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Self-assembly processes of octahedron-shaped PdL cages Shohei Komine, Satoshi Takahashi, Tatsuo Kojima, Hirofumi Sato, and Shuichi Hiraoka J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b12890 • Publication Date (Web): 28 Jan 2019 Downloaded from http://pubs.acs.org on January 29, 2019

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Self-Assembly Processes of Octahedron-Shaped Pd6L4 Cages Shohei Komine,a Satoshi Takahashi,a Tatsuo Kojima,a Hirofumi Sato,b,c and Shuichi Hiraokaa,* a Department

of Basic Science, Graduate School of Arts and Sciences, The University of Tokyo 3-8-1 Komaba, Meguro-ku, Tokyo 153-8902, Japan b Department of Molecular Engineering, Kyoto University, Kyoto 615-8510, Japan. c Elements Strategy Initiative for Catalysts and Batteries, Kyoto University, Kyoto 615-8510, Japan. ABSTRACT: The self-assembly processes of two kinds of octahedron-shaped M6L4 cages consisting of cis-protected Pd(II) complexes and organic tritopic ligands were investigated. Whether kinetically trapped species larger than the cages are produced or the M6L4 cage is assembled without the formation of such kinetic traps is determined by a balance between the rates of oligomerization and intramolecular cyclization, which is affected by slight changes in the chemical structure of the tritopic ligand. A numerical analysis of the experimental data based on a reaction network model where 249 reactions between the possible 56 species were considered revealed the self-assembly pathways of one of the two M6L4 cages.

INTRODUCTION Intramolecular reactions take place faster than intermolecular reactions as long as two reaction sites connected in a molecule can efficiently encounter each other. In this case, high effective concentration of the two reaction sites prefers the intramolecular reaction.1 However, this effect depends on the nature of the linker connecting the two reaction sites. When the linker is too short, structural strain in the transition structure heightens the energy barrier of the reaction. On the other hand, when the linker is too long, the intramolecular cyclization competes with the intermolecular oligomerization, which is the main reason for the difficulty in the formation of macrocycles.2 Thus, efficient cyclization is achieved only when an appropriate linker is chosen. The self-assembly of closed structures where the components are cross-linked to each other, such as self-assembled cages, capsules, and macrocycles, intrinsically involves the competition between intra- and intermolecular reactions (cyclization (cross-link) vs. oligomerization) in the self-assembly process, where both cyclization and oligomerization are needed to produce welldefined assembled structures. A bias toward one of the two reactions (e.g. only oligomerization) leads to species far from the final assembly under kinetic control. Thus, it is valuable to reveal how the components organize the two types of reactions in the self-assembly process to produce the thermodynamically most stable final product exclusively over other possible structures for in-depth understanding of molecular self-assembly. Octahedron-shaped M6L4 cages from cis-protected Pd(II) or Pt(II) complexes and C3-symmetric tritopic ligands are a class of discrete crossed structures reported by Fujita3a and Stang3b. Six metal ions are placed on the apexes of the octahedron and a half of the faces of the octahedron are occupied by the tritopic ligands to form an octahedron-shaped cage with T symmetry. Although many years has passed since their development in 1990s, the self-assembly process of the M6L4

family3 has not been discussed so far. The M6L4 cages consisting of a relatively small number of components are good examples to investigate how oligomerization and cyclization (cross-link) are controlled in the self-assembly process.

Figure 1. A scheme of the self-assembly of octahedron-shaped Pd6L4 cages from [PdPy*2]2+ (Pd: Pd(TMEDA), Py*: 3chloropyridine) and tritopic ligand (1 or 2).

Here, we report the self-assembly processes of octahedronshaped M6L4 cages from tritopic ligands (L = 1 or 2 in Figure 1) and cis-protected Pd(II) complexes (Pd: [Pd(TMEDA)]2+) where two coordination sites of the Pd(II) ion are occupied by a chelate ligand (TMEDA: N,N,N′,N′tetramethylethylenediamine) (Figure 1). In the self-assembly of the [Pd614](BF4)12 cage, intramolecular cyclization reactions in linear or branched oligomers are slower than oligomerization, so the oligomerization preferentially takes place in the beginning of the self-assembly but does not produce kinetically trapped species. Instead, linear and

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branched oligomers consisting of not more components than the [Pd614](BF4)12 cage are efficiently produced without over oligomerization. Slow intramolecular cyclization reactions in the linear and branched oligomers lead to partial cage structures, where further cross-link reactions take place quickly to afford the [Pd614](BF4)12 cage. In contrast, the selfassembly of the [Pd624](BF4)12 cage took place, accompanied with 43% of kinetically trapped species. These results indicate that though the tritopic ligand 1 and 2 are geometrically quite similar, slight differences in the structural and electronic property of the tritopic ligands alter the self-assembly pathways. As to the self-assembly of the [Pd614](BF4)12 cage, the experimental results were numerically analyzed by a network model where 249 of elementary reactions between 56 of all possible intermediates consisting of not more components than the cage were considered using limited number of rate constants. This analysis enabled us to deduce the probable intermediates and major assembling pathways that cannot be revealed by experiments only.

RESULTS AND DISCUSSION Experimental approach for the investigation of selfassembly processes. A main difficulty in the investigation of self-assembly processes arises from the fact that many transient intermediates cannot be observed by experimental techniques. To settle this issue, QASAP (quantitative analysis of selfassembly process) enables us to obtain the information about the intermediates as average composition of all the intermediates by quantifying all the substrates and the products.4 For example, here we consider the self-assembly of a [Pd6L4]12+ cage from L and [PdX2]2+ (eq.1). 6·[PdX2]2+ + 4·L ⇄ [Pd6L4]12+ + 12·X (1) where X is a monodentate leaving ligand. Any intermediates of the self-assembly can be indicated by [PdaLbXc]2a+ (a, b, and c are 0 or positive integer). In QASAP, the following two parameters are defined for the investigation of self-assembly processes. 2𝑎 –𝑐 𝑛= (2) 𝑏 𝑎 𝑘 = (3) 𝑏 The n value indicates the average number of Pd moieties that attach to a single tritopic ligand L, while the k value indicates the ratio between the Pd moieties and the tritopic ligands in a given intermediate. The (n, k) values for all the possible intermediates with different composition consisting of not more components than the cage (32 isomers) are plotted in Figure 2. The information obtained by QASAP is the average composition of all the intermediates, Pd⟨a⟩L⟨b⟩X⟨c⟩, so the n and k values for Pd⟨a⟩L⟨b⟩X⟨c⟩, ⟨n⟩ and ⟨k⟩, are defined as follows. 2〈𝑎〉 ― 〈𝑐〉 〈𝑛〉 = (4) 〈𝑏〉 〈𝑎〉 〈𝑘〉 = (5) 〈𝑏〉 The self-assembly processes of the [Pd614](BF4)12 and [Pd624](BF4)12 cages can be discussed on the basis of the change in the (⟨n⟩, ⟨k⟩) value with time on the (n, k) map.

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Figure 2. An n-k map for the self-assembly of a [Pd6L4]12+ cage. Species not containing more components than the cage, [PdaLbXc] 2a+ (a ≤ 6, b ≤ 4), are plotted. X is a leaving monodentate ligand.

Self-assembly process of the [Pd614](BF4)12 cage. The self-assembly of the [Pd614](BF4)12 cage3g,t was carried out by mixing [PdPy*2](BF4)2 (Py*: 3-chloropyridine) and tritopic ligand 1 in a mixed solvent of CD3NO2, CDCl3, and CD3OD (7:3:2, v/v/v) at 298 K, which was monitored by timedependent 1H NMR spectroscopy (Figures 3 and S1 and Tables S1–S5). The reason why Py* was used as a leaving ligand is because the coordination ability of Py* is slightly weaker than that of the pyridyl groups of the tritopic ligands (1 and 2) to shift the equilibrium toward the products and because the Pd–Py* coordination bond is strong enough to perfectly retain in the solvent used for QASAP. The quantification of all the substrates and the products in eq. 1 is required for QASAP, so the mixed solvent that solubilizes all the species in eq. 1 was used. All the 1H NMR signals for the substrates and the products were assigned by (H,H)-COSY spectroscopy and based on the original reports of the [Pd6L4]12+ cages. As has been observed in coordination selfassemblies, the signals of  protons in the pyridyl rings coordinating to Pd(II) ion (Ha, He and Hh) were observed in lower field compared with free ligands. Most of the substrates ([PdPy*2](BF4)2 and 1) were consumed within 1 h and the signals of the [Pd614](BF4)12 cage appeared after 2 h, indicating that the growth of the intermediates took place within 2 h. Signals that can be assigned neither to the substrates nor to the products were observed (Figure 3a) but their assignment was impossible due to the complexity and weakness of the signals. Compared with the intermediates, all the substrates ([PdPy*2](BF4)2 and 1) and the products ([Pd614](BF4)12 and Py*) can easily be quantified by 1H NMR spectroscopy using an internal standard (Figure 4a). The self-assembly of the [Pd614](BF4)12 cage proceeded smoothly under this condition to produce the cage in 87% yield after 2 days. The existence ratio of all the intermediates (Int) was determined based on the tritopic ligand 1 and is also plotted in Figure 4a. During the first 1 h, Int dramatically increased to reach 96% yield and turned to decrease after 2 h to start to produce the [Pd614](BF4)12 cage. It should be noted that more


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[PdPy*2](BF4)2 remained in the reaction mixture than the tritopic ligand 1, indicating that the ratio between Pd2+ and 1 in Int ([Pd]/[1], which is the ⟨k⟩ value) is lower than that in the cage (6/4); the ⟨k⟩ value should be smaller than 1.5. The self-assembly process was analyzed by the change in the (⟨n⟩, ⟨k⟩) value with time (Figure 5a). The ⟨n⟩ and ⟨k⟩ values increased with time from 5 to 55 min to reach (⟨n⟩, ⟨k⟩) = (1.89, 1.29) and then stayed around (1.85, 1.20) until 6 h. The ⟨n⟩ and ⟨k⟩ values dramatically decreased after 6 h. Considering that most of the [Pd614](BF4)12 cages were produced from 2 to 12 h, the almost constant (⟨n⟩, ⟨k⟩) values of Int during the formation of the cage suggest that the intermediates whose (n, k) values are close to the (⟨n⟩, ⟨k⟩) values from 50 min to 6 h are predominantly produced and that the reactions of these intermediates are the ratedetermining steps in the self-assembly of the cage.5 The average (⟨n⟩, ⟨k⟩) value from 50 min to 6 h, (1.85, 1.20), is near to the (n, k) values of [Pd413Py*2](BF4)8 and [Pd514Py*2](BF4)10, which are indicated as (4,3,2) and (5,4,2), respectively, in Figure 5a. Slightly smaller ⟨n⟩ values than those of (4,3,2) and (5,4,2) is probably because the species whose n values are smaller than 2, which are small fragmentary species deduced from the (n, k) map (Figure 2), coexisted in the reaction mixture. The decrease in the ⟨n⟩ and ⟨k⟩ values after 6 h should arise from the increase in the proportion of the small fragmentary species in Int by the conversion of (4,3,2) and (5,4,2) to the cage. The conversion of (4,3,2) and (5,4,2) into the [Pd614](BF4)12 cage (6,4,0), which mainly takes place after 1 h, requires the incorporation of Pd unit(s) in Int, which is consistent with the result that the consumption of [PdPy*2](BF4)2 continued until the end of the self-assembly (a red line in Figure 4a).

Figure 3. 1H NMR monitor for the self-assembly of the Pd6L4 cages (L = 1 or 2). (a) 1H NMR spectra (500 MHz, CD3NO, CDCl3, and CD3OD (7:3:2, v/v/v), 298 K) for the self-assembly of the [Pd614](BF4)12 cage from [PdPy*2](BF4)2 ([Pd] = 3.0 mM) and 1 ([1]0 = 2.0 mM). (b) 1H NMR spectra (500 MHz, CD3NO, CDCl3, and CD3OD (7:3:2, v/v/v), 298 K) for the self-assembly of the [Pd624](BF4)12 cage from [PdPy*2](BF4)2 ([Pd] = 3.0 mM) and 2 ([2]0 = 2.0 mM).



Figure 4. Existence ratios of the substrates ([PdPy*2](BF4)2 and tritopic ligand (1 or 2)), the products ([Pd6L4](BF4)12 (L = 1 or 2) and Py*), and the intermediates (Int) for the self-assembly of (a) the [Pd614](BF4)12 cage from [PdPy*2](BF4)2 ([Pd] = 3.0 mM) and 1 ([1]0 = 2.0 mM) in CD3NO, CDCl3, and CD3OD (7:3:2, v/v/v) at 298 K and (b) the [Pd624](BF4)12 cage from [PdPy*2](BF4)2 ([Pd] = 3.0 mM) and 2 ([2]0 = 2.0 mM) in CD3NO, CDCl3, and CD3OD (7:3:2, v/v/v) at 298 K. The ratios of [Pd6L4](BF4)12 (L = 1 or 2) were indicated based on L. All the ratios were determined by 1H NMR spectroscopy using an internal standard.

The self-assembly of the [Pd614](BF4)12 cage was monitored by ESI-TOF mass spectrometry. However, it was found that though various conditions were tested, even the signal of the cage was not detected in a solution mainly containing the [Pd614](BF4)12 cage, only to show signals for small fragments of the cage. The characterization of the [Pd614]12+ cage by mass spectrometry was also not reported in the original paper of the cage.3g,t These results indicate that the investigation of the self-assembly process of the cage by mass measurements is highly challenging. The [Pd614](BF4)12 cage was smoothly produced even under a mild condition where large kinetically trapped species are sometimes produced,6 so it is reasonable to consider that the self-assembly of the [Pd614](BF4)12 cage takes place mainly through intermediates consisting of not more components than the cage, [Pda1bPy*c](BF4)2a (a ≤ 6, b ≤ 4). Such intermediates are classified into nine groups (A – I) shown in Figure 6. For example, group A contains the intermediates consisting of one tritopic ligand and one to three Pd2+ units, (1,1,1), (2,1,2), and (3,1,3). Red broken circles in Figure 6 indicate the position where a [PdPy*]2+ unit can be placed. As a simplified point of view, the self-assembly process of the [Pd6L4]12+ cage can be classified into the following three types of reaction:

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Figure 5. An n-k plot for the self-assembly of the Pd6L4 cage from [PdPy*2](BF4)2 and tritopic L (1 or 2) in CD3NO, CDCl3, and CD3OD (7:3:2, v/v/v) at 298 K (a) for [Pd614](BF4)12 cage, [Pd] = 3.0 mM, [1]0 = 2.0 mM. (b) for the [Pd624](BF4)12 cage. [Pd] = 3.0 mM, [2]0 = 2.0 mM. Blue lines indicate the change in the (⟨n⟩, ⟨k⟩) values with time. Red crosshairs indicate the (n, k) values for [PdaLbPy*c](BF4)2a, (a, b, c).

type 1: oligomerization to increase the number of the components (Pd2+ or L) in the intermediates by intermolecular process, which mainly takes place to produce linear and branched oligomers (groups A, B, C, D, and F) but also takes place after the formation of the cyclized intermediates, E, G, H, and I type 2: cyclization of linear or branched intermediates (A, B, C, D, and F) to produce groups E, G, and H type 3: cross-link in partially crossed structures (intramolecular reactions in groups G, H, and I) The n-k analysis suggests that (4,3,2) and (5,4,2) are longlived intermediates, indicating that the reactions of (4,3,2) and (5,4,2) are slow (Figure 5a). (4,3,2) belongs to group C (linear oligomers), while (5,4,2) to groups D (linear oligomers) and F (branched oligomers). The reactions of (4,3,2) and (5,4,2) mainly contain intramolecular cyclization steps, so the intramolecular cyclization reactions in (4,3,2) and (5,4,2) to produce (4,3,1) and (5,4,1), respectively, are the rate-


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determining steps in the self-assembly of the [Pd614](BF4)12 cage. Once (4,3,1) and (5,4,1) are produced by the intramolecular cyclization, the following reactions (mainly cross-link reactions) take place quickly probably because the structures of groups E, G, and H resemble the octahedron. One of the significant features in the self-assembly of the [Pd614](BF4)12 cage is the prevention of over oligomerization. This will be discussed by comparing the self-assembly processes of the [Pd614](BF4)12 and [Pd624](BF4)12 cages in a later section. Theoretical analysis of the experimental results by a network model. QASAP for the [Pd614](BF4)12 cage revealed that the cyclization reactions of linear and branched intermediates, [Pd413Py*2](BF4)8 and [Pd514Py*2](BF4)10, are the ratedetermining steps in the self-assembly. To obtain more information about the self-assembly process from the experimental results, the experimental data were numerically analyzed by a network model.7 As QASAP indicates that most of the intermediates produced in the self-assembly of the [Pd614](BF4)12 cage contain not more components than the cage ([Pda1bPy*c](BF4)2a, a ≤ 6, b ≤ 4), all the possible structural isomers excluding enantiomers (total 56 species including the substrates and the products) were explicitly considered and their reaction network that contains 249 reactions between the 56 species was constructed (Figure S3). In this analysis, six individual rate constants (k1, k–1, k2, k–2, k3, and k–3 in Figure 6) were used as variable parameters to reproduce the time-variation of the existence ratios of the substrates and the products and the (⟨n⟩, ⟨k⟩) value. Details on the analytical methodology and the practical procedure are described in reference 7 and the supporting information. We found that several parameter sets reproduce the experimental results and that these data show several common features as follows: 1. The same rate constants were obtained in the oligomerization steps (k1 = 100.9 min–1 M–1 and k–1 = 100.5 min– 1 M–1) in every case.

2. The rate constant of the cyclization (k2) is always smaller than those of the oligomerization (k1) and the cross-link (k3). 3. The rate constant of the reverse reaction in the cyclization (k–2) is relatively large, while the rate constants of the reverse reactions in the oligomerization (k–1) and the cross-link (k–3) are much smaller than those of the forward reactions, (k3 >> k– 3 and k1 >> k–1). 4. When the rate constants of the oligomerization (k1) and the cross-link (k3) are compared, some k3 values are larger than k1 values (k1 < k3). The other k3 values are not (k1 > k3). Two representative examples where k1 > k3 and k1 < k3 are shown in Figure 7. In both cases, the time-development is similar for the nine groups of intermediates (A – I), the cage, and the (⟨n⟩, ⟨k⟩) value. In the beginning of the self-assembly, linear oligomers, A–D, increase with time. It should be mentioned that the number of branched oligomers, F, is significantly small, which suggests that the cyclization mainly takes place in linear oligomers, C and D. In other words, the reactions of C → D and C → E are preferred to the reactions of C → F. This is partly due to fewer possibilities of the reactions to form F from C. The intermediates in E, which are produced by the cyclization of C, exist in a non-negligible amount, while the amount of G and H, which are mainly produced by the cyclization of D, is small. Although the conversion of E into H requires intermolecular reaction(s) (at least the incorporation of L is essential), the intermediates in G and H except (4,4,0) can be converted into I by the intramolecular cross-link, whose rate constant of the backward reaction (k–3) is much smaller than that of the forward one (k3). Thus, the observed species in G and H in Figure 7c and f are only (4,4,0), which cannot be transformed into I without intermolecular reactions. In other words, (5,4,1) and (6,4,2) in groups G and H are quickly converted into (5,4,0) and (6,4,1), respectively by fast cross-link, so (5,4,1) and (6,4,2) are not observed. The intermediates in A and B remains at the end of the self-assembly, though other intermediates significantly decrease. This should be the reason for the decrease in the (⟨n⟩, ⟨k⟩) value after 3 h.



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Figure 6. A brief summary of the self-assembly pathways of the [Pd614](BF4)12 cage from [PdPy*2](BF4)2 and 1. All the intermediates can be classified into nine groups (A – I) based on the connection of tritopic ligands. Groups A – D are linear intermediates with a different number of tritopic ligands. Group F is branched oligomers. Group E is crossed intermediates with three tritopic ligands. Groups G, H, and I are crossed intermediates with four tritopic ligands, whose structures resemble the octahedron. Red broken circles in the structures A – I indicate possible positions in the tritopic ligand L where a [PdPy*]2+ unit binds. For example, in (2,1,2) of group A, one of the two red broken circles is replaced with one [PdPy*]2+, while both red broken circles are replaced in (3,1,3). (a, b, c) in red indicates the species whose (n, k) value is close to the experimentally obtained (⟨n⟩, ⟨k⟩) values in Figure 5a (self-assembly of the [Pd614](BF4)12 cage). Rate constants (k1, k–1, k2, k–2, k3, and k–3) were used in the numerical analysis of the experimental data for the self-assembly of the [Pd614](BF4)12 cage. A full reaction network where all the 249 reactions between all the 56 possible species (Pda1bPy*c, a ≤ 6, b ≤ 4) are indicated is shown in Figure S3.

Self-assembly process of the [Pd624](BF4)12 cage. The self-assembly of the [Pd624](BF4)12 cage was carried out under the same condition as that of the [Pd614](BF4)12 cage and was monitored by 1H NMR spectroscopy (Figures 3b and S2). Although the 1H NMR signals for intermediates were observed, complicated signals prevented us from characterizing these signals. All the substrates (2 and [PdPy*2](BF4)2) and the products ([Pd624](BF4)12 and Py*) were quantified using an internal standard. The time-variation of the existence ratios for these species and all the intermediates (Int) is shown in Figure 4b. The yield of the [Pd624](BF4)12 cage is 57% after the convergence of the selfassembly, suggesting that about half of the substrates were converted into kinetically trapped species. The formation of several-tenths-nm-sized species, which is much larger than the

cage (ca. 3 nm), was confirmed by DLS and AFM measurements for the reaction mixture containing 43% of kinetically trapped species (Figure 8). Thus quite larger species than the cage were kinetically trapped in the selfassembly of the [Pd624](BF4)12 cage by over oligomerization. Larger species than the final assemblies were sometimes produced transiently6 or lastingly8 during coordination selfassembly. The conversion of the kinetically trapped species into the cage was not attained by heating the reaction mixture but the yield of the [Pd624](BF4)12 cage from [PdPy*2](BF4)2 and 2 was improved when the self-assembly was conducted in CD3CN and CD2Cl2 (4:1, v/v) at 343 K (72%). These results suggest that CD3CN with higher coordination ability than CD3NO2 promotes the ligand exchanges in or between the intermediates to prevent the formation of kinetically trapped species.


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Figure 7. Two representative examples of the time-variation of the substrates ([PdPy*2]2+ and 1), the products ([Pd614]12+ and Py*), and the (⟨n⟩, ⟨k⟩) value numerically calculated by six rate constants shown in Figure 6 (k1, k–1, k2, k–2, k3, and k–3), which were determined so that the experimental data could be reproduced. (a)–(c) one of the examples where k1 > k3. (k1, k–1, k2, k–2, k3, k–3) = (100.9 min–1 M–1, 100.5 min–1 M–1, 10–2.5 min–1, 10–2.1 min–1 M–1, 100.2 min–1, 10–1.7 min–1 M–1). (d)–(f) one of the examples where k1 < k3. (k1, k–1, k2, k–2, k3, k–3) =



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(100.9 min–1 M–1, 100.5 min–1 M–1, 10–2.5 min–1, 10–2.3 min–1 M–1, 102.5 min–1, 10–1.2 min–1 M–1). The data colored in red and blue in (a), (b), (d), and (e) are experimental and numerical results, respectively.

over oligomerization. In other words, the relative difference in the coordination ability between multitopic ligands and leaving ligands would be one of the factors that affect the preference of the self-assembly pathways. The rotational freedom of the 4-pyridyl groups in perfectly planar 1 is more restricted than in 2 due to weak intramolecular hydrogen bond in 1, which would also affect the rates of the reactions. The formation of the [Pd624](BF4)12 cage started at 1 h, which is slightly faster than that of the [Pd614](BF4)12 cage (2 h). This result suggests that the on-pathway of the selfassembly of the [Pd624](BF4)12 cage is as simple as that of the [Pd614](BF4)12 cage, during whose self-assembly intermediates containing not more components than the cage were mainly produced.

CONCLUSIONS

Figure 8. Characterization of kinetically trapped species produced during the self-assembly of the [Pd624](BF4)12 cage from [PdPy*2](BF4)2 and 2 in CD3NO, CDCl3, and CD3OD (7:3:2, v/v/v) at 298 K measured after 2 days (a mixture of the [Pd624](BF4)12 cage (57%) and kinetically trapped species (43%) determined based on 2 using an internal standard). (a) DLS data. (b) AFM image. (c) AFM image for a solution of the [Pd624](BF4)12 cage (80%) prepared from PdCl2, 2, and AgBF4 in CD3CN and CD2Cl2 (4:1, v/v) at 343 K.

The rate of the release of Py* in the self-assembly of the [Pd624](BF4)12 cage is faster than that of the [Pd614](BF4)12 cage (Figure 4b). Similarly, the consumption of the substrates is faster in the self-assembly of the [Pd624](BF4)12 cage. These results indicate that the ligand exchange between Py* and pyridyl groups in the tritopic ligand 2 took place faster. On the other hand, the formation of the [Pd624](BF4)12 cage is slower than that of the [Pd614](BF4)12 cage. This suggests that during the self-assembly of the [Pd624](BF4)12 cage, the reaction took place towards the formation of species whose structures are far from the octahedron-shaped cage. As a consequence, much faster oligomerization than the cyclization led to a large amount of kinetically trapped species in the self-assembly of the [Pd624](BF4)12 cage. The difference in the self-assembly processes between the two cages arises from structural and/or electronic difference(s) between the geometrically same tritopic ligands 1 and 2. Slower ligand exchange between Py* and the pyridyl groups in 1, which would be due to the electron-deficient 1,3,5-triazine ring in 1, may prevent the

The self-assembly processes of octahedron-shaped M6L4 cages from cis-protected Pd(II) complexes and tritopic ligands were investigated. The [Pd614](BF4)12 cage composed of 1,3,5triazine-based tritopic ligands were assembled in high yield under a mild condition, while in the self-assembly of the [Pd624](BF4)12 cage composed of 1,3,5-triethynylbenzenebased tritopic ligand 2, about half of the substrates were converted into kinetically trapped species with several-tenthsnm in length. Considering that whether large kinetically trapped species are produced or not is determined by the balance between the rates of oligomerization and the cyclization, the formation of such kinetically trapped species is due to the over oligomerization (k1 >> k2). This was experimentally confirmed by the fact that the release of Py* for the [Pd624](BF4)12 cage is faster than that for the [Pd614](BF4)12 cage, though the production of the [Pd624](BF4)12 cage is slower than that of the [Pd614](BF4)12 cage. These results indicate that slight difference in the ligand structure between 1 and 2 affects the relative rates of the elementary reactions (oligomerization, cyclization, and crosslink). QASAP and numerical analysis indicate that the cyclization is slower than the oligomerization and the crosslink in the self-assembly of the [Pd614](BF4)12 cage (k1, k3 > k2). The numerical analysis also indicates that the cyclization reactions mainly take place from the linear intermediates (C and D) and that the relative difference in the rate constants between the oligomerization (k1) and the cross-link (k3) does not affect the trend of the self-assembly process of the [Pd614](BF4)12 cage. Considering our recent finding that selfassembly processes are affected by molecules that are not components of the final product (solvent, leaving ligand, and counter anion),9 the self-assembly processes of the [Pd614](BF4)12 and [Pd624](BF4)12 cages revealed by QASAP in this research would be more or less altered by changing the self-assembly condition. This idea is supported by the improvement of the yield of the [Pd624](BF4)12 cage by changing the solvent and the reaction temperature.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. 1H NMR spectra, analytical procedures, and analytical data (PDF)


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AUTHOR INFORMATION Corresponding Author *[email protected].

ORCID Satoshi Takahashi: 0000-0002-0889-5449 Tatsuo Kojima: 0000-0001-7799-8153 Hirofumi Sato: 0000-0001-6266-9058 Shuichi Hiraoka: 0000-0002-9262-4747

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT This research was supported by JSPS Grants-in-Aid for Scientific Research on Innovative Areas “Dynamical Ordering of Biomolecular Systems for Creation of Integrated Functions” (25102001, 25102002, and 25102005) and The Asahi Glass Foundation.

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