Design and syntheses of novel calix[4](aza)crowns: Neutral receptors for α-amino acids

Article abstract of DOI:10.1080/00397910600978150

A series of novel calix[4](aza)crowns 2a-2d containing acylhydrazone groups was designed and synthesized via 1+1 condensation of calix[4]-1,3-substituted benzaldehyde derivative 1 with bis-hydrazides in 85-90% yields. They showed good complexation abiliti

Full text of DOI:10.1080/00397910600978150

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Design and Syntheses of Novel Calix[4]
(aza)crowns: Neutral Receptors for α‐Amino
Acids
a
a
a
a
b
Fafu Yang , Yanqing Ji , Hongyu Guo , Jianrong Lin & Qi Peng
a
College of Chemistry and Materials Science, Fujian Normal University ,
Fuzhou, China
b
State Key Laboratory of Structural Chemistry , Fujian Institute of Research
on the Structure of Matter, Chinese Academy of Sciences , Fuzhou, China
Published online: 25 Jul 2007.
To cite this article: Fafu Yang , Yanqing Ji , Hongyu Guo , Jianrong Lin & Qi Peng (2007) Design and
Syntheses of Novel Calix[4](aza)crowns: Neutral Receptors for α‐Amino Acids, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:1, 79-85, DOI:
10.1080/00397910600978150
To link to this article: http://dx.doi.org/10.1080/00397910600978150
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Synthetic Communications , 37: 79–85, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600978150
Design and Syntheses of Novel
Calix[4](aza)crowns: Neutral Receptors
for a-Amino Acids
Fafu Yang, Yanqing Ji, Hongyu Guo, and Jianrong Lin
College of Chemistry and Materials Science, Fujian Normal University,
Fuzhou, China
Qi Peng
State Key Laboratory of Structural Chemistry, Fujian Institute of
Research on the Structure of Matter, Chinese Academy of Sciences,
Fuzhou, China
Abstract: A series of novel calix[4](aza)crowns 2a–2d containing acylhydrazone
groups was designed and synthesized via 1þ1 condensation of calix[4]-1,3-substituted
benzaldehyde derivative 1 with bis-hydrazides in 85–90% yields. They showed good
complexation abilities toward a-amino acids and exhibited complexation selectivity
toward tryptophane.
Keywords: amino acid, aza, calix[4]arene, complexation
Calixarenes are important supramolecular building blocks. They can be
modified by introduction of many kinds of functional groups and/or structural
[
1,2]
groups to create a specific interaction to target guest molecules.
lar, the recognition of amino acids is an interesting theme in biomimetic
In particu-
[
chemistry. Up to now, although some hydrophilic calixarene derivatives
3]
[
4,5]
[6]
[7]
containing carboxylic acid,
phosphonates,
or sulphonate
were
reported to bind amino acids or their esters, the calixarene-based neutral
receptor for amino acids has received little attention. Vicens and Tuntulani
Received in R.O.C. September 1, 2006
Address correspondence to Fafu Yang, College of Chemistry and Materials
Science, Fujian Normal University, Fuzhou 350007, China. E-mail: yangfafu@fjnu.
edu.cn
79

8
0
F. Yang et al.
had reported calix[4](aza)crowns containing a normal crown ether and tren
unit, which could bind cations and anions cooperatively,
[8,9]
but they had no
complexation abilities towards zwitterionic a-amino acids. In this article,
we report the design and syntheses of novel calix[4](aza)crowns, which are
effective neutral receptors for zwitterionic a-amino acids.
The synthetic route is shown in Fig. 1. By reacting p-tert-butylcalix[4]
arene with p-tosyloxyethoxyl-benzaldehyde (mol ratio ¼ 1 : 2) in a K CO /
2
3
MeCN system for 48 h, calix[4]-1,3-substituted benzaldehyde derivative 1
was obtained in a yield of 78%. By further reacting compound 1 with
oxalyl dihydrazide, propane diacid dihydrazide, tartaric acid dihydrazide, or
adipic acid dihydrazide in a diluted solution, a series of novel calix[4](aza)-
crowns 2a–2d was obtained via 1 þ 1 condensation in 85–90% yields. All
new compounds were conveniently obtained by crystallization in methanol,
and the total yields were more than 70%. Compounds 2a–2d were the first
examples of calix[4](aza)crowns containing acylhydrazone groups.
The structures of all new compounds were characterized by ESI-MS
1
1
spectra, H NMR spectra, and elemental analyses. In the H NMR spectra
of compounds 1 and 2a–2d, two singlets (1:1) for the tert-butyl groups and
one AB system for the methylene bridges of the calix[4]arene skeleton
certainly indicated that calix[4]arene moiety adopted the cone conformation
as showed in Fig. 1.
Examination of the CPK molecular models revealed that compounds 2a–
d were highly preorganized for binding guests. Because the structures of
2
compounds 2a–2d were similar to the calix[4](aza)crowns reported by
[
8,9]
Vicens and Tuntulani,
which could bind cations and anions cooperatively,
compounds 2a–2d might be effective receptors for a-amino acids, which
were zwitterionic compounds containing ammonium cations and carboxylate
anions. Thus, the percentage extractions of compounds 2a–2d and compound
1 toward a series of a-amino acids from water into CHCl at room temperature
3
were studied, and the results are summarized in Table 1. The extraction
Figure 1. The synthetic routes of compounds 2a–2d.

Table 1. Percentage extraction (E %) of hosts 2a–2d and 1 toward a series of a-amino acids from water into
2
4
a
CHCl
3
at the concentration of 5 ꢀ 10 M (3 as reference compound)
Host
Glycine
Tryptophane
Histidine
Lysine
Proline
Threonine
Isoleucine
Arginine
2
2
2
2
1
3
a
b
c
17.2
16.1
18.5
17.5
1.8
34.2
51.5
40.3
42.6
,1
16.5
16.4
15.4
16.1
,1
5.1
4.9
5.2
5.4
1.9
—
10.9
11.5
9.5
8.6
8.9
8.5
8.7
1.2
—
7.2
7.4
7.2
7.1
2.2
—
4.5
4.3
4.2
4.9
,1
—
d
10.0
1.3
b
98
49
—
—
a
According to the extraction method in Ref. 10.
These data quoted from Ref. 3.
b

8
2
F. Yang et al.
[
3]
percentages of compound 3, which was an effective neutral zwitterionic
amino acid receptor composed of xanthone and crown ether subunits, are
quoted for comparison.
Table 1 showed that compound 1 possessed little complexation abilities;
however, compounds 2a–2d showed good complexation abilities for tested
a-amino acids as expected. These results certainly suggest that the complexa-
tion abilities of compounds 2a–2d for amino acids were attributed to the intro-
duction of the azacrown moiety. It was interesting that the extraction
percentages of compounds 2a–2d were similar, which means the length of
crown ether chain has little influence on the complexation abilities. On the
other hand, all hosts showed excellect complexation selectivity for trypto-
phane; the extraction percentage of calix[4](aza)crown 2b was as high as
51.5%. Comparing with the neutral zwitterionic amino acids receptor 3,
compound 2b showed not only a little higher extraction percentage but also
outstanding extraction selectivity for tryptophane.
Because compound 2b possessed the highest extraction percentage for
tryptophane, the complexation behavior of compound 2b with tryptophane
[11]
was further studied in DMSO/CHCl (9:1) solution by UV-vis spectrum.
3
The results are shown in Figs. 2 and 3. In Fig. 2, the absorbance A of
compound 2b at 274 nm declined gradually with the increase of concentration
of tryptophane. These results certainly indicated some kind of complexation
behavior occurred and could reduce the UV-vis absorbance. Figure 3
showed the shift curve of absorbance A at 274 nm when compound 2b is at
2
4
1
.0 ꢀ 10 M and tryptophane at 0, 0.2, 0.4, 0.6, 0.8, 1.0, 2.0,
2
4
Figure 2. UV-vis spectra of 2b (1.0 ꢀ 10 M) with tryptophane (0, 0.2, 0.4, 0.6,
2
4
0
.8, 1.0, 2.0, 3.0 ꢀ 10 M).

Calix[4](aza)crowns
83
2
4
Figure 3. Shift curve of absorbance A of 2b (1.0 ꢀ 10 M) with tryptophane (0,
2
4
0
.2, 0.4, 0.6, 0.8, 1.0, 2.0, 3.0 ꢀ 10 M).
2
4
3
had no change when [guest]/[host] . 1. These results indicated that the
.0 ꢀ 10 M. A declined gradually when [guest]/[host] , 1, and A almost
host and guest prefered to form stable 1:1 complexation.
EXPERIMENTAL
1
Melting points are uncorrected. H NMR spectra were recorded in CDCl on a
3
Bruker-ARX 500 instrument at room temperature, using TMS as an internal
standard. ESI-MS spectra were obtained from DECAX-30000 LCQ Deca
XP mass spectrometer. Elemental analyses were performed on a Vario
EL III elemental analyzer. All solvents were purified by standard
procedures. P-tert-butylcalix[4]arene, p-tosyloxyethoxyl-benzaldehyde, and
bis-hydrazides were prepared according to the published procedures.
Synthesis of p-tert-Butylcalix[4]arene 1,3-bis-Benzaldehyde
Derivative 1
A mixture of p-tert-butylcalix[4]arene (2 mmol, 1.48 g) p-tosyloxyethoxyl-
benzaldehyde (4 mmol, 1.28 g), and K CO (8 mmol, 1.10 g) was stirred in
2
3
refluxing acetonitrile (100 mL) for 2 days under an N atmosphere. After dis-
2
tilling the solvent under reduced pressure, the residue was treated with 30 mL

8
4
F. Yang et al.
of HCl (10%, W/V) and extracted with 40 mL of CHCl . The organic layer
3
was separated, dried over anhydrous MgSO , filtered, and concentrated. By
4
precipitation with methanol, compound 1 was obtained in 78% yield. Mp
1
1
99–2028C. H NMR (500 MHz, CDCl ) d: 1.00 [s, 18H, C(CH ) ], 1.27
3
3 3
[
(
s, 18H, C(CH ) ], 3.31 (d, J ¼ 13.0 Hz, 4H, ArCH Ar), 4.32–4.36
2
3
2
m, 12H, OCH and ArCH Ar), 6.84 (s, 4 H, ArH), 7.02 (d, J ¼ 8.5 Hz, 4H,
2 2
ArH), 7.26 (s, 4 H, ArH), 7.32 (s, 2H, ArCHO), 7.82 (d, J ¼ 8.5 Hz, 4H,
þ
ArH), 9.89 (s, 2H, OH); MS m/z (%): 967.3 (MNa , 100). Anal. calcd for
C H O : C, 78.78; H, 7.68; found C, 78.72; H, 7.71.
6
2 72 8
Synthesis of Novel Calix[4](aza)crowns 2a–2d
A mixture of compound 1 (0.30 g, 0.32 mmol) and oxalyl dihydrazide (0.05 g,
0
.42 mmol) was refluxed in 80 mL of MeOH-CHCl (1:1, V/V), using 0.5 mL
3
of acetic acid as catalyst. The materials disappeared as monitored by thin-layer
chromatography (TLC) (approximately 24 h). The solvent was removed under
reduced pressure, and the residue was treated with MeOH to give compound
2a as white powder in 86% yield. Using propane diacid dihydrazide, tartaric
acid dihydrazide, or adipic acid dihydrazide instead, compounds 2b, 2c, and
1
2
d were obtained in yields of 88%, 89%, and 90%. 2a: mp 207–2108C. H
NMR (500 MHz, CDCl ) d: 0.97 [s, 18H, C(CH ) ], 1.30 [s, 18H,
C(CH ) ], 3.31 (d, J ¼ 13.0 Hz, 4H, ArCH Ar), 4.13–4.40 (m, 12H, OCH
3
3 3
2
3
2
2
and ArCH Ar), 6.70–7.94 (m, 16 H, ArH), 7.88 (s, 2H, CH 55 N), 8.23 (bs,
2
þ
2H, NHCO), 9.95 (s, 2H, OH); MS m/z (%): 1049.6 (MNa , 90). Anal.
calcd. for C H O N : C, 74.83; H, 7.26; N, 5.45; found C, 74.77; H, 7.29;
6
4 74 8 4
1
N, 5.35. 2b: mp 214–2168C. H NMR (500 MHz, CDCl ) d: 0.98 [s, 18H,
3
C(CH ) ], 1.29 [s, 18H, C(CH ) ], 3.32 (d, J ¼ 12.0 Hz, 4H, ArCH Ar),
3
3
2 3
2
4.30–4.39 (m, 14H, OCH , COCH CO and ArCH Ar), 6.71–7.65
2 2 2
(
OH); MS m/z (%): 1063.8 (MNa , 100). Anal. calcd. for C H O N : C,
m, 16 H, ArH), 7.74 (s, 2H, CH 55 N), 9.16 (s, 2H, NHCO), 10.08 (s, 2H,
þ
6
5 76 8 4
7
1
4.97; H, 7.35; N, 5.39; found C, 75.06; H, 7.28; N, 5.34. 2c: mp
1
79–1828C. H NMR (500 MHz, CDCl ) d: 1.03 [s, 18H, C(CH ) ], 1.25
3
3 3
[
(
(
s, 18H, C(CH ) ], 3.30 (d, J ¼ 13.0 Hz, 4H, ArCH Ar), 4.29–4.37
2
3
2
m, 14H, CHCO, OCH and ArCH Ar), 6.68–7.69 (m, 16 H, ArH), 7.74
2 2
s, 2H, CH 55 N), 9.16 (s, 2H, NHCO), 9.54 (bs, 2H, OH), 10.8 (s, 2H, OH);
þ
MS m/z (%): 1109.6 (MNa , 90). Anal. calcd. for C H O N : C, 72.92;
6
6 78 10 4
1
H, 7.23; N, 5.16; found C, 72.97; H, 7.19; N, 5.12. 2d: mp 201–2038C. H
NMR (500 MHz, CDCl ) d: 1.07 [s, 18H, C(CH ) ], 1.26 [s, 18H,
C(CH ) ], 1.95–2.08 (m, 4H, CH ), 2.93 (bs, 4H, CH CO), 3.34
3
3 3
2
3
2
2
(
d, J ¼ 12.5 Hz, 4H, ArCH Ar), 4.16–4.30 (m, 8H, OCH ), 4.40
2
2
(
CH 55 N), 8.63 (s, 2H, NHCO), 11.50 (s, 2H, OH); MS m/z (%): 1105.7
(
found C, 75.33; H, 7.72; N 5.11.
d, J ¼ 12.5 Hz, 4H, ArCH Ar), 6.81–7.79 (m, 16 H, ArH), 8.52 (s, 2H,
2
þ
MNa , 100). Anal. calcd. for C H O N : C, 75.39; H, 7.63; N, 5.17;
6
8 82 8 4

Calix[4](aza)crowns
85
ACKNOWLEDGMENT
Financial support from the National Natural Science Foundation of China (No.
0402002) and Fujian Natural Science Foundation of China (No. E0220002
and 2006J0155) is gratefully acknowledged.
2
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