Double-threaded dimer and supramolecular oligomer formed by stilbene modified cyclodextrin: Effect of acyl migration and photostimuli

Article abstract of DOI:10.1021/jo101936t

We observed changing supramolecular structures of stilbene-α- cyclodextrin (StiO-α-CD) by photoirradiation and migration. Stilbene derivatives show photoinduced isomerization under irradiation with λ =340 nm to give 2-cis-StiO-α-CD and with λ =254 nm to give 2-trans-StiO-α-CD. Photoisomerization of StiO-α-CD shows the photostationary state during 30 min. 2D NMR and diffusion coefficient studies revealed that 2-trans-StiO-α-CD forms a double-threaded dimer but 2-cis-StiO-α-CD changes to a supramolecular oligomer by photoirradiation. We found that the mutual migration of a stilbene group (StiO) on α-CD occurs under neutral conditions. The StiO group of α-CD (StiO-α-CD) moves between the C2 and C3 positions on the secondary hydroxyl group of StiO-α-CD (the wider rim of α-CD) to give 3-trans-StiO-α-CD. 3-trans-StiO-α-CD forms a supramolecular oligomer, whereas 3-cis-StiO-α-CD changes to a double-threaded dimer, indicating that 3-StiO-α-CDs gives the opposite results in the supramolecular structures of 2-StiO-α-CDs. The thermal isomerization (migration) is very slow. It takes about 300 h to reach the equilibrium state. Moreover, the migration rate constant (k_trans3→2) of the trans-StiO group from the C3 position to the C2 position of α-CD is faster than k _trans2→3 from the C2 position to the C3 position of α-CD. On the other hand, k_cis2→3 of the cis-StiO group from the C2 position to the C3 position of α-CD is faster than k_cis3→2 from the C3 position to the C2 position, meaning k_cis2→3 > k_cis3→2, which is the opposite result for k _trans3→2 > k_trans2→3. The formation of a stable double-threaded dimer would suppress the migration of the StiO group of StiO-α-CDs in aqueous solutions.

Full text of DOI:10.1021/jo101936t

pubs.acs.org/joc
Double-Threaded Dimer and Supramolecular Oligomer Formed
by Stilbene Modified Cyclodextrin: Effect of Acyl Migration
and Photostimuli
Akira Kanaya, Yoshinori Takashima, and Akira Harada*,†
Department of Macromolecular Science, Graduate School of Science, Osaka University, Toyonaka,
Osaka 560-0043, Japan
harada@chem.sci.osaka-u.ac.jp
Received September 30, 2010
We observed changing supramolecular structures of stilbene-R-cyclodextrin (StiO-R-CD) by photo-
irradiation and migration. Stilbene derivatives show photoinduced isomerization under irradiation
with λ =340 nm to give 2-cis-StiO-R-CD and with λ =254 nm to give 2-trans-StiO-R-CD.
Photoisomerization of StiO-R-CD shows the photostationary state during 30 min. 2D NMR and
diffusion coefficient studies revealed that 2-trans-StiO-R-CD forms a double-threaded dimer but
2-cis-StiO-R-CD changes to a supramolecular oligomer by photoirradiation. We found that the
mutual migration of a stilbene group (StiO) on R-CD occurs under neutral conditions. The StiO
group of R-CD (StiO-R-CD) moves between the C2 and C3 positions on the secondary hydroxyl
group of StiO-R-CD (the wider rim of R-CD) to give 3-trans-StiO-R-CD. 3-trans-StiO-R-CD forms a
supramolecular oligomer, whereas 3-cis-StiO-R-CD changes to a double-threaded dimer, indicating
that 3-StiO-R-CDs gives the opposite results in the supramolecular structures of 2-StiO-R-CDs. The
thermal isomerization (migration) is very slow. It takes about 300 h to reach the equilibrium state.
Moreover, the migration rate constant (ktrans3f2) of the trans-StiO group from the C3 position to the
C2 position of R-CD is faster than ktrans2f3 from the C2 position to the C3 position of R-CD. On the
other hand, kcis2f3 of the cis-StiO group from the C2 position to the C3 position of R-CD is faster
than kcis3f2 from the C3 position to the C2 position, meaning kcis2f3 > kcis3f2, which is the opposite
result for ktrans3f2 > ktrans2f3. The formation of a stable double-threaded dimer would suppress the
migration of the StiO group of StiO-R-CDs in aqueous solutions.
Introduction
such as artificial molecular muscles,6,7 drug delivery sys-
tems,8 biosensors, and shape memory materials. Previously,
stimuli responsive supramolecular assemblies9 have been
controlled by chemical,10 electrical,11 or photochemical
External stimuli responsive supramolecular assemblies are
expected to serve as remotely actuated nanomaterials1-5
†Phone þ81-6-6850-5445; Fax þ81-6-6850-5445
(1) Lyshevski, S. E. Nano- and Micro-Electromechanical Systems:Funda-
mentals of Nano- and Microengineering; CRC Press: Boca Raton, FL, 2005.
(2) Ozin, G. A.; Manners, I.; Fournier-Bidoz, S.; Arsenault, A. Adv.
Mater. 2005, 17, 3011–3018.
492 J. Org. Chem. 2011, 76, 492–499
Published on Web 12/23/2010
DOI: 10.1021/jo101936t
r
2010 American Chemical Society

Kanaya et al.
JOCArticle
stimuli,12-16 but photostimuli have been widely exploited to
modulate the conformation of supramolecular assemblies
with photochromic chromophores. Photochromic chromo-
phores can be classified into two types: thermally reversible
and photochemically reversible.17 We have focused on stil-
benederivatives as photochemically reversiblechromophores.
Some stilbene derivatives represent thermally irreversible
photochromic compounds, meaning that the geometry of the
stilbene derivative depends on the wavelength. Previously,
Janus [2]rotaxanes containing CD as a rotor have been
reported independently by Kaneda,18 Easton,19 and our
group.20 A photoresponsive Janus [2]rotaxane has been re-
ported by Easton and co-workers.19 They utilized a stilbene
moiety as a photoresponsive moiety and demonstrated photo-
responsive switching of the location of the R-CD moiety. We
have reported the preparation of a double-threaded dimer and
supramolecular oligomers with cinnamoyl-R-cyclodextrins
(2-CiO-R-CD and 3-CiO-R-CD).21 However, these supramo-
lecular complexes cannot change the structures by external
stimuli. Although the stilbene amide R-CD (3-Sti-R-CDs)
achieved the formation of a double-threaded dimer and that
of nonthreaded supramolecular self-assembly by photoirra-
diation with an increase in the concentration,22 it is still
difficult to establish the controlling formation of a double-
threaded dimer and supramolecular oligomers. The structure
of the supramolecular polymers formed by the stilbene bis(β-
CD) dimer with the adamantyl dimer is controlled by an
external stimulus. The conformation of the stilbene bis(β-CD)
dimer in aqueous solution is photochemically controlled.
When the stilbene bis(β-CD) is in trans conformation, a
supramolecular dimer is formed in aqueous solution, whereas
in its cis conformation of the stilbene bis(β-CD) dimer,
supramolecular linear polymers were observed.23
Herein, we investigate the reversible structural control of
supramolecular complexes with cyclodextrin-stilbene deri-
vatives by photoirradiation because the association constant
of R-CD for trans-stilbene is larger than that for cis-stilbene
(trans-stilbene, Ka=1260 M-1; cis-stilbene, Ka=360 M-1).24
The stilbene (StiO) group was introduced into the secondary
hydroxyl group of R-CD through an ester bond as a flexible
linker (StiO-R-CDs). Unexpectedly, the StiO group on
2-StiO-R-CDs migrated between adjacent hydroxyl groups to
give 3-StiO-R-CDs under neutral conditions. This paper
reports the migration and formation of supramolecular com-
plexes with the isomers of StiO-R-CDs (2-trans-StiO-R-CD,
3-trans-StiO-R-CD, 2-cis-StiO-R-CD, and 3-cis-StiO-R-CD).
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FIGURE 1. Schematic illustration of the isomerization of 2-trans-
stilbene-R-CD (2-trans-StiO-R-CD) and 3-trans-StiO-R-CD. Photo-
irradiation isomerizes trans-StiO-R-CDs to cis-StiO-R-CDs. StiO
groups migrate under neutral conditions. The kinetic rate (k) at
1 mM were described in the scheme.
Results and Discussion
Migration of Acyl-r-CD in D2O. Figure 1 shows the
chemical structure of R-CDs modified with stilbene groups
(StiO-R-CD). R-CDs modified with stilbene (StiO) group on
the secondary hydroxyl group was prepared by the reaction
of succinimidyl-N-(4-stilbene carbonyl) with R-CD and so-
dium hydride in N,N dimethylformamide (DMF). These
products were purified to give 2-trans-StiO-R-CD and
3-trans-StiO-R-CD (Figure 1), which were separated by
reversed phase chromatography.25 Photoirradiation at λ=
340 nm caused the trans-StiO group to isomerize into a cis-
StiO group, and irradiation at 254 nm recovered from cis- to
trans-forms. After photoirradiation with UV light (λ=340
nm), 80% of trans-StiO-R-CD isomerized to cis-StiO-R-CD
(trans/cis=20:80). Photoisomerization of StiO-R-CD showed
the photostationary state by 30 min at 2.1 mM. The mixed
isomers were separated by preparative reversed phase HPLC.
Figure 2a shows the changes in the 1H NMR spectra of 3-trans-
StiO-R-CD to 2-trans-StiO-R-CD in D2O (1 mM) at 45 °C. The
peak intensities of 3-trans-StiO-R-CD decreased with time,
while those of 2-trans-StiO-R-CD increased to reach a ratio of
4:1 for 2-trans-StiO-R-CD and 3-trans-StiO-R-CD (Figure 2b).
Observation of the migration of 2-trans-StiO-R-CD by 1H
NMR under the same conditions yielded a ratio of 2-trans-
StiO-R-CD and 3-trans-StiO-R-CD 4:1. Although it is
known that silyl groups such as tert-butyldimethylsilyl
groups migrate between vicinal hydroxyl groups under
FIGURE 2. (a) Time course of the 1H NMR spectra of the migra-
tion from 3-trans-StiO-R-CD to 2-trans-StiO-R-CD in D2O (1 mM)
at 45 °C. (b) Plots of rate of the StiO-R-CD contents vs time.
TABLE 1. Apparent Migration Rates (k) of StiO-R-CDs at 0.5 and
1.0 mM Aqueous Solutions at 45 °C
rate constant/s-1
concentration/mM
0.5
trans-StiO-R-CD
cis-StiO-R-CD
k2f3
k3f2
k2f3
k3f2
1.6 ꢀ 10-6
1.1 ꢀ 10-5
6.6 ꢀ 10-7
3.8 ꢀ 10-6
-
-
1.0
4.0 ꢀ 10-5
1.9 ꢀ 10-5
strong basic conditions,26-33 it is not known if the acyl
groups migrated under neutral conditions. To the best of
our knowledge, the mutual migration of an ester group
under neutral conditions has yet to be reported.
Figure 1 shows the migration scheme of the StiO groups.
Table 1 summarizes the migration rate constants (k) of the
StiO group in D2O, which were very slow. The migration rate
constants (ktrans2f3) of the trans-StiO group from the C2
position to the C3 position of R-CD decreased as the con-
centration of 2-trans-StiO-R-CD increased. The ktrans3f2 of
(25) Although three kinds of StiO-R-CD (2-trans-StiO-R-CD, 3-trans-
StiO-R-CD, and 6-trans-StiO-R-CD) are prepared by in the mixture of R-CD
and Succinimidyl-N-(4-stilbene carboxylate), 6-trans-StiO-R-CD having the
StiO group at the primary hydroxyl group forms little. Main product of the
reaction gives 2-trans-StiO-R-CD and 3-trans-StiO-R-CD because the sec-
ondary hydroxyl group forms the hydrogen bond network to activate the
nucleophilicity.
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494 J. Org. Chem. Vol. 76, No. 2, 2011

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FIGURE 3. The 500 MHz ROESY spectrum of 2-trans-StiO-R-CD in D2O at 25 °C (1 mM, mixing time=200 ms).
the trans-StiO group from the C3 position to the C2 position
of R-CD was faster than ktrans2f3 (ktrans3f2 (=3.8 ꢀ 10-6) >
ktrans2f3 (=6.6 ꢀ 10-7)). On the other hand, the migration
rate constant (kcis2f3) of the cis-StiO group from the C2
position to the C3 position of R-CD was faster than ktrans2f3
,
meaning kcis2f3 (=4.0 ꢀ 10-5) > ktrans2f3 (=6.6 ꢀ 10-7). It
should be noted that kcis2f3 was faster than kcis3f2 of the cis-
StiO group, meaning kcis2f3 (=4.0 ꢀ 10-5) > kcis3f2 (=1.9 ꢀ
10-5). The kcis of cis-StiO-R-CDs led to the opposite order of
ktrans of trans-StiO-R-CDs as shown in Figure 1.
As shown in Figure 2a, peaks of 2-trans-StiO-R-CD and
3-trans-StiO-R-CD showed a downfield shift and upfield
shift, respectively. We hypothesized that the peak shifts are
correlated with the formation of supramolecular complexes.
which led to a decrease in the migration rates. The proton of
the 2-StiO group showed downfield shift with the complex
formation between the hydrophobic R-CD cavity and the
StiO group, whereas those of the 3-StiO group showed
upfield shift with the dissociation.
Formation of Supramolecular Complexes of trans-StiO-r-
CDs. 2-trans-StiO-R-CD and 3-trans-StiO-R-CD were puri-
fied by preparative reversed phase HPLC to verify the supra-
molecular structures from StiO-R-CDs. The 2D ROESY
NMR spectrum of 2-trans-StiO-R-CD in D2O (1 mM)
indicated that the stilbene proton peaks are correlated with
the inner protons (C(3)-H and C(5)-H) of R-CD and the
stilbene group is included from the secondary hydroxyl group
side (wider rim) (Figure 3). The correlation peaks of the 2D
ROESY spectrum of 3-trans-StiO-R-CD were similar to those
of 2-trans-StiO-R-CD (Supporting Information Figure S11).
These results confirmed the formation of supramolecular
complexes.
FIGURE 4. Plots of diffusion coefficients (Ds) of 2-transStiO-R-
CD (red •), 3-transStiO-R-CD (blue 2), and R-CD (green •) in D2O
at 30 °C. Plot (9) shows 2-cinnamoyl-R-CD (2-CiO-R-CD), which
formed a double threaded dimer above 10 mM.
previous study on a double-threaded dimer formed by
2-cinnamoyl-R-CD (2-CiO-R-CD; 9) showed a constant
value above 10 mM, which reached 2.3ꢀ10-10 m2/s at 32
mM.21 The maximum degree of polymerization for the
3-trans-StiO-R-CD was calculated by the following equa-
tion, nmax=(KC)1/2, where K is the association constant and
C is the concentration.34-40 The association constants (Ka)
of R-CD with trans-stilbene carboxylic acid sodium salt and
cis-stilbene carboxylic acid sodium salt as model compounds
were estimated by modifying the Benesi-Hildebrand equa-
tion.41 For systems with a 1:1 inclusion complex between the
guest and host, R-CD exhibited KtSti =(1.6 ( 0.2) ꢀ 103 M-1
for trans-stilbene carboxylic acid carboxylic acid sodium salt
and KcSti = (2.5 ( 1.0) ꢀ 102 M-1 for cis-stilbene carboxylic
The molecular size of the supramolecular complexes from
trans-StiO-R-CDs was determined using the pulse field gra-
dient spin-echo (PFG) NMR technique to give the diffusion
coefficients (D). The apparent D of supramolecular com-
plexes formed by 3-trans-StiO-R-CD (blue 2) decreased as
the concentration increased, and reached 1.7 ꢀ 10-10 m2/s at
40 mM (Figure 4), indicating that 3-trans-StiO-R-CD forms
a supramolecular oligomer at concentrations above 10 mM
in aqueous solutions. Additionally, the molecular size of the
supramolecular oligomer depends on the concentration. Our
(34) Odin, G. Principles of Polymerization; McGraw-Hill: New York,
1991.
(35) Markau, K.; Schneider, J.; Sund, A. Eur. J. Mol. Biochem. 1972, 24,
293.
(36) Oosawa, F.; Kasai, M. J. Mol. Biol. 1962, 4, 10.
(37) Sund, H.; Marku, K. Int. J. Polym. Mater. 1976, 4, 251.
(38) Burchard, W. Trends Polym. Sci. 1993, 1, 192.
(39) Bruce Martin, R. Chem. Rev. 1996, 96, 3043.
(40) Zhao, D.; Moore, J. S. Org. Biomol, Chem. 2003, 1, 3471.
(41) (a) Benesi, H. A.; Hildebrand, J. H. J. Am. Chem. Soc. 1949, 71, 2703.
(b) Connors, K. A. Cyclodextrins. In Comprehensive Supramolecular Chem-
istry; Szejtli, J., Osa, T., Eds.; Pergamon: Oxford, U.K., 1996; Vol. 3, p 205.
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Kanaya et al.
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FIGURE 6. 2D ROESY NMR spectrum of 2-cis-StiO-R-CD
(5 mM) at 20 °C. Spectrum shows the partial area between the inner
protons of cis-StiO-R-CDs and the stilbene group.
FIGURE 5. MALDI-TOF mass spectra of crude products reacted
by (a) 2-AmStiO-R-CD with TNBS Na and (b) 3-AmStiO-R-CD
with TNBS Na.
acid carboxylic acid sodium salt (Figure S28). Using KtSti
=
based on nmax=(KC)1/2, 3-trans-StiO-R-CD formed nmax
8 at 40 mM. The apparent D of supramolecular complexes
formed by 2-trans-StiO-R-CD was 2.7ꢀ10-10 m2/s at 1 mM,
whereas the concentration dependency of 2-trans-StiO-R-
CD for D was not measured because 2-trans-StiO-R-CD (red •)
was slightly soluble in water and immediately formed a powder
crystal above 1.0 mM.
FIGURE 7. Plots of diffusion coefficients (D) of 2-cis-StiO-R-CD
(red (), 3-cis-StiO-R-CD (blue 2), and R-CD (green •) in D2O at
30 °C. Plot (9) shows 2-cinnamoyl-R-CD (2-CiO-R-CD), which
formed a double-threaded dimer above 10 mM.
cated peak splitting, indicating that a symmetric structure is
formed. As shown above, 2-trans-StiO-R-CD and 3-trans-
StiO-R-CD formed a double-threaded dimer and the supra-
molecular oligomer, respectively.
To elucidate the supramolecular structure of 2-trans-StiO-
R-CD and 3-trans-StiO-R-CD in D2O, we prepared trans-
StiO-R-CD analogues (2-AmStiO-R-CD and 3-AmStiO-R-
CD) with an amino group on the stilbene group, which was
attached to the trinitrobenzene group (TNB) that served as a
stopper. After the formation of supramolecular complexes
with AmStiO-R-CDs in an aqueous solution, these supra-
molecular complexes were reacted with trinitrobenzene sul-
fonate sodium salt (TNBS Na) to prevent supramolecular
complexes decomposition in organic media and by the laser
impacts of MALDI-TOF mass spectrometry. The mass
spectrum of 2-AmStiO-R-CD did not display polymeric
species, but dimeric species, whereas that of 3-AmStiO-R-
CD showed polymeric species (Figure 5). The peak intervals
were av 1.4 kDa, which corresponds to the TNB-NH-StiO-
R-CD unit. The 1H NMR spectrum of the double-threaded
dimer formed by 2-AmStiO-R-CD did not exhibit compli-
Formation of Supramolecular Complexes with cis-StiO-r-
CDs. We thought that cis-StiO-R-CDs would not form
supramolecular complexes in aqueous solutions because
the association constant (KcSti) of R-CD for cis-stilbene
carboxylate is KtSti>KcSti. However, the 2D-ROESY NMR
spectrum of cis-StiO-R-CDs in D2O showed that the edge of
cis-stilbene protons (E and F) are correlated with the inner
protons (C(3)-H) of R-CD (Figure 6 and Supporting Infor-
mation Figure S33), suggesting that the cis-StiO group is
shallowly included in the R-CD cavity to form supramole-
cular complexes. The apparent D of the supramolecular
complexes formed by 2-cis-StiO-R-CD decreased as the
concentration increased, and reached 1.5 ꢀ 10-10 m2/s at
40 mM (Figure 7), indicating that 2-cis-StiO-R-CD forms a
496 J. Org. Chem. Vol. 76, No. 2, 2011

Kanaya et al.
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FIGURE 8. Illustration of the formation of supramolecular complexes using StiO-R-CDs.
supramolecular oligomer above 10 mM in aqueous solu-
tions, similar to 3-trans-StiO-R-CD (Figure 8a). On the other
hand, the apparent D of 3-cis-StiO-R-CD showed a constant
value over 10 mM and reached 2.2 ꢀ 10-10 m2/s at 40 mM,
which is similar to the double-threaded dimer formed by
2-CiO-R-CD (Figure 8b). These results indicate that 2-cis-
StiO-R-CD and 3-cis-StiO-R-CD form a supramolecular
oligomer and a double-threaded dimer in aqueous solutions,
respectively. (Figure 8)
StiO-R-CDs, and the acyl migration is intricately interrelated to
the formation of supramolecular complexes.
Experimental Section
Preparation of 4-Stilbene Carboxylic Acid.42
2D NMR and diffusion coefficient studies for StiO-R-CDs
confirmed that 2-trans-StiO-R-CD forms a double-threaded
dimer and 2-cis-StiO-R-CD formed a supramolecular oligo-
mer with an increase in the concentration, whereas 3-trans-
StiO-R-CD surprisingly formed a supramolecular oligomer
and 3-cis-StiO-R-CD formed a double-threaded dimer, in-
dicating that StiO-R-CDs recognize the structure of guest
molecule and the substitutional position of a guest molecule
on R-CD.
Styrene (1.7 g, 16 mmol) and 4-iodobenzoic acid (4.0 g, 11
mmol) were dissolved in N,N-dimethylformamide (DMF; 20
mL) and triethylamine (20 mL). The solution was refluxed in the
presence of triphenylphosphine (94 mg, 0.36 mmol) and
palladium(II) acetate (67 mg, 0.31 mmol) for 24 h. After
removing the solvent, ethyl acetate (200 mL) was added, and
the soluble part was washed with three portions of water (60
mL). The organic layer was reprecipitated in hexane (400 mL) to
give 4-stilbene carboxylic acid (pale brown powder, 1.6 g, 44%).
1H NMR (500 MHz, DMSO-d6) δH 12.8 (br s, 1H, OH),
7.92-7.91 (d, J=7.8 Hz, 2H, 3-position of stilbene), 7.69-7.67
(d, J=7.8 Hz, 2H, 2-position of stilbene), 7.64-7.62 (d, J=7.8
Hz, 2H, 20-position of stilbene), 7.41-7.38 (t, J = 8.1 Hz, 2H, 30-
position of stilbene), 7.40-7.29 (d, J = 16 Hz, 2H, olefin of
stilbene), 7.31-7.28 (m, J=7.3 Hz, 1H, 40-position of stilbene).
TLC (ethyl acetate/hexane 1:1): Rf=0.30 (relative to the solvent
front). IR (KBr): 3300-2500 (O-H), 1680 (CdO), 1425 (O-H),
1290 (C-O) cm-1. FAB-MS: m/z, 224 (Mþ), 207, 178, 154, 135,
Conclusion
We successfully prepared a double-threaded dimer and
supramolecular oligomer consisting of StiO-R-CDs. Although
we initially speculated that 2-cis-StiO-R-CD would not form a
supramolecular complex, it indeed formed a supramolecular
oligomer even though the association constant of R-CD for the
cis-StiO group is relatively small. The supramolecular oligomer
formed by 2-cis-StiO-R-CD might be stabilized due to π-π
stacking interactions between the stilbene groups. Interestingly,
3-trans-StiO-R-CD formed a supramolecular oligomer,
whereas 3-cis-StiO-R-CD formed a double-threaded dimer.
2-StiO-R-CD and 3-StiO-R-CD exhibited opposite behaviors
in regards to the formation of supramolecular complexes. R-
CD accurately recognized the substitution position of the StiO
group on a glucopyranose unit as well as the structure of
substituent groups. As described previously, kcis2f3 of the cis-
StiO group was faster than ktrans2f3 of the trans-StiO group,
whereas the association constant (Ka) of R-CD for trans-
stilbene carboxylic acid was larger than that of cis-stilbene
carboxylic acid (KtSti > KcSti). Although ktrans3f2 > ktrans2f3
for the trans-StiO group, kcis2f3 > kcis3f2 for the cis-StiO
group. StiO-R-CDs mostly form the monomer or the dimer at
1 mM. The formation of a double-threaded dimer would
suppress the migration of the StiO group of StiO-R-CDs in
aqueous solutions. Herein, we successfully observed the for-
mation of supramolecular complexes with cis-trans isomers of
107. Mp: 254-255 °C. Anal. Calcd for C15H12O2 0.17H2O: C,
3
79.26; H, 5.47. Found: C, 79.27; H, 5.49.
Preparation of Succinimidyl-N-(4-stilbene carbonyl).
4-Stilbene carboxylic acid (5.1 g, 23 mmol) and N-hydroxyl
succinimide (3.2 g, 24 mmol) were dissolved in tetrahydrofuran
(THF; 150 mL). The solution was cooled to 0 °C, and then N,N0-
dicyclohexyl carbodiimide (DCC; 5.8 g, 28 mmol) was added.
The resulting solution was stirred for 24 h. The precipitate was
removed via filtration, and the filtrate was evaporated under
reduced pressure. The residue was washed with 2-propanol and
purified by column chromatography (silica gel, CHCl3) (3.0 g,
42%). 1H NMR (500 MHz, DMSO-d6, 30 °C) δH 8.08 (d, J=8.5
Hz, 2H, 3-position of stilbene), 7.86 (d, J = 8.5 Hz, 2H,
2-position of stilbene), 7.68 (d, J=7.4 Hz, 2H, 20-position of
(42) Nishimura, D.; Oshikiri, T.; Takashima, Y.; Hashidzume, A.;
Yamaguchi, H.; Harada, A. J. Org. Chem. 2008, 73, 2496.
J. Org. Chem. Vol. 76, No. 2, 2011 497

Kanaya et al.
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stilbene), 7.53 (d, J=16.5 Hz, 1H, -CHdCH-Ph), 7.40-7.43 (t,
J=7.4 Hz, 2H, 30-position of stilbene), 7.38-7.42 (d, J=16.5 Hz,
1H, -CHdCH-Ph), 7.33 (t, J=7.4 Hz, 1H, 40-position of stil-
bene), 2.89 (s, 4H, succinimidyl moiety). 13C NMR (125 MHz,
DMSO-d6, 30 °C) δ 170.31 (CdO of succinimidyl moiety), 161.47
(-O-CdO), 144.02 (1-Ph), 136.33 (10-Ph), 132.71 (4-Ph),
130.46 (3-Ph), 128.79 (30-Ph), 128.54 (-CHdCH-Ph-(CdO)),
127.16 (20-Ph), 127.04 (2-Ph), 126.87 (40-Ph), 122.76 (-CHd
CH-Ph-(CdO)), 25.51 (CH2 of succinimidyl moiety). Anal. Calcd.
20-position of stilbene), 7.54-7.48 (m, 3H, 30- and 40-position of
stilbene), 7.36 (d, J=16.2 Hz, 1H, -CHdCH-Ph-(CdO)), 7.24
(d, J=16.2 Hz, 1H, -CHdCH-Ph-(CdO)), 6.08 (br, 1H, C(3)H
of CD), 5.26-4.86 (m, 6H, C(1)H of CD), 4.50-3.20 (m, others
of CD).
1H NMR (DMSO-d6, 30 °C, 500 MHz) δH 7.95 (d, J=8.5 Hz,
2H, 3-position of stilbene), 7.69 (d, J=8.5 Hz, 2H, 2-position of
stilbene), 7.64 (d, J = 7.3 Hz, 2H, 20-position of stilbene),
7.41-7.28 (m, 5H, 30,40-position and olefin of stilbene),
5.52-5.23 (m, 11H, O(2, 3)H of CD), 4.92-5.71 (m, 6H, C(1)
H of CD), 4.52-4.42 (m, 6H, O(6)H of CD), 3.91-3.06 (m,
overlaps with HOD, others of CD). 13C NMR (DMSO-d6,
30 °C, 125 MHz) δ 165.5 (-O-CdO), 140.9 (1-Ph), 136.7 (10-Ph),
130.6 (-CHdCH-Ph-(CdO)), 130.0 (4-Ph), 129.9 (3-Ph), 128.8
(30-Ph), 128.1 (40-Ph), 127.6 (-CHdCH-Ph-(CdO)), 126.6 (20-
Ph) 126.02 (2-Ph), 102.2, 102.0, 101.9, 101.6, 82.6, 82.2, 82.1,
81.9, 79.2, 74.9, 73.2, 73.1, 72.8, 72.4, 72.3, 72.2, 72.1, 72.0, 71.9,
71.6, 71.1, 70.9, 60.1, 60.0 (C(1-6) of CD). MALDI-TOF MS:
m/z=1201.7 ([C50H70O31 þ Na]þ=1201.4), 1217.7 ([C50H70O31
þ K]þ=1217.1). Anal. Calcd for C51H70O31(H2O)8.2: C, 46.17;
H, 6.56. Found: C, 45.94; H, 6.26.
for C19H15NO4 0.04CHCl3: C, 70.13; H, 4.65; N, 4.30. Found: C,
3
70.08; H, 4.67; N 4.36. Mp: 267-268 °C.
Preparation of 4-Stilbene Carbonyl Modified r-Cyclodextrin
(StiO-r-CD) at the Secondary Hydroxyl Groups.
Preparation of 4-(40-Aminostilbene) Carboxylic Acid.
Dried R-CD (0.68 g, 0.70 mmol) was dissolved in 10 mL of
dried DMF. Sodium hydride (60% in oil suspension; 29 mg, 0.73
mmol) was added to the solution, which was then stirred for 12 h
at room temperature. Succinimidyl-N-(4-stilbene carbonyl)
(0.24 g, 0.70 mmol) dissolved in 5 mL of dried DMF was
gradually added to the R-CD solution while stirring. After 1 h,
the solution was poured into acetone (200 mL). The precipitate,
which contained two isomers of 4-stilbene carbonyl modified
R-CD, was collected by centrifugation and washed with acetone
twice. Reverse-phase preparative HPLC was performed to sepa-
rate the isomers. The resulting precipitate was dissolved in 25
mL of distilled water, and an aliquot of the solution (5.0 mL)
was injected onto the HPLC system. Lyophilization of each
eluent gave 58 mg of Fraction 1 (the former peak of the two main
peaks) and 28 mg of Fraction 2 (the latter peak of the two main
peaks). Fractions 1 and 2 were identified as 3-StiO-R-CD and
4-Vinyl aniline 90% (0.59 g, 4.4 mmol) and 4-iodobenzoic acid
(1.1 g, 4.4 mmol) were dissolved in DMF (6.0 mL) and triethyl-
amine (6.0 mL). The solution was refluxed in the presence of
triphenylphosphine (12 mg, 0.043 mmol) and palladium(II) acetate
(9.9 mg, 0.043 mmol) for 48 h. After removing the solvent, ethyl
acetate (100 mL) was added, and the soluble part was extracted with
2 M hydrochloric acid solution (100 mL ꢀ 3). Neutralizing the
aqueous layer with an aqueous sodium hydroxide solution yielded a
precipitate of 40-aminostilbene-4-carboxylic acid (yellow powder,
0.17 g, 16%). 1H NMR (500 MHz, DMSO-d6) δH 12.6 (br s, 1H,
OH), 7.87 (d, J=8.3 Hz, 2H, 3-position of stilbene), 7.58 (d, J=8.3
Hz, 2H, 2-position of stilbene), 7.31 (d, J=8.5 Hz, 2H, 20-position
of stilbene), 7.20 (d, J=16.3 Hz, 1H, -CHdCH-Ph-NH2), 6.95 (d,
J= 16.3 Hz, 1H, -CHdCH-Ph-NH2), 5.44 (s, 2H, NH2). Mp:
292-300 °C dec.
2-StiO-R-CD, respectively, after characterizing by 1H NMR, 13
C
Preparation of 4-(40-Aminostilbene) Carbonyl Modified r-Cyclo-
dextrin (AmStiO-r-CD) at the Secondary Hydroxyl Groups.
NMR, and various 2D NMR (COSY, TOCSY, and HBQC).
1
Characteristic Data of 2-trans-StiO-r-CD. H NMR (D2O,
25 °C, 1 mM, 500 MHz) δH 8.45 (d, J=8.2 Hz, 2H, 3-position of
stilbene), 8.08 (d, J=8.2 Hz, 2H, 2-position of stilbene), 7.63 (t,
J=7.4 Hz, 2H, 30-position of stilbene), 7.57 (t, J=7.4 Hz, 1H, 40-
position of stilbene), 7.51 (d, J=7.4 Hz, 1H, 20-position of stil-
bene), 7.30-7.39 (d, 16.4 Hz, 2H, olefin of stilbene), 5.01-5.64
(m, 6H, C1H of CD). 1H NMR (DMSO-d6, 30 °C, 500 MHz) δH
8.08 (d, J=8.5 Hz, 2H, 3-position of stilbene), 7.72 (d, J=8.5 Hz,
2H, 2-position of stilbene), 7.65 (d, J=7.4 Hz, 2H, 20-position of
stilbene), 7.38-7.44 (m, 3H, 30-position and -CHdCH-Ph of
stilbene), 7.29-7.36 (m, 2H, 40-position and -CHdCH-Ph of
stilbene), 5.40-5.70 (m, 11H, O(2, 3)H of CD), 4.75-5.14 (m,
6H, C(1)H of CD), 3.15-4.67 (m, overlaps with HOD, others
of CD). 13C NMR (DMSO-d6, 30 °C, 125 MHz) δ 165.6
(-O-CdO), 141.6 (1-Ph), 136.6 (10-Ph), 131.1 (4-Ph), 130.2
(-CHdCH-Ph), 128.7 (3,5-Ph), 128.4 (30, 50-Ph), 128.2 (40-Ph),
127.4 (-CHdCH-Ph), 126.8, 126.3, 102.2, 102.0, 101.9, 101.8,
98.8, 82.4, 82.2, 82.1, 82.0, 73.7, 73.3, 73.2, 73.1, 72.5, 72.4,
72.2, 72.1, 72.0, 71.7, 69.6, 60.0-59.9 (C(1-6) of CD). MALDI-
TOF MS: m/z=1201.0 ([C50H70O31 þ Na]þ=1201.4), 1217.1
([C50H70O31 þ K]þ = 1217.1). Anal. Calcd for C50H70-
O31(H2O)7.4: C, 46.18; H, 6.57. Found: C, 45.84; H, 6.22.
Dried R-CD (0.30 g, 0.31 mmol) was dissolved in 5 mL of
dried DMF. Sodium hydride (60% in oil suspension; 12 mg, 0.31
mmol) was added to the solution, which was stirred for 12 h at
room temperature. 4-(40-Aminostilbene) carboxylic acid (73 mg,
0.31 mmol) and N,N0-dicyclohexyl carbodiimide (DCC; 76 mg,
0.38 mmol) were dissolved in DMF/DMSO=50/50 (5 mL) and
stirred for 24 h at 0 °C. The solution was gradually added to the
R-CD solution while stirring. After 3 h, the mixture solution was
poured into acetone (150 mL). The precipitate was collected by
1
Characteristic Data of 3-trans-StiO-r-CD. H NMR (D2O,
25 °C, 5 mM, 500 MHz) δH 8.54 (br d, 2H, 3-position of stilbene),
8.09 (br d, 2H, 2-position of stilbene), 7.59 (t, J =7.4 Hz, 2H,
498 J. Org. Chem. Vol. 76, No. 2, 2011

Kanaya et al.
JOCArticle
centrifugation and washed with acetone twice. Reverse-phase
preparative HPLC was performed to separate the isomers. The
resulting precipitate was dissolved in 25 mL of distilled water
and an aliquot of the solution (5.0 mL) was injected onto the
HPLC system. Lyophilization of each eluent gave 59 mg of
Fraction 1 (the former peak of the two main peaks) and 27.6 mg
of Fraction 2 (the latter peak of the two main peaks). Fractions 1
and 2 were identified as 3-AmStiO-R-CD and 2-AmStiO-R-CD,
respectively, after characterization by 1H NMR, 13C NMR, and
various 2D NMR (COSY, TOCSY, and HBQC).
J = 8.5 Hz, 2H, 20-position of stilbene), 7.20 (d, J = 16.2 Hz,
1H, -CHdCH-Ph-NH2), 6.96 (d, J = 16.2 Hz, 1H, -CHdCH-
Ph-NH2), 6.56 (d, J = 8.5 Hz, 2H, 30-position of stilbene),
5.54-5.26 (m, 11H, O(2, 3)H of CD), 4.91-4.71 (m, 6H, C(1)H
of CD), 4.53-4.42 (m, 6H, O(6)H of CD), 3.92-3.07 (m,
overlaps with HOD, others of CD). 13C NMR (DMSO-d6,
30 °C, 125 MHz) δ 165.7 (-O-CdO), 149.3 (40-Ph), 142.0 (1-Ph),
131.5 (4-Ph), 139.9 (3-Ph), 128.6 (-CHdCH-Ph-(CdO)), 128.1
(20-Ph), 125.2 (2-Ph), 124.3 (10-Ph), 121.7 (-CHdCH-
Ph-(CdO)), 113.8 (30-Ph), 102.2, 102.1, 102.0, 101.9, 101.6,
82.5, 82.2, 82.1, 81.9, 79.2, 73.2, 73.1, 72.9, 72.4, 72.3, 72.2,
72.1, 71.9, 71.8, 71.6, 71.1, 70.9, 60.1, 60.0, 59.9 (C(1-6) of CD).
MALDI-TOF MS: m/z = 1217.4 ([C50H70O31 þ Na]þ = 1216.4),
Characteristic Data of 2-AmStiO-r-CD. 1H NMR (DMSO-
d6, 30 °C, 500 MHz) δH 8.01 (d, J=8.5 Hz, 2H, 3-position of
stilbene), 7.59 (d, J=8.5, 2H, 2-position of stilbene), 7.32 (d, J = 8.6
Hz, 2H, 20-position of stilbene), 7.22 (d, J=16.3 Hz, 1H, -CHd
CH-Ph-NH2), 6.96 (d, J=16.3 Hz, 1H, -CHdCH-Ph-NH2), 6.57
(d, J=8.6 Hz, 2H, 30-position of stilbene), 5.69-5.38 (m, 11H, O(2,
3)H of CD), 5.12-4.75 (m, 6H, C(1)H of CD), 4.57-4.40 (m, 6H,
O(6)H of CD), 4.65, 4.20, 4.08, 3.84-3.16 (m, overlaps with HOD,
others of CD). 13C NMR (DMSO-d6, 30 °C, 125 MHz) δ 165.7
(-O-CdO), 149.3 (40-Ph), 142.0 (1-Ph), 131.5 (4-Ph), 139.9 (3-
Ph), 128.6 (-CHdCH-Ph-(CdO)), 128.1 (20-Ph), 125.2 (2-Ph),
124.3 (10-Ph), 121.7 (-CHdCH-Ph-(CdO)), 113.8(30-Ph), 102.2,
102.1, 102.0, 101.9, 101.6, 82.5, 82.2, 82.1, 81.9, 79.2, 73.2, 73.1,
72.9, 72.4, 72.3, 72.2, 72.1, 71.9, 71.8, 71.6, 71.1, 70.9, 60.1, 60.0,
59.9 (C(1-6) of CD). MALDI-TOF MS: m/z = 1219.5 ([C50-
H70O31 þ Na]þ=1216.4), 1235.6 ([C50H70O31 þ K]þ=1232.4).
1234.5 ([C50H70O31 þ K]þ = 1232.4). Anal. Calcd for C51H71NO31
3
10.6H2O: C, 44.23; H, 6.71; N, 1.01. Found: C, 43.91; H, 6.34; N 1.07.
Acknowledgment. The authors thank Mr. S. Adachi and
Mr. H. Okuda (Osaka University) for their support with the
2D-NMR experiments. This work was supported by the
“Core Research for Evolutional Science and Technology”
program of the Japan Science and Technology Agency,
Japan.
Supporting Information Available: Typical chromatograms,
1H NMR spectra, 13C NMR spectra, plots of diffusion coeffi-
cients, determination of pseudo-first-order rate constants, 2D
ROESY NMR spectra, circular dichroism spectra, and deter-
mination of association constants. This material is available free
of charge via the Internet at http://pubs.acs.org.
Anal. Calcd for C51H71NO31 9.9H2O: C, 44.63; H, 6.67; N, 1.02.
3
Found: C, 44.38; H, 6.36; N 1.12.
Characteristic Data of 3-AmStiO-r-CD. 1H NMR (DMSO-
d6, 30 °C, 500 MHz) δH 7.89 (d, J = 8.4 Hz, 2H, 3-position of
stilbene), 7.56 (d, J = 8.4, 2H, 2-position of stilbene), 7.31 (d,
J. Org. Chem. Vol. 76, No. 2, 2011 499