Nitrogen and Oxygen Bridged Calixaromatics: Synthesis, Structure, Functionalization, and Molecular Recognition

Pedersen, Lehn, and Cram established supramolecular chemistry through their pioneering work with crown ethers, cryptands, and spherands. Since then, the hallmark of supramolecular science has been an increasing sophistication in the design and construction of macrocyclic molecules, as manifested in cyclodextrin derivatives, calixarenes, resorcinarenes, cyclotriveratrylenes, cucurbiturils, calixpyrroles, cyclophanes, and many other examples. Indeed, macrocyclic compounds provide unique models for the study of noncovalent molecular interactions. They also constitute building blocks for constructing high-level molecular and supramolecular architectures and fabricating molecular devices and advanced materials. As a postgraduate in the Huang laboratory in the late 1980s, I became interested in the calix[n]arenes because of their unique conformational structures and versatile complexation properties. The notion of introducing heteroatoms, and particularly nitrogen, into the bridging position of conventional calixarenes was particularly intriguing. Nitrogen, unlike methylene, can adopt either an sp(2) or sp(3) electronic configuration, providing different conjugation systems with adjacent aromatic rings. Consequently, depending on the configuration and conjugation, a range of C-N bond lengths and C-N-C bond angles is possible. The conformation and cavity size in heteroatom-bridged calixarenes might thus be tuned through the bridging heteroatoms and the number of aromatic rings. Furthermore, because heteroatom linkages significantly affect the electron density and distribution on aromatic rings, the electronic features of macrocyclic cavities might be regulated by heteroatoms. Given the essentially limitless combinations possible, only synthetic hurdles would prevent access to numerous diverse heteracalixaromatics. We began a systematic study on nitrogen- and oxygen-bridged calixarenes in 2000, years later than originally envisioned. Before this study, very few heteracalixaromatics had been reported, owing to the formidable synthetic challenges involved. Apart from thiacalixarene, the synthesis of nitrogen- and oxygen-bridged calixarenes appeared very difficult. But since our first publications in 2004, we have been delighted to see the rapid and tremendous development of the supramolecular chemistry of this new generation of macrocycles. In this Account, I summarize the synthesis of N- and O-bridged calixaromatics and their regiospecific functionalization on the rims and bridging positions, focusing on the fragment coupling approach and contributions from our laboratory. I describe the construction of molecular cages based on heteracalixaromatics and discuss the effect of both bridging heteroatoms and substituents on macrocyclic conformations and cavity sizes. Molecular recognition of neutral organic molecules and charged guest species is also demonstrated. The easy accessibility, rich molecular diversity, unique conformation, and cavity tunability of heteracalixaromatics make them invaluable macrocycles for research in supramolecular chemistry. New heteracalixaromatics, with well-defined conformations and cavity properties, will provide powerful tools for probing noncovalent interactions, leading to the development of new molecular sensing and imaging systems. Multicomponent molecular self-assembly of heteracalixaromatics as functional modules with metals, metal clusters, or charge-neutral species should result in multidimensional solid and soft materials with diverse applications. The profitable incorporation of heteracalixaromatics into molecular devices can also be anticipated in the future. Moreover, the construction of enantiopure, inherently chiral heteracalixaromatics should provide important applications in chiral recognition and asymmetric catalysis.