Molecular design and synthesis of a calix[6]crown-based lithium- selective ionophore

Article abstract of DOI:10.1016/S0040-4039(00)00729-2

Several 1,4-bridged calix[6]arene tetraesters were prepared from 1,4-p- tert-calix[6]crown-4's by etherifying with ethyl bromoacetate. It was found that the 1,4-p-tert-calix[6]crown-4 tetraethylester (3a) and the 1,4-p-tert- calix[6]benzocrown-4 tetramethylester (4b) exhibit very high selectivity toward lithium and sodium ions, respectively. The ion selectivity is very sensitive to the structure of polyoxyethylene spacer and the R in the ester moiety. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00729-2

Tetrahedron Letters 41 (2000) 4815±4818
Molecular design and synthesis of a calix[6]crown-based
lithium-selective ionophore
Yuanyin Chen,* Fafu Yang and Shuling Gong
Department of Chemistry, Wuhan University, Wuhan 430072, China
Received 6 March 2000; accepted 4 May 2000
Abstract
Several 1,4-bridged calix[6]arene tetraesters were prepared from 1,4-p-tert-calix[6]crown-4's by etherifying
with ethyl bromoacetate. It was found that the 1,4-p-tert-calix[6]crown-4 tetraethylester (3a) and the 1,4-p-
tert-calix[6]benzocrown-4 tetramethylester (4b) exhibit very high selectivity toward lithium and sodium
ions, respectively. The ion selectivity is very sensitive to the structure of polyoxyethylene spacer and the R
in the ester moiety. # 2000 Elsevier Science Ltd. All rights reserved.
Calixarenes are cyclic oligomers prepared via cyclic condensation of p-substituted phenols with
formaldehyde under alkaline conditions. They have been used as versatile building blocks for
arti®cial receptors in supramolecular chemistry enabling the design and construction of more
elaborated molecules and assemblies.1 4 In order to preorganize the host it is usually desirable to
prepare the calixarenes with well-de®ned structural features suitable for complexation. It is well
known that in calix[4]arenes the ring conversion is inhibited simply through the introduction of
substituents bulkier than an ethyl group onto the lower rim and the calix[4]arene conformation
can thus be immobilized. Also, the ion selectivity is dependent on cooperation of the conformation
and substituents. It was reported that OCH2COOR, OCOCH2NR2 etc. are favorable groups for
the coordination of alkali metal ions. By skillful combination of conformation and the length and
properties of the polyoxyethylene spacer and substituents, a series of excellent ionophores for
Na+, K+ and Cs+ ions have been synthesized but not for the lithium ion.1 4 As the studies of these
ionophores of calix[4]arenes approaches maturity, increasing attention is being devoted to some
of the larger members of the family which possess a larger p-basic cavities and hydroxyl arrays,
such as calix[6]arenes. However, the conformational freedom of these larger molecules limits their
application to serve as receptors, and the large cavity is unfavorable for complexation of a small
cation. As a result, the studies of recognition behavior of calix[6]arenes are very scarce,5,6
especially on how to recognize lithium ion selectively.
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00729-2

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As early as 1989,7 it was reported that p-tert-butylcalix[6]arene hexaacetates exhibit high
anity towards alkali metal cations with increasing of ionic radius but had little selectivity due to
their ¯exible conformation. Recently, we have found that p-tert-butylcalix[6]-1,3-crown-3 show
some lithium ion selectivity.5 It is known that the binding sites exist deep in the cavity of the calix
crown and the intramolecular bridges at the lower or upper rim can reduce the conformational
¯exibility; in addition, the coordination of alkali metal ions is promoted by OCH2COOR
residues, so it is of interest to observe what happens when both polyoxyethylene spacer and ester
groups are incorporated into one caliz[6]arene. In this paper we wish to report our investigation
on the synthesis of p-tert-calix[6]-1,4-crown-4's and their tetraesters as well as the complexation
ability of the tetraesters towards alkali metal ions. As expected, the complexation ability varies
remarkably according to the di€erent structure of polyoxyethylene spacer and the di€erent ester
groups. Moreover, it was found that one of the tetraesters, p-tert-butylcalix[6]benzocrown-4
tetramethylesters 4b, exhibits outstanding lithium ion selectivity which has not been observed in
calixarene chemistry, and another one, the p-tert-butylcalix[6]crown-4 tetraethylester 3a shows
outstanding sodium ion selectivity.
The synthetic route is depicted in Scheme 1. Reacting p-tert-butylcalix[6]arene 1 with triethylene
glycol ditosylates or 1,2-bis(tosyloxyethoxy)benzene in K2CO3/toluene a€orded calix[6]-1,4-
crown-4 2a and 2b in yields of 40 and 55%, respectively. By using toluene as the solvent instead
of MeCN, the yields were almost double and the work up was simpli®ed in comparison with that
described in the previous method.5 Further treatment of 2 with ethyl bromoacetate in the
presence of NaH (caution!) as a base in dioxane gave 3a and 3b in high yields of 85, and 83%,
respectively. Compounds 4a and 4b were obtained by ester exchange reactions of 3 in near
quantitative yields. The structures and conformations of 2, 3 and 4 as shown in Scheme 1 were
1
1
con®rmed by H NMR, FAB-MS and elemental analysis.9 The H NMR spectra of these
compounds show two singlets in a ratio of 1:2 for the tert-butyl groups, which indicates that they
are 1,4-bridged calix[6]arene tetrasubstituted products. Two pairs of doublets (ratio 1:2) with an
AB pattern for the methylene protons of the calix[6]arene skeleton and an AB system for the
protons of the OCH2CO, reveals that the calixarene adopts a cone conformation.5,6
Scheme 1. Reagents and conditions: (i) K2CO3/toluene; (ii) NaH/dioxane, BrCH2COOEt; (iii) methanol/toluene

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Examination of the CPK molecular models revealed that these compounds were highly pre-
organized for binding cations. The percentage extraction of hosts 2, 3 and 4 as well as p-tert-
butylcalix[6]arene hexacetates7 5 and 25-diethylphosphoryl-26,27,28-trimethoxy-p-tert-butyl-
calix[4]arene8 6 (the most e€ective ionophore towards Li+ in previous literature) towards Li+,
Na+, K+ etc. from water into CHCl3 at 20ꢀC are summarized in Table 1. It can be seen that 3b, 4a
and 6 show high anities for lithium ion but no selectivity. The ionophore 5a and 5b exhibit high
extraction capabilities for alkali metal cations with increasing ion radius, but low extraction
capabilities for lithium ion, and 2a, 2b show lower complexation ability towards alkali metal
cations. However, this is not the case for 3a and 4b which show outstanding selectivity towards
Na+ and Li+, respectively. To the best of our knowledge, 4b is the ®rst example with high lithium
ion selectivity, and also, 3a is an outstanding selective ionophore for the sodium ion, especially, in
calix[6]arene chemistry. The increase of complexation ability towards alkali metal cations could
be attributed to the combination of the triethylene glycol spacer reducing the ¯exibility of con-
formation, the newly created small cavity in the calix[6]crown-4's and the favorable in¯uence of
esters groups on the complexation of alkali metal cations. The high selectivity may be due to the
cooperation of the appropriate structure of the polyoxyethylene spacer and the appropriate alkyl
chain in the ester moiety that can create an appropriate size of cavity and thus improve com-
plexation selectivity.
Table 1
Percentage extraction (%E) of picrate salts from water into CHCl3 at 20ꢀC. Arithmetic mean of several experiments
a
Ð standard deviation on the mean: sN-141
In conclusion, this paper describes not only the synthesis and the outstanding complexation
behavior towards alkali metal cations of 1,4-bridged calix[6]crown tetreacetates, but also
demonstrates how to design highly selective ionophores for small alkali ions, especially the
lithium ion. This may be helpful in designing and synthesizing other selective ionophores and in
promoting studies on recognition properties of calix[6]arene derivatives.
Acknowledgements
Financial support from the National Natural Science Foundation of China is gratefully
acknowledged.
References
1. Shinkai, S. Tetrahedron 1993, 49, 8933.
2. Bohmer, V. Angew. Chem., Int. Ed. Engl. 1995, 34, 713.

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3. Takeshita, M.; Shinkai, S. Bull. Chem. Soc. Jpn. 1993, 68, 1088.
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5. Li, J. S.; Chen, Y. Y.; Lu, X. R. Tetrahedron 1999, 55, 10365.
6. Casnati, A.; Jacopezzi, P.; Opochini, A.; Ugozzoli, F.; Cacciapaglia, R.; Mandolini, L.; Ungaro, R. Tetrahedron
1995, 51, 591.
7. Arnaud-Neu, F.; Collins, E. M.; Deasy, M.; Ferguson, G.; Harris, S. J.; Kaitner, B.; Marques, E.; Schwing-Weill,
M. J.; Seward, E. M. J. Am. Chem. Soc. 1989, 111, 8681.
8. Akabori, S.; Itabashi, H.; Shimura, H.; Inoue, M. Chem. Commun. 1997, 2137.
9. The characteristics of 2 were in accordance with Ref. 5. 1H NMR (300 MHz, CDCl3). Compound 3a: 1.13 (s, 36H,
ArC(CH3)3); 1.30 (t, 12H, J=7.8 Hz, CH3); 1.35 (s, 18H, ArC(CH3)3); 2.79 (bs, 4H, OCH2); 3.01 (bs, 4H, OCH2);
3.37 (d, 2H, J=15.0 Hz, ArCH2Ar); 3.95 (s, 4H, OCH2); 4.25±4.37 (m, 16H, COOCH2 and OCH2CO); 4.37 (d,
4H, J=15.3 Hz, ArCH2Ar); 4.43 (d, 4H, J=15.3 Hz, ArCH2Ar); 4.59 (d, 2H, J=15.0 Hz, ArCH2Ar); 6.98, 7.24,
7.65 (s each, 4H each, ArH). MS (FAB): m/z=1431 (MH+). Anal. calcd for C88H118O16: C, 73.82; H, 8.31. Found:
C, 73.80; H, 8.35. Compound 3b: 0.90 (s, 36H, ArC(CH3)3); 1.10 (t, 12H, J=7.5 Hz, CH3); 1.37 (s, 18H,
ArC(CH3)3); 3.15 (bs, 4H, OCH2); 3.33 (d, 2H, J=15.3 Hz, ArCH2Ar); 3.56 (m, 4H, OCH2); 4.08 (bs, 8H,
OCOCH2); 4.42 (d, 4H, J=13.3 Hz, OCH2CO); 4.49 (d, 4H, J=13.3 Hz, OCH2CO); 4.52 (d, 4H, J=15.6 Hz,
ArCH2Ar); 4.71 (d, 4H, J=15.6 Hz, ArCH2Ar); 4.78 (d, 2H, J=15.3 Hz, ArCH2Ar); 6.61 (s, 4H, ArH); 6.88 (s,
8H, ArH); 7.30 (s, 4H, ArH). MS (FAB) m/z=1480 (M+2H+). Anal. calcd for C92H118O16: C, 74.67; H, 8.04.
Found: C, 74.72; H, 7.95. Compound 4a: 0.85 (s, 36H, ArC(CH3)3); 1.38 (s, 18H, ArC(CH3)3); 2.92 (bs, 4H,
OCH2); 3.18 (bs, 4H, OCH2); 3.34 (d, 2H, J=15.0 Hz, ArCH2Ar); 3.43 (d, 4H, J=15.6 Hz, ArCH2Ar); 3.67 (bs,
4H, OCH2); 3.79 (s, 12H, OCH3); 4.51 (d, 4H, J=15.6 Hz, ArCH2Ar); 4.62 (d, 4H, J=13.6 Hz, OCH2CO); 4.72
(d, 4H, J=13.6 Hz, OCH2CO); 4.84 (d, 2H, J=15.0 Hz, ArCH2Ar); 6.63, 6.95, 7.27 (s each, 4H each, ArH). MS
(FAB) m/z=1375 (MH+). Anal. calcd for C84H110O16: C, 73.33; H, 8.06. Found: C, 73.40; H, 8.01. Compound 4b:
0.86 (s, 36H, ArC(CH3)3); 1.38 (s, 18H, ArC(CH3)3); 3.17 (bs, 4H, OCH2); 3.32 (d, 2H, J=15.3 Hz, ArCH2Ar);
3.51 (bs, 12H, OCH3); 3.56 (s, 4H, OCH2); 4.44±4.54 (m, 12H, OCH2CO and ArCH2Ar); 4.67 (d, 4H, J=15.0 Hz,
ArCH2Ar); 4.72 (d, 2H, J=15.3 Hz, ArCH2Ar); 6.62 (s, 4H, ArH); 6.94 (s, 8H, ArH); 7.30 (s, 4H, ArH). MS
(FAB) m/z=1423 (MH+). Anal. calcd for C88H110O16: C, 74.23; H, 7.79. Found: C, 73.27; H, 7.72.