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 catalysts for this transformation
have been adopted industrially due to their limited scope and/or poor
recyclability. The majority 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 Lewis/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 defective framework MOF-808-py-Nox produces
a heterogeneous catalyst that facilitates amide bond formation with
broad functional group compatibility from amines and carboxylic acids,
esters, or primary amides. Extensive density functional theory (DFT)
calculations using cluster models support that the formation of a
hydrogen-bonding network at the defect sites facilitates amide bond
formation in this material. MOF-808-py-Nox can be recycled
at least five times without losing significant crystallinity, porosity,
or catalytic activity and can be employed in continuous flow. This
defect engineering strategy can be potentially generalized to produce
libraries of catalytically active MOFs with different combinations
of colocalized functional groups.