Crystal Clear: Decoding Isocyanide Intermolecular Interactions through Crystallography

The isocyanide group is the chameleon among the functional groups in organic chemistry. Unlike other multiatom functional groups, where the electrophilic and nucleophilic moieties are typically separated, isocyanides combine both functionalities in the terminal carbon. This unique feature can be rationalized using the frontier orbital concept and has significant implications for its intermolecular interactions and the reactivity of the functional group. In this study, we perform a Cambridge Crystallographic Database-supported analysis of isocyanide intramolecular interactions to investigate the intramolecular interactions of isocyanides in the solid state, excluding isocyanide-metal complexes. We discuss examples of different interaction classes, including the isocyanide as a hydrogen bond acceptor (RNC···HX), halogen bonding (RNC···X), and interactions involving the isocyanide and carbon atoms (RNC···C). The latter interaction serves as an intriguing illustration of a Bürgi-Dunitz trajectory and represents a crucial experimental detail in the well-known multicomponent reactions such as the Ugi- and Passerini-type mechanisms. Understanding the spectrum of intramolecular interactions that isocyanides can undergo holds significant implications in fields such as medicinal chemistry, materials science, and asymmetric catalysis.