New water-soluble iminecalix[4]arene with a deep hydrophobic cavity

Article abstract of DOI:10.1016/j.tetlet.2009.10.058

We report the synthesis of a new water-soluble iminecalix[4]arene host 4c with a deep hydrophobic cavity. The negatively charged four carboxylate functions on the top of the cavity play a major role in the recognition of charged molecular species. The

Full text of DOI:10.1016/j.tetlet.2009.10.058

Tetrahedron Letters 50 (2009) 7346–7350
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Tetrahedron Letters
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New water-soluble iminecalix[4]arene with a deep hydrophobic cavity
Satish Balasaheb Nimse a, Junghoon Kim b, Van-Thao Ta a, Hyung-Sup Kim b, Keum-Soo Song b,
Chan-Yong Jung b, Van-Thuan Nguyen a, Taisun Kim a,
*
a Institute for Applied Chemistry and Department of Chemistry, Hallym University, Chuncheon 200-702, Republic of Korea
b Biometrix Technology, Inc., 202 BioVenture Plaza, Chuncheon 200-161, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
We report the synthesis of a new water-soluble iminecalix[4]arene host 4c with a deep hydrophobic cav-
ity. The negatively charged four carboxylate functions on the top of the cavity play a major role in the
recognition of charged molecular species. The 1H NMR titration experiments revealed that host 4c binds
with cationic (10–12) and neutral guests (6–9) in water with high binding constants in the order of 104–
105 MÀ1. Cationic guest 9 showed highest binding constant of 2.81 Â 105 MÀ1 with host 4c amongst all
tested guests. Selectivity over anionic guests (13–17) is established by the presence of negative charges
at the top of the deep hydrophobic cavity, as guests 15 and 17 were not recognized by host 4c. Neutral
pyridine derivatives with hydrophobic chains at para positions showed high binding constants of
6.02 Â 104–2.23 Â 105 MÀ1. The data obtained for the recognition of the guests by host 4c revealed that
the ionic as well as the hydrophobic–hydrophobic interactions are crucial in the molecular recognition in
aqueous medium.
Received 28 September 2009
Accepted 13 October 2009
Available online 31 October 2009
Keywords:
Molecular recognition
Host–guest chemistry
Calix[4]arenes
Hydrophobic cavity
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
constants. Low binding ability of anionic guests 13–17 was attrib-
uted to the negative charges positioned on the top of the deep
Calix[4]arene and its functionalized derivatives represent an
important class of supramolecules having enormous applica-
tions.1,2 Owing to their relatively easy synthesis and high versatil-
ity, Schiff base derivatives of calix[4]arenes have been used as
molecular platforms in the development of artificial receptors for
recognition of neutral and charged molecular species.3,4
Though generally examined for recognition behavior in the or-
ganic mediums, the development of calix[4]arenes Schiff base
derivatives for recognition of aromatic guests in aqueous medium
is comparatively nascent.5 The recognition of aromatic guest mol-
ecules by synthetic hosts in aqueous medium, where the entire
biological process takes place, is of particular interest in host–guest
chemistry.6,7
In this context, a new molecular host with four carboxylate
groups on the top of the deep hydrophobic cavity generated by
Schiff base functions on the wide rim of calix[4]arene seems to
be promising for the recognition of the neutral as well as cationic
aromatic guests. Pyridine derivatives have been extensively stud-
ied as guest molecules. When protonated, these guest molecules
showed strong binding toward hosts, while merely recognized in
their neutral forms.8 We describe herein a deep hydrophobic pock-
et synthetic receptor 4c that binds cationic aromatic guests (10–
12) and neutral pyridine guests (6–9) in water with high binding
hydrophobic cavity.
The iminecalix[4]arene derivatives 2a–c, obtained by selective
modification of the wide rim of aminocalix[4]arene9 keeping nar-
row rim free for further modifications, were used as precursors.10
As shown in Scheme 1, the reaction of iminecalix[4]arenes 2a–c
with ethyl 2-bromoacetate in acetonitrile in the presence of K2CO3
at 80 °C afforded compounds 3a–c with 86.36–87.23% yields.11
The synthesis of the target host 4c is depicted in Scheme 1. The
hydrolysis of compound 3c in THF–water mixture using sodium
hydroxide as a base led to the formation of host 4c as a salt in a
good yield.12 The residual THF in completely dried host 4c was
found difficult to be eliminated and hence the obtained material
was used as it is. The imine bonds were reported to be unstable un-
der acidic conditions.13 Therefore, the whole process to obtain host
4c was carried out under basic environment at 5–10 °C. The nega-
tive charges on the wide and the narrow rim of 4c enable its solu-
bility in water (0.02 M) at pH/pD 8.5. The products of alkaline
hydrolysis of compounds 3a and 3b were insoluble in aqueous
alkaline solutions.
All the compounds shown in Scheme 1 were characterized by
analysis of their 1H NMR, 13C NMR, and MALDI-TOF spectra. The
tetra o-alkylation of compound 2c was established from the close
observation of 1H NMR signals in compound 3c for singlet of imine
protons, singlet of calixarene aromatic protons, pair of doublets for
methylene bridge protons of calix[4]arene, and singlet of methy-
lene protons on 2-ethoxy-2-oxoethoxy functions. These protons
* Corresponding author. Fax: +82 33 256 3421.
E-mail address: tskim@hallym.ac.kr (T. Kim).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.058

S. B. Nimse et al. / Tetrahedron Letters 50 (2009) 7346–7350
7347
Scheme 1. Reagents and conditions: (i) R–Ph–CHO, CH3CN, N2, 2 h, 92.45–95.72%; (ii) Br–CH2COOCH2CH3, K2CO3, CH3CN, N2, 80 °C, 8 h, 86.36–87.23%; (iii) aq NaOH, THF–
water (2:1).
appeared at d = 8.47 ppm, d = 7.16 ppm, d = 4.36, and d = 3.59 ppm,
respectively, in a ratio of 1:2:1:1:2. The tetra o-alkylation was also
confirmed from 1H NMR spectrum of 3c which showed the absence
of phenolic hydroxyl group peak at d = 10.15 ppm observed in
starting compound 2c. Similar patterns were found for compounds
3a and 3b.
The 1H NMR titration experiments indicated that the signals for
the protons of guests 6–12, 14, 16, and 17 were markedly affected
by the addition of host 3c, whereas there was no change in the pro-
tons of guests 13 and 15. Host 5 showed significant recognition
properties for guests 10, 11, 12, and 16 amongst all tested guests.
As shown in Figure 1, the signals for the methyl and methylene
protons at d = 1.13 ppm and d = 2.61 ppm, respectively, in guest 8
and the signal for the proton para to the trimethylammoniomethyl
moiety at d = 7.51 ppm in guest 10 were markedly affected by
The 1H NMR spectrum of compound 3c showed a typical AB pat-
tern for methylene bridge protons represented by two pairs of dou-
blets at d = 3.59 and d = 4.36 ppm for the axial and equatorial
protons, respectively, which indicated that compound 3c existed
in a symmetrical cone conformation. This was further confirmed
by the observation of a distinct signal at d = 30.24 ppm for the
methylene carbon in the 13C NMR spectrum.14
the addition of host 4c; they shifted to upfields and
Dd (dcomplex
À
dfree guest) reached the maximum values of À2.70, À1.29, and
À2.19 ppm, respectively, upon the addition of 1 equiv of host 4c.
There was no change in the protons of guest 8 upon addition of host 5.
Host 4c obtained by the complete hydrolysis of esters in com-
pound 3c was characterized by 1H NMR spectroscopy. The absence
of methyl peak at d = 3.91 ppm for four methyl ester moieties of
benzylimido functions on the wide rim, the methylene and methyl
peaks at d = 4.38 ppm and d = 1.41 ppm, respectively, for four ester
moieties on the narrow rim ascertained complete hydrolysis of es-
ters and formation of carboxylate salts. The 1H NMR signal for four
imine protons in host 4c at d = 8.49 ppm exhibited stability of
imine bonds during hydrolysis. Imine linkage on the top of wide
rim not only extends the conjugated aromatic system but also in-
creases the depth of the hydrophobic cavity. Similar to 3c, host 4c
showed a typical AB pattern for methylene bridge protons repre-
sented by two pairs of doublets at d = 3.61 ppm and d = 4.74 ppm
for the axial and equatorial protons, respectively, which indicated
that host 4c existed in a vase-shaped conformation.
Preliminary recognition characteristic of host 4c was investi-
gated by 1H NMR experiments in deuterated sodium phosphate
buffer (20 mM, pH 8.5) using guests 6–17 as neutral, cationic,
and anionic guests and the results were compared with those of
host 5. Host 5 as shown in Scheme 2 was obtained by previously
reported method.15 These experiments revealed significant com-
plexation-induced upfield shifts (CIUS) for proton signals in guests,
reasonably the averaged signal because of the fast exchange on
NMR timescale between the free and complexed guest.
A close comparison of the Dd values of protons of the guest 8
after complexation with host 4c shows that the aromatic proton
(or methyl, or methyl and methylene protons) at the 4-position
of pyridine guests gives the highest
Dd value, followed by the aro-
matic protons at the 3- and 2-positions, which indicates that the
pyridine guests penetrate into the cavity of host 4c from the p-po-
sition of the N atom as illustrated in Figure 2a. In case of guest 10,
after complexation with host 4c, only a slight upfield shift is ob-
served for the protons of the trimethylammoniomethyl moiety
while the aromatic protons experience a CIUS that follows the or-
der Hpara > Hmeta > Hortho. This indicates that the aromatic nucleus of
the guest is selectively included in the cavity of host 4c as illus-
trated in Figure 2b.
As shown in Table 1, host 4c showed maximum association con-
stant Ka of 2.81 Â 105 for guest 10, the least association constant of
2.90 Â 102 for guest 16 while the association constant for guests 6–
9 were in the above-mentioned range. 10, 11, 12, and 16 were the
only guests recognized by the host 5 amongst all tested guests and
the binding constants were comparable to the values reported in
the literature.17 The high binding ability of host 4c for the guests
6–12 is attributed to its deep cavity generated by tetra benzylimi-
do groups on the wide rim of calix[4]arene. This proposition can be
supported by the recognition behavior of host 5 which showed
limited or no recognition ability for the guests 6–17.
The guest concentration was kept constant (1 Â 10À3 M) while
the host concentration was varied from 8 Â 10À4 to 3 Â 10À3 M,
and the chemical shifts of the protons of guest were recorded at
each concentration. The obtained 1H NMR data were analyzed by
the well-known method of nonlinear least square regression anal-
ysis,16 which allowed the calculation of association constant (Ka).
The results of 1H NMR experiments run for hosts 4c and 5 with
guests 6–17 have been presented in Table 1.
As shown in Figure 2, the plausible special orientation of com-
plex between host 4c and molecules of guests 8 and 10 is pre-
sented by the energy-minimized structure generated by SpartanÒ
(MM+Force Field).
Host 4c showed high binding affinity for cationic guests 10–12
with lower or no binding affinity for anionic guests 13–17. The
binding constants of host 5 for cationic guests 10–12 as well as
anionic guests 13–17 were relatively lower than those recorded

7348
S. B. Nimse et al. / Tetrahedron Letters 50 (2009) 7346–7350
Scheme 2. Host 5 and guests 6–17.
Table 1
Association constants (Ka MÀ1) for binding of guests by hosts 4c and 5; pD 8.5 (20 mM sodium phosphate buffer)
Guest
6
7
8
9
10
11
12
13
14
15
16
17
Host 4c
Host 5
6.02 Â 104
1.47 Â 105
2.23 Â 105
1.70 Â 105
2.81 Â 105
9.00 Â 104
4.46 Â 104
ans
ns
5.22 Â 102
ns
ns
2.90 Â 102
8.91 Â 102
ns
ns
ns
ns
1.29 Â 102
0.52 Â 102
1.09 Â 103
ns
8.542 Â 102
ns
a
ns indicates no change in chemical shift.
Figure 1. Partial 1H NMR (D2O at 298 K) spectra of guests 8 and 10 upon titration with host 4c. (1a) (a) host 4c, (b) guest 8, (c) 8 + 0.25 equiv of 4c, (d) 8 + 0.5 equiv of 4c, (e)
8 + 0.75 equiv of 4c, (f) 8 + 1 equiv of 4c, residual THF (d), methyl protons (w), methylene protons (N) in guest 8; (1b) (a) host 4c, (b) guest 10, (c) 10 + 0.25 equiv of 4c, (d)
10 + 0.5 equiv of 4c, (e) 10 + 0.75 equiv of 4c, (f) 10 + 1 equiv of 4c, ortho protons ( ), meta protons (N), para protons (w) in guest 9.
for host 4c. From the recognition behavior of host 4c for all the
guests, it is clearly seen that the four carboxylate groups on the
top of the deep hydrophobic pocket play an important role. As
can be seen in Figure 2b, the positively charged trimethylammon-
iomethyl moiety in guest 10 comes in the vicinity of negatively
charged carboxylate functions on the top of the hydrophobic cavity
burying phenyl group in the deep gorge. Such orientation of guest
10 in the cavity of the host 4c leads to the favorable electrostatic
interaction along with hydrophobic interactions in deep cavity. In
the case of anionic guests, such favorable electrostatic interaction
is not possible, hence host 4c showed poor or no binding affinity
for guests 13–17.
were observed for these guests upon titration with host 5. Host 4c
showed highest Ka value of 2.23 Â 105 MÀ1 for guest 8 amongst
neutral guests 6–9. From Table 1, the increasing order of affinity
of the guests 6–8 for host 4c can be presented as 6 < 7 < 8. Guest
8 with a longer alkyl chain at the para position had the maximum
association constant. The association constant decreases with de-
crease in the chain length at the para position of the pyridine
guests, hence pyridine (6) showed less binding affinity than 4-
methyl pyridine (7) and 4-ethyl pyridine (8). This indicates that
deep hydrophobic cavity of host 4c welcomes a hydrophobic
open-chain substituent at the 4-position of pyridine guests. It is
interesting to notice that without any ionic interactions, these neu-
tral pyridine derivatives (guests 6–8) showed strong binding char-
acteristics with the deep hydrophobic pocket of host 4c. As can be
The neutral pyridine derivatives (guests 6–9) showed high
binding constants with host 4c, while no effects on chemical shifts

S. B. Nimse et al. / Tetrahedron Letters 50 (2009) 7346–7350
7349
Figure 2. Energy-minimized structure of complex between host 4c and molecule of guests 8 and 10 by SpartanÒ (MM+ Force Field) (a) complex between host 4c and guest 8
(side view); (b) complex between host 4c and guest 10 (side view).
seen in Figure 2a, the alkyl moiety at the para position of the guest
8 is buried deep into the hydrophobic cavity of host 4c, thus
References and notes
1. Gutsche, C. D. Calixarenes Revisited; The Royal Society of Chemistry: Cambridge,
1998.
enhancing hydrophobic interactions along with –CHÁ Á Á
p interac-
tions and stacking interactions. Relatively more hydrophilic
p–p
2. (a) Oh, S. W.; Moon, J. D.; Lim, H. J.; Park, S. Y.; Kim, T.; Park, J.; Han, M. H.;
Snyder, M.; Choi, E. Y. J. Fed. A. Soc. Exp. Biol. 2005, 19, 1335; (b) Jung, H.; Song,
K.; Kim, T. Bull. Korean Chem. Soc. 2007, 28, 1792; (c) Demody, D. L.; Crooks, M.
R.; Kim, T. J. Am. Chem. Soc. 1996, 118, 11912; (d) Dermody, D. L.; Lee, Y.; Kim,
T.; Crooks, R. M. Langmuir 1999, 15, 8435; (e) Lee, Y.; Lee, E. K.; Cho, Y. W.;
Matsui, T.; Kang, I.; Kim, T.; Han, M. H. Proteomics 2003, 3, 2289.
3. (a) Kuhnert, N.; Le-Gresley, A. Tetrahedron Lett. 2005, 46, 2059; (b) Kuhnert, N.;
Le-Gresley, A. Tetrahedron Lett. 2008, 49, 1274; (c) Liang, Z.; Liu, Z.; Gao, Y.
Spectrochim. Acta, Part A 2007, 68, 1231; (d) Klimentová, J.; Vojtíšek, P. J. Mol.
Struct. 2007, 826, 48; (e) Wang, H. W.; Feng, Y. Q.; Xue, J. Q.; Xiao, C. Chin. Chem.
Lett. 2008, 19, 901.
4. (a) Tamburini, S.; Tomasin, P.; Vigato, P. A.; Casnati, A.; Domiano, L. Inorg. Chim.
Acta 1997, 254, 209; (b) Durmaz, M.; Alpaydin, S.; Sirit, A.; Yilmaz, M.
Tetrahedron: Asymmetry 2006, 17, 2322; (c) Wei, X. Q.; Lu, Z. Y.; Zou, P.; Xie, M.
G. Chin. Chem. Lett. 2003, 14, 263.
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Singh, S. P. Tetrahedron 2008, 64, 741; (c) Bhalla, V.; Kumar, M.; Katagiri, H.;
Hattori, T.; Miyano, S. Tetrahedron Lett. 2005, 46, 121.
6. (a) Shinkai, S.; Araki, K.; matsuda, T.; Nishiyama, N.; Ikeda, H.; Takasu, I.;
Iwamoto, M. J. Am. Chem. Soc. 1990, 112, 9053; (b) Oshovsky, G. V.; Reinhoudt,
D. N.; Verboom, W. Angew. Chem., Int. Ed. 2007, 46, 2366; (c) Biros, S. M.; Rebek,
J. Chem. Soc. Rev. 2007, 36, 93.
7. Shinkai, S.; Araki, K.; Matsuda, T.; Nishiyama, N.; Ikeda, H.; Takasu, I.; Iwamoto,
M. J. Am. Chem. Soc. 1990, 112, 9053.
8. (a) Liu, Y.; Yang, E.; Chen, Y.; Guo, D.; Ding, F. Eur. J. Org. Chem. 2005, 4581; (b)
Liu, Y.; Ma, Y.; Chen, Y.; Guo, D.; Li, Q. J. Org. Chem. 2006, 71, 6468; (c) Liu, Y.;
Guo, D.; Zhang, H.; Ma, Y.; Yang, E. J. Phys. Chem. B 2006, 110, 3428.
9. Wageningen, A. M. A.; Snip, E.; Verboom, W.; Reinhoudt, D. N.; Boerrigter, H.
Liebigs Ann./Recueil 1997, 2235.
10. Typical procedure for the synthesis of compound 2: 0.5 g of 1 (1.03 mmol) and
150 mL of acetonitrile were taken in a dried round-bottomed flask, and the
mixture was stirred at room temperature under nitrogen atmosphere. Then
benzaldehyde (0.87 g, 8.26 mmol) was injected to the reaction mixture with
stirring and the reaction was continued for 2 h. After completion, hexane was
added to the reaction mixture, stirred for 5 min, and then filtered to obtain the
solid product; the filter cake was washed three times with hexane and dried
under vacuum. The final compound 2a was recrystallized from 1:50 mixture of
dichloromethane and hexane (100 mL). Using this method, compounds 2b and
2c were also obtained by reacting 1 with suitable aldehydes. Compound 2a:
light pink solid (95.72% yield). 1H NMR (CDCl3, 300 MHz, 298 K) d (ppm): 10.15
(s, 4H, OH), 8.34 (s, 4H, N@CH), 7.82–7.78 (m, 8H, Ar), 7.40–7.38 (m, 12H, Ar),
7.01 (s, 8H, Ar), 4.31 (d, 4H, ArCH2Ar, J = 13.0 Hz), 3.63 (d, 4H, ArCH2Ar,
J = 13.0 Hz). 13C NMR (300 MHz, CDCl3): 159.26, 147.53, 146.28, 136.40,
131.32, 128.87, 128.86, 128.82, 121.90, 32.47. MALDI-TOF: m/z = 837.37
[M+H]+. Compound 2b: light pink solid (94.75% yield). 1H NMR (CDCl3,
300 MHz, 298 K) d (ppm): 10.20 (s, 4H, OH), 8.31 (s, 4H, N@CH), 7.69 (d, 8H,
Ar), 7.20 (d, 8H, Ar), 7.00 (s, 8H, Ar), 4.30 (d, 4H, ArCH2Ar, J = 14.2 Hz), 3.58 (d,
4H, ArCH2Ar, J = 13.7 Hz), 2.38 (s, 12H, Ar-CH3). 13C NMR (300 MHz, CDCl3):
159.23, 147.34, 146.39, 141.71, 133.84, 129.61, 128.85, 128.77, 121.84, 32.48,
21.38. MALDI-TOF: m/z = 893.39 [M+H]+. Compound 2c: dark khaki solid
guest 9 showed low binding constant with host 4c than guest 8.
Comparable Ka values for neutral and cationic guests were found
because the hydrophobic interactions are predominant and the
electrostatic interaction only enhances the binding of the cationic
guests in the cavity of host 4c.
In this Letter, we have shown that the water-soluble imineca-
lix[4]arene derivative bearing tetra carboxylate groups on the top
of the deep hydrophobic cavity has been successfully synthesized
in prominent yield. From the complexation studies of host 4c for
the tested guests, it can be concluded that the deep hydrophobic
cavity of host 4c plays a major role in recognition of the guests
in aqueous medium. This phenomenon is supported by comparing
the results obtained for host 4c with host 5, which did not recog-
nize most of the tested guests. As can be seen from the recognition
behavior of cationic guests and neutral pyridine derivatives, hydro-
phobic interactions along with –CHÁ Á Á
p and p–p stacking interac-
tions proved to be crucial in the molecular recognition process in
aqueous medium. The electrostatic interaction also plays a major
role in molecular recognition, as it imparts high binding affinity
to the host for cationic guests as compared to anionic guests. Based
on our knowledge, it is the first time to report huge Ka values for
neutral pyridine guests. We are currently working on the molecu-
lar recognition of host 4c with pyridine derivatives and structurally
similar aromatic compounds.
Acknowledgments
This research was financially supported by the Ministry of Edu-
cation, Science and Technology (MEST) and Korea Industrial Tech-
nology Foundation (KOTEF) through the Human Resource Training
Project for Regional Innovation.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.10.058.

7350
S. B. Nimse et al. / Tetrahedron Letters 50 (2009) 7346–7350
Compound 3c: yellow solid (87.03%) 1H NMR (300 MHz, CDCl3, 298 K)
(92.45% yield). 1H NMR (CDCl3, 300 MHz, 298 K) d (ppm): 10.71 (s, 4H, OH),
d
8.41 (s, 4H, N@CH), 8.05 (d, 8H, Ar), 7.86 (d, 8H, Ar), 7.05 (s, 8H, Ar), 4.32 (d, 4H,
ArCH2Ar, J = 14.2 Hz), 3.61 (d, 4H, ArCH2Ar, J = 13.1 Hz), 3.98 (s, 12H, Ar-
COOCH3). 13C NMR (300 MHz, CDCl3): 166.66, 157.85, 147.95, 145.68, 140.10,
132.27, 130.09, 128.77, 128.60, 122.05, 52.61, 32.39. MALDI-TOF: m/z = 893.39
[M]+.
(ppm): 8.47 (s, 4H, N@CH), 8.02 (d, 8H, ArH), 7.83 (d, 8H, ArH), 7.16 (s, 8H, Ar),
4.53 (s, 8H, O–CH2–COO), 4.43–4.38 (q, 8H, COOCH2), 4.36 (d, 4H, Ar-CH2-Ar,
J = 13.1 Hz), 3.91 (s, 12H, Ar-COOCH3), 3.59 (d, 4H, Ar-CH2-Ar, J = 13.1 Hz), 1.41
(t, 12H, –CH3).13
C NMR (300 MHz, CDCl3, 298 K): 171.28, 166.53, 159.92,
150.71, 149.46, 139.75, 135.58, 132.37, 129.98, 128.79, 122.24, 73.68, 62.36,
52.508, 30.24, 14.56. MALDI-TOF: m/z = 1413.44 [M]+, m/z = 1436.42 [M+Na]+.
12. Typical procedure for the synthesis of compound 4: Compound 3c (0.1 g,
0.070 mmol) was dissolved in a 2:1 mixture of THF and water (6 mL), and a
solution of NaOH (0.045 g, 1.1 mmol) in water (4 mL) was added. The reaction
mixture was kept at room temperature overnight and at 5 °C for another 12 h.
The solution was filtered and the filter cake (crystalline compound) was dried
under vacuum to obtain crystalline compound 4c with a yield of 99.00%. 1H
NMR (300 MHz, D2O, 298 K) d (ppm): 8.49 (s, 4H, N = CH), 7.87, 7.76 (dd, 16H,
ArH), 7.27 (s, 8H, Ar), 4.74 (d, 4H, Ar-CH2-Ar, J = 13.2 Hz), 4.53 (s, 8H, O–CH2–
COO), 3.64 (d, 4H, Ar-CH2-Ar, J = 13.2 Hz). 13C NMR (300 MHz, D2O, 298 K)
176.08, 167.54, 151.50, 146.56, 142. 72, 139.17, 136. 91, 130.05, 129.03,
128.28, 127. 74, 61.34, 29.67.
13. Guo, T.; Zheng, Q.; Yang, L.; Huang, Z. J. Inclusion Phenom. Macrocyclic Chem.
2000, 36, 327.
14. (a) Jaime, C.; Mendoza, J. D.; Prados, P.; Nieto, P. M.; Sanchez, C. J. Org. Chem.
1991, 56, 3372; (b) Shu, C. M.; Liu, W. C.; Ku, M. C.; Tang, F. S.; Yeh, M. L.; Lin, L.
G. J. Org. Chem. 1994, 59, 3730.
15. Casnati, A.; Ting, Y.; Berti, D.; Fabbi, M.; Pochini, A.; Ungaro, R.; Sciotto, D.;
Lombardo, G. G. Tetrahedron 1993, 43, 9815.
16. Macomber, R. S. J. Chem. Educ. 1992, 69, 375.
11. Typical procedure for the synthesis of compound 3: To a solution of 2a (0.5 g,
0.59 mmol), K2CO3 (0.83 g, 5.9 mmol), NaI (1.33 g, 8.9 mmol), and acetonitrile
(30 mL), ethyl 2-bromoacetate (0.99 g, 5.9 mmol) was added and then the
solution was refluxed with stirring under argon atmosphere for 12 h. The
reaction mixture was then evaporated in vacuo and the residue was dissolved
in 50 mL of dichloromethane and filtered. The filtrate was concentrated and
hexane was added. The precipitate was filtered and dried under vacuum to
obtain compound 3a. Using this method, compounds 3b and 3c were obtained
from 2b and 2c, respectively. Compound 3a: Light yellow solid (86.36%) 1H
NMR (300 MHz, CDCl3, 298 K) d (ppm): 8.33 (s, 4H, N@CH), 7.76 (d, 8H, ArH),
7.41–7.39 (t, 12H, ArH), 7.05 (s, 8H, Ar), 4.50 (s, 8H, O–CH2–COO), 4.42–4.37 (q,
8H, COOCH2), 4.33 (d, 4H, Ar-CH2-Ar, J = 11.5 Hz), 3.52 (d, 4H, Ar-CH2-Ar,
J = 11.5 Hz), 1.42 (t, 12H, –CH3).13C NMR (300 MHz, CDCl3, 298 K): 171.35,
161.12, 150.37, 149.99, 135.94, 134.70, 131.70, 129.19, 129.09, 122.04, 73.79,
62.50, 30.38, 14.67. MALDI-TOF: m/z = 1181.38 [M]+, m/z = 1203.37 [M+Na]+.
Compound 3b: bright yellow solid (87.27%) 1H NMR (300 MHz, CDCl3, 298 K) d
(ppm): 8.29 (s, 4H, N@CH), 7.65 (d, 8H, ArH), 7.18 (d, 8H, ArH), 7.04 (s, 8H, Ar),
4.51 (s, 8H, O–CH2–COO), 4.41–4.35 (q, 8H, COOCH2), 4.30 (d, 4H, Ar-CH2-Ar,
J = 12.0 Hz), 3.50 (d, 4H, Ar-CH2-Ar, J = 12.0 Hz), 2.38 (s, 12H, Ar-CH3),1.43 (t,
12H, –CH3).13C NMR (300 MHz, CDCl3, 298 K): 171.25, 160.88, 150.06, 142.16,
140.07, 135.41, 133.27, 129.81, 128.97, 121.86, 73.66, 62.40, 30.28, 21.93,
14.58. MALDI-TOF: m/z = 1260.52 [M+Na]+, m/z = 1259.52 [M+Na-1]+.
17. Arena, G.; Casnati, A.; Contino, A.; Lombardo, G. G.; Sciotto, D.; Ungaro, R. Chem.
Eur. J. 1999, 5, 738.