Kai Wu,Tanya K. Ronson,Leonard Goh,Weichao Xue,Andrew W. Heard,Pingru Su,Xiaopeng Li,Mladen Vinković,Jonathan R. Nitschke
A Diverse Array of Large Capsules Transform in Response to Stimuli
The allosteric regulation of biomolecules, such as enzymes, enables them to adapt and alter their conformation to fit specific substrates, expressing different functionalities in response to stimuli. Different stimuli can also trigger synthetic coordination cages to change their shape, size, and nuclearity by reconfiguring the dynamic metal–ligand bonds that hold them together. Here we demonstrate an abiological system consisting of different organic subcomponents and ZnII metal ions, which can respond to simple stimuli in complex ways. A ZnII20L12 dodecahedron transforms to give a larger ZnII30L12 icosidodecahedron through subcomponent exchange, as an aldehyde that forms bidentate ligands is displaced in favor of one that forms tridentate ligands together with a penta-amine subcomponent. In the presence of a chiral template guest, the same system that produced the icosidodecahedron instead gives a ZnII15L6 truncated rhombohedral architecture through enantioselective self-assembly. Under specific crystallization conditions, a guest induces a further reconfiguration of either the ZnII30L12 or ZnII15L6 cages to yield an unprecedented ZnII20L8 pseudo-truncated octahedral structure. The transformation network of these cages shows how large synthetic hosts can undergo structural adaptation through the application of chemical stimuli, opening pathways to broader applications.
A Diverse Array of Large Capsules Transform in Response to Stimuli

The allosteric regulation of biomolecules, such as enzymes, enables them to adapt and alter their conformation to fit specific substrates, expressing different functionalities in response to stimuli. Different stimuli can also trigger synthetic coordination cages to change their shape, size, and nuclearity by reconfiguring the dynamic metal–ligand bonds that hold them together. Here we demonstrate an abiological system consisting of different organic subcomponents and ZnII metal ions, which can respond to simple stimuli in complex ways. A ZnII20L12 dodecahedron transforms to give a larger ZnII30L12 icosidodecahedron through subcomponent exchange, as an aldehyde that forms bidentate ligands is displaced in favor of one that forms tridentate ligands together with a penta-amine subcomponent. In the presence of a chiral template guest, the same system that produced the icosidodecahedron instead gives a ZnII15L6 truncated rhombohedral architecture through enantioselective self-assembly. Under specific crystallization conditions, a guest induces a further reconfiguration of either the ZnII30L12 or ZnII15L6 cages to yield an unprecedented ZnII20L8 pseudo-truncated octahedral structure. The transformation network of these cages shows how large synthetic hosts can undergo structural adaptation through the application of chemical stimuli, opening pathways to broader applications.

Self-assembled metal–organic cages possessing well-defined cavities find an increasing range of applications, in molecular recognition, chemical separation, stabilization of reactive species, and catalysis, to give recent examples. In analogy to biological systems, metal–organic cages can also transform between structures that assemble from a common set of subcomponents. The dynamic nature of such cages, with different cavity sizes and shapes, could lead to different functionalities. The reversible formation of the coordination bonds that knit cages together enables them to reconfigure in response to an external stimulus. Different stimuli have been employed to trigger structural transformations, including light, temperature, guest templates, solvents, redox, pH, variation of concentration and added subcomponents. The application of one of these stimuli leads to a shift in the thermodynamic balance of the system, triggering bond breaking and reformation in order to reach a new equilibrium. Moreover, structural transformations triggered by different stimuli also provide a means to form cages with increased structural complexity, which are not accessible through direct coordination-driven self-assembly. Such structural transformations have involved sequences of two or three distinct transformations, leaving room for the development of more complex rearrangements.

Here we demonstrate a network of transformations, shown in Figure 1, between cages that each incorporated a pyrrole-centered penta-amine subcomponent A. Different stimuli, such as the addition of subcomponents, metal ions, or a change in temperature, triggered the transformation of one cage into another. The use of graph theory to extend our original series of truncated polyhedra allowed us to characterize a new pseudo-truncated octahedral structure, which crystallized with either D4, D2, or C2 symmetry. In contrast to the structural diversity we obtained previously, here a complex transformation network between four large cages and one sandwich structure was realized, with different stimuli triggering structural interconversions. In this system, ZnII20L12 dodecahedron Zn-1 transformed into ZnII30L12 icosidodecahedron Zn-2 following the addition of 6-formyl-2,2′-bipyridine C (Figure 1). We infer that this transformation proceeded as a result of the stronger affinity of the tridentate ligand for ZnII over the bidentate ligand. In the presence of Lacour’s Δ-TRISPHAT anion (G), icosidodecahedron Zn-2 transformed to ZnII15L6 truncated rhombohedron Zn-3 in solution, where these chiral anions appear to fit well at the edges of the polyhedron, templating its formation. Finally, both ZnII30L12Zn-2 and ZnII15L6Zn-3 transformed into the truncated octahedral architecture of ZnII20L8Zn-4 during crystallization in the presence of G. We hypothesized that penta-amine A would condense with methylformylpyridine B to generate a pentakis(bidentate) ligand, which would bind to six-coordinate zinc(II) to form M5nL3n structures such as ZnII20L12 dodecahedron Zn-1. The reaction of zinc(II) bis(trifluoromethanesulfonyl)imide (Zn(NTf2)2, 20 equiv) with penta-amine A (12 equiv) and B (60 equiv) yielded ZnII20L12 cage Zn-1 in CD3CN, as confirmed by NMR spectra, including two-dimensional (2D) NMR techniques (Figures S7–S10). A 1H diffusion-ordered spectroscopy (DOSY) experiment indicated the formation of a single species, with a diffusion coefficient (D) of 2.19 × 10–10 m2 s–1, corresponding to a solvodynamic radius of 2.7 nm (Figures 2b, S11 and S12). The results are in line with the expected size of Zn-1, consistent with the crystal structure of a previously described CoII analog. Electrospray ionization mass spectrometry (ESI-MS) further confirmed its ZnII20L12 composition, while traveling wave ion mobility-mass spectrometry (TWIM-MS) data excluded the presence of other isomers (Figure 2d,e). Small-angle X-ray scattering (SAXS) analysis offers a statistically robust method for the structural characterization of large cages. The structure of Zn-1 in CD3CN was first confirmed by NMR and ESI-MS and further probed by SAXS analysis, revealing the self-assembly of a hollow core–shell spherical cage with an inner radius (rinner) of 1.48 nm and a shell thickness (dthickness) of 1.36 nm (Figure 2c). A distinct strategy was previously developed to construct a series of progressively larger capsules with formulas of M5nL2n, where n = 1, 2, 3, or 6, by increasing the dihedral angles between pentagonal faces at vertices. We reasoned that M5nL2n structures with values of n missing from this series might be obtained by modifying the angles between the pentagonal faces of these structures. Based on graph theory we proposed a structure for the ZnII20L8 cage (n = 4, Figure S1), having a measured angle of ∼90°. Although ESI-MS signals corresponding to this ZnII20L8 species were found in certain samples of icosidodecahedron Zn-2, we were unable to isolate this cage for structural elucidation (Figure S37). To optimize the selective formation of the ZnII20L8 cage, an anionic template potentially capable of stabilizing the propeller-like configuration of the pentaphenylene pyrrole core of the structure was sought. Δ-TRISPHAT (G), with a complementary configuration, was chosen to stack with and bind to the propeller-like pentapyrrole backbone. The reaction of penta-amine A (12 equiv) and flexible formylbipyridine C (60 equiv) with Zn(NTf2)2 (30 equiv) in the presence of G (18 equiv) resulted in ZnII15L6Zn-3 (Figure 1), which was observed together with 10–13 G anions in HR-ESI-MS (Figure S23), instead of ZnII30L12Zn-2. We infer the structure of Zn-3 to have the same truncated rhombohedral framework as a reported truncated rhombohedron with CoII centers. Tetrabutylammonium G could not be removed even by washing with diethyl ether three times, highlighting the strong interactions between host and guest, which might lead to the cage transformation as discussed below. This truncated rhombohedral structure possesses eight triangular windows and three edge window pockets, where two pentagonal faces share the same edge. These 11 binding pockets may bind 11 G anions, consistent with our ESI-MS results. The interactions between Zn-3 and G were inferred to drive the transformation from Zn-2 to Zn-3 and to stabilize the otherwise disfavored Zn-3 (Figure 1). We hypothesized that the interactions between enantiopure G and Zn-3 might transfer stereochemical information so as to produce Zn-3 stereoselectively, considering that the average dihedral angle φ between pentagonal faces along a common edge of Zn-3 was ca. 82°, comparable to the dihedral angle of ∼88° between two tetrachlorocatecholate groups of G (Figure S24). Circular dichroism (CD) was employed to study this induction process. The CD spectrum of Zn-3 displayed clear Cotton effects around 250–450 nm from ligand π–π* transitions, indicating chiral induction of the Zn-3 framework by G (Figure S25). Due to the lack of metal-to-ligand charge transfer (MLCT) transitions, the handedness of ZnII centers could not be assigned in solution state by CD spectroscopy. The stereochemistry of pairs of ZnII centers that bound G in Zn-3 was inferred to possess Δ handedness according to the crystal structures of Co-3 and Zn-4, with the same type of window pockets that also bound G tightly (see below). G thus acted as a template not only to stabilize the otherwise disfavored Zn-3 framework but also to control the enantioselectivity of the self-assembly process. When Co(NTf2)2 was used instead of Zn(NTf2)2 under otherwise identical conditions to those used to produce Zn-3, truncated rhombohedral CoII15L6 cage Co-3 was obtained, as confirmed by HR-ESI-MS (Figure S28). CD spectra (Figure S25) revealed similar Cotton effects to those observed in the case of Zn-3, suggesting chiral induction also occurred in this case. Although numerous attempts to obtain the crystal structure of Zn-3 invariably led to its transformation to a new ZnII20L8 cage, Zn-4 (see below), we were able to grow crystals of Co-3 suitable for single-crystal X-ray diffraction. X-ray crystallographic analysis confirmed the formation of the truncated rhombohedral cage Co-3 (Figure 3, M5nL2n series, n = 3). Co-3 crystallized in the chiral P3121 space group, with one and a half whole cage units in the asymmetric unit. Three out of 11 G anions bound at the pores where pentagonal faces share edges. The driving forces for this binding were inferred to be arene stacking between phenylene rings from different ligand arms and the tetrachlorocatecholate rings of G, as well as electrostatic interactions between anionic G and cationic CoII centers (Figure 3a). All CoII centers were bound by two tridentate ligand arms, with three out of the 15 CoII centers adopting opposite Λ handedness, resulting in different CoII···CoII distances (Figure 3b). Having identified the interactions between Co-3 and chiral G, we then sought to use G to influence the stereochemistry of Zn-2 for structural determination. Vapor diffusion of toluene into a CH3CN solution of Zn-2 in the presence of G, however, led to the formation of the new ZnII20L8 cage Zn-4 (M5nL2n series, n = 4) instead of Zn-2 (Figure 4a). We inferred this transformation to be driven both entropically, by the formation of a smaller assembly, and enthalpically, through the formation of multiple interactions between host and guest, as discussed below. Zn-4 crystallized in the chiral I422 space group with one-eighth of a cage in the asymmetric unit. The four equatorial ZnII centers of Zn-4 have the same Λ handedness, and the other 16 adopt the opposite Δ handedness (Figure 4c). Two distinct ZnII···ZnII distances between ZnII centers with opposite handedness around the equatorial plane, 13.63 and 17.41 Å, were observed (Figure 4a), where a pentatopic ligand bridges pairs of zinc ions, and the ZnII···ZnII distance where two tridentate ligand coordination vectors point away from each other is longer than the case where the vectors point toward each other (Figure S45). This opposing conformation of one out of the five ligand arms results in opposite handedness of the bound ZnII center, which we inferred to result in a reduction of strain within this irregular structure. Aromatic stacking and electrostatic interactions between G and Zn-4 (Figure 4b) were inferred to induce the structural transformation of Zn-2 into Zn-4. Multiple CH···Cl and CH···O interactions between host and guest, observed in the crystal structure (Figure S46), may also contribute to the stability of Zn-4. The structure of Zn-4 thus consists of two 4-sided windows in the axial direction, four 4-sided windows at the equatorial plane, and eight pentagonal faces capped by ligands. It has an unprecedented pseudo-truncated octahedral architecture with approximate D4 symmetry (Figure 4c,d), distinct from a regular truncated octahedron, an Archimedean solid with Oh symmetry. The replacement of toluene with benzene also yielded single crystals of Zn-4, which crystallized in the chiral I222 space group, with a quarter of a cage in the asymmetric unit. The distorted pseudo-truncated octahedral framework of this conformation of Zn-4 has the same connectivity, but approximate D2 symmetry (Figure S44), with two rhomboid instead of square windows on the top and bottom. Two other distinct truncated octahedral forms of Zn-4 were also characterized through X-ray crystallography. These crystallized in the F222 and P4322 space groups and were obtained by using tetrahydrofuran (THF) and diethyl ether as antisolvents, respectively. The four different solid-state structures of Zn-4 reflect the ability to adapt its configurations in response to the environment, due to its inherent structural flexibility (Figure S44). The different structures of Zn-4 are discussed in Section 6 of the Supporting Information. The existence of Zn-4, as an isomer of the ZnII20L8 cage predicted by graph theory, can be understood by extending the M5nL2n structure series with 3-sided windows to 4-sided windows (Figure S2). We further tried to extend the M5nL2n structure series to include architectures with 5-sided windows; however, no integer solution was obtained in this case. We then continued to use a combination of 4-sided and 5-sided faces as windows, i.e., the extension of pseudo-truncated octahedron Zn-4 by replacing the top and bottom 4-sided windows with 5-sided pentagonal windows. This modification led to an M25L10 truncated pentagonal bipyramid architecture (Figure S3). We infer that the minor species previously observed in the ESI-MS of icosidodecahedron Co-2 may correspond to such a structure. To characterize Zn-4 in solution, a mass spectrum was measured immediately after dissolving crystalline samples in CH3CN (Figure S38). Species corresponding to G8⊂Zn-4 in a succession of charge states were found, consistent with the crystal structure, where eight G anions bound in the window pockets. Notably, we also found signals corresponding to truncated rhombohedron Zn-3, indicating that Zn-4 transformed into Zn-3 upon dissolution. We infer that in solution the strong packing effects of the eight G holding the pseudo-truncated octahedral architecture together in the solid state will be weakened considerably, leading to partial transformation into the truncated rhombohedron Zn-3 in solution. Upon dissolution, Zn-4 thus converted to the more thermodynamically stable product Zn-3 as the strength of the packing effects mediated by G became less pronounced. The metastability of Zn-4 thus precluded SAXS measurements. This reversible chiral-guest-induced structural transformation upon crystallization encouraged us to explore the sequential transformation among the series of M5nL2n and M5nL3n cages, using different stimuli. A hierarchical network of transformations was thus developed, as shown in Figure 5. The network of Figure 5 charts the ways in which different structures may emerge upon the application of sets of different signals. Starting from penta-amine A, aldehyde B, and ZnII ions, dodecahedron Zn-1 with pentakis(bidentate) ligands (State 1, ZnII20L12, n = 4) formed upon application of Signal I, which is heating to 80 °C. Further application of this Signal I together with Signal II, which is aldehyde C and ZnII ions, to Zn-1 (State 1) resulted in formation of product Zn-2 (State 2). Upon the application of Signal IV, i.e., anion G, Zn-2 (State 2) transformed into truncated rhombohedron Zn-3 (State 3, ZnII15L6, n = 3) in solution. Both Zn-2 (State 2) and Zn-3 (State 3) transformed into the pseudo-truncated octahedral topology of Zn-4 (State 4, ZnII20L8, n = 4) upon crystallization, with State 2 requiring Signal IV as well to attain State 4. Alternatively, starting from penta-amine A, aldehyde C, and ZnII ions (State 0′), the application of Signal III, a temperature of 35 °C, resulted in the formation of ZnII5L2 sandwich structure Zn-5 (State 1′, Figures S29–S36). This metastable State 1′ converted into State 2 upon application of Signal I. The application of Signal I and Signal IV to State 0′ provided an alternative path to State 3, whereby heating and templation transformed Zn-5 into Zn-3. Starting from State 0 or 0′, five different pathways may be traced through the network to State 4, involving the different transitional States 1–3. Figure 5 thus represents a kind of logic diagram, showing how different physical inputs are translated into chemical structure outputs. This transformation network could show the way toward the construction of systems that are capable of more complex guest uptake and release through signal-driven structural transformations. By exploiting the flexible coordination sphere of zinc(II) and the differing coordination preferences of multitopic and multidentate ligands, a transformation network between five complex metal–organic structures, with M5nL2n or M5nL3n formulas, was thus designed. Such transformations rely on the dynamic nature of subcomponent self-assembly, which allows disassembly and reassembly depending on the overall thermodynamic stability of the system. Peripheral guest binding to shape the structure of the metal–organic cages parallels allosteric interactions and control seen in enzymes, where the active site conformation is modified by distant binding. The network reported here in this work sets the stage for future work focusing on tailoring cage cavities for precise control of guest uptake and release.