**4. Discussion**

Clearly the aldol condensation of two molecules of **ID** to bindone is catalysed by the presence of the cage. A plausible mechanism is that the hydrophobic, but cationic surface of the cage stabilises the enolate anion of **ID**, e ffectively reducing its p *K*a, so that when close to the cage, it can be deprotonated even at pH 3.4 when the expected p *K*a is 7. We emphasise that 'soft' anions such as phenolates have already been shown to have a higher a ffinity for the cage surface than more highly solvated anions such as hydroxide or chloride [9]. It is also significant that Raymond and co-workers observed that the basicity of an amine could be increased by >4 p *K*a units when the amine is bound inside a cage host with a charge of −12 [42]: the charge of +16 on **H w** implies that a comparable increase in the acidity of **ID** (i.e., stabilisation of the enolate anion) is plausible if the anion is interacting with the cage surface. As the cage can also bind neutral **ID** inside the cavity through the hydrophobic e ffect (*cf.* the crystal structure), we can see how the cage plays the role of bringing together a neutral substrate and an anion with which it can react through two orthogonal interactions, but this time resulting in a C–C bond forming reaction.

This particular reaction is an old one [45,46] and in itself not of the highest importance. The catalysis we observed is very slow in absolute terms; and looking at the reaction in more detail is made di fficult by the poor solubility of bindone in water. The importance of these results, however, is that they open the possibility of using the cage to stabilise enolate anions and accumulate them around substrates attracted to the cage via the hydrophobic e ffect. Whether the reaction occurs inside the cavity or outside, this opens up the general possibility of using the cationic/hydrophobic surface of this cage and others like it as a general catalyst for aldol-type reactions, which would have substantial synthetic utility. We note that Mukherjee et al. have recently reported the condensation reactions of relatively acidic ketones with hydrophobic aldehydes using a trigonal prismatic [Pd<sup>2</sup>+]6 coordination cage as a catalyst, which allows the reactions to proceed under much milder conditions than in the absence of a catalyst [58]. This can be attributed in part to the hydrophobicity of the cavity that increased the thermodynamic driving force for the elimination of water, and its expulsion into the bulk solvent, but the role of the positive charge of the cage in stabilising anionic intermediates has also been suggested [58], which is exactly in agreemen<sup>t</sup> with what we propose.

**Supplementary Materials:** The following are available online at http://www.mdpi.com/2624-8549/2/1/4/s1.

**Author Contributions:** Synthesis and catalysis measurements: C.M., C.G.P.T., and J.R.P.; data analysis, C.M.; crystallography, S.P.A. and C.G.P.T.; project supervision and manuscript preparation: M.D.W. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by the EPSRC, gran<sup>t</sup> number EP/K003224/1; and the European Union (H2020-MSCA-ITN gran<sup>t</sup> 'NOAH', project ref. 765297).

**Acknowledgments:** We thank the Diamond Light Source for the X-ray beamtime (proposal MT19876) and the staff of beamline I-19 for their assistance. Mr. Mark Cooper is thanked for his assistance with some of the early experimental measurements as part of an undergraduate project.

**Conflicts of Interest:** The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
