Synthesis and metal ion complexation studies of proton-ionizable calix[4]azacrown ethers in the 1,3-alternate conformation

Article abstract of DOI:10.1021/jo9912754

A series of novel N-chromogenic calix[4]arene azacrown ethers were synthesized as selective extractants of potassium ion. 1,3-Alternate calix[4]arene azacrown ethers were prepared by reacting 25,27-dipropyloxy- 26,28-bis(5-chloro-3-oxapentyloxy) calix[4]arenes with p-toluenesulfonamide in the presence of potassium carbonate. The coupling reaction of calix[4]arene azacrown ether with 2-hydroxy-5-nitrobenzyl bromide in the presence of triethylamine in THF gave the chromogenic calix[4]arene azacrown ether in moderate yield. These compounds show high potassium selectivity over other metal ions as shown by two-phase extraction, bulk liquid membrane, and ¹H NMR studies on a ligand-metal complex. It is assumed that the OH of the chromogenic group attached on nitrogen can assist the complexation by encapsulation of the metal.

Full text of DOI:10.1021/jo9912754

2386
J . Org. Chem. 2000, 65, 2386-2392
Syn th esis a n d Meta l Ion Com p lexa tion Stu d ies of P r oton -Ion iza ble
Ca lix[4]a za cr ow n Eth er s in th e 1,3-Alter n a te Con for m a tion
J ong Seung Kim,*,† Ok J ae Shon,† J ong Won Ko,‡ Moon Hwan Cho,‡ Ill Yong Yu,† and
J acques Vicens§
Department of Chemistry, Konyang University, Nonsan 320-711, Korea, Department of Chemistry,
Kangwon National University, Chuncheon 200-701, Korea, and Ecole Europeenne de Chimie Polymeres et
Materiaiaux (ECPM), 25, rue Becquerel, Strasbourg, F-67087 Cedex, France
Received August 10, 1999
A series of novel N-chromogenic calix[4]arene azacrown ethers were synthesized as selective
extractants of potassium ion. 1,3-Alternate calix[4]arene azacrown ethers were prepared by reacting
25,27-dipropyloxy-26,28-bis(5-chloro-3-oxapentyloxy) calix[4]arenes with p-toluenesulfonamide in
the presence of potassium carbonate. The coupling reaction of calix[4]arene azacrown ether with
2-hydroxy-5-nitrobenzyl bromide in the presence of triethylamine in THF gave the chromogenic
calix[4]arene azacrown ether in moderate yield. These compounds show high potassium selectivity
over other metal ions as shown by two-phase extraction, bulk liquid membrane, and 1H NMR studies
on a ligand-metal complex. It is assumed that the OH of the chromogenic group attached on
nitrogen can assist the complexation by encapsulation of the metal.
In tr od u ction
uents.12 Phenol-containing lariat azacrown ethers have
been shown to be able to selectively extract cations from
water into an organic phase. For instance, N-(2-hydroxy-
5-nitrobenzyl)-aza-15-crown-5 (1) and N-(2-hydroxy-5-
nitrobenzyl)-aza-18-crown-6 (2) were synthesized, and the
extractability of alkali metal ions was measured. Com-
pound 1 showed Li+ selectivity whereas 2 showed K+
selectivity due to size agreement between the metal ion
and the cavity of the corresponding azacrown ether.13
Azacrown ethers are often used as precursors for
structurally modified macrocyclic ion-complexing agents
due to the attachment of pendant groups to the secondary
nitrogen atom. Most often, pendant groups such as
carboxylic acid,1-4 chromogenic,1 and fluorogenic groups5
are involved in the metal ion-binding process that is
centered within the macrocyclic polyether ring and alter
the complexation behavior relative to that of the parent
crown ether.6,7 The use of chromogenic moieties to evalu-
ate metal ion complexation by crown ethers was intro-
duced by Pedersen early in the development of crown
ether chemistry.8,9 In his method, the concentration of
picrate anion extracted from an aqueous phase into an
organic layer using crown ether was determined by UV
spectrophotometry. One of the primary goals in designing
spectrophotometric reagents for the determination of
metal ions is their potential use in clinical diagnostic
instruments.10 For this purpose, instead of using chro-
mogenic anion extraction during metal ion extraction for
the determination of metal ions, several researchers have
developed crown ethers with a chromogenic moiety
covalently attached to the crown ether structure.11 Phe-
nolic groups are widely used as proton-ionizable substit-
* To whom correspondence should be addressed.
† Konyang University.
Calix[4]arenes have been shown to be useful 3-D
molecular building blocks for the synthesis of receptors
with specific properties.14 They can exist in four different
conformations: cone, partial cone, 1,2-alternate, and 1,3-
alternate.15,16 Calixcrown ethers have also attracted
intense interest as cesium-selective extractants. It has
been reported that 1,3-dialkoxycalix[4]arene crown-6
derivatives are exceptionally selective ionophores for
cesium ion due to the complexation of cesium ion not only
with the crown ether but also with the two aromatic rings
‡ Kangwon National University.
§ Ecole Europeenne de Chimie Polymeres et Materiaiaux.
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Commun. 1985, 1336.
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(6) Tsukube, H.; Adachi, H.; Morosawa, S. J . Chem. Soc., Perkin
Trans. 1 1989, 89.
(7) Inoue, Y.; Ouchi, M.; Hosoyama, K.; Hakushi, T.; Liu, Y.; Takeda,
Y. J . Chem. Soc., Dalton Trans. 1991, 1291.
(8) Pedersen, C. J . J . Am. Chem. Soc. 1967, 89, 2495.
(9) Pedersen, C. J . J . Am. Chem. Soc. 1967, 89, 7017.
(10) Czech, B. P.; Gebauer, C. R.; Kumar, A.; Sy-Icaza, S.; Barczak,
C.; Chapoteau, E.; Babb, D. A.; Czech, A.; Bartsch, R. A. Clin. Chem.
1986, 32, 1173.
(11) Vo¨gtle, F.; Weber, E. In Host-Guest Complex Chemistry,
Macrocycles; Springer-Verlag: Berlin, 1985; pp 84, 90, 189, 217.
(12) (a) McDaniel, C. W.; Bradshaw, J . S.; Izatt, R. M. Heterocycles
1990, 30, 665. (b) Nakamura, H.; Sakka, H.; Takagi, M.; Ueno, K.
Chem. Lett. 1981, 1305.
10.1021/jo9912754 CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/28/2000

Proton-Ionizable Calix[4]azacrown Ethers
J . Org. Chem., Vol. 65, No. 8, 2000 2387
Sch em e 1. P r op osed Syn th etic Rou te for
Com p ou n d 8
(cation/π-interaction) when fixed in the 1,3-alternate
conformation.17-21
From this point of view, it is possible that the combi-
nation of N-chromogenic azacrown ether and calixcrown
ether would result in an optimized structure for metal
ion encapsulation due to (1) electrostatic interactions
between the metal ion and both the oxygens and a
nitrogen as electron donors, (2) π-metal interactions
between the metal ion and two rotated aromatic nuclei
of the 1,3-alternate calixarene, and (3) an extra pendant
chromogenic group attached to nitrogen, which can
promote metal complexation by 3-D encapsulation under
basic conditions. With this in mind, we sought to syn-
thesize chromogenic calixazacrown ethers and to inves-
tigate their complexation behavior toward alkali metal
ions through bulk liquid membrane, solvent extraction,
1
and H NMR studies.
Resu lts a n d Discu ssion
Scheme 1 shows our first approach to receptor 8.
N-Tosyl tetraethylene glycol 5 was prepared in good yield
by reacting p-toluenesulfonamide with 2-(2-chloroethoxy)-
ethanol in the presence of K2CO3 in DMF.22 Glycol 5 was
further transformed into dimesylate 6 by reaction with
mesyl chloride in the presence of NEt3 in CH2Cl2. 1,3-
Dipropyl calix[4]arene 7 in a cone conformation was
synthesized by reacting calix[4]arene with 1-iodopropane
using K2CO3 in refluxing acetonitrile. 1,3-Dipropyl calix-
[4]arene 7 was then reacted with dimesylate 6 in the
presence of Cs2CO3 according to a “cesium effect” occur-
ring in cyclization.23 Surprisingly, under our experimen-
tal conditions we isolated biscalixarene 9 instead of the
desired 1,3-bridged calix[4]arene 8. The dimeric structure
Sch em e 2. Alter n a te Syn th etic Meth od for
Ca lix[4]a r en e Aza cr ow n Eth er 11
(13) (a) Gutsche, C. D. Calixarenes; Royal Society of Chemistry:
Cambridge, 1989. (b) Gutsche, C. D. In Synthesis of Macrocycles:
Design of Selective Complexing Agents; Izatt, R. M., Christensen, J .
J ., Eds.; Wiley: New York, 1987; p 93. (c) Calixarenes: A Versatile
Class of Macrocyclic Compounds; Vicens, J ., Bo¨hmer, V., Eds.; Klu-
wer: Dordrecht, 1991. (d) Bo¨hmer, V.; McKervey, M. A. Chemie in
unserer Zeit 1991, 195. (e) Gutsche, C. D. Calixarenes, Monographs in
Supramolecular Chemistry; Stoddart, J . F., Ed.; Royal Society of
Chemistry: Cambridge, U. K., 1989; Vol. 1. (f) Gutsche, C. D. In
Inclusion Compounds; Atwood, J . L., Davies, J . E. D., MacNicol, D.
D., Eds.; Oxford University Press: New York, 1991; Vol. 4, pp 27-63.
(g) Van Loon, J .-D.; Verboom, W.; Reinhoudt, D. N. Org. Prep. Proc.
Int. 1992, 24, 437-462. (h) Ungaro. R.; Pochini, A. In Frontiers in
Supramolecular Organic Chemistry and Photochemistry; Schneider,
H.-J ., Eds.; VCH: Weinheim, Germany, 1991; pp 57-81.
(14) Andreetti, G. D.; Ugozzoli, F.; Ungaro, R.; Pochini, A. In
Inclusion Compounds; Atwood, J . L., Davies, J . E. D., MacNicol, D.
D., Eds.; Oxford University Press: New York, 1991; Vol. 4, pp 64-
125.
(15) Casnati, A.; Pochini, A.; Ungaro, R.; Ugozzoli, F.; Arnaud, F.;
Fanni, S.; Schwing, M.-J .; Egberink, R. J . M.; de jong, F.; Reinhoudt,
D. N. J . Am. Chem. Soc. 1995, 117, 2767.
(16) Kim, J . S.; Suh, I. H.; Kim, J . K.; Cho, M. H. J . Chem. Soc.,
Perkin Trans. 1 1998, 2307.
(17) Kim, J . S.; Ohki, A.; Ueki, R.; Ishizuka, T.; Shimotashiro, T.;
Maeda, S. Talanta 1999, 48, 705-710.
(18) Kim, J . S.; Ohki, A.; Cho, M. H.; Kim, J . K.; Ra, D. Y.; Cho, N.
S.; Bartsch, R. A.; Lee, K. W.; Oh, W. Z. Bull. Kor. Chem. Soc. 1997,
18, 1014.
(19) Kim, J . S.; Lee, W. K.; Ra, D. Y.; Lee, Y. I.; Choi, W. K.; Lee, K.
W.; Oh, W. Z. Microchem. J . 1998, 59, 464.
(20) Kim, J . S.; Pang, J . H.; Yu, I. Y.; Lee, W. K.; Suh, I. H.; Kim,
J . K.; Cho, M. H.; Kim, E. T.; D. Y. Ra. J . Chem. Soc., Perkin Trans.
2 1999, 837.
(21) Kruizinga, W. H.; Kellogg, R. M. J . Am. Chem. Soc. 1981, 103,
5183.
(22) Anelli, P. L.; Montanari, F.; Quici, S.; Ciani, G.; Sironi, A. J .
Org. Chem. 1988, 53, 5292. (The reaction conditions are similar, but
the workup and purification processes are somewhat different.)
(23) Gokel, G. W.; Garcia, B. J . Tetrahedron. Lett. 1977, 4, 317.
of 9 was confirmed by 1H NMR, 13C NMR, and mass
spectrometry. We then decided to use a different pathway
(see Scheme 2) to receptor 11. 1,3-Dipropyl calix[4]arene
7 was first reacted with ethylene glycol ditosylate in
refluxing acetonitrile in the presence of Cs2CO3. The
product calixarene 10 was shown to be in the 1,3-
alternate conformation. Compound 10 was reacted with
diethanolamine in the presence of NaH to afford 1,3-
dipropyl calix[4]azacrown 11 in only 10% yield. The use

2388 J . Org. Chem., Vol. 65, No. 8, 2000
Kim et al.
Sch em e 3. Syn th etic Sch em e for Ch r om ogen ic
Ca lix[4]a r en e Aza cr ow n Eth er s 3 a n d 4
and 14 are consistent with those expected for the 1,3-
alternate conformations. The use of Cs2CO3 as a base for
this cyclization gave a lower yield than with K2CO3. For
detosylation, sodium-mercury amalgam in a mixture of
1,4-dioxane and methanol provided 11 and 15 in good
yield. A chromogenic pendant arm was attached to the
nitrogens of 11 and 15 using 2-bromomethyl-4-nitrophe-
nol in the presence of triethylamine to give final products
3 and 4, respectively, in quantitative yield after reaction
at room temperature. The synthesis of 11 and its
analogues as mentioned above allows us to synthesize
N-substituted calix[4]arene azacrown ethers for further
synthesis and complexation studies.
The ratio of ligand 3 to potassium ion was assessed by
high-resolution mass spectrometry. Ionophore 3 was
reacted with potassium picrate in chloroform. The mo-
lecular ion peak (M + 1) for 3 occurred at m/z 817.3, and
the parent ion peak appeared at m/z 855.2, which
corresponds to a 1:1 complex of 3‚K+. No other mass
fragmentation (e.g., 1:2 or 2:1) complexes were observed.
Complexation selectivity was initially measured by 1H
NMR spectroscopy, as shown in Figure 1. Ligand 3 was
chosen to investigate NMR behavior because it showed
the best selectivity for potassium ion in bulk liquid
membrane and solvent extraction experiments. Com-
pound 3 is blocked in a 1,3-alternate conformation based
on its NMR spectrum (A, Figure 1): a singlet peak at δ
1
3.84 in H NMR for bridging four methylene hydrogens
(Ar-CH2-Ar) and one signal at 38.8 ppm in the 13C NMR
spectrum for bridging methylene carbons (Ar-CH2-Ar).
In the case of ligand-metal picrate complex, the NMR
spectral patterns changed remarkably with respect to
splitting and chemical shift, as indicated in Figure 1.
First, in the case of 3‚Na+ (spectrum B), no peaks were
observed for picrate anion or complexed ligand. All of the
peaks are identical to those of the parent ligand 3,
indicating that complexation with Na+ did not occur.
Interestingly, 3‚K+ (spectrum C) gave rise to remarkable
changes in both chemical shift values and splitting
patterns.
The area under a picrate anion peak at δ 8.84 was
87% of that of the parent ligand, implying that 87% of
the ligand-metal ion complex was formed in chloroform.
This percentage was confirmed by changes in the chemi-
cal shift of bridged -CH2- (δ 4.01) between azacrown
and nitrophenol units as well as those of protons for
-CH2CH2N- (δ 2.66). In addition, a multiplet pair of
-OCH2CH2CH3 at δ 1.21-1.15 and a triplet pair of
-OCH2CH2CH3 at δ 0.71 were shifted downfield to δ 1.51
and 1.83, respectively, which indicates strong complex-
ation with potassium ion. In the case of 3‚Rb+ (spectrum
D), about 60% complexation was calculated from the
change in the chemical shift and integration of the shifted
peak. For 3‚Cs+ (spectrum E), a tiny peak of the picrate
and no significant changes in the chemical shift were
observed, which indicate no complexation with cesium
ion. A singlet at 3.80 ppm corresponding to ArCH2Ar was
split into a multiplet in the case of complexation with
potassium and rubidium ion due to a loss of symmetry.
This potassium-selective response in NMR with respect
to changes in the chemical shift and peak splitting are
in good agreement with the results of two-phase extrac-
tion and selective metal ion transport experiments (vide
infra).
of different bases (K2CO3, Cs2CO3) in various solvents
(DMF, acetonitrile, THF) did not improve the yields.
Interestingly, we found that the best way to prepare
cyclization products 8 and 14 was as indicated in Scheme
3. First alkylation of compound 7 with monotosylates
gave tetraalkylated calix[4]arenes 12 and 13, respec-
tively, which are blocked in a 1,3-alternate conformation
based on the 1H NMR spectra (CDCl3), which show a
singlet peak at δ 3.70 for the bridging methylene hydro-
gens of the calix[4]arene framework. The 13C NMR
spectra for these compounds reveal one signal around
38.0 ppm, which is characteristic of the 1,3-alternate
conformation. Cyclization of 12 and 13 using p-toluene-
sulfonamide in the presence of K2CO3 in DMF provided
the desired products 8 and 14, respectively, in moderate
yield (see Experimental Section). The NMR spectra of 8
Metal-binding properties were estimated using UV-
vis absorption spectroscopy. Two-phase extractions were

Proton-Ionizable Calix[4]azacrown Ethers
J . Org. Chem., Vol. 65, No. 8, 2000 2389
F igu r e 2. Metal ion-dependent changes in the UV spectrum
of calixazacrown ether 3.
Ta ble 1. Solven t Extr a ction Resu lts for Alk a li Meta l
Ion s Usin g Va r iou s Or ga n ic Liga n d sa
extractability %b
compound
Lsti+
Na+
K+
Rb+
Cs+
1
2
3
4
36.05
9.79
17.44
7.45
14.19
10.74
3.57
17.55
65.56
32.24
30.59
19.89
26.01
25.47
13.81
5.41
9.01
1.57
5.95
10.42
a
Source phase (aqueous solution of metal nitrate, 3 mL), MNO3
) 1.2 mM, pH )12 adjusted by tetramethylammonium hydroxide;
organic phase (ClCH2CH2Cl, 3 mL), (carrier) ) 0.1 mM. b Extract-
ability ) (concentration of extracted metal)/(concentration of
organic ligand) × 100%: the average value of three independent
determinations.
droxide. Under neutral conditions, no significant changes
in the UV spectra were observed. The most selective and
distinctive UV band was observed with pH 12, as shown
in Figure 2. Significant bathochromic shifts from 326 nm
(parent ligand only) to 428 nm (phenoxide band) were
observed upon ligand-metal complexation. In addition,
for K+, a very prominent hyperchromic shift was ob-
served, indicating that the potassium ion is selectively
encapsulated by the azacrown cavity, assisted by the
simultaneous attachment of a nitrophenoxy to nitrogen.
There were no detectable spectral changes upon the
extraction of Na+.
Two-phase extraction experiments using various ligands
were carried out, and the results are described in Table
1. pH-dependent extraction was also carried out. Under
neutral conditions, a small amount of metal ion was
extracted, but no selectivity was observed. At pH 12, the
selectivity for potassium ion was greater than those for
other alkali metal ions. An increase in the ring size of
the azacrown ether (n ) 1 f 2) enhanced both K+/Na+
and K+/Cs+ selectivity, indicating that the ring size
agreed with the size of the potassium ion. For calixarene
3, extractability was not as high as that with 2, but the
selectivities toward K+/Na+ and K+/Cs+ were increased.
As indicated earlier, for 4 the cavity is too large to accept
the potassium ion, resulting in decreased extractability.
We also used a bulk liquid membrane to measure
transport rates of metal ions from an aqueous source
phase into an aqueous receiving phase through an
F igu r e 1. 1H NMR spectra of 3 (A) and 3M+Pic- (B-E) in
CDCl3. Closed (b) and open (O) circles are for complexed and
uncomplexed ligand, respectively.
carried out using various organic ligands with a nitro-
phenol unit as a chromogenic sidearm. The proton-
ionizable chromogenic calixarene can extract certain
cations from a basic aqueous phase to an organic phase
by complexation. Upon complexation, calixarene aza-
crown ether undergoes proton-dissociation on the pen-
dant phenolic group of the chromophores to yield an
anion which in turn interacts intramolecularly with a
metal ion complexed by the azacrown ether moiety.25 The
ability of the calixarene azacrown ether to extract metal
ion can be estimated by UV-spectral changes. In this
extraction experiment, the pH of the aqueous phase was
varied from 7 to 13 using tetramethylammonium hy-
(24) Kimura, K.; Tanaka, M.; Iketani, S.; Shono, T. J . Org. Chem.
1987, 52, 836.
(25) Bartsch, R. A.; Yang, I. W.; J eon, E. G.; Walkowiak, W.;
Charewicz, W. A. J . Coord. Chem. 1992, 27, 75.

2390 J . Org. Chem., Vol. 65, No. 8, 2000
Kim et al.
Ta ble 2. Sin gle Ion Tr a n sp or t Va lu es for Alk a li Meta l
Ion s th r ou gh a Bu lk Liqu id Mem br a n e Usin g Va r iou s
Or ga n ic Liga n d sa
moiety but also with two aromatic nuclei (cation/π-
interaction) in the 1,3-alternate conformation.
In conclusion, calix[4]arene azacrown ethers were
synthesized with moderate yield in a 1,3-alternate con-
formation. Attachment of a proton-ionizable group as a
pendant unit onto the nitrogen of the calix[4]arene
azacrown framework was also successful. Complexation
studies by 1H NMR, two-phase extraction, and bulk liquid
membrane were carried out to give high potassium ion
selectivity. This potassium selectivity may be due to
electrostatic interaction between the metal ion and the
polyether cavity composed of oxygens and nitrogen as
electron donors, and π-metal interaction between the
metal ion and two aromatic rings of the 1,3-alternate
calixarene. In addition, an extra pendant chromogenic
nitrophenol group attached to nitrogen may play a role
in this metal complexation by encapsulation under basic
conditions.
b
transport rate (10-8 mol‚s-1‚m-2
)
compound
Li+
Na+
K+
Rb+
Cs+
2
11
3
92.54
0.00
248.75
99.99
4.20
9.87
75.38
128.55
172.11
115.31
117.82
134.21
109.17
19.89
160.74
a
Transport conditions: source phase (aqueous solution of metal
hydroxide, 0.8 mL, 0.1 M); membrane phase (ClCH2CH2Cl, 3.0
mL), (carrier) ) 1.0 mM; i.d. of glass vial ) 18 mm, stirred by 13
mm Teflon-coated magnetic stirring bar driven by
a Hurst
Synchronous motor; receiving phase (0.1 M aqueous HNO3, 5.0
b
mL). The average value of three independent determinations.
The experimental values deviate from the reported values by an
average of 10%.
Ta ble 3. Com p etitive Tr a n sp or t Ra te of Alk a li Meta l
Ion s th r ou gh a Bu lk Liqu id Mem br a n e Usin g Va r iou s
Or ga n ic Liga n d sa
b
transport rate (10-8 mole‚s-1‚m-2
)
Exp er im en ta l Section
compound
K+/Li+/Na+
K+/Rb+/Cs+
Unless specified otherwise, reagent-grade reactants and
solvents were obtained from chemical suppliers and used as
received. Dry solvents were prepared as follows: tetrahydro-
furan was freshly distilled from sodium metal ribbon or
chunks; benzene and pentane were stored over sodium ribbon,
respectively. Acetonitrile was dried over molecular sieves (3
Å) and distilled over diphosphorus pentaoxide. DMF was dried
over 4 Å molecular sieves. Compounds 1,12 2,12 and 717 were
prepared according to methods described in the literature.
Syn t h esis. N-(2-H yd r oxy-5-n it r ob en zyl)-25,27-b is-(1-
p r op yloxy)ca lix[4]a r en e Aza cr ow n -5 (3), 1,3-Alter n a te.
Under nitrogen, to a solution of 1.0 g (1.51 mmol) of calix[4]-
arene azacrown ether (11) and 0.24 mL (3.31 mmol) of
triethylamine in 100 mL of THF was added dropwise 0.38 g
(1.6 mmol) of 2-bromomethyl-4-nitrophenol over 30 min at 0
°C. Upon complete addition, the reaction solution was stirred
for 8 h at 0 °C, and then stirred for an additional 6 h at 65 °C.
Removal of THF in vacuo gave a yellow oil. The crude product
was extracted several times with CH2Cl2 (100 mL) and water
(100 mL). Column chromatography using ethyl alcohol/ethyl
acetate (v/v) ) 1:1 as an eluent on silica gel gave the desired
product as a yellow solid in 73% yield. Mp 150-152 °C. IR
(deposit, cm-1): 3358 (O-H). FAB MS m/z (M+) calcd 816.20,
found 816.48. Anal. Calcd for C49H56N2O9: C, 72.05; H, 6.86.
Found: C, 72.12; H, 6.76.
2
11
3
18.35/0.00/9.72
60.92/0.00/6.59
125.65/0.00/2.88
12.39/0.00/4.01
25.16/3.10/0.45
45.50/49.11/3.81
22.10/10.26/0.59
11.32/16.39/35.09
4
a
Transport conditions: same as Table 1 except that the source
phase (0.8 mL) is composed of 0.034 M of each metal hydroxide
and 0.066 M of the corresponding metal nitrate. The average
value of three independent determinations. The experimental
values deviate from the reported values by an average of 10%.
b
organic bulk membrane. The source and receiving phases
consist of 0.8 mL of 0.1 M alkali metal hydroxide and
5.0 mL of 0.1 M HNO3, respectively. Organic medium
consists of a solution of 3.0 mL of 1.0 mM ligand in 1,2-
dichloroethane. The measured flux values from a single
transport experiment in bulk liquid membrane are shown
in Table 2. For 11, stirring for 24 h at room temperature
gave transport rates of 0.00, 4.20, 128.55, 117.82, and
19.89 (unit: 10-8 mol s-1 m-2) for Li, Na, K, Rb, and Cs
ion, respectively, indicating potassium selectivity. No
transport of lithium ion was observed. However, attach-
ment of the nitrophenol group as a pendant group to a
N-azacrown framework enhanced the lithium transport
rate. It has been reported that the nitrophenol unit is
well matched with lithium ion under pH conditions high
enough for OH to be deprotonated.12 Compound 3 shows
high potassium selectivity over sodium ion, but a large
amount of lithium ion was also transported. A competi-
tive ion transport experiment, which is the most ap-
plicable in an industrial setting, provides high potassium
selectivity, as shown in Table 3 i.e., lithium ion is not
easily encapsulated into the calixarene cavity in the
presence of potassium ion. This potassium selectivity is
increased in the case of 3 suitable for potassium ion. For
4, a slow transport rate was observed for all of the alkali
metal ions. This may be due to the fact that the large-
cavity azacrown has to undergo considerable folding/
twisting to bring the binding sites into close proximity
with the cation, and such ordering would be entropically
unfavorable. High potassium ion selectivity in this single
and competitive ion transport indicates that the ring size
of an azacrown cavity containing a calix[4]arene network
agrees well with the diameter of potassium ion. In this
study, for potassium selectivity, we assume a mechanism
similar to that proposed by Reinhoudt,16 where the
complexed ion interacts not only with the azacrown ether
N-(2-Hyd r oxy-5-n it r ob en zyl)-25,27-bis-(1-p r op yloxy)-
ca lix[4]a r en e Aza cr ow n -5 (4), 1,3-Alter n a te. Compound 4
was prepared almost the same as for 3 and isolated as a yellow
oil in 75% yield. IR (neat, cm-1): 3345 (O-H). FAB MS m/z
(M+) calcd 904.12, found 904.48. Anal. Calcd for C53H64N2O11
C,67.69; H, 7.07. Found: C, 67.71; H, 7.11.
:
N,N-Bis[2-(2-h yd r oxyeth oxy)eth yl]-p-tolu en esu lfon a -
m id e (5).22 Under nitrogen, a solution of K2CO3 (10.49 g, 0.076
mol) and 2-(2-chloroethoxy)ethanol (9.46 g, 0.076 mol) in 70
mL of predried DMF was refluxed for 1 h. p-Toluenesulfona-
mide (5.0 g, 0.029 mol) in 20 mL of dried DMF was added
dropwise for 1 h, and the reaction mixture was then refluxed
for an additional 4 h. After a white precipitate was filtered,
removal of DMF in vacuo gave a brownish oil. One hundred
milliliters of NaHCO3 and 100 mL of CH2Cl2 were added. The
organic layer was separated and washed twice with brine. The
CH2Cl2 solution was dried over MgSO4, filtered, and evapo-
rated in vacuo to give an oil. Column chromatography on silica
gel with ethyl acetate:hexane (1:1) as an eluent (Rf ) 0.2)
provided 6.43 g (68% yield) of the desired product as a colorless
oil. IR (neat, cm-1): 3400 (O-H), 1334 (SO2), 1153 (SO2).
N,N-Bis[2-[2-[(m eth ylsu lfon yl)oxy]eth oxy]eth yl]-p-tol-
u en esu lfon a m id e (6).22 A solution of 5 (2.0 g, 5.76 mmol)
and triethylamine (3.99 mL, 28.78 mmol) in 50 mL of CH2Cl2
was cooled to 0 °C. Methanesulfonyl chloride (1.7 mL, 23.02
mmol) dissolved in 10 mL of CH2Cl2 was added dropwise over

Proton-Ionizable Calix[4]azacrown Ethers
J . Org. Chem., Vol. 65, No. 8, 2000 2391
30 min. The reaction temperature was raised to 25 °C, and
the mixture was stirred for an additional 2 h to complete the
reaction. One hundred milliliters of ice-water was added
carefully, and the organic solution was separated and washed
with 5% NaHCO3 (100 mL × 2) and brine (100 mL × 2). The
CH2Cl2 solution was dried over MgSO4, filtered, and evapo-
rated in vacuo to give an oil. Recrystallization using 50 mL of
diethyl ether gave 6 as a white solid in 68% yield. Mp 102-
103 °C. IR (KBr pellet, cm-1): 1350 (SO2), 1181 (SO2), and 1124
(C-O).
N-Tosyl 25,27-Bis(1-p r op yloxy)ca lix[4]a r en e Aza -
cr ow n -5 (8). Under nitrogen, to a three-neck round-bottom
flask were added K2CO3 (0.96 g, 6.95 mmol), 30 mL of predried
DMF, 12 (1.00 g, 1.38 mmol), and p-toluenesulfonamide (0.23
g, 1.38 mmol), and the mixture was refluxed for 24 h. DMF
was completely removed in vacuo, and 100 mL of 10% aqueous
NaHCO3 solution and 100 mL of CH2Cl2 were added. The
organic layer was separated and washed with water (50 mL
× 2), dried over MgSO4, and then filtered. Evaporation of CH2-
Cl2 in vacuo gave a yellowish oil which was purified by column
chromatography (Rf ) 0.3) using ethyl acetate:hexane (1:8) to
provide 0.9 g (72%) of 8 as a white solid. Mp 168-171 °C. IR
(KBr pellet, cm-1): 1340 (SO2), 1092 (SO2). FAB MS m/z (M+)
calcd 819.2, found 820.3. Anal. Calcd for C49H57NO8S: C, 71.79;
H, 6.96. Found: C, 71.52; H, 6.94.
Dou bly 25,27-Bis(1-p r op yloxy)ca lix[4]a r en e Aza cr ow n
Eth er (9), 1,3-Alter n a te. Under nitrogen, a solution of 1,3-
dipropyloxy calix[4]arene 7 (1.59 g, 2.91 mmol), 6 (0.99 g, 1.97
mmol), and Cs2CO3 (3.2 g, 9.83 mmol) in 50 mL of acetonitrile
was refluxed for 24 h. The mixture was cooled to room
temperature, and excess Cs2CO3 was filtered out. The aceto-
nitrile was removed in vacuo, and 50 mL of water and 50 mL
of CH2Cl2 were then added. The organic layer was separated
and washed sequentially with 10% aqueous NaHCO3 solution
and 100 mL of water. The CH2Cl2 solution was dried over
MgSO4, filtered, and evaporated in vacuo to give an oil.
Column chromatography on silica gel with ethyl acetate:
hexane (1:3) as an eluent (Rf ) 0.5) provided a solid which
could be recrystallized using 50 mL of diethyl ether to give 9
as a white solid (34% yield). Mp 212-214 °C. IR (KBr pellet,
cm-1): 1343 (SO2), 1096 (SO2). FAB MS m/z (M+) calcd 1562.1,
found 1695.1 (ligand Cs+).
25,27-Bis(1-p r op yloxy)-26,28-b is(5-ch lor o-3-oxa p en t -
yloxy)ca lix[4]a r en e (12), 1,3-Alter n a te. A solution of 1,3-
dipropyl calix[4]arene 7 (0.92 g, 1.81 mmol), 2-(2-chloroethoxy)-
ethanol p-toluenesulfonate (1.84 g, 3.62 mmol), and Cs2CO3
(1.2 g, 3.62 mmol) in 50 mL of acetonitrile was heated at reflux
for 24 h under nitrogen. The reaction mixture was allowed to
cool to room temperature, and 100 mL of 10% HCl aqueous
solution and 50 mL of CH2Cl2 were then added. The organic
phase was separated and dried over MgSO4. The organic
solution was filtered and then evaporated in vacuo to afford a
brownish oil. Column chromatography on silica gel with ethyl
acetate:hexane (1:8) as an eluent (Rf ) 0.5) provided 0.78 g
(60% yield) of 12 as a white solid. Mp 149-151 °C. IR (KBr
pellet, cm-1): 1050 (C-O). FAB MS m/z (M+) calcd 721.77,
found 722.60. Anal. Calcd for C42H50Cl2O6: C, 69.90; H, 6.93.
Found: C, 69.71; H, 6.96.
25,27-Bis(8-ch lor o-3,6-d ioxa octyloxy)-26,28-bis(1-p r o-
p yloxy)ca lix[4]a r en e (13), 1,3-Alter n a te. Compound 13 was
prepared by almost the same method that used for 12. 78%
yield. Mp 150-154 °C. IR (KBr pellet, cm-1): 1050 (C-O). FAB
MS m/z (M+) calcd 809.01, found 810.10. Anal. Calcd for C46H58
-
Cl2O8: C, 68.23; H, 7.17. Found: C, 68.31; H, 7.20.
N-Tosyl 25,27-Bis(1-p r op yloxy)ca lix[4]a r en e Aza -
cr ow n -7 (14), 1,3-Alter n a te. Compound 14 was prepared by
the method that was used for 8. 70% yield. Mp 170-172 °C.
IR (KBr pellet, cm-1): 1344 (SO2), 1094(SO2). FAB MS m/z
(M+) calcd 907.20, found 907.70. Anal. Calcd for C53H65
NO10S: C, 7.12; H, 7.16. Found: C, 70.20; H, 7.06.
-
25,27-Bis(1-p r op yloxy)ca lix[4]a r en e a za cr ow n -7 (15),
1,3-Alter n a te. Detosylation of 14 was performed according
to the method used for 11. Yellowish oil. 48% yield, IR (neat,
cm-1): 3324 (N-H). FAB MS m/z (M+) calcd 753.01, found
754.40 (M + 1). Anal. Calcd for C46H59NO8: C, 73.30; H, 7.83.
Found: C, 73.41; H, 7.71.
1
1H NMR of Com p lex. H NMR samples for metal picrate
complexes were prepared as follows. A mixture of ligand 3 (20
mg) and excess metal picrate (over at least 5 equiv) in CHCl3
(10 mL) was stirred for 1 h. After filtration of the precipitated
metal picrate, the filtrate was dried in vacuo to give a yellow
solid complex 3‚M+Pic-, which is soluble in CDCl3.
3‚Na+Pic-: no peak was considerably different from that
with free ligand 3.
3‚K+Pic-: δ 8.84 (s, 2 H, Pic-H), 8.09 (d, 2 H, Ar-H), 7.90
(s, 1 H, Pic-H), 7.44-6.88 (m, 12 H, Ar-H), 4.01 (s, 2 H, NCH2-
Ar), 3.89-3.39 (m, 24 H, OCH2CH2O, OCH2CH2CH3), 2.66 (s,
4 H, OCH2CH2NCH2), 1.53-1.47 (m, 4 H, OCH2CH2CH3), 0.70
(t, 6 H, OCH2CH2CH3).
25,27-Bis(2-p-tolu en esu lfon yloxyeth yloxy)-26,28-bis(1-
p r op yloxy)ca lix[4]a r en e (10), 1,3-Alter n a te. Under nitro-
gen, a solution of 1,3-dipropyloxycalix[4]arene 7 (1.0 g, 1.96
mmol), ethyleneglycol di-p-toluenesulfonate (1.17 g, 4.1 mmol),
and Cs2CO3 (1.41 g, 4.3 mmol) in 50 mL of acetonitrile was
refluxed for 24 h. After cooling to room temperature, to this
reaction mixture were added 50 mL of 10% HCl aqueous
solution and 50 mL of CH2Cl2. The organic layer was separated
and washed twice with 100 mL of 10% NaHCO3 aqueous
solution and brine. The CH2Cl2 solution was dried over MgSO4,
filtered, and evaporated in vacuo to give a brownish oil.
Column chromatography on silica gel with ethyl acetate:
hexane (1:5) as an eluent (Rf ) 0.6) provided 10 as a colorless
oil in 37% yield. IR (KBr pellet, cm-1): 1451(SO2), 1192(SO2).
Anal. Calcd for C52H56O10S2: C, 69.02; H, 6.19. Found: C,
69.10; H, 6.26.
25,27-Bis(1-p r op yloxy)ca lix[4]a r en e Aza cr ow n -5 (11),
1,3-Alter n a te. Under nitrogen, to a solution of 10 mL of 1,4-
dioxane and 2 mL of methanol were carefully added 0.37 g
(2.56 mmol) of N-tosyl 25,27-bis(1-propyloxy)calix[4]arene
azacrown-5 (8) and 6.0 g of 6% Na(Hg) amalgam. The reaction
mixture was refluxed for 2 days at 80 °C. After cooling to room
temperature, the solvent was evaporated in vacuo. Fifty
milliliters of CH2Cl2 and 50 mL of water were added, and the
organic layer was separated. The CH2Cl2 layer was washed
twice with 10% aqueous Na2HPO4 solution and then dried over
MgSO4. After filtration of magnesium sulfate, removal of the
solvent in vacuo gave a yellow oil. Upon recrystallization from
30 mL of diethyl ether, 11 was obtained as a crystalline solid
(52% yield). Mp 187-189 °C. IR (KBr pellet, cm-1): 3312 (N-
H). FAB MS m/z (M+) calcd 665.0, found 665.7. Anal. Calcd
for C42H51NO6: C, 75.78; H, 7.67. Found: C, 75.81; H, 7.65.
3‚Rb+Pic-: δ 8.84 (s, 2 H, Pic-H), 8.09 (m, 3 H, Ar-H), 7.42-
6.82 (m, 12 H, Ar-H), 3.97 (s, 2 H, NCH2Ar, complexed),
3.92 (s, 2 H, NCH2Ar, uncomplexed), 3.92-3.36 (m, 24 H,
OCH2CH2O, OCH2CH2CH3), 2.71 (s, 4 H, OCH2CH2NCH2,
uncomplexed), 2.63 (4 H, OCH2CH2NCH2, complexed), 1.52-
1.49 (m, 4 H, OCH2CH2CH3, complexed), 1.22-1.13 (m, 4 H,
OCH2CH2CH3, uncomplexed), 0.85 (t, 6 H, OCH2CH2CH3,
complexed), 0.65 (t, 6 H, OCH2CH2CH3, uncomplexed).
3‚Cs+Pic-: δ 8.12 (d, 2 H, Ar-H), 7.62 (s, 1 H, Pic-H), 7.12-
6.81 (m, 12 H, Ar-H), 3.89 (s, 8 H, ArCH2Ar), 3.59 (s, 4 H,
OCH2CH2O), 3.50-3.31 (m, 8 H, OCH2CH2O and OCH2CH2-
CH3), 3.23 (s, 4 H), 2.70 (s, 4 H, OCH2CH2NCH2), 1.22-1.13
(m, 4 H), 0.65 (t, 6 H, OCH2CH2CH3).
Tw o-P h a se Extr a ction . Solvent extraction was based on
the microextraction technique reported by Bartsch and co-
workers.26 This method is fast and requires only a small
amount of organic ligand. An aqueous solution (3.0 mL) of 0.1
mM alkali metal nitrate in 0.01 M tetramethylammonium
hydroxide (for pH adjustment) and 0.1 mM (3.0 mL) organic
ligand in 1,2-dichloroethane in a 10-mL centrifuge tube were
mixed by vortex mixer for 5 min. After centrifugation, a 1.00-
mL sample of the aqueous layer was taken, and the concentra-
(26) (a) Gokel, G. In Crown Ethers & Cryptands; Stoddart, J . F.,
Ed.; The Royal Society of Chemistry: London, U. K, 1991; p 81. (b)
Lee, S. S.; J ung, J . H.; Yu, S. H.; Cho, M. H. Thermochim. Acta 1995,
259, 133.

2392 J . Org. Chem., Vol. 65, No. 8, 2000
Kim et al.
tion of metal ion in the aqueous phase was determined by an
atomic absorption spectrometer.
of the aqueous receiving phase was collected, and the flux
values (moles transported/s m2) were determined using a
Perkin-Elmer 2380 atomic absorption spectrophotometer.
Blank experiments in which no organic ligand was present
were performed to determine membrane leakage.
Tr a n sp or t of Alk a li Meta l Ion s in
a Bu lk Liqu id
Mem br a n e System . Liquid membrane transport experiments
were carried out using a bulk liquid membrane apparatus
consisting of a bulk, stirred organic phase that separates the
aqueous and receiving phases.27 The two aqueous phases were
separated by a 1,2-dichloroethane phase which constituted the
membrane. The details of the transport conditions for single
and competitive experiments are summarized in the footnotes
of Tables 2 and 3, respectively. Each experiment was repeated
three times in a room maintained at 25 ( 1 °C. Three millilters
Ack n ow led gm en t. This research was fully sup-
ported by a Grant from the Korea Research Foundation,
Korea (1998-001-D00499).
Su p p or tin g In for m a tion Ava ila ble: NMR data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(27) Cho, M. H.; Seon-Woo, K. W.; Hea, M. Y.; Lee, I. C.; Yoon, C.
J .; Kim, S. J . Bull. Kor. Chem. Soc. 1988, 9, 5.
J O9912754