Rotaxanes are dumbbell-shaped mechanically interlocked molecules in which one or more ring-shaped molecules are threaded through a linear segment, known as the axle. To keep the ring from sliding off, two bulky groups, sometimes called stoppers, are added to the ends of the axle. Making a rotaxane has always been as challenging as its structure suggests.
A recent study introduced a fresh approach to rotaxane synthesis, abandoning the traditional strategy of starting with a pre-made ring to build the axle inside it. Instead, the researchers used an inverted active-template synthesis, in which the axle itself serves as a guide for the ring to form around it.
They used flexible chains called oligo(ethylene glycol) (OEG) as the axle. The trick lies in the oxygen atoms along these chains, which use hydrogen bonding to grab hold of the ring's building blocks, pulling them into exactly the right position to click into place and form the ring around the axle. This method enabled them to create rotaxanes with yields of up to 70% and containing up to four rings threaded through the linear axle.
The findings were published in Nature Chemistry.
Going the other way round
What makes rotaxanes so valuable is their unique structure. It gives them the stability and tunable properties needed for applications ranging from targeted drug delivery and biosensing to designing precise molecular machines.
For a long time, rotaxanes were mainly synthesized using two approaches: threading, where the axle was built through an already made ring, and clipping, which involved assembling the ring around the axle. Both methods involved having the components carefully arranged before being permanently linked together.
The axle takes the lead
Then came a new technique called active-template synthesis, in which the ring takes a more active role by accelerating the reaction that forms the axle. This usually depends on the ring carrying specific recognition features, such as a metal ion or carefully positioned functional groups, that help catalyze the formation of an axle within the ring.
Reversing these roles—so that instead of the ring directing the formation of the axle, the flexible axle guides the ring as it forms around it—has been a long-standing challenge for researchers. This study successfully did that.
The researchers used a new inverted methodology to build molecular machines called rotaxanes. Instead of using a pre-made ring to help build an axle, they used the axle as a guide to help a ring form around it. They started with a flexible OEG chain fitted with bulky stoppers at both ends, ensuring that any ring formed around it could not slip off.
They then added two simple building blocks—a diester and a diamine—which react to form a ring. All of these components were mixed in toluene, the liquid solvent in which the assembly took place.
Stacking rings with higher efficiency
The team also explored whether multiple rings could be threaded onto a single long axle. They first tried a one-pot approach, repeatedly adding ring-building blocks to a long axle, resulting in a mixture of rotaxanes with two to five interlocked components.
They found a step-by-step approach to be more efficient, adding one ring at a time, because once the first ring was in place, adding the next rings became much easier. Once the rotaxanes were complete, the researchers removed these temporary building blocks via a skeletal-editing step, leaving behind less crowded, minimalist rotaxanes.
What the X-rays revealed
The flexible OEG axle did more than just hold the structure together: It actively accelerated ring formation via hydrogen bonding, thereby producing rotaxanes with multiple rings in high yields. X-ray images helped explain how the OEG chains did so.
The images revealed that the rings were packed into a tightly wound helical stack, where hydrogen bonds and π-stacking stabilized the growing structure and helped guide the next ring into place.
A broader route to molecular machines
This work shows that mechanically interlocked molecules no longer need to be built around particular functional groups or structural motifs. With the inverted active-template method, chemists can now build rotaxanes in a cleaner, metal-free way, expanding what is possible for molecular machines, switches and new-age responsive materials.
Written for you by our author Sanjukta Mondal, edited by Sadie Harley, and fact-checked and reviewed by Andrew Zinin—this article is the result of careful human work. We rely on readers like you to keep independent science journalism alive. If this reporting matters to you, please consider a donation (especially monthly). You'll get an ad-free account as a thank-you.
Publication details
Jiankang Zhong et al, Inverted metal-free active template synthesis of rotaxanes via axle‑mediated macrocyclization, Nature Chemistry (2026). DOI: 10.1038/s41557-026-02188-5
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Citation: Self‑building molecular rings bring next‑generation drug delivery and smart materials closer (2026, July 12) retrieved 12 July 2026 from https://phys.org/news/2026-07-selfbuilding-molecular-nextgeneration-drug-delivery.html
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