Heptakis(2,3-di-O-carboxymethyl)-β-cyclodextrin as a pH-sensitive host

Article abstract of DOI:10.1246/cl.2004.1086

Acid-dissociation of heptakis(2,3-di-O-carboxymethyl)-β-cyclodextrin occurred between pD 2 and 6. At pD 2.0, 1-pyrene-sulfonate was included into the host cavity with a binding constant of 2300 ± 100 M^-1, while no complexation occurred at pD > 6.0. Much sharper pH-dependency in complexation proceeded with 1-anilino-8-naphthalenesulfonate and 2-(p-methyl-anilino)-6-naphthalenesulfonate.

Full text of DOI:10.1246/cl.2004.1086

1086
Chemistry Letters Vol.33, No.9 (2004)
Heptakis(2,3-di-O-carboxymethyl)-ꢀ-cyclodextrin as a pH-sensitive Host
Koji Kano,ꢀ Yasuhiro Horiki, Takahiro Mabuchi, and Hiroaki Kitagishi
Department of Molecular Science and Technology, Faculty of Engineering, Doshisha University,
Kyotanabe, Kyoto 610-0321
(Received May 31, 2004; CL-040608)
Acid-dissociation of heptakis(2,3-di-O-carboxymethyl)-ꢀ-
cyclodextrin occurred between pD 2 and 6. At pD 2.0, 1-pyrene-
sulfonate was included into the host cavity with a binding con-
stant of 2300 ꢁ 100 Mꢂ1, while no complexation occurred at
pD > 6:0. Much sharper pH-dependency in complexation pro-
ceeded with 1-anilino-8-naphthalenesulfonate and 2-(p-methyl-
anilino)-6-naphthalenesulfonate.
CH2Cl2 (25 mL) containing 10-drops of an ethereal solution of
BF3 (46%) was added ethyl diazoacetate (9.3 mmol) in CH2Cl2
within 3 h at ꢂ10 ꢃC and the mixture was stirred overnight at
room temperature. The crude products were treated by silica
gel column chromatography to isolate 2 (42% yield). TOFMS
spectrum of 2 indicated that all secondary OH groups were trans-
formed to the OCH2CO2Et groups. 2 (9.3 mmol) was dispersed
in a mixed solution of ethanol and 70% aq acetic acid (2:3,
30 mL) and the solution was stirred overnight at 60 ꢃC. After
the reaction, 1 M aq NaOH was added to the reaction mixture un-
til the pH of the solution became 12.5 and the resulting solution
was stirred for 3 h. After neutralization, the solvent was evapo-
rated and the residues obtained were dissolved in water and dia-
lyzed (Spectro/pro M.W.C.O.1000) to afford pure 2,3-di-
CO2Na-ꢀ-CD (58% yield).6
Native cyclodextrins (CDs) can act as substructures of func-
tional host molecules. Among many modified CDs, polycationic
and polyanionic CDs are very interesting because of their strong
ability to form inclusion complexes assisted by Coulomb inter-
actions with oppositely charged guest molecules. Heptakis(6-
amino-6-deoxy)-ꢀ-CD in a protonated form (per-NH3þ-ꢀ-CD)
and heptakis(6-carboxymethylthio-6-deoxy)-ꢀ-CD in a dissoci-
ated form (per-CO2ꢂ-ꢀ-CD) are well-known polycationic and
polyanionic CDs,1 respectively, which bind oppositely charged
chiral guests enantioselectively.2,3 Looking at these polyionic
hosts from a different viewpoint, these hosts are expected to
show pH-dependent inclusion phenomena. For example, per-
CO2H-ꢀ-CD might include an anionic guest into its cavity and
pour out the guest when it dissociates to per-CO2ꢂ-ꢀ-CD at
higher pH. Unfortunately, however, neutral per-CO2H-ꢀ-CD
as well as per-NH2-ꢀ-CD is insoluble in water. Heptakis(2,3-
di-O-carboxymethyl)-ꢀ-CD (2,3-diCO2H-ꢀ-CD) is one of the
candidates of a pH-sensitive host which can dissolve in acidic
aqueous solution. Although 2,3-diCO2H-ꢀ-CD is a known mate-
rial (CA Registry Number: 185150-02-1) and has been used as a
chiral selector in capillary electrophoresis,4 no details for synthe-
sis have been disclosed. In this communication, we report the
synthesis of 2,3-diCO2H-ꢀ-CD and its interesting behavior as
a pH-sensitive host for anionic guests.
1
In order to determine pKa of 2,3-diCO2H-ꢀ-CD, H NMR
spectral changes of this CD in D2O containing 0.1 M NaCl were
measured as a function of pD at 25 ꢃC. A sigmoid pD-titration
curve measured by following the chemical shifts of the methyl-
ene protons at the 7-position (see Figure 1) of 2,3-diCO2H-ꢀ-CD
indicated that the dissociation of 2,3-diCO2H-ꢀ-CD was initiat-
ed at pD 2 and completed at pD 6. The apparent pKa value was
ca. 5.
-
SO3
-O3S
NH
ANS
CH3
PyS
NH
A synthetic route is shown in Scheme 1. To a solution of
heptakis(6-O-tert-butyldimethylsilyl)-ꢀ-CD5 (1, 3 mmol) in
TNS
-O3S
Since 2,3-diCO2H-ꢀ-CD has fourteen hydrophilic CO2H
groups at a wider rim of ꢀ-CD, this CD can dissolve even in
acidic aqueous solution. In acidic D2O solution, 2,3-diCO2H-
ꢀ-CD included 1-pyrenesulfonate (PyS) into its cavity.
CH3
Si C(CH3)3
CH3
O
OH
N2CHCO2Et /
BF3, CH2Cl2
O
O
TBDMSCl / DMF
rt / one night
HO
HO
rt / 12 h
OH
OH
1
Figure 1 shows H NMR spectra (TSP as an external standard)
O
O
7
7
of 2,3-diCO2H-ꢀ-CD in D2O at pD 2.0 (DCl) in the absence
and the presence of PyS. In the absence of PyS, the methylene
protons at the 7- (4.360 ppm, J ¼ 33 and 17 Hz) and 8-positions
(4.719 ppm, J ¼ 77 and 16 Hz) of 2,3-diCO2H-ꢀ-CD showed
the AB patterns. Such a novel coupling pattern having extremely
large coupling constants was also observed with the methylene
protons of heptakis(3-O-ethoxycarbonylmethyl)-ꢀ-CD in
CD3OD.1b Upon complexation with PyS, the signals due to the
methylene protons at the 7- and 8-positions shifted to 4.268
(J ¼ 39 and 17 Hz) and 4.352 ppm (144 and 16 Hz), respective-
1
β-CD
CH3
Si
C(CH3)3
CH3
OH
O
6
4
O
O
5
CH3CO2H / H2O
80 oC / 12 h
NaOH / H2O
rt / 3 h
2
1
3
O
O
O
O
8
O
O
7
7
7
CO2Na
CO2Et
CO2Na
CO2Et
2,3-diCO2Na-β-CD
2
Scheme 1. Synthetic route of 2,3-diCO2Na-ꢀ-CD.
Copyright Ó 2004 The Chemical Society of Japan

Chemistry Letters Vol.33, No.9 (2004)
1087
in the absence of the CD, indicating that PyS was not bound to
2,3-diCO2ꢂ-ꢀ-CD at all at pD > 6:0.
2, 3-diCO2H-β-CD + PyS
H-8
In order to generalize pH-dependent inclusion of 2,3-
diCO2H-ꢀ-CD, 1-anilino-8-naphthalenesulfonate (ANS) and 2-
(p-methylanilino)-6-naphthalenesulfonate (TNS) were used as
the guests. Both fluorophores are well known as hydrophobic flu-
orescent probes. Figure 2 shows the relative fluorescence inten-
sity changes of ANS and TNS in aqueous solutions containing
2,3-diCO2H-ꢀ-CD and/or 2,3-diCO2ꢂ-ꢀ-CD as a function of
pH. In acidic solution at pH 2, the fluorescence intensity of
TNS was much larger than that of ANS. This is reasonably inter-
preted in terms of the difference in K values. The size of TNS is
suitable to be included into the CD cavity.7 The K values of ANS
and TNS for complexation with 2,3-diCO2H-ꢀ-CD, which were
determined in D2O at pD 2.0 (DCl) containing 0.1 M NaCl from
the 1H NMR titration, were 71 ꢁ 4 and 6300 ꢁ 400 Mꢂ1, respec-
tively. In both cases, sharp pH-dependency was observed. The
acid-dissociation of 2,3-dꢂiCO2H-ꢀ-CD causes electrostatic re-
pulsion between the CO2 groups of the host and the anionic
host and guest leading to ejection of the guest from the CD cav-
ity. The pH-dependency curves shown in Figure 2 do not neces-
sarily correspond to the pH-titration curve for determining pKa
of 2,3-diCO2H-ꢀ-CD. The pH-sensitivity in ejection of a guest
from the CD cavity should depend on the nature of the guest.
PyS has a larger hydrophobic part as compared with ANS and
TNS. Therefore, the PyS molecule might tend to resist the ejec-
tion from the cavity of partially dissociated 2,3-diCO2H-ꢀ-CD.
H-5
H-6
H-3
H-4
H-1
H-2
H-8
H-7
H-5
H-6
H-3
H-4
2, 3-diCO2H-
β-CD
H-1
H-2
3.5
4.5
δ / ppm
4.0
5.0
Figure 1. 1H NMR spectra of 2,3-diCO2H-ꢀ-CD (5 ꢄ 10ꢂ4 M)
in D2O containing 0.1 M NaCl in the absence and the presence of
PyS (5 ꢄ 10ꢂ4 M) at pD 2.0 (DCl).
This study was supported by a Grant-in-Aid for Scientific
Research B (KAKENHI 14340224) from the Ministry of
Education, Culture, Sports, Science and Technology, Japan
and a Sekisui Foundation.
References and Notes
1
a) K. Tsujihara, H. Kurita, and M. Kawazu, Bull. Chem. Soc.
Jpn., 50, 1567 (1977). b) F. Guillo, B. Hamelin, L. Jullien, J.
Canceill, J.-M. Lehn, L. De Robertis, and H. Driguez, Bull.
Soc. Chim. Fr., 132, 857 (1995). c) A. Gadelle and J. Defaye,
Angew. Chem., Int. Ed. Engl., 30, 78 (1991).
Figure 2. Changes in the chemical shift of the proton at the 2-
position of PyS (5 ꢄ 10ꢂ4 M) in D2O at pD 2.0 and in the fluo-
rescence intensities of ANS (2 ꢄ 10ꢂ5 M) and TNS (5 ꢄ 10ꢂ6
M) in H2O at pH 2.0 in the presence of 2,3-diCO2H-ꢀ-CD
and/or 2,3-diCO2ꢂ-ꢀ-CD as a function of pD or pH at 25 ꢃC.
The initial concentrations of 2,3-diCO2Na-ꢀ-CD were 2:5 ꢄ
10ꢂ3, 5 ꢄ 10ꢂ4, and 1 ꢄ 10ꢂ4 M for PyS, ANS, and TNS, re-
spectively. ANS and TNS were excited at 400 and 335 nm, re-
spectively.
2
3
4
T. Kitae, T. Nakayama, and K. Kano, J. Chem. Soc., Perkin
Trans. 2, 1998, 207; K. Kano, S. Arimoto, and T. Ishimura,
J. Chem. Soc., Perkin Trans. 2, 1995, 1661.
a) K. Kano and H. Hasegawa, J. Am. Chem. Soc., 123, 10616
(2001). b) K. Kano, H. Hasegawa, and M. Miyamura,
Chirality, 13, 474 (2002).
For example; a) H. Jin, F. Li, J. Gu, R. Fu, Y. Liu, and R. Dai,
Fenxi Huaxue, 24, 1387 (1996); CAN 126:162355. b) H.
Wang, J. L. Gu, F. H. Fang, J. D. Ji, H. D. Tian, and R. N.
Fu, Anal. Chim. Acta, 359, 39 (1998).
K. Takeo, H. Mitoh, and K. Uemura, Carbohydr. Res., 187,
203 (1989).
ly. Upfield shifts were observed with the protons at the wider rim
of 2,3-diCO2H-ꢀ-CD and slight downfield shifts were measured
with the protons at the narrower rim. These results definitely in-
dicate that the PyS molecule is bound to the OCH2CO2H group
side of 2,3-diCO2H-ꢀ-CD. Job’s plot for 1H NMR signals of 2,3-
diCO2H-ꢀ-CD revealed the formation of a 1:1 complex. The
binding constant (K) for complexation of PyS with 2,3-
diCO2H-ꢀ-CD was determined from 1H NMR titration to be
2300 ꢁ 100 Mꢂ1 in D2O containing 0.1 M NaCl at pD 2.0
(DCl) and 25 ꢃC. 2,3-diCO2H-ꢀ-CD poured out PyS as increas-
ing pD as shown in Figure 2, where changes in the chemical shift
of the proton at the 2-position of PyS are shown as a function of
pD. The chemical shift at pD > 6:0 was the same as that of PyS
5
6
Analytical data for 2,3-diCO2Na-ꢀ-CD: IR (KBr): 3418,
2932, 1607, 1427, 1331, 1030 cmꢂ1 1H NMR (400 MHz,
.
D2O, TSP) ꢁ 3.586 (dd, 1H, J ¼ 9:0 and 3.0 Hz), 3.794–
3.979 (m, 4H), 4.360 (dd, 2H, J ¼ 33 and 17 Hz), 4.719
(dd, 2H, J ¼ 77 and 16 Hz). Anal. Calcd. for
.
C70H77O63Na14 18H2O: C, 32.59; H, 4.69%. Found: C,
32.38; H, 4.48%.
M. V. Rekharsky and Y. Inoue, Chem. Rev., 98, 1875 (1998).
7
Published on the web (Advance View) July 26, 2004; DOI 10.1246/cl.2004.1086