An atropisomeric M₂L₄ cage mixture displaying guest-induced convergence and strong guest emission in water

Abstract

Introduction of atropisomeric axes into a bent bispyridine ligand leads to the quantitative formation of a complex mixture of atropisomeric M₂L₄ cages upon treatment with metal ions. Whereas the isomer ratio of the obtained cage mixture, consisting of up to 42 isomers, is insensitive to temperature and solvent, the quantitative convergence from the mixture to a single isomer is accomplished upon encapsulation of a large spherical guest, namely fullerene C₆₀. The observed isomerization with other guests depends largely on their size and shape (e.g., <10 and 82% convergence with planar triphenylene and bowl-shaped corannulene guests, respectively). Besides the unusual guest-induced convergence, the present cage mixture displays the strongest guest emission (Φ_F = 68%) among previously reported M_nL_m cages and capsules, upon encapsulation of a BODIPY dye in water.

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Introduction

Biological assemblies such as viral capsids and ferritins display well-organized, spherical nanoarchitectures yet consist of unsymmetrical protein subunits bearing flexible moieties before assembly (Fig. 1a).¹ On the other hand, synthetic chemists are apt to design highly symmetrical subunits with sufficient conformational rigidity to precisely construct spherical nanostructures through hydrogen bonding² and coordination-driven self-assemblies,³e.g., a spherical M₂L₄ cage (Fig. 1b).⁴ The cavity size and properties of such artificial assemblies are also highly controllable by the use of the well-designed components.⁵ In contrast, desymmetrized, synthetic subunits with one or more isomerizable moieties give rise to a complex mixture of product isomers via self-assembly (e.g., Fig. 1c). So far, no rational method has been reported to converge such complex, artificial mixtures (so-called dynamic combinatorial libraries)⁶ into a single, three-dimensional isomer.

Fig. 1 Schematic representation of the self-assemblies of (a) a biological nanostructure, (b) an M₂L₄ cage from symmetrical ligands and metal ions, and (c) a complex mixture of M₂L₄ cage isomers from desymmetrized ligands and metal ions studied herein.

Herein we report the design and synthesis of bent bispyridine ligand 1 with two atropisomeric axes (Fig. 2a). Treatment of the isomerizable and desymmetrized ligands with metal ions leads to the quantitative formation of a complex mixture of atropisomeric M₂L₄ cages 2 (Fig. 2b). Although the isomer ratio of the resultant cages is insensitive to temperature and solvent, the selective and quantitative convergences from the complex mixture to a single isomer are demonstrated upon encapsulation of spherical corannulene dimer and fullerene C₆₀, respectively. In addition, the present cage mixture displays the strongest guest emission (Φ_F = 68%), as compared to previously reported M_nL_m cages and capsules,⁷ upon encapsulation of a fluorescent BODIPY dye.

Fig. 2 Schematic representation of (a) bispyridine ligand 1 (R = –OCH₂CH₂OCH₃) and, (b) the optimized structures of the atropisomers in equilibrium (DFT calculation, B3LYP/6-31* level, R = –OCH₃) and the formation of M₂L₄ cage 2 as a complex isomeric mixture.

As the simplest model, we chose a highly symmetrical M₂L₄ structure to examine its desymmetrization and convergence. It has been established that bent bispyridine ligands with a virtual C_2v symmetry generate M₂L₄ cages or capsules as a single isomer upon complexation with metal ions (Fig. 1b).⁴ Their host abilities have been widely investigated by many groups so far.^8,9 Thus we introduced atropisomeric axes¹⁰ into the ligand and designed 1,4-naphthylene-embedded, bent ligand 1 (Fig. 2a). The new bispyridine ligand adopts three atropisomers owing to hindered rotation around the phenyl–naphthyl bonds so that the corresponding atropisomeric M₂L₄ cage, possessing a spherical hydrophobic cavity (∼1 nm in diameter), is anticipated to be present as an equilibrium mixture of up to 42 isomers (Fig. 3).

Fig. 3 Schematic representation of the possible 42 isomers of M₂L₄ cage 2. These isomers are in equilibrium in solution.

Results and discussion

Formation of a complex mixture of M₂L₄ cages

First we observed the quantitative formation of a complex mixture of M₂L₄ cage 2 isomers by mixing atropisomeric ligand 1, PdCl₂(DMSO)₂, and AgNO₃ (in a 2 : 1 : 2 ratio) in DMSO-d₆ for 1 h at room temperature (Fig. 2).^11,12a As expected, the ¹H NMR spectrum of the product mixture showed complicated and broadened, aromatic signals in the range of 9.7 to 6.6 ppm, in contrast to the simple and sharp signals observed for free ligand 1 (Fig. 4a and b). The ¹H DOSY NMR spectrum revealed that these proton signals have the same diffusion constant (D = 1.2 × 10⁻¹⁰ m² s⁻¹; Fig. 4c),^12b indicating the existence of Pd(II)-linked cage 2 as an isomeric mixture in equilibrium. The exclusive formation of M₂L₄ assemblies 2 was unambiguously confirmed by ESI-TOF MS analysis: prominent peaks were observed at m/z 759.9, 1033.9, and 1582.3, assignable to the [2 – n·NO₃⁻]ⁿ⁺ species (n = 4, 3, and 2, respectively; Fig. 4d). In a manner similar to 2, Pt(II)-analogue 2′ was formed quantitatively and its M₂L₄ structure was confirmed by NMR and MS analyses.¹¹ The existence of various isomers of 2′ was also established by the complicated and broadened ¹H NMR signals (Fig. S23†).

Fig. 4 ¹H NMR spectra (500 MHz, DMSO-d₆, r.t.) of (a) ligand 1 and (b) a complex mixture of cage isomers 2. (c) ¹H DOSY NMR (500 MHz, DMSO-d₆, 298 K) and (d) ESI-TOF MS (DMSO, r.t.) spectra of isomers 2. Optimized structures of 2: (e) an all-syn isomer and (f and g) an all-anti isomer (substituents and counterions are omitted for clarity).

The theoretical calculation of cage 2 indicated that differences in energy are relatively small among representative isomers (ΔE < 1.8 kcal mol⁻¹; e.g., Fig. 4e, f and S22†),¹¹ supporting the complex signals observed in the ¹H NMR spectrum (Fig. 4b). The optimized structure of 2 (e.g., an all-anti isomer, Fig. 4g) clarified that the spherical cavity (∼580 ų) is surrounded by eight naphthalene panels and the cavity diameter is 1.3 nm. Although the cavity shape and size are almost identical to those of anthracene-based M₂L₄ capsule 3 reported previously (Fig. S1†),^9,11 the bent polyaromatic ligands of 2 are proximate to each other yet unstacked.

Guest-induced convergence to a single isomer

Whereas the isomer ratio of cage 2 remained intact even upon changing the solvent (e.g., CD₃CN, CD₃OD, and D₂O) and temperature (e.g., −10 to 110 °C), guest encapsulation allowed the complex mixture to convert into a single isomer in water. When a simple planar and hydrophobic guest, triphenylene (Tp; excess), was mixed with a D₂O solution of 2 (0.6 mM) at room temperature for 1 h (Fig. 5a), the ¹H NMR signals of 2 changed from completely broad¹³ to slightly sharp (Fig. 5b and c), due to the quantitative incorporation of the guests (2 equiv.) into the host cavity through the hydrophobic effect.¹⁴ The NMR signals were unchanged even at elevated temperature (e.g., 80 °C). The ESI-TOF MS analysis of the product clearly supported the formation of 1 : 2 host–guest complex 2·(Tp)₂ (Fig. S27c†). This result indicated the possibility of wide-ranging host abilities of 2 in water and selective isomerization of 2 through an appropriate guest stimulus.¹⁵

Fig. 5 (a) Schematic representation of the guest-induced convergence of a complex mixture of 2. ¹H NMR spectra (500 MHz, D₂O, r.t.) of (b) cage 2, (c) 2·(Tp)₂, (d) 2·Ad, (e) 2·(Cor)₂, and (f) 2·C₆₀. (g) ESI-TOF MS spectrum (H₂O) of 2·C₆₀ and the expansion and simulation of the [2·C₆₀ – 4·NO₃⁻]⁴⁺ signals.

Next, the treatment of small spherical adamantane (Ad) and bowl-shaped corannulene (Cor) with cage mixture 2 gave rise to host–guest complexes 2·Ad and 2·(Cor)₂ in a quantitative manner, respectively, under the same aqueous conditions (Fig. 5a).¹⁵ Interestingly, the resultant ¹H NMR spectra revealed further conversion from the complex mixtures to a single isomer upon binding of the sterically demanding guests, whose shapes are similar to the spherical cavity of 2. The percentages of the generated, major host isomer accommodating Ad and (Cor)₂ guests were estimated to be 75 and 82, respectively (Fig. 5d and e), on the basis of the reference proton signal of the methoxy groups of 2 around 2.96–2.83 ppm. The aliphatic proton signals of bound Ad appeared around −0.7 ppm, due to the aromatic shielding effect of 2 (Fig. S28a†). The eleven aromatic signals were clearly observed in the ¹H NMR spectrum of 2·(Cor)₂ (Fig. 5e). Noteworthy, a similar ¹H NMR spectrum was obtained from a mixture of cage 2′, which is an analogue of 2 with Pt(II) ions, and excess Cor in D₂O at room temperature for 7 h (Fig. S30†).¹¹ The finding revealed that the naphthalene panels embedded in the spherical framework of 2 can flip even at ambient temperature, because the bonds between the Pt(II) hinges and the pyridyl groups are fixed under these conditions.

The quantitative conversion of the mixture into a single isomer was accomplished upon incorporation of spherical fullerene C₆₀ (C₆₀) into cage 2. Mixing of cage 2 with excess C₆₀ in D₂O at 100 °C for 24 h yielded 1 : 1 host–guest complex 2·C₆₀ exclusively. Intense ESI-TOF MS peaks at m/z = 940.2 and 1274.2 were assignable to [2·C₆₀ – n·NO₃⁻]ⁿ⁺ species (n = 4 and 3; Fig. 5g). Notably, the ¹H NMR spectrum of 2·C₆₀ exhibited only eleven signals in the aromatic region, indicating the presence of a single isomer (∼100% selectivity; Fig. 5f). In the ¹³C NMR spectrum of 2·C₆₀, a single signal for the C₆₀ guest was observed at 140.1 ppm (Fig. S32†), in a manner similar to that of the previous C₆₀-incorporated M₂L₄ capsule (141.2 ppm).^9a The broadened, new UV-visible absorption bands derived from the guest were also found around 400–730 nm (Fig. S36†).¹⁶ In short, these results revealed that the “atropisomeric” dynamic combinatorial library⁶ of cage 2 can be strictly controlled by its size (volume) and shape complementary guest molecules.

Crystallographic analysis of the single isomer

The direction of the eight naphthalene panels on 2·C₆₀ was eventually determined by X-ray crystallographic and theoretical analyses.^11,17,18 As we expected, the crystal structure showed that one molecule of C₆₀ is fully captured by the cage-shaped M₂L₄ framework of 2 (Fig. 6a). Remarkably, all the bent bispyridine ligands adopted a syn conformation and aligned roundly in the same direction (Fig. 6b), most probably to avoid the steric repulsion between the naphthalene panels of the adjacent ligands. The π-stacking interactions between C₆₀ and the naphthalene panels were observed at eight positions (d = 3.2–3.4 Å in interplanar distance; Fig. S38†). The theoretical calculations of 2·C₆₀ (R = –H) on the basis of the present crystal structure indicated that the energy of the all-syn isomer (Fig. 6a) is 10.6 kcal mol⁻¹ lower than that of an all-anti isomer (Fig. 6c) in the gas phase. The cage framework possesses four small openings (approximately 4 × 5 Ų) between the polyaromatic ligands, in contrast to previous M₂L₄ capsule 3 with an anthracene-based, closed shell.⁹ Preliminary host–guest studies showed the selective binding of one molecule of functionalized fullerenes (e.g., diethyl malonate-derivatized C₆₀) by the present cage in water (Fig. S40†).¹¹

Fig. 6 X-ray crystal structure of 2·C₆₀ (all-syn isomer): (a) space-filling representation for C₆₀ and (b) space-filling representation for the naphthalene panels (the substituents are replaced by H atoms for clarity). (c) Optimized structure of 2·C₆₀ (all-anti isomer, R = –H).

Strong emission of an encapsulated BODIPY derivative

Finally, we encountered that naphthalene-based Pt(II)-cage 2′ displays very strong guest emission upon encapsulation of a BODIPY dye in water.¹⁹ After stirring a mixture of cage 2′ and water-insoluble, pentamethyl boron-dipyrromethene PMB (9 equiv.) in D₂O at 80 °C for 1.5 h (Fig. 7a), the formation of 1 : 1 host–guest complex 2′·PMB was evidenced by NMR, MS, and UV-visible analyses. The obtained, broad ¹H NMR signals indicated the existence of a complex isomeric mixture including the guest dye (Fig. S41a†). The 1 : 1 host–guest ratio of the product was confirmed by the ESI-TOF MS spectrum, which shows clear MS peaks for [2′·PMB – n·NO₃⁻]ⁿ⁺ species (n = 4, 3; Fig. S41b†). The UV-visible spectrum of the pale yellow solution of 2′·PMB in water showed new absorption bands in the range of 410–550 nm, derived from encapsulated PMB (Fig. 7b). The observed bands were slightly red-shifted (Δλ = 10 nm) with respect to those of free PMB in CH₃CN and their intensity indicated the encapsulation efficiency being ∼25%. The optimized structure of 2′·PMB (R = –H) suggested that a slightly bent PMB framework is fully accommodated in the polyaromatic shell of 2′ (Fig. 7c).¹¹

Fig. 7 (a) Schematic representation of the formation of highly emissive host–guest complex 2′·PMB. (b) UV-visible spectra and photograph (H₂O, r.t.) of 2′·PMB, 2′, and PMB (in CH₃CN). (c) Optimized structure of 2′·PMB (R = –H, all-syn isomer). (d) Fluorescence spectrum (H₂O, r.t., 80 μM based on 2′, λ_ex = 500 nm) of 2′·PMB and its photograph (λ_ex = 365 nm).

Host–guest complexes featuring high emissivity in water have attracted considerable attention related to biomolecular sensors. However, the majority of coordination cages and capsules disturb guest emission upon encapsulation, owing to the heavy metal effect.^3–6 Our previous studies exceptionally demonstrated strong fluorescence (λ_max = 535 nm, Φ_F = 48%) from a 1 : 1 host–guest complex, composed of anthracene-based capsule 3 and PMB in water.^7c Notably, the aqueous solution of 2′·PMB emitted much stronger green fluorescence with a quantum yield of 68% at λ_max = 514 nm, upon irradiation at 500 nm (Fig. 7d). The band shape and maximum wavelength are similar to those of free PMB in ethanol (λ_max = 522 nm, Φ_F = 78%). To the best of our knowledge, this represents the strongest guest emission in coordination host compounds reported so far.⁷ As compared to capsule 3 with a relatively rigid cavity,⁹ the flexible naphthalene-based cavity of 2′ is able to adjust to the shape of the bulky PMB guest (Fig. 7c), which reduces the steric host–guest repulsion. Once the cage encapsulates the guest, the flexibility of the naphthalene panels is largely suppressed due to the efficient host–guest interactions. These effects might suppress emission quenching processes, observed in the case of 3·PMB, to a large degree (ΔΦ_F = +20%).¹⁹

Conclusions

We have challenged the perfect conversion of a complex mixture of atropisomeric M₂L₄ cages into a single isomer by an external stimulus. The cage mixture including up to 42 isomers was generated upon incorporation of two atropisomeric axes into the bent bispyridine ligands of a common and highly symmetrical M₂L₄ structure. Unusual convergence of the mixed isomers was demonstrated upon encapsulation of guest molecules. Particularly, the encapsulation of a fullerene guest led to the quantitative formation of a single isomer, due to its size and shape complementarity to the spherical host cavity. Thus, the present system can be regarded as a novel dynamic combinatorial library capable of incorporating large guests up to 1 nm. The isomer structure (all-syn) of the M₂L₄ cage was fully characterized by NMR, MS, UV-visible, X-ray crystallographic, and theoretical analyses. As an additional host function, the cage mixture encapsulated a fluorescent BODIPY dye and the resultant 1 : 1 host–guest complex exhibited intense guest emission (Φ_F = ∼70%) in water. We believe that the present study is a small yet first “synthetic” step to approach large and well-organized, biological capsules, composed of multiple unsymmetrical subunits, in vitro.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by JSPS KAKENHI (Grant No. JP18H01990/JP19H04566) and “Support for Tokyotech Advanced Researchers (STAR)”. We thank Prof. Munetaka Akita and Dr Naoki Noto for helpful discussion and L. C. thanks the JSPS and Humboldt Postdoctoral Fellowship.

Notes and references

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11. See the ESI.† The geometry optimizations of the cages and host–guest complexes were performed with molecular mechanics (MM) calculations (Forcite module, Materials Studio, version 5.5.3). Particularly, the optimized structures and energies of all-syn/anti2·C₆₀ isomers were calculated on the basis of the crystal structure.
12. (a) Ligand 1 was synthesized in three steps using 3-pyridineboronic acid pinacol ester, 1,4-dibromonaphthalene, and 1,5-dibromo-2,3,4-tri(2-methoxyethoxy)-benzene;¹¹; (b) The diffusion constant indicates the product size (outer diameter) being approximately 2 nm..
13. In the ¹H NMR spectrum, the signals of a mixture of 2 in D₂O (Fig. 5b) are much broader than those in DMSO-d₆ (Fig. 4b), because of strong interactions between the naphthalene-based bispyridine ligands, induced by the hydrophobic effect.
14. The ESI-TOF MS analysis of the products elucidated the host–guest ratios (except for the labile 2·Ad complex under MS conditions). In addition, the ratios were also estimated by the ¹H NMR integrations of the products after disassembly in DMSO-d₆ (at 80 °C for 1 h under high dilution conditions).
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16. The absorption bands of the electron-deficient C₆₀ guest are sensitive to the polyaromatic host framework due to the efficient host–guest interactions.^7f The electron-donating properties of the host framework are decreased by the replacement of the anthracene panels with naphthalene panels so that large blue shifts of the guest absorption bands were observed in 2·C₆₀ as compared with an anthracene-based host–guest analogue.^9a.
17. The brown block crystals of 2·C₆₀ were obtained by slow concentration of a 2 : 1 acetonitrile/water solution of 2·C₆₀ over 3 weeks at room temperature. Whereas there have been many reports on the successful X-ray crystallographic analysis of M₂L₄ hosts,^4,8,9 reports on host–guest complexes including one C₆₀ guest are still rare.¹⁸.
18. (a) C. García-Simón, M. Costas and X. Ribas, Chem. Soc. Rev., 2016, 45, 40–62; (b) B. Chen, J. J. Holstein, S. Horiuchi, W. G. Hiller and G. H. Clever, J. Am. Chem. Soc., 2019, 141, 8907–8913.
19. Cage 2′ was chosen for this study due to the pronounced heavy-atom fluorescence quenching effect of the Pd(II)-analogue. A detailed study of the emission dynamics has been performed with 3·PMB, using fluorescence lifetime and femtosecond transient absorption measurements.^7c.

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Footnotes

† Electronic supplementary information (ESI) available. CCDC 1907426. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d0sc03223a

‡ These authors contributed equally.

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