Amide Bond Activation: The Power of Resonance

The amide bond represents the most fundamental functional group in numerous areas of chemistry, such as organic synthesis, drug discovery, polymers, and biochemistry. Although typical amides are planar and the amide N–C(O) bond is notoriously difficult to break due to nN→π⁎C=O resonance, over the past 5 years remarkable breakthroughs have been achieved in the activation of amides by complementary mechanisms that ultimately hinge on ground-state destabilization of the amide linkage. In this review, we present an overview of the main reactivity manifolds employed in the activation of amides by selective N–C(O) cleavage pathways along with their main applications in catalytic as well as stoichiometric synthesis. This cutting-edge platform clearly demonstrates how to harness the power of amidic resonance to achieve a host of previously elusive transformations of amides and holds the promise to change the landscape of how chemists perceive the traditionally unreactive amide bonds into readily modifiable linchpin functional groups that can be readily triggered for the desired reactivity.