Researchers from the group of Prof. Pau Ballester at ICIQ have reported a self-assembled dynamically covalent molecular cage that promotes intermolecular azide–alkyne Huisgen cycloadditions, while showing that subtle changes in cavity size modulate the catalytic performance. The study was published in Nature Communications.
The researchers found that small geometric changes in the molecular cage strongly affect the balance between reaction acceleration and product release. For one pair of reactants, the cage produces moderate acceleration while allowing catalytic turnover, as the product binds only weakly to the cage and can be replaced by a new reacting pair of substrates. The presence of an additional methylene group in one of the substrates leads to larger accelerations but also much stronger product binding, ultimately preventing catalyst turnover due to product inhibition.
“This work wraps up nearly 20 years of our group’s effort to study reactions inside confined spaces. With the new cage, a very small structural change gives our maximum acceleration so far and, for the first time, catalytic turnover in this system. What we find especially interesting is that turnover still happens despite strong substrate binding. Together with kinetic analysis and DFT, these results highlight what our research is about and move us a step forward in understanding confined catalysis,” explains Dr. Gemma Aragay, Group Scientific Coordinator and author of this work.
The study describes a tetra-imine bis-calix[4]pyrrole cage, termed TI-1, featuring a rigid aromatic cavity with two convergent polar hemispheres. TI-1 binds pairs of reactive substrates (pyridine N-oxide derivatives) within its cavity with high affinity (Michaelis complex), and organizes their reactive ends (alkyne and azide) in a proper geometry for reaction. Interestingly, the cage promotes the exclusive accelerated formation of the 1,4-disubstituted triazole regioisomer. The synthetic cage operates similarly to enzymes, which catalyze chemical transformations with high specificity and efficiency by confining substrates within well-defined binding pockets, where reactive partners are brought into close proximity and preorganized for reaction.
By comparing TI-1 with a closely related cage, the study demonstrates that variations of less than one ångström in cavity size can finely tune the balance between reaction acceleration and product release. These findings shed light on a recurring limitation in confined catalysis of bimolecular reactions, whereby strong product binding often prevents synthetic molecular containers from operating under truly catalytic conditions.
Reference publication
Balancing acceleration and turnover in [1 + 1] tetra-imine bis-calix[4]pyrrole reactor for Huisgen cycloadditions
Li, Y.; Aragay, G.; Ballester, P.
Nat Commun 2026
DOI: 10.1038/s41467-026-72315-w
La entrada Cycloadditions in confined molecular cages se publicó primero en ICIQ.