Templated Synthesis of Glycoluril Oligomers and Monofunctionalized Cucurbit[6]uril Derivatives

Abstract

The molecular recognition properties exhibited by molecular containers have inspired supramolecular chemists to generate diverse and specialized macrocycles. The family of hosts known as cucurbiturils (CB[n]) have become a popular platform for molecular recognition due to their high binding affinities and selectivity in water. As CB[n] branch into increasingly complex applications it becomes important to find efficient pathways to prepare monofunctionalized CB[n] derivatives bearing reactive functional groups. Chapter 1 presents a literature review of the synthesis, properties, mechanism of formation, and applications of the CB[n] family. We use this background information to explain our key hypothesis, that templated reactions offer potential routes to obtain glycoluril oligomer building blocks that allow the preparation of monofunctionalized CB[n] compounds. Chapter 2 describes the templated synthesis of glycoluril hexamer (6C) in a one step synthetic procedure on the gram scale using the p-xylylenediammonium ion (II-11). Hexamer 6C undergos cyclization with (substituted) phthalaldehdyes II-12, II-14, II-15, II-18 under acidic conditions at room temperature to deliver monofunctionalized CB[6] derivatives II-13, II-15, II-16, and II-19. Furthermore, the reaction kinetics for CB[6] cyclization between hexamer and formaldehyde or phthalaldehyde is influenced by the size and shape of ammonium ion templates. The larger size of the p- xylylenediammonium ion (II-11) allows it to act as a negative template by discouraging transformation of hexamer and paraformaldehyde to form CB[6]. However, II-11 and hexanediammonium ion (II-20) act as positive templates during the reaction of 6C and phthalaldehyde II-12 by giving (±)-II-21 as an intermediate along the mechanistic pathway to CB[6] derivative II-13. Finally, a fluorescence turn-on assay was investigated using the fluorophore and metal-ion binding (e.g., Eu3+) of naphthalene- CB[6] derivative II-19. The synthesis of monofunctionalized CB[6] derivatives in high yields has broad implications toward tailor-made approaches to CB[n] derived functional systems in the future. Chapter 3 describes the high yield synthesis of glycoluril pentamer (5C) by the 3,5- dimethylphenol induced fragmentation of bis-ns-CB[10] under acid conditions. The access to large quantities of 5C and 6C and previously reported tetramer III-4 allowed for a comparison of host-guest recognition properties of acyclic CB[n]-type receptors toward alkaneammonium ions in water.