Di-ionizable p-tert-butylcalix[4]arene-1,2-monothiacrown-3 ligands in the cone conformation: synthesis and metal ion extraction

Article abstract of DOI:10.1016/j.tet.2008.07.115

A series of di-ionizable calix[4]arene-1,2-crown-3 compounds with a sulfur-containing unit bridging the proximate phenolic oxygens have been synthesized. The ionizable groups are oxyacetic acid and N-(X)sulfonyl oxyacetamide groups with X=methyl, phenyl, 4-nitrophenyl, and trifluoromethyl, which 'tunes' the acidity of the latter. The efficiency and selectivity of these novel ligands are assessed for competitive solvent extractions of alkali metal cations and of alkaline earth metal cations from aqueous solutions into chloroform. Also the efficiencies for single species extractions of Pb²⁺ and of Hg²⁺ are determined. The results are compared with those reported previously for related ligands in which only oxygen heteroatoms are present in the crown ether unit.

Full text of DOI:10.1016/j.tet.2008.07.115

Tetrahedron 64 (2008) 9843–9849
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Di-ionizable p-tert-butylcalix[4]arene-1,2-monothiacrown-3 ligands
in the cone conformation: synthesis and metal ion extraction
*
Dongmei Zhang, Jennifer D. Crawford, Richard A. Bartsch
Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409-1061, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 June 2008
Received in revised form 31 July 2008
Accepted 31 July 2008
Available online 7 August 2008
A series of di-ionizable calix[4]arene-1,2-crown-3 compounds with a sulfur-containing unit bridging the
proximate phenolic oxygens have been synthesized. The ionizable groups are oxyacetic acid and
N-(X)sulfonyl oxyacetamide groups with X¼methyl, phenyl, 4-nitrophenyl, and trifluoromethyl, which
‘tunes’ the acidity of the latter. The efficiency and selectivity of these novel ligands are assessed for
competitive solvent extractions of alkali metal cations and of alkaline earth metal cations from aqueous
solutions into chloroform. Also the efficiencies for single species extractions of Pb2þ and of Hg2þ are
determined. The results are compared with those reported previously for related ligands in which only
oxygen heteroatoms are present in the crown ether unit.
Keywords:
Calixarenes
Crown ethers
Molecular recognition
Solvent extraction
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
ring size included both carboxylic acid and N-(X)sulfonyl carbamoyl
groups in which the acidity was tuned by variation of the electron-
In calixarene-crown ethers,1,2 also known as calixcrowns, a cal-
ixarene scaffold is combined with a crown ether unit connecting
two phenolic oxygens in the former with a polyether chain. Most
common are calix[4]crowns, which combine a calix[4]arene plat-
form and a polyether fragment. The first example of this ligand
family, p-tert-butylcalix[4]arene-1,3-crown-6 ether, was reported
in 1983.3 Metal ion complexation studies have mainly focused on
dialkylated-1,3-bridged calix[4]arene-crown ethers, which have
been found to exhibit high binding affinity and selectivity in alkali
and alkaline earth metal cation extractions.4–6 In contrast, much
less is known about the properties of regioisomeric 1,2-bridged
calix[4]crowns,7 presumably because they are more difficult to
synthesize. Also, initial studies suggested that they exhibit poor
binding ability for metal cations with little selectivity.8–13 Com-
pared with un-functionalized calix[4]arenes with phenolic groups
on the lower rim, analogues with pendant proton-ionizable groups
are found to be much more efficient interfacial carriers for metal
cations.14–16
withdrawing ability of X.21,22
Surprisingly, di-ionized calix[4]arene-1,2-crown-4 ethers in the
cone conformation were found to be efficient extractants for alka-
line earth metal cations with extraordinarily high selectivity for
Ba2þ 17,20
Since the crown ether ring is too small to accommodate
.
Ba2þ, we proposed extraction complexes in which the large divalent
metal ion was sandwiched between the four polyether oxygens
on one side and two ionized groups on the other. The Ba2þ extrac-
tion selectivity was lower for analogues with larger crown-5 and
crown-6 polyether units18 and essentially disappeared with smaller
crown-3 rings.19
In addition to variations of the crown ether ring size and identity
of the pendant acidic groups in di-ionizable calix[4]arene-1,2-
crown compounds, one or more of the oxygen atoms in the crown
ether ring could be replaced with sulfur. This substitution should
Recently, we undertook the synthesis and evaluation of di-ion-
izable calix[4]arene-1,2-crown ether ligands (Fig. 1) as a new class
of metal ion extractants.17–20 For this series of ligands, the polyether
ring was varied from crown-3 (n¼1) to crown-4 (n¼2) to crown-5
(n¼3) to crown-6 (n¼4). The ionizable groups for each polyether
Z
OH
NHSO2CH3
NHSO2C6H5
NHSO2C6H4-4-NO2
NHSO2CF3
OCH2C(O)Z
OCH2C(O)Z
O
O
O
n
(n = 1-4)
Figure 1. Di-ionizable p-tert-butylcalix[4]arene-1,2-crown ether ligands.
* Corresponding author. Tel.: þ1 806 742 3069; fax: þ1 806 742 1289.
E-mail address: richard.bartsch@ttu.edu (R.A. Bartsch).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.07.115

9844
D. Zhang et al. / Tetrahedron 64 (2008) 9843–9849
OCH2C(O)Z
O
O
OCH2C(O)Z
OCH2C(O)Z
O
O
S
O
OCH2C(O)Z
Z
1
OH
6
7
2
3
4
5
NHSO2CH3
NHSO2C6H5
NHSO2C6H4-4-NO2
NHSO2CF3
8
9
10
Figure 2. Di-ionizable p-tert-butylcalix[4]arene-1,2-monothiacrown-3 ligands 1–5 and their -crown-3 analogues 6–10.
favor complexation of softer metal ions. We now report on the
synthesis of di-ionizable calix[4]arene-1,2-monothiacrown-3
compounds 1–5 (Fig. 2) in which a sulfur atom is part of the linkage
that joins the two proximal phenolic oxygens. Metal ion com-
plexing behavior of new ligands 1–5 is assessed by solvent ex-
tractions of alkali and alkaline earth metal cations, as well as Hg2þ
and Pb2þ. The results are compared with those reported previously
for the all-oxygen analogues 6–10.
hydrolysis of 12 with aqueous Me4NOH in THF at reflux gave diacid
1 in 91% yield.
Diacid 1 was converted into the corresponding di(acid chloride)
by reaction with oxalyl chloride. Conversion to the di(acid chloride)
was verified by IR spectroscopy with the disappearance of the
carbonyl group absorption at 1740 cmꢀ1 and the appearance of
a new carbonyl group absorption for the di(acid chloride) at
1810 cmꢀ1. The resultant crude di(acid chloride) was mixed with
the appropriate sulfonamide anion in THF to afford ligands 2–5 in
yields of 30, 81, 40, and 76%, respectively. A fair amount of mono-
substituted by-product was obtained from the preparation of 2.
Increasing the reaction time from 12 h to 2 days increased its yield
by 7%.
2. Results and discussion
2.1. Synthetic routes
The conformations for compounds 1–5, 11, and 12 were estab-
lished by their 1H and 13C NMR spectra. There were no peaks be-
tween 35 and 40 ppm in the 13C NMR spectra for the seven
compounds, showing that all four benzene rings have syn ar-
rangements. In their 1H NMR spectra, the bridging methylene
group protons were split into three pairs of doublets, with the in-
tegration ratio of 1:2:1. In addition, the two methylene protons in
the side arms (–OCH2C(O)–) of 1–5 and 12 are diastereotopic and
exhibited the expected AX patterns. These observations verify that
the thiacrown ether rings are attached to the calix[4]arene
The synthesis of di-ionizable p-tert-butylcalix[4]arene-1,2-
monothiacrown-3 compounds 1–5 was performed as depicted in
Scheme 1. The first step involved assembling the thiacrown ether
unit onto the calix[4]arene scaffold by a Mitsunobu reaction.23
Thus, p-tert-butylcalix[4]arene was treated with triphenylphos-
phine (TPP) and diethylazodicarboxylate (DEAD) and then reacted
with 2,20-thiodiethanol to form thiacrown 11 in 29% yield. Reaction
of 11 with NaH in THF and then ethyl bromoacetate overnight at
room temperature produced a 61% yield of diester 12. Basic
a
b
c
OCH2CO2Et
O
O
O
O
OH
OH OH
OH
OH
OH
OCH2CO2Et
12
S
S
11
e
d
OCH2C(O)NHSO2X
O
O
OCH2CO2H
O
O
S
OCH2CO2H
OCH2C(O)NHSO2X
X
S
1
2 CH3
C H
3
4 C66H54-4-NO2
5 CF3
Scheme 1. Synthesis of di-ionizable p-tert-butylcalix[4]arene-1,2-monothiacrown-3 ligands 1–5 in the cone conformation. (a) HOCH2CH2SCH2CH2OH, TPP, DEAD, toluene, rt, 3 h;
(b) NaH, BrCH2CO2Et, THF, rt, overnight; (c) 10% aq Me4NOH, THF, reflux, 12 h; (d) oxalyl chloride, C6H6, reflux, 10 h, 12 h; (e) NaH, NH2SO2X, THF, rt, overnight.

D. Zhang et al. / Tetrahedron 64 (2008) 9843–9849
9845
framework via proximate phenolic positions and the compounds
are in the cone conformation.
phase versus the equilibrium pH of the aqueous phase are shown in
Figure 4.
With ligands 1–5, all four of the alkaline earth metal cation
species are extracted into the chloroform phases from weakly
acidic, neutral, and alkaline aqueous phases. From alkaline solu-
tions, the combined metal loading of the organic phase approaches
100% as would be expected for extraction complexes comprised of
a divalent metal cation and the di-ionized calix[4]arene-1,2-mon-
othiacrown-3 ligand. Under the conditions of high loading, the
dicarboxylic acid ligand 1 exhibits an extraction selectivity of
Ca2þ>Ba2þ>Mg2þ>Sr2þ. With the change to N-(X)sulfonyl oxy-
acetamide acidic functions in ligands 2–5, the best extracted cation
is Ba2þ with diverse patterns for the other three alkaline earth
metal cations.
Comparison of the extraction profiles shown in Figure 4 for
ligands 1–5 with those reported for analogues 6–10 in which the
sulfur heteroatom in the bridging unit is replaced with oxygen
reveals better selectivity among the alkaline earth metal cations for
the former.
2.2. Competitive solvent extraction of alkali metal cations
Aqueous solutions containing Liþ, Naþ, Kþ, Rbþ, and Csþ
(10.0 mM in each) chlorides were extracted with 1.0 mM solutions
of ligands 1–5 in chloroform. Plots of metal ion loadings of the
organic phase versus the equilibrium pH of the aqueous phase are
presented in Figure 3. Note that the metal loadings were negligible
when the aqueous phases are highly acidic. This verifies that the
ligands are ineffective extractants in their non-ionized forms. The
maximal combined alkali metal cation loadings observed for li-
gands 1–5 were all close to 200%, which is consistent with the
formation of 2:1 metal ion-di-ionized ligand extraction complexes.
Under the conditions of high metal loading (i.e., alkaline aque-
ous phase pH), Naþ extraction selectivity is observed for all five of
the di-ionizable calixthiacrown ligands. However, the plots for li-
gands 1 (Z¼OH), 2 (Z¼NHSO2Me), and 5 (Z¼NHSO2CF3) differ from
those for ligands 3 (Z¼NHSO2Ph) and 4 (Z¼NHSO2C6H4-4-NO2) in
that the latter are Liþ-selective for extractions from acidic aqueous
solutions, whereas the former are Naþ selective. This suggests some
type of special favorable interaction of the mono-ionized ligand
with Liþ when the acidic function contains an aryl group.
Comparison of the extraction profiles shown in Figure 3 for li-
gands 1–5 with those reported for analogues 6–1019 in which sulfur
in the bridging unit is replaced with oxygen reveals considerable
similarity. However, careful scrutiny reveals that for the same acidic
function, the di-ionizable calixthiacrown ligand extracts Liþ with
greater propensity. This is most apparent for the comparison of
dicarboxylic acid ligands 1 and 6. Since Liþ is a hard metal ion, this
is opposite to the effect expected when a soft sulfur ligation site is
replaced with harder oxygen.
2.4. Single species solvent extraction of Pb2D
Aqueous solutions of Pb2þ (1.0 mM) nitrate were extracted with
0.50 mM solutions of di-ionizable calix[4]arene-1,2-mono-
thiacrown-3 compounds 1–5 in chloroform. Plots of metal loading
of the organic phase versus the equilibrium pH of the aqueous
phase are presented in Figure 5a. For comparison, published data
for single species Pb2þ extractions by all-oxygen crown ether ana-
logues 6–10 are shown in Figure 5b.
All five of the ligands 1–5 exhibit essentially quantitative metal
loading for the formation of 1:1 extraction complexes of Pb2þ with
the di-ionized extractants. The pH for half loading, pH0.5, is a qual-
itative measure of ligand acidity. For the N-(X)sulfonyl carbox-
amides 2–5, the pH0.5 values are 4.9, 4.9, 4.0, and 3.3, respectively,
in accord with the electron-withdrawing power of the X group. For
the dicarboxylic acid ligand 1, the pH0.5 value is 3.7.
2.3. Competitive solvent extraction of alkaline earth metal
cations
Comparison of the Pb2þ extraction profiles for the di-ionizable
calix[4]arene-1,2-monothiacrown-3 ligands 1–5 (Fig. 5a) and their
di-ionizable calix[4]arene-1,2-crown-3 analogues 6–1019 (Fig. 5b),
respectively, reveals that with the same acidic function the former
Aqueous solutions containing Mg2þ, Ca2þ, Sr2þ, and Ba2þ
(2.0 mM in each) chlorides were extracted with 1.0 mM solutions of
ligands 1–5 in chloroform. Plots of metal loading of the organic
120
(a)
(b)
(c)
(d)
(e)
100
80
60
40
20
0
0
2
4
6
8
10 12
0
2
4
6
8
10 12
0
2
4
6
8
10 12
0
2
4
6
8
10 12
0
2
4 6 8 10 12 14
pH
Figure 3. Percent metals loading of the organic phase versus the equilibrium pH of the aqueous phase for competitive solvent extraction of alkali metal cations into chloroform by
di-ionizable p-tert-butylcalix[4]arene-1,2-monothiacrown-3 ethers (a) 1; (b) 2; (c) 3; (d) 4; (e) 5. (B¼Liþ, 6¼Naþ, 7¼Kþ, >¼Rbþ, þ¼Csþ).

9846
D. Zhang et al. / Tetrahedron 64 (2008) 9843–9849
100
90
80
70
60
50
40
30
20
10
0
0
2
4
6
8
0
2
4
6
8
0
2
4
6
8
0
2
4
6
8
0
2
4
6
8
10
pH
Figure 4. Percent metals loading versus the equilibrium pH of the aqueous phase for competitive solvent extraction of alkaline earth metal ions into chloroform by di-ionizable
p-tert-butylcalix[4]arene-1,2-monothiacrown-3 ethers 1–5 (B¼Mg2þ, 6¼Ca2þ, 7¼Sr2þ, >¼Ba2þ).
are generally better extractants. The differences are striking for the
All four of the N-(X)sulfonyl carbamoyl calix[4]arene-1,2-thia-
crown ligands 2–5 exhibit essentially quantitative metal loading for
the formation of 1:1 extraction complexes of Hg2þ with the di-
ionized extractants. For the dicarboxylic acid compound 1, the
maximal metal loading diminishes slightly to 90%. For the
N(X)sulfonyl carboxamide ligands 2–5, the pH0.5 values are 2.3, 1.9,
1.1, and 0.8, respectively, in agreement with the electron-with-
drawing power of X. For the dicarboxylic acid ligand 1, the pH0.5
value is 1.5.
N-(X)sulfonyl carboxamides with X¼CH3 and X¼C6H5. Thus, calix-
[4]arene-1,2-monothiacrown-3 ligands
2
and
3
effectively
transport Pb2þ into the organic phase; whereas their calix[4]arene-
1,2-crown-3 analogues 7 and 8 are very weak Pb2þ extractants.
Thus, replacement of a soft sulfur ligation site in the crown ring
with a hard oxygen atom leads to less efficient complexation of
Pb2þ, a borderline metal ion. This effect appears to be more pro-
nounced for the less acidic ionizable groups.
Comparison of the Hg2þ extraction profiles for the di-ionizable
calix[4]arene-1,2-monothiacrown-3 ligands 1–5 (Fig. 6a) and
their di-ionizable calix[4]arene-1,2-crown-3 analogues 6–1019
(Fig. 6b), respectively, reveals that with the same acidic function
the former are generally more efficient extractants. This is par-
ticularly evident for the dicarboxylic acid ligands 1 and 6. For the
thiacrown-3 extractant 1, approximately 90% maximal metal
loading is achieved. On the other hand, the reported data for
crown-3 compound 6 only approached a maximum of 20% metal
loading.
2.5. Single species solvent extraction of Hg2D
Aqueous solutions of Hg2þ (0.25 mM) nitrate were extracted
with 0.25 mM solutions of di-ionizable calix[4]arene-1,2-mono-
thiacrown-3 compounds 1–5 in chloroform. Plots of metal loading
of the organic phase versus the equilibrium pH of the aqueous
phase are presented in Figure 6a. For comparison, previously
reported data for single species Hg2þ extractions by all-oxygen
crown ether analogues 6–1019 are shown in Figure 6b.
100
(b)
(a)
80
60
40
20
0
0
1
2
3
4
5
6
0
1
2
3
4
5
6
7
pH
Figure 5. Percent metal loading versus the equilibrium pH of the aqueous phase for Pb2þ extraction from aqueous phases into chloroform by (a) di-ionizable p-tert-butyl-
calix[4]arene-1,2-monothiacrown-3 ethers 1–5 (,¼1, B¼2, 6¼3, 7¼4, >¼5) and (b) di-ionizable p-tert-butylcalix[4]arene-1,2-crown-3 ethers 6–10 (,¼6, B¼7, 6¼8, 7¼9,
>¼10).

D. Zhang et al. / Tetrahedron 64 (2008) 9843–9849
9847
100
80
60
40
20
0
(a)
(b)
X=OH
X=NHSO2CH3
X=NHSO2Ph
X=NHSO2PhNO2
X=NHSO2CF3
0
1
2
3
4
5
6
0
pH
1
2
3
4
5
6
7
Figure 6. Percent metal loading versus the equilibrium pH of the aqueous phase for Hg2þ extraction from aqueous phase into chloroform by (a) di-ionizable p-tert-butylca-
lix[4]arene-1,2-monothiacrown-3 ethers 1–5 (,¼1, B¼2, 6¼3, 7¼4, >¼5) and (b) di-ionizable p-tert-butylcalix[4]arene-1,2-crown-3 ethers 6–10 (,¼6, B¼7, 6¼8, 7¼9,
>¼10).
2.6. Conclusions from the metal ion extraction studies
BrandÒ centrifuge, respectively. The pH of the aqueous phase from
an extraction experiment was determined with a Fisher Accumet
AR25 pH meter with a Corning 476157 combination pH electrode.
To probe the influence of replacing a hard oxygen ligation site in
the crown ring of di-ionizable calix[4]arene-1,2-crown-3 ligands
6–10 with soft sulfur, the series of di-ionizable calix[4]arene-1,2-
monothiacrown-3 compounds 1–5 was prepared. Since the crown
rings in both ligand series are too small to accommodate metal ions
within their central cavities, extraction complexes are envisioned in
which a divalent metal cation is sandwiched between the crown
ring on one side and the two ionized groups on the other. Metal ion
complexation by ligands 1–5 was probed by competitive extrac-
tions from aqueous solutions into chloroform for alkali metal cat-
ions and for alkaline earth metal cations and by single species
extractions of Pb2þ and Hg2þ. For alkaline earth metal ion extrac-
tions, the thiacrown ligands 2–5 are more selective for Ba2þ than
their crown analogues 7–10. For borderline Pb2þ and soft Hg2þ, the
thiacrown ligands 1–5 are more efficient extractants than crown
analogues 6–10.
3.1.1. 5,11,17,23-Tetrakis(1,1-dimethylethyl)-25,26-calix[4]arene-
25,26-monothiacrown-3 (11) in the cone conformation
To a mixture of p-tert-butylcalix[4]arene (23.00 g, 35.5 mmol),
2,20-thiodiethanol (6.49 g, 53.2 mmol), and TPP (27.92 g,
106.5 mmol) in 600 mL of toluene, a 40% solution of DEAD (46.35 g,
106.5 mmol) in toluene (135 mL) was added dropwise. The mixture
was stirred at room temperature for 3 h and evaporated to dryness
in vacuo. The residue was extracted with hexane (3ꢂ300 mL). The
combined extracts were filtered and evaporated in vacuo. Chro-
matography on silica gel with hexanes–EtOAc (49:1) as eluent gave
a white solid (7.55 g, 29%) with mp 110–115 ꢁC. IR: 3338 (O–H),1247
(C–O) cmꢀ1 1H NMR:
. d 1.19 (s, 18H, CH3), 1.21 (s, 18H, CH3), 3.17–
3.26 (m, 2H, OCH2CH2S), 3.29–3.41 (m, 6H, ArCH2Ar, OCH2CH2S),
3.93 (t, J¼10.0 Hz, 2H, OCH2CH2S), 4.33 (d, J¼13.0 Hz, 2H, ArCH2Ar),
4.35 (d, J¼13.5 Hz, 1H, ArCH2Ar), 3.62–4.68 (m, 2H, OCH2CH2S),
5.05 (d, J¼12.0 Hz, 1H, ArCH2Ar), 6.99 (d, J¼2.5 Hz, 2H, ArH), 7.01 (d,
J¼2.5 Hz, 2H, ArH), 7.02 (d, J¼2.5 Hz, 2H, ArH), 7.14 (d, J¼2.5 Hz, 2H,
3. Experimental
3.1. General
ArH). 13C NMR:
d 31.2, 31.3, 31.5, 32.7, 33.0, 33.9, 34.2, 36.9, 53.4,
125.3, 125.5, 125.9, 126.4, 128.8, 128.9, 133.6, 134.8, 142.9, 147.5,
149.0, 150.2. Anal. Calcd for C48H62O4S: C, 78.43; H, 8.50. Found: C,
78.75; H, 8.41%.
Melting points were determined with a Mel-Temp melting point
apparatus. Infrared (IR) spectra were recorded with a Perkin–Elmer
Model 1600 FT-IR spectrometer as deposits from CH2Cl2 solution on
NaCl plates. The 1H and 13C NMR spectra were recorded with
a Varian Unity INOVA 500 MHz FT-NMR (1H at 500 MHz and 13C at
126 MHz) spectrometer in CDCl3 with Me4Si as internal standard
3.1.2. 5,11,17,12-Tetrakis(1,1-dimethylethyl)-27,28-bis[(ethoxy-
carbonyl)methoxy]calix[4]arene-25,26-monothiacrown-3 (12)
in the cone conformation
unless mentioned otherwise. Chemical shifts (
d
) are given in parts
p-tert-Butylcalix[4]arene-1,2-thiacrown-3 (11) (2.00 g, 2.72 mmol)
in THF (40 mL) was added dropwise to a mixture of NaH (0.96 g,
8.16 mmol) in THF (40 mL). After stirring for 2 h, ethyl bromoace-
tate (2.72 g, 16.32 mmol) was added. The mixture was stirred
overnight and the excess NaH was destroyed by careful addition of
dilute HCl. The solvent was evaporated in vacuo and the residue
was dissolved in CH2Cl2. The mixture was washed with dilute HCl
and water, dried over MgSO4, and evaporated in vacuo. Chroma-
tography on silica gel with EtOAc–hexanes (3:97) gave a white solid
(1.13 g, 46%) with mp 61–63 ꢁC. IR: 1759 (C]O), 1248 and 1128 (C–
per million downfield from TMS and coupling constants (J) values
are in hertz. Elemental analysis was performed by Desert Analytics
Laboratory of Tucson, Arizona.
Reagents were obtained from commercial suppliers and used
directly, unless otherwise noted. Acetonitrile (MeCN) was dried
over CaH2 and distilled immediately before use. Tetrahydrofuran
(THF) was dried over sodium with benzophenone as an indicator
and distilled just before use. Cs2CO3 was activated by heating at
150 ꢁC overnight under high vacuum and stored in a desiccator.
For use in the metal ion extractions, reagent-grade chloroform
was washed with an equal volume of DI water to remove the
stabilizing ethanol and stored in the dark. Vortexing and centrifu-
gation of two-phase extraction mixtures were performed with
a Glas-Col Multi-Pulse vortexer and a Becton-Dickinson Clay Adams
O) cmꢀ1 1H NMR:
. d 1.04 (s, 18H, CH3), 1.12 (s, 18H, CH3), 1.34 (t,
J¼7.0 Hz, 6H, CH2CH3), 3.02–3.09 (m, 2H, OCH2CH2S), 3.12 (d,
J¼12.5 Hz, 1H, ArCH2Ar), 3.17 (d, J¼12.5 Hz, 2H, ArCH2Ar), 3.25 (d,
J¼12.5 Hz, 1H, ArCH2Ar), 3.46–3.54 (m, 2H, OCH2CH2S), 3.72–3.79
(m, 2H, OCH2CH2S), 4.24–4.32 (m, 4H, OCH2CH3), 4.50 (d, J¼13.0 Hz,

9848
D. Zhang et al. / Tetrahedron 64 (2008) 9843–9849
1H, ArCH2Ar), 4.52 (d, J¼16.0 Hz, 2H, OCH2CO), 4.71–4.77 (m, 2H,
OCH2CH2S), 4.78 (d, J¼12.5 Hz, 2H, ArCH2Ar), 4.90 (d, J¼16.0 Hz, 2H,
OCH2CO), 5.29 (d, J¼12.0 Hz, 1H, ArCH2Ar), 6.78 (d, J¼2.5 Hz, 2H,
ArH), 6.80 (d, J¼2.5 Hz, 2H, ArH), 6.86 (d, J¼2.5 Hz, 2H, ArH),
ArH), 6.96 (d, J¼2.0 Hz, 2H, ArH), 9.55 (s, 1H, NH). 13C NMR:
d 29.7,
31.2, 31.40, 31.42, 31.60, 31.63, 31.7, 33.9, 34.0, 36.1, 41.7, 53.4, 74.7,
76.6, 124.9, 125.6, 125.9,126.7, 132.3, 132.3, 133.0, 134.8, 145.7, 146.4,
152.4, 152.7, 169.3. Anal. Calcd for C54H72O10S3N2: C, 64.51; H, 7.22;
N, 2.79. Found: C, 64.60; H, 7.06; N, 2.60%.
6.90 (d, J¼2.5 Hz, 2H, ArH). 13C NMR:
d 14.3, 30.9, 31.3, 31.4, 31.5,
31.7, 31.79, 33.82, 33.9, 35.0, 60.7, 72.1, 75.9, 124.8, 125.2, 125.4,
125.6, 132.4, 134.0, 134.2, 135.0, 145.0, 145.4, 152.7, 153.0, 170.2.
Anal. Calcd for C56H74O8S$1.5H2O: C, 71.99; H, 8.31. Found: C, 71.85;
H, 8.38%.
3.2.2. 5,11,17,23-Tetrakis(1,1-dimethylethyl)-27,28-bis-
[N-(benzene)sulfonyl carbamoyl-methoxy]calix[4]arene-
25,26-monothiacrown-3 (3) in the cone conformation
The product was obtained as a pale yellow solid (0.75 g, 81%)
with mp 138–140 ꢁC. IR: 3260 (N–H), 1721 (C]O), 1361 and 1163
3.1.3. 5,11,17,23-Tetrakis(1,1-dimethylethyl)-27,28-bis(carboxy-
methoxy)calix[4]arene-25,26-monothiacrown-3 (1) in the cone
conformation
(S]O), 1236 and 1125 (C–O) cmꢀ1. 1H NMR:
d 1.00 (s, 18H, CH3), 1.13
(s, 18H, CH3), 3.05–3.18 (m, 6H, ArCH2Ar, OCH2CH2S), 3.23 (d,
J¼13.0 Hz, 2H, ArCH2Ar), 3.66–3.74 (m, 2H, OCH2CH2S), 4.21
(d, J¼13.0 Hz, 2H, ArCH2Ar), 4.29 (d, J¼13.0 Hz, 1H, ArCH2Ar), 4.30
(d, J¼15.5 Hz, 2H, OCH2CO), 4.55–4.61 (m, 2H, OCH2CH2S), 5.03 (d,
J¼15.5 Hz, 2H, OCH2CO), 5.42 (d, J¼12.0 Hz, 1H, ArCH2Ar), 6.68 (d,
J¼2.5 Hz, 2H, ArH), 6.73 (d, J¼2.5 Hz, 2H, ArH), 6.82 (d, J¼2.5 Hz, 2H,
ArH), 6.93 (d, J¼2.0 Hz, 2H, ArH), 7.49–7.56 (m, 6H, ArH), 8.07–8.13
A solution of diester 12 (1.13 g, 1.25 mmol) in THF (30 mL) and
10% aq Me4NOH (30 mL) was refluxed overnight. The solvent was
evaporated in vacuo and the residue was dissolved in CH2Cl2
(100 mL). The organic layer was washed with 1 N HCl until pH 1 and
then with brine (100 mL) and water (100 mL), dried over MgSO4,
and evaporated in vacuo to give a white solid (0.90 g, 85%) with mp
202–205 ꢁC. IR: 3217 (O–H), 1760 (C]O), 1246 and 1127 (C–
(m, 4H, ArH), 9.62 (s, 1H, NH). 13C NMR:
d 31.2, 31.3, 31.4, 31.5, 31.7,
O) cmꢀ1. 1H NMR:
d
1.07 (s, 18H, CH3), 1.12 (s, 18H, CH3), 3.07–3.14
33.8, 33.9, 35.9, 74.6, 76.4, 124.9, 125.5, 125.8, 126.4, 126.7, 128.6,
129.0, 129.2, 132.1, 132.3, 132.8, 133.0, 134.1, 134.8, 138.3, 145.6,
146.3, 152.4, 152.5, 167.9. Anal. Calcd for C64H76O10S3N2$0.2H2O: C,
67.84; H, 6.80; N, 2.47. Found: C, 67.40; H, 6.52; N, 2.87%.
(m, 2H, OCH2CH2S), 3.15 (d, J¼12.5 Hz, 1H, ArCH2Ar), 3.27 (d,
J¼13.0 Hz, 2H, ArCH2Ar), 3.31 (d, J¼13.0 Hz, 1H, ArCH2Ar), 3.67–
3.75 (m, 2H, OCH2CH2S), 4.33 (d, J¼13.0 Hz, 2H, ArCH2Ar), 4.49 (d,
J¼13.0 Hz, 1H, ArCH2Ar), 4.58 (d, J¼16.5 Hz, 2H, OCH2CO), 4.59–
4.66 (m, 2H, OCH2CH2S), 4.78 (d, J¼16.0 Hz, 2H, OCH2CO), 5.59 (d,
J¼12.5 Hz, 1H, ArCH2Ar), 5.29 (d, J¼12.0 Hz, 1H, ArCH2Ar), 6.86 (d,
J¼2.0 Hz, 2H, ArH), 6.88 (d, J¼2.5 Hz, 2H, ArH), 6.91 (d, J¼2.5 Hz, 2H,
3.2.3. 5,11,17,23-Tetrakis(1,1-dimethylethyl)-27,28-bis-
[N-(4-nitrobenzene)sulfonyl carbamoyl-methoxy]calix[4]-
arene-25,26-monothiacrown-3 (4) in the cone conformation
The crude product was purified by chromatography on silica gel
with MeOH–CH2Cl2 (1:250 to 1:100) as eluent. The product was
washed with 6 N HCl, dried over MgSO4 and evaporated in vacuo to
give a yellow solid (0.40 g, 40%) with mp 165–167 ꢁC. IR: 3219 (N–
ArH), 6.97 (d, J¼2.5 Hz, 2H, ArH). 13C NMR:
d 25.6, 30.6, 31.2, 31.4,
31.5, 31.6, 33.9, 34.0, 36.0, 68.0, 71.7, 77.6, 109.9, 124.8, 125.5, 125.9,
126.1, 133.1, 133.2, 133.3, 135.2, 145.6, 146.8, 151.4, 152.5, 171.6. Anal.
Calcd for C52H66O8S: C, 73.38; H, 7.82. Found: C, 73.12; H, 7.54%.
H), 1722 (C]O), 1350 and 1161 (S]O), 1246 and 1125 (C–O) cmꢀ1
1H NMR:
1.00 (s, 18H, CH3), 1.13 (s, 18H, CH3), 3.05–3.23 (m, 6H,
.
3.2. General procedure for 5,11,17,23-tetrakis(1,1-dimethyl-
ethyl)-27,28-bis[N-(X)sulfonyl carbamoyl-methoxy]calix[4]-
arene-25,26-monothiacrown-3 compounds 2–5 in the cone
conformation
d
ArCH2Ar, OCH2CH2S), 3.26 (d, J¼13.0 Hz, 2H, ArCH2Ar), 3.70–3.79
(m, 2H, OCH2CH2S), 4.18 (d, J¼13.0 Hz, 2H, ArCH2Ar), 4.28 (d,
J¼15.5 Hz, 2H, OCH2CO), 4.46 (d, J¼13.0 Hz, 1H, ArCH2Ar), 4.55–
4.63 (m, 2H, OCH2CH2S), 5.20 (d, J¼16.0 Hz, 2H, OCH2CO), 5.38 (d,
J¼12.0 Hz, 1H, ArCH2Ar), 6.69 (d, J¼2.5 Hz, 2H, ArH), 6.76 (d,
J¼2.5 Hz, 2H, ArH), 6.83 (d, J¼2.5 Hz, 2H, ArH), 6.94 (d, J¼2.5 Hz, 2H,
ArH), 8.27–8.32 (m, 4H, ArH), 8.34–8.39 (m, 4H, ArH), 9.66 (s, 1H,
Oxalyl chloride (1.06 mL, 12.35 mmol) was added to diacid 1
(0.70 g, 0.82 mmol) in benzene (50 mL) and the mixture was
refluxed for 10 h. After verifying conversion to the di(acid chloride)
by IR spectrophotometry, the solvent was evaporated in vacuo. The
appropriate sulfonamide (2.05 mmol) in THF (5 mL) was added to
NaH (0.295 g, 12.3 mmol) in THF (20 mL) and the mixture was
stirred at room temperature for 2 h. The di(acid chloride) solution
was added and the mixture was stirred overnight (the reaction
mixture was stirred for 2 days in the preparation for 2). The excess
NaH was destroyed by careful addition of water. The THF was
evaporated in vacuo. To the residue was added CH2Cl2 and the
mixture was washed with 6 N HCl, dried over MgSO4 and evapo-
rated in vacuo.
NH). 13C NMR:
d 29.7, 31.2, 31.3, 31.66, 33.9, 34.0, 35.9, 74.4, 76.5,
124.2, 124.9, 125.5, 126.0, 126.9, 130.2, 132.1, 132.2, 132.8, 134.8,
143.6, 145.8, 146.6, 150.8, 152.4, 152.5, 168.3. Anal. Calcd for
C64H74O14S3N4$0.6C6H6: C, 64.12; H, 6.18; N, 4.42. Found: C, 64.39;
H, 5.96; N, 4.07%.
3.2.4. 5,11,17,23-Tetrakis(1,1-dimethylethyl)-27,28-bis-
[N-(trifluoromethane)sulfonyl carbamoyl-methoxy]calix-
[4]arene-25,26-monothiacrown-3 (5) in the cone conformation
The crude product was purified by chromatography on silica gel
with MeOH–CH2Cl2 (1:99) as eluent. The product was washed with
6 N HCl, dried over MgSO4 and evaporated in vacuo to give a white
solid (0.70 g, 76%) with mp 156–158 ꢁC. IR: 2963 (N–H), 1751
(C]O), 1364 and 1131 (S]O), 1260 and 1131 (C–O) cmꢀ1. 1H NMR:
3.2.1. 5,11,17,23-Tetrakis(1,1-dimethylethyl)-27,28-bis[N-
(methane)sulfonyl carbamoyl-methoxy]calix[4]arene-
25,26-monothiacrown-3 (2) in the cone conformation
The crude product was purified by chromatography on silica gel
with MeOH–CH2Cl2 (1:500 to 8:500) as eluent to give a white solid
(0.22 g, 37%) with mp 170–172 ꢁC. IR: 3231 (N–H), 1722 (C]O),
d 1.02 (s, 18H, CH3), 1.15 (s, 18H, CH3), 3.08–3.24 (m, 5H, ArCH2Ar,
OCH2CH2S), 3.33 (d, J¼13.0 Hz, 2H, ArCH2Ar), 3.41 (d, J¼13.5 Hz, 1H,
ArCH2Ar), 3.70–3.79 (m, 2H, OCH2CH2S), 4.21 (d, J¼13.0 Hz, 2H,
ArCH2Ar), 4.48–4.62 (m, 5H, OCH2CO, OCH2CH2S, ArCH2Ar), 5.25 (d,
J¼17.5 Hz, 2H, OCH2CO), 5.43 (d, J¼12.5 Hz, 1H, ArCH2Ar), 6.74–6.83
(m, 4H, ArH), 6.87 (d, J¼2.0 Hz, 2H, ArH), 6.96 (d, J¼2.0 Hz, 2H, ArH).
1345 and 1153 (S]O), 1245 and 1125 (C–O) cmꢀ1. 1H NMR:
d 1.03 (s,
18H, CH3), 1.15 (s,18H, CH3), 3.12–3.25 (m, 5H, ArCH2Ar, OCH2CH2S),
3.32 (d, J¼13.0 Hz, 2H, ArCH2Ar), 3.39 (d, J¼13.5 Hz, 1H, ArCH2Ar),
3.41 (s, 6H, SO2CH3), 3.72–3.80 (m, 2H, OCH2CH2S), 4.25 (d,
J¼12.5 Hz, 2H, ArCH2Ar), 4.40 (d, J¼16.0 Hz, 2H, OCH2CO), 4.59
(d, J¼13.0 Hz, 1H, ArCH2Ar), 4.61–4.67 (m, 2H, OCH2CH2S), 5.16 (d,
J¼16.0 Hz, 2H, OCH2CO), 5.40 (d, J¼12.5 Hz, 1H, ArCH2Ar), 6.79 (d,
J¼2.5 Hz, 2H, ArH), 6.80 (d, J¼2.5 Hz, 2H, ArH), 6.88 (d, J¼2.5 Hz, 2H,
13C NMR:
d 30.8, 31.0, 31.2, 31.4, 31.5, 31.6, 31.7, 33.9, 34.0,
35.9, 53.4, 74.3, 117.8, 120.4, 125.0, 125.7, 126.0, 126.9, 132.1, 132.3,
132.8, 134.8, 145.8, 146.8, 152.3, 152.5, 167.5. Anal. Calcd for
C54H66O10S3F6N2$0.4C6H6: C, 59.19; H, 6.02; N, 2.45. Found: C,
59.13; H, 6.36; N, 2.44%.

D. Zhang et al. / Tetrahedron 64 (2008) 9843–9849
9849
3.3. Procedure for competitive extraction of alkali metal
cations
temperature and then centrifuged for 10 min. A 0.50-mL portion of
the aqueous phase was removed and diluted to 5.00 mL with DI
water. The pH of the aqueous phase was measured. A 1.0-mL por-
tion of the diluted sample was added to 100 mL of 1.0 N H2SO4 in
a glass reaction bottle, which was then connected to a Shimadzu
MVU-1A mercury vaporizer unit. The Hg2þ in the sample was re-
duced using 5.0 mL of SnCl2 solution, prepared by dissolving 20 g of
SnCl$H2O in 40 mL of concd HCl and diluting the solution to 200 mL
with DI water. The reduced mercury vapor was then pumped
through a flow cell and the mercury concentration was measured at
253.6 nm with a Shimadzu AA-630 spectrophotometer. The vapor
was then pumped to a waste receptacle, where it was re-oxidized
using a 0.5% solution of KMnO4 in 5% H2SO4.24
An aqueous solution of the alkali metal chlorides with LiOH or
HCl for pH adjustment (2.0 mL, 10.0 mM in each alkali metal cation
species) and 2.0 mL of a 1.0 mM solution of the ligand in chloroform
in a metal-free, capped, polypropylene, 15-mL centrifuge tube was
vortexed for 10 min at room temperature. The tube was centrifuged
for 10 min for phase separation. A 1.5-mL portion of the organic
phase was removed and added to 3.0 mL of 0.10 M HCl in a new, 15-
mL, polypropylene centrifuge tube. The tube was vortexed for
10 min and centrifuged for 10 min. The aqueous phase from this
stripping was diluted 10-fold with DI water and the alkali metal
cation concentrations were determined with a Dionex DX-120 on
chromatograph with a CS12A column with conductivity detection
and membrane suppression (Dionex Model CMMS-II). The pH of
the aqueous phase from the initial extraction step was determined.
Acknowledgements
We thank the Division of Chemical Sciences, Geosciences, and
Biosciences of the Office of Basic Energy Sciences of the U.S. De-
partment of Energy (Grant DE-FG02-90ER1446) for support of this
research.
3.4. Procedure for competitive extraction of alkaline earth
metal cations
An aqueous solution of the alkaline earth metal chlorides with
Ba(OH)2 or HCl for pH adjustment (2.0 mL, 2.0 mM in each alkaline
earth metal cation species) and 2.0 mL of 1.0 mM solution of the
ligand in chloroform in a metal-free, capped, polypropylene, 15-mL
centrifuge tube was vortexed for 10 min at room temperature. The
tube was centrifuged for 10 min for phase separation. A 1.5-mL
portion of the organic phase was removed and added to 3.0 mL of
0.10 M HCl in a new, 15-mL, polypropylene centrifuge tube. The
tube was vortexed for 10 min and centrifuged for 10 min. The
aqueous phase from this stripping was diluted 10-fold with DI
water and the alkaline earth metal cation concentrations were
determined with a Dionex DX-120 ion chromatograph with a CS12A
column with conductivity detection and membrane suppression
(Dionex Model CMMS-II). The pH of the aqueous phase from the
initial extraction step was determined.
References and notes
1. Casnati, A.; Ungaro, R.; Asfari, Z.; Vicens, J. In Calixarenes 2001; Asfari, Z.,
Bo¨hmer, V., Harrowfield, J., Vicens, J., Eds.; Kluwer Academic: Boston, 2001;
p 365.
2. Salorinne, K.; Nissinen, M. J. Inclusion Phenom. Macrocyclic Chem. 2008, 61, 11.
3. Alfieri, C.; Dradi, E.; Pochini, A.; Ungaro, R.; Andreeti, G. D. J. Chem. Soc., Chem.
Commun. 1983, 1075.
4. Dijkstra, P. J.; Brunink, J. A.; Bugge, K.-E.; Reinhoudt, D. N.; Harkema, S.; Ungaro,
R.; Ugozzoli, F.; Ghidini, E. J. Am. Chem. Soc. 1989, 111, 7567.
5. Ghidini, E.; Ugozzoli, F.; Ungaro, R.; Harkema, S.; El-Fadl, A. A.; Reinhoudt, D. N.
J. Am. Chem. Soc. 1990, 112, 6979.
6. Lamare, V.; Dozol, J.-F.; Ugozzoli, F.; Casnati, A.; Ungaro, R. Eur. J. Org. Chem.
1998, 1559.
7. Yamamoto, H.; Sakaki, T.; Shinkai, S. Chem. Lett. 1994, 1559.
8. Arduini, A.; Casnati, A.; Doni, L.; Pochini, A.; Ungaro, R. J. Chem. Soc., Chem.
Commun. 1990, 1597.
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R. Supramol. Chem. 1993, 1, 235.
10. Arduini, A.; Domiano, L.; Pochini, A.; Secchi, A.; Ungaro, R.; Ugozzoli, F.; Struck,
O.; Verboom, W.; Reinhoudt, D. N. Tetrahedron 1997, 53, 3762.
11. Arnaud-Neu, F.; Caccamese, S.; Fuangswadi, S.; Pappalardo, S.; Parisi, M. F.;
Petringa, A.; Principato, G. J. Org. Chem. 1997, 62, 8041.
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13. Mathieu, A.; Asfari, Z.; Thuery, P.; Nierlich, M.; Faure, S.; Vicens, J. J. Inclusion
Phenom. Macrocyclic Chem. 2001, 40, 173.
14. Ungaro, R.; Pochini, A.; Andretti, G. D. J. Inclusion Phenom. 1984, 2, 199.
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16. Ogata, M.; Fujimoto, K.; Shinkai, S. J. Am. Chem. Soc. 1994, 116, 4505.
17. Tu, C.; Surowiec, K.; Purkiss, D. W.; Bartsch, R. A. Tetrahedron Lett. 2006, 46,
3443.
18. Tu, C.; Liu, D.; Surowiec, K.; Purkiss, D. W.; Bartsch, R. A. Org. Biomol. Chem.
2006, 4, 2933.
3.5. Procedure for single species extraction of Pb2D
An aqueous solution (2.0 mL) of 1.0 mM Pb(NO3)2 with TMAOH
or HNO3 for pH adjustment and 2.0 mL of a 0.50 mM solution of the
ligand in chloroform in a metal-free, capped, polypropylene, 15-mL
centrifuge tube was vortexed for 10 min at room temperature and
then centrifuged for 10 min for phase separation. A 1.5-mL portion
of the organic phase was removed and added to 3.0 mL of 4.0 M
HNO3 in a new, 15-mL, polypropylene centrifuge tube. The tube was
vortexed for 10 min and then centrifuged for 10 min. A 2.0-mL
sample of the aqueous phase after this stripping was diluted to
10 mL with DI water in a volumetric flask for determination of the
Pb2þ by atomic absorption using the absorption at 283.3 nm.
19. Zhang, D.; Cao, X.; Purkiss, D. W.; Bartsch, R. A. Org. Biomol. Chem. 2007, 4, 1251.
20. Tu, C.; Surowiec, K.; Bartsch, R. A. Tetrahedron 2007, 63, 4184.
21. Talanova, G. G.; Hwang, H.-S.; Talanov, V. S.; Bartsch, R. A. Chem. Commun. 1998,
419.
3.6. Procedure for single species extraction of Hg2D
22. Talanova, G. G.; Hwang, H.-S.; Talanov, V. S.; Bartsch, R. A. Chem. Commun. 1998,
1329.
23. Csokai, V.; Gru¨n, A.; Bitter, I. Tetrahedron Lett. 2003, 44, 4681.
24. This method replaces the Hg2þ photometric analysis as the mercury dithizo-
nate complex used previously.17–20 Test experiments were run to verify that the
same results were obtained with both analytical procedures.
An aqueous solution (3.0 mL) of 0.25 mM Hg(NO3)2 with
TMAOH or HNO3 for pH adjustment and 3.0 mL of 0.25 mM ligand
solution in chloroform in a metal-free, capped, polypropylene,
15-mL centrifuge tube were vortexed for 10 min at room