Abstract
Supramolecular synthesis is a powerful strategy for assembling complex molecules, but to do this by targeted design is challenging. This is because multicomponent assembly reactions have the potential to form a wide variety of products. High-throughput screening can explore a broad synthetic space, but this is inefficient and inelegant when applied blindly. Here we fuse computation with robotic synthesis to create a hybrid discovery workflow for discovering new organic cage molecules, and by extension, other supramolecular systems. A total of 78 precursor combinations were investigated by computation and experiment, leading to 33 cages that were formed cleanly in one-pot syntheses. Comparison of calculations with experimental outcomes across this broad library shows that computation has the power to focus experiments, for example by identifying linkers that are less likely to be reliable for cage formation. Screening also led to the unplanned discovery of a new cage topology—doubly bridged, triply interlocked cage catenanes.
Highlights
Supramolecular synthesis is a powerful strategy for assembling complex molecules, but to do this by targeted design is challenging
New structures often involve small, iterative changes to known molecules. To relate this to our own activity, since 2009 we have published an average of three new cage molecules per year (Fig. 1a), with a variation on the cage topology every couple of years or so (Fig. 1b)[4,21,22,23,24]
33 cages were synthesised in pure form, and a further 16 cages could be identified along with side-products; this significantly exceeds the total number of cage molecules reported by our research group over the last 9 years (Fig. 1a)
Summary
We used computation to assess the possible model cage topologies (see Supplementary Methods) that might be formed by the reaction of a triamine precursor, (2,4,6-trimethylbenzene-1,3,5-triyl)trimethanamine, with a representative example of the three different aldehyde types; meta and paradialdehydes, and trigonal trialdehydes (Fig. 2), investigated in the high-throughput screen (Fig. 3a). This energy normalisation using formation energies, rather than relative energies per sub-unit, allows us to directly compare the energies of the cages regardless of their size or topology. Tri4Tri[4] cages (22– 26) were in general somewhat less energetically favoured than Tri2Di3cages (average formation energies per imine bond of −10 and −16 kJ mol−1, respectively), the experimental ‘hit rate’ for these two topologies across the array was rather similar (Fig. 3c). The Tri4Di6cages had larger cavities with diameters ranging from 2.3 to 11.2 Å, with the smaller cavities
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