Cooperative capture synthesis: yet another playground for copper-free click chemistry

Abstract

Click chemistry describes a family of modular, efficient, versatile and reliable reactions which have acquired a pivotal role as one of the most useful synthetic tools with a potentially broad range of applications. While copper(I)-catalysed alkyne–azide cycloaddition is the most widely adopted click reaction in the family, the fact that it is cytotoxic restricts its practice in certain situations, e.g., bioconjugation. Consequently, researchers have been exploring the development of copper-free click reactions, the most popular example so far being strain-promoted alkyne–azide cycloadditions. An early example of copper-free click reactions that is rarely mentioned in the literature is the cucurbit[6]uril (CB6) catalysed alkyne–azide cycloaddition (CB-AAC). Despite the unique ability of CB-AAC to generate mechanically interlocked molecules (MIMs) – in particular, rotaxanes – its slow reaction rate and narrow substrate acceptance limit its scope. In this Tutorial Review, we describe our efforts of late in developing the fundamental principles and practical applications of a new copper-free click reaction – namely, cooperative capture synthesis, whereby introducing a cyclodextrin (CD) as an accelerator in CB-AAC, hydrogen bonding networks are formed between the rims of CD and CB6 in a manner that is positively cooperative, giving rise to a high level of pre-organisation during efficient and quick rotaxane formation. For example, [4]rotaxanes can be prepared nearly quantitatively within a minute in water. Furthermore, we have demonstrated that CB-AAC can accommodate a wider substrate tolerance by introducing pillararenes as promoters. To date, we have put cooperative capture synthesis into practice by (i) preparing polyrotaxanes containing up to 200 rings in nearly quantitative yields, (ii) trapping conformational isomers of polymacrocycles as rings in rotaxanes, (iii) demonstrating solid-state fluorescence and Förster resonance energy transfer (FRET) processes by fixing the fluorophores in a rotaxane and (iv) establishing the principle of supramolecular encryption in the preparation of dynamically and reversibly tunable fluorescent security inks.