Defect-Engineered Metal−Organic Frameworks as Bioinspired Heterogeneous Catalysts for Amide Bond Formation

The synthesis of amides from amines and carboxylic acids is the most widely carried out reaction in medicinal chemistry. Yet, most amide couplings are still conducted using stoichiometric reagents, leading to significant waste; few synthetic cata-lysts for this transformation have been adopted industrially due to their limited scope and/or poor recyclability. The majori-ty of catalytic approaches focus on a single activation mode, such as enhancing the electrophilicity of the carboxylic acid partner using a Lewis acid. In contrast, nature effortlessly forges and breaks amide bonds using precise arrays of Lew-is/Brønsted acidic and basic functional groups. Drawing inspiration from these systems, herein we report a simple defect engineering strategy to colocalize Lewis acidic Zr sites with other catalytically active species within porous metal-organic frameworks (MOFs). Specifically, the combination of pyridine N-oxide and Zr open metal sites within the framework MOF-808-py-Nox produces a heterogeneous catalyst that facilitates amide bond formation with broad functional group compat-ibility. We propose that the formation of a hydrogen-bonding network at the defect sites helps to lower the energy barrier for amide bond formation. MOF-808-py-Nox can be recycled at least five times without losing crystallinity or catalytic activity. This defect engineering strategy can be potentially generalized to produce libraries of catalytically active MOFs with differ-ent combinations of colocalized functional groups, mimicking the complexity of enzyme active sites.