Synthesis of bridged and metallobridged bis(β-cyclodextrin)s containing fluorescent oxamidobisbenzoyl linkers and their selective binding towards bile salts

Article abstract of DOI:10.1002/chem.200501187

A series of β-cyclodextrin (β-CD) dimers containing fluorescent 2,2′-oxamidobisbenzoyl and 4,4′-oxamidobisbenzoyl linkers - that is, 6,6′-[2,2′-oxamidobis(benzoylamino)]ethyleneamino-6,6′-deoxy- bis(β-CD) (2), 6,6′-[2,2′-oxamidobis(benzoylamino)] diethylenediamino-6,6′-deoxy-bis(β-CD) (3), 6,6′-[4,4′- oxamidobis(benzoylamino)]ethyleneamino-6,6′-deoxy-bis(β-CD) (4), and 6,6′-[4,4′-oxamidobis(benzoylamino)]-diethylenediamino-6, 6′-deoxy- bis(β-CD) (5) - were synthesized from the corresponding oxamidobis(benzoic acid)s through treatment with mono[6-aminoethyleneamino-6- deoxy]-β-CD or mono[6-diethylenetriamino-6-deoxy]-β-CD. Further treatment of 2-5 with copper perchlorate gave their Cu^II complexes 6-9 in satisfactory yields. The conformation and binding behavior of 2-9 towards two bile salt guests - sodium cholate (CA) and sodium deoxycholate (DCA) - was comprehensively investigated by circular dichroism, 2D NMR spectroscopy, and fluorescence spectroscopy in TrisHCl buffer solution (pH 7.2) at 25 °C. Thanks to the cooperative host-linker-guestbinding mode, the stoichiometric 1:1 complexes formed by bis(β-CD)s 2-5 with bile salts gave high stability constants (K_S values) of up to 103-104M^-1. Significantly, benefiting from the intramolecular 1:2 or 2:4 binding stoichiometry, the resulting complexes of metallobis(β-CD)s 6-9 with bile salts gave much higher K_S values of up to 10⁶-10⁷M ^-2. The enhanced binding abilities of bis(β-CD)s and metallobridged bis(β-CD)s are discussed from the viewpoints of induced-fit interactions and multiple recognition between host and guest.

Full text of DOI:10.1002/chem.200501187

DOI: 10.1002/chem.200501187
Synthesis of Bridged and Metallobridged Bis(b-cyclodextrin)s Containing
Fluorescent Oxamidobisbenzoyl Linkers and Their Selective Binding towards
Bile Salts
[
a]
Yu Liu,* Hong-Mei Yu, Yong Chen, and Yan-Li Zhao
Abstract: A series of b-cyclodextrin (b-
CD) dimers containing fluorescent 2,2’-
oxamidobisbenzoyl and 4,4’-oxamido-
bisbenzoyl linkers—that is, 6,6’-[2,2’-ox-
amidobis(benzoylamino)]ethyleneami-
CD. Further treatment of 2–5 with
copper perchlorate gave their Cu
guest binding mode, the stoichiometric
1:1 complexes formed by bis(b-CD)s
II
ACHTREUNG
complexes 6–9 in satisfactory yields.
The conformation and binding behav-
ior of 2–9 towards two bile salt
guests—sodium cholate (CA) and
sodium deoxycholate (DCA)—was
comprehensively investigated by circu-
lar dichroism, 2D NMR spectroscopy,
and fluorescence spectroscopy in Tris-
HCl buffer solution (pH 7.2) at 258C.
Thanks to the cooperative host–linker–
2–5 with bile salts gave high stability
3
constants (K values) of up to 10 –
S
4
ꢀ1
10 m . Significantly, benefiting from
the intramolecular 1:2 or 2:4 binding
stoichiometry, the resulting complexes
no-6,6’-deoxy-bis
oxamidobis(benzoylamino)]diethylene-
diamino-6,6’-deoxy-bis(b-CD) (3), 6,6’-
4,4’-oxamidobis(benzoylamino)]ethyle-
neamino-6,6’-deoxy-bis(b-CD) (4), and
,6’-[4,4’-oxamidobis(benzoylamino)]-
diethylenediamino-6,6’-deoxy- bis(b-
CD) (5)—were synthesized from the
corresponding oxamidobis(benzoic
A
C
H
T
R
E
U
N
G
(b-CD) (2), 6,6’-[2,2’-
A
H
E
G
of metallobis
A
H
R
U
G
[
salts gave much higher K values of up
S
6
7
ꢀ2
A
H
R
U
to 10 –10 m . The enhanced binding
abilities of bis(b-CD)s and metallo-
bridged bis(b-CD)s are discussed from
6
ACHTREUNG
A
H
R
U
G
ACHTREUNG
the viewpoints of induced-fit interac-
tions and multiple recognition between
host and guest.
Keywords: bile salts · cyclodextrins ·
acid)s through treatment with mono[6-
aminoethyleneamino-6-deoxy]-b-CD or
mono[6-diethylenetriamino-6-deoxy]-b-
fluorescence
spectroscopy
·
molecular recognition
[
6–7]
Introduction
to the design and synthesis of functional CD derivatives
and to investigations into their molecular recognition behav-
ior with various guest molecules.
[8–13]
Cyclodextrins (CDs), a class of macrocyclic oligosaccharides
Besides functional sub-
consisting of six, seven, or eight glucose units linked by a-
stituents, metal ions have also been introduced into CD sys-
tems as additional recognition sites to enhance the binding
abilities and molecular selectivities of CDs further.
1,4-glucose bonds, are capable of encapsulating various or-
[14–16]
ganic, inorganic, and biological molecules within their trun-
cated cone-shaped hydrophobic cavities to form stable host–
guest inclusion complexes or supramolecular species and
have thus been extensively used as molecular receptors and
Bile salts, on the other hand, are surfactant-like molecules
that act to assist in the digestion of fats through the forma-
tion of micelles and micellar aggregates. Moreover, they can
also interact with drugs used for the treatment of hyperlipi-
demia, such as neomycin, clidamycin, kanamycin, and linco-
[1–5]
chiral selectors in many fields of chemistry and biology.
However, the binding abilities of native CDs are generally
limited, which is unfavorable to their application as enzyme
mimics and to a greater extent as antibody mimics. To im-
prove the original binding abilities and molecular selectivi-
ties of native CDs, a great deal of effort has been devoted
[17]
mycin. Because of the attractive properties of both CDs
and bile salts, molecular binding between bile salts and CDs
[18]
has been widely studied. Choi et al. studied inclusion com-
plex formation by b-CD and its dimers with cholesterol by
Monte Carlo docking simulations, molecular dynamics cal-
culations, and non-equilibrium molecular dynamics simula-
[
a] Prof. Y. Liu, H.-M. Yu, Dr. Y. Chen, Dr. Y.-L. Zhao
Department of Chemistry
[19]
tions. Tato and co-workers studied the complex geometry
State Key Laboratory of Elemento-Organic Chemistry
Nankai University, Tianjin 300071 (P. R. China)
Fax : (+86)22-2350-3625
of b-CD and its derivatives in D O by ROESY experiments,
2
observing different binding modes upon inclusion complexa-
[20]
E-mail: yuliu@nankai.edu.cn
tion with bile salts. Cramer et al. reported the first kinetic
3858
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Chem. Eur. J. 2006, 12, 3858 –3868

FULL PAPER
measurements performed on a
series of naphthylazobenzene-
b-CD/bile
while Reinhoudt et al.
ported microcalorimetric
salt
complexes,
[
21]
re-
a
study on the cooperative bind-
ing of bile salts by CD dimers
in a basic environment, show-
ing enhanced binding abilities
towards cholate and deoxycho-
late. We have recently also re-
ported some significant results
on the fluorescence sensing
and binding modes of bridged
bis
A
C
H
T
R
E
U
N
G
(b-CD)s towards bile salts,
demonstrating that bis
AHCTREUNG
(b-CD)s
can form stoichiometric inclu-
sion complexes (either 1:1 or
[22]
1
:2) with bile salts.
An in-
depth comparative study on
the molecular binding behav-
ior of bis
A
C
H
T
R
E
U
N
G
(b-CD)s and metallo-
bridged bis
ACHTREUNG
(b-CD)s with bile
salts has yet to be reported,
however, though such studies
would be very important for
elucidation of the molecular
recognition mechanism and
control of the binding behavior
of synthetic receptors. In this
work we have synthesized a
series of bis
A
C
H
T
R
E
U
N
G
(b-CD)s with fluo-
rescent
oxamidobisbenzoyl
II
linkers and their Cu com-
plexes, and have comparatively
investigated their selective
binding
behavior
towards
some optically inert bile salt
guest molecules. Here, the ox-
amidobisbenzoyl linker can act
not only as a sensing site for a
guest but also as a coordinat-
ing site for metal ions. First,
the fluorescent oxamidobisbenzoyl linkers may undergo sub-
stantial conformational changes upon complexation with op-
tically inert bile salts, producing appreciable fluorescence
changes. Second, both the oligo(ethylenediamine) moieties
and the carbonyl groups in the linker have the ability to co-
ordinate to transition-metal ions, therefore enabling us to
modify and potentially to switch the original binding ability
through the metal coordination and the cooperative multiple
recognition. Our particular interest is in exploration of the
factors governing the molecular multiple recognition mecha-
nism, especially of how metal coordination affects the bind-
Results and Discussion
Synthesis: As illustrated in Scheme 1, the oxamidobisbenzo-
yl-linked bis(b-CD)s 2–5 were synthesized in moderate
AHCTREUNG
yields from oxamido-linked bis(benzoic acid)s and mono[6-
aminoethyleneamino-6-deoxy]-b-CD or mono[6-diethylene-
triamino-6-deoxy]-b-CD. Care should be taken to keep the
mixture anhydrous and at a low temperature during these
reactions, particularly at the initial stage, to achieve smooth
and clean transformations without undesirable products.
II
Further treatment of bis
A
H
R
U
G
II
ing behavior of bis
A
C
H
T
R
E
U
N
G
(b-CD)s. This approach should serve to
gave their Cu complexes 6–9 in satisfactory yields (over
50%). The quantities of reactants used were consistent with
the reaction stoichiometry, as determined by spectrophoto-
further our understanding of this developing but little inves-
tigated area in the field of supramolecular chemistry.
Chem. Eur. J. 2006, 12, 3858 –3868
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3859

Y. Liu et al.
Scheme 1. Synthesis of CD derivatives.
metric titration. The compositions of the products were veri-
fied by elemental analysis.
preciable change (within measurement concentration range)
at 200–400 nm under comparable experimental conditions.
These observations indicate that Cu ion coordinates to the
II
Metal coordination behavior and stoichiometry: To investi-
bis
A
H
R
U
G
A
H
R
U
G
gate the coordination behavior of bis(b-CD)s in the pres-
ence of Cu ions, spectrophotometric titrations were per-
A
H
R
U
G
Jobꢁs experiments were also performed to explore the coor-
II
II
dination stoichiometry of bis
A
H
R
U
G
formed at 258C in aqueous solution. A typical titration
ous solution. The adsorption wavelengths used were 306 nm
II
II
II
II
curve obtained by titration of bis
A
H
R
U
G
for 2/Cu , 305 nm for 3/Cu , 284 nm for 4/Cu , and 286 nm
II
shown in Figure 1. The absorbance intensity of bis
A
H
R
U
G
for 5/Cu systems. We had previously demonstrated that the
II
at 305 nm gradually decreases, while the absorbance intensi-
ties at 250 and 350 nm gradually increase with the addition
coordination of bis
stoichiometry.
A
H
R
U
G
[23]
Here, this 1:2 stoichiometry was also ob-
served in the case of the 3/Cu complex, which indicates
that one bis(b-CD) 3 moiety can bind two Cu ions. When,
II
of varying amounts of Cu perchlorate. In the control ex-
II
periments, the UV/Vis spectrum of Cu ion displayed no ap-
A
H
R
U
G
3860
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ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 3858 –3868

Bridged Bis(b-cyclodextrin)s with Fluorescent Oxamidobisbenzoyl Linkers
FULL PAPER
II
Figure 1. UV/Vis spectral changes of 3 upon addition of Cu perchlorate
ꢀ
5
ꢀ3
II
in aqueous solution ([3] = 8”10 moldm ; [Cu ] from a to k = 0,
0
1
.082, 0.164, 0.205, 0.3075, 0.410, 0.615, 0.820, 1.025, 1.435, and 1.845”
ꢀ
4
ꢀ3
0
moldm ).
however, the 2,2’-oxamidobis(benzoylamino) linkers in the
bis(b-CD)s 2 and 3 were exchanged for 4,4’-oxamidobis(ben-
zoylamino) linkers, the resultant bis(b-CD)s 4 and 5 each
adopted a different coordination stoichiometry with Cu
ACHTREUNG
AHCTREUNG
II
II
II
ion. The Jobꢁs plots for either 4/Cu or 5/Cu complexes
each display a maximum at 0.4 corresponding to a 2:3 bis(b-
CD)/Cu coordination stoichiometry, which indicates that—
AHCTREUNG
II
II
besides each bis
two bis(b-CD) components also participate in the binding of
the third Cu ion. These bis
chiometries were also verified by elemental analysis results.
A
C
H
T
R
E
U
N
G
(b-CD) unit associating with one Cu ion—
ACHTREUNG
II
II
A
H
R
U
G
ꢀ4
ꢀ3
Figure 2. Circular dichroism spectra of hosts 2–9 (1.0”10 moldm ) in
aqueous buffer solution (pH 7.2) at 258C.
Conformations of bis
A
H
R
U
G
A
H
R
U
CD)s: It is well known that the inclusion of a chromophoric
achiral guest/moiety in a chiral host such as a CD may pro-
duce induced circular dichroism (ICD) signals at wave-
Cotton
effect
peak
around
235 nm
(De
=
[24]
ꢀ3
ꢀ1
ꢀ1
lengths at which the guest chromophore has absorbance.
2.68 dm mol cm ) and a moderate positive Cotton effect
ꢀ
3
ꢀ1
ꢀ1
In a control experiment, an aqueous solution of an oxami-
do-linked bis(benzoic acid) gave neither a circular dichroism
signal nor a rotatory signal, confirming that the oxamido-
linked bisbenzoyl group is an achiral chromophore in aque-
ous solution. Therefore, in order to examine the conforma-
tions of hosts 2–9, their circular dichroism spectra were
measured at 258C in Tris-HCl buffer solution (pH 7.2). As
peak around 272 nm (De = 0.60 dm mol cm ) for the
1
1
L and L transitions, respectively. When the 2,2’-oxamido-
a
b
bis(benzoylamino) linker in bis
the 4,4’-oxamidobis(benzoylamino) linker, the resultant bis-
(b-CD) 4 displays ICD signals similar to but stronger than
those of 2, giving two positive Cotton effect peaks around
A
H
R
U
G
AHCTREUNG
ꢀ
3
ꢀ1
ꢀ1
238 (De
= 0.67 dm mol cm ) and 312 nm (De =
ꢀ
3
ꢀ1
ꢀ1
1
1
can be seen from Figure 2a, bis
A
H
R
U
G
0.23 dm mol cm ) for the L and L transitions. Bis
A
C
H
T
R
E
U
N
G
(b-
a
b
lar circular dichroism spectra in the absence of guest mole-
cule, but the intensities of the ICD signals are clearly differ-
ent, indicating different degrees of interactions between the
CD) 5, possessing the longer linker, displays relatively weak
ICD signals, giving two positive Cotton effect peaks around
ꢀ
3
ꢀ1
ꢀ1
246 nm (De = 0.28 dm mol cm ) and 278 nm (De =
ꢀ
3
ꢀ1
ꢀ1
1
1
aromatic linker and two chiral cavities in the bis
A
H
R
U
G
0.26 dm mol cm ) for the L and L transitions. From a
generally accepted empirical rule
a
b
[
25–27]
circular dichroism spectrum of 2 displays two positive
for the signs of ICD
Cotton
effect
peaks
around
and
233 nm
311 nm
(De
(De
=
=
signals induced by CDs and from our previous report on the
ꢀ
ꢀ
3
3
ꢀ1
ꢀ1
[23]
0
0
.52 dm mol cm )
.12 dm mol cm ), attributable to the L and L transi-
conformation of bis
ACHTREUNG
ꢀ1
ꢀ1
1
1
midobisbenzoyl linkers in the bis
ACHTREUNG
a
b
tions, respectively, of the phenyl moieties in the linker
group. As a higher-order homologue of 2, bis(b-CD) 3 gives
the strongest ICD signals, displaying a strong positive
only shallowly included in the b-CD cavities with an accli-
vous orientation to form self-included complexes, whilst that
in 3 is deeply buried in the CD cavity.
AHCTREUNG
Chem. Eur. J. 2006, 12, 3858 –3868
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www.chemeurj.org
3861

Y. Liu et al.
Since self-inclusion of linkers often weakens the binding
abilities of bis(b-CD)s toward guests, appropriate adjust-
ment of the linker conformation is necessary in the design
of functional bis(b-CD)s. In this work we tried to introduce
metal centers into the linker groups of the bis(b-CD)s to
alter their conformation and thus to abolish the disadvanta-
geous self-inclusion. As can be seen in Figure 2b, the circu-
lar dichroism spectra of 6 or 7 each show both a positive
and a negative Cotton effect peak, clearly different from the
circular dichroism spectrum of 2 or 3, each showing two pos-
itive Cotton effect peaks. This result indicates that, after the
metal coordination, the linker group of 6 or 7 is now located
outside the CD cavity, producing the opposite ICD signal to
that of 2 or 3 around 310 nm. On the other hand, the circu-
lar dichroism spectra of 8 and 9 still resemble those of 4 and
tons and the CD H3/H5/H6 protons. As can be seen in
Figure 3, the cross-peaks A and B are attributable to NOE
correlations between the CD H3/H5/H6 protons and the Ha/
ACHTREUNG
A
C
H
T
R
E
U
N
G
H protons of the 4,4’-oxamidobisbenzoyl linker. These re-
b
A
H
R
U
G
sults unambiguously show that the linker group is embedded
in the CD cavity, which is in excellent agreement with the
results obtained in the circular dichroism experiments.
Moreover, cross-peak C, attributable to NOE correlations
between the ethyleneamino protons of the linker group, and
the H5/H6 protons of CD are also observed. Since the H5/
H6 protons are located near to the narrow opening of the
CD cavity, while the H3 protons are near to the wide open-
ing, we can conclude that the linker group of 4 is self-includ-
ed in the CD cavity from the narrow opening, and a possible
conformation of 4 based on these results is shown in
5
, which indicates that 4 and 5 each retain their original con-
formation after the metal coordination.
D NMR spectroscopy has become an essential method
Figure 4. ROESY spectra of other bis(b-CD)s (2, 3, and 5)
were also measured under identical conditions, giving the
same results as deduced from the ICD experiments. Un-
A
H
R
U
G
2
for the study of the conformations of CDs and their com-
plexes, since it may be concluded that two protons are close-
ly located in space—0.4 nm apart at most—if an NOE cross-
peak is detectable between the relevant protons in the
NOESY or ROESY spectrum. It is therefore possible to es-
timate the orientation of a linker group in a CD cavity with
the aid of the assigned NOE correlations. If the linker group
is self-included in the CD cavity, NOE correlations between
the linker group protons and the H3/H5/H6 protons of the
CD should be observed. Figure 3 illustrates a representative
ROESY spectrum of 4 in a pH 7.2 buffer solution, showing
three appreciable cross-peaks between the linker group pro-
fortunately, the conformations of metallobridged bis(b-CD)s
A
C
H
T
R
E
U
N
G
6–9 could not be estimated by 2D NMR, due to the para-
II
magnetic disturbance of Cu .
Figure 4. Possible conformation of 4.
Spectral titration: Many investigations have demonstrated
that fluorophore-attached CDs may undergo substantial
conformational changes upon guest inclusion and thus give
rise to relevant fluorescence changes. Moreover, the intro-
duction of guest molecules certainly changes the microenvir-
onmental hydrophobicity around the fluorophore, which
also affects the fluorophore emission to some extent. In this
work, the fluorescence intensities both of bis
A
H
R
U
G
metallobridged bis(b-CD)s gradually increased with the ad-
AHCTREUNG
dition of bile salts (Figure 5). This property might allow
their application as fluorescence sensors for the molecular
recognition of bile salts.
The stoichiometries for the inclusion complexation of
hosts 2–9 with representative guests were determined by
Jobꢁs experiments by fluorescence spectroscopy. The emis-
sion wavelengths used were 408 nm for 2/bile salt, 402 nm
for 3/bile salt, 417 nm for 4/bile salt, 415 nm for 5/bile salt,
4
07 nm for 6/bile salt, 401 nm for 7/bile salt, 414 nm for 8/
bile salt, and 411 nm for 9/bile salt systems. Within the ex-
amined concentration range, each of the Jobꢁs plots for the
1
ꢀ3
ꢀ3
inclusion complexation of bis
A
H
R
N
(b-CD)s 2–5 with bile salts
Figure 3. H ROESY spectrum of 4 (2.6”10 moldm ) in pH 7.2 buffer
solution at 258C with a mixing time of 400 ms.
shows a maximum at a bis(b-CD) molar fraction of 0.5, con-
AHCTREUNG
3862
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Chem. Eur. J. 2006, 12, 3858 –3868

Bridged Bis(b-cyclodextrin)s with Fluorescent Oxamidobisbenzoyl Linkers
FULL PAPER
Figure 5. a) Fluorescence spectral changes of bis
A
H
R
U
G
2
(1.91”
ꢀ
5
ꢀ3
1
0
0
ꢀ
3
ꢀ3
.1512, 0.189, 0.2835, 0.378, 0.756, 1.323, and 1.70”10 moldm ) in Tris-
HCl buffer solution (pH 7.2) at 258C (lex = 315 nm). b) Nonlinear least-
squares analysis of the differential intensity (DF) to calculate the com-
plex formation constant (K ).
S
firming the 1:1 binding stoichiometry between host and
guest (Figure 6a). For the inclusion complexation of metal-
lobridged bis
the Jobꢁs plots shows a maximum at a bis
fraction of 0.33 (Figure 6b), which indicates a 1:2 stoichiom-
etry between each bis(b-CD) unit and guest. The metallo-
bridged bis(b-CD) 6 or 7, each possessing one bis(b-CD)
unit, may only bind two bile salts to form a stoichiometric
:2 inclusion complex. On the other hand, the metallobridg-
ed bis(b-CD) 8 or 9, each possessing two bis(b-CD) units,
A
C
H
T
R
E
U
N
G
(b-CD)s 6–9 with bile salts, however, each of
AHCTREUNG
(b-CD) unit molar
AHCTREUNG
A
C
H
T
R
E
U
N
G
ACHTREUNG
Figure 6. a) Jobꢁs plot of 4/CA system at 417 nm ([4] + [CA] = 1.0”
ꢀ4
ꢀ3
1
0
moldm ). b) Jobꢁs plot of 9/CA system at 411 nm ([bis(b-CD) unit]
A
H
R
U
G
1
ꢀ5
ꢀ3
+
[CA] = 1.5”10 moldm ).
A
C
H
T
R
E
U
N
G
ACHTREUNG
each of which can form a stoichiometric 1:2 inclusion com-
plex with two guest molecules, may adopt a intramolecular
Table 1. Stability constants (K
for the inclusion complexation of bis(b-CD)s 2–5 with bile salts in Tris-
HCl buffer solution (pH 7.2) at 258C.
S
) and Gibbs free energy changes (ꢀDG8)
ACHTREUNG
2
:4 stoichiometry upon inclusion complexation with bile
salts.
With the 1:1 host/guest stoichiometry, the complexation of
ꢀ1
ꢀ1
Host
Guest
K
S
[m
]
logK
S
ꢀDG8
A
C
H
T
R
E
U
N
G
[kJmol ]
bile salts (guest) with bis
Equation (1).
A
H
R
U
G
2
CA
DCA
CA
DCA
CA
DCA
CA
18500
12200
8130
4.27
4.09
3.91
–
24.34
23.31
22.31
–
3
4
5
KS
[
a]
ƒ
!
H þG ƒH ÁG
ð1Þ
11900
11500
8820
4.08
4.06
3.95
3.27
23.25
23.17
22.51
18.67
The stability constant (K ) for the host–guest inclusion
S
complexation can be obtained from analysis of sequential
changes of fluorescence intensity (DF) at various guest con-
centrations, by use of a nonlinear least-squares curve-fitting
DCA
1870
[
a] The guest-induced variations in the fluorescence intensities are too
small for the K value to be determined.
S
[14c,22c]
method.
For each host examined, the plot of DF as a
function of [G] gives an excellent fit, verifying the validity
0
of the 1:1 inclusion complexation stoichiometry. Figure 5
(
insert) shows a typical curve-fitting plot for the fluores-
By treating one bis(b-CD) moiety in 6–9 as a host unit,
A
H
R
U
G
cence titration of CA with bis(b-CD) 2. We find that there
are no serious differences between the experimentally meas-
ured and the calculated data. When repeated measurements
A
H
R
U
G
the stoichiometric 1:2 inclusion complexation of two bile
salts (G) with a host unit (H) can be expressed by Equa-
tion (2), and the complex stability constant (K ) is given by
S
are made, the K values are reproducible within error limits
Equation (3), where [H], [G], and [H·2G] represent the
equilibrium concentrations of host unit, guest, and complex,
respectively.
S
of 5%. The K values obtained are listed in Table 1, along
S
with the free energy changes of complex formation (ꢀDG8).
Chem. Eur. J. 2006, 12, 3858 –3868
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3863

Y. Liu et al.
KS
ƒ
!
H þ2 G ƒH Á2 G
ð2Þ
ð3Þ
2
KS ¼ ½H Á2 GŠ=½HŠ½GŠ
The fluorescence intensity (F) is proportional to the con-
centration of fluorophore (c) in dilute solution [Eq. (4)].
F ¼ e c
ð4Þ
F
From Equation (4) we can obtain Equations (5) and (6).
(
In this case the guest is nonfluorescent), where [H] signi-
0
fies the initial concentration of host unit and e and e ’ rep-
F
F
resent the molar fluorescence intensities of free host unit
and inclusion complex.
F0 ¼ e ½HŠ0
ð5Þ
ð6Þ
F
ꢀ
5
ꢀ3
Figure 7. a) Fluorescence spectral changes of host 7 (1.36”10 moldm
)
0
upon addition of CA (from a to k = 0, 0.0298, 0.0745, 0.1192, 0.149,
0.2235, 0.298, 0.596, 0.745, 1.043, 1.192”10 moldm ) in Tris-HCl buffer
solution (pH 7.2) at 258C (lex = 315 nm). b) Linear least-squares analysis
F ¼ e ½HŠþe ½H Á2 GŠ ¼ e ð½HŠꢀ½H Á2GŠÞ
F
F
F
0
ꢀ
3
ꢀ3
0
0
þe ½H Á2 GŠ ¼ e ½HŠþðe ꢀe Þ½H Á2GŠ
F
F
0
F
F
S
plot to calculate the complex formation constant (K ).
By subtracting Equation (5) from Equation (6), we obtain
Equation (7), where DF and De denote the changes in the
F
fluorescence intensity and molar fluorescence intensity of
host unit upon complexation with guest molecules.
S
Table 2. Complex formation constant (K ) and Gibbs free energy change
(ꢀDG8) for the inclusion complexation of metallobridged bis
A
H
R
U
G
with bile salts in Tris-HCl buffer solution (pH 7.2) at 258C.
0
ꢀ2
ꢀDG8 [kJmolꢀ1
DF ¼ FꢀF0 ¼ ðe ꢀe Þ½H Á2 GŠ ¼ De ½H Á2 GŠ
ð7Þ
Host
Guest
S
K [m
]
logKS
]
F
F
F
7
7
7
7
7
7
7
6
CA
DCA
CA
DCA
CA
DCA
CA
5.73”10
2.03”10
9.93”10
3.47”10
3.96”10
3.78”10
2.95”10
7.76
7.31
8.00
7.54
7.60
7.58
7.47
6.79
44.26
41.70
45.62
43.02
43.35
43.23
42.62
38.76
We also have Equations (8) and (9).
7
8
9
½
HŠ ¼ ½HŠꢀ½H Á2 GŠ
ð8Þ
ð9Þ
0
½
GŠ ¼ ½GŠꢀ2 ½H Á2 GŠ
0
6
DCA
6.2”10
By combining Equations (3), (7), (8), and (9), and by ne-
2
3
glecting the terms [H·2G] and [H·2G] in a similar way to
[28]
[29]
Tamaki
and Bender
for the spectral changes on the
from either the narrow or the wide opening of the CD,
which should result in dramatically different binding behav-
ior between host and guest. It is therefore very important to
investigate the binding modes between these bis
metallobridged bis(b-CD)s and bile salts for elucidation of
complex formation, we can derive Equation (10).
2
½
HŠ½GŠ
1
½GŠð½GŠþ4 ½HŠÞ
0
0
0
0
0
¼
þ
ð10Þ
A
H
R
U
G
DF
De K
De
F
F
S
AHCTREUNG
the mechanism of molecular recognition. Figure 8 and
Figure 9 illustrate some typical H ROESY spectra for inclu-
The complex stability constant (K ) for each host–guest
S
1
combination can be determined from the approximate
sion complexation of bis(b-CD)s with bile salts. The nota-
A
H
E
N
2
linear plot of [H] [G] /DF against [G] ([G] +4[H] ).
0
0
0
0
0
tions used are Hn for CD protons and Pn for bile salt pro-
tons, where n is the carbon number indicated in the com-
pound structures above. In the control experiments the
ROESY spectra of bile salts show the intramolecular NOE
correlations between the bile salt protons, which should help
us easily recognize the NOE correlations between host and
Figure 7 illustrates typical fluorescence titration curves for
the inclusion complexation of metallobridged bis(b-CD) 7
AHCTREUNG
with CA and the curve-fitting result. The complex stability
constants (K ) and the free energy changes calculated from
S
the slope and intercept are listed in Table 2. When repeated
measurements were made the K values were reproducible
S
guest from the ROESY spectra of bis(b-CD)/bile salt com-
A
H
E
N
within error limits of 5%.
[22b]
1
plexes.
As can be seen in Figure 8, the H ROESY spec-
Binding mode: As can be seen from the compound struc-
tures above, the bile salts CA and DCA have similar frame-
works, each containing four rings (A–D) and a carboxylate
side chain, but with a small difference in the C-7 substituent
trum for the resulting complex of 3/CA in pH 7.2 buffer sol-
ution displays complicated NOE cross-peaks, which come
not only from the intermolecular correlations between b-CD
and the bile salt, but also from the intramolecular correla-
tions of 3 or CA. Among them, peak A corresponds to the
NOE correlations between the ethyleneamino protons of
the linker group and the CDꢁs H5/H6 protons, and peak C
(
R): a hydroxy group in CA and a hydrogen atom in DCA.
Upon inclusion complexation with a CD, the A-ring or the
carboxylate group of a bile salt can enter the CD cavity
3864
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Chem. Eur. J. 2006, 12, 3858 –3868

Bridged Bis(b-cyclodextrin)s with Fluorescent Oxamidobisbenzoyl Linkers
FULL PAPER
Figure 8. a) ROESY spectrum of the 3/CA complex with a mixing time
of 200 ms at 298 K. b) Possible binding mode of 3 with CA.
Figure 9. a) ROESY spectrum of the 4/CA complex with a mixing time
of 200 ms at 298 K. b) Possible binding mode of 4 with CA.
corresponds to the NOE correlations between the CAꢁs P21
protons and the CDꢁs H3/H5/H6 protons. Meanwhile, cross-
peaks B, D, and E correspond to the NOE correlations be-
tween the protons in the D-ring of CA and the CDꢁs H3
protons. These NOE correlations, along with the 1:1 binding
stoichiometry, jointly indicate a “host–linker–guest” binding
an inherent advantage for this binding mode. Under our ex-
perimental conditions, the carboxylate group of CA is not
protonated and should exist as a carboxylate anion, while
the ꢀNHꢀfragments in the linker group of bis
A
C
H
T
R
E
U
N
G
(b-CD)
should be partly protonated. Therefore, the electrostatic in-
+
teractions between the protonated amino groups (ꢀNH2 ꢀ)
[22a,c]
mode
plexation with bis
between 3 and CA. That is, upon inclusion com-
in the linker and the anionic carboxylate tail of CA may to
some extent favor the inclusion complexation of 3 with CA.
A similar binding mode is also observed for the inclusion
complexation of 3 with DCA by analysis of the ROESY
spectrum of the 3/DCA complex.
ACHTREUNG
(b-CD), the carboxylate tail and the D-
ring of CA enter into one CD cavity of 3 from the wide
opening, while the linker group of 3 is partially self-included
in the other CD cavity, as illustrated in Figure 8b. There is
Chem. Eur. J. 2006, 12, 3858 –3868
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www.chemeurj.org
3865

Y. Liu et al.
With a shallowly self-included conformation, bis
A
H
R
U
G
may consequently explain the enhanced fluorescence of bis-
2
, 4, and 5 show a binding mode different from that of 3—
A
H
R
U
G
which possesses a deeply self-included conformation—upon
inclusion complexation with bile salts. In the H ROESY
modes, the bile salt is located near to the oxamidobisbenzoyl
linker, so the fluorophore in the linker may be efficiently
protected from the deactivating water attack by steric
shielding by the closely located bulk bile salt guests. In addi-
tion, the introduction of a hydrophobic bile salt guest should
certainly increase the microenviromental hydrophobicity
around the fluorophore, which should also contribute to the
1
spectrum of the 4/CA complex (Figure 9a), peaks A, C, and
D correspond to the NOE correlations between the D-ring
protons of CA and the CDꢁs H3 protons, whilst peak B cor-
responds to NOE correlations between the CAꢁs P21 pro-
tons and the CDꢁs H3/H5/H6 protons. Moreover, a clear
cross-peak (peak E) corresponding to NOE correlation be-
tween the CAꢁs P23 protons and the aromatic protons in the
linker group of 4 is observed, while the NOE correlations
between the ethyleneamino protons of the linker group and
the CDꢁs H5/H6 protons become very weak. From these
ROESY data and the 1:1 binding stoichiometry of 4 with
CA, we can deduce a possible binding mode of 4/CA com-
plex as illustrated in Figure 9b. That is, the carboxylate tail
and D-ring of CA enter the CD cavity from the wide open-
ing, and the carboxylate tail is located close to the linker
group. On the other hand, the linker group is mostly moved
out from the CD cavity after complexation with CA. Close
examination of the ROESY spectra of 2/CA, 2/DCA, 4/
DCA, 5/CA, and 5/DCA complexes consistently demon-
strates a similar binding mode to the 4/CA complex.
enhanced fluorescence of the bis(b-CD)s.
A
H
R
U
G
Binding ability: Many investigations have demonstrated that
several weak noncovalent forces, including van der Waals
forces, hydrophobic interactions, hydrogen bonding, and
dipole–dipole interactions, contribute cooperatively to inclu-
sion complexation by CDs, and a good match of the size
and shape of the host to those of the guest should greatly
favor host–guest inclusion complexation, since the strength
of these interactions is closely related to the distance and
contact surface area between host and guest. Native and
modified monomeric CDs display relatively limited binding
ability towards guest molecules, probably because of weak
hydrophobic interactions. However, bis
A
H
R
U
G
bridged bis(b-CD)s have greatly enhanced binding abilities
AHCTREUNG
Although the paramagnetic disturbance caused by the co-
ordinated Cu ions makes it impossible to measure the
in relation to the parent CDs, owing to a multiple recogni-
II
tion mechanism. As can be seen in Table 1, the K values
S
2
D NMR spectra of metallobridged bis
A
H
R
U
G
for the inclusion complexation of CA and DCA with bis
A
C
H
T
R
E
U
N
G
(b-
3
4
ꢀ1
deduce their binding modes through their structures and
binding stoichiometries. We have demonstrated that, for the
CD)s 2–5 are in the range of 10 to 10 m , higher than the
1
3
ꢀ1
K values (10 to 10 m ) reported for the inclusion com-
S
inclusion complexation of bile salts with bis
carboxylate tails of bile salts enter the CD cavity through
A
H
R
U
G
plexation of these bile salts with native or monomodified b-
[12,22b]
CDs.
herent advantage of the cooperative “host–linker–guest”
binding mode of bis(b-CD)s 2–5. In addition to the associa-
These enhanced binding abilities highlight the in-
the wide opening, due to the electrostatic attraction from
+
the protonated amino groups (ꢀNH ꢀ) in the linker. In the
ACHTREUNG
2
cases of the metallobridged bis
A
H
R
U
G
tion of the CD cavity with a guest molecule, the linker
group provides some additional binding interactions towards
the accommodated guest. These factors jointly contribute to
trostatic attraction from the coordinated Cu ions in the
linker group may also favor the penetration of the carboxy-
late tail of bile salt into the CD cavity through the wide
opening. Moreover, the 1:2 or 2:4 binding stoichiometry in-
the stronger binding abilities achieved by bis
tion to monomeric CDs.
A
H
R
U
G
dicates that each CD cavity of a metallobridged bis
A
H
R
U
G
It is also interesting to compare the “host selectivity” se-
is occupied by a bile salt, so we can deduce the possible
binding modes of 6–9 as illustrated in Figure 10.
We have demonstrated that, upon inclusion complexation
quence for each bile salt. The order of K values for the in-
S
clusion complexation of bis
2>4>5>3. That is, the bile salts CA and DCA are better
bound by bis(b-CD) 2, which possesses the shortest linker
group, than by the long-linked bis(b-CD)s. This may be at-
tributable to the strict size-fit between these bile salts and
the short-linked bis(b-CD) 2, which consequently gives
A
H
R
U
G
with bile salts, bis
binding modes, while the metallobridged bis
adopt either the 1:2 or the 2:4 binding modes. These results
A
C
H
T
R
E
U
N
G
(b-CD)s 2–5 adopt “host–linker–guest”
ACHTREUNG
A
H
R
U
ACHTREUNG
AHCTREUNG
strong van der Waals and hydrophobic interactions between
host and guest.
Significantly, metallobridged bis
enhanced binding abilities with regard to the bis
. As can be seen in Table 2, the Gibbs free energy changes
ꢀDG8) for the inclusion complexation of 6–9 with bile salts
38.76–45.62 kJmol ) are almost twice as high as those for
ACHTREUNG
AHCTREUNG
5
(
(
ꢀ
1
ꢀ
1
the inclusion complexation of 2–5 (18.67–24.34 kJmol ) and
are even higher than our previously reported values (23.5–
ꢀ
1
3
5.6 kJmol ) for metallo biquinolino-bridged bis
A
C
H
T
R
E
U
N
G
(b-
Figure 10. Possible binding modes of metallobridged bis
bile salts.
A
H
R
U
G
[22c]
CD)s.
These significant enhancements in the binding abil-
3866
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ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 3858 –3868

Bridged Bis(b-cyclodextrin)s with Fluorescent Oxamidobisbenzoyl Linkers
FULL PAPER
ities may be attributable to a more complicated multiple
recognition mechanism involving the cooperative binding of
several CD cavities, conformation adjustment by the metal
coordination, and additional binding interactions between
the metal-coordinated linker group and the accommodated
guest molecules. Upon inclusion complexation with guest
treatment of p-toluenesulfonyl chloride with b-CD in alkaline aqueous
solution. 6-OTs-b-CD was then converted into mono(6-aminoethylami-
no-6-deoxy)-b-CD or mono(6-diethylenetriamino-6-deoxy)-b-CD in ca.
[
30]
7
0% yield upon heating in excess ethylenediamine or diethylenetriamine
[31,32]
at 708C for 7 h.
Sodium cholate (CA) and deoxycholate (DCA) were
purchased from Acros and were used as received. 6,6’-[2,2’-Oxamidobis-
II
(
benzoylaminoethyleneamino)]-6,6’-deoxy-bis
A
H
R
U
G
complex (6) were prepared by our recently reported procedures.
A
molecules, each metal-coordinated bis(b-CD) unit associates
A
H
R
U
Tris-HCl buffer solution (pH 7.2) was used as solvent throughout the
spectral measurements.
II
with two bile salts, and the coordinated Cu ions enter into
electrostatic interactions with the anionic carboxylate tails
of the accommodated bile salts. In addition, the coordina-
Apparatus: Elemental analyses were performed on a Perkin–Elmer-
2400C instrument. NMR spectra were recorded on a Varian Mercury
VX300 instrument. Circular dichroism and UV/Vis spectra were recorded
in a conventional quartz cell (light path 10 mm) on a JASCO J-715S
II
tion of Cu ions shortens the effective length of linker
group to some extent and thus improves the size relation-
ship between the host and the guest. As a cumulative result
spectropolarimeter and
a Shimadzu UV-2401PC spectrophotometer
fitted with a PTC-348WI temperature controller to keep the temperature
at 258C, respectively. Fluorescence spectra were measured in a conven-
tional quartz cell (10”10”45 mm) at 258C on a JASCO FP-750 spec-
trometer with a constant-temperature water bath, with excitation and
emission slits of 10 nm.
of these factors, metallobridged bis(b-CD)s 6–9 show much
A
H
E
G
high binding abilities than monomeric and dimeric CDs.
The importance of the multiple recognition mechanism is
more clearly demonstrated by comparing the binding abili-
6
,6’-[2,2’-Oxamidobis(benzoylaminodiethylenediamino)]- 6,6’-deoxy-bis-
ties of these bis
A
C
H
T
R
E
U
N
G
(b-CD)s and metallobridged bis(b-CD)s for
A
H
R
U
G
AHCTREUNG
(b-CD) (3): Mono(6-diethylenetriamino-6-deoxy)-b-CD (1 mmol) was
CA and DCA. As can be seen in Table 1 and Table 2, all of
the hosts examined (except for 3) display higher binding
abilities for CA than for DCA. One possible reason for the
stronger affinities for CA may involve hydrogen bond inter-
actions between the 7-hydroxy group of CA and the 2- and
dissolved in DMF (30 mL) in the presence of a small amount of 4 Š mo-
[33]
lecular sieves, and DCC (1 mmol) and 2,2’-oxamidobis(benzoic acid)
(0.5 mmol) were then added. The mixture was stirred for two days in an
ice bath and for another two days at room temperature, and was then al-
lowed to stand for 5 h until no more precipitation deposited. The precipi-
tate was removed by filtration and the filtrate was evaporated to dryness
under reduced pressure. The residue was dissolved in a minimal amount
of hot water and was then poured into acetone (150 mL), and the precipi-
tate formed was collected by filtration. This procedure was repeated
twice. The crude product obtained was purified on a column of Sepha-
3-hydroxy groups of CD. We have demonstrated that the
carboxylate tail and the D-ring of CA enter into the CD
cavity through the wide opening. In this binding mode, the
7-hydroxy group of CA is located outside the CD cavity and
dex G-25 with water as eluent. After drying in vacuo, a pure sample of 3
near to the wide opening of CD, and so can easily interact
with the 2- and 3-hydroxy groups of CD through hydrogen
bond interactions, which subsequently strengthen the host–
guest association.
1
was obtained in 27% yield. H NMR (300 MHz, D
2
2
O, TMS): d = 2.63–
(m, 2H),
7.34–7.42 (m, 2H), 7.81–7.84 (m, 2H), 8.38–8.42 ppm (m, 2H); UV/Vis
.93 (m, 16H), 3.25–3.83 (m, 84H), 4.86 (m, 14H), 7.10–7.16
ACHTREUNG
ꢀ
1
ꢀ1
(
water): lmax (e)
calcd for C108
H 6.85, N 3.19.
,6’-[4,4’-Oxamidobis(benzoylaminoethyleneamino)]-6,6’-deoxy-bis
CD) (4): Compound 4 was prepared in 25% yield from 4,4’-oxamidobis-
=
305 nm (10470m cm ); elemental analysis (%)
H
170
O
72
N
8
·19H O: C 42.19, H 6.82, N 3.64; found: C 42.29,
2
6
A
C
H
T
R
E
U
N
G
(b-
Conclusion
[
33]
A
H
R
U
G
1
In summary, we have successfully synthesized a series of bis-
cedure similar to that employed in the synthesis of 3. H NMR
300 MHz, D O, TMS): d = 2.55–3.22 (m, 8H), 3.41–3.74 (m, 84H), 4.89
(s, 14H), 7.21–7.23 (m, Ar 4H), 7.50–7.53 ppm (m, Ar 4H); UV/Vis
water): lmax (e) = 284 nm (8130m cm ); elemental analysis (%) calcd
·16H O: C 42.57, H 6.59, N 2.86; found: C 42.58, H
(
2
A
C
H
T
R
E
U
N
G
(b-CD)s bearing fluorescent oxamidobisbenzoyl linkers and
II
their Cu complexes as fluorescence sensors for the molecu-
ꢀ
1
ꢀ1
(
lar recognition of bile salts. Significantly, the introduction of
for C104
H
160
O
72
N
6
2
metal ions into bis
conformations of the bis
binding behavior of bis(b-CD)s and even change their bind-
ing stoichiometries. These results provide a convenient and
powerful method for controlling the binding behavior of di-
meric receptors in aqueous solution, which should be useful
for the design and synthesis of new supramolecular systems
and further improve understanding of molecular multiple
recognition mechanism in supramolecular systems.
A
C
H
T
R
E
U
N
G
(b-CD)s can not only alter the original
6.64, N 2.87.
6,6’-[4,4’-Oxamidobis(benzoylaminodiethylenediamino)]-6,6’-deoxy-bis
CD) (5): Compound 5 was prepared in 20% yield from 4,4’-oxamidobis-
A
H
R
U
G
A
C
H
T
R
E
U
N
G
(b-
AHCTREUNG
[33]
A
H
R
U
G
and mono(6-diethylenetriamino-6-deoxy)-b-CD by a
1
(
2
4
ꢀ
1
ꢀ1
(water): lmax(e) = 286 nm (7240m cm ); elemental analysis (%) calcd
·10H O: C 44.54, H 6.58, N 3.85; found: C 44.38, H
for C108
H
170
O
72
N
8
2
6
.47, N 4.07.
Bis(b-CD)-Cu complex 7: Bis(b-CD) 3 was added dropwise to a dilute
II
II
A
H
R
U
G
A
H
R
U
G
aqueous solution of a slight excess of Cu perchlorate in an ice/water
bath. Several drops of chloroform were further added, and the resultant
solution was kept at 58C for 2 days. The precipitate formed was collected
by centrifugation, washed successively with a small amount of ethanol
and diethyl ether, and then dried in vacuo to give complex 7 in 68%
Experimental Section
Materials: All chemicals were reagent grade and were used without fur-
ther purification unless noted otherwise. b-CD of reagent grade was re-
crystallized twice from water and dried in vacuo at 958C for 24 h prior to
use. N,N-Dimethylformamide (DMF) was dried over calcium hydride for
two days and was then distilled under reduced pressure prior to use.
ꢀ
1
ꢀ1
yield as a blue solid. UV/Vis (water): lmax (e) = 310 nm (6170m cm );
elemental analysis (%) calcd for C108 ·2Cu(ClO ·24H O: C
5.16, H 5.96, N 3.04; found: C 35.14, H 5.64, N 2.74.
H
170
O
72
N
8
A
H
R
U
G
4
)
2
2
3
II
II
Bis
A
H
R
U
G
A
H
R
U
G
Mono
A
C
H
T
R
E
U
N
G
[6-O-(p-toluenesulfonyl)]-b-CD (6-OTs-b-CD) was prepared by
58% yield as a green solid by a procedure similar to that used in the syn-
Chem. Eur. J. 2006, 12, 3858 –3868
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3867

Y. Liu et al.
ꢀ
1
ꢀ1
thesis of 7. UV/Vis (water): lmax (e) = 279 nm (8510m cm ); elemental
analysis (%) calcd for C104 ·1.5Cu(ClO ·14H O: C 36.87, H
.59, N 2.48; found: C 36.59, H 5.32, N 2.41.
[15] a) E. Rizzarelli, G. Vecchio, Coord. Chem. Rev. 1999, 188, 343–364;
b) B. Zhang, R. Breslow, J. Am. Chem. Soc. 1997, 119, 1676–1681.
[16] H. F. M. Nelissen, A. F. J. Schut, F. Venema, M. C. Feiters, R. J. M.
Nolte, Chem. Commun. 2000, 577–578.
H
160
O
72
N
6
A
H
R
U
4
)
2
2
5
II
II
Bis
A
C
H
T
R
E
U
N
G
(b-CD)-Cu complex 9: Bis(b-CD)-Cu complex 9 was prepared in
A
H
R
U
G
[
17] K. D. R. Setchell, J . M. Street, J. Sjovall in The Bile Acids, Vol. 4
(Eds.: K. D. R. Setchell, D. Kritcheveky, P. P. Nair), Plenum Press,
New York, London, 1988, Chapter 12, pp. 543.
5
0% yield as a green solid by a procedure similar to that used in the syn-
ꢀ
1
ꢀ1
thesis of 7. UV/Vis (water): lmax (e) = 280 nm (5500m cm ); elemental
analysis (%) calcd for C108 ·1.5Cu(ClO ·12H O: C 38.81, H
.85, N 3.35; found: C 38.45, H 5.83, N 3.41.
H
170
O
72
N
8
A
H
R
U
G
4
)
2
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Received: September 27, 2005
Published online: March 3, 2006
3868
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