For decades, chemists believed that assembling rotaxanes required carefully designed molecular recognition between a ring and an axle, or rod-shaped, unit. Researchers have now flipped this paradigm, showing that a flexible molecular chain can instead direct the formation of the ring around itself (Nat. Chem. 2026, DOI: 10.1038/s41557-026-02188-5).
Rotaxanes consist of a ring threaded onto a molecular axle and are key components of molecular machines, switches, and sensors. Traditionally, chemists have assembled them by engineering complementary interactions between the ring and axle. “We wondered if an open-chain analog of the crown ether could do a similar thing to generate a rotaxane,” says David Leigh of the University of Manchester who led the study.
The idea proved correct. Instead of relying on permanent recognition motifs, the flexible oligo(ethylene glycol) axle adopts a crown ether-like conformation that organizes the reacting components as the macrocycle forms around it. After the ring closes, the axle becomes mechanically trapped; thus eliminating the need for the recognition motifs required in conventional template synthesis. The strategy therefore allows rotaxanes to be built from a much wider range of macrocycles. “I think we were all surprised—not just that it worked but that it worked so well,” Leigh says.
Scott Cockroft, a supramolecular chemist at the University of Edinburgh who was not involved in the study, says this discovery brings the field “full circle.” Crown ethers originally transformed supramolecular chemistry by acting as molecular hosts and templates. “Here, the concept is inverted: the same [ethylene glycol] motif in a linear chain instead helps new rings to form around it,” he says.
Using this metal-free strategy, the researchers synthesized a range of [2]rotaxanes and higher-order [n]rotaxanes from simple building blocks, culminating in a structurally striking [5]rotaxane featuring a helical stack of interlocked rings. “It actually worked better the more rings we tried to squeeze on,” Leigh says. “We were extremely surprised—again!”
The result was unexpected because long, flexible chains rarely fold into rings, and doing so around an axle should be harder still. “It’s statistically unlikely to link two ends of a long chain of atoms,” says Euan Kay, who runs the NanoSupra Research Group at St Andrews University, and who was not involved in the study. “Forming a macrocycle around a molecular axle to make a rotaxane is even more unlikely.”
X-ray crystal structures reveal that the interlocked rings actually stabilize one another through hydrogen bonding and aromatic stacking, helping the flexible axle fold into the shape needed to form the next ring. “The molecule gets better at building itself as it becomes more crowded and interlocked, and paradoxically, seemingly harder to synthesize,” Cockroft says.
Kay says another standout feature is the combination of the inverted template strategy with skeletal editing, which erases the chemical scaffolding used to build the ring. The final interlocked molecules give little indication of how the components were assembled, he adds. “This traceless chemistry adds a touch of magic to the overall synthetic strategy.”
By eliminating complementary recognition motifs, the approach could greatly expand the range of accessible rotaxanes. “What the result shows is that molecular recognition does not always have to mean a rigid lock-and-key fit,” Leigh says. “Weak interactions, if they are arranged in the right way, even momentarily, can be enough to greatly accelerate an otherwise slow chemical reaction.”
