Self-assembly of a cavitand-based capsule by dynamic boronic ester formation

Article abstract of DOI:10.1002/anie.200802293

Be my guest: Two molecules of a cavitand tetraboronic acid and four molecules of a bis(catechol) linker quantitatively assemble into a capsule (see picture for two views), with highly selective guest-recognition, by dynamic boronic ester formation. The on

Full text of DOI:10.1002/anie.200802293

Angewandte
Chemie
DOI: 10.1002/anie.200802293
Supramolecular Chemistry
Self-Assembly of a Cavitand-Based Capsule by Dynamic Boronic Ester
Formation**
Naoki Nishimura and Kenji Kobayashi*
Carcerands and hemicarcerands, in which two calix[4]resor-
cinarene cavitands are held together by four covalent link-
ages, have been developed by Cram and others. They have
attracted considerable attention from the viewpoint of
stabilization of reactive intermediates and as microvesicles
for drug delivery by the confinement of guest molecules inside
the capsules away from bulk phases.[1] Error correction
through thermodynamic equilibration, minimization of syn-
thetic effort by use of modular subunits, and control of
assembly processes through subunit design are characteristics
of supramolecular approaches to self-assembly. On the basis
of this concept, cavitand-based capsules have been con-
structed under thermodynamic control using noncovalent
interactions such as hydrogen bonds,[2] metal coordination,[3]
ionic interactions,[4] and solvophobic interactions.[5] As an
alternative strategy, dynamic covalent chemistry offers great
advantages in supramolecular syntheses because dynamic
covalent bonds contain reversible covalent bond-forming and
-breaking processes under thermodynamic control.[6] The
reversibility of the imine bond-forming reaction has been
applied to cavitand-based capsule synthesis.[7] Boronic ester
formation is another reliable synthon for dynamic covalent
chemistry.[8] Herein, we report the self-assembly of tetrakis-
(dihydroxyboryl) cavitand 1 (as a bowl-shaped aromatic
cavity) and 1,2-bis(3,4-dihydroxyphenyl)ethane 2 into capsule
3 by dynamic boronic ester formation (Scheme 1).[9] Capsule 3
encapsulates one molecule of guest such as 4,4’-disubstituted-
biphenyl or 2,6-disubstituted-anthracene derivatives in a
highly selective recognition event. We also present the on/
off control of capsule formation with guest encapsulation by
removal/addition of methanol.
Taken in isolation, the cavitand tetraboronic acid 1[2d,10]
Scheme 1. Formation of capsule 3 from 1 and 2. Molecular models of
and the bis(catechol)-linker 2[11] both have low solubilities in
3 and guest encapsulating capsule 4@3 are calculated at the PM3
level of Spartan ’06.[12] The heptyl side chains of 1 are replaced by
methyl groups. Guests 4–7 (bottom) have been encapsulated in 3.
CDCl3. However, a 2:4 heterogeneous mixture of 1 and 2 in
CDCl3 gave a homogeneous solution upon heating at 508C for
3 h and quantitatively produced capsule 3, wherein two
[*] N. Nishimura, Prof. Dr. K. Kobayashi
Department of Chemistry, Faculty of Science
Shizuoka University
molecules of 1 at the polar positions are indirectly held
together by eight boronic ester bridges involving four
molecules of 2 at the equatorial positions (Scheme 1). A
molecular model of 3, calculated with Spartan ꢀ06[12] at the
PM3 level, shows that 3 possesses an inner cavity of the
approximate dimensions 8.4 Š ” 19.4 Š (interatomic dis-
tance) and four equatorial portals of approximately 6.8 Š ”
11.5 Š. Calculations suggest the linker unit adopts an
approximate anti-conformation and the northern polar cav-
itand unit is twisted by ca. 12.48 with respect to the southern
polar cavitand unit about a C4 polar axis. The 1H NMR
spectrum of the reaction mixture showed a highly sym-
836 Ohya, Suruga-ku, Shizuoka 422-8529 (Japan)
Fax: (+81)54-238-4933
E-mail: skkobay@ipc.shizuoka.ac.jp
Prof. Dr. K. Kobayashi
PRESTO, JST
4-1-8 Honcho Kawaguchi, Saitama 332-0012 (Japan)
[**] This work was supported in part by a Grant-in-Aid from the Ministry
of Education, Science, Sports, Culture, and Technology (Japan) (No.
17350067).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200802293.
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metrical single species and disappearance of the OH groups
from units 1 and 2 (Figure 1c vs. 1a, 1b), indicating the
quantitative formation of 3. The chemical shift changes of 3
relative to 1 and 2, Dd (dcomplexÀdfree), are 0.14, À0.20, 0.10, and
0.12 ppm for Ha-Hd of unit 1, respectively, and 0.42, 0.49, and
0.45 ppm for He-Hg of unit 2, respectively.
Figure 2. 1H NMR spectra (400 MHz, C6D6, 238C): a) capsule 3 (heter-
ogeneous after heating at 508C for 3 h, [1]=5 mm and [2]=10 mm),
b) 4@3 + 4 (homogeneous after heating at 508C for 3 h, [1]=5 mm,
[2]=10 mm, and [4]=5 mm), c) 5@3 + 5, d) 6@3 + 6, and e) 7@3
+ 7. The signals marked “e and f” indicate peaks representing
encapsulated and free guests, respectively. The signals marked “s” are
spinning sidebands of the residual solvent.
mixture (after evaporation of solvents) showed the disap-
pearance of the OH groups from 1 and 2, indicating formation
of the boronic ester, but not hydrogen bonds (Figure S3).[13]
Figure 1. 1H NMR spectra (400 MHz, CDCl3, 238C): a) [2]=10 mm if
soluble (heterogeneous), b) [1]=5 mm if soluble, c) capsule 3 (homo-
geneous after heating at 508C for 3 h, [1]=5 mm and [2]=10 mm),
and d) 4@3:free-3=48:52 after heating [3]=2.5 mm and
[4]=12.5 mm at 508C for 3 h, depicting peaks representing 3 from 4@
&
1
The H NMR signals of 4@3 in C6D6 were shifted upfield by
2.85 ppm for the acetoxy protons and downfield by 1.01 and
0.78 ppm for the aromatic protons relative to those of free 4.
The association constant of 3 with 4 was estimated to be Ka =
4.9 ” 105 mÀ1 in C6D6 at 408C by a competitive encapsulation
*
*
3 ( ), free 3 ( ), 4 from 4@3 ( ), and free 4 (&). The signals marked
a–g are assigned in Scheme 1. The signals marked s are spinning
sidebands of the residual solvent.
1
experiment with 5. The H NMR spectrum of 5@3 in C6D6
When 5 equiv of 4,4’-diacetoxybiphenyl 4 was added to a
solution of 3 (2.5 mm) in CDCl3, three species were inde-
pendently observed after heating (Figure 1d); that is, 52%
guest-free 3, excess 4, and 48% guest encapsulating capsule
4@3. This result indicates that the exchange of 4 in and out of
gave Dd = À2.87 (CH3) and 0.18 ppm (CH2) for the ethoxy
groups and Dd = 0.83 and 0.82 ppm for the aromatic protons
of 5 (Figure 2c), and Ka = 1.30 ” 104 mÀ1 at 408C. The thermo-
dynamic parameters of 5@3 in C6D6 were DH8 = À26.3 kcal
molÀ1 and DS8 = À65.2 calmolÀ1 KÀ1 (Figure S4),[13] indicating
a major enthalpic contribution.
1
3 is slow on the NMR time scale. The H NMR signals of 4
encapsulated in 3 were shifted upfield by 4.04 ppm for the
acetoxy protons and 0.04 and 0.06 ppm for the aromatic
protons relative to those of free 4. This result shows that the
acetoxy groups are oriented to both aromatic cavity ends of 3
(Scheme 1). Based on the integration ratio, capsule 3
encapsulates one molecule of 4. The association constant
was estimated to be Ka = 82mÀ1 in CDCl3 at 238C. The vanꢀt
Hoff plots gave thermodynamic parameters of DH8 =
À1.9 kcalmolÀ1 and DS8 = 2.3 calmolÀ1 KÀ1 (see Supporting
Information, Figure S1).[13] Thus, the encapsulation of 4 in 3 in
CDCl3 is both enthalpically and entropically driven. By
Thus, the association behavior of capsule 3 with a guest in
C6D6 differs significantly from that in CDCl3. The value of
Ka(in C6D6)/Ka(in CDCl3) for a guest encapsulated within 3
(guest@3) is approximately 1600–6000. The small Ka and
considerable entropic contribution for guest@3 in CDCl3 (see
above) strongly suggest that CDCl3 acts as a guest competitor
for 3.[15] In fact, when pure 4@3, which was prepared in
benzene and dried in vacuo, was dissolved in CDCl3, the
release of 4 encapsulated in 3 into the bulk phase of CDCl3
immediately occurred at 238C. The ratio of 4@3:free-3 was
60:40 after 3 min and 48:52 after 24 h, reaching an equilibrium
(Figure S5).[13] This result agrees completely with that shown
in Figure 1d.
comparison, Ka for 3 with 4,4’-diethoxybiphenyl 5 was 8.1mÀ1
.
Heating a 2:4 mixture of 1 and 2 in C6D6 at 508C for 3 h
did not give a homogeneous system, although 3 was quanti-
In addition to 4,4’-diacetoxybiphenyl 4 and 4,4’-diethoxy-
biphenyl 5, capsule 3 also encapsulates 4-acetoxy-4’-ethoxy-
biphenyl 6 and 2,6-diacetoxyanthracene 7 (Figure 2d and e).
In contrast, encapsulations of 4-ethoxy-4’-methoxybiphenyl,
[13,14]
tatively formed (Figure 2a and Figure S2).
In contrast,
heating this mixture in the presence of 1 equiv of 4 relative to
1 gave a homogeneous solution and quantitatively produced
4@3, as shown in Figure 2b. The IR spectrum of this reaction
4-ethoxy-4’-n-propoxybiphenyl,
4-acetoxy-4’-methoxybi-
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phenyl, and 4,4’-bis(methoxycarbonyl)biphenyl were not
detected in C6D6. Thus, 3 strictly discriminates a one-carbon
atom difference in guests, as well as functional groups. The
encapsulation ability of guests in 3 increased in the order 5
(relative binding ability = 1) < 6 (5.9) < 7 (8.8) < 4 (38.2), as
evaluated by competitive encapsulation experiments (Fig-
ure S6). [13]
The on/off control of capsule formation with guest
encapsulation was achieved by chemical stimulus; namely,
the removal and addition of methanol (Figure 3).[16] Addition
derived from 1 and incorporating a C2 symmetric chiral
bis(catechol) linker in place of 2.
Received: May 16, 2008
Published online: July 10, 2008
Keywords: calixarenes · cavitands · molecular recognition ·
.
self-assembly · supramolecular chemistry
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Figure 3. On/off control of capsule formation withguest encapsulation
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C6D6 (1000 equiv of CD3OD), c) 1 (5 mm) in 5% (v/v) CD3OD-C6D6,
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[13] See the Supporting Information.
[14] The solubility of 3 in C6D6 at 238C was 1.3 mm based on the
1H NMR integration ratio with p-dimethoxybenzene as an
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of 5% CD3OD (1000 equiv) to a solution of 4@3 in C6D6
caused immediate dissociation of the boronic ester bonds of 3
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(Figure 3a vs. 3b, 3c). This mixture was restored to the
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heating in C6D6 at 508C for 3 h (Figure 3d and e).
In summary, we have demonstrated 1) the self-assembly of
cavitand-based capsule 3 by dynamic boronic ester formation,
2) guest encapsulation by 3 with a highly selective recognition
event, 3) a significant solvent effect for guest encapsulation,
and 4) the on/off control of capsule formation with guest
encapsulation by the removal and addition of methanol. Our
next projects are the elucidation of the guest encapsulation
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asymmetric guest recognition of a chiral capsule[18] to be
Angew. Chem. Int. Ed. 2008, 47, 6255 –6258
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Communications
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3
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time scale.
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