A sphere-in-sphere complex by orthogonal self-assembly

Article abstract of DOI:10.1002/anie.201104670

Russian dolls: Two covalently tethered, curved bispyridinyl ligands and Pd^II ions have been shown to self-assemble into a sphere-in-sphere complex (6.3 nm in diameter; see X-ray structure). The two ligands did not form heteroleptic mixed complexes, but instead assembled into two distinct homogeneous [M₁₂L₂₄] cuboctahedra, reminiscent of a double-shell viral capsid. Copyright

Full text of DOI:10.1002/anie.201104670

Communications
DOI: 10.1002/anie.201104670
Self-Assembly
A Sphere-in-Sphere Complex by Orthogonal
Self-Assembly**
Qing-Fu Sun, Takashi Murase, Sota Sato, and Makoto Fujita*
Angewandte
Chemie
10318
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 10318 –10321

Sphere-shaped viral capsids often possess double-shell struc-
tures with independent inner and outer shells formed from
different subunits.[1] The self-assembly processes of the two
shells are orthogonal, that is, they do not interfere with each
other. Structural orthogonality greatly facilitates the highly
essential functional subdivision in complex biological assem-
bly systems.[2,3] We and others have previously reported
several artificial spherical molecules that have a structural
resemblance to the hollow-shell virus capsids,[4–18] but the
formation of a subdivided complex structure such as a double-
shell virus capsid by orthogonal self-assembly has never been
reported.[19]
The simple model compound 1 was synthesized to
examine orthogonal self-assembly. The dual, linked bispyr-
idinyl ligand 1 displays two, effectively identical, coordination
sites A and B. Thus, when treated with metal ions, a random
assortment of various heteroleptic, oligomeric complexes
would be expected. However, we now report that simple
treatment of ligand 1 with PdII ions results in the giant sphere-
in-sphere complex 2 consisting of 24 PdII ions and 24 ligands
assembled into two spherical shells (Scheme 1). The ortho-
gonal self-assembly of 2 is analogous to the high fidelity of
protein assembly, where individual subunits unfailingly locate
their predetermined positions.
The synthesis of 1 was achieved in two high-yielding steps
based on the Mitsunobu reaction of bidentate pyridinyl units
of two different lengths, which were synthesized by proce-
dures similar to those previously reported by our research
group (for details, see the Supporting Information).[17–21] The
triethylene glycol (TEG) chain was chosen as a linker, as it
not only provides the required spacer length but also
improves the overall flexibility and solubility of the ligand.
Ligand 1 was treated with an equimolar amount of
Pd(NO3)2 (both 5 mm) in [D6]dimethyl sulfoxide
([D6]DMSO) at 808C for 6 h. All the signals became
broadened in the 1H NMR spectrum (Figure 1a), thus
suggesting the formation of a giant structure whose tumbling
motions are slow on the NMR time scale. Moreover, the
number of signals in the aromatic region remained
unchanged, which indicates that the complex has a highly
symmetrical structure. All the PyHa and PyHb (Py = pyridyl)
signals shifted clearly downfield as a result of coordination to
the PdII centers. Diffusion-ordered NMR spectroscopy
(DOSY) showed a single band at D = 3.16 ꢀ 10À11 m2 sÀ1
(logD = À10.50), which is much smaller than that of the
free ligand 1 at D = 1.58 ꢀ 10À10 m2 sÀ1 (logD = À9.80) in
Scheme 1. Self-assembly of sphere-in-sphere complex 2.
[D6]DMSO (Figure 1b). These observations were consistent
with the formation of the sphere-in-sphere complex 2.
The composition of 2 was confirmed as [Pd24(1)24] by cold-
spray ionization time-of-flight mass spectrometry (CSI-TOF-
MS).[22] Mass analysis of the complex was immensely difficult
because of its very high molecular weight and the relatively
weak PdII–N interactions. Nevertheless, after optimizing the
conditions and examining several counterions, the triflate
(TfOÀ) salt of 2 was found to afford a series of signals
corresponding to [2(TfOÀ)m]m+ (m = 20–12), thus confirming
the molecular weight of 2 ([Pd24(C54H42N4O4)24]48+·48(TfOÀ))
as 29172.31 Da. Notably, the finely resolved isotopic distri-
bution observed at each MS signal was also in perfect
agreement with the simulated pattern (Figure 2).
Ultimately, the giant, sphere-in-sphere structure of 2 was
unambiguously determined by single-crystal X-ray analysis
(Figure 3).[23] Suitable single crystals were obtained by slow
diffusion of ethyl acetate vapor into a solution of 2 (TfOÀ salt)
in DMSO over about 2 months. A small yellowish block
crystal was sealed in a capillary for data collection. The poor
scattering nature of this kind of complex meant that high-flux
synchrotron diffraction was essential to obtain high quality
data to solve the structure.
[*] Q.-F. Sun, Dr. T. Murase, Dr. S. Sato, Prof. Dr. M. Fujita
Department of Applied Chemistry, School of Engineering
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-8656 (Japan)
E-mail: mfujita@appchem.t.u-tokyo.ac.jp
[**] This research was supported by the CREST project of the Japan
Science and Technology Agency (JST), for which M.F. is the principal
investigator, and also in part by KAKENHI and MEXT. Synchrotron
X-ray diffraction studies were performed at KEK and SPring-8.
In the crystal state, the two independent spherical frame-
works of 2, with diameters of 6.3 and 3.5 nm, were clearly
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201104670.
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www.angewandte.org 10319

Communications
Figure 3. Crystal structure of the sphere-in-sphere complex 2. All
atoms are depicted as sphere models. Atoms of the interior sphere are
in pink, and the exterior sphere are in blue. Counterions (TfOÀ) and
the TEG linkers are omitted for clarity.
Figure 1. a) 1H NMR (500 MHz, [D6]DMSO, 300 K) spectra of ligand 1
and complex 2 (NO3À salt). b) 1H DOSY (500 MHz, [D6]DMSO, 300 K)
spectrum of complex 2 (the region for ligand 1 is also indicated by a
blue dotted line).
intermediates predominates over self-assembly. In fact, we
had previously observed a significant kinetic trap in the self-
assembly of multicomponent [M12L24] spheres.[25] To our
surprise, despite the formation of numerous oligomers, all of
them still remain in equilibrium, roaming around indefinitely
on the potential surface. A highly symmetric [M12L24]
cuboctahedral framework[17] is the only stable structure and
thus ligand 1 eventually finds pathways where sites A and B
form the homoleptic complexes that lead to orthogonal,
sphere-in-sphere [M12L24] shells.
We also observed that the formation of the inner and the
outer shells is simultaneous and at no stage in the self-
assembly were detectable, resolved intermediary structures,
such as a preformed inner or outer shell, observed. When, for
example, 0.5 equivalents of Pd(NO3)2 were used for complex-
ation with ligand 1, the 1H NMR spectra revealed the
formation of only 2 (ca. 50%), concomitant with remaining
free ligand 1 (ca. 50%), but no intermediary structures were
observed (see Figure S7 in the Supporting Information).
1H DOSY experiments also confirmed the formation of the
sphere-in-sphere complex (see Figure S8 in the Supporting
Information).
In summary, we have succeeded in the self-assembly of the
first artificial sphere-in-sphere molecule. Previously, we
demonstrated that giant, multicomponent discrete aggregates
can act as kinetic traps, which endow stability,[25] and that
[MnL2n] spherical complexes are subject to geometrical
constraints that favor unique n values.[18] Here, we used two
tethered ligands to enforce structural subdivisions that
necessitated self-assembly in an orthogonal fashion with
high fidelity. We believe that our synthetically simple systems
can help deepen the mechanistic understanding of the hidden
mechanisms and emergent behavior that generates the
beautiful and highly complex structures found in biology.
Figure 2. CSI-TOF mass spectrum of complex 2 (TfOÀ salt), with an
inset showing the observed and simulated isotopic patterns of the 17+
signal.
visible, but the majority of the triethylene glycol tethers and
counterions were severely disordered and could not be
resolved. The inner sphere remained highly spherical whereas
the outer sphere exhibited oval distortion, presumably
because of packing effects. The inner sphere is held in place
by 24 linkers, in particular by 8 linkers that are distributed
symmetrically around the core and exhibit a relatively
extended conformation.[24]
In the early stages of self-assembly, numerous oligomeric
complexes are generated by the random coordination of sites
A and B at every PdII center. We anticipated that the
formation of numerous oligomers would make it extremely
difficult to find the right pathway to assemble the sphere-in-
sphere structure; furthermore, as the degree of oligomeriza-
tion increases, the unfavorable kinetic trap of oligomeric
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Angew. Chem. Int. Ed. 2011, 50, 10318 –10321

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Experimental Section
Synthesis of 2 (NO3À salt): Ligand 1 (2.97 mg, 3.66 mmol) was treated
with Pd(NO3)2 (0.85 mg, 3.7 mmol) in DMSO (0.730 mL) at 808C for
6 h. 1H NMR spectroscopy confirmed the quantitative formation of 2.
An excess amount of a mixture of ethyl acetate and diethyl ether (1:1
in volume) was added to the solution of sphere 2 and the precipitate
was collected by centrifugation and dried in vacuo to give 2 as a
yellow solid (71% yield). M.p. > 3008C (decomp). 1H NMR
(500 MHz, [D6]DMSO, 300 K): d = 9.63 (br, 96H), 9.41 (br, 96H),
8.50 (br, 96H), 8.21 (br, 96H), 8.01 (br, 120H), 7.69 (br, 144H), 7.59
(br, 48H), 7.22 (br, 24H), 4.34 (br, 96H), 3.93 (br, 96H), 3.78 (br,
48H), 3.71 ppm (br, 48H). Diffusion coefficient ([D6]DMSO, 300 K):
D = 3.16 ꢀ 10À11 m2 sÀ1 13C NMR (150 MHz, [D6]DMSO, 300 K): d =
.
161.2 (C), 160.6 (C), 151.9 (CH + CH), 149.8 (C + C), 136.9 (C), 134.9
(CH + C), 132.7 (CH), 128.2 (CH), 124.8 (CH + CH + CH + C), 118.9
(CH), 117.3 (C), 115.7 (CH), 93.6 (C), 88.0 (C), 74.0 (CH2), 67.0
~
(CH2 + CH2 + CH2 + CH2), 68.4 (CH2). IR (KBr): n = 3425, 3095,
2916, 2879, 2362, 2341, 1673, 1611, 1551, 1491, 1407, 1379, 1215, 1114,
1074, 1025, 952, 825, 770, 698, 643, 523 cmÀ1. Elemental analysis calcd
for C1296H1008N144O240Pd24·120DMSO: C 53.68%, H 5.07%, N 5.87%;
found: C 53.74%, H 4.88%, N 6.05%.
Synthesis of complex 2 (TfOÀ salt): Complexation was carried out
as above, but using Pd(TfO)2 as the metal source. 1H NMR
spectroscopy and CSI-TOF-MS confirmed the quantitative formation
of 2. 1H NMR (500 MHz, [D6]DMSO, 300 K): d = 9.59 (br, 96H), 9.39
(br, 96H), 8.48 (br, 96H), 8.21 (br, 96H), 8.00 (br, 120H), 7.68 (br,
144H), 7.60 (br, 48H), 7.21 (br, 24H), 4.35 (br, 96H), 3.93 (br, 96H),
3.77 (br, 48H), 3.71 ppm (br, 48H). CSI-TOF-MS (TfOÀ salt,
CH3CN): m/z calcd for [MÀ17TfOÀ]17+ 1566.9967, found 1566.9940;
these signals are those with the highest intensities.
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Crystal data of 2 (TfOÀ salt): Space group I4/m, a = b = 46.292(7),
c = 72.767(15) ꢁ, V= 155936(44) ꢁ3, Z = 2, T= 293 K. Anisotropic
least-squares refinement for all atoms on two spherical frameworks
and isotropic refinement for the other atoms on 11821 independent
merged reflections (Rint = 0.0914) converged at residual wR2 = 0.5848
for all data; residual R1 = 0.2487 for 7095 observed data [I > 2s(I)],
and GOF = 2.417. Full experimental details and crystallographic
analysis are given in the Supporting Information.
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[23] CCDC-823489 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
[24] Only the oxygen atoms of these PEG linkers could be located in
the crystallographic analysis, which enabled their extended
conformation to be elucidated.
Received: July 6, 2011
Revised: August 8, 2011
Published online: September 8, 2011
Keywords: coordination modes · entropic effects · N ligands ·
.
palladium · self-assembly
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