Inverted metal-free active template synthesis of rotaxanes via axle‑mediated macrocyclisation

We report a one‑step, inverted metal‑free active‑template strategy in which an oligo(ethylene glycol) chain both accelerates amide bond formation and promotes macrocyclisation around itself. By transposing the usual roles played by the ring and axle in active template synthesis, the approach obviates the need for permanent structural motifs in the macrocycle, generating [2]rotaxanes in up to 70% yield from simple building blocks. Longer chains enable the iterative synthesis of [n]rotaxanes with as many as four macrocycles on an octa(ethylene glycol) thread. X-Ray crystallography of a [5]rotaxane shows a helical stack of threaded macrocycles, stabilised by -stacking and bifurcated C-H…O…H-N hydrogen bonding between the rings. These features rationalise an observed acceleration of macrocyclisation, and the improved yields of higher order rotaxanes, as the axle becomes progressively more crowded. Skeletal editing to delete the newly formed amides affords minimalist rotaxanes consisting of an oligo(ethylene glycol) axle threaded through a cyclohydrocarbon. Axle-mediated macrocyclisation, aided by emergent cooperativity from axle crowding, expands the possibilities for cyclic components of rotaxanes beyond that of well-established macrocycles such as cyclobis(paraquat-p-phenylene), crown ethers, cyclodextrins, pillararenes, etc.