Abstract
Despite having significant applications in the construction of controlled delivery systems with high anti-interference capability, to our knowledge dual-controlled molecular release has not yet been achieved based on small molecular/supramolecular entities. Herein, we report a dual-controlled release system based on coordination cages, for which releasing the guest from the cage demands synchronously altering the coordinative metal cations and the solvent. The cages, Hg5L2 and Ag5L2, are constructed via coordination-driven self-assembly of a corannulene-based ligand. While Hg5L2 shows a solvent-independent guest encapsulation in all the studied solvents, Ag5L2 is able to encapsulate the guests in only some of the solvents, such as acetone-d6, but will liberate the encapsulated guests in 1,1,2,2-tetrachloroethane-d2. Hg5L2 and Ag5L2 are interconvertible. Thus, the release of guests from Hg5L2 in acetone-d6 can be achieved, but requires two separate operations, including metal substitutions and a change of the solvent. Dual-controlled systems as such could be useful in complicated molecular release process to avoid those undesired stimulus-responses.
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Introduction
Capabilities regarding the controlled release of chemical substances are crucial for many applications, including drug delivery1, gene transfection carriers2, controllable catalysis3, and stimuli-responsive functional materials4. In the past decades, various entities, from the macroscopic capsules5 to polymers6 and molecular assemblies7,8, have been designed as carriers for controlled releasing drugs or chemicals. Recently, attention has been devoted to the systems with complicated release functions9.
Supramolecular cages possess a rigid and isolated (fully or partially) three-dimensional inner space10,11. Though such a structural characteristic is greatly beneficial for molecular encapsulation and provides the cages special potentials in reactive intermediate storages12,13, catalysis14, purification15,16, etc., it gives, on the other hand, the controlled release of the encapsulated guests when required being quite challenging. Nonetheless, substantial progress has still been made. A widely used approach in this regard is the disassembly of the cage architectures17,18,19,20,21,22,23,24,25,26. Besides, competitive molecules (including solvents) were also used for expelling the guests included27,28,29,30,31. Other rational designs include denaturing the cages/guests for a significant decrease of the host–guest affinities by various stimuli, such as light32,33,34,35,36, metal-coordinations37,38, electrolyte39, transmetallation40, redox41,42,43, reactions44,45 and changes in pH46,47,48 or temperatures43,49,50. Despite these elegant studies demonstrated a high efficiency in release of guests, the releases themselves typically respond to only a single stimulus, leaving cage systems that can realize precisely controlled release in complicated situations unexplored to a large extent.
Dual control is a regulation that requires at least two separate control strategies operating in concert to perform a task (Fig. 1a). Dual control process has been widely used in high-risk areas of bank transaction51 and mechanical engineering52,53 to protect information or sensitive functions. In biology, it is adopted to generate a single, integrated response while information from several different sources is received simultaneously54,55. Theoretically, employment of such a dual-modality in controlled release would eliminate the uniqueness of the relevance of the release to a certain stimulus, reducing the correlation between the release and other functions relating to the particular stimulus, thus helping to construct anti-interference guest-release systems that are crucial for many applications of such systems in the future, including the drug delivery, gene transfection carriers and controllable catalysis. To date, a few dual-controlled systems have been constructed based on polymers/biopolymers56,57 and mesoporous nanoparticles58,59,60 for liberating drugs and chemicals61,62. Nevertheless, establishing such a function based on small molecular/supramolecular entities remains an unmet challenge.
Herein, we present, to the best of our knowledge, the first example of a dual-controlled guest release system based on coordination cages, using 1,3,5,7,9-penta(2,2’-bipyridin-5-yl)corannulene (1) as the ligand (Fig. 1b). We show that the complexation of 1 with Hg(II) and Ag(I) cations can produce two kinds of well-defined cage complexes, Hg5L2 and Ag5L2. Whereas the Hg5L2 cages show a solvent-independent guest encapsulation in the studied cases, the guest encapsulation and release from Ag5L2 are controlled by the solvents. These two kinds of cages are interconvertible through transmetallation, thus giving the guest release from Hg5L2 to be dually regulated by the metal cations and the solvents (Fig. 1c), while the liberation from Ag5L2 ones is solvent-gated only. Dual-controlled systems, as such, may find applications in complicated cargo release process63.
Results and discussion
Design and synthesis
Different from those cage systems undergoing significant structural and geometric changes upon stimuli64, the ones we attempted to obtain are supposed to change moderately in the cavity shape and volume upon the changes of complexed metal ions. Such features would allow the cages to alter their host capabilities moderately while concurrently maintaining the overall binging inclinations, thus facilitating fine-tuning of their guest-binding behaviors. In this regard, we were drawn to the molecular cages constructed by coordination-driven self-assembly with two high-symmetry building blocks65. Within such kind of cages, the metal components are limited in number and therefore function more like a simple linker rather than an important assembly organizer (as that in cages assembled from many small chelating ligands66). As a result, changing the coordinated metal cations would give rise to moderate changes in the size, shape, and other properties of the capsular inner space.
Corannulene is an excellent building block for constructing molecular cages due to the C5v symmetry in its structure and the high reactivity67. In particular, corannulene possesses a curved π-surface and a dynamic, switchable molecular chirality in solution68, which can provide theoretically the corresponding cages a lot of intriguing properties that are in sharp contrast to those assembled via planar π-conjugated systems67,69. Nevertheless, the properties of corannulene-based molecular cages, including those in the aspect of host–guest interactions, had not been examined for quite a long time. We recently reported the first example of corannulene-based molecular cage70,71, constructed by coordination-driven self-assembly of 1,3,5,7,9-penta(pyridyl-3-yl)corannulene ligands and Ag+ cations. However, this cage is not suitable for the present purpose because the involved linear bidentate coordination is, to some extent, unfavorable to the modulation of the inner cavity due to the lack of diversity in the coordination pattern. We, therefore, envisioned substituting 2,2’-bipyridin-5-yl (bpy) groups for the pyridyl-3-yl ones on the ligand. Given the presence of various coordination geometries for metal cations with coordination numbers four or six, we expected that, by deliberate choice of metal species, overall the size/shape of the inner cavity could be tuned, thus providing an effective strategy towards controlling guest encapsulations. An iso-butoxy side chain was introduced on the tail of each bpy unit for enhanced solubility.
Our synthetic approach to the bpy ligand is outlined in Fig. 2. Initially, O-alkylation of 2-bromo-5-iso-butoxypyridine (2) with alkyl iodide provided 3. Treatment of 3 with n-BuLi and ZnCl2 generated the organozinc in situ, which then underwent Negishi cross-coupling reaction to give 4. Finally, the Suzuki coupling of 4 with 1,3,5,7,9-pentakis(Bpin)corannulene (5) provided the target ligand 1 (Supplementary Methods 1 and 2; Supplementary Data). The structure of 1 was confirmed by nuclear magnetic resonance (NMR) and high-resolution mass spectra. (see Supplementary Figs. 14−17 and 30 in the Supplementary Information (SI)).
Metal complexation and the formation of Ag5L2 and Hg5L2 cages
To explore the feasibility of access to the desired cages and to expand the pool of suitable metal cations, several kinds of metal ions with the potential to coordinate bpy to form four- or six-coordinate complexes72, including Ag+, Hg2+, Fe3+, Cu+, Mg2+, Ni2+, and Zn2+ ions, were first preliminarily screened. Mixing 1 with Fe(OTf)3, Ni(ClO4)2, Zn(OTf)2 or Zn(ClO4)2 at the ratio of 2:5 (mol/mol) in common solvents or solvents mixture gave no or extremely broad signals in the 1H NMR spectra, even after the samples were heated at elevated temperature (Supplementary Fig. S1). When the ligand was combined with Mg(OTf)2, no obvious changes were observed, indicative of the absence of coordination. With AgOTf, Hg(OTf)2 or Cu(CH3CN)4PF6 as the salt, in the solvent mixture of CD3CN/CDCl3, the 1H NMR spectrum showed a new set of intense signals (Supplementary Figs. 1 and 2), suggestive of a promising formation of well-defined cage complexes. However, the Cu+ cages tend to decompose under ambient conditions, as evidenced by the disappearance of its 1H NMR signals in three hours. The Ag+ and Hg2+ complexes are stable enough in solutions; we thus mainly focused on these two cations in the following studies.
It is noteworthy that while both Ag+ and Hg2+ cations possess the ability to form complexes of several different coordination numbers, they have a flexible coordinating sphere, thus having weak coordination geometry preferences and being able to tolerate, to some extent, the distortion from the ideal geometries73,74, which may contribute to the formation of stable molecular cages in the studied cases. Besides, Ag+ and Hg2+ complexes favor associative ligand exchanges. This character would promote the interconversion between different structures/configurations (if they exist) and greatly help the complexes to rapidly reach the most favourite ones.
Theoretically, the inherent chirality of corannulene causes the existence of four different stereo configurations (P,M,P/M,P,M and P,P,P/M,M,M)70 for the desired Ag+ and Hg2+ cages. In addition, due to the long bpy substituents as well as the possible bowl-to-bowl inversion of the corannulene moieties, the cages, on the whole, may adopt a clam-shell-like, biconvex structure, or a sunken, biconcave-lens-like geometry75. Therefore, totally eight stereoisomers (containing four pairs of enantiomers) are imaginable for each cage, including biconvex-P,M,P/M,P,M and biconvex-P,P,P/M,M,M as well as biconcave-P,M,P/M,P,M and biconcave-P,P,P/M,M,M. For better understanding of the relationships between different isomers, density functional theory (DFT) (B3LYP-D3(BJ)//LANL2DZ/6-31 G(d)) calculations76 were carried out. Careful examinations revealed the possible existence of three pairs of enantiomers for the isolated [Ag512]5+ cage, including biconvex-P,M,P/M,P,M, biconvex-P,P,P/M,M,M and biconcave-P,M,P/M,P,M; for [Hg512]10+, two pairs are obtained as minima, including biconvex-P,M,P/M,P,M and biconcave-P,M,P/M,P,M (Fig. 3, Supplementary Method 15 and Supplementary Tables 15–17, SI). The other stereoisomers do not represent any minima (local or global) on the corresponding potential energy surface. For examples, optimizations starting from biconcave-(P,P,P/M,M,M)-[Ag512]5+ and biconvex-(P,P,P/M,M,M)-[Hg512]10+ will give rapidly the geometries of biconvex-(M,P,M/P,M,P)-[Ag512]5+ and biconcave-(M,P,M/P,M,P)-[Hg512]10+, respectively.
The energy-minimized structures of all the obtained stereoisomers of [Ag512]5+ and [Hg512]10+ possess a helical, D5-symmetric geometry. Notably, the biconcave configuration is, to some extent, conducive to releasing the strain associated with the metal complexations. In energy, biconvex-[(P,M,P/M,P,M)-Ag512]5+ lies in ca. 14 kcal mol−1 lower than that of biconvex-[(P,P,P/M,M,M)-Ag512]5+, but is ca. 9 kcal mol−1 higher than that of biconcave-[(P,M,P/M,P,M)-Ag512]5+ (Fig. 3a). Similarly, for [Hg512]10+, the energy level of the biconvex-P,M,P/M,P,M conformers is ca. 9 kcal mol−1 higher than the biconcave-P,M,P/M,P,M ones (Fig. 3b). By the same token, biconvex-[(P,M,P/M,P,M)-Hg512]10+ is more flat (6.9 Å in height, Supplementary Table 15), compared to biconvex-[(P,M,P/M,P,M)-Ag512]5+ (height = 9.1 Å).
To further confirm the formation of the cages, more experiments were carried out. 1H NMR titration of Ag(OTf) to 1 in 5:95 (v/v) CD3CN/CDCl3 clearly showed that, upon the addition of Ag+ cations, the signals of ligands gradually became weaker, and a new set of signals corresponding to the cages appeared (Fig. 4a and Supplementary Figs. 3 and 18, 19, SI). Based on the results of DFT calculations, it is reasonable to assign this new set of signals to the racemic [biconcave-(P,M,P)/(M,P,M)-Ag512]·[OTf]5. The complexation induced significant upfield shifts of the protons, which are supposed to be located in the inner cavity, such as Ha, Hb, and Hg, as ascribed to the strong shielding of the cage (Fig. 4a). In particular, as an important indicator for the formation of cages, the methylene protons Hi on the isobutyl side chains split into two sets upon complexation, which results from the inequivalence between the proton directed inward and outward of the cage70. Additional evidence for the formation of cage complexes was also provided by the electrospray ionization—high-resolution mass spectrometry (ESI-HRMS) spectrum (Supplementary Fig. 31 and Supplementary Table 5), in which a series of prominent signals assignable to [Agm12·(OTf)n]m–n (m ≤ 5) can be clearly observed. 2D diffusion ordered spectroscopy (DOSY) spectrum indicated the formation of a single product with a diffusion coefficient of D = (1.42 ± 0.01) × 10−10 m2 s−1, which is much smaller than that of the ligand in the same solvent (D = (3.76 ± 0.05) × 10−10 m2 s−1) (Supplementary Method 7, Supplementary Figs. 24−27 and Supplementary Table 4).
Except 5:95 (v/v) CD3CN/CDCl3 (dielectric constant, ε ≈ 6.4), other three kinds of solvents, including acetone-d6 (ε = 21), CD3CN (ε = 37), and 1,1,2,2-tetrachloroethane-d2 (CDCl2CDCl2, ε = 8.5) were also investigated. The Ag5L2 cages exhibited well-resolved 1H NMR spectra in acetone-d6 and CDCl2CDCl2 (Fig. 4b and Supplementary Fig. 4d); nevertheless, in CD3CN, broadened, overlapped signals were observed, which is probably due to the aggregation of the cages in this solvent (Supplementary Fig. 4a).
For the construction of the Hg2+ cages, initially, we found that the titration of Hg(OTf)2 to 1 gave very messy spectra. Nevertheless, adding 2.5 equiv. of the Hg2+ cations in a whole produced a distinct new set of signals, which can be assigned to biconcave-[(P,M,P/M,P,M)-Hg512]·[OTf]10 according to the results of DTF calculations, in all the cases of 5:95 (v/v) CD3CN/CDCl3, CD3CN, acetone-d6, and CDCl2CDCl2 (Fig. 4 and Supplementary Figs. 53 and 54). The formations of the Hg2+ cage are well confirmed by the split of Hi signal in the 1H NMR spectra as well as the corresponding HRMS (Supplementary Fig. 93 and Supplementary Table 12) and 2D NMR spectra (Supplementary Figs. 83–86 and 91).
Solvent-dependent guest encapsulation and release from Ag5L2
Since no valuable results can be obtained from our isothermal titration calorimetry (ITC) experiments, the binding behaviour of the cages was investigated by 1H NMR spectroscopy at 298 K. Considering the concave surface of corannulene, three kinds of molecules, including pseudo-spherical adamantane (Ad) and two of its derivatives, namely, 1-adamantanemethanol (Ad-MeOH) and 1-adamantanecarboxylic acid (Ad-COOH), was chosen as the guests in the studies.
The guests competed successfully (but laboriously) for the inner space of Ag5L2 with the solvent molecules in 5:95 (v/v) CD3CN/CDCl3. For example, titration of Ad to Ag5L2 produced an obvious attenuation of the signals of the cages and, meanwhile, the appearance and gradual enhancement of a new set of signals corresponding to the stable host–guest complexes (Supplementary Method 4 and Supplementary Fig. 5). A 1:1 encapsulation is strongly suggested by the ESI-HRMS of the cage-guest complexes (Supplementary Fig. 32 and Supplementary Table 5); and the DTF calculations showed that the cage can accommodate only one guest molecule as well (Fig. 3a and Supplementary Table 16). 1H NMR titration of Ad-MeOH or Ad-COOH gave very similar results (Supplementary Figs. 6, 7, 33, 34 and Supplementary Table 5). Notably, the DFT calculations predicted Ad⊂[biconvex-(P,M,P)/(M,P,M)-Ag5L2]5+ complexes of 15 kcal mol−1 lower in energy in the gas phase (Fig. 3a), compared to that of Ad⊂[biconvex-(P,P,P)/(M,M,M)-Ag5L2]5+ ones, and a cage collapse for biconcave-[(P,M,P/M,P,M)-Ag512]5+ with Ad included due to their too small cavities, such that the cages might adopt biconvex-P,M,P/M,P,M conformations upon the guest complexations.
In acetone-d6, addition of the studied guests to Ag5L2 resulted in also the guest inclusions as observed in the 1H NMR spectra (Fig. 5b, Supplementary Method 5 and Supplementary Figs. 8−10). The signals of the host–guest complexes are pretty dispersed, thus being assignable, providing a good chance to explore the encapsulation behaviors. A closer examination of the 1H NMR spectra indicated that the complexation induced obvious changes in chemical shift for the protons that are supposed to be located in the inner cavity, i.e., Ha and Hb, which is due to the σ−π interaction between the encapsulated guest and the host. The encapsulated guests experience a highly shielded nano-environment, thus showing one set of signals in the range of (–1.5–(–2.0)) ppm) (Fig. 5b). The encapsulation was unambiguously verified further by the 2D NOESY spectrum, which exhibited strong correlations between the protons of Ad and Ha/Hc of the cages (Supplementary Figs. 20–23). Interestingly, in the 1H NMR spectra, the protons that are supposed to stay far from the encapsulated molecules, including He, Hf and Hg, also shifted to some extent, which is probably caused by a slight deformation of the cage upon guest encapsulations. In fact, the encapsulation-induced expansion was supported by the DFT calculations, which predicted a height of 10.0 Å for the energy-minimized structure of Ad⊂biconvex-[(P,M,P)/(M,P,M)-Ag5L2]5+ (Supplementary Tables 15, 16), a little larger than that of the free cages (ca. 9.1 Å).
Ag5L2 includes the studied guests in CD3CN as well. This is indicated by the appearance of a set of well-resolved signals in the 1H NMR titration experiments, despite the cage itself cannot show distinct signals in such a solvent (Fig. 5biii–iv, Supplementary Method 6 and Supplementary Figs. 11–13). In addition, the DOSY spectrum showed all signals from Ag5L2 and Ad diffusing at the same rate (Fig. 5bv and Supplementary Figs. 28, 29).
Though the 1H NMR signals of the cage-guest complexes in 5:95 (v/v) CD3CN/CDCl3 are not assignable due to the weak host–guest association (giving the coexist of Ad⊂Ag5L2 and Ag5L2) and the aggregation of the signals themselves, the molar ratio (χ) of Ad⊂Ag5L2 against Ag5L2 can still be derived from the integrations of the signals corresponding to the free cage and the cage-guest complex (Supplementary Methods 4 and Supplementary Table 1), which provided further the association constant (Ka) of 23.4 ± 3.2 M–1, 21.7 ± 1.6 M–1 and 23.1 ± 6.5 M–1 for Ad, Ad-MeOH, and Ad-COOH, respectively (Table 1). The association constants in acetone-d6 and CD3CN can be determined in a similar manner (Supplementary Methods 5, 6 and Supplementary Tables 2, 3). Besides, compared to the case of 5:95 (v/v) CD3CN/CDCl3, the cage has ~3 orders of magnitude greater affinity for each guest in acetone-d6, and it is enhanced further when changing the solvent to CD3CN (Table 1). Nevertheless, in each particular solvent, the association constant is close to one other for different guests, as a comprehensive result of the interactions between the guests and the coordination cages as well as the solvents. Notably, overall, the guest-binding affinities are higher in more polar solvents. This could be first ascribed to a weaker competition from the solvent molecules for the guests with respect to host binding. Besides, in the cases of Ad-COOH and Ad-OH, looser ion-pairs between [Ag512]5+ and the counter anions (OTf‒) present in such situations, which is greatly conducive to the electrostatic interactions between the constituent metal cations and the included guests.
In contrast to those in the solvents mentioned above, Ag5L2 showed much different binding behavior in CDCl2CDCl2. In such a solvent, addition of the studied guests to Ag5L2 gave no changes in the 1H NMR spectrum. Moreover, when the samples of guest⊂Ag5L2 complexes prepared in CD3CN were dried under vacuum and then re-dissolved in CDCl2CDCl2, with increasing the standing time, at room temperature, the 1H NMR signals of the cage-guest complexes became (fast or gradually) weaker, along with the appearance of a new set of signals corresponding to the free cages, indicating that the encapsulated guests were expelled by the solvent molecules in such cases. The release processes were then monitored by 1H NMR spectroscopy at various temperatures, in which the range of temperature investigated (301−208 K, 292−279 K, and 288−274 K for Ad, Ad-MeOH and Ad-COOH, respectively) was carefully chosen to give the changes measurable at reasonable time scales (Supplementary Method 8 and Supplementary Figs. 35−52). First-order rate constants, k, for the release, were obtained by monitoring the decay of the signals of the cage-guest complexes and the thriving of the free cages (Supplementary Tables 8–10). Using the rate constants obtained, the enthalpic (ΔH⧧) and entropic (ΔS⧧) contributions to the transition state were calculated from Eyring plots (Supplementary Table 6). Other kinetic parameters at 298 K were next calculated using a linear extrapolation method (Supplementary Table 7)77.
The results show that the release rates in CDCl2CDCl2 follow the order of Ad-MeOH > Ad > Ad-COOH, but are basically of the same order of magnitude (Table 1). In all cases, the formation of activated complexes (the transition state) is an exothermic process (Supplementary Table 7). In the transition states, the inner cavity of the cage should be crowded with the studied guest and solvent molecules. The cage therefore needs energy to adjust itself to overcome the steric hindrance of the molecules inside. Compared to the other two kinds of guests, passing through the transition state in the case of Ad-COOH is less enthalpically but more entropically favored. This is probably due to the self-association of Ad-COOH in CDCl2CDCl2, which is a process associated with exotherm and an entropic reduction.
Solvent-independent guest encapsulation in Hg5L2
With the data indicative of a solvent-controlled guest binding and release from cage Ag5L2 in hand, we next set out to study the binding behaviors of Hg5L2. Considering that the DFT calculations predicted a smaller height for the cavity of biconvex-[(P,M,P/M,P,M)-Hg512]10+ compared to biconvex-[(P,M,P/M,P,M)-Ag512]5+, we expected that the Hg2+ cage could bind the studied guests in a different manner.
DFT calculations provide a predictive insight into the encapsulation in Hg5L2, which showed that the inner cavity of biconcave-P,M,P/M,P,M are too small to accommodate Ad (inclusion of the guest will give a disassembly of the cage) so that only Ad⊂biconvex-[(P,M,P)/(M,P,M)-Hg512]10+ can be formed (Fig. 3b). The guest encapsulations lead to a larger deformation in the cage structure compared to that in the case of Ag5L2, particularly regarding the expansion of the inner cavity (from 6.9 Å for Hg5L2 to 9.5 Å for Ad ⊂Hg5L2 in height, compared to that from 9.1 Å for Ag5L2 to 10.0 Å for Ad⊂Ag5L2, Supplementary Table 15).
Experimentally, encapsulations of the guests with Hg5L2 are kinetically much harder than those in the cases of Ag5L2 as expected (Supplementary Method 9). In all the studied solvents, directly adding the studied guests to Hg5L2 at ambient temperature gave no changes in the 1H NMR spectra, suggestive of higher encapsulation energy barriers. We thus tried different procedures to achieve the encapsulations.
Overall, the encapsulation barriers in CD3CN and in acetone-d6 is apparently similar to each other. Two procedures (labeled Procedure A and B, Supplementary Method 10) were utilized to prepare the cage-guest complexes in such cases. In Procedure A (from Cages to Cage-guest Complexes), to the ligand in CD3CN (or acetone-d6), 2.5 equiv. of Hg2+ cations and the guests were added in sequence, and the obtained samples were sonicated for 30 min at ambient temperature. In Procedure B (One-Pot Construction), the mixtures of the ligand and the guest in CD3CN (or acetone-d6) were added 2.5 equiv. of Hg2+ cations, followed by a sonication at ambient temperature. Both procedures resulted in the same outcomes. In the 1H NMR spectra, the guest encapsulations gave rise to the disappearance of the cage signals and the presence of the new ones corresponding to the host–guest complexes (Supplementary Figs. 6b, 55–60, 87–90, 92, and 94 and Supplementary Table 13). Particularly, distinct resonances from the encapsulated guests in the inner cavity can be clearly observed in a high-field region of −1.0 ~−3.0 ppm.
In 5:95 (v/v) CD3CN/CDCl3, it is hard to produce the cage-guest complexes by sonicating the mixtures of the cage and the guests, or the mixtures of the ligand, Hg2+ cations and the guests, at ambient temperature. Nevertheless, by heating the mixtures of the cage and the guests at 50 °C for 2–3 days (Procedure C, Supplementary Method 11), the desired encapsulations can still be achieved (Supplementary Fig. 61). Alternatively, the complexes can be first prepared in CD3CN or acetone-d6, followed the replacement of the solvent with 5:95 (v/v) CD3CN/CDCl3 (Procedure D, Solvent-replacement Method, Supplementary Method 11 and Supplementary Figs. 62–64).
With CDCl2CDCl2 as the solvent, the encapsulations are even harder, which cannot be achieved via Procedure C. However, taking Ad as an example, when heating the mixtures of the cage and a large excess of the guest (200 equiv.) at 90 °C for 6 days, the cages underwent a complete transformation to the cage–guest complexes (Procedure E, Fig. 6c, Supplementary Method 12) (Supplementary Fig. 65). The same result can be obtained by heating the mixtures of the ligand, Hg2+ cations and the guests at 90 °C for 3 days (Procedure F, Supplementary Method 12) (Supplementary Figs. 66 and 67). Nevertheless, the simplest way to prepare the cage-guest complexes in such a situation still points to Procedure D, except that the solvent, CD3CN or acetone-d6, was finally replaced by CDCl2CDCl2 after the accomplishment of the guest encapsulations (Supplementary Method 11) (Supplementary Figs. 68−70).
We next assessed the stabilities of the Hg5L2-guest complexes in the studied solvents (or solvent mixture) at room temperature. In the investigations, the Hg5L2-guest complexes were first prepared in acetone-d6 according to Procedure A and then dried. Since a large amount of guest was used in the procedure, to get a clear observation on the possible release of the guests as well as to avoid the possible exchange of the guest molecules between inside and outside of the cage cavity, the free guests in the obtained solid mixtures were next removed completely by solvent-washing using cyclohexane. After the pure cage-guest complexes were re-dissolved in the studied solvents (or solvent mixture), decays of the complexes were monitored at 25 °C by 1H NMR spectroscopy for 2 days, and the stabilities of the complexes were assessed according to whether the signals of the free cages and the free guests reappear in the spectra (Methods, the main text).
The results show that, in all the studied solvents, particularly in the cases of CDCl2CDCl2, no included guest molecules were expelled from the cages (Fig. 6b, c Supplementary Table 11 and Supplementary Figs. 71–82). This is very interesting because such results are unambiguously indicative of a solvent-independent guest encapsulation for the Hg2+ cages in the studied cases (Fig. 6a).
Ag5L2 ⇆ Hg5L2 conversions
Transmetallations have been proven to be an effective way to achieve guest release from cages, as we mentioned above40. Given that the main difference in guest encapsulation between Ag5L2 and Hg5L2 is shown in CDCl2CDCl2, we then set about investigating the possibility of the interconversion of Ag5L2 ⇆ Hg5L2 in CDCl2CDCl2 (Fig. 7a).
The strength of the association between Hg2+ cations and ligand 1 is much larger than that for Ag+ ones. Therefore, the conversion from Ag5L2 to Hg5L2 can be readily achieved by adding the Hg2+ cations to the solution of Ag5L2, as evidenced by the reappearance of Hg5L2 signals in the 1H NMR spectrum (Fig. 7b, Supplementary Method 14 and Supplementary Fig. 97). Comparatively, the conversion from Hg5L2 to Ag5L2 is much more complicated in methodology. Our attempts in this regard were baffled for a long time until we were drawn to the function of EDTA as the competitive chelating agent. EDTA can form very stable complexes with most metal cations. In particular, in water at 25 °C, the stability constant of Hg2+-EDTA (HgEDTA) complexes is ca. 14 orders of magnitude higher than that of Ag+-EDTA (AgEDTA) (logK = 21.6 and 7.2 in the case of Hg2+ and Ag+, respectively)78. We thus tried to use the Ag+ cations in AgEDTA to displace the Hg2+ ones in Hg5L2.
In our experiment, an aqueous solution of AgEDTA was first prepared by mixing Na2EDTA and 1.5 equiv. of AgNO3 in water. The solution was transferred to a vial containing a solution of Hg5L2 in CDCl2CDCl2 and the obtained bilayer mixture was vigorously stirred at 28 °C. To monitor the ion-exchange process, a series of samples taken regularly from the mixture and washed with water was characterized by 1H NMR spectroscopy (Supplementary Method 13). As shown in Fig. 7c and Supplementary Fig. 95, as expected, the metal cation-exchanges occurred on the water-CDCl2CDCl2 interface, giving rise to an immediate disappearance of the signals of Hg5L2 in the organic phase and, finally (ca. 40 min later), the only one set of district signals corresponding to Ag5L2. The exchanges process should be a non-synergistic one: A stepwise ion-exchange is strongly suggested by the loss of C5-symmetry for the cage in the 1H NMR spectrum (can be clearly observed at t = 23 and 27 min, Fig. 7c and Supplementary Fig. 95B); and the intermediates, in which the two types of metal ions (Ag+ and Hg2+) were coordinated to form heterometallic cages, were evidenced by the HR ESI-MS of the sample t = 23 min (Fig. 7d, Supplementary Fig. 96 and Supplementary Table 14), which showed a series of intense peaks assignable to mixed-metal cages with different stoichiometries for the composition of cooridnated Ag+ and Hg2+ cations.
Metal-cation-and-solvent-gated guest release
We finally explored the possibility of the conversion from Hg5L2 to Ag5L2 with the guests included (Fig. 8a). Based on the binding properties of Ag5L2, in CDCl2CDCl2, such conversion means theoretically a complete guest release from the cages after the obtained mixture is stored at room temperature for, at most, a couple of hours (Supplementary Table 6).
Experimentally, the samples of guest⊂Hg5L2 complexes in acetone-d6 were first prepared according to Procedure A. The free guests were removed, and the solvent was changed to CDCl2CDCl2, followed by the same transmetallation procedure (Fig. 8b) as that for the conversion from Hg5L2 to Ag5L2 in the absence of guests. A series of samples were taken regularly from the vigorously stirring mixture of Hg5L2 in CDCl2CDCl2 and aqueous AgEDTA. The organic-phase solutions of these samples were washed with water immediately, followed characterizations via 1H NMR spectroscopy (Methods, the main text).
Basically, two series of spectra were obtained in each case. The first series of spectra (Supplementary Figs. 98, 100, and 102) were recorded soon after the samples were sucked out of the bilayer mixture and washed with water, which was used to detect the species in the organic-phase solution of the stirring bilayer mixture; and another series of spectra (Fig. 8c, Supplementary Figs. 99, 101, and 103) were recorded after these samples were stored further at 28 °C for 4 h (to get fully released for the guests).
The results showed that the cation-exchanges indeed occurred in the vigorously stirring mixture to give guest⊂Ag5L2 complexes. However, we were surprised to observe that it was more difficult to liberate the included guests from Ag5L2 cages in the stirring bilayer mixtures (Supplementary Figs. 98, 100, and 102), compared to those in the cases of guest⊂Ag5L2 in pure CDCl2CDCl2 (Supplementary Table 6 and 7). Taking the case of Ad as an example, strong signals of the included Ad can still be observed in the 1H NMR spectrum even the mixture was stirred for 2 h (Supplementary Fig. 98A). This is probably due to the presence of HgEDTA in the systems, binding exohedrally to the silver cages thus hindering the release of the guests. Nevertheless, for the samples those were washed with water (HgEDTA removed) and then stored for 4 h, no signals of the included Ad were observable, as long as the mixture of Ad⊂Hg5L2/AgEDTA was stirred at 28 °C for no <5 min (t = 5–120 min, Fig. 8c and Supplementary Fig. 99), indicative of a complete Ad release from the silver cages in these cases. Notably, it seems that Ad can even be released from some heterometallic cages, given that, at t = 5 or 10 min, the Hg2+ cations in the cages have not been completely replaced by the Ag+ ones (Fig. 8c and Supplementary Fig. 99). Similar phenomena were also observed in the cases of Ad-MeOH and Ad-COOH (Supplementary Figs. 101 and 103). All these demonstrate that the release of the guests from Hg5L2 can be synergistically controlled by metal cations and solvents.
Conclusion
In summary, we have demonstrated the synthesis, characterization and host–guest chemistry of two 1,3,5,7,9-penta(2,2’-bipyridin-5-yl)corannulene-based coordination cages, Hg5L2 and Ag5L2. Host–guest studies with the cages and three adamantane-based guests (Ad, MeOH and Ad-COOH) revealed that, while the former can encapsulate the guest molecules to form stable host–guest complexes in all four kinds of solvents (or solvent mixture), including acetone-d6, CD3CN, 5:95 (v/v) CD3CN/CDCl3 and CDCl2CDCl2, the latter shows a guest encapsulation capability in three kinds of the solvents and a guest-release behavior in CDCl2CDCl2. The two kinds of coordination cages are interconvertible. Therefore, to release the included guests from Hg5L2 in some solvents, such as acetone-d6, both the solvent and the metal cations have to be changed. This thus, in fact, represents a dual-controlled guest release system, performing the task only if there are the right metal cations and, at the same time, the right solvent. Such kind of anti-interference release systems may cooperate with a single-controlled guest release system, such as Ag5L2 in the studied case, to find applications in programmable synthesis, in which different reactants or catalysts are sequentially released under rational stimuli.
Methods
Stability studies on guest⊂Hg5L2 complexes in solutions
Three kinds of complexes, including Ad⊂[Hg512]·[OTf]10, Ad-MeOH⊂[Hg512]·[OTf]10, and Ad-COOH⊂[Hg512]·[OTf]10, and four different solvent systems, including (i) CD3CN, (ii) acetone-d6, (iii) 95:5 (v/v) CDCl3/CD3CN and (iv) CDCl2CDCl2, were investigated. The complexes in CD3CN and in acetone-d6 were prepared according to Procedure A (Supplementary Method 10), and those in 95:5 (v/v) CDCl3/CD3CN and in CDCl2CDCl2 were constructed via Procedure D (Supplementary Method 11). Since, in all the cases, the Hg5L2-guest complexes were prepared using much excess amount of guest compared to that of the cage, to get a clearer observation on the possible release of the guest from the cage as well as to avoid the possible change of the guest molecules between inside and outside of the cage cavity, after the cage-guest complexes were constructed, the free guest in the obtained mixture was first removed by solvent-washing. Then, decays of the complexes were monitored. Typical procedures for the construction of Hg5L2-guest complexes, the free-guest elimination and the stability studies are as follows.
(a) Construction of Hg5L2-guest complexes and free-guest elimination. To a sample of ligand 1 (2 mM, 0.5 mL) in acetone-d6, Hg(OTf)2 (200 mM, acetone-d6) was added to give a 1 mM Hg5L2 cage solution. To this solution, 8 equivalents of guest (50 mM, acetone-d6) was added. The mixture was sonicated at ambient temperature for 30 min, then evacuated under reduced pressure to dryness. The residue was re-dissolved in cyclohexane (4 ml) to give a turbid mixture. This mixture was sonicated at ambient temperature for 10 min and centrifuged, then the top homogenous solution was removed with a pipet. The solvent-washing procedure was repeated for total 5 times. Finally, the obtained solid was evacuated under high vacuum, and then re-dissolved into one of the studied solvents (or solvent mixture). 1H NMR spectra of the solids showed that all the free-guests were removed, as evidenced by the disappearance of the free-guest signals which typically showed at δ = 1.4 − 2.0 ppm (Supplementary Figs. 71A−79B and 80−82).
(b) Stability studies. The stability of the cage-guest complexes in different solvents (acetone-d6, CD3CN, 5:95(v/v) CD3CN/CDCl3 or CDCl2CDCl2) was measured by 1H NMR spectroscopy. Decays of the complexes can be assessed according to the ratio (based on signal integrals) of the cage-guest complexes to the free cages or guests that reappeared in the spectra. The complexes in the solution were monitored for two days. The obtained spectra are shown in Supplementary Figs. 71A−79B and 80−82, which shown that no guest molecules released from the cage cavity in all the cases. The results can be expressed as shown in Supplementary Table 11.
Guest⊂Hg5L2→guest + Ag5L2 conversion
To ligand 1 (1 equiv), the guest (4 equiv), and Hg(OTf)2 (2.5 equiv) in a vial, solvent acetone was added, and the mixture was sonicated at ambient temperature for 30 min. The obtained solution was checked by 1H NMR spectroscopy at the end of the sonication to make sure that the host–guest complexes had completely formed. The solution was next transferred to a centrifuge tube, evacuated under reduced pressure to dryness. The solid residue was washed with cyclohexane (HPLC Grade). After the free guest has been confirmed to be completely removed by 1H NMR spectroscopy, the host–guest complexes were further dried under high-vacuum and then re-dissolved in CDCl2CDCl2 (4 ml) to give a 1 mM solution. The solution was transferred to a vial (I.D. 25 mm, 10 ml) with a magnetic stir bar (olive shape, diameter 9 mm, length 15 mm). To this solution, an aqueous solution of (1:1.5, equiv/equiv) Na2EDTA/AgNO3 (50 mM, 4 ml) was added. The mixture was vigorously stirred (950 rpm) at 28 °C. Samples were taken regularly from the mixture, and washed immediately with brine (×3) and pure water (×2), followed by drying with sodium sulfate. The series of samples were characterized by 1H NMR spectroscopy after been diluted twofold with CDCl2CDCl2.
Basically, two series of spectra were obtained for each case. The first series of spectra (Supplementary Figs. 98A, B, 100A, B and 102A, B) were recorded soon after the samples were sucked out of the bilayer mixture and washed with water, which was used to detect the species in the organic-phase solution of the stirring bilayer mixture; and another series of spectra (Fig. 8c, Supplementary Figs. 99A, B, 101A, B, and 103A, B) were recorded after these samples were stored further at 28 °C for 4 h (to get fully released for the guests). The obtained time-dependent 1H NMR spectra showed that Guest⊂[Hg512]·[OTf]10 has successfully turned into [Ag512]·[OTf]10 with the guests released at the end of the conversion.
Data availability
All data are included in this article, Supplementary Information and Supplementary Data (NMR spectra). The data are available from the corresponding author upon reasonable request.
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Acknowledgements
We acknowledge the financial support from the National Natural Science Foundation of China (21971021 and 22371018 to Y.W.; 22271019 to H.J.).
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Y. Wang and H. Jiang conceived and designed the experimental studies and supervised the work. Y. Yao, C. Shao., S. Wang, Q. Gong, and J. Liu conducted ligand synthesis and performed complexation studies. Y. Wang conducted computational studies. Y. Wang wrote the paper.
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Yao, Y., Shao, C., Wang, S. et al. Dual-controlled guest release from coordination cages. Commun Chem 7, 43 (2024). https://doi.org/10.1038/s42004-024-01128-z
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DOI: https://doi.org/10.1038/s42004-024-01128-z
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