Self-assembled conjoined-cages

A self-assembled coordination cage usually possesses one well-defined three-dimensional (3D) cavity whereas infinite number of 3D-cavities are crafted in a designer metal-organic framework. Construction of a discrete coordination cage possessing multiple number of 3D-cavities is a challenging task. Here we report the peripheral decoration of a trinuclear [Pd3L6] core with one, two and three units of a [Pd2L4] entity for the preparation of multi-3D-cavity conjoined-cages of [Pd4(La)2(Lb)4], [Pd5(Lb)4(Lc)2] and [Pd6(Lc)6] formulations, respectively. Formation of the tetranuclear and pentanuclear complexes is attributed to the favorable integrative self-sorting of the participating components. Cage-fusion reactions and ligand-displacement-induced cage-to-cage transformation reactions are carried out using appropriately chosen ligand components and cages prepared in this work. The smaller [Pd2L4] cavity selectively binds one unit of NO3−, F−, Cl− or Br− while the larger [Pd3L6] cavity accommodates up to four DMSO molecules. Designing aspects of our conjoined-cages possess enough potential to inspire construction of exotic molecular architectures.

The early examples of multi-3D-cavity coordination cages were reported by Lehn and co-workers 17 . Initially, a specific Cu(I)based box-shaped cationic [M 6 (L a ) 3 (L b ) 2 ] cage containing a 3Dcavity was prepared using a linear bis-bidentate ligand (L a ) and trigonal planar tris-bidentate ligand (L b ) 27 . Subsequently, the linear ligand L a was modified by adding more binding units on its backbone. The modified L a being tris-bidentate and tetrakisbidentate in nature, afforded [M 9 (L a ) 3 4 ] cages with two and three 3D-cavities, respectively 17 . The general formula of these cationic cages is [M 3n (L a ) 3 (L b ) n ] where M is Cu (I) or Ag(I), n is 2, 3, or 4 and the number of cavities is "n -1". Schmittel et al. 18 prepared another Cu(I)-based [M 6 (L a ) 3 (L b ) 2 ] cage and then subjected the three bound ligands L a to postmodification using two units of a tripodal linker to obtain one unit of a bound macrobicyclic cyclophane entity. Thus, a [M 6 (cyclophane)(L b ) 2 ] type cationic compound, containing three 3D-cavities was prepared. Hardie and co-workers prepared a Cu(II)-based neutral dumbbell-shaped [M 3 (L a ) 2 (dmf) 3 ] cage where L a represents a tri-anionic tripodal tris-monodentate ligand. Two units of the trinuclear cage were linked using a neutral bis-monodentate linear linker (L b ), to afford a neutral [{M 3 (L a ) 2 (dmf)(H 2 O)} 2 (μ-L b )] architecture that contains identical 3D-cavities 19 . A few years ago, we prepared a Pd(II)-based cationic double-decker [M 3 L 4 ] cage possessing two identical 3Dcavities (Fig. 1a) 20 . We prepared the [M 3 L 4 ] cage using Pd(NO 3 ) 2 and an "E-shaped" neutral tris-monodentate ligand in 3:4 ratio. Our design enables the creation of tuneable cavities by keeping the donor units of the ligand intact and simply modifying the spacer moieties. A few other [Pd 3 L 4 ] complexes were subsequently reported by the research groups of Clever, Yoshizawa and Crowley [21][22][23] , by suitably modifying the spacer units in the ligand backbones to realize bigger sized [Pd 3 L 4 ] double-cavities. The Crowley group introduced an additional donor site in the ligand design, creating a tetrakis-monodentate ligand that allowed the formation of a [Pd 4 L 4 ] complex with three 3D-cavities arranged in a linear fashion 23 . The environment of central cavity, by virtue of its position, has to be different from a terminal cavity, however, there are subtle differences in the frameworks of the central versus terminal cavities in the design of Crowley. In short, a few examples of [M n L 4 ] multi-cavity cages (where M is Pd(II), "n" is 3 or 4) with "n − 1" cavities ( Fig. 1a) are known. In contrast to the multiple binding sites of the multi-3D-cavity cages, there exist single-3D-cavity systems capable of accommodating multiple variety of guests in site-specific manner 28,29 . It is pertinent to note that a variety of 3D-metal−organic frameworks possessing an infinite number of conjoined-cages in their architectures are known 7 . As described above, only a handful of multi-3D-cavity self-assembled cages are known in literature, where the cavities are usually arranged in a linear fashion in their superstructures and the maximum number of cavities is three.
The processes of construction of coordination cages are sometime classified under narcissistic and integrative selfsorting 30,31 that are comparable to certain biological processes [32][33][34] . Dynamic behaviors of the coordination cages with respect to post-modifications such as cage-fusion reactions 35 and ligand-displacement-induced cage-to-cage transformations 36 are important studies of current interest. Construction of multi-3D-cavity cages, understanding related self-sorting processes and subjecting the cages to post-modifications are therefore attractive and fundamental aspects of supramolecular coordination chemistry.
In the present work, we report a family of rationally designed modular multi-cavity Pd(II)-based coordination cages where 3Dcages of two varieties, namely [Pd 2 L 4 ] and [Pd 3 L 6 ] are conjoined in a linear or lateral manner (Fig. 1b). We have named such architectures as "self-assembled conjoined-cages". A family of conjoined 3D-cages of [Pd 4 (L a ) 2 (L b ) 4 ], [Pd 5 (L b ) 4 (L c ) 2 ] and [Pd 6 (L c ) 6 ] formulations containing two, three, and four cavities, respectively, has been prepared (Fig. 1b). The smaller peripheral cavity of the conjoined-cages selectively binds certain anions while the larger central cavity contains solvent molecules. Dynamic behaviors of the conjoined-cages depicting cage-fusion reactions and ligand-displacement-induced cage-to-cage transformations are studied. Narcissistic and integrative self-sorting processes are demonstrated in connection with the synthesis of the cages.

Results
Design and synthesis of the ligands.  20 and L2 by a modified method 43 . 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       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 concepts 44 . 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 ] complexes [45][46][47] . The amide linkages are somewhat rigid and are capable of interacting with counteranions 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.  7 , 4a (Fig. 3f). The 1 H NMR spectrum of the solution (Fig. 4d) showed a single set of peaks where a downfield shift was seen in the positions of the pyridineα 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 1 H NMR study. 1 H 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. 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 (L b ) 4 (L c ) 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 1 H NMR study, yielding [(NO 3 ) 2 ⊂ Pd 5 (L5) 4 (L6) 2 ](NO 3 ) 8 , 5a. The 1 H 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 counteranions 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 1 H 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 (L c ) 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.
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 1 H 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 routes 30 . An unsuccessful cagefusion reaction (or no change) belongs in the category of narcissistic self-sorting. One such example of narcissistic selfsorting 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-tocage 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 1 H 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.

Discussion
This article demonstrated the construction of multi-3D-cavity coordination cages via decoration of a [Pd 3 L 6 ] core with one or more [Pd 2 L 4 ] units in a linear or lateral fashion, respectively. The metal component used for the preparation of the cages was Pd (NO 3 ) 2 and the cages formed (2a, 4a, 5a, and 6a) were found to encapsulate NO 3 − in their [Pd 2 L 4 ] moieties. The encapsulated NO 3 − could be replaced by halides like F − , Cl − , or Br − by using corresponding TBAX. Notably, AgCl could be also used as a source of Cl − ion. In fact, Clever and co-workers 48 used sparingly soluble AgCl as a source of Cl − that displaced bound BF 4 − ion from the cavity of certain coordination cages, resulting in consumption of AgCl and retention of the more soluble AgBF 4 in solution.
We have also demonstrated the use of AgCl where the Cl − ion displaced bound NO 3 − ion from the cavity of some coordination cages whereupon the more soluble AgNO 3 remained in solution 49 6 ] cages is feasible only when the smaller cavity is occupied by NO 3 − , F − , Cl − , or Br − , irrespective of the counter-anion present outside the cavity/cavities. Although the formation of the larger cavity (i.e., [Pd 3 L 6 ] entity) is anion independent, this did not help in the formation of corresponding conjoined-cages (4a, 5a, and 6a) since the formation of [Pd 2 L 4 ] entity is essential.
Synthesis of the heteroleptic complex 4a through the combination of Pd(NO 3 ) 2 , L3 and L5 in a single-pot is a perfect example of integrative self-sorting behavior 30,31 since the homoleptic complexes formed by L3 and L5 were not observed in the final product profile. Integrative self-sorting was also observed for synthesis of the heteroleptic complex 5a from its components, i.e., Pd(NO 3 ) 2 , L5 and L6. The formation of these heteroleptic complex is probably driven by the propensity of the L3-like fragment present in L5 (and L6) to form [Pd 3 L 6 ]-like entities.
The cages 4a and 5a are hitherto unknown examples of heteroleptic complexes wherein ligands of different denticity are coordinated to Pd(II) 8 . Thus, the present set of cages are unique due to their structural features and associated binding properties. The concept of making conjoined-cages, in an effortless manner opens a plethora of possibilities where suitable ligand design can help construct hitherto unknown architectures with unique structures.

Methods
General. The deuterated solvent DMSO-d 6 was obtained from Sigma-Aldrich. NMR spectra were recorded in DMSO-d 6 at room temperature (r.t.) on Bruker AV400 and AV500 spectrometers at 400 and 500 MHz for 1 H NMR, COSY, NOESY and at 100 and 125 MHz for 13 C NMR. Chemical shifts are reported in parts per million (ppm) relative to residual solvent protons (2.50 ppm for DMSOd 6 in 1 H NMR and 39.50 in 13 C NMR). The ESI mass spectra were recorded on Agilent Q-TOF spectrometers. Single crystal X-ray diffraction analysis was carried out using a Bruker D8 VENTURE instrument. The ligand L1 was synthesized as reported previously 20 .
Synthesis and characterization of the ligands. Triethylamine (0.24 mL, 1.685 mmol) was added in a dropwise manner to a stirred suspension of nicotinoyl chloride hydrochloride (0.300 g, 1.685 mmol) and 3-pyridylcarbinol (0.184 g, 0.16 mL, 1.685 mmol) in dry dichloromethane (DCM) (30 mL) maintained at 0-5°C. The mixture was stirred at room temperature for 24 h under nitrogen atmosphere. In order to neutralize the acid, NaHCO 3 solution (10% w/v) was added slowly to the mixture until the evolution of CO 2 has ceased. The organic layer was washed with distilled water, separated and dried over anhydrous sodium sulfate. Purification of the crude product by column chromatography Triethylamine (1.02 mL, 7.246 mmol) was added in a dropwise manner to a stirred suspension of nicotinoyl chloride hydrochloride (1.290 g, 7.246 mmol) and resorcinol (0.400 g, 3.633 mmol) in dry DCM (50 mL) maintained at 0-5°C. The mixture was stirred at room temperature for 24 h under nitrogen atmosphere. In order to neutralize the acid, NaHCO 3 solution (10% w/v) was added slowly to the mixture until the evolution of CO 2 has ceased. The organic layer was washed with distilled water, separated and dried over anhydrous sodium sulfate. Complete evaporation of the solvent yielded the ligand L3 as an off-white solid ( To a suspension of nicotinic acid (0.500 g, 4.065 mmol) and resorcinol (0.112 g, 1.018 mmol) in 50 mL dry DCM maintained at 0-5°C, dimethylaminopyridine (DMAP) (0.062 g, 0.507 mmol) was added followed by N-ethyl-N´-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl) (0.195 g, 1.017 mmol). The reaction mixture was stirred for 12 h under nitrogen atmosphere. In order to neutralize the acid, NaHCO 3 solution (10% w/v) was added slowly to the mixture until the evolution of CO 2 has ceased. The organic layer was washed with distilled water, separated and dried over anhydrous sodium   Fig. 6 Ligand-displacement-induced cage-to-cage transformations. Initial-cage/ligand-input/final-cage/displaced-ligand a system 3a/L5/4a/L3; b system 3a/L6/6a/L3; c system 4a/L6/6a/L3&L5; d system 5a/L6/6a/L5; e system 4e/L3/4a/L5; f system 4e/L6/6a/L5; g system 3a/L5&L6/5a/L3 (stoichiometry are provided in the figure. The complex 4e coexists with 4f).