Pd(μ-L)₄Pt vs. Pd(μ-L)₄RuCl₂: chlorido ancillary ligands as defining factors in the host–guest interactions of M(μ-L)₄M′ heterodimetallic supramolecular architectures

Abstract

In supramolecular architectures, the interactions between host and guest molecules are governed by non-covalent forces such as hydrogen (H) bonding, hydrophobic and electrostatic interactions. We alter here the cavity microenvironment to control the interactions between guest and host molecules and study the effects of introducing axial chlorido ligands through the use of an octahedral building block in M(μ-L)₄M′ architectures. We prepared the heterodimetallic Pd(μ-L)₄Pt C⁴_Pt and Pd(μ-L)₄RuCl₂C⁴_Ru architectures and demonstrated the role of ‘classic’ non-covalent forces in their host–guest chemistry with anionic and neutral molecules, while the cages also underwent disassembly and reassembly upon addition of external stimuli. This culminated in the isolation of a 1 : 1 host–guest complex between C⁴_Pt and the dianionic 1,5-naphthalenedisulfonate which was characterized by single crystal X-ray diffraction studies. These showed the guest occupied the central cavity and was held in place by H bonding. The endo-chlorido ligand in C⁴_Ru played an important role in the capture of neutral guest molecules. In particular, it allowed for finetuning of the cavity properties of the supramolecular architectures by limiting the formation of H bonds and restricting the cavity size while offering alternative interactions.

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Introduction

In recent decades, self-assembled metallosupramolecular architectures (MSAs), such as M₂L₄-type cages, have been designed and studied for a wide range of applications.^1–5 For example, [Pd₂L₄]⁴⁺ (or [Pd(μ-L)₄Pd]⁴⁺) MSAs have been examined for their use as catalysts,^6–8 as luminescent materials,^9,10 in medical applications,^11,12 for molecular recognition and, of particular interest, for their ability to encapsulate drugs and other molecules in host–guest chemistry.^5,13–15 In most cases for these cage-like hosts, binding of guest molecules is facilitated by non-covalent forces such as hydrogen (H) bonding, hydrophobic and coulombic interactions.^16–19

The synthetic principles that direct the construction of high-symmetry architectures are well-understood.^3,20 These same strategies have also been used to great effect in installing secondary metal centers, which serve as structural and/or behavioral components.^21–26 However, recently lower-symmetry MSAs have been attractive targets as they may facilitate the introduction of different chemical properties into a single cage molecule. To this end many heteroditopic ligand scaffolds have been employed to generate lower symmetry architectures such as heteroleptic,^27–31 pseudo-heteroleptic,^32–34 and multi-cavity Pd(II)-based architectures.^{18,29,35–39}

Another strategy, however, is to introduce non-symmetry by installation of different metal centers at either end of cage architectures to yield, for example, heterodimetallic MM′L₄ compounds. Such a strategy has been implemented to incorporate metal centers such as Fe,⁴⁰ Cu,⁴¹ Ru,⁴² Pt^43–46 and others, into [PdML₄] systems. The first syntheses of heterodimetallic [Pd(μ-L)₄Pt] cages were reported by Lisboa et al. using subcomponent self-assembly.⁴³ In a different approach, Pearcy et al. established a stepwise approach by sequential coordination of initially the more kinetically inert Pt(II) center followed by the more labile Pd(II) center to heterotopic imidazole and pyridyl N-donor scaffolds.⁴⁶ Preston and co-workers recently introduced an alternative Pt-based building block for the construction of kinetically robust Pt₂L₄ cages.⁴⁷ In such MSAs, the different coordination properties of two metal centers or of different coordination motifs in ditopic ligands can be exploited for stimulus-induced partial (and reversible) disassembly of the host molecule, and release of a molecular guest.^17,40,43 For example, a [Pd(μ-L)₄Pt]⁴⁺ cage was found to bind benzoquinone and 2,6-diaminoanthraquinone guests strongly,⁴³ and also showed interactions with cisplatin and 5-fluorouracil. Only a few other examples of such MSAs have been reported since.^44,46–49

Based on a preliminary study, in which we explored the preparation and sulfonate binding ability of [Pd(μ-L)₄Pt]⁴⁺ in comparison to cages featuring an octahedral trans-Ru(II)Cl₂ moiety in place of the Pt center ([Pd(μ-L)₄RuCl₂]²⁺; Fig. 1), we develop here a broad understanding of how the introduction of such a moiety to the cavity affects the guest binding properties of heterodimetallic architectures. Furthermore, we assessed the stimulus-responsive abilities of these cages for disassembly and reassembly, and the effect on binding of anionic guests.

Fig. 1 Schematic structure of Pd(μ-L)₄RuCl₂ cages. Pd(II), red; Ru(II), orange; Cl, green; bridging ligand, grey.

Results and discussion

Making use of a modular approach in the subcomponent self-assembly of heterobimetallic MSAs,^{43,44,46–49} we aimed to introduce rational changes to PdML₄ MSAs by altering the Pd⋯M distances through variation of the bridging ligands, exploring the impact of ancillary Cl ligands on M and the effects of coulombic, H bonding and hydrophobic interactions. We previously reported Pd(μ-L)₄RuCl₂ MSAs C¹_Ru–C³_Ru (Fig. 2) that allowed discrimination between small, similarly sized, anionic guest molecules by restricting the cavity size with axially-coordinated ligands to the Ru center while maintaining the stimulus-responsive reversible opening and closing of PdPt analogs.⁴⁹

Fig. 2 Model structures for the systematic variation of Pd(μ-L)₄M MSAs C¹_Pt–C⁴_Pt and C¹_Ru–C⁴_Ru which feature different functionalities to control guest binding. M = Pt or RuCl₂.

Extension of the Pd⋯M distances compared to previously reported heterodimetallic MSAs C¹_Pt–C³_Pt and C¹_Ru–C³_Ru, and therefore enlargement of the cage cavity, was achieved by non-symmetric functionalization of 4,4′-methylenedianiline (MDA). MDA has been used to generate homometallic MSA with large accessible cavities.^50,51 While the MDA unit can undergo hydrophobic interactions with guest molecules to accommodate a wider array of guests, we introduced an amide motif at the Pd end of the cage instead of the alkynyl linker that was used previously.⁴⁹ The amide function can in principle act as either an H bond donor or acceptor. The second metal coordination site was built using an imine formation reaction between the free amino groups of the MDA units and the 3-pyridinecarboxaldehyde (3-PA) complex precursors [Pt(3-PA)₄](BF₄)₂ (Pt_pyald)⁴³ or trans-[Ru(3-PA)₄Cl₂] (Ru_pyald).⁴⁹ The synthesis of the non-symmetrically functionalized precursor 1 was achieved via amide coupling with nicotinic acid and N-Boc-4,4′-methylenedianiline in the presence of triethylamine (TEA) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) under reflux. Removal of the protecting Boc group was achieved in a 1 : 5 trifluoroacetic acid : chloroform mixture to ultimately give pyridylamine derivative 2 (Scheme 1). Preparation of the cages C⁴_Pt and C⁴_Ru was accomplished through self-assembly between 2, [Pd(CH₃CN)₄](BF₄)₂, and Pt_pyald or Ru_pyald in stoichiometric ratios of 4 : 1 : 1 at room temperature in dry DMSO, with a reaction time of ca. 24 h. The longer reaction time required relative to previously reported systems is likely due to the higher degree of flexibility of the linker in this case and the need to self-correct.⁵¹ This helps to overcome the initial formation of the kinetically favored [Pd₂(2)₄]⁴⁺ complex where ligand 2 is coordinated through the pyridyl and aniline N atoms, which has been previously observed by Chand and co-workers (Fig. S31–S33†).³²

Scheme 1 Synthetic route to low-symmetry PdPt C⁴_Pt and PdRu C⁴_Ru cages. Reaction conditions: (i) nicotinic acid, HATU, TEA, CH₃CN, reflux, 16 h. (ii) TFA : CHCl₃ (1 : 5), 3 h. (iii) [Pd(CH₃CN)₄](BF₄)₂, Pt_pyald or Ru_pyald, DMSO, 24 h.

The formation of C⁴_Pt and C⁴_Ru was tracked by ¹H NMR spectroscopy, with each cage showing quantitative conversion after 24 h. The ¹H NMR spectra showed the steady diminution of the aldehyde and amine peaks from 2 and Pt_pyald or Ru_pyald, respectively, with the appearance of imine signals at ca. δ 8.5–8.6 ppm. In addition, the pyridyl protons (H-1–H-4) shifted downfield upon coordination of the pyridyl-amide motifs to the Pd(II) center. Electrospray ionization-mass spectrometry (ESI-MS) data obtained showed a major peak for [C⁴_Pt(–4BF₄)]⁴⁺ at m/z 467.6310 (m/z_calc 467.6311) with an isotopic pattern consistent with a PdPt system (Fig. S22†). For C⁴_Ru a major peak at m/z 924.2015 was observed (m/z_calc 924.2011) corresponding to [C⁴_Ru(–2BF₄)]²⁺ (Fig. S30†). ¹H DOSY NMR spectroscopy confirmed the resonances observed for C⁴_Pt and C⁴_Ru in each case corresponded to a single species, with diffusion coefficients of 1.16 × 10⁻¹⁰ and 2.78 × 10⁻¹⁰ m² s⁻¹, respectively. These values are consistent with larger assemblies compared to those of previously reported hetero- and homodimetallic cages.^{43,44,46,48,50,51}C⁴_Pt was isolated in high yield (92%) after the addition of ethyl acetate to the DMSO solution, whereas C⁴_Ru could not be isolated in pure form by precipitation. However, NMR studies showed quantitative formation of this compound in solution and therefore solutions of C⁴_Ru in DMSO or DMSO-d₆ were prepared as stock solutions for further studies. The molecular structure of C⁴_Pt (Fig. 3) was determined by single crystal X-ray diffraction analysis. The structure featured three of the amide carbonyl moieties facing outwards, allowing the amide-NH groups to serve as H bond donors to encapsulated BF₄⁻ within the cavity, an orientation which is essential for binding of guests with H bond accepting properties (vide infra). Near the Pt center, three of the imine lone pairs are not available as H bond acceptors for guests due to their exo orientation. The structure is the largest heterodimetallic PdPtL₄ MSA reported so far with the Pd⋯Pt distance measuring at 15.48 Å, while C¹_Pt–C³_Pt (as well as C²_Ru and C³_Ru) were in the range of 9.5–11.5 Å.⁴⁹ In contrast, the molecular structure of C⁴_Ru (Fig. 3) features all four carbonyl oxygen atoms oriented towards the cavity and no classical H bond donors available for host–guest binding, while ‘non-classic’ short C–H⋯O bonds were observed to a co-crystallized guest DMSO molecule. In solution, the cages are more flexible, as shown by cross-peaks for the amide NH and imine CH protons to the neighboring endocyclic pyridyl protons in the NOESY spectra of both C⁴_Pt and C⁴_Ru (Fig. S18 and S26†). Although the Pd⋯M distances for C⁴_Ru and C⁴_Pt, are similar (15.21 and 15.48 Å respectively) the presence of the endo-chlorido ligand in C⁴_Ru reduces its cavity size considerably (Fig. 3). A significant difference was found in the packing for the two cages. They both stack linearly along the Pd⋯M axis, however, the intermolecular Pd⋯Ru distance is significantly shorter at 5.76 Å compared to the corresponding Pd⋯Pt spacing of 8.36 Å. This appears driven by electrostatic interactions between the exo-chlorido ligand of one C⁴_Ru cage and the secondary coordination sphere of the Pd center of a neighboring molecule of C⁴_Ru (Ru–Cl⋯Pd 3.34 Å).

Fig. 3 Molecular structures of C⁴_Pt (left) and C⁴_Ru (right). The Pd⋯Pt and Pd⋯Cl intra-cage distances are highlighted by dashed lines. Hydrogen atoms, solvents and counteranions have been omitted for clarity. Due to the space group for C⁴_Pt, the representation is a combination of the Pt-imine and Pd-amide ends, superimposed at the bridging methylene groups (see Fig. S60† for clarity).

Disassembly and reassembly reactions

Similar to the previously reported Pd(μ-L)₄Pt and Pd(μ-L)₄RuCl₂ cage assemblies,⁴⁹ the larger cavity cages C⁴_Pt and C⁴_Ru showed selective disassembly at the palladium center upon addition of 4-dimethylaminopyridine (DMAP). Addition of DMAP to C⁴_Pt or C⁴_Ru in DMSO-d₆ resulted in decreasing intensities of the signals assigned to the heterodimetallic architectures in the ¹H NMR spectra. This was accompanied by the appearance of resonances attributed to the monometallic ‘open-form’ [PtL₄]²⁺ and [RuCl₂L₄] complexes, as well as a new set of peaks corresponding to [Pd(DMAP)₄]²⁺ (Fig. 4).

Fig. 4 Stacked ¹H NMR spectra (DMSO-d₆, 298 K, 400 MHz) of the disassembly of C⁴_Pt upon addition of DMAP, and subsequent reassembly on addition of p-TsOH. Shifts in peaks are indicated with dashed lines. Spartan ′24®⁵² MMFF models of the closed and open forms of C⁴_Pt have been included for visualization. [Pd(DMAP)₄](BF₄)₂, (HDMAP)(TsO).

Upon addition of p-toluenesulfonic acid (p-TsOH), the DMAP in [Pd(DMAP)₄]²⁺ is protonated and the Pd ion re-coordinates to the accessible pyridyl nitrogen donors to reassemble the respective MSA. This process was slower than observed previously for [PdPtL₄]⁴⁺ cages (1 day compared to several hours for the smaller MSAs), most likely due to the greater length and higher flexibility of the bridging ligands.^43,46,49

Host–guest chemistry

For the PdPt and PdRu MSAs C¹_Pt–C³_Pt and C¹_Ru–C³_Ru, the anionic guests mesylate (MsO) and tosylate (TsO) were found to bind in the cavities of C³_Pt and/or C³_Ru, and interactions with the neutral guests 5-fluorouracil and, to a minor extent, cisplatin were also observed.⁴⁹ The binding of guest molecules was influenced by the presence of H bond accepting and H bond donating groups, by coulombic and hydrophobic interactions, as well as steric constraints. In particular, the presence of the axial, endo-Cl ligand in C³_Ru restricted the accessibility of the cage and partially compensated for the positive charge at the Ru center.

With the design of C⁴_Pt and C⁴_Ru, it was anticipated that the steric constraints associated with guest binding would be relaxed and this would allow for easier access of guests into the cavities. Therefore, C⁴_Pt and C⁴_Ru were studied for their ability to interact with the MsO (CH₃SO₃⁻) and TsO (C₇H₇SO₃⁻) mono-anions as well as the larger di-anion 1,5-naphthalene disulfonate (NDS; C₁₀H₆S₂O₆²⁻) by ¹H NMR spectroscopy and host–guest modelling. Larger disulfonates have been found by others to bind into the cavities of Pd₂L₄ cages.^53–57 For the mono-anionic guests, the modelling studies suggested that two guests would fit into the cavities of C⁴_Pt and C⁴_Ru, whereas for the larger di-anionic NDS a single molecule would fill the space (Fig. S63 and S64†). In contrast, it was found that NDS could not bind effectively in the cavity of C⁴_Ru and the smaller C³_Pt (Fig. S65†). The binding constants (Table 1) were calculated from the NMR studies using the stoichiometries inferred by the Spartan ′24^® docking models (ESI†).

Table 1 Binding constants K or K₁ observed for the MSAs C⁴_Pt and C⁴_Ru with MsO, TsO and NDS as guests as compared to C¹_Pt–C³_Pt and C¹_Ru–C³_Ru⁴⁹

MSA	Binding constants M^−1
	MsO	TsO	NDS
C^1Ru	75 ± 2	297 ± 66	—
C^2Pt	279 ± 11	237 ± 13	—
C^2Ru	209 ± 4	189 ± 7	—
C^3Pt	(1.30 ± 0.18) × 10^4	(3.50 ± 1.48) × 10^4	—
C^3Ru	314 ± 5	93 ± 3	—
C^4Pt	453 ± 5	581 ± 10	> 10^5
C^4Ru	283 ± 32	370 ± 44	1053 ± 168

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Titrations of MsO into a solution of C⁴_Pt in DMSO-d₆ monitored by ¹H NMR spectroscopy showed interactions both inside and outside of the cage (Fig. S36 and S37†). For the interior protons H-1 and H-15, a plateau in the change of chemical shifts was reached at [G] : [H] ratios of ca. 6, whereas the exterior protons H-2 and H-14 did not plateau up to a [G] : [H] ratio of ca. 10. For C⁴_Ru, only very minor shifts for the interior protons were observed (Fig. S46 and S47†), indicating the role the endo-chlorido ligand plays in blocking H-15 from forming H bonds to guest molecules. In general, the binding constants observed for C⁴_Pt and C⁴_Ru were very small in comparison to C³_Ru and, in particular, to C³_Pt. The weaker binding may be due to a mismatch between cavity and guest size.⁴⁹ The larger TsO guest interacted with protons inside and outside the cavity of C⁴_Pt without reaching a plateau within 10 eq. of guest added (Fig. S38 and S39†), while it mainly interacted with the exo-cavity proton H-2 of C⁴_Ru (Fig. S48 and S49†). The binding constants were slightly larger for both MSAs than observed for MsO which may be explained by favorable hydrophobic interactions, as also seen between two molecules of TsO in the cavity of C⁴_Pt in modelling studies (Fig. S64†). As for MsO, the interaction with C³_Pt was significantly more pronounced than for C⁴_Pt (Table 1). The much larger cavity of C⁴_Pt may not favor the encapsulation of MsO and TsO. The endo-chlorido ligand of the RuCl₂ motif of C⁴_Ru reduces the cavity size compared to C⁴_Pt and this is reflected by the smaller binding constant observed for TsO.

Significant shifts of signals in the ¹H NMR spectra were observed when titrating NDS into solutions of C⁴_Pt (e.g., H-15 shifted by ca. 0.4 ppm downfield, the amide proton H-5 by 0.1 ppm upfield), which can be explained by a combination of the sulfonate groups being excellent H bond acceptors, and also having a doubly negative charge compared to the single negative charges of MsO and TsO. The binding constant K obtained for NDS encapsulation by C⁴_Pt was overall the highest at > 10⁵ M⁻¹ and demonstrates selectivity for this type of guest (Fig. 5). The binding of NDS in the cavity of C⁴_Pt is likely driven by a combination of coulombic interactions of the sulfonate groups with both Pd(II) and Pt(II) metal centers as well as H bonding to the endo-α-pyridyl protons H-1 and H-15, similar to the interactions observed for quinones and other guests with related structures in previously reported homometallic MSAs.^17,43 These interactions result in a pseudo-chelate effect where the guest interacts with both “ends” of the cage cavity. Binding of NDS to C⁴_Ru was observed to be much weaker (K = 1053 ± 168 M⁻¹) which reflects the effective blockage of the imine proton H-15 by the endo chlorido ligand (with loss of the chelate effect), the reduced effective charge at the Ru center and steric constraints, which consequently places the opposite sulfonate moiety into a non-ideal position or orientation for effective hydrogen bonding to protons H-1 and H-5 (Fig. S65†).

Fig. 5 Absolute changes in chemical shifts of H-1, H-5, and H-15 in the ¹H NMR spectra of C⁴_Pt and C⁴_Ru (inset) upon titration with up to 10 eq. NDS.

The interactions observed by NMR spectroscopy were supported by X-ray diffraction analysis of a crystal in which C⁴_Pt was found to have encapsulated NDS (C⁴_Pt⊂NDS; Fig. 6). Each flexible arm adopted a unique orientation in space, as also seen in the molecular structure of C⁴_Pt, to allow for the accommodation of a single NDS molecule in the cavity. The sulfonate motifs form hydrogen bonds to two of the amide groups and two of the α-pyridyl protons at the Pd end of C⁴_Pt. At the Pt center, the second sulfonate motif formed H bonds to the endo-facing α-pyridyl protons. Host–guest complex formation was supported by coulombic interactions of the sulfonate groups of NDS with both the Pd and Pt centers, as seen for 1,8-naphthalimide sulfonates in Pd₂L₄ cages.⁵⁶ However, the observed solid state structure is a snapshot of one possible host–guest conformation, and the solution NMR data is consistent with dynamic interconversion between different conformations (Fig. S40†).

Fig. 6 Molecular structure of C⁴_Pt⊂NDS drawn at 50% probability level. Solvents and counteranions have been omitted for clarity. The dashed lines indicate H bonds between the NDS oxygen atoms and protons of C⁴_Pt.

Investigation of the host guest properties of C⁴_Pt and C⁴_Ru conducted by ESI-MS confirmed the NMR spectroscopic data. Mass spectra of 1 : 1 mixtures of C⁴_Pt and MsO, TsO or NDS gave peaks at m/z 655.1681, 680.5120, and 1079.2435 which were assigned to [C⁴_Pt(–4BF₄) + MsO]³⁺, [C⁴_Pt(–4BF₄) + TsO],³⁺, and [C⁴_Pt(–4BF₄) + NDS]²⁺, respectively (Fig. 7 and S42–S44†), demonstrating interactions between the host and guest molecules. In competitive studies with 1 : 1 : 1 : 1 mixture of the anionic guests and C⁴_Pt, the stronger binding of NDS to C⁴_Pt was evidenced by the appearance of only the C⁴_Pt⊂NDS peak, with no evidence of peaks corresponding to the C⁴_Pt, C⁴_Pt⊂MsO, or C⁴_Pt⊂TsO species (Fig. 7 and S45†). This may be likened to properties similar to the chelate effect found for multidentate ligands in metal complexes. Furthermore, the lower binding constants observed for C⁴_Ru⊂MsO, C⁴_Ru⊂TsO and C⁴_Ru⊂NDS were consistent with the absence of host–guest complexes detected by ESI-MS.

Fig. 7 Stacked mass spectra of C⁴_Pt, C⁴_Pt incubated with MsO, TsO, or NDS (1 : 1) as well as with a mixture of guests (1 : 1 : 1 : 1).

Modelling (Spartan ′24^®, MMFF) of the host–guest chemistry of C⁴_Pt and C⁴_Ru with the neutral molecules cisplatin (cis), oxaliplatin (ox) and 5-fluorouracil (5-FU) within the cavities of C⁴_Pt and C⁴_Ru suggested 1 : 1, 1 : 2, and 1 : 3 adducts were possible (Fig. S66–S70†). Mixtures of these guests with C⁴_Pt or C⁴_Ru at molar ratios of 5 : 1 in DMSO-d₆ caused no shifts of proton resonances in the ¹H NMR spectra, most likely due to competition with DMSO for the binding site(s) within the cavities. However, qualitative guest-binding studies¹⁷ of cis, ox, and 5-FU with saturated solutions of C⁴_Pt or C⁴_Ru in CD₃CN or 10% DMSO/CD₃CN, respectively, could be carried out using ¹H NMR spectroscopy (Fig. 8). The ¹H NMR spectra of C⁴_Pt⊂cis and C⁴_Pt⊂5-FU showed significant shifts of internally facing resonances (H-1, H-5 and H-15) while no effects on the externally facing protons H-2 and H-14 were observed (Fig. 8, S52 and S56†). Incubation with ox resulted in less pronounced changes but shifts of the endo-facing protons were still visible. These data point towards interactions of the drugs within the cage cavity, rather than externally around the Pd and Pt centers, as was seen with the anionic guests in addition to endo-bonding (vide supra). The overall changes in chemical shifts, however, were less pronounced than those of previously reported MM′L₄ MSAs with smaller cavities.⁴⁹ Based on the relative change in chemical shift of these internal protons, we can conclude that the guest species are bound closer to the Pd center, likely due to H bond formation between the carbonyl oxygen atoms and the platinum guests and the NH protons in the case of 5-FU. Analogous studies with C⁴_Ru revealed prominent shifts of the amide NH (H-5) and imine CH (H-11; Fig. S56†) with only minor shifts of exo-facing protons, also suggesting interaction within the cavity of C⁴_Ru. Broadening of peaks H-12, H-14, and H-15 was observed in CD₃CN (Fig. S56; † and to a lesser extent in DMSO-d₆), which may be explained at least in part by C–H⋯Cl interactions with the exo- and endo-chlorido ligands at the Ru center.

Fig. 8 (top) ¹H NMR spectra (CD₃CN, 298 K, 400 MHz) of C⁴_Pt and mixtures of C⁴_Pt with 5-FU, cis, or ox (1 : 5). Shifts of endo-facing protons H-1, H-5, and H-15 are shown with dashed red lines. Vertical grey lines indicate the same chemical shift for the corresponding peak of C⁴_Pt (top spectrum). (bottom) ESI-mass spectrum of a 1 : 5 mixture of C⁴_Ru and cis.

The mass spectra of 1 : 5 mixtures of C⁴_Pt or C⁴_Ru and 5-FU indicated only weak interactions, with the 5-FU adducts being detected at <5% abundances relative to the MSAs (Table S1, Fig. S53 and S57†). Mixtures of both MSAs with the platinum complexes however revealed for C⁴_Pt host–guest complexes with up to two molecules of cis and 3 eq. of ox and even higher-level interaction with C⁴_Ru with up to six molecules of cis or ox attached to the cage (Fig. 8, S54, S55, S58, S59 and Table S1†). Some of these interactions will occur on the outside of the cavity, facilitated by the chlorido ligands, as molecular modelling suggested a maximum of three molecules of cis or ox are able to be bound within C⁴_Pt or C⁴_Ru (Fig. S66–S70†). The higher number of adducts observed for C⁴_Ru may be due to interactions between the exo-chlorido ligands and the Pt centers of the guests as found in the molecular structure of C⁴_Ru (vide supra). The differences between cis/ox and 5-FU to act as guest molecules can be explained by the H bond donating properties of the former. HCD (higher energy collisional dissociation) fragmentation of the isolated host–guest ions of [C⁴_Pt]⁴⁺ and [C⁴_Ru]⁴⁺ showed release of the guest molecules at NCE 10 (normalised collision energy) with the parent cage ions [C⁴_Pt]⁴⁺ and [C⁴_Ru]⁴⁺ remaining intact at m/z 467.6302 and m/z 924.2015, respectively (see Fig. S53–S55 and S57–S59†). The relative intensities of the host:guest ions versus the host ions at NCE 10 reflect differences in the gas phase stability of the inclusion complexes with the neutral guest molecules and decrease in the order ox > cis > 5-FU for C⁴_Pt and 5-FU > ox > cis for C⁴_Ru.

Conclusions

Heterodimetallic M(μ-L)₄M′ MSAs based on non-symmetric bridging ligands have been shown to disassemble and reassemble upon the addition of external stimuli as well as host a variety of guest molecules in their cavities. We obtained the Pd(μ-L)₄Pt C⁴_Pt and Pd(μ-L)₄RuCl₂C⁴_Ru MSAs via subcomponent self-assembly using a 4,4′-methylenedianiline-based linker. This approach resulted in the largest Pd(μ-L)₄M cages known so far. With inter-metal distances of 15.48 and 15.21 Å for C⁴_Pt and C⁴_Ru, respectively, they are much larger than the closely related C¹_Pt–C³_Pt and C¹_Ru–C³_Ru MSAs. C⁴_Pt and C⁴_Ru underwent rapid selective opening at the Pd center upon addition of four eq. of DMAP to liberate palladium(II) as [Pd(DMAP)₄]²⁺, however the kinetics of reassembly with addition of p-TsOH were much slower than found for the equivalent smaller cages, which can be explained by the increased flexibility and length of the bridging ligands. The sulfonate-containing guests MsO and TsO were bound only weakly in the cavities of C⁴_Pt and C⁴_Ru. However, the 2⁻ charged guest NDS interacted strongly with C⁴_Pt although the binding constant to C⁴_Ru was 2 orders of magnitude lower. This lower binding constant can be attributed to the endo-chlorido ligand at the Ru center preventing H bonding to the internal α-pyridyl protons as well as reducing the coulombic interactions between the cage and the guest. Single crystal X-ray crystallographic studies demonstrated that the host–guest complex C⁴_Pt⊂NDS formed with one NDS guest occupying the cavity. The smaller MSAs C³_Pt and C³_Ru allowed effective discrimination between MsO and TsO based on size and coulombic interactions. However, these cages were too small to bind NDS effectively. The binding constants observed for C⁴_Pt and C⁴_Ru with MsO and TsO were significantly smaller when compared to C³_Pt which we explain by a mismatch between cavity and guest size.

¹H NMR spectroscopy and ESI-MS also demonstrated binding with the neutral guests cis, ox, and 5-FU within the cavity of both cages, with the number of guest molecules incorporated determined by the sizes and H bond donor properties of the guest molecules.

This study presents the second example of a M(μ-L)₄M′ cage with an octahedral metal center and demonstrates that the chlorido ligands coordinated to the Ru center have a larger role to play in tuning the host–guest interaction than anticipated from studies on smaller cages. Introduction of chlorido co-ligands expands the range of possible interactions that can occur between the host and guest molecules but also changes the overall charge of the cage and reduces direct accessibility to host metal centers, which are both important areas to further explore in the search for new applications of supramolecular architectures.

Data availability

The data supporting this article have been included as part of the ESI.†

Author contributions

Hayden B. Gearing: synthesis, binding studies, original draft; Monika Cziferszky: mass spectrometry studies; Tilo Söhnel: crystallography; L. James Wright: conceptualization, funding, writing – review and editing; James D. Crowley: supervision, conceptualization, funding, writing – review and editing; Christian G. Hartinger: supervision, conceptualization, funding, writing – review and editing.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

H. B. G. thanks the University of Auckland for a PhD scholarship. The work was supported by the Marsden Fund Council from Government funding (UOA1726), administered by the Royal Society of New Zealand. We are grateful to Dr Timothy Christopher and Dr Githal Arachchige for collecting the X-ray diffraction and mass spectrometry data.

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Footnote

† Electronic supplementary information (ESI) available: The syntheses of the MSAs, characterization data, additional figures of the molecular structures, experimental data for the disassembly and reassembly reactions, as well as host guest binding studies by NMR, ESI-MS and molecular modelling. CCDC 2389021–2389023. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d5sc00209e

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