Coordination sphere interactions drive isomer selection in heteroleptic Pd(II) cages with low-symmetry ligands

Abstract

The targeted formation of low-symmetry coordination cages represents a significant design challenge but offers the potential to engineer bespoke molecular hosts with precision. In this work, we have combined the design principles of geometric complementarity and coordination sphere engineering to direct the site- and orientation-selective self-assembly of heteroleptic Pd₂L^A₂L^B₂-type coordination cages from low-symmetry ligands. The effects of different combinations of heterocyclic donors and their locations within the cage structures on isomer distributions were studied, providing insights on shifts in the balance between non-covalent interactions in the first and second coordination spheres of the cages. For cages with one low-symmetry ligand, switching between selective formation of syn- (up to 77%) or anti-isomers (up to 76%) was achieved simply through minor structural changes (swapping a hydrogen atom for a fluorine) or changing the location of heterocycles within the cage structure between the different ligand scaffolds. Furthermore, the selective (up to ∼62%) assembly of particular isomers of heteroleptic cages formed from two low-symmetry ligand scaffolds was demonstrated and rationalised.

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Introduction

Coordination cages are discrete, three-dimensional, metal–organic assemblies with appreciable internal cavities capable of binding guest species.¹ Host–guest chemistry within these confined spaces has been exploited for binding anions,² pollutants,³ drugs⁴ and gases,⁵ and for use in catalysis,⁶ stabilisation of reactive species⁷ and molecular separations.⁸

Most commonly, coordination cages are assembled from single, high-symmetry ligands, generally resulting in highly symmetrical architectures. More structurally sophisticated, low-symmetry cages, however, have the potential to exhibit bespoke properties and behaviours.⁹ As such, there has been interest in developing strategies for the site-selective assembly of heteroleptic (mixed-ligand) cages¹⁰ (Fig. 1a), and the orientation-selective assembly of cages from low-symmetry ligands¹¹ (Fig. 1b). In both instances, without sufficient driving force, statistical mixtures of isomers (and other assemblies) can form. Very recently, solutions to the challenge of incorporating low-symmetry ligands into heteroleptic cages (Fig. 1c) have also begun to be investigated.¹²

Fig. 1 Approaches to reduced symmetry coordination cages include (a) heteroleptic cages with combinations of ligands, (b) homoleptic cages assembled from low-symmetry ligands, and (c) heteroleptic cages assembled from (i) one or (ii) two low-symmetry ligands in which isomer selectivity can be tuned through structural design (this work).

Geometric complementarity between ligands has been used to drive the formation of heteroleptic structures,¹³ and similar design ideas have enabled the orientation-selective assembly of low-symmetry ligands.¹⁴ Coordination sphere engineering – using non-covalent interactions, such as steric bulk or hydrogen bonding (HB), to direct the coordination environment around metal ions¹⁵ – is another strategy that has been successfully employed within both heteroleptic¹⁶ and low-symmetry ligand systems.¹⁷

We recently investigated the self-assembly of homoleptic Pd_nL_2n assemblies from low-symmetry ligands that incorporated either quinoline or picoline donors in combination with unsubstituted pyridines.¹⁸ Molecular modelling demonstrated that arranging the bulky quinoline/picoline donors trans to each other would give the lowest energy assemblies. Although experimentally this held true for ligands with picoline donors, quinolines unexpectedly favoured formation of cis-Pd_nL_2n species. This difference in isomer selectivity was shown to be due to HB interactions between acidic protons of the coordinating donor units and solvent molecules. Such intermolecular non-covalent interactions within the second coordination spheres of the Pd(II) ions of the cages could therefore override primary structural factors (i.e. steric bulk) in dictating self-assembly outcomes.

Within this previous work we reported a preliminary investigation of the heteroleptic cage Pd₂1AB₂2AA₂ (see below) which, due to the unsymmetrical structure of ligand 1AB, could exist as syn- and anti-isomers (Fig. 2). Chemical intuition, combined with molecular modelling, suggested the anti-isomer, with bulky quinoline groups situated far apart, would be lower in energy. The experimentally observed predominant formation of the more sterically encumbered syn-isomer, however, again suggested stabilising interactions in the second coordination sphere of the cage were superseding repulsive steric interactions in the first coordination sphere.

Fig. 2 Self-assembly of low-symmetry ligands 1 and ligands 2/3/4 with Pd(II) ions forms syn- and anti-isomers, the latter of which are calculated (GFN2-xTB) to be lower in energy.

Stemming from this initial result, we were motivated to investigate a wider range of heteroleptic structures to observe the impact on isomer selectivity. In this regard, we wished to explore how isomer selectivity was influenced by (i) the identity of the symmetrical ligand; (ii) the combination of different heterocyclic donors on the unsymmetrical ligand, and (iii) the relative locations of the different donors within the cages. Finally, we also sought to achieve (iv) the selective formation of particular isomers of Pd₂L^A₂L^B₂ cages assembled from two low-symmetry ligands. Gaining insights into how the, often subtle, balance of interactions that drive self-assembly outcomes can be shifted through design of structure and function will aid in the future development of structurally sophisticated metal–organic assemblies.

Results and discussion

System design and nomenclature

In this work we explored ligand scaffolds 1 and 2 (Fig. 2) that have previously been shown by Severin to be geometrically matched and able to undergo integrative self-assembly with Pd(II) ions to form cis-[Pd₂1₂2₂]⁴⁺ heteroleptic cages.¹⁹ Ligands 3 and 4 are isostructural to 2 except that the core benzene unit is replaced with a pyridine and toluene, respectively. Each ligand has two N-heterocyclic donors. A two letter combination is used within each ligand name to signify which heterocycles are incorporated into the ligand: pyridine (A), quinoline (B), 2-picoline (C), 2-fluoropyridine (D), and 8-fluoroquinoline (E). Ligand 2AA, for example, has a 1,3-diethynylbenzene core (2) and two pyridyl donors (A).

All ligands used in this work were synthesised using standard techniques and characterised by NMR spectroscopy and high resolution mass spectrometry (HR-MS). Details can be found in the SI.

All the cages in this work are tetracationic and prepared as the BF₄⁻ salts. For clarity, however, the charge and counterions are generally omitted from the main text. For example, [Pd₂1AA₂2AA₂](BF₄)₄ may be written as Pd₂1AA₂2AA₂. Formation of the heteroleptic cages was confirmed by NMR spectroscopy, ¹H DOSY and electrospray ionisation (ESI) MS. Details can be found in the SI.

Quinoline donor on diverging ligand

Ligand 1AB incorporates two different donors: an unsubstituted pyridine (A), and a bulkier quinoline (B). We previously reported the self-assembly of heteroleptic cage Pd₂1AB₂2AA₂ (Fig. 3a) in CD₃CN that formed predominantly as the intuitively more sterically encumbered syn-isomer.¹⁸ This result is contrary to chemical intuition and molecular modelling (GFN2-xTB/MeCN²⁰ calculated in Orca²¹) of the cationic cage architecture alone (Fig. 2) which does not consider intermolecular interactions. This indicated that interactions beyond the primary structure of the cage were influencing isomer selectivity.

Fig. 3 Partial ¹H NMR spectra (400 MHz, CD₃CN, 298 K), with major syn-isomer peaks labelled, of (a) [Pd₂1AB₂2AA₂](BF₄)₄, (b) [Pd₂1AB₂3AA₂](BF₄)₄, and (c) [Pd₂1AB₂4AA₂](BF₄)₄. (d) Partial NOESY spectrum (600 MHz, CD₃CN, 298 K) of [Pd₂1AB₂2AA₂](BF₄)₄ with key peaks used to identify the syn- (s) and anti-isomers (a).

To explore the generality of this design, the self-assembly of 1AB with alternative symmetric ligands 3AA and 4AA (featuring pyridyl and tolyl core units, respectively) was investigated. To this end, 1AB and 3AA/4AA were combined in a 1 : 1 ratio with [Pd(CH₃CN)₄](BF₄)₂ (used as the source of Pd(II) throughout this work) in MeCN and equilibrated at 70 °C for 24 h. Formation of the desired [Pd₂1₂3/4₂]⁴⁺ cage structures was confirmed by ESI-MS, and the existence of both syn- and anti-isomers demonstrated by NMR spectroscopy (Fig. 3b and c).

The syn- and anti-isomers of these cages could be readily distinguished by NOESY (e.g. Fig. 3d); interactions between protons from the two ends of 1AB (e.g. H_B⋯H_I) would only be expected from the antiparallel arrangement present in the anti-isomer (and were only observed for the minor species in each instance).

Both Pd₂1AB23AA₂ and Pd₂1AB₂4AA₂ formed the syn-isomer as the major product in similar amounts to the previously reported Pd₂1AB₂2AA₂ (77 ± 5%; Fig. S292). The identity of the core unit in ligand 2/3/4 was therefore shown not to materially affect isomer selectivity.

Picoline donor on diverging ligand

Ligand 1AC features a 2-picolyl donor (C) in combination with an unsubstituted pyridine (A). In contrast to 1AB, 1AC does not possess acidic exohedral protons adjacent to the coordinating atoms of the bulky donor. Based on this, it was predicted that the heteroleptic cages with 2AA, 3AA and 4AA would all form predominantly as the anti-isomers to avoid steric clash between the picolyl units. It was somewhat surprising, therefore, that all three of the cages also formed the syn-isomers as the major products (∼66 ± 5%; Fig. S293) in CD₃CN (Fig. 4a and b).

Fig. 4 (a) Partial ¹H NMR spectrum (600 MHz, CD₃CN, 298 K), with major syn-isomer peaks labelled, of [Pd₂1AC₂2AA₂](BF₄)₄. (b) Partial NOESY spectrum (600 MHz, CD₃CN, 298 K) of [Pd₂1AC₂2AA₂](BF₄)₄ with key peaks used to identify the syn- (s) and anti-isomers (a). (c) Visualisation of the coordination sphere sites of anti- and syn-Pd₂1AC₂2AA₂ cage isomers from geometry-optimised models (GFN2-xTB). (d) SCXRD structures of syn-[Pd₂1AC₂3AA₂]⁴⁺, showing endohedral BF₄⁻ counterion and exohedral CH₃CN solvent molecule interacting with the cage, and anti-[Pd₂1AC₂4AA₂]⁴⁺.

This selectivity was rationalised by comparing the coordination environments of the syn- and anti-isomers (Fig. 4c). A single picolyl unit on both faces of the anti-isomers is sufficient to significantly block interactions with both external coordination spheres of the cages. In contrast, the syn-isomers provide two different coordination spheres: one with two picolyl units, and a second, unencumbered, tetrapyridyl environment. The latter provides a single site with acidic protons H_B and H_b′ that could engage in HB interactions to stabilise the otherwise unfavourable accumulation of steric bulk at the other end of the cage. This idea was supported by single crystal X-ray diffraction (SCXRD) studies (see below). As such, intermolecular non-covalent interactions on just one face of the cages are sufficient to overcome intramolecular steric interactions.

It is noted that Pd₂1AC₂4AA₂ did not form exclusively as the heteroleptic assemblies. This was most likely the result of partial occlusion of the cavity by the tolyl methyl group, inhibiting access for anions/solvents necessary as templates.

The solid-state structures of Pd₂1AC₂3AA₂ and Pd₂1AC₂4AA₂ were determined by SCXRD (Fig. 4d). Intriguingly, Pd₂1AC₂4AA₂ crystallised as the minor anti-isomer; this is presumably simply a facet of solid-state packing interactions. The structure of syn-Pd₂1AC₂3AA₂ revealed an acetonitrile molecule engaging in quadfurcated hydrogen bond interactions with the tetrapyridyl face of the cage (C–H⋯N 2.62–2.72 Å), supporting the idea that such interactions could stabilise the syn-isomers in solution.²²

Alternative donor combinations on diverging ligand

To see how modifications to the donor units affected isomer selectivity, four variants of 1AB were prepared (Fig. 5). 1BC and 1BD possess quinoline donors (B) combined with 2-picoline (C) or 2-fluoropyridine (D), respectively, whilst an 8-fluoroquinoline (E) donor was incorporated with an unsubstituted pyridine (A) into ligand 1AE. In each of these ligands, compared to 1AB, acidic protons on either the pyridine (1BC and 1BD) or quinoline (1AE) were replaced with moieties that could not act as HB donors. Finally, 1CE, with both picoline and 8-fluoroquinoline donors, was also synthesised.

Fig. 5 Summary of the observed syn/anti ratios in CD₃CN for combinations of low-symmetry ligands 1, with various donor combinations, and symmetrical ligand 2AA.

In the case of Pd₂1BC₂2AA₂, a 1 : 1 mixture of the syn- and anti-isomers formed (Fig. S294), demonstrating a loss of selectivity. Computational modelling revealed an insignificant (∼1 kJ mol⁻¹) energy difference between the two isomers. As such, it can be concluded that the sum of interaction energies in the first and second coordination spheres for each isomer are virtually identical.

Both Pd₂1BD₂2AA₂ and Pd₂1AE₂2AA₂ (Fig. 6a and b) formed predominantly (∼70% each) as the anti-isomers (confirmed by NOESY analysis, e.g. Fig. 6c). As the substitution of hydrogen atoms for fluorine is widely regarded to have minimal impact on steric bulk,²³ additional steric hindrance beyond that of Pd₂1AB₂2AA₂ would not seem to be a major factor in the observed inversion of isomer selectivity. The loss of acidic protons capable of forming HB interactions, combined with electrostatic repulsion between fluorine atoms, seem more likely to be the major driving forces in promoting formation of the anti-isomer with these systems. As such, Pd₂1CE₂2AA₂, with no acidic exohedral protons on ligand 1, was expected to form almost exclusively as the anti-isomer. Although this was indeed the major product (∼76%), the formation of significant amounts of the syn-isomer suggested that it was still possible to achieve substantive non-covalent interactions in the second coordination spheres of the syn-isomer.

Fig. 6 Partial ¹H NMR spectra (600 MHz, CD₃CN, 298 K) of (a) [Pd₂1BD₂2AA₂](BF₄)₄ and (b) [Pd₂1AE₂2AA₂](BF₄)₄ with major anti-isomer peaks labelled; partial NOESY spectrum (600 MHz, CD₃CN, 298 K) of [Pd₂1AE₂2AA₂](BF₄)₄ with key peaks used to identify the major anti-isomer; (d) partial ¹H NMR spectrum (400 MHz, CD₃CN, 298 K) of [Pd₂1CE₂2AA₂](BF₄)₄ with major anti-isomer peaks labelled; (e) geometry-optimised models (GFN2-xTB) of the major anti-isomers of these cages.

The combinations of donor heterocycles investigated demonstrated varying isomer ratios could be achieved (24 to 77% syn). The energy-raising steric interactions between quinoline and picoline units in 1AB and 1AC in syn-Pd₂1₂2AA₂ could be offset by stabilising non-covalent interactions with the cages, whilst repulsive interactions between fluorinated heterocycles in 1BD and 1AE were sufficient to promote formation of anti-isomers. Indeed, inversion of the isomer selectivity between favouring anti and syn could be achieved through simply replacing a proton with a fluorine (1AE and 1BD vs. 1AB), demonstrating the potential for minor structural modifications to be used to drastically alter self-assembly profiles.

Bulky donors on converging ligand

Having observed preferential formation of the syn-isomers of Pd₂1AB₂2AA₂ and Pd₂1AC₂2AA₂, it was sought to determine whether there would be any impact on isomer selectivity from locating the bulky donors on the converging ligand, 2, instead of the diverging ligand. To this end, the heteroleptic cages assembled from 1AA and unsymmetric 2AB/2AC (Fig. 7a) were examined.

Fig. 7 (a) Structure of ligands 1AA, 2AB and 2AC. Partial ¹H NMR spectra (600 MHz, CD₃CN, 298 K), with major anti-isomer peaks labelled, of (b) [Pd₂1AA₂2AB₂]⁴⁺ and (c) [Pd₂1AA₂2AC₂]⁴⁺. (d) Structures of anti-isomers of P-[Pd₂1AA₂2AB₂]⁴⁺ (SCXRD) and M-[Pd₂1AA₂2AC₂]⁴⁺ (GFN2-xTB geometry-optimised model).

In contrast to the previously studied systems with 1AB and 1AC, NMR analysis (in CD₃CN; Fig. 7b and c) of the Pd₂1AA₂2AB/2AC₂ cages showed the anti-isomers to be the major species for both (∼73% (Fig. S298) and ∼70% (Fig. S299) with 2AB and 2AC, respectively). The solid-state structure of anti-[Pd₂1AA₂2AB₂](BF₄)₄ was also determined by SCXRD (Fig. 7d; the cage crystallised as a racemic mixture of the P and M enantiomers).²⁴ This subtle design change was thus sufficient to shift the balance between coordination sphere interactions driving the isomer selectivity. Geometry-optimised models of the syn- and anti-isomers of cis-[Pd₂1AA₂2AB/2AC₂]⁴⁺ suggested the former were more sterically crowded compared to the cis-[Pd₂1AB/1AC₂2AA₂]⁴⁺ systems, manifested as an increase in relative computed energy compared to the anti-isomers (ΔE = 18.3 and 16.1 kJ mol⁻¹ for the 2AB and 2AC cages, respectively). Thus, by slightly increasing the steric hindrance between bulky donors in the syn-isomers, simply through changing their location within the cages, this became the major driving force in isomer selectivity.

Cages assembled from two low-symmetry ligands

Finally, the self-assembly of four possible cages from pairs of low-symmetry ligands, namely 1AB, 1AC, 2AB and 2AC, were investigated (Fig. 8a). For such cis-Pd₂L^A₂L^B₂ systems there are six possible isomers (excluding enantiomers, I–VI; Fig. 8) depending upon the relative orientation of the two different low-symmetry ligands. Based on previous results it was anticipated that isomer VI would inherently be the lowest energy isomer based on steric arguments due to the trans arrangement of bulky donor units. This was supported by molecular modelling (GFN2-xTB) that showed VI to be the lowest energy isomer by at least 13 kJ mol⁻¹ for all four ligand combinations (Table S8–S11). Selective formation of this isomer would suggest minimising steric hindrance was the primary driving force dictating relative ligand orientation, whilst formation of other isomers would indicate alternative interactions were prominent.

Fig. 8 (a) The selective formation of particular isomers of Pd₂L^A₂L^B₂-type cages (GXN2-xTB geometry-optimised models shown) from combinations of ligands 1AB/1AC and 2AB/2AC was observed. Partial ¹H NMR spectra (600 MHz, 298 K) of (b) [Pd₂1AB₂2AB₂](BF₄)₄ (d₆-DMSO) with peaks assigned to major isomer V labelled (# = minor isomer; * = [Pd₂2AB₄]⁴⁺); and (c) [Pd₂1AC₂2AC₂](BF₄)₄, (d) [Pd₂1AB₂2AC₂](BF₄)₄, and (e) [Pd₂1AC₂2AB₂](BF₄)₄ (all CD₃CN) with peaks assigned to major product, isomer VI, labelled.

For the combination of 1AB and 2AB an ill-defined mixture formed in CD₃CN that defied analysis. Repeating the self-assembly in d₆-DMSO resulted in more tractable NMR data (Fig. 8b). Signals in the ¹H NMR spectrum could be readily identified for the homoleptic assembly of 2AB (∼30% yield). Two additional sets of signals, however, belonged to Pd₂1AB₂2AB₂ cage isomers (the formation of which was confirmed by ESI-MS) forming approximately 35% and 13% of the mixture. NOESY allowed assignment of the major cage isomer as V. As such, preferential formation of a cis arrangement of quinoline donors was observed, suggesting that interactions in the second coordination sphere were the major drivers of isomer selectivity for this system.

A single major species was observed to form in ∼62% yield (Fig. S301) from the equilibrated 1 : 1 : 1 mixture of 1AC, 2AC and [Pd(CH₃CN)₄](BF₄)₂ in CD₃CN (Fig. 8c). ESI-MS confirmed the anticipated formulation of the assembled heteroleptic structure. NOE coupling (Fig. 9) of both methyl groups (H_G of 1AC and H_k of 2AC) with both external ortho pyridyl protons (H_B of 1AC and H_b of 2AC) was consistent with only two possible isomers, with the picolyl units arranged either cis (III) or trans (VI) to each other. NOE coupling (Fig. 9 inset) exclusively between internal protons H_A and H_l and between H_H and H_a (and not H_A⋯H_a or H_H⋯H_l) and the lack of coupling between H_b and H_B, however, confirmed that the major product formed was isomer VI. Thus, alleviation of steric hindrance appeared to be the primary driving force in isomer selectivity.

Fig. 9 Partial NOESY spectrum (600 MHz, CD₃CN, 298 K) of [Pd₂1AC₂2AC₂](BF₄)₄ identifying the major product as isomer VI.

Similarly, both Pd₂1AB₂2AC₂ and Pd₂1AC₂2AB₂ (Fig. 8d and e, respectively) formed isomer VI as the major species (each ∼45% yield; Fig. S302 and S303), with pairs of quinoline and picoline donors arranged trans to each other on opposite faces of the cage. Again, this suggested minimising steric interactions was the major driving force at play.

These results are consistent with the earlier systems examined. For alternative isomers than VI to be formed, suitable sites for non-covalent interactions would need to be accessible. This is possible with isomer I, but having all four bulky heterocycles on one face raises the system energy too much (ΔE >40 kJ mol⁻¹ relative to VI). Isomers that provide a syn orientation of 2AB or 2AC (II and V) were previously shown to be relatively unfavourable, while isomers III and IV would place picoline and quinoline units adjacent to each other, inhibiting access to the acidic quinolyl protons. Thus, the preferential formation of isomer VI can be rationalised based on the principles established in this work.

Conclusions

We have investigated the self-assembly of heteroleptic Pd₂L^A₂L^B₂-type coordination cages from low-symmetry ligands incorporating different combinations of heterocyclic donors. Integrative self-assembly of the two ligands is directed by geometric complementarity, while the relative orientation of the low-symmetry scaffolds (i.e. isomer selectivity) is driven by coordination sphere interactions. Isomer selectivity could be changed by relatively subtle structural variations, including exchanging a proton for a fluorine atom, or changing the relative locations of heterocycles within the cage structures.

In the case of cages assembled with one low-symmetry ligand, this allowed formation of cages primarily as the syn-isomer (up to ∼77%), primarily as the anti-isomer (up to ∼76%), or an approximately equal mixture of the two. Selective formation of particular isomers of heteroleptic cages assembled from two low-symmetry ligands (up to ∼62%) was also demonstrated, the assembly of which could be rationally explained from the underlying design principles delineated from this work. As such, we have shown how ligand design can be used to promote interactions in the first or second coordination spheres as the major drivers of isomer selectivity.

Through the combined computational and experimental investigations of the systems explored, it has been possible to gain insight into how structural designs can modulate the relative impact of both intramolecular (first coordination sphere) and intermolecular (second coordination sphere) interactions in directing self-assembly outcomes. In the continued pursuit of developing ever more structurally sophisticated metallo-supramolecular assemblies, understanding (i) how different directing strategies can be used in a synergistic manner, and (ii) the effects of environment (e.g. solvent) on thermodynamic self-assembly processes, will enable the design of increasingly structurally and functionally advanced, precision-engineered systems capable of exhibiting bespoke and nuanced properties and behaviours.

Author contributions

PM carried out the synthesis, characterisation and data analysis. PM and LM collected and analysed the SCXRD data. JEML conceived and directed the project, secured funding, performed molecular modelling, aided data analysis and wrote the manuscript. All authors contributed to editing and approved the final manuscript.

Conflicts of interest

There are no conflicts to declare.

Data availability

CCDC 2390755 ([Pd₂1AA₂2AB₂](BF₄)₄), 2390756 ([Pd₂1AC₂4AA₂](BF₄)₄) and 2390758 ([Pd₂1AC₂3AA₂](BF₄)₄) contain the supplementary crystallographic data for this paper.^25a–c

The data supporting this article have been included as part of the SI. See DOI: https://doi.org/10.1039/d5sc04881h.

Acknowledgements

We thank Dr Cécile Le Duff for assistance with the collection of NMR data, Dr Christopher Williams for the collection of MS data, and HWB-NMR staff at the University of Birmingham for providing open access to their NMR spectrometers. Dr Dan Preston (ANU) is thanked for useful discussions and optimism. This work was supported by the Royal Society (URF\R1\221740 and RF\ERE\221016) and the University of Birmingham (including a PhD studentship to PM). JEML is a Royal Society University Research Fellow.

References

1. (a) A. Schmidt, A. Casini and F. E. Kühn, Coord. Chem. Rev., 2014, 275, 19; (b) T. R. Cook and P. J. Stang, Chem. Rev., 2015, 115, 7001; (c) M. D. Ward, C. A. Hunter and N. H. Williams, Acc. Chem. Res., 2018, 51, 2073; (d) D. Zhang, T. K. Ronson and J. R. Nitschke, Acc. Chem. Res., 2018, 51, 2423; (e) B. S. Pilgrim and N. R. Champness, ChemPlusChem, 2020, 85, 1842; (f) S. Lee, H. Jeong, D. Nam, M. S. Lah and W. Choe, Chem. Soc. Rev., 2021, 50, 528; (g) J. E. M. Lewis, Chem. Commun., 2022, 58, 13873; (h) T. Teteishi, M. Yoshimura, S. Tokuda, F. Matsuda, D. Fujita and S. Furukawa, Coord. Chem. Rev., 2022, 467, 214612; (i) A. J. McConnell, Chem. Soc. Rev., 2022, 51, 2957; (j) R. Banerjee, D. Chakraborty and P. S. Mukherjee, J. Am. Chem. Soc., 2023, 145, 7692; (k) S. Sharma, M. Sarkar and D. K. Chand, Chem. Commun., 2023, 59, 535; (l) C. J. T. Cox, J. Hale, P. Molinska and J. E. M. Lewis, Chem. Soc. Rev., 2024, 53, 10380.
2. (a) R. Custelcean, Chem. Soc. Rev., 2014, 43, 1823; (b) D. Preston, K. M. Patil, A. T. O'Neil, R. A. S. Vasdev, J. A. Kitchen and P. E. Kruger, Inorg. Chem. Front., 2020, 7, 2990; (c) B. J. J. Timmer and T. J. Mooibroek, Chem. Commun., 2021, 57, 7184; (d) S. J. Allison, J. Bryk, C. J. Clemett, R. A. Faulkner, M. Gingner, H. B. S. Griffiths, J. Harmer, P. J. Owen-Lynch, E. Pinder, H. Wurdak, R. M. Phillips and C. R. Rice, Nat. Commun., 2021, 12, 3898; (e) V. Sivalingam, S. Krishnaswamy and D. K. Chand, Chem.–Eur. J., 2023, 29, e202300891; (f) S. Sudan, D. W. Chen, C. Berton, F. Fadaei-Tirani and K. Severin, Angew. Chem., Int. Ed., 2023, 62, e202218072; (g) W.-L. Jiang, B. Huang, X.-L. Zhao, X. Shi and H.-B. Yang, Chem, 2023, 9, 2655; (h) Y.-L. Lai, m. Xie, X.-C. Zhou, X.-Z. Wang, X.-W. Zhu, D. Luo, X.-P. Zhou and D. Li, Angew. Chem., Int. Ed., 2024, 63, e202402829; (i) J. I. Virtue, S. Tsoukatos, M. R. Johnston and W. M. Bloch, Chem. Sci., 2024, 15, 19119.
3. (a) E. G. Percástegui, Chem. Commun., 2022, 58, 5055; (b) I. A. Riddell, M. M. J. Smulders, J. K. Clegg and J. R. Nitschke, Chem. Commun., 2011, 47, 457; (c) C. G. P. Taylor, J. R. Piper and M. D. Ward, Chem. Commun., 2016, 52, 6225; (d) S. Ganta and D. K. Chand, Inorg. Chem., 2018, 57, 3634; (e) A. Platzek, S. Juber, C. Yurtseven, S. Hasegawa, L. Schneider, C. Drechsler, K. E. Ebbert, R. Rudolf, Q.-Q. Yan, J. J. Holstein, L. V. Schäfer and G. H. Clever, Angew. Chem., Int. Ed., 2022, 61, e202209305; (f) T. K. Ronson, J. P. Carpenter and J. R. Nitschke, Chem, 2022, 8, 557.
4. (a) J. E. M. Lewis, E. L. Gavey, S. A. Cameron and J. D. Crowley, Chem. Sci., 2012, 3, 778; (b) Y.-R. Zheng, K. Suntharalingam, T. C. Johnstone and S. L. Lippard, Chem. Sci., 2015, 6, 1189; (c) A. Schmidt, V. Molano, M. Hollering, A. Pöthig, A. Casini and F. E. Kühn, Chem.–Eur. J., 2016, 22, 2253; (d) Y. Fang, X. Lian, Y. Huang, G. Fu, Z. Xiao, Q. Wang, B. Nan, J.-P. Pellois and H.-C. Zhou, Small, 2018, 14, 1802709; (e) F. J. Rizzuto, J. P. Carpenter and J. R. Nitschke, J. Am. Chem. Soc., 2019, 141, 9087; (f) G. Li, T. K. Ronson, R. Lavendomme, Z. Huang, C. Fuertes-Espinosa, D. Zhang and J. R. Nitschke, Chem, 2023, 9, 1549; (g) Y.-H. Huang, Y.-L. Lu, Z.-M. Cao, X.-D. Zhang, C.-H. Liu, H.-S. Xu and C.-Y. Su, J. Am. Chem. Soc., 2024, 146, 21677; (h) G. Montà-González, D. Bastante-Rodríguez, A. García-Fernández, P. J. Lusby, R. Martínez-Máñez and V. Martí-Centelles, Chem. Sci., 2024, 15, 10010.
5. (a) A. J. Gosselin, C. A. Rowland and E. D. Bloch, Chem. Rev., 2020, 120, 8987; (b) Q.-W. Zeng, L. Hu, Y. Niu, D. Wang, Y. Kang, H. Jia, W.-T. Dou and L. Xu, Chem. Commun., 2024, 60, 3469; (c) J. Roukala, J. Zhu, C. Giri, K. Rissanen, P. Lantto and V.-V. Telkki, J. Am. Chem. Soc., 2015, 137, 2411; (d) D. Preston, K. F. White, J. E. M. Lewis, R. A. S. Vasdev, B. F. Abrahams and J. D. Crowley, Chem.–Eur. J., 2017, 23, 10559; (e) J. S. Wright, A. J. Metherell, W. M. Cullen, J. R. Piper, R. Dawson and M. D. Ward, Chem. Commun., 2017, 53, 4398; (f) C. A. Rowland, G. R. Lorzing, A. J. Gosselin, B. A. Trump, G. P. A. Yap, C. M. Brown and E. D. Bloch, J. Am. Chem. Soc., 2018, 140, 11153; (g) J.-L. Zhu, D. Zhang, T. K. Ronson, W. Wang, L. Xu, H.-B. Yang and J. R. Nitschke, Angew. Chem., Int. Ed., 2021, 60, 11789.
6. (a) C. J. Brown, F. D. Toste, R. G. Bergman and K. N. Raymond, Chem. Rev., 2015, 115, 3012; (b) Y. Xue, X. Hang, J. Ding, B. Li, R. Zhu, H. Pang and Q. Xu, Coord. Chem. Rev., 2021, 430, 213656; (c) T. K. Piskorz, V. Martí-Centelles, R. L. Spicer, F. Duarte and P. J. Lusby, Chem. Sci., 2023, 14, 11300; (d) M. Yoshizawa, M. Tamura and M. Fujita, Science, 2006, 312, 251; (e) M. D. Pluth, R. G. Bergman and K. N. Raymond, Science, 2007, 316, 85; (f) J. L. Bolliger, A. M. Belenguer and J. R. Nitschke, Angew. Chem., Int. Ed., 2013, 52, 7958; (g) X. Jing, C. He, Y. Yang and C. Duan, J. Am. Chem. Soc., 2015, 137, 3967; (h) V. Martí-Centelles, A. L. Lawrence and P. J. Lusby, J. Am. Chem. Soc., 2018, 140, 2862; (i) W. Cullen, A. J. Metherell, A. B. Wragg, C. G. P. Taylor, N. H. Williams and M. D. Ward, J. Am. Chem. Soc., 2018, 140, 2821; (j) A. Paul, M. A. Shipman, D. Y. Onabule, S. Sproules and M. D. Symes, Chem. Sci., 2021, 12, 5082; (k) S. M. Bierschenk, J. Y. Pan, N. S. Settineri, U. Warzok, R. G. Bergman, K. N. Raymond and F. D. Toste, J. Am. Chem. Soc., 2022, 144, 11425; (l) E. O. Bobylev, J. Ruijter, D. A. Poole III, S. Mathew, B. de Bruin and J. N. H. Reek, Angew. Chem., Int. Ed., 2023, 62, e202218162; (m) R. G. DiNardi, S. Rasheed, S. S. Capomolla, M. H. Chak, I. A. Middleton, L. K. Macreadie, J. P. Violi, W. A. Donald, P. J. Lusby and J. E. Beves, J. Am. Chem. Soc., 2024, 146, 21196.
7. (a) M. Yoshizawa, T. Kusukawa, M. Fujita and K. Yamaguchi, J. Am. Chem. Soc., 2000, 122, 6311; (b) P. Mal, B. Breiner, K. Rissanen and J. R. Nitschke, Science, 2009, 324, 1697; (c) M. Yamashina, Y. Sei, M. Akita and M. Yoshizawa, Nat. Commun., 2014, 5, 4662; (d) M. Canton, A. B. Grommet, L. Pesce, J. Gemen, S. Li, Y. Diskin-Posner, A. Credi, G. M. Pavan, J. Andréasson and R. Klajn, J. Am. Chem. Soc., 2020, 142, 14557; (e) S. Hasegawa, S. L. Meichsner, J. J. Holstein, A. Baksi, M. Kasanmascheff and G. H. Clever, J. Am. Chem. Soc., 2021, 143, 9718; (f) R. Sumida, Y. Tanaka, K. Niki, Y. Sei, S. Toyota and M. Yoshizwa, Chem. Sci., 2021, 12, 9946; (g) M. Ray, S. Krishnaswamy, A. K. Pardhan and D. K. Chand, Chem. Mater., 2023, 35, 6702; (h) J. C. Dorrat, R. J. Young, C. G. P. Taylor, M. B. Tipping, A. J. Blok, D. R. Turner, A. I. McKay, S. Ovenden, M. D. Ward, G. H. Dennison and K. L. Tuck, Dalton Trans., 2023, 52, 11802.
8. (a) D. Zhang, T. K. Ronson, Y.-Q. Zou and J. R. Nitschke, Nat. Rev. Chem., 2021, 5, 168; (b) C. Zhu, H. Tang, K. Yang, Y. Fang, K.-Y. Wawng, Z. Xiao, X. Wu, Y. Li, J. A. Powell and H.-C. Zhou, J. Am. Chem. Soc., 2021, 143, 12560; (c) P.-F. Cui, X.-R. Liu, Y.-J. Lin, Z.-H. Li and G.-X. Jin, J. Am. Chem. Soc., 2022, 144, 6558; (d) L.-J. Wang, S. Bai and Y.-F. Han, J. Am. Chem. Soc., 2022, 144, 16191; (e) D. Chakraborty, R. Saha, J. K. Clegg and P. S. Mukherjee, Chem. Sci., 2022, 13, 11764; (f) C.-W. Zhou, X.-Z. Wang, M. Xie, R.-Q. Xia, D. Luo, Z.-X. Lian, G.-H. Ning, W. Lu, X.-P. Zhou and D. Li, Angew. Chem., Int. Ed., 2023, 62, e202315020; (g) A. Ghosh, J. Pruchyathamkorn, C. F. Espinosa and J. R. Nitschke, J. Am. Chem. Soc., 2024, 146, 2568.
9. (a) S. Pullen, J. Tessarolo and G. H. Clever, Chem. Sci., 2021, 12, 7269; (b) C. T. McTernan, J. A. Davies and J. R. Nitschke, Chem. Rev., 2022, 122, 10393; (c) J. E. M. Lewis, Trends Chem., 2023, 5, 717; (d) Z. T. Avery, J. L. Algar and D. Preston, Trends Chem., 2024, 6, 352.
10. (a) W. M. Bloch and G. H. Clever, Chem. Commun., 2017, 53, 8506; (b) D. Bardhan and D. K. Chand, Chem.–Eur. J., 2019, 25, 12241.
11. (a) J. E. M. Lewis and J. D. Crowley, ChemPlusChem, 2020, 85, 815; (b) D. Tripathy, N. B. Debata, K. C. Naik and H. S. Sahoo, Coord. Chem. Rev., 2022, 456, 214396.
12. (a) D. Preston and J. D. Evans, Angew. Chem., Int. Ed., 2023, 62, e202314378; (b) M. Parbin, V. Sivalingam and D. K. Chand, Angew. Chem., Int. Ed., 2024, 63, e202410219; (c) A. Kumar, S. Krishnaswamy and D. K. Chand, Angew. Chem., Int. Ed., 2025, 64, e202416332; (d) M. R. Black, S. Bhattacharyya, S. P. Argent and B. S. Pilgrim, J. Am. Chem. Soc., 2024, 146, 28233; (e) S. Sharma, D. John and D. K. Chand, Chem.–Asian J., 2025, 20, e202401941; (f) H. Yu, Z. Guo, J. Tang, N. Han, J. Shi, M. Li, H. Zhang and M. Wang, Chem. Sci., 2025, 16, 6114.
13. (a) J.-R. Li and H.-C. Zhou, Nat. Chem., 2010, 2, 893; (b) Q.-F. Sun, S. Sato and M. Fujita, Angew. Chem., Int. Ed., 2014, 53, 13510; (c) W. M. Bloch, Y. Abe, J. J. Holstein, C. M. Wandtke, B. Dittrich and G. H. Clever, J. Am. Chem. Soc., 2016, 138, 13750; (d) W. M. Bloch, J. J. Holstein, W. Hiller and G. H. Clever, Angew. Chem., Int. Ed., 2017, 56, 8285; (e) J. A. Findlay, K. M. Patil, M. G. Gardiner, H. I. MacDermott-Opeskin, M. L. O'Mara, P. E. Kruger and D. Preston, Chem.–Asian J., 2022, 17, e202200093; (f) K. Wu, J. Tessarolo, A. Baksi and G. H. Clever, Angew. Chem., Int. Ed., 2022, 61, e202205727; (g) K. Wu, E. Benchimol, A. Baksi and G. H. Clever, Nat. Chem., 2024, 16, 584.
14. (a) D. Ogata and J. Yuasa, Angew. Chem., Int. Ed., 2019, 58, 18424; (b) J. E. M. Lewis, A. Tarzia, A. J. P. White and K. E. Jelfs, Chem. Sci., 2020, 11, 677; (c) S. S. Mishra, S. V. K. Kompella, S. Krishnaswamy, S. Balasubramanian and D. K. Chand, Inorg. Chem., 2020, 59, 12884; (d) J. E. M. Lewis, Chem.–Eur. J., 2021, 27, 44454; (e) R.-J. Li, A. Marcus, F. Fadaei-Tirani and K. Severin, Chem. Commun., 2021, 57, 10023; (f) H. Yu, J. Li, C. Shan, T. Lu, X. Jiang, J. Shi, L. Wojtas, H. Zhang and M. Wang, Angew. Chem., Int. Ed., 2021, 60, 26523; (g) A. Tarzia, J. E. M. Lewis and K. E. Jelfs, Angew. Chem., Int. Ed., 2021, 60, 20879; (h) R.-J. Li, A. Tarzia, V. Posligua, K. E. Jelfs, N. Sanchez, A. Marcus, A. Baksi, G. H. Clever, F. Fadaei-Tirani and K. Severin, Chem. Sci., 2022, 13, 11912; (i) J. de Montmollin, A. B. Solea, D. W. Chen, F. Fadaei-Tirani and K. Severin, Inorg. Chem., 2024, 63, 4583; (j) S. E. Walker, N. Kyratzis, D. U. Sawant, A. I. McKay, K. L. Tuck and D. R. Turner, Inorg. Chem., 2024, 63, 15659; (k) J. A. Gome, Z. T. Avery, N. R. Lawson, O. G. Stansfield, J. D. Evans, M. G. Gardiner, T. U. Connell and D. Preston, Angew. Chem., Int. Ed., 2025, 64, e202503473.
15. M. Yoshizawa, M. Nagao, K. Kumzawa and M. Fujita, J. Organomet. Chem., 2005, 690, 5383.
16. (a) D. Preston, J. E. Barnsley, K. C. Gordon and J. D. Crowley, J. Am. Chem. Soc., 2016, 138, 10578; (b) R. Zhu, W. M. Bloch, J. J. Holstein, S. Mandal, L. V. Schäfer and G. H. Clever, Chem.–Eur. J., 2018, 24, 12734; (c) R.-J. Li, J. Tessarolo, H. Lee and G. H. Clever, J. Am. Chem. Soc., 2021, 143, 3865; (d) B. Chen, J. J. Holstein, A. Platzek, L. Schneider, K. Wu and G. H. Clever, Chem. Sci., 2022, 13, 1829; (e) Y. Liu, S.-H. Liao, W.-T. Dai, Q. Bai, S. Lu, H. Wang, X. Li, Z. Zhang, P. Wang, W. Lu and Q. Zhang, Angew. Chem., Int. Ed., 2023, 62, e202217215; (f) Z. Guo, H. Yu, J. Shi, N. Han, G. Wu, H. Zhang, B. Li and M. Wang, Angew. Chem., Int. Ed., 2025, 64, e202425369; (g) Y.-M. Tan, L.-M. Zhang, Q. Bai, Z. Zhang, P. Wang and Q. Zhang, Chem. Sci., 2025, 16, 4625.
17. (a) R. A. S. Vasdev, D. Preston, C. A. Casey-Stevens, V. Martí-Centelles, P. J. Lusby, A. L. Garden and J. D. Crowley, Inorg. Chem., 2023, 62, 1833; (b) B. E. Barber, E. M. G. Jamieson, L. E. M. White and C. T. McTernan, Chem, 2024, 10, 2792.
18. P. Molinska, A. Tarzia, L. Male, K. E. Jelfs and J. E. M. Lewis, Angew. Chem., Int. Ed., 2023, 62, e202315451.
19. R.-J. Li, J. de Montmollin, F. Fadaei-Tirani, R. Scopelliti and K. Severin, Dalton Trans., 2023, 52, 6451.
20. C. Bannwarth, S. Ehlert and S. Grimme, J. Chem. Theory Comput., 2019, 153, 1652.
21. (a) F. Neese, Wiley Interdiscip. Rev.: Comput. Mol. Sci., 2012, 2, 73; (b) F. Neese, Wiley Interdiscip. Rev.: Comput. Mol. Sci., 2018, 8, e1327.
22. The effects of different solvents on isomer distributions for Pd₂1AB₂2AA₂ and Pd₂1AC₂2AA₂, and differences in interactions of ⁻OTs anions with the syn- and anti-isomers, are described in the SI Section S4.
23. D. O'Hagan, Chem. Soc. Rev., 2008, 37, 308.
24. M. C. Biagini, M. Ferrari, M. Lanfranchi, L. Marchió and M. A. Pellinghelli, J. Chem. Soc., Dalton Trans., 1999, 1575.
25. (a) P. Molinska, L. Male and J. E. M. Lewis, CCDC [2390755]: Experimental Crystal Structure Determination, 2025,  DOI:10.5517/ccdc.csd.cc2l7s4s; (b) P. Molinska, L. Male and J. E. M. Lewis, CCDC [2390756]: Experimental Crystal Structure Determination, 2025,  DOI:10.5517/ccdc.csd.cc2l7s5t; (c) P. Molinska, L. Male and J. E. M. Lewis, CCDC [2390758]: Experimental Crystal Structure Determination, 2025,  DOI:10.5517/ccdc.csd.cc2l7s7w.

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