Broadening the catalytic region from the cavity to windows by M6L12 nanospheres in cyclizations

Supramolecular cages have received tremendous attention as they can contain catalysts that exhibit confinement effects in the cavity, leading to excellent performances. Herein, we report an example wherein the catalytic region is extended from the cage cavity to the windows, and investigate its confinement effect by utilizing the Pd6LAu12 cage that contains rigidly fixed and isolated gold complexes at the windows. Pd6LAu12 exhibit three features of particular interest while assessing their properties in gold-catalyzed cyclization reactions. First, the catalysts experience a cage effect as they display higher reactivity and selectivity compared to the monomeric analogue, as a result of substrate pre-organization at the windows. Second, the metal complexes are physically separated by the cage structure, preventing the formation of less active dinuclear gold complexes making it more stable under hydrous conditions. Third, the cage windows present the characteristics of enzymatic catalysis via Michaelis–Menten-type mechanism analysis. This contribution presents an alternative way to engineer supramolecular catalysts through extending the catalytic region.


Introduction
Over the past few decades, supramolecular chemistry has experienced tremendous developments, particularly for potential applications in drug transport, 1 recognition and storage, 2 sensing, 3 and catalysis. 4Inspired by the ingenious protein structures of enzymes in nature providing well-dened pockets around the active sites, supramolecular coordination cages have been explored to emulate the specic microenvironment of enzymes.Several examples have demonstrated that synthetic mimics can provide an ideal reaction container to regulate the reactivity. 5By applying supramolecular strategies, a catalytic system could be formed in which single or multiple active sites reside in a conned micro-environment.In such a microenvironment, the orientation and rotation of substrates and catalysts can be restricted, explaining some of the unusual selectivity displayed by these encaged catalysts.In addition, the restriction of substrate and intermediate conformations within the cavity can be entropically favorable, leading to improved activity. 6Based on these successes, supramolecular strategies in transition metal catalysis developed as a fruitful tool for catalysis tuning, as specic activity and unprecedented selectivity can be achieved.
A powerful strategy to produce pyridine-coordinated palladium M n L 2n (n = 6, 12, 24) cages was pioneered by Fujita. 7The combination of the ditopic bispyridine building blocks and palladium complexes typically afforded self-assembled structures such as M 6 L 12 , M 12 L 24 and M 24 L 48 , 8,9 depending on the bend angle of the bispyridine building blocks.The M 12 L 24 nanospheres are amongst the most widely studied, as they can be functionalized with facile endohedral or exohedral binding groups, thereby generating a conned microenvironment suited for potential applications. 10We previously reported the utilization of Fujita-type M 12 L 24 nanospheres that were decorated internally with 24 gold complexes to provide systems with extremely high local concentration of gold species. 11It led to d 10 -d 10 aurophilic interaction and, as a result, enhanced the reactivity in cyclization reactions. 11More recently, we reported that an M 12 L 24 nanosphere was able to bind catalysts and substrates via hydrogen bonding interactions. 12In this case, sulfonated gold catalysts were strongly xed in a guanidinium containing nanocage, and carboxylate-containing substrates were bound more weakly via the remaining guanidine units, providing the ability to pre-organize the substrates and the catalysts within the microenvironment.In the gold-catalyzed cyclization of carboxylate-containing substrates this preorganization resulted in higher reaction rates.More recently, this guanidinium-functionalized nanosphere was used to accelerate reactions via a dinuclear mechanism, such as dinuclear Cu(I)-catalyzed cyclization 13 and ruthenium-catalyzed water oxidation. 14These examples demonstrate that the generation of a high local concentration by encapsulation of multiple transition metal catalysts (and/or substrates) is an interesting new tool to control catalyst properties.Note that these examples have reported the encapsulation of transition metal catalysts that are connected via exible linkers or via weak non-covalent interactions in the cavity, facilitating the catalysis due to the connement effect of the cavity.However, similar nanospheres in which the metal catalysts are rigidly xed and physically isolated on the rims of the cage windows 15 and whether the windows could present the connement effect in catalysis have not been well explored yet.
Recently, Nitschke and co-workers reported a subcomponent tetrahedral cage that was functionalized with N-heterocyclic carbene (NHC) moieties in the middle of each edge. 16They reported a cage that contained NHC-gold complexes as part of the cage backbone and used it as a template to generate gold nanoparticles.Other literature research 17,18 reported the construction and host guest studies of cages containing NHC moieties.However, the catalytic properties of these formed cages containing NHC were not explored.In this contribution, we report an example wherein the catalytic region is extended from the cage cavity to the windows on the cage surface area by the Pd 6 L AuCl 12 nanospheres that contain rigidly xed and physically isolated NHC-AuCl moieties at the cage window, and investigate its connement effect of the windows and enzymatic catalytic behavior in catalysis (Fig. 1).These types of NHC-gold complexes have previously been explored in cyclization reactions 19 of alkynes, 20 allenes 21 and alkenes, 22 and then we set out to assess the catalytic performances of the Pd 6 L Au 12 cage in gold-catalyzed cyclization reactions.Application of Pd 6 L Au 12 nanospheres in the cyclization of allenol and hex-4-ynoic acid shows enhanced activity and selectivity.In addition, the physically separated complexes cannot form dinuclear complexes, making the Pd 6 L Au 12 nanospheres more stable, especially under hydrous conditions.With this cage we have a clear example which shows that catalysis can favorably take place at the cage windows, and the systems display Michaelis-Menten kinetics, a feature also found in enzymatic catalysis.

Synthesis and characterization of ligands and cages
The NHC-functionalized ditopic ligand was designed by embedding the rigid NHC moiety between two 3-pyridyl groups to allow coordination to palladium required for the selfassembly, leading to structures in which the NHC moiety is implemented in a rigid fashion.The pure ditopic pyridyl ligand was obtained in 2 steps with an overall yield of 85% (Fig. S1-S10 †) and will be indicated as L free in this paper to emphasize that it is metal free.Needle-shaped crystals of L free were obtained from vapor diffusion of diethyl ether into a solution of L free in acetonitrile over two weeks.The crystal structure of L free shows that the ligand adopts a concave bending mode in which the imidazolium ring points inward, and the two neighboring aromatic rings display a bend angle of 133°(Fig.4a, Tables S4  and S5 †).
Aer treating the NHC-based ditopic pyridine compound with a stoichiometric amount of Au(tht)Cl, the gold complex of the ligand was obtained, which is denoted as L AuCl (Fig. S11-S16 †).Slow diffusion of isopropyl ether into the acetonitrile solution of L AuCl led to square-shaped crystals.The colorless crystal of L AuCl allowed solving the solid-state structure by SCXRD.The structure shows that pyridine groups were oriented differently when compared to that of L free and the bend angle is rather different (146°compared to 133°), as a result of the coordination of gold on the imidazolium ring (Fig. 4a, Tables S6  and S7 †).The properties of both L free and L AuCl in solution state were investigated by multiple spectroscopic NMR experiments and high-resolution mass spectrometry (HRMS) (all the spectral details can be found in the ESI †).
These two ditopic ligands were used to make coordination cages by self-assembly using palladium as the metal source.A solution containing L free and Pd(MeCN) 4 (BF 4 ) 2 with a ratio of 2 : 1 in DMSO-d 6 (Fig. 2a) was stirred in a N 2 atmosphere.Aer stirring vigorously for 12 h at 298 K, the light-yellow solid was collected by precipitation in excess amount of diethyl ether.Analysis of the compound by various techniques showed that the self-assembled Pd 3 L free 6 cage was formed.The product was fully characterized by NMR spectroscopy and HR-MS (Fig. S17-S37 †).
The relative shis and broadened resonances of the ligand backbone in the 1 H NMR spectrum indicated the coordination between L free and palladium precursor (Fig. 2b).Compared to that of L free , the signals of pyridine protons H 4 (Dd = −0.66ppm; Fig. 2b) and H 5 (Dd = −1.06ppm; Fig. 2b) presented typical shis, indicating the coordination with Pd 2+ in line with the cage formation. 23The aromatic protons H 8 (Dd = −0.30ppm; Fig. 2b) and H 9 (Dd = 0.06 ppm; Fig. 2b) no longer produced an identical chemical shi but split into two singlets and shied individually, demonstrating that these protons resided in different chemical environments, because the neighboring aromatic rings could not be rotated due to the rigidity of the cage structure.Apparently, the aromatic rings are no longer able to rotate rapidly on the NMR time scale, due to the steric hindrance and rigidity experienced within the structure.Notably, the resonance signals of the isopropyl CH protons H 10 , H 11 and H 12 in the 1 H NMR spectra of the cage were also split, clearly indicating the distinct chemical environment.
Diffusion-ordered NMR spectra (DOSY) in DMSO-d 6 at 298 K exhibited a clear single narrow band around log D = −10.078(R H z 2.61 nm, according to the Stokes-Einstein equation) (Fig. S22 †).The composition of the Pd 3 L free 6 cage was clearly proven by high-resolution cold spray ionization mass spectrometry (HR-CSI-MS) in acetonitrile.A single set of species with various charged states (3+, 4+, 5+, 6+, 7+, 8+ and 9+) was observed (Fig. 2c).All signals were assigned to a structure having the formula Pd 3 L free 6 (BF 4 ) 12 with a progressive loss of BF 4 − counterions during the MS measurement (Fig. S23 †).
Clearly, for all of the charged states, the experimental values precisely matched with the calculated isotopic distributions (Fig. S24-S37 †).
According to the structural information, we propose that this cage holds a double crown ring by combining two rings connected via three Pd 2+ metal nodes.The modeled structure shows an average diameter of 26 Å (Fig. 4b), which is in line with that obtained from the DOSY NMR spectra (Fig. S22 †).The top view of the structure is displayed showing the rings connected to the palladium nodes (Fig. 4b).The structure consists effectively of three small rings (Pd 2 L free 2 ) connected to one another.The torsion angle of L free in the coordination state is 139°, which is larger than its angle in the free state.The structure contained three Pd 2 L free 2 rings, showing the symmetry of Pd 3 -L free 6 , which also matched the splitting of isopropyl protons in the NMR results (Fig. 2b).A similar structure of trigonal prismatic Pd 3 L 6 containing PF 6 − was reported as the basic building block for the formation of crystal mesoporous supramolecular materials. 17The crystals of Pd 3 L 6 (PF 6 ) 12 crystallize in the monoclinic space group.Its framework contains three Pd 2+ metal centers and six ligands.The calculated structure presents a triangular prism skeleton with three small rings of Pd 2 L 2 .The structural analysis of Pd 3 L 6 (PF 6 ) 12 sufficiently veries our modeling of Pd 3 L free 6 (BF 4 ) 12 .A solution containing L AuCl and palladium salt in DMSO-d 6 was stirred at room temperature for 4 hours (Fig. 3a).A single set of slightly broadened signals was observed in the 1 H NMR spectra (Fig. 3b 3b).Moreover, the resonance signals of isopropyl groups [H 8 ] in the cage structure did not shi too much but rather broadened with respect to the signals of L AuCl (Fig. 3b), indicating that a highly symmetric cage had formed.DOSY showed a single band at log D = −10.10(R H z 2.75 nm, according to the Stokes-Einstein equation) (Fig. S43 †), consistent with the cage size measured from the single crystal structural analyses (Fig. 4c).HR-CSI-MS measurements for the solution of the Pd 6 L AuCl 12 cage in acetonitrile supported the composition of the desired cage, as a set of prominent peaks with different charge states were observed at 2162.6811, 1786.8977, and 1509.9297;this result precisely agreed with the simulated values of Pd 6 L AuCl 12 with the respective amount of counterions (Fig. S44-S46 †).Furthermore, a series of peaks with a certain amount of additional coordinated solvent molecules could also be recognized (Fig. S45 †).The simulated isotopic distribution of the +6 charged species (Fig. 3c) clearly shows that the cage structure contains some solvent molecules, which results in partly overlapping peaks.By slow diffusion of diethyl ether vapor into an acetonitrile solution of Pd 6 L AuCl 12 over three weeks, rhombus-shaped single crystals of the Pd 6 L AuCl 12 cage were obtained.Single-crystal X-ray diffraction (SCXRD) analysis shows that Pd 6 L AuCl 12 crystallized in a triclinic space group (Fig. 4c, Tables S8 and S9 †).The Pd 6 L AuCl 12 cage presents a highly symmetric octahedron geometry, which contains six Pd 2+ cations that occupy the vertices and are linked together by twelve L AuCl ligands as the edges.For all the NHC-gold species embedded in Pd 6 L AuCl 12 , the bending mode is similar to the free style of L AuCl .However, comparing with the bend angle of L AuCl (146°) in the free state of the structure, this bend in the coordination state has an even larger torsion angle (162°).We hypothesize that this larger torsion angle is derived from the twist of L AuCl during its coordination to palladium.In the solid state, all the gold centers reside at the windows of the Pd 6 L AuCl 12 cage instead of in the cavity.The distance between the gold atoms and the neighboring one is 10 Å.It indicates that the distance of goldgold in the crystal structure is quite large compared to the actual distance for the aurophilic interactions between two gold atoms (approximately 3 Å), as reported in the literature. 24Therefore, the gold centers here in the Pd 6 L AuCl 12 cage are rather isolated and exposed at the window as observed in the solid-state structure.
A similar structure of self-assembly Pd 6 L 12 (NO 3 − salt), containing NHC-AuI moieties in ligands, was also reported and applied for anion (PF 6 − and BF 4

−
) encapsulations. 18The crystals crystallize in a triclinic space group.The highly symmetric octahedral structure contains six Pd 2+ metal centers and twelve ligands.The bend angle (174.1°) in the coordination state is closer to linearity than that in the Pd 6 L AuCl 12 cage (162°).

Modeling of the cage structures
As such, Pd 6 L AuCl 12 contains a unique inversion of exohedralfacing gold catalysts that are xed on the edges of the windows and exhibits a high symmetry in the solid state (Fig. 4c).While the crystal structure shows a uniform and highly symmetric organization of the gold faces in the solid state, it is known that  crystallization preferentially isolates highly symmetric structures. 25To understand the possible solution-state structure of Pd 6 L AuCl 12 we adapted molecular dynamics simulations (MD) 26 to assess the number of endohedral (i.e., inward facing) or exohedral (i.e., solvent-facing) facing ligands in Pd 6 L AuCl 12 .Model cages featured a varying number of endohedral-facing gold centers, where the relative energy of each conguration (Fig. 5a) could be directly used for computing the distribution of ligand orientations (Fig. 5b).The larger number of congurations accessible by spheres featuring some endo-or exohedrally facing ligands results in an entropic preference for mixed cages (Fig. 5a).Combined with the relatively low energy penalty (<2 kcal mol −1 ) of including a few endohedral ligands, our model predicts that the plurality of the Pd 6 L AuCl 12 cages features 1-2 endohedral-facing gold centers (Fig. 5a), while a majority of gold sites (87%) (Fig. 5b) are exohedral and remain well separated, as conrmed by UV-vis spectroscopy 11 (Fig. S49 †) owing to the steric bulk of the cage.This was further conrmed by the crystal structure.Noticeably, gold centers in both the Pd 6 L Au 12 and the Pd 6 L AuCl 12 cages are located on the periphery of the cage windows rather than in the cavity itself, exposing a high concentration of isolated metal centers.
As we observed by CSI-HRMS, L free forms Pd 3 L free 6 doublecrown ring assemblies, while gold-containing building blocks afford Pd 6 L AuCl 12 octahedral cages (Fig. 2c and 3c).As reported by Fujita, a small difference in the bend angle of the bidental ligand block may result in the formation of different nanostructures. 8L free exhibits a concave binding mode with a bend angle of 133°, while L AuCl adopts a convex binding mode with an angle of 146°, probably because pyridine groups in L AuCl are ipped (Fig. 4a).The torsion angle of L free (139°) is smaller than that of L AuCl (162°).As both windows in the two cages feature similar triangular geometry, we hypothesize that this torsion angle change drives the divergent outcomes for the selfassembly of these ligands.
Intrigued by these structural differences, we employed MD 26 simulations to understand the topological preference of L free and gold-containing congeners, L Au and L AuCl (Fig. 5d).While the ligands feature a similar molecular structure, we observed signicant differences in the charge distribution between the metalized and non-metalized ligands in their coordination states (Fig. S47 †).Surprisingly, L free (coordination state) possesses higher charge densities (i.e., increased polarization) on the ortho positions of the pyridine groups compared to its gold-complexed congeners (L AuCl and L Au ) in self-assembled structures.This charge difference may account for the divergent self-assembly outcomes we have observed.
In line with our CSI-HRMS measurements (Fig. 2c), our MD 26 simulations predict that L free favorably self-assembles into double-crowned Pd 3 L free 6 assemblies, with a minor population of the Pd 4 L free 8 (Fig. 5c).While, the Pd 4 L free 8 could not be detected by 1 H NMR (Fig. 2b) or DOSY experiments (Fig. S22 †), the combination of CSI-HRMS and computational evidence supports the Pd 4 L free 8 at low concentrations.In contrast, MD simulations of L AuCl and L Au predict the observed Pd 6 L AuCl 12 and Pd 6 L Au 12 octahedral cages as the dominant product of selfassembly (Fig. 5c).
Cyclization of allenol (Pd 6 L Au 12 vs.NHC-Au + ) As we have already revealed, Pd 6 L AuCl 12 creates a unique conguration featuring exposed and isolated gold centers on the edges of the cage.We anticipated that these structural characteristics may result in differences in catalysis compared to the mononuclear complex and also compared to previously reported structures in which the complexes are nearer to one another.Inspired by our recent precedents applied in goldcatalyzed cycloisomerizations, in which the gold complexes were furnished inside a well-dened cage via exible linkers that exhibited aurophilic interactions and led to a highly enhanced reactivity, we started our studies of Pd 6 L Au 12 in the cycloisomerization of allenol (1). 27ll experiments were precisely carried out under the same benchmark reaction conditions described above and were performed in pre-dried deuterated acetonitrile under argon at room temperature for 25 h (Tables 1 and S1 †).In the gold-catalyzed cycloisomerization of allenol (substrate 1), the catalytic result could in principle yield two products, the 5-membered ring (product 2) and the 6-membered ring (product 3).In all reactions, we found that the 5-membered ring (product 2) was the only product formed.With no surprise, the NHC-AuCl complex was found to have no reactivity, and even aer pre-activation by AgBF 4 , the complex only displayed a low reactivity to generate product 2 in 30% yield.As expected, the Pd 6 L AuCl 12 cage was completely inactive, in contrast to our previously reported exible system, indicating that the gold complexes are well separated at the cage window, to prevent aurophilic interactions that were reported to be important in the exible system, and the system did not give any conversions of allenol (substrate 1).Gratifyingly, the preactivated Pd 6 L Au 12 cage displayed a moderate yield of product 2

Fig. 1
Fig. 1 (a) Charge effect of rigid NHC metallization-triggered supramolecular configurations.(b) The Pd 6 L Au 12 cage presents the features of enzymatic catalysis at the cage window for gold-catalyzed cyclization of allenol.The structures of L free , L AuCl and Pd 6 L AuCl 12 are their single crystal X-ray structures.The structure of Pd 3 L free 6 is a modelled structure.Color coding: C: gray; N: dark blue; Au: yellow; Pd: light blue; Cl: bright green; B: dark green; F: violet; O: red; H: white.

Fig. 2
Fig. 2 Synthesis and characterization of the gold-free cage (Pd 3 L free 6 ).(a) Synthesis of the self-assembly of the gold-free cage (Pd 3 L free 6 ).The structure of L free is the SCXRD structure and the structure of Pd 3 L free 6 is a modelled structure.Color coding: C: gray; N: dark blue; Pd: light blue; B: dark green; F: violet.(b) 1 H NMR of the Pd 3 L free 6 and free ligand (L free ) in DMSO-d 6 (at 298 K).(c) HR-CSI-MS of the gold-free cage (Pd 3 L free 6 with minimal Pd 4 L free 8 ) (red) and simulated isotopic distribution of Pd 3 L free 6 [M-3BF 4

Fig. 4
Fig. 4 (a) Single crystal X-ray structures of L free and L AuCl .(b) MD simulated structures of Pd 3 L free 6 , ball-and-stick and space-filling models.(c) Single crystal X-ray structures of Pd 6 L AuCl 12 , ball-and-stick model and space-filling models.Color coding: C: gray; N: dark blue; Au: yellow; Pd: light blue; Cl: bright green; B: dark green; F: violet.