Russian-Doll-Like Molecular Cubes

Russian-Doll-Like Molecular Cubes

Article

⊥

Die Liu,* Kaixiu Li, Mingzhao Chen,* Tingting Zhang, Zhengguang Li, Jia-Fu Yin, Lipeng He,

Jun Wang, Panchao Yin, Yi-Tsu Chan, and Pingshan Wang*

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sı Supporting Information

ABSTRACT: Nanosized cage-within-cage compounds represent a

synergistic molecular self-assembling form of three-dimensional

architecture that has received particular research focus. Building

multilayered ultralarge cages to simulate complicated virus capsids

is believed to be a tough synthetic challenge. Here, we synthesize

two large double-shell supramolecular cages by facile self-assembly

of presynthesized metal−organic hexatopic terpyridine ligands with

metal ions. Diﬀering from the mixture of prisms formed from the

inner tritopic ligand, the redesigned metal−organic hexatopic

ligands bearing high geometric constraints that led to the exclusive

formation of discrete double-shell structures. These two unique

nested cages are composed of inner cubes (5.1 nm) and outer huge

truncated cubes (12.0 and 13.2 nm) with six large bowl-shape subcages distributed on six faces. The results with molecular weights

of 75 232 and 77 667 Da were among the largest synthetic cage-in-cage supramolecules reported to date. The composition, size and

shape were unambiguously characterized by a combination of H NMR, DOSY, ESI-MS, TWIM-MS, TEM, AFM, and SAXS. This

work provides an interesting model for functional recognition, delivery, and detection of various guest molecules in the ﬁeld of

supramolecular materials.

INTRODUCTION

ligands and rationally controlling the self-assembly process.

The typical and perfect work was the giant polyhedral cage

■

Artiﬁcial synthetic cages are inspiring species, which could

provide biomimetic microenvironments to study the weak

interactions within a cavity. Just like the ubiquitous, elegant,

[

M L ] obtained by subtle control over the bent angle and

48 96

7b,17

geometry of bipyridine ligands from Fujita’s group.

addition, the multicomponent heteroleptical coordination-

driven self-assembly is an alternative strategy to construct the

and functional self-assemblies in living organisms, the resulting

cage complexes have precise spatial structures and, more

important, consequent powerful functionalities, such as guest

desired intricate and huge 3D architectures. Another strategy

to construct well-deﬁned megastructures is using the

hierarchical stepwise coordination reaction, which could

avoid the unwanted self-sorting or oligomers in a multiligands

system and to ﬁnally generate the predeﬁned structures via

recognition, chemical separations, catalysis, and so on.

Although the ultralarge three-dimensional molecular architec-

tures are prevalent in biological systems such as various

spherical virus capsids, it is full of challenges to artiﬁcially

obtain the nanoscale ones with accurate size and geometry

using the chemical synthetic method, especially for very large

self-assembled structures. In comparing with the single-shell

thermodynamically driven assembly.

Even though these sophisticated and giant synthetic metallo-

supramolecular cages have been well-established, before

mimicking the functionality of biological systems, it remains

necessary to construct supramolecular architectures with

comparable size to biological molecules. For example, most

virus capsids vary in diameter from tens to hundreds of

nanometers and the smallest animal viruses are about 20 nm,

notably the artiﬁcially synthesized well-deﬁned supramolecules

nanosized containers, the double-shell ones, such as cage-

within-cage structures, are attractive but rarer in nonbiological

chemistry.

Coordination-driven supramolecular self-assembly is an

appropriate strategy to synthesize the desired supramolecules

due to its high directionality and moderate bonding strength.

Indeed, multitudinous 3D polyhedral and cage-like architec-

tures have been expediently generated via coordination

Received: November 7, 2020

Published: December 30, 2020

reaction of the ligands and metal ions, represented by the

prominent work of Fujita, Stang, Nitschke, Raymond,

Clever, and others. Among these excellent works, many

eﬀorts have been dedicated to construct complex and giant 3D

supramolecular structures by means of precisely designing the

2020 American Chemical Society

J. Am. Chem. Soc. 2021, 143, 2537−2544

537

Journal of the American Chemical Society

and metal ions. As shown in Figure 1 , the nonplanar tritopic

Article

7b,20

larger than 10 nm in diameter are rare.

It is worth

mentioning that the synthesis of multilayered 3D structures is

of importance to further understanding of the interaction

behaviors and potential applications in the ﬁeld of supra-

molecular materials. However, only a few examples about

complex-in-complex cages were reported so far. The ﬁrst

artiﬁcial sphere-in-sphere architecture was obtained by Fujita

and co-workers by employing two tethered ligands. The

groups of Li and Mukherjee developed the square planar

coordination self-assembly through tetramonodentate ligands

with M ions (M = Pd and Pt). Diﬀerent types of double-

shell supramolecules and nanoclusters were also demonstrated

by Schmitt, Wang, Sun, and others very recently.

Terpyridine-based supramolecular double-shell structures,

however, have not been reported to the best of our knowledge.

In this paper, two huge double-shell Russian-doll-like cubes

were rationally designed and synthesized by the self-assembly

of preorganized metal−organic multitopic terpyridine ligands

Figure 2. (A) Schematic illustration of self-assembly of tripodal

organic ligand 3 into a mixture of octamer, decamer, and dodecamer;

(

B) DOSY NMR spectra (500 MHz, 298 K) of the mixtures in

CD CN/DMF-d ; (C) ESI-MS of multiple resultant products.

Multimer complexes are named M_n, where n designates the number

of repeat ligands and x is the number of charges.

assembly of ligand 3 with Zn ions was performed by precisely

mixing two components with 2/3 ratio in CHCl /CH CN/

CH OH. With the fact that ligand 3 possess the rigid ridge

,1,1-triphenylethane core and the bent angle of tpy moieties is

ca. 109°, which is similar to the adjacent edge angle (108°) of

dodecahedron, we expected that the 3 could form the desired

single cage-like dodecahedrons. Unfortunately, both H NMR

Figure 1. Cartoon representation of a mixture formed from tritopic

ligand and a giant double-decker Russian-doll-like cube from the

branched ligand with increasing coordination numbers.

and 2D Diﬀusion-ordered spectroscopy (DOSY) NMR spectra

indicate the forming of mixed assemblies. As shown in Figure

, the H NMR spectrum of resultant products showed

ligand was assembled to form a mixture of octamer, decamer,

dodecamer, and other oligomers instead of single species. Most

interestingly, by introducing the aﬃliated outer layer through a

characteristic signals shift of terpyridine ligands after complex-

,6’’

ing, the expected upﬁeld shift of the tpyH proton from 8.75

to 7.91 ppm was observed. Besides, there are several obvious

overlapped peaks corresponding to the same proton, for

example, two discernible singlets around 9.18 ppm contributed

rigid ⟨Tpy-Ru -Tpy⟩ connection to increase coordination

numbers, the redesigned hexatopic units (L1 and L2) could be

accurately assembled to generate the discrete double-shell

architectures (L1 Zn and L2 Zn ) due to the high

to tpyH ′ ′ proton (see Figure S40). Furthermore, the DOSY

spectrum displayed three signal bands with log D (D is

diﬀusion coeﬃcient) = −10.30, −10.39, and −10.46,

respectively (Figure 2B), demonstrating the formation of a

mixture in CD CN/DMF-d . Further, the components of the

geometric constraints. These two unique nested cages are

composed of inner cubes and outer huge truncated cubes.

Viewed from another perspective, six large bowl-shape

subcages were distributed on six faces, which may provide a

new type of functional supramolecular hosts for shape-, size-,

resultant mixture were characterized by the electrospray

ionization mass spectrometry (ESI-MS), in which a series of

sequential charged peaks assigned to octamer, decamer,

dodecamer, and others were clearly observed (Figure 2C).

Synthesis of Metal−Organic Hexatopic Ligands and

Assembly of Russian-Doll-Like Cubes. Above results

indicate that the tripodal ligands have a ﬂexible structure,

which could bend to form compact geometry. In order to

obtain more complicated discrete assemblies, the new metal−

organic ligands were synthesized by stepwise method using the

and charge-selective guests.

RESULTS AND DISCUSSION

■

One Step, Self-Assembly of a Tripodal Organic

Ligand with Zn . Initially, the tripodal ligand 3 was

synthesized by Suzuki Coupling reaction of bromo-substituted

compound 1 and 4′-(4-boronatophenyl)[2,2′:6′,2″]terpyridine

with Pd catalyst (Scheme S1). As shown in Figure 2, the self-

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Article

Scheme 1. (A) Synthesis of Metallo-Organic Ligands L1 and L2 and (B) Energy-Minimized Structure of Russian-Doll-Like

Cube C2

Reagents and conditions: (i) N-ethyl morpholine, CH OH:CHCl (1:1, v:v), reﬂux, 1 d; (ii) N-ethyl morpholine, CH OH:CHCl (1:1, v:v),

reﬂux, 1 d; (iii) Pd(PPh ) , K CO , CH CN:CH OH (5:1, v:v), reﬂux, 6 d.

Figure 3. H NMR spectra (500 MHz, CD CN, 298 K) of (A) Metallo-organic ligand L2 and (B) Russian-doll-like cube C2; (C and D) DOSY

NMR spectra (500 MHz, 298 K) of C1 and C2 in CD CN, which showed narrow single bonds, conﬁrming that only one species exists in the

solution.

irreversible ⟨Tpy-Ru -Tpy⟩ units as connections. As shown in

Scheme 1, bromo-substituted complex 13 was generated by

stepwise coordination reactions, in which tetrapodal terpyr-

with adducts 12 to aﬀord the desired products. The ﬁnal

multitopic terpyridine ligand L1 was obtained by a six

simultaneous Suzuki couplings of complex 13 with 4′-(4-

boronatophenyl)[2,2′:6′,2″]terpyridine catalyzed by [Pd-

(PPh ) ] and puriﬁcation by column chromatography

idine compound 5 was ﬁrst reacted with RuCl adducts 8 to

produce mononuclear complex 9 and then when complexed

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Al O ) and subsequent recrystallization. With similar process,

Article

(

the larger metal−organic ligand L2 was also successfully

synthesized. The structures of L1 and L2 were undoubtedly

characterized by NMR spectra and ESI-MS (the detailed

analyses are available in the Supporting Information). As

observed from Figure 3, the H NMR of L2 showed four

singlets around 9.13 ppm assigned to the tpyH ′ ′ protons for

⟨

Tpy-Ru -Tpy⟩ moieties and two singlets at 8.88 and 8.85

ppm with 1:1 integrated ratio attributed to the tpyH ′ ′ of free

terpyridyl fragments, and all of signal assignments were

performed by 2D COSY and 2D-NOESY NMR spectra

(

Figure S32). As well, the ESI-MS spectrum of complex L2

showed the clear and sequential peaks at 838.83(7+),

025.28(6+), 1286.31(5+), and 1677.85(4+), supporting the

desired structure (Figure S38).

The self-assembly of Russian-Doll-Like Cubes C1 (or C2)

was performed by precisely mixing ligand L1 (or L2; 1 equiv)

and Zn(NO ) ·6H O (3 equiv) in CH CN at 85 °C for 24 h,

giving a translucent red solution. After cooling to room

temperature, excess lithium bis(triﬂuoromethylsulfonyl)imide

(

LiNTf ) solution was added to generate a precipitate, which

was washed with plenty of H O to give complexes C1 (or C2).

The H NMR spectrum of cubes C1 and C2 was showed in

Figures S49 and 3, respectively, in which a broad signal pattern

was observed due to the slow tumbling motion resulting from

the formation of giant complexes. However, both H NMR

results were similar to those for corresponding ligands L1 and

L2, indicating that the resultant products are highly sym-

metrical. Moreover, all protons signals could be completely

assigned via the 2D-COSY and NOESY NMR spectra (The

detailed analyses are available in the Supporting Information).

In comparison of metal−organic ligand L2, the obvious

resonance peak change for complex C2 was easily found,

including obvious downﬁeld shifts from 8.9 to 9.1 ppm for the

3 ,3

signals of tpyH ′ ′ and tpyH ′ ″ of free terpyridine segments,

owing to the tangential electron-withdrawing eﬀects upon

coordination and a dramatic upﬁeld shift (δ = 0.9 ppm) for

Figure 4. (A) ESI-MS and (B) 2D ESI TWIM-MS plot (m/z vs drift

time) of complex C1 and (C) ESI-MS and (D) 2D ESI TWIM-MS

plot (m/z vs drift time) of complex C2. The charge states of intact

assemblies are marked.

tpyH ′ ″ protons due to the electron shielding eﬀect (Figure

B). Similar signals shift were also observed for complex C1

(Figure S49). Such characteristic change of the tpy moieties

demonstrates that the assembled complex was designedly

produced. Single and discrete self-assembled structures of C1

and C2 were further supported by diﬀusion-ordered NMR

spectroscopy (DOSY) spectrum (Figure 3C), in which all of

resonance signals for the complex were on a narrow band with

log D = −10.03 (C1) and −10.12 (C2), respectively,

supporting the respective formation of one discrete species

ular cubes. Unfortunately, the experimental isotope pattern of

each charge state for both C1 and C2 were indistinct possibly

due to resolution limits by high molecular weight and/or the

large cavity encapsulating the solvent molecules. Alternatively,

the ESI-TWIM-MS experiments aﬀorded additional structural

evidence, in which one dominant series of continuous charge

signal distributions ranging from 30 to 39 derived from

in CD CN. In addition, the experimental hydrodynamic radius

complex C1 and 31 to 44 for complex C2 with a narrow drift

time were discernible, and no signal peaks of other oligomer

were found, which indicated that the formation here was

discrete and rigid structures, as well no other isomers or

structural conformers exist (Figure 4B,D).

(

rH) of C1 and C2 which derived from the Stokes−Einstein

equation was ca. 6.2 and 7.4 nm, respectively.

The composition and structure of Russian-doll-like cubes C1

and C2 were fully characterized by ESI mass spectrum and

traveling-wave ion mobility-mass spectrometry (TWIM-MS).

As displayed in Figure 4A,C, a series of sequential peaks with

Size Characterization by Transmission Electron

Microscopy (TEM), Atomic Force Microscopy (AFM),

and Small-Angle X-ray Scattering (SAXS). Many attempts

to grow X-ray single crystals for Russian-doll-like cubes C1 and

C2 were unsuccessful to date probably because the huge

molecular frameworks and solvent molecules or counterions in

the cavity. To provide more structural evidence, the TEM and

AFM measurements were performed by drop-casting dilute

charge states varying from 24 to 46 for complex C1 and 31

to 51 for complex C2 were detected, respectively. These

continuous signals matched well with the simulated m/z from

t h e t h e o r e t i c a l m o l e c u l a r f o r m u l a o f

112+

−

(

Zn Ru C₂₆₈₀H₁₇₆₀N₃₃₆O ) ·112(NTf ) with the molec-

24 32 24 2

ular weight 75232.41 Da for complex C1 and

112+

−

−6

(

Zn Ru C₂₈₇₂H₁₈₈₈N₃₃₆O ) ·112(NTf ) with the molec-

solutions of C1 and C2 in MeCN at a concentration of ∼10

ular weight 77667.55 Da for complex C2, demonstrating the

M onto superthin carbon ﬁlm-coated Cu grid or freshly cleaved

formation of desired octameric Russian-doll-like supramolec-

mica sheet. As depicted in Figure 5C,D, TEM images displayed

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Figure 5. (A and B) Representative energy-minimized structures from molecular modeling of C1 and C2; (C and D) TEM images of C1 and C2,

E and F) AFM images of C1 and C2, and (G) SAXS proﬁles of the C1 and C2.

(

mounts of uniform dots with an average diameter of 12.0 ± 0.1

nm for complex C1 and 13.2 ± 0.2 nm for complex C2, which

were consistent with the size simulated from molecular

modeling (see also Figure S56). As well, the AFM images

well with the theoretical models. In addition, the discrepancy

between the theoretical plots of a small cubic structures and

experimental scattering data of C1 and C2 excludes the

possibility of the formation of small nanocages (Figure S60).

The less-resolved peaks with low amplitude may be due to the

existence of large void areas in the framework structures, which

veriﬁes the incompact structures of Russian-doll-like cubes C1

and C2.

(

Figures 5E,F, S57, and S58) showed a series of dots with

average height of 8.2 and 9.5 nm, which were in accordance

with the calculated height from model structure of 8.6 and 9.8

nm for C1 and C2, respectively. Furthermore, Dynamic light

scattering experiments (DLS) have been also employed to

measure the molecular sizes of the supramolecular complexes

CONCLUSIONS

■

(

Figure S59), conﬁrmed the size distribution correlates well

In conclusion, we herein report a synthetic approach to

Russian-doll-like cubes whose molecular weight and size were

among the largest cage-within-cage supramolecules. The inner

cubic shell and the outer huge truncated cube were bridged

through eight ⟨Tpy-Ru -Tpy⟩ connectivities. This successful

result shows that mutil-topic ligands with high geometric

constraints are important for the generation of single species.

The cage-within-cage structures were conﬁrmed by a series of

with the size of optimized molecular models (12.0 and 13.2

nm).

With the above structural composition and size information

in mind, small-angle X-ray scattering (SAXS) measurement

were further performed for C1 and C2, respectively, in

solutions to access more structural information and the SAXS

datum were summarized in Figure 5G. Theoretical SAXS plots

were aﬀorded using the Crysol software on the basis of the

optimized structure models of C1 and C2, generated from the

Material Studio platform. The experimental SAXS curves ﬁtted

quite well with the simulated data, especially the oscillation

features and local minimum, suggesting that the overall

morphology of the two samples in solutions are consistent

experiments including H NMR, DOSY, ESI-MS, TWIM-MS,

TEM, AFM, and SAXS, suggesting that the designed double-

shell cages have a molecular weight up to 77 667 Da and

possess a size up to 13.2 nm. This strategy used in this study

will pave a new avenue toward precisely constructing more

giant supramolecules. In addition, the large bowl-shape

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https://pubs.acs.org/doi/10.1021/jacs.0c11703.

Article

subcages within the assemblies that may provide a new type of

functional supramolecular hosts for shape-, size-, and charge-

selective guests. Such exquisite and huge self-assembled

architectures will also arouse more interest and further research

on exactly where is the end for the size of well-deﬁned artiﬁcial

synthetic assemblies.

Luminescent Materials and Devices, South China University

of Technology, Guangzhou 510640, China

Lipeng He − Department of Chemistry, National Taiwan

University, Taipei 10617, Taiwan

Jun Wang − Department of Organic and Polymer Chemistry;

Hunan Key Laboratory of Micro & Nano Materials Interface

Science; College of Chemistry and Chemical Engineering,

Central South University, Changsha, Hunan 410083, China

Panchao Yin − South China Advanced Institute for Soft

Matter Science and Technology & State Key Laboratory of

Luminescent Materials and Devices, South China University

of Technology, Guangzhou 510640, China; orcid.org/

0000-0003-2902-8376

ASSOCIATED CONTENT

sı Supporting Information

■

The Supporting Information is available free of charge at

Experimental procedures and characterization data,

including H, C, COSY, NOESY, and DOSY spectra

of the new compounds and ESI-MS spectra, TEM, and

AFM images of related compounds (PDF )

Yi-Tsu Chan − Department of Chemistry, National Taiwan

University, Taipei 10617, Taiwan; orcid.org/0000-0001-

9658-2188

Movie of the Russian-doll-like cube C1 (MOV)

Movie of the Russian-doll-like cube C2 (MOV)

Complete contact information is available at:

https://pubs.acs.org/10.1021/jacs.0c11703

Author Contributions

D.L. and K.L. contributed equally to this work.

⊥

AUTHOR INFORMATION

■

Corresponding Authors

Notes

Die Liu − Institute of Environmental Research at Greater Bay

Area; Key Laboratory for Water Quality and Conservation of

the Pearl River Delta, Ministry of Education; Guangzhou Key

Laboratory for Clean Energy and Materials, Guangzhou

University, Guangzhou 510006, China; Email: chem-ld@

gzhu.edu.cn

Mingzhao Chen − Institute of Environmental Research at

Greater Bay Area; Key Laboratory for Water Quality and

Conservation of the Pearl River Delta, Ministry of Education;

Guangzhou Key Laboratory for Clean Energy and Materials,

Guangzhou University, Guangzhou 510006, China;

Email: jinyulinzhao@foxmail.com

Pingshan Wang − Institute of Environmental Research at

Greater Bay Area; Key Laboratory for Water Quality and

Conservation of the Pearl River Delta, Ministry of Education;

Guangzhou Key Laboratory for Clean Energy and Materials,

Guangzhou University, Guangzhou 510006, China;

Department of Organic and Polymer Chemistry; Hunan Key

Laboratory of Micro & Nano Materials Interface Science;

College of Chemistry and Chemical Engineering, Central

South University, Changsha, Hunan 410083, China;

orcid.org/0000-0002-1988-7604; Email: chemwps@

csu.edu.cn

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

This research was supported by the National Natural Science

Foundation of China (22001047 for D.L. and 21971257 for

P.W.), the Science and Technology Research Project of

Guangzhou, China (No. 202002010007), and the Hunan

Science and Technology Plan Project, China (No.

2019TP1001).

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NOTE ADDED AFTER ASAP PUBLICATION

■

This paper published ASAP on December 30, 2020 with an

error in Figure 5. The ﬁgure was replaced and the revised

paper reposted on January 5, 2021.

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