Amide Bond Activation: The Power of Resonance

Amide bond twisting is a modern tool to modulate amidic resonance and achieve an array of previously elusive transformations of amides. The importance of amides in various areas of chemistry has stimulated the rapid development of new generic strategies for amide bond activation. A wide range of new twisted and ground-state-destabilized amides have been prepared, in some cases achieving a full twist of the amide bond in practical acyclic templates. The activation of traditionally inert amide bonds can be achieved by acyl, decarbonylative, radical, and acyl addition pathways, providing enticing opportunities for reaction discovery. Mechanistic studies have provided evidence for the role of twist and ground-state-destabilization as the driving force in amide bond activation. 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. 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. carboxylic acid derivatives in which a nitrogen atom is attached to a carbonyl group. a process describing heterolytic bond cleavage. a process that creates bonds between two different fragments using a metal catalyst. a process in which bonds are broken homolytically. a process in which one amide bond is converted to another amide bond. an amide in which the geometry of the six atoms comprising the amide bond is not planar. a set of parameters used to describe the geometric distortion of amide bonds.