Enzymes are nature’s master catalysts, speeding up chemical reactions with pinpoint accuracy, but the artificial capsules designed to mimic them have been too fragile and too unpredictable to be useful. This project tackles both problems head-on by building robust, covalent capsules—molecular cages held together by strong chemical bonds—that incorporate halogen- and chalcogen-bonding catalytic motifs. Unlike the hydrogen-bonding catalysts commonly used, these sigma-hole interactions are more directional, more tuneable, and less sensitive to solvents and temperature, allowing researchers to rationally design confined spaces where reactions can be precisely controlled. If successful, this work could transform how chemists build enzyme-like catalysts from scratch. Instead of relying on trial-and-error or weak, non-directional forces to drive reactions inside a capsule, researchers would have a stable, modular platform for engineering catalytic activity. The immediate impact is primarily fundamental: it will generate new knowledge about how confinement and directional electrostatic interactions alter reactivity, filling a gap that has held back the field for decades. In the longer term, such precision-engineered capsules could underpin cleaner, more efficient industrial processes—for example, in pharmaceutical synthesis or fine chemical manufacturing—where controlling which product forms and reducing waste matters enormously.
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Through evolution, nature has developed enzymes that are capable of catalysing reactions at astonishing rates and with remarkable precision in the selectivity of both substrates used and products generated. Supramolecular chemists have long been fascinated by these natural examples and have sought to develop synthetic analogues for their own use. Since the 1980s, structurally simple macrocycles have been shown to enhance rates of reaction and change product distributions, demonstrating that host systems much simpler than enzyme scaffolds could potentially be engineered to display similar activity. This early work inspired chemists to design enzyme mimics from the bottom-up, exploiting the simplicity of these artificial systems as an advantage for ostensibly facile structural tuning and modification to develop precision-engineered, bio-inspired catalysts. Many capsule-type supramolecular architectures have been studied for reactivity within their internal cavities that differs from that observed in bulk solution. Although there have been a number of impressive examples of rate acceleration and regio-/stereoselectivity, the great potential promised by these systems has not been fully realised. There are two key reasons for this. First, the majority of the hosts studied are prepared under thermodynamic control. Whilst this allows large systems to be readily assembled from simple building blocks, they tend to be kinetically unstable under a wide range of conditions (solvent, reactive species, temperature). To achieve wider use, more robust systems are needed. Second, previously reported host systems often rely on non-directional solvophobic effects to drive reagents inside their cavities, generating a relatively high local concentration that promotes reactivity. The lack of directionality makes these systems impossible to rationally design and tune for specific applications. The use of specific and directional electrostatic interactions would provide a route for precision molecular engineering of reactivity. This project will address both of these key issues (low stability and functional tuneability) that have plagued the development of artificial capsules as enzyme mimetics to date. Kinetically robust covalent capsules will be prepared that incorporate tuneable organocatalytic motifs, allowing precision molecular engineering of confined catalytic spaces within these capsule structures. Specifically, halogen-bonding and chalcogen-bonding catalytic motifs will be investigated, as these offer higher directionality, tuneability and lower solvent dependency than hydrogen-bonding analogues, making them more suitable for use under a wide range of conditions. Using this approach, this project will generate prototype systems of catalytic capsules with all the requisite characteristics to enable their translation to real-world applications, whilst enhancing our fundamental understanding of reactivity under confinement. Invaluable data on catalysis using sigma-hole interactions will be generated, providing a knowledge base from which to expand research in this area that, despite its many promises, has languished behind hydrogen-bond congeners in the field of organocatalysis. This project will deliver a range of catalytic capsules with unprecedented properties and tuneability, impacting both fundamental, curiosity-driven investigations, as well as application-focussed research. The realisation of such systems will represent a step-change in efforts towards the bottom-up synthesis of artificial enzyme mimetics.
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