Design and synthesis of the ligands

The complexation of Pd(II) with suitable nonchelating bidentate ligands is known to yield [Pd m L 2m ] complexes. The value of “m” can be qualitatively related to the angle subtended by the two coordination vectors of the bound ligand. While [Pd 2 L 4 ] complexes are common and have been widely explored6,37,38,39, molecules with [Pd 3 L 6 ], [Pd 4 L 8 ], [Pd 5 L 10 ], [Pd 6 L 12 ], [Pd 7 L 14 ], [Pd 8 L 16 ], [Pd 9 L 18 ], [Pd 12 L 24 ], [Pd 30 L 60 ], [Pd 48 L 96 ] architectures possessing a single-3D-cavity are also known6,40,41,42. In order to accomplish the multi-3D-cavity targets shown in Fig. 1b, the first step was to identify two nonchelating bidentate ligands; one capable of forming a [Pd 2 L 4 ] and the other a [Pd 3 L 6 ] complex. Mere identification of any two capable ligands is not sufficient, since the backbones of the chosen ligands need to be integrated in such a manner that the hybrid ligands so obtained can sustain [Pd 2 L 4 ] and [Pd 3 L 6 ] entities within the same superstructure. The objectives include the construction of tetra, penta and hexanuclear complexes shown in Fig. 1b. The ligands designed for this purpose are shown in Fig. 2. The bidentate ligands L2 and L3 yielded [Pd 2 L 4 ] and [Pd 3 L 6 ] architectures, respectively. The builds of L2 and L3 are integrated in the designs of the tri-/tetradentate ligands L5/L6.

Fig. 2: Structure of the ligands. The ligands L1–L6. Full size image

The ligand L1 was prepared as reported20 and L2 by a modified method43. The new ligands L3–L6 were synthesized as described hereafter. The ligands L2 and L3 were obtained by condensation of nicotinoyl chloride hydrochloride with 3-pyridylcarbinol and resorcinol, respectively. The ligand L4 was obtained by selective cleavage of one of the ester linkages of L1, whereas selective condensation of nicotinic acid with resorcinol resulted in the ligand L4′. The ligand L5 was synthesized by condensation of L4 with L4′, whereas the ligand L6 was prepared by condensation of L4 with resorcinol. The ligands were characterized by nuclear magnetic resonance (NMR) spectroscopy and electrospray ionization mass spectrometry (ESI-MS) techniques. Ligand L1 upon complexation with Pd(NO 3 ) 2 forms a double-decker architecture [(NO 3 ) 2 ⊂ Pd 3 (L1) 4 ](NO 3 ) 4 , 1a20.

[Pd 2 L 4 ] entity

Complexation of Pd(NO 3 ) 2 with the ligand L2 in 1:2 ratio was carried out in dimethyl sulfoxide (DMSO)-d 6 . Spontaneous assembly of the components resulted in the complex [NO 3 ⊂ Pd 2 (L2) 4 ](NO 3 ) 3 , 2a within 10 min at room temperature (Fig. 3a). The 1H NMR spectrum of the solution (Fig. 4a) contained multiple sets of signals showing complexation induced downfield shift for relevant protons. Multiple sets of signals are typically associated with either the existence of a dynamic equilibrium of two or more complexes44 of different formulations or a single complex44 with multiple isomers where the environment around the bound ligand units differs in each isomer. The ligand L2, being unsymmetrical, can exist in two possible orientations when bridged between two metal centers. Consequently, four isomeric molecular architectures of [Pd 2 L 4 ] composition (diastereomers) differing in the relative orientations of the bound ligand units are possible. While a statistical mixture of diastereomers in 2a was supported by the 1H NMR spectrum of the sample, the [Pd 2 L 4 ] composition was proposed based on ESI-MS studies. The addition of one equivalent of TBAX (tetra-n-butylammonium salts) (X = F−, Cl− or Br−) to a solution of 2a resulted in the corresponding anion exchanged products [X ⊂ Pd 2 (L2) 4 ](NO 3 ) 3 , 2b–2d within 5 min at 70 °C (Fig. 3b), which exhibited downfield shift of pyridine-α protons. The presence of a NO 3 − ion in the cavity and its templating role was further supported by the fact that complexation of Pd(BF 4 ) 2 with the ligand L2 in 1:2 ratio provided a mixture of several unidentified products. This mixture could be converted to [X ⊂ Pd 2 (L2) 4 ](BF 4 ) 3 , 2a′-2d′ (X = NO 3 −, F−, Cl−, and Br−, respectively), by the addition of one equivalent of the corresponding TBAX, within 5 min at 70 °C. The representative complexes 2b and 2a′ were also characterized by ESI-MS studies. The crystal structure of 2c supported the [Pd 2 L 4 ] architecture (Fig. 5a) with an encapsulated Cl− ion. The two possible orientations for each ligand strand perhaps introduce partial occupancies for –C(O)– and –CH 2 – at both ends of the –C(O)OCH 2 – spacer moiety. The occupancies could not be resolved properly, and the crystal structure represents a mixture of the four isomeric complexes.

Fig. 3: Synthetic scheme for the complexes 2a−2d, 3a−6a, and 4e/4f. Self-assembled coordination cages featuring one or more 3D-cavity constructed by complexation of Pd(NO 3 ) 2 with appropriate ligand(s) to afford a/b/c/d/e homoleptic complexes; f/g heteroleptic complexes via integrative self-sorting; k mixture of homoleptic complexes via narcissistic self-sorting. Cage-fusion reactions to yield h/i heteroleptic complexes (however, no fusion in the case of j). Full size image

Fig. 4: Characterization of the complexes 2a−6a and 4e/4f. Partial 1H NMR spectra (400 MHz, DMSO-d 6 , 300 K) of a cage 2a (diastereomeric mixture), b cage 3a (trinuclear), c mixture of 4e and 4f (tri- and hexanuclear), d cage 4a (tetranuclear), e cage 5a (pentanuclear), and f cage 6a (hexanuclear). Full size image

Fig. 5: Crystal structures showing the cationic portions. a Cage 2c (binuclear), b cage 3a (trinuclear), c cage 4acI (tetranuclear), d cage 5c (pentanuclear), and e cage 6c (hexanuclear) (encapsulated guests, counter-anions, solvents, and hydrogen atoms are excluded for clarity. ORTEP diagram for complexes and suitable crystal structures showing encapsulated guests are available in the Supplementary Figs. 134–143). Full size image

[Pd 3 L 6 ] entity

The complexation of Pd(NO 3 ) 2 with the ligand L3 in 1:2 ratio was carried out in DMSO-d 6 . Spontaneous assembly of the components resulted in the complex [Pd 3 (L3) 6 ](NO 3 ) 6 , 3a within 10 min at room temperature (Fig. 3c) and the 1H NMR spectrum of the solution (Fig. 4b) showed a single set of signals where a downfield shift was seen in the positions of the pyridine-α protons. The [Pd 3 L 6 ] composition of 3a was proposed based on ESI-MS studies. Synthesis of the complexes [Pd 3 (L3) 6 ](X) 6 , 3b–3f (for X = BF 4 −, ClO 4 −, OTf−, PF 6 − and SbF 6 −, respectively) was completed within 10 min at room temperature and the 1H NMR spectra of these complexes are all comparable (except for minor differences in the signal of H g3 ). Thus, the role of anion templation in the formation of these trinuclear complexes (3a–3f) was ruled out. However, encapsulation of solvent molecules in the cavity of the complexes is likely. ESI-MS study of the representative complex [Pd 3 (L3) 6 ](BF 4 ) 6 , 3b supported the [Pd 3 L 6 ] composition.

1H NMR spectra of the complex 3a were recorded at various concentrations. At a very low concentration (1 mM with respect to Pd(II)) the complex 3a started dissociating, releasing approximately 19% of uncoordinated ligand L3. Interestingly, ~7% of L3 existed as a binuclear complex [Pd 2 (L3) 4 ](NO 3 ) 4 , 3g, of the [Pd 2 L 4 ] variety, while the trinuclear 3a remained the major species. At higher concentration, (30 mM with respect to Pd(II)) approximately ~6% of L3 existed as a tetranuclear complex [Pd 4 (L3) 8 ](NO 3 ) 8 , 3h, of the [Pd 4 L 8 ] variety, whereas the trinuclear 3a remained the major species (see Supplementary Fig. 30). The evolution of the smaller 3g and larger sized 3h (Supplementary Discussion 1 and Supplementary Table 1) at lower and higher concentrations, respectively, were proposed based on entropic concepts44. The formation of 3g and 3h was also confirmed using ESI-MS data (see Supplementary Figs. 31, 32). Attempts to grow single crystals of these complexes proved unsuccessful. PM6 optimized structures of 3g and 3h are given in lieu of the crystal structures (see Supplementary Fig. 132).

The bidentate ligand L3 possesses a central aromatic spacer and two terminal 3-pyridyl moieties connected by ester linkages. A few ligands of comparable designs with amide linkages are known, which form [Pd 2 L 4 ] complexes45,46,47. The amide linkages are somewhat rigid and are capable of interacting with counter-anions inside the corresponding cavity, when suitably oriented thereby influencing the formation of smaller [Pd 2 L 4 ] complexes. The observed strong preference of L3 towards the formation of a [Pd 3 L 6 ] complex was rather surprising. Probably, the ester linkages are not suitable for anion binding and their flexible nature allows conformational changes when required. In any case, we needed a ligand, which would yield a [Pd 3 L 6 ] architecture, regardless of the counter-anion present, within a reasonable concentration range. The ligand L3 fits this requirement and satisfies few other criteria necessary to achieve the targets (shown in Fig. 1b). The crystal structure of the complex 3a revealed a bent conformation of the bound ligand moieties, where the donor atoms are present at the convex face of the curved ligand (Fig. 5b). Four DMSO molecules are located inside the cavity and the counter-anions are present outside.

Conjoined-cages and differential binding

The next target was a [Pd 4 (La) 2 (Lb) 4 ] complex that can be visualized as a linear conjoin of a [Pd 2 L 4 ] cage with a [Pd 3 L 6 ] cage. Therefore, complexation of Pd(NO 3 ) 2 (4 equiv.) with a mixture of the ligands L3 (2 equiv.) and L5 (4 equiv.) was carried out in DMSO-d 6 . Integrative self-sorting of these components required 4 h at room temperature or 1 h at 70 °C, as revealed by monitoring of 1H NMR spectra, yielding [NO 3 ⊂ Pd 4 (L3) 2 (L5) 4 ](NO 3 ) 7 , 4a (Fig. 3f). The 1H NMR spectrum of the solution (Fig. 4d) showed a single set of peaks where a downfield shift was seen in the positions of the pyridine-α protons. Addition of TBAX (X = F−, Cl−, or Br−) to a solution of 4a resulted in the corresponding anion exchanged products [X ⊂ Pd 4 (L3) 2 (L5) 4 ](NO 3 ) 7 , 4b–4d (for X = F−, Cl−, and Br−, respectively) within 5 min at 70 °C. Addition of AgCl to a solution of 4a took longer time for the complete anion exchange when carried out at room temperature, however, at an initial stage partial anion exchange was observed (a mixture of 4a and 4c) as confirmed by 1H NMR study. 1H NMR spectra of the solution recorded at an intermediate stage revealed the presence of a mixture of 4a and 4c. Such a mixture was used for growing single crystals and crystals were obtained from two of the crystallization conditions. Crystal structures obtained from both the samples displayed partial occupancies of encapsulated NO 3 −/Cl− ion. The crystal structure of 4acI, revealed the formation of a tetranuclear complex where two cavities are linearly conjoined (Fig. 5c). The smaller cavity accommodated a NO 3 −/Cl− ion (with partial occupancies) and four DMSO molecules were present inside the bigger cavity. The counter-anions and a few solvent molecules were located outside the cavities. The crystal structure of 4acII is provided in the Supplementary Information.

As explained earlier, the complexation of Pd(NO 3 ) 2 with ligand L3 yielded the homoleptic complex 3a. It is also relevant to discuss the complexation behavior of Pd(NO 3 ) 2 with ligand L5. Since the ligand L5 structurally resembles a combination of L2 and L3, hence the binding sites of L5 are suited for making [Pd 2 L 4 ] and [Pd 3 L 6 ] entities. Therefore, we pondered reasonable architectures where all three donor sites of L5 and all four acceptor sites around Pd(II) are completely utilized and the anticipated [Pd 2 L 4 ] and [Pd 3 L 6 ] like entities are sustained. A structure could not be readily visualized, nevertheless, complexation of Pd(NO 3 ) 2 with ligand L5 in 3:4 ratio was performed in DMSO-d 6 by stirring the mixture for 1 h at 70 °C (Fig. 3d). 1H NMR spectrum of the solution (Fig. 4c) exhibited two sets of signals, which appear downfield relative to the corresponding ligand protons. The 1H, 13C, H-HCOSY, and NOESY NMR data along with description about the complexes are given in supplementary section (see Supplementary Figs. 96–100 and Supplementary Discussions 2–4). While the 1H NMR spectra recorded at different temperatures (30 to 100 °C range) (see Supplementary Fig. 101) did not show any noticeable change those recorded at different concentrations (see Supplementary Fig. 102) showed changes in the relative intensities of the signals, indicating the coexistence of two well-defined complexes. Their architectures could not be readily predicted. ESI-MS data provided evidence to propose the formation of [NO 3 ⊂ Pd 3 (L5) 4 ](NO 3 ) 5 , 4e and [(NO 3 ) 2 ⊂ Pd 6 (L5) 8 ](NO 3 ) 10 , 4f (see Supplementary Fig. 103). The structures of 4e and 4f are such that the L2-like fragment of L5 got manifested in the [Pd 2 L 4 ] form (in both 4e and 4f), whereas the L3-like fragment of L5 evolved in the [Pd 2 L 4 ] (in 4e) and [Pd 4 L 8 ] (in 4f) forms (see Supplementary Fig. 95). This observation is in line with the fact that the complexation of Pd(NO 3 ) 2 with ligand L3 resulted in very small proportions of [Pd 2 (L3) 4 ](NO 3 ) 4 , 3g and [Pd 4 (L3) 8 ](NO 3 ) 8 , 3h at low and high concentrations, respectively. Addition of AgCl to a mixture of 4e and 4f resulted in the anion exchanged products [Cl ⊂ Pd 3 (L5) 4 ](NO 3 ) 5 , 4g and [(Cl) 2 ⊂ Pd 6 (L5) 8 ](NO 3 ) 10 , 4h within 30 min at room temperature (see Supplementary Fig. 104). The compositions of 4g and 4h were also supported by ESI-MS data (see Supplementary Fig. 105). Attempts to grow single crystals of these complexes proved unsuccessful. PM6 optimized structures of 4g and 4h are given in lieu of the crystal structures (see Supplementary Fig. 133).

A [Pd 5 (Lb) 4 (Lc) 2 ] type complex that approximates a lateral conjoining of two [Pd 2 L 4 ] cavities around a [Pd 3 L 6 ] core was our next target. The complexation of Pd(NO 3 ) 2 (5 equiv.) with a mixture of the ligands L5 (4 equiv.) and L6 (2 equiv.) was carried out in DMSO-d 6 in anticipation of the integrative self-sorting behavior of the system (Fig. 3g). The self-sorting of the components occurred within 4 h at room temperature (or 1 h at 70 °C), as revealed by 1H NMR study, yielding [(NO 3 ) 2 ⊂ Pd 5 (L5) 4 (L6) 2 ](NO 3 ) 8 , 5a. The 1H NMR spectrum of the solution (Fig. 4e) showed a single set of peaks where pyridine-α proton signals appear downfield relative to those of the ligands. The composition of 5a was proposed based on ESI-MS data. Addition of TBAX (X = F, Cl, or Br) to a solution of 5a resulted in the corresponding anion exchanged products [(X) 2 ⊂ Pd 5 (L5) 4 (L6) 2 ](NO 3 ) 8 , 5b–5d (for X = F−, Cl−, and Br−, respectively) within 5 min at 70 °C. The crystal structure of the complex 5c revealed laterally conjoined cavities as anticipated (Fig. 5d). The two smaller cavities accommodated a Cl− ion each and four DMSO molecules were present inside the larger cavity. The counter-anions and a few solvent molecules were located outside the cavities.

The complexation of Pd(NO 3 ) 2 with the ligand L6 in 1:1 ratio was carried out in DMSO-d 6 (Fig. 3e). Spontaneous assembly of the components resulted in the complex [(NO 3 ) 3 Pd 6 (L6) 6 ](NO 3 ) 9 , 6a within 1 h at room temperature or 20 min at 70 °C. The 1H NMR spectrum of the solution (Fig. 4f) showed a single set of signals where the peaks of pyridine-α protons showed a downfield shift. The [Pd 6 L 6 ] composition of 6a was proposed based on ESI-MS data. Since the ligand L6 structurally resembles a combination of L2 and L3, complexation of Pd(II) with L6 affords the targeted [Pd 6 (Lc) 6 ] complex. Thus, our objective of synthesizing a complex containing three [Pd 2 L 4 ] cavities laterally conjoined with a [Pd 3 L 6 ] core was successfully accomplished.

Addition of TBAX (X = F−, Cl−, or Br−) to a solution of 6a resulted in the corresponding anion exchanged products [(X) 3 ⊂Pd 6 (L6) 6 ](NO 3 ) 9 , 6b–6d (for X = F−, Cl−, and Br−, respectively) within 5 min at 70 °C. The composition of 6a and 6c were also supported by ESI-MS data. The crystal structure of the complex 6c revealed laterally conjoined cavities as anticipated (Fig. 5e). The three smaller cavities accommodated a Cl− ion each and three DMSO molecules were present inside the larger cavity. The counter-anions and a few solvent molecules were located outside the cavities.

It was interesting to note that a combination of Pd(BF 4 ) 2 , L3 and L5 in 4:2:4 ratio resulted in a mixture of several unidentified products. The mixture of products could, however, be converted to [X ⊂ Pd 4 (L3) 2 (L5) 4 ](BF 4 ) 7 , 4a′−4d′ (X = NO 3 −, F−, Cl−, and Br−, respectively) by addition of the corresponding TBAX and the process was complete in 1 h at 70 °C. Similarly, a mixture of products was obtained when (i) Pd(BF 4 ) 2 , L5 and L6 were combined in 5:4:2 ratio or (ii) Pd(BF 4 ) 2 and L6 were combined in 1:1 ratio. These mixtures could be converted to discrete (i) [(X) 2 ⊂ Pd 5 (L5) 4 (L6) 2 ](BF 4 ) 8 , 5a′−5d′ and (ii) [(X) 3 ⊂Pd 6 (L6) 6 ](BF 4 ) 9 , 6a′−6d′ complexes via the addition of TBAX (X = NO 3 −, F−, Cl−, or Br−).

Cage-fusion reactions

Cage-fusion reactions were investigated by combining any two cages, from the pool of 3a, 4a, 5a, 6a, and 4e. Although 4e and 4f coexist, for ease of understanding and calculation, the presence of 4f was neglected. The cage-fusion reactions were monitored by recording 1H NMR spectra of the solutions as a function of time. The combination of the two homoleptic systems 3a and 4e in 1:3 ratio in DMSO-d 6 resulted in the heteroleptic system 4a within 4 h at room temperature or 20 min at 70 °C (Fig. 3h). In another instance, the combination of the homoleptic systems 6a and 4e in 1:3 ratio in DMSO-d 6 resulted in the heteroleptic system 5a, within 4 h at 70 °C (no changes occurred at room temperature) as shown in Fig. 3i. The L3-like fragment might prefer to form a [Pd 3 L 6 ] entity, however, this fragment in the complex 4e exists in the less preferred [Pd 2 L 4 ] form. Consumption of 4e and the formation of 4a or 5a containing the preferred [Pd 3 L 6 ] entity is considered as the driving force of the cage-fusion reactions. However, a mixture of the homoleptic complexes 3a and 6a remained unchanged even after stirring for 24 h at 70 °C (Fig. 3j). Presumably, the complex 6a is quite stable and requires higher energy for a reshuffle in its architecture. No cage-fusion was observed when the heteroleptic complexes 4a and 5a were allowed to interact with each other. Similarly, no fusion was observed in experiments involving a homoleptic-heteroleptic pair of complexes such as 3a/4a, 3a/5a, 4e/4a, 4e/5a, 6a/4a, and 6a/5a (see Supplementary Methods and Supplementary Figs. 106–117, for all the cage-fusion reactions).

The integrative self-sorting phenomenon could be demonstrated in terms of the synthesis of 4a and 5a in separate reactions using Pd(NO 3 ) 2 and appropriate ligands as shown in Fig. 3f, g. These two integrative self-sorted complexes could also be prepared by cage-fusion reactions as discussed above. Thus, a cage-fusion reaction or direct combination of corresponding metal and ligand components yield the same final product, presumably through different routes30. An unsuccessful cage-fusion reaction (or no change) belongs in the category of narcissistic self-sorting. One such example of narcissistic self-sorting is observed when Pd(NO 3 ) 2 is mixed with the ligands L3 and L6 in one-pot (Fig. 3k and Supplementary Fig. 110), yielding a mixture of the corresponding homoleptic complexes 3a and 6a only.

Ligand-displacement-induced cage-to-cage transformations

Subsequently, a variety of ligand-displacement-induced cage-to-cage transformations were attempted as shown in Fig. 6. A chosen cage was mixed with a calculated amount of externally added ligand(s), whereupon the bound ligand(s) are partially or completely displaced by the incoming ligand(s), leading to complete disappearance of the original cage and formation of a different cage. For example, the cage 3a could be transformed to the cage 6a in a cage-to-cage fashion via the interaction of 3a (2 equiv.) with L6 (6 equiv.) whereupon L3 (12 equiv.) and 6a (1 equiv.) were obtained (Fig. 6b). The list of successful cage-to-cage transformations include the conversion of 3a to 4a, 5a or 6a (Fig. 6a, g, b); conversion of 4e to 4a or 6a (Fig. 6e, f); conversion of 4a to 6a (Fig. 6c); and conversion of 5a to 6a (Fig. 6d). The cage-to-cage transformations were monitored by recording 1H NMR spectra of the solutions as a function of time. All these transformations were complete in about 1 h at 70 °C. Fourteen different combinations were tried out of which seven (mentioned above) were successful (see Supplementary Methods and Supplementary Figs. 118–131, for all ligand-displacement reactions). The cages produced are probably more stable than the reactant cages in a qualitative sense.