Defect-Engineered Metal–Organic\nFrameworks\nas Bioinspired Heterogeneous Catalysts for Amide Bond Formation

The synthesis of amides from amines and carboxylic acids\nis the\nmost widely carried out reaction in medicinal chemistry. Yet, most\namide couplings are still conducted using stoichiometric reagents,\nleading to significant waste; few synthetic catalysts for this transformation\nhave been adopted industrially due to their limited scope and/or poor\nrecyclability. The majority of catalytic approaches focus on a single\nactivation mode, such as enhancing the electrophilicity of the carboxylic\nacid partner using a Lewis acid. In contrast, nature effortlessly\nforges and breaks amide bonds using precise arrays of Lewis/Brønsted\nacidic and basic functional groups. Drawing inspiration from these\nsystems, herein we report a simple defect engineering strategy to\ncolocalize Lewis acidic Zr sites with other catalytically active species\nwithin porous metal–organic frameworks (MOFs). Specifically,\nthe combination of pyridine <i>N</i>-oxide and Zr open metal\nsites within the defective framework <b>MOF-808-py-Nox</b> produces\na heterogeneous catalyst that facilitates amide bond formation with\nbroad functional group compatibility from amines and carboxylic acids,\nesters, or primary amides. Extensive density functional theory (DFT)\ncalculations using cluster models support that the formation of a\nhydrogen-bonding network at the defect sites facilitates amide bond\nformation in this material. <b>MOF-808-py-Nox</b> can be recycled\nat least five times without losing significant crystallinity, porosity,\nor catalytic activity and can be employed in continuous flow. This\ndefect engineering strategy can be potentially generalized to produce\nlibraries of catalytically active MOFs with different combinations\nof colocalized functional groups.