‐directed design of artificial CAs with self‐modulating Zr‐OH sites for carbon dioxide hydration reactions is reported. By modulating the Lewis acid sites (Zr‐OH) in the UiO66‐NH 2 framework with monocarboxylic acids, such as formic acid, acetic acid (AC), and trifluoroacetic acid, a competitive coordination mechanism between modulators and organic linkers is covered, which significantly enhances the density and accessibility of Zr‐OH active sites. Among the modulated frameworks, UiO66‐NH 2 ‐AC exhibits exceptional hydration catalytic performance, surpassing all previously reported MOF‐based CA mimics and many other catalysts. Furthermore, the catalytic mechanism of the self‐modulating Zr‐OH sites is systematically elucidated, demonstrating that CO 2 insertion into the Zr‐OH moiety of UiO66‐NH 2 to form a bidentate carbonate intermediate—a process strikingly analogous to the catalytic cycle of natural CA. This work not only advances the design of high‐performance CA mimics for CO 2 ‐related applications but also provides fundamental insights into the spatial configuration‐directed design and reaction role of self‐regulating active sites in enzyme‐mimetic catalysis.