Hydrogen bonding-mediated self-assembly of rigid and planar metallocyclophanes and their recognition for mono- and disaccharides

Article abstract of DOI:10.1016/j.tet.2004.08.099

A hydrogen bonding approach has been developed to facilitate the self-assembly of a new series of rigid and planar metallocyclophanes. Two new anthranilamide derivatives 1 and 2, which are incorporated with two acetylene units, respectively, have been synthesized and characterized. X-ray analysis (for 1), 1D and 2D ¹H NMR and IR experiments reveal that, due to the formation of intramolecular three-centered hydrogen bonding, both compounds adopt rigid and planar conformations with the two acetylene units located at the same side of the anthranilamide skeleton. Two new metallocyclophanes 17 and 18 have been constructed in moderate yields from the reaction of 1 and 2 with trans-Pt(PEt₃)₂Cl₂, respectively, in dichloromethane in the presence of diethylamine and cupric chloride. Fluorescent and ¹H NMR investigations reveal that both 17 and 18 can efficiently complex mono- and disaccharide derivatives in chloroform, with a binding selectivity for disaccharides, which is driven by intermolecular hydrogen bonding. Graphical Abstract

Full text of DOI:10.1016/j.tet.2004.08.099

Tetrahedron 60 (2004) 10253–10260
Hydrogen bonding-mediated self-assembly of rigid and planar
metallocyclophanes and their recognition for mono-
and disaccharides
a
b
b
a
Ying-Qi Chen,a, Xiao-Zhong Wang, Xue-Bin Shao, Jun-Li Hou, Xin-Zhi Chen,
*
Xi-Kui Jiangb and Zhan-Ting Lib,
*
aInstitute of Pharmaceutical Engineering, College of Materials Science and Chemical Engineering, Yuquan Campus, Zhejiang University,
Hangzhou, Zhejiang 310027, China
bShanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
Received 1 July 2004; revised 25 August 2004; accepted 27 August 2004
Abstract—A hydrogen bonding approach has been developed to facilitate the self-assembly of a new series of rigid and planar
metallocyclophanes. Two new anthranilamide derivatives 1 and 2, which are incorporated with two acetylene units, respectively, have been
synthesized and characterized. X-ray analysis (for 1), 1D and 2D 1H NMR and IR experiments reveal that, due to the formation of
intramolecular three-centered hydrogen bonding, both compounds adopt rigid and planar conformations with the two acetylene units located
at the same side of the anthranilamide skeleton. Two new metallocyclophanes 17 and 18 have been constructed in moderate yields from the
reaction of 1 and 2 with trans-Pt(PEt3)2Cl2, respectively, in dichloromethane in the presence of diethylamine and cupric chloride. Fluorescent
1
and H NMR investigations reveal that both 17 and 18 can efficiently complex mono- and disaccharide derivatives in chloroform, with a
binding selectivity for disaccharides, which is driven by intermolecular hydrogen bonding.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
project to develop new hydrogen bonding-mediated build-
ing blocks for constructing novel generation of functional
supramolecular architectures. Previously, we have reported
the self-assembly of a new class of oligoanthranilamides
whose straight, rigid, and planar conformations could be
stabilized by intramolecular three-centered hydrogen bond-
ing.6 In this paper, we report that similar approach has been
successfully utilized to control the rigid conformation of
acetylene precursors for the generation of a new series of
rigid and planar metallocyclophanes. We also report the
binding behavior of the new metallocyclophanes towards
mono- and disaccharides in chloroform.
In the past decade, the development of supramolecular
macrocyclic architectures has received intensive interest.1
Among various non-covalent forces, the coordination
bonding motif between transition metal ions and organic
ligands has proven itself to be a highly useful tool for their
preparation.2 In order to overcome the entropic disadvant-
age and to achieve high assembling efficiency, rigid
aromatic ligands are usually used. Over years a large
number of metallosupramolecular assemblies have been
constructed from covalently bonded aromatic ligands.
Nevertheless, functional metallocyclophanes are still rela-
tively rare despite their perceived advantages over the
constituent building blocks.3
2. Results and discussion
A number of metallocyclophanes have been constructed
from linear bisphenylacetylene ligands and coordinatively
unsaturated metal complexes.7 Previously, Hamilton and
Gong have revealed that intramolecular three-centered
hydrogen bonding can induce 1,3-substituted anthranila-
mide derivatives to adopt folding, rigid and planar
conformation.8 Recently, we have also reported that similar
hydrogen bonding approach could be used to induce 1,4-
substituted anthranilamides to generate unfolding, rigid and
Following the increasing applications of hydrogen bonding
for controlling the folding and unfolding conformations of
unnatural organic molecules,4,5 we had recently initiated a
Keywords: Hydrogen bonding; Self-assembly; Metallocyclophane;
Molecular recognition; Saccharide.
* Corresponding authors. Tel.: C86 571 87952693 (Y.-Q.C.); tel.: C86 21
64163300; fax: C86 21 64166128 (Z.T.L.);
e-mail addresses: yqchen@zju.edu.cn; ztli@mail.sioc.ac.cn
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.08.099

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Y.-Q. Chen et al. / Tetrahedron 60 (2004) 10253–10260
straight conformations.6 To explore the possibility of the
intramolecular three-centered hydrogen bonding to control
the rigidity and directionality of new bisphenylacetylene
ligands for self-assembly of new kinds of metallocyclo-
phanes, compounds 1 and 2 were designed and synthesized.
The two acetylene units of both compounds were expected
to be parallel to each other at the same side due to the
formation of intramolecular hydrogen bonding. Such an
arrangement should remarkably facilitate the formation of
corresponding metallocyclophanes.
selectively reduced to amine 8 in 92% yield by zinc in water
and THF solution of ammonia. Treatment of 8 with diacyl
chloride 9 in dichloromethane with triethylamine as a base
produced compound 1 in 68% yield.
For the preparation of compound 2 (Scheme 2), ester 12 was
first produced in 96% yield from the reaction of 11 and
iodine in the presence of silver sulfate in methanol. The
coupling reaction of 12 with 5, catalyzed by Pd(0), in hot
pyrrolidine produced 13 in 72% yield. Compound 13 was
then treated with potassium hydroxide in hot aqueous THF
to give 14 in 91% yield. The latter was treated with
potassium hydroxide again in hot benzene to afford 15 in
78% yield. Compound 15 was then coupled with diamine 16
in the presence of DCC and HOBt in dichloromethane to
afford 2 in 63% yield.
The synthetic route of compound 1 is shown in Scheme 1. In
brief, compound 3 was first octylated in hot DMF in the
presence of potassium carbonate to give bromide 4 in 98%
yield. The latter was then coupled with compound 5 in THF
with Pd(0) as catalyst to produce compound 6 in 68% yield.
Hydrolysis of 6 with potassium hydroxide in refluxing
benzene afforded acetylene 7 in 80% yield, which was then
Scheme 2.
1
Compounds 1 and 2 have been identified by H NMR and
MALDI-TOF mass spectroscopy, and microanalysis. 1H
NMR spectrum in chloroform-d revealed typical three-
centered hydrogen bonding for both compounds (NH: 9.90
and 9.99 ppm, respectively). 1H NMR experiments in
chloroform-d revealed very small concentration dependence
(!0.01 ppm) within the range of 20–0.3 mM and low
temperature dependence (!4.0!10K3 ppm/K within the
region of 10–55 8C) for the NH and aromatic proton signals
of both compounds.8 These observations are well consistent
with the results observed in structurally similar rigid and
straight oligoanthranilamides.6 The observations also
exclude any important intermolecular aggregation for both
1
compounds. 2D-NOESY H NMR studies in chloroform-d
(10 mM) also revealed moderate strength of NOE connec-
tions between the NH and the neighboring OCH3 and OCH2
Scheme 1.

Y.-Q. Chen et al. / Tetrahedron 60 (2004) 10253–10260
10255
signals (see the structures). In addition, all the NH stretching
frequencies (n) of their IR spectra, measured in chloroform
(4 mM) and with the KBr disk method, are !3310 cmK1
and independent of concentration changes.9 All the results
support that intramolecular three-centered hydrogen bond-
ing is formed, which induces the rigid and planar
conformation as shown in the text.
Single crystals of compound 2 were obtained by slow
evaporation of its dichloromethane and methanol solution at
room temperature. The X-ray structure of the compound is
provided in Figure 1. It can be found that the compound
adopts a nearly perfect planar conformation. The two
acetylene units are nearly parallel, located at the same side
due to the existence of two three-centered hydrogen
bonding, which is well consistent with the above spectral
observations.
Figure 1. The crystal structure of compound 2, revealing two typical three-
centered NH–O hydrogen bonds and a rigid and planar conformation.
Treatment of compounds 1 and 2 with trans-Pt(PEt3)2Cl2 in
dichloromethane in the presence of diethylamine and cupric
chloride produced metallocyclophanes 17 and 18 in 20 and
15% yields, respectively (Scheme 3).7 Both 17 and 18 are
soluble in common organic solvents such as chloroform and
dichloromethane.
Scheme 3.
(259 nm), obtained in chloroform, is significantly increased,
compared to that of their constituents 1 (258 nm) and 2
(248 nm), respectively.
Compounds 17 and 18 were identified by 1H and 13C NMR
and MALDI-TOF mass spectroscopy, and microanalysis.
1H NMR spectrum of 17 and 18 in chloroform-d showed the
signal of NH in the downfield area (9.80 and 9.97 ppm,
respectively), indicating the existence of three-centered
hydrogen bonding in the new metallocyclophanes. 2D-
NOESY 1H NMR experiments revealed NOEs between
the NH and the neighboring OCH3 and OCH2 signals, as
shown in Scheme 3. The IR spectrum obtained in chloro-
form showed the NH stretching frequency at 3330 and
3325 cmK1, respectively, which are typically those of
amides involved in intramolecular hydrogen bonding.9 All
these results indicate that the metallocyclophanes also
possess rigid and planar conformation due to the formation
of intramolecular three-centered hydrogen bonding. The
maximum absorbance wavelength of 17 (267 nm) and 18
Molecular modeling revealed that both 17 and 18 possess a
rigid cavity with all the C]O oxygen located to the center
of the cavity. The distances between the two Pt atoms are
˚
about 12.3 and 10.6 A in 17 and 18, respectively, whereas
the distances between the two oxygen atoms of one side are
˚
about 12.9 and 13.8 A, respectively. Such an arrangement of
all the carbonyl groups with the oxygen atoms pointing to
the inner of the cavity is very favorable for binding multi-
hydroxyl molecules. The binding behaviors of metallo-
cyclophanes 17 and 18 towards mono- and disaccharide
derivatives 19–25 were then investigated in chloroform.10
The long aliphatic chains were introduced into the
saccharides to provide solubility in less polar solvents like
chloroform. Compounds 19–23 and 25 were prepared
according to reported methods, while the synthetic route

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Y.-Q. Chen et al. / Tetrahedron 60 (2004) 10253–10260
remarkably upon addition of 17 or 18. These observations
indicate that the metallocyclophanes are able to complex the
saccharides in chloroform. Job’ plots for the mixture
solution of 17 with 21 in chloroform-d revealed largest
1
downfield shifting for the CH2OH signal in the H NMR
spectrum when the ratio of 17 and 21 is 1:1,11 which
supported a 1:1 binding stoichiometry between the metallo-
cyclophane and the saccharide. Similar 1:1 stoichiometry
was also observed with the fluorescent method for the
system of 17 and 24. Quantitative binding studies were then
1
preformed with both the fluorescent and H NMR titration
methods,12 and the corresponding association constants
K
assoc were derived by fitting the data to a 1:1 binding mode,
which are listed in Table 1. As an example, the plot of the
emission intensity of 17 vs [25] in chloroform is provided in
Figure 2.
Figure 2. Fluorescent spectra of metallocyclophane 17 (5.5!10K5 M,
excitation wavelengthZ375 nm) in chloroform at 23 8C, increased
gradually with the addition of disaccharide 25 (from 0 to 1.2!10K3 M).
It can be found that both 17 and 18 exhibit greater binding
ability for disaccharides than for monosaccharides. This
selectivity might suggest that, in addition to the expected
binding between the C]O and OH groups, the OH groups
of the longer disaccharides can also bind the ether oxygen or
amide nitrogen of 17 and 18. Table 1 also shows that, for all
the saccharide guests, 17 displays greater binding ability
than 18, which may be ascribed to its larger cavity and
consequently a reduced hindrance of the PEt3 units. Since
the binding between the metallocyclophanes and the
saccharides are a dynamic process, we are not able to
establish the exact binding pattern of the complexes at the
present stage, but the 1:1 binding mode seems to indicate
that the binding takes place in the cavity of the
metallocyclophanes. The binding ability of 1 and 2 towards
19 was also investigated in chloroform-d with the 1H NMR
titration method, which gave a Kassoc value of 58 and
32 MK1 for complexes 1$19 and 2$19, respectively.
Scheme 4.
for compound 24 is provided in Scheme 4. Initially, we had
tried to prepare the n-dodecyl derivative of lactose similar to
other saccharides, which was found to be insoluble in
chloroform.
Adding 19–25 to the solution of 17 or 18 in chloroform led
to important increase of the fluorescent emission of both
1
compounds. The hydroxyl signals of the saccharides in H
NMR spectrum in chloroform-d also moved downfield
Table 1. Association constants Kassoc (MK1) of complex between 17 and 18 and mono- and disaccharide derivatives 19–25 in chloroform at 23 8Ca
17
18
17
18
19
20
20b
21
1.4!103
5.6!103
5.4!103
3.4!103
7.4!102
2.1!103
2.4!103
1.1!103
22
23
24
25
3.0!103
6.4!103
2.5!104
4.3!104
9.4!102
2.9!103
9.4!103
7.8!103
a
With error of less than 20%.
Determined by the 1H NMR titration method.
b

Y.-Q. Chen et al. / Tetrahedron 60 (2004) 10253–10260
10257
1
3. Conclusion
yellow oil (7.57 g, 98%). H NMR (CDCl3, 300 MHz): d
0.85–0.90 (m, 3H), 1.27–1.48 (m, 10H), 1.79–1.84 (m, 2H),
4.06 (t, JZ6.2 Hz, 2H), 6.96 (d, JZ6.6 Hz, 1H), 7.59 (d, d,
J1Z6.6 Hz, J2Z2.2 Hz, 1H), 7.93 (d, JZ2.2 Hz, 1H). MS
(EI): m/z 329 [M]C. Anal. Calcd for C14H20BrNO3: C,
50.92; H, 6.10. Found: C, 51.14; H, 6.22.
In summary, we have demonstrated that intramolecular
hydrogen bonding can be utilized to rigidify the confor-
mation of bisphenylacetylene building blocks and conse-
quently facilitate the self-assembly of a new series of rigid
and planar metallocyclophanes. The hydrogen bonded
metallocyclophanes represent a new series of synthetic
receptors for saccharide derivatives albeit in the less polar
chloroform. In principle, the spatial separation of the two
acetylene units in the assembled building blocks can be
increased conveniently by introducing longer oligo-anthra-
nilamide linkers, which would lead to the formation of new
metallocyclophanes with extended cavity size. Moreover,
replacing the acetylene units with other functional groups
such as pyridyl units would also provide new opportunity to
construct other kinds of metallocyclophanes. Investigations
along these lines are being performed in our laboratory.
4.1.3. 2-Methyl-4-(3-nitro-4-octyloxy-phenyl)-but-3-yn-
2-ol (6). To a solution of compounds 4 (2.10 g,
6.30 mmol) and 5 (0.87 g, 10.0 mmol) in THF (30 mL)
was added [Pd(PPh3)4] (0.24 g, 0.30 mmol, 5%), CuI
(60.0 mg, 0.30 mmol) and triethylamine (2.0 mL). The
reaction mixture was stirred at 50 8C for 12 h and then
poured into concentrated in vacuo. The resulting residue
was triturated with ethyl acetate (150 mL) and the organic
phase was washed with water (50 mL), brine (50 mL), dried
over sodium sulfate. After removal of the solvent under
reduced pressure, the resulting brown oil was subjected to
flash chromatography (CH2Cl2/petroleum ether 1:2) to give
compound 6 (1.43 g, 68%) as a yellow oil. 1H NMR (CDCl3,
300 MHz):d 0.86–0.90 (m, 3H), 1.27–1.50 (m, 10H), 1.61
(s, 6H), 1.80–1.85 (m, 2H), 4.09 (t, JZ6.5 Hz, 2H), 6.99 (d,
JZ6.6 Hz, 1H), 7.53 (d, d, J1Z6.5 Hz, J2Z2.2 Hz, 1H),
7.87 (d, JZ2.2 Hz, 1H). MS (EI): m/z 333 [M]C. Anal.
Calcd for C19H27NO4: C, 68.44; H, 8.16; N, 4.20. Found: C,
68.12; H, 8.04; N, 4.05.
4. Experimental
4.1. General methods
1
The H NMR spectra were recorded on 400 or 300 MHz
spectrometers in the indicated solvents. Chemical shifts are
expressed in parts per million (d) using residual solvent
protons as internal standards. Chloroform (d 7.26 ppm) was
used as an internal standard for chloroform-d. Elemental
analysis was carried out at the SIOC Analytical Center.
Unless otherwise indicated, all commercially available
materials were used as received. All solvents were dried
before use following standard procedures. All reactions
were carried out under an atmosphere of nitrogen. Silica gel
(1–4 m) was used for column chromatography. Compounds
19,13 20,14 21,15 22,16 23,17 2518 were prepared according to
reported methods.
4.1.4. 4-Ethynyl-2-nitro-1-octyloxy-benzene (7). A sus-
pension of compound 6 (1.20 g, 3.60 mmol) and potassium
hydroxide (0.28 g, 5.00 mmol) in benzene (60 mL) was
refluxed for 3 h and then concentrated in vacuo. The
resulting residue was triturated with dichloromethane
(60 mL) and the organic phase was washed with dilute
hydrochloric acid (1 N, 20 mL), water (20 mL), brine
(20 mL), and dried over sodium sulfate. After removal of
the solvent in vacuo, the crude product was purified with
column chromatography (CH2Cl2/petroleum ether 1:3) to
afford compound 7 as a yellow solid (0.81 g, 80%). 1H NMR
(CDCl3, 300 MHz): d 0.86–0.90 (m, 3H), 1.25–1.49 (m,
10H), 1.78–1.88 (m, 2H), 3.07 (s, 1H), 4.10 (t, JZ6.5 Hz,
2H), 7.00 (d, JZ6.6 Hz, 1H), 7.59–7.62 (d, d, J1Z6.6 Hz,
J2Z2.2 Hz, 1H), 7.94 (d, JZ2.2 Hz, 1H). MS (EI): m/z 275
[M]C. Anal. Calcd for C16H21NO3: C, 69.79; H, 7.69; N,
5.09. Found: C, 70.02; H, 7.81; N, 4.97.
4.1.1. 4-Bromo-2-nitro-phenol (3). A suspension of
4-bromophenol (6.92 g, 40.0 mmol), oxone (24.4 g,
40.0 mmol), wet silica gel (0.40 g) and sodium nitrile
(2.76 g, 40.0 mmol) in dichloromethane (120 mL) was
stirred at room temperature for 2 h. The solid was filtered
and the filtrate was washed with water (30 mL!3), brine
(30 mL), dried over sodium sulfate, and evaporated in
vacuo. The resulting residue was recrystallized from ethanol
to afford compound 3 as a yellow sheet crystal (7.60 g,
88%). Mp 88–89 8C (87 8C, lit.19). 1H NMR (CDCl3,
300 MHz): d 7.07–7.10 (d, JZ6.5 Hz, 1H), 7.67 (d, d,
J1Z6.5 Hz, J2Z2.2 Hz, 1H), 8.25 (d, JZ2.2 Hz, 1H), 10.5
(s, 1H). MS (EI): m/z 219 [M]C.
4.1.5. 5-Ethynyl-2-octyloxy-phenylamine (8). To a sol-
ution of compound 7 (0.70 g, 2.50 mmol) in THF (20 mL)
was added zinc powder (0.65 g, 10.0 mmol) and concen-
trated ammonia solution (30 mL). The mixture was stirred
under reflux 3 h. After the solid was filtered, the filtrate was
concentrated in vacuo and the resulting residue triturated
with dichloromethane (150 mL). The organic phase was
washed with aqueous sodium carbonate (0.5 N, 50 mL),
water (50 mL), brine (50 mL), and dried over sodium
sulfate. The solvent was then distilled under reduced
pressure, the crude product was subjected to flash
chromatography (CH2Cl2/petroleum ether 1:2.5) to give
4.1.2. 4-Bromo-2-nitro-1-n-octyloxy-benzene (4). A mix-
ture of compound 2 (5.00 g, 25.0 mmol), 1-bromooctane
(6.00 g, 30.0 mmol) and potassium carbonate (4.00 g,
30.0 mmol) in DMF (80 mL) was stirred at 100 8C for 2 h,
and then poured into water (250 mL). The mixture was
extracted with ethyl acetate (75 mL!3) and the combined
organic phase was washed with water (100 mL), brine
(100 mL), and dried over sodium sulfate. After the solvent
was removed under reduced pressure, the resulting crude
product was purified with column chromatography
(petroleum ether/AcOEt 8:1) to give compound 4 as a
1
compound 8 (5.62 g, 92%) as a pale yellow oil. H NMR
(CDCl3, 300 MHz): d 0.87–0.91 (m, 3H), 1.26–1.48 (m,
10H), 1.76–1.85 (m, 2H), 2.94 (s, 1H), 3.81 (br, 2H), 3.98
(t, JZ6.4 Hz, 2H), 6.68 (d, JZ6.6 Hz, 1H), 6.85 (d, d, J1Z
6.6 Hz, J2Z2.2 Hz, 1H), 6.89 (d, JZ2.2 Hz, 1H). MS (EI):

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Y.-Q. Chen et al. / Tetrahedron 60 (2004) 10253–10260
m/z 245 [M]C. Anal. Calcd for C16H23NO: C, 78.32; H,
9.45; N, 5.71. Found: C, 78.22; H, 9.43; N, 5.69.
Calcd for C21H30O4: C, 72.80; H, 8.73. Found: C, 72.67; H,
8.88.
4.1.6. N,N0-bis-(5-Ethynyl-2-octyloxy-phenyl)-4,6-bis-
octyloxy-isophthalamide (1). Compound 9 was prepared
from the reaction of oxalyl chloride and the corresponding
diacid20 in the presence of catalytic amount of DMF. After
the volatile materials were removed under reduced pressure,
the resulting oily compound 9 was used for the next step
with further purification. To a solution of compound 9
(0.30 g, 0.29 mmol) in dichloromethane (30 mL) was added
a solution of compound 8 (0.15 g, 0.61 mmol) and
triethylamine (0.5 mL). After stirring at room temperature
for 0.1 h, the mixture was washed with water, brine, dried
over sodium sulfate. Upon removal of the solvent under
reduced pressure, the resulting brown oil was subjected to
flash chromatography (CH2Cl2/EtOAc 100:1) to give 1
4.1.9. 5-(3-Hydroxy-3-methyl-but-1-ynyl)-2-octyloxy-
benzoic acid (14). Compound 13 (2.00 g, 5.80 mmol) and
potassium hydroxide (0.56 g, 10.0 mmol) were added to a
mixture of methanol (50 mL) and water (20 mL). The
mixture was stirred under reflux for 2 h and concentrated to
about 20 mL. The solution was neutralized with dilute
hydrochloric acid (2 N) and then extracted with dichloro-
methane (30 mL!2). The combined organic phase was
washed with water (20 mL!3), brine (20 mL), and dried
over sodium sulfate. Upon removal of the solvent under
reduced pressure, the resulting brown residue was subjected
to flash chromatography (CH2Cl2/EtOAc 10:1) to give
1
intermediate 14 (1.75 g, 91%) as a yellow oil. H NMR
(CDCl3, 300 MHz): d 0.85–0.90 (m, 3H), 1.25–1.49 (m,
10H), 1.60 (s, 6H), 1.88–1.93 (m, 2H), 4.22–4.26 (t, JZ
6.6 Hz, 2H), 6.96 (d, JZ6.4 Hz, 1H), 7.56 (d, d, J1Z6.4 Hz,
J2Z2.3 Hz, 1H), 8.22 (d, JZ2.3 Hz, 1H). MS (EI): m/z 332
[M]C. Anal. Calcd for C20H28O4: C, 72.26; H, 8.49. Found:
C, 72.27; H, 8.64.
1
(0.18 g, 68%) as a light green solid. Mp 201 8C. H NMR
(CDCl3, 300 MHz): d 0.84–0.88 (m, 12H), 1.25–1.43 (m,
40H), 1.77–1.82 (m, 4H), 1.89–1.94 (m, 4H), 2.98 (s, 2H),
4.04 (t, JZ6.6 Hz, 4H), 4.22 (t, JZ6.5 Hz, 4H), 6.49 (s,1H),
6.78 (d, JZ6.5 Hz, 2H), 7.17 (d, d, J1Z6.5 Hz, J2Z2.2 Hz,
2H), 8.80 (d, JZ2.2 Hz, 2H), 9.07 (s, 1H), 9.80 (s, 2H). IR:
n 3315, 3224, 2955, 2925, 2854, 2103, 1664, 1580, 1537,
1423, 1232, 1021, 799, 676 cmK1. MS (MALDI-TOF): m/z
877 [M]C. Anal. Calcd for C56H80N2O6: C, 76.67; H, 9.19;
N, 3.19. Found: C, 76.35; H, 8.98; N, 3.42.
4.1.10. 5-Ethynyl-2-octyloxy-benzoic acid (15). To a
solution of acid 13 in benzene (80 mL) was added potassium
hydroxide (0.56 g, 10.0 mmol). The mixture was refluxed
for 3 h. After normal workup, the crude product was
chromatographed (CH2Cl2) to afford compound 15 as a pale
yellow solid (1.50 g, 78%). Mp 63–64 8C. 1H NMR (CDCl3,
300 MHz): d 0.86–0.90 (m, 3H), 1.25–1.48 (m, 10H), 1.89–
1.94 (m, 2H), 3.06 (s, 1H), 4.26 (t, JZ6.5 Hz, 2H), 6.99 (d,
JZ6.6 Hz, 1H), 7.64 (d, d, J1Z6.5 Hz, J2Z2.2 Hz, 1H),
8.32 (d, JZ2.2 Hz, 1H), 10.84 (br, 1H). MS (EI): m/z 274
[M]C. Anal. Calcd for C17H22O3: C, 74.42; H, 8.08. Found:
C, 74.30; H, 8.17.
4.1.7. 5-Iodo-2-octyloxy-benzoic acid methyl ester (12). A
mixture of compound 1120a (14.0 g, 53.0 mmol), iodine
(14.0 g, 55.0 mmol) and silver sulfate (17.0 g, 55.0 mmol)
in methanol (200 mL) was stirred at room temperature for
0.5 h and then concentrated in vacuo. The resulting residue
was triturated with ethyl acetate (300 mL). The organic
phase was washed with water (120 mL!2), brine (120 mL),
and dried over sodium sulfate. After the solvent was
distilled under reduced pressure, the resulting residue was
subjected to flash chromatography (dichloromethane) to
4.1.11. N,N0-bis-(5-Ethynyl-2-octyloxy-benzoyl)-4,6-bis-
methoxy-1,3-phenylenediamine (2). A solution of com-
pounds 15 (0.14 g, 0.50 mmol) and 1621 (42.0 mg,
0.25 mmol), in dichloromethane (20 mL) was stirred in ice
bath for 30 min. A solution of HOBt (90.0 mg, 0.58 mmol)
and DCC (0.12 g, 0.58 mmol) in dichloromethane (10 mL)
was added. Stirring was continued for another 12 h and the
solid was filtered. The filtrate was evaporated in vacuo and
the resulting residue was purified by column chromato-
graphy (silica gel, CH2Cl2/EtOAc 10:1) to give compound 2
as a yellow solid (0.11 g, 63%). Mp 197 8C. 1H NMR
(CDCl3, 300 MHz): d 0.84–0.88 (m, 6H), 1.25–1.51 (m,
20H), 1.92–2.01 (m, 4H), 3.01 (s, 2H), 3.90 (s, 6H), 4.18 (t,
JZ6.6 Hz, 4H), 6.54 (s, 1H), 6.93 (d, JZ6.5 Hz, 2H), 7.54
(d, d, J1Z6.5 Hz, J2Z2.2 Hz, 2H), 8.50 (d, JZ2.2 Hz, 2H),
9.53 (s, 1H), 9.97 (s, 2H). IR: n 3351, 3298, 3251, 2106,
1
give compound 12 (19.9 g, 96%) as a pale yellow oil. H
NMR (CDCl3, 300 MHz): d 0.85–0.90 (m, 3H), 1.25–1.48
(m, 10H), 1.76–1.83 (m, 2H), 3.87 (s, 3H), 3.98 (t, JZ
6.4 Hz, 2H), 6.72 (d, JZ6.6 Hz, 1H), 7.68 (d, d, J1Z6.6 Hz,
J2Z2.2 Hz, 1H), 8.04 (d, JZ2.2 Hz, 1H). MS (EI): m/z 390
[M]C. Anal. Calcd for C16H23IO3: C, 49.24; H, 5.94. Found:
C, 49.11; H, 6.21.
4.1.8. 5-(3-Hydroxy-3-methyl-but-1-ynyl)-2-octyloxy-
benzoic acid methyl ester (13). A suspension of
compounds 12 (4.00 g, 10.3 mmol), 5 (1.30 g, 15.0 mmol),
Pd(PPh3)4 (0.38 g, 0.50 mmol, 5%), and CuI (0.10 g,
0.50 mmol) in pyrrolidine (30 mL) was stirred at 60 8C for
2 h and then concentrated under reduced pressure. The
resulting residue was triturated with ethyl acetate (150 mL)
and the organic phase was washed with dilute hydrochloric
acid (1 N, 50 mL), water (50 mL), brine (50 mL), and dried
over sodium sulfate. After the solvent was distilled under
reduced pressure, the resulting crude product was subjected
to flash chromatography (CH2Cl2) to give compound 13
(2.58 g, 72%) as a yellow oil. 1H NMR (CDCl3, 300 MHz):
d 0.86–0.90 (m, 3H), 1.28–1.50 (m, 10H), 1.60 (s, 6H),
1.77–1.84 (m, 2H), 3.87 (s, 3H), 4.02 (t, JZ6.6 Hz, 2H),
6.88 (d, JZ6.5 Hz, 1H), 7.47 (d, d, J1Z6.5 Hz, J2Z2.2 Hz,
1H), 7.85 (d, JZ2.2 Hz, 1H). MS (EI): m/z 346 [M]C. Anal.
1662, 1542, 1470, 1421, 1249, 1201, 1027, 810, 684 cmK1
.
MS (MALDI-TOF): m/z 680 [M]C, 703 [MCNa]C, 719
[MCK]C. Anal. Calcd for C42H52N2O6: C, 74.08; H, 7.70;
N, 4.11. Found: C, 74.05; H, 7.73; N. 3.82.
4.1.12. Metallocyclophane 17. To a solution of compounds
1 (0.10 g, 0.11 mmol) and trans-PtCl2(PEt3)2 (60.0 mg,
0.11 mmol) in dichloromethane (100 mL) was added
diethylamine (0.5 mL) and cupric chloride (5 mg) with
stirring. The mixture was stirred at room temperature for
12 h and washed with dilute hydrochloric acid (1 N, 20 mL),

Y.-Q. Chen et al. / Tetrahedron 60 (2004) 10253–10260
10259
water (20 mL!3), brine (30 mL), and dried over sodium
sulfate. The solvent was removed in vacuo and the resulting
residue purified by column chromatography (CH2Cl2/
MeOH 200:1) to afford compound 17 as a light yellow
solid (58 mg, 20%). Mp 253 8C (decomp.). 1H NMR
(CDCl3, 300 MHz): d 0.84–0.88 (m, 24H), 1.19–1.44 (m,
116H), 1.77–1.82 (m, 8H), 1.93–1.98 (m, 8H), 2.22–2.29
(m, 24H), 4.05 (t, JZ6.5 Hz, 8H), 4.26 (t, JZ6.6 Hz, 8H),
6.53 (s, 2H), 6.72 (d, JZ6.5 Hz, 4H), 6.95 (d, d, J1Z6.5 Hz,
J2Z2.2 Hz, 4H), 8.78 (d, JZ2.2 Hz, 4H), 9.27 (s, 2H), 9.90
(s, 4H). 13C NMR (CDCl3): d 8.1, 8.5, 14.2, 16.3, 16.5, 16.7,
22.6, 22.7, 22.71, 25.9, 25.9, 28.9, 29.3, 29.3, 29.4, 29.4,
29.5, 29.8, 31.8, 31.8, 31.9, 68.9, 70.0, 111.0, 116.7, 128.7,
145.5, 159.6, 162.0. IR: n 3358, 2958, 2928, 2855, 2101,
1666, 1577, 1531, 1481, 1230, 1035, 766, 670 cmK1. MS
(MALDI-TOF): m/z 2613 [MCH]C. Anal. Calcd for
C136H216N4O12P4Pt2: C, 62.46; H, 8.37; N, 2.14. Found:
C, 62.72; H, 8.53; N, 2.05.
the solvent was removed under reduced pressure. The
resulting residue was triturated with chloroform (100 mL)
and the organic phase was washed with water (20 mL!3),
brine (20 mL) and dried over magnesium sulfate. Upon
removal of the solvent with a rotavapor, the resulting crude
product was purified by column chromatography (CH2Cl2/
MeOH 8:1) to give 24 as a white solid (0.14 g, 67%). Mp
134 8C. 1H NMR (CDCl3, 300 MHz): d 0.88–0.92 (m, 6H),
1.29–1.37 (m, 34H), 1.59–1.63 (m, 4H), 2.45–2.48 (t, JZ
5.3 Hz, 2H), 3.29–3.31 (m, 4H), 3.47–3.60 (m, 8H), 3.71–
3.87 (m, 6H), 4.36–4.385 (d, JZ5.7 Hz, 1H). MS (ESI): m/z
692 [MCH]C. Anal. Calcd for C36H69NO11$H2O: C, 60.90;
H, 10.08; N, 1.97. Found: C, 60.72; H, 10.02; N. 1.87.
4.1.16. Crystal data for compound 1. C43H54N2O6Cl2,
˚
MZ765.78, triclinic, space group P-1, aZ11.415(4) A, bZ
˚
˚
12.505(4) A, cZ15.308(5) A, aZ94.678(7), bZ99.096(7),
3
˚
gZ103.542(6), UZ2081.7(12) A , ZZ2, calcd densityZ
1.222 Mg/m3, absorption coefficientZ0.204 mmK1, 12,824
reflections collected (unique 9300), RintZ0.1294, crystal
size: 0.488!0.350!0.148 mm.
4.1.13. Metallocyclophane 18. A suspension of compounds
2 (0.10 g, 0.16 mmol), trans-PtCl2(Et3P)2 (83.0 mg,
0.16 mmol), cupric acid (5.0 mg), and diethylamine
(0.5 mL) in dichloromethane (150 mL) was stirred at
room temperature for 12 h. After workup as described 17,
the resulting crude product was purified by column
chromatography (CH2Cl2/MeOH 40:1) to afford 18 as a
light yellow solid (52 mg, 15%). Mp 250 8C (decomp.). 1H
NMR (CDCl3, 300 MHz): d 0.84–0.88 (m, 12H), 1.21–1.50
(m, 80H), 1.95–2.00 (m, 8H), 2.20–2.28 (m, 24H), 3.90
(s,12H), 4.14 (t, JZ6.6 Hz, 8H), 6.54 (s, 2H), 6.82 (d, JZ
6.3 Hz, 4H), 7.29 (d, d, J1Z6.3 Hz, J2Z2.2 Hz, 4H), 8.38
(d, JZ2.2 Hz, 4H), 9.99 (s, 2H), 10.15 (s, 4H). 13C NMR
(CDCl3): d 9.7, 15.4, 17.5, 17.7, 18.0, 24.0, 27.2, 30.5, 30.6,
30.7, 33.1, 56.9, 70.8, 96.2, 101.5, 113.2, 122.8, 123.4,
135.6, 137.5, 146.1, 155.7, 163.7. IR: n 3353, 2960, 2929,
2855, 2101, 1666, 1542, 1469, 1421, 1201, 1036, 768,
733 cmK1. MS (MALDI-TOF): m/z 2242 [MCK]C. Anal.
Calcd for C108H160N4O12P4Pt2: C, 58.42; H, 7.26; N, 2.52.
Found: C, 58.76; H, 6.90; N, 2.14.
4.1.17. Binding studies. For the fluorescent titration
experiments, 2.5 mL of the mixture solution with the fixed
concentration of 17 or 18 and the changing concentration of
saccharide guests was placed in a cuvette and the fluorescent
spectra (usually 15–20 spectra) were sequentially recorded
at 23 8C. The values of the emission strength at fixed
wavelengths were used. Origin 6.0 software was used to fit
the data to a 1:1 binding isotherm: DIZ(DImax/[H])!
{0.5[G]C0.5([H]CKd)-0.5[[G]2C(2[S](Kd-[H])C(KdC
[H])2)1/2]}, where [H] is the concentration of metallocyclo-
phane, [G] is the concentration of saccharide, and KdZ
(Kassoc)
K1. Association constants reported are the average
values of two experiments. The 1H NMR titration followed
the same principle.
Acknowledgements
4.1.14. Compound 28. The method by Stadler et al. was
used to prepare this compound.22 A mixture of lactose 26
(1.70 g, 5.00 mmol) and lauryl amine 27 (1.00 g,
5.50 mmol) in methanol (10 mL) was stirred at 65 8C
overnight and then concentrated under reduced pressure.
The resulting residue was subject to column chromato-
graphy (CH2Cl2/MeOH 2:1) to afford compound 28 as a
pale yellow solid (1.35 g, 53%). 1H NMR (CD3OD,
300 MHz): d 0.88–0.93 (m, 3H), 1.29–1.37 (m, 18H),
1.509–1.52 (m, 2H), 2.58–2.67 (m, 1H), 2.84–2.91 (m, 1H),
3.10–3.16 (t, JZ4.6 Hz, 1H), 3.30–3.31 (m, 2H), 3.33–3.37
(m, 1H), 3.49–3.60 (m, 4H), 3.70–3.87 (m, 5H), 4.34–4.37
(d, JZ5.0 Hz, 1H). MS (ESI): m/z 510 [MCH]C.
C24H47NO10: C, 56.56; H, 9.30; N, 2.75. Found: C, 55.67;
H, 9.43; N, 2.62.
We thank the Ministry of Science and Technology (No.
G2000078101), the National Natural Science Foundation,
and the State Laboratory of Bioorganic and Natural
Products Chemistry of China for support of this work.
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