Proton di-ionizable p-tert-butylcalix[4]arene-crown-6 compounds in cone, partial-cone and 1,3-alternate conformations: Synthesis and alkaline earth metal cation extraction

Article abstract of DOI:10.1039/b501822f

Novel proton di-ionizable p-tert-butylcalix[4]arene-crown-6 compounds in cone, partial-cone and 1,3-alternate conformations are synthesized to compare the efficiency and selectivity with which they extract alkaline earth metal ions. In these ligands, a cr

Full text of DOI:10.1039/b501822f

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A R T I C L E
Proton di-ionizable p-tert-butylcalix[4]arene-crown-6 compounds in
cone, partial-cone and 1,3-alternate conformations: synthesis and
alkaline earth metal cation extraction†
Hui Zhou, Kazimierz Surowiec, David W. Purkiss and Richard A. Bartsch*
Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas,
79409-1061, USA. E-mail: richard.bartsch@ttu.edu; Fax: +1(806) 742 1289;
Tel: +1(806) 742 3069
Received 4th February 2005, Accepted 3rd March 2005
First published as an Advance Article on the web 24th March 2005
Novel proton di-ionizable p-tert-butylcalix[4]arene-crown-6 compounds in cone, partial-cone and 1,3-alternate
conformations are synthesized to compare the efficiency and selectivity with which they extract alkaline earth metal
ions. In these ligands, a crown-6 polyether unit links alternate aromatic rings of the calix[4]arene framework. To the
remaining lower-rim positions are attached oxyacetic acid or N-(X)sulfonyl oxyacetamide groups. Changing the
conformation varies the spatial relationship between a polyether-complexed divalent metal ion and the ionized side
arms of the ligands. This is found to markedly affect the efficiency and selectivity in competitive solvent extraction of
alkaline earth metal ions from aqueous solutions into chloroform by the di-ionizable calix[4]arene-crown-6 ligands.
was also incorporated into calix[4]arenes.11 These di-ionizable
Introduction
calix[4]arenes show an unexpectedly high extraction effi-
Calixarenes are cyclic oligomers derived from condensation
ciency and selectivity for some soft metal ions, such as Pb2+
reactions of phenols and formaldehyde under basic or acidic
and Hg2+.
conditions. These molecules have been studied extensively since
The first example of a proton-ionizable calix[4]arene-crown
the establishment of facile synthetic procedures by Gutsche
ether was recorded in 1984, when p-tert-butylcalix[4]crown-
and coworkers.1 In the calixarene family, calix[4]arenes are the
5-di(oxyacetic acid) was reported by Ungaro et al.10a This
most popular because their more rigid, vase-like structure makes
ligand exhibited a quite high extraction efficiency from aqueous
them ideal candidates for the complexation of neutral molecules
solutions into dichloromethane of divalent metal cations (except
or cations.2 The parent calix[4]arene can be easily modified
Mg2+). In addition, this ligand showedbetter selectivities for Ca2+
with functional groups at either the wide and narrow rims, or
and Pb2+ than the non-ionizable analogues studied. Recently,
both, which not only greatly increases the solubility in organic
Chen and coworkers prepared the crown-6 analog and found it
solvents, but also enhances the binding ability and/or selectivity
to exhibit high selectivity for Ra2+ over the light alkaline earth
for guest molecules or ions.
Among the calix[4]arene derivatives, calix[4]arene-crown
metal cations.12 For these two earlier studies, the di-ionizable
calix[4]arene ligands were in the cone conformation.
ethers, also called calix[4]crowns, have been found to be efficient
In this paper, we report the preparation of three series of pro-
cation extractants. Early studies showed that the conformation
of mobile calix[4]arene-crowns is controlled by the complexed
ton di-ionizable p-tert-butylcalix[4]arene-crown-6 compounds in
the cone, partial-cone and 1,3-alternate conformations (Fig. 1).
cations. For example, 1,3-dimethoxycalix[4]arene-crown-6 ex-
Alkaline earth metal cation complexation by these di-ionizable
ists in a cone conformation both in the solid-state and in
calix[4]arene-crown-6 ligands is evaluated in competitive solvent
solution. Although the complex with Na+ retains the cone
extraction from aqueous solutions into chloroform.
conformation, the Cs+ complex adopts a 1,3-alternate confor-
1
mation. The H-NMR spectrum and X-ray crystal structure
of this complex showed that binding involves participation of
both the crown ether moiety and two rotated aromatic nuclei
Results and discussion
(cation–p-interaction).3 These studies led to the synthesis of
conformationally rigid calix[4]arene-crowns for selective cation
recognition. Among them, 1,3-alternate conformers have been
studied more extensively due to their high Cs+/Na+ selectivity.3–8
Calix[4]arene-crowns with other conformations have also been
prepared.5,9 However, metal ion complexation behavior studies
are rare except for one that reports a partial cone isomer with a
K+/Na+ selectivity of 1.18 × 104, the highest observed to date
for a synthetic ionophore.9
Synthesis of cone di-ionizable p-tert-butylcalix[4]arene-crown-6
ligands
Crown ether ring formation (Scheme 1) by reaction of p-tert-
butylcalix[4]arene13 (4), pentaethylene glycol ditosylate and a
base was more difficult than anticipated. It was reported that
direct ring formation by reaction of 4 with pentaethylene glycol
ditosylate and t-BuOK in benzene gave only 38% yield.9 An
alternative route was employed for the synthesis of calix[4]arene-
crown-6.14 However, when we attempted to adapt this alternative
route, which involves cleavage of the methyl ether protecting
groups in 1,3-dimethoxy-p-tert-butylcalix[4]arene-crown-5, we
found that the crown ether ring was also cleaved under this
condition. Similar results have been reported by Ferguson and
coworkers.15 Kim et al. report that refluxing calix[4]arene and
tetra- and pentaethylene glycol ditosylates in MeCN using
exactly one equivalent of K2CO3 gave calix[4]arene-crown-
5 and -crown-6, respectively, in 70–75% yields.16 When this
method was utilized with 4 as the calix[4]arene reactant,
p-tert-butylcalix[4]arene-crown-6 (5) was obtained in 82% yield.
Incorporation of pendant proton-ionizable groups, such
as carboxylic acid, into calix[4]arenes increases their metal
ion extraction efficiencies compared to their non-ionizable
analogues.10 A novel type of proton-ionizable function, the
N-(X)sulfonyl carboxamide group, whose acidity is “tunable”
by changing the X group from methyl to trifluoromethyl,
1
† Electronic supplementary information (ESI) available: IR, H-NMR
and 13C-NMR spectra for compounds 1a–e, 2a–e, 3a–e and compounds
5–7. See http://www.rsc.org/suppdata/ob/b5/b501822f/
1 6 7 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 6 7 6 – 1 6 8 4
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

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Fig. 1 Conformationally rigid, di-ionizable p-tert-butylcalix[4]arene-crown-6 compounds in the cone, partial-cone and 1,3-alternate conformations.
Scheme 1 Synthesis of cone di-ionizable p-tert-butylcalix[4]arene-crown-6 ligands 1a–e. Reagents and conditions: a) TsO(CH2CH2O)5Ts, K2CO3,
MeCN, reflux; b) BrCH2CO2Et, NaH, THF, rt; c) 10% aqueous NMe4OH, THF, reflux; d) i) (COCl)2, C6H6, reflux; ii) XSO2NH2, NaH, THF, rt.
The 1H-NMR spectrum of 5 showed a cone conformation
Table 1 Chemical shifts (ppm) of the OCH2C(O)R protons for the
three conformers
according to the ArCH2Ar signals, which appear as two doublets
at 4.35 and 3.29 ppm.
Cone Partial-cone
1,3-Alternate
Anti-a Anti-
The p-tert-butylcalix[4]arene-crown-6 (5) was reacted with
ethyl bromoacetate and NaH in THF at room temperature
to give the cone conformer of 1,3-di(ethoxycarbonylmethoxy)-
p-tert-butylcalix[4]arene-crown-6 (6) in 82% yield. The 1H-
NMR spectrum of 6 verified this conformation. Subsequent
hydrolysis with tetramethylammonium hydroxide (TMAOH)
in aqueous THF gave cone 1,3-di(carboxymethoxy)-p-tert-
butylcalix[4]arene-crown-6 (1a) quantitatively. Di(carboxylic
acid) 1a was treated with oxalyl chloride in benzene to give
the corresponding di(acid chloride), which was reacted with
the sodium salt forms of appropriate sulfonamides to give final
products 1b–e in 47–74% yields.
R
Syn-a Syn-
OH
4.97
5.17
5.02
5.07
5.23
4.87
4.70
4.53
4.56
4.76
3.79
2.08
1.47
1.44
1.60
4.07
3.54
3.16
3.21
3.45
NHSO2CH3
NHSO2C6H5
NHSO2C6H4-4-NO2
NHSO2CF3
a To the crown ether ring.
NaOH in aqueous EtOH, gave a 90% yield of partial cone
1,3-di(carboxymethoxy)-p-tert-butylcalix[4]arene-crown-5. No
other isomers were isolated. When we applied these reaction con-
ditions to p-tert-butylcalix[4]arene-crown-6 (5), partial cone 1,3-
di(carboxymethoxy)-p-tert-butyl-calix[4]arene-crown-6 (2a) was
obtained in 72% yield after a simple recrystallization (Scheme 2).
In this case, cone conformer 1a was also isolated in 6% yield.
Di(carboxylic acid) 2a was converted into the corresponding
di(acid chloride) using oxalyl chloride, followed by reaction
with the sodium salt forms of appropriate sulfonamides to give
ligands 2b–2e in 46–90% yields.
The cone conformation for products 1b–e was confirmed
1
by their H- and 13C-NMR spectra. For the former, a typical
AB pattern was observed for the methylene bridge (ArCH2Ar)
protons that is two widely separated doublets at d 4.08–4.51 and
2.84–3.27 (J = 12.6 ∼ 12.9 Hz). In the 13C-NMR spectra, the four
methylene bridge carbons have one peak with a chemical shift
around 31 ppm, which is typical for the bridge carbons in the
syn-orientation. The OCH2C(O) protons for cone conformers
1b–e gave singlets at d 4.97–5.23 (Table 1).
Synthesis of partial cone di-ionizable
p-tert-butylcalix[4]arene-crown-6 compounds
The 1H-NMR spectra of the partial cone conformers
exhibited two sets of doublets for the ArCH2Ar protons,
one set was very close together and buried in the signals for
the crown ring protons. The 13C-NMR spectra showed two
signals for the ArCH2Ar carbons. One at around 31 ppm
corresponds to the bridges in the syn-orientation, as in the cone
During our attempts to synthesize 1,3-alternate conform-
ers, we observed that reaction of p-tert-butylcalix[4]arene-
crown-5 with ethyl bromoacetate and KH (instead of NaH)
in THF at room temperature, followed by hydrolysis with
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 6 7 6 – 1 6 8 4
1 6 7 7

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Scheme 2 Synthesis of partial cone di-ionizable p-tert-butylcalix[4]arene-crown-6 ligands 2a–e. Reagents and conditions: a) i) BrCH2CO2Et, KH,
THF, rt; ii) NaOH, aqueous EtOH, reflux; c) i) (COCl)2, C6H6, reflux; ii) XSO2NH2, NaH, THF, rt.
conformers, and the other at around 38 ppm corresponds to the
methylene bridges in the anti-orientation, as in the 1,3-alternate
conformers (vide infra).
Synthesis of 1,3-alternate di-ionizable
p-tert-butylcalix[4]arene-crown-6 compounds
A distinguishing features in the 1H-NMR spectra of the partial
cone isomers is a small upfield shift for the syn-OCH2C(O)
protons on the same side as the crown ether ring and a large
upfield shift for the anti-OCH2C(O) protons on the side opposite
to the crown ether ring, which is caused by the shielding effects of
the aromatic rings. As shown in Table 1, while the di(carboxylic
acid) derivative 2a exhibits only a slight upfield shift for the
syn-OCH2C(O) protons, the di-N-(X)sulfonylcarboxamides 2b–
e show a somewhat larger upfield shift of 0.47–0.51 ppm, which
could result from shielding by the aromatic ring at the 3-
position. The anti-OCH2C(O) protons exhibit very large upfield
shifts for 2b–e in the range of 3.09–3.73 ppm. Even for the
dicarboxylic acid 2a, an upfield shift of 1.18 ppm was observed
for the anti-OCH2CO protons. This indicates that the anti-
OCH2C(O) groups in the partial cone isomers are buried deeply
in the hydrophobic pocket formed by the three aromatic rings.
In addition to electronegativity, it appears that the size of
the ionizable group influences the magnitude of upfield shift
(Table 1). The larger the X group in OCH2C(O)NHSO2X, the
greater is the upfield shift for the anti-OCH2C(O) protons.
Since it is well known that the 1,3-alternate conformation
can be obtained using Cs+ as a template cation, this prin-
ciple was followed.5,14 In this case, it was necessary to per-
form the O-alkylation first, followed by the crown ether
ring formation. To reduce hydrolysis during the reaction,
tert-butyl bromoacetate was used instead of ethyl bromoac-
etate. Thus, p-tert-butylcalix[4]arene (4) was reacted with tert-
butyl bromoacetate and K2CO3 in refluxing MeCN to pro-
duce 88% yield of 1,3-di(tert-butoxycarbonylmethoxy)-p-tert-
butylcalix[4]arene (7) (Scheme 3). Compound 7 was reacted with
pentaethylene glycol ditosylate and two equivalents of Cs2CO3 in
refluxing MeCN to provide 57% yield of 1,3-alternate 1,3-di(tert-
butoxycarbonylmethoxy)-p-tert-butylcalix[4]arene-crown-6 (8).
Diester 8 was hydrolyzed with NaOH in aqueous EtOH. Af-
ter acidification, 1,3-alternate 1,3-di(carboxymethoxy)-p-tert-
butylcalix[4]arene-crown-6 (3a) was obtained in 97% yield.
Dicarboxylic acid 3a was converted into the final products 3b–e
under the same reaction conditions as those employed for the
cone and partial-cone isomers. Yields of di-ionizable p-tert-
butylcalix[4]arene-crown-6 were in the range 52–86%.
Scheme 3 Synthesis of 1,3-alternate di-ionizable p-tert-butylcalix[4]arene-crown-6 ligands 3a–e. Reagents and conditions: a) BrCH2CO2But, K2CO3,
MeCN, reflux; b) TsO(CH2CH2O)5Ts, Cs2CO3, MeCN, reflux; c) NaOH, aqueous EtOH, reflux; d) i) (COCl)2, C6H6, reflux; ii) XSO2NH2, NaH,
THF, rt.
1 6 7 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 6 7 6 – 1 6 8 4

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1
The H-NMR spectra of the 1,3-alternate isomers exhibit a
singlet or two closely spaced doublets for the ArCH2Ar protons
at around 4.0 ppm. The 13C-NMR spectra show one signal for
the ArCH2Ar carbons at around 39 ppm, which corresponds
to the bridges in the anti-orientation. The two anti-OCH2C(O)
protons show a singlet at d 3.02–4.07, which is an upfield shift
of 0.90–2.03 ppm compared to the cone isomers, resulting from
the shielding effect of two aromatic rings (Table 1).
Competitive solvent extraction of alkali metal cations by
di-ionizable calix[4]arene-crown-6 ligands 1a–e, 2a–e and 3a–e
Upon ionization of the new ligands 1a–e, 2a–e and 3a–e, fixed
conformations for the calix[4]arene units control the spatial
relationship for a crown-complexed divalent metal ion with
respect to the two anionic centers required for electroneutrality
of the extraction complex (Fig. 2). Upon ionization, the cone di-
ionizable calix[4]arene-crown-6 compounds 1a–e form complex
9 with an anionic center over each side of the crown unit.
Alternatively, the partial cone di-ionizable calix[4]arene-crown-
6 compounds 2a–e produce complex 10 with one anionic
center in close proximity to the complexed divalent metal ion
and one in a remote location. Finally the 1,3-alternate di-
ionizable calix[4]arene-crown-6 compounds 3a–e form complex
11 in which anionic centers are remote from the complexed
divalent metal ion. To probe the influence of these differing
spatial arrangements upon the efficiency and selectivity of
divalent metal ion complexation, competitive solvent extraction
of alkaline earth metal cations from aqueous solutions into
chloroform by ligands 1a–e, 2a–e and 3a–e were performed.
Fig. 3 Percent metals loading vs. equilibrium pH of the aqueous phase
for competitive solvent extraction of alkaline earth metal ions into
chloroform by tert-butylcalix[4]arene-crown-6 dicarboxylic acids; a) 1a,
b) 2a, and c) 3a (ꢀ = Mg2+, ᭺ = Ca2+, ꢁ = Sr2+, ꢁ = Ba2+).
Fig. 2 Depiction of spatial relationships between a crown-complexed
divalent metal ion and the anionic centers formed by ionization of
ligands 1a–e, 2a–e and 3a–e.
Fig. 4 Percent metal loading vs. equilibrium pH of the aqueous
phase for competitive solvent extraction of alkaline earth metal ions
into chloroform by tert-butylcalix[4]arene-crown-6 di(N-(X)sulfonyl
carboxamides); a) 1b, b) 1c, c) 1d and d) 1e (ꢀ = Mg2+, ᭺ = Ca2+
,
ꢁ = Sr2+, ꢁ = Ba2+).
Earlier studies of solvent extraction by proton-ionizable lariat
ethers demonstrated that the selectivity in competitive metal
ion extraction may be quite different from that obtained by ex-
trapolating the results of single species extractions.17 Therefore,
competitive solvent extractions of Mg2+, Ca2+, Sr2+ and Ba2+
were utilized in the present investigation.
For competitive solvent extractions of aqueous alkaline earth
metal cation (10.0 mM in each) solutions by 1.0 mM solutions
of di-ionizable calix[4]arene ligands 1a–e, 2a–e and 3a–e in
chloroform, plots of metal ion loading of the organic vs. the
equilibrium pH of the aqueous phase are presented in Figs. 3–6.
Fig. 3 records the results of competitive alkaline earth metal
ion solvent extraction by calix[4]arene-crown-6 di(carboxylic
acids) 1a, 2a and 3a in the cone, partial cone and 1,3-alternate
conformations, respectively. Cone ligand 1a exhibits very high
extraction selectivity for Ba2+ over the other three alkaline
earth metal ion species and 100% maximum metals loading
(for formation of a 1 : 1 metal ion–ligand complex). The Ba2+
selectivity observed in competitive solvent extraction is much
higher than would be expected from the single species extraction
results reported by Chen et al.12 Both the extraction efficiency
and selectivity are markedly affected by ligand conformation in
the order: cone ꢀ 1,3-alternate ꢀ partial cone. The 1,3-alternate
ligand is a much weaker extractant than the corresponding cone
ligand and the selectivity is Ba2+ > Ca2+ ꢀ Sr2+, Mg2+. The partial
Fig. 5 Percent metal loading vs. equilibrium pH of the aqueous
phase for competitive solvent extraction of alkaline earth metal ions
into chloroform by tert-butylcalix[4]arene-crown-6 di(N-(X)sulfonyl
carboxamides); a) 2b, b) 2c, c) 2d and d) 2e (ꢀ = Mg2+, ᭺ = Ca2+
,
ꢁ = Sr2+, ꢁ = Ba2+).
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 6 7 6 – 1 6 8 4
1 6 7 9

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C6H5 < C6H4-4-NO2 < CF3. Comparison of Fig 4 and Fig. 6
shows that each of the cone ligands 1b–e is an appreciably more
efficient extractant than its 1,3-alternate analogue.
Taken together, the results obtained with the calix[4]arene-
crown-6 di(carboxylic acid) and di(N-(X)sulfonyl carboxamide)
ligands 1a–e, 2a–e and 3a–e clearly demonstrate energetically
most favorable extraction complexes of the type represented in 9
in which the calix[4]arene unit is in the cone conformation. This
places one ionized group over and one under the polyether-
complexed alkaline earth metal ion.
Experimental
General
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
1
Fig. 6 Percent metal loading vs. equilibrium pH of the aqueous
phase for competitive solvent extraction of alkaline earth metal ions
into chloroform by tert-butylcalix[4]arene-crown-6 di(N-(X)sulfonyl
solution on NaCl plates. The H- and 13C-NMR spectra were
recorded with a Varian Unity INOVA 500 MHz FT-NMR (1H-
500 MHz and 13C- 126 MHz) spectrometer in CDCl3 with TMS
as an internal standard. Elemental analysis was performed by
Desert Analytics Laboratory of Tucson, Arizona.
carboxamides); a) 3b, b) 3c, c) 3d and d) 3e (ꢀ = Mg2+, ᭺ = Ca2+
,
ꢁ = Sr2+, ꢁ = Ba2+).
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 a high vacuum and then stored in a desiccator.
Pentaethylene glycol ditosylate18 and p-tert-butylcalix[4]arene
(4)13 were prepared by literature procedures.
cone isomer exhibits such a weak extraction propensity
that it is difficult to discern its selectivity. These results
reveal an energetically most favorable arrangement when
the calix[4]arene unit of the di-ionized ligand is in the cone
conformation, which allows positioning of one ionized group
above and the other below the plane of the crown–divalent
metal ion complex (as represented in 9). Although it might be
anticipated that the one proximal and one distal ionized groups
(represented by 10) might be more energetically favorable than
having two distal ionized groups (represented by 11), this is
not the case. Perhaps a greater symmetry in the latter is a
counteracting factor.
To probe the effect of changing to a different class of ionizable
group in which the acidity can be systematically varied, solvent
extractions were performed with the calix[4]arene-crown-6 di(N-
(X)sulfonyl carboxamide) ligands 1b–e, 2b–e and 3b–e, which
are in the cone, partial cone and 1,3-alternate conformations,
respectively. Fig. 4 presents the results for competitive solvent
extractions for alkaline earth metal cations from aqueous
solution by cone ligands 1b–e in which the X group is varied
as CH3, C6H5, C6H4-4-NO2 and CF3. With this group of
substitutents, the ligand acidity is expected to increase in the
order of CH3 ∼ C6H5 < C6H4-4-NO2 < CF3 as the electron-
withdrawing power of the X group is increased. As is seen, very
high Ba2+ extraction selectivity is observed for all four ligands
with 100% maximal metal loading. The pH for half loading,
pH0.5, is a measure of the ligand acidity. For 1b–e, the pH0.5
values are 6.6, 6.3, 5.1 and 2.1, respectively, which is in accord
with the electron-withdrawing power the X group.
Fig. 5 presents the results for competitive alkaline earth metal
ion extraction by the partial-cone calix[4]arene-crown-6 di(N-
(X)sulfonyl carboxamide) ligands 2b–e. Both the extraction
efficiency and selectivity are markedly diminished for 2b–e com-
pared with their cone conformation analogues 1b–e. Although
Ba2+ is the best extracted alkaline earth metal cation, appreciable
amounts of Sr2+ are also transferred into the organic phase.
As before, the alkaline earth metal ion extraction propensity
increases as the X group is varied CH3 ∼ C6H5 < C6H4-4-
NO2 < CF3.
In Fig. 6 are shown the results for competitive alkaline
earth metal solvent extraction by the 1,3-alternate calix[4]arene-
crown-6 di(N-(X)sulfonyl carboxamide) ligands 3b–e. For lig-
ands 3c and 3d, the apparent extraction of Mg2+ at the highest
pH values is attributed to transfer of colloidal Mg(OH)2 into the
organic phase. At lower pHs, very high Ba2+ selectivity is evident
with the extraction efficiency increasing in the order CH3 ∼
Cone 5,11,17,23-tetrakis(1,1-dimethylethyl)-25,27-bis(carboxy-
methoxy)calix[4]arene-crown-6 (1a). A mixture of 6 (5.40 g,
5.28 mmol), THF (250 mL) and 10% Me4NOH (250 mL)
was refluxed for 12 h. The THF was evaporated in vacuo and
the resulting aqueous mixture was cooled in an ice-bath and
acidified with 6 N HCl. The mixture was extracted with CH2Cl2
(2 × 100 mL). The combined organic layers were washed with
water (2 × 50 mL) and dried over MgSO4. After evaporation of
the THF in vacuo, 1a (4.54 g, 89%) was obtained as a white solid
(mp 257–259 ◦C). mmax(film)/cm−1 3233 (COOH), 1756 (C O).
=
dH 10.94 (2 H, bs, CO2H), 7.13 (4 H, s, ArH), 6.54 (4 H, s,
ArH), 4.97 (4 H, s, OCH2CO), 4.47 (4 H, d, J 12.9, ArCH2Ar),
3.93 (4 H, m, OCH2CH2O), 3.87 (4 H, m, OCH2CH2O), 3.79
(8 H, s, OCH2CH2O), 3.75 (4 H, m, OCH2CH2O), 3.22 (4H,
d, J 12.9, ArCH2Ar), 1.34 (18 H, s, C(CH3)3), 0.83 (18 H, s,
C(CH3)3). dC 171.11, 153.13, 151.20, 146.11, 145.38, 134.94,
131.96, 125.82, 125.09, 75.61, 71.74, 70.53, 70.51, 70.47, 69.93,
34.09, 33.63, 31.62, 31.29, 30.99. Found: C, 72.28; H, 8.03%.
C58H78O12 requires C, 72.02; H, 8.13%.
General procedure for preparation of cone 5,11,17,23-
tetrakis(1,1-dimethylethyl)-25,27-bis[N-(X-sulfonyl)carbamoyl]-
calix[4]arene-crown-6 compounds 1b–e. A solution of 1a
(1.50 g, 1.55 mmol) and oxalyl chloride (1.57 g, 12.37 mmol)
in benzene (60 mL) was refluxed for 5 h. The solution was
evaporated in vacuo and dried under a high vacuum for 30 min.
The residue was dissolved in THF (20 mL) and added to a
mixture of the appropriate sulfonamide (4.65 mmol) and NaH
(0.58 g, 24.17 mmol) in THF (40 mL) under nitrogen at room
temperature. The reaction mixture was stirred for 12 h (except
for p-nitrobenzenesulfonamide, 3 h). The reaction was quenched
with a small amount of water and the THF was evaporated
in vacuo. The residue was dissolved in CH2Cl2 (100 mL) and
washed with 10% aqueous K2CO3 solution (2 × 5 0 mL),
10% HCl (50 mL) and water (2 × 50 mL). The organic layer
was dried over MgSO4 (except for trifluoromethyl derivatives).
Evaporation of CH2Cl2 in vacuo gave the crude product, which
was purified by recrystallization or chromatography.
1 6 8 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 6 7 6 – 1 6 8 4

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Cone 5,11,17,23-tetrakis(1,1-dimethylethyl)-25,27-bis[N-(meth-
anesulfonyl)carbamoyl]calix[4]arene-crown-6 (1b). Chromato-
graphy on silica gel with CH2Cl2–MeOH (50 : 1) as eluent,
yield 73%, white solid, mp 266–268 ◦C. mmax(film)/cm−1 3300–
ice-bath and acidified with 6 N HCl. The solution was extracted
with CH2Cl2 (2 × 100 mL). The combined organic layers were
washed with water (2 × 50 mL) and dried over MgSO4. After
evaporation of the CH2Cl2 in vacuo, the crude product was
recrystallized from CH2Cl2–MeOH to give 2a (6.90 g, 72%)
as a white solid with mp 244–246 ◦C. mmax(film)/cm−1 2700–
2800 cm−1 (N–H); 1734, 1718 cm−1 (C O). dH 10.57 (2 H, s, NH),
=
7.11 (4 H, s, ArH), 6.45 (4 H, s, ArH), 5.17 (4 H, s, OCH2CO),
4.58 (4 H, d, J 12.9, ArCH2Ar), 3.92 (8 H, q, OCH2CH2O), 3.85
(4 H, d, OCH2CH2O), 3.81 (8 H, s, OCH2CH2O), 3.23 (4 H, d, J
12.9, ArCH2Ar), 3.18 (6 H, s, CH3SO2), 1.33 (18 H, s, C(CH3)3),
0.82 (18 H, s, C(CH3)3). dC 170.62, 152.37, 152.20, 145.59, 144.87,
135.31, 131.57, 125.77, 124.72, 73.96, 70.41, 70.23, 69.97, 69.28,
41.35, 34.02, 33.53, 32.09, 31.61, 31.01. Found: C, 64.12; H, 7.56;
N, 2.77%. C60H84O14N2S2 requires C, 64.26; H, 7.55; N, 2.50%.
=
3300 (COOH), 1758 (C O). dH 7.5–9.0 (2 H, bs, COOH), 7.23
(2 H, s, ArH), 7.14 (2 H, s, ArH), 6.98 (2 H, d, J 2.44, ArH),
6.77 (2 H, d, J 2.32, ArH), 4.87 (2 H, s, OCH2CO), 4.57
(2 H, d, J 12.6, ArCH2Ar), 4.21 (2 H, m, OCH2CH2O),
3.88 (2 H, d, J 15.5, ArCH2Ar), 3.79 (2 H, s, OCH2CO),
3.64–3.77 (8 H, m, OCH2CH2O, ArCH2Ar), 3.54–3.64 (6 H,
m, OCH2CH2O), 3.45–3.52 (2 H, m, OCH2CH2O), 3.34–3.45
(4 H, m, OCH2CH2O), 3.12 (2 H, d, J 12.6, ArCH2Ar), 1.50 (9 H,
s, C(CH3)3), 1.33 (9 H, s, C(CH3)3), 1.10 (18 H, s, C(CH3)3). dC
170.34, 168.47, 152.26, 150.89, 149.79, 148.03, 146.90, 146.48,
135.66, 134.66, 133.14, 132.39, 128.03, 127.25, 125.69, 124.34,
73.64, 71.06, 70.77, 70.73, 70.55, 69.36, 66.13, 38.56, 34.34,
34.12, 33.91, 31.58, 31.52, 30.91, 30.63. Found: C, 72.38; H,
8.36%. C58H78O12 requires C, 72.02; H, 8.03%;
Cone 5,11,17,23-tetrakis(1,1-dimethylethyl)-25,27-bis[N-(ben-
zenesulfonyl)carbamoyl]calix[4]arene-crown-6 (1c). Chromato-
graphy on silica gel with EtOAc–hexanes (3 : 1) as eluent,
yield 72%, white solid, mp 267–270 ◦C. mmax(film)/cm−1 3300–
2800 cm−1 (N–H); 1721 cm−1 (C O). dH 10.80 (2 H, s, NH), 8.07
=
(4 H, m, PhH), 7.59 (2 H, m, PhH), 7.47 (4 H, m, PhH), 6.94 (4 H,
s, ArH), 6.38 (4 H, s, ArH), 5.02 (4 H, s, OCH2CO), 4.38 (4 H,
d, J 12.9, ArCH2Ar), 3.87 (4 H, m, OCH2CH2O), 3.81 (4 H,
m, OCH2CH2O), 3.75 (8 H, s, OCH2CH2O), 3.67 (4 H, m,
OCH2CH2O), 3.04 (4 H, d, J 12.9, ArCH2Ar), 1.29 (18 H, s,
C(CH3)3), 0.78 (18 H, s, C(CH3)3). dC 168.80, 152.39, 151.79,
145.16, 144.74, 139.32, 134.98, 133.44, 131.59, 128.62, 128.38,
125.65, 124.63, 73.93, 70.57, 70.48, 70.16, 69.92, 69.54, 33.94,
33.49, 31.99, 31.59, 30.98. Found: C, 67.58; H, 7.22; N, 2.48%.
C70H88O14N2S2 requires C, 67.50; H, 7.12; N, 2.25%.
General procedure for preparation of partial cone 5,11,17,23-
tetrakis(1,1-dimethylethyl)-25,27-bis[N-(X-sulfonyl)carbamoyl]-
calix[4]arene-crown-6 compounds 2b–e. The procedure
followed that utilized for the cone isomers 1b–e.
Partial cone 5,11,17,23-tetrakis(1,1-dimethylethyl)-25,27-bis-
[N -(methanesulfonyl)carbamoyl]calix[4]arene-crown-6 (2b).
Recrystallization from CH2Cl2–MeOH, yield 62%, white solid,
mp 269–272 ◦C. mmax(film)/cm−1 3300–2800 cm−1 (N–H);
1721 cm−1 (C O). dH 10.62 (1 H, s, NH), 8.46 (1 H, s, NH),
=
Cone 5,11,17,23-tetrakis(1,1-dimethylethyl)-25,27-bis[N-(p-
nitrobenzenesulfonyl)carbamoyl]calix[4]arene-crown-6 (1d).
Chromatography on silica gel with EtOAc–hexanes (1 : 2) as
7.22 (2 H, s, ArH), 7.09 (2 H, d, ArH), 6.98 (2 H, s, ArH), 6.91
(2 H, d, ArH), 4.70 (2 H, s, OCH2CO), 4.54 (2 H, d, J 12.4,
ArCH2Ar), 3.93 (2 H, m, OCH2CH2O), 3.64–3.89 (14 H, m,
ArCH2Ar, OCH2CH2O), 3.60 (2 H, m, OCH2CH2O), 3.48 (2 H,
m, OCH2CH2O), 3.25 (2 H, d, J 12.6, ArCH2Ar), 3.05 (3 H,
s, CH3SO2), 3.02 (3 H, s, CH3SO2), 2.08 (2 H, s, OCH2CO), 1.42
(9 H, s, C(CH3)3), 1.17 (27 H, d, C(CH3)3). dC 170.13, 166.54,
152.46, 151.98, 151.66, 146.45, 146.06, 145.25, 136.20, 133.41,
133.09, 131.97, 127.19, 126.26, 125.54, 125.49, 74.32, 71.98,
70.94, 70.43, 70.07, 70.04, 68.85, 41.24, 40.60, 38.15, 34.07,
33.92, 33.90, 31.65, 31.20, 31.16, 30.97. Found: C, 64.42; H,
7.47; N, 2.47%. C60H84O14N2S2 requires C, 64.26; H, 7.55; N,
2.50%.
◦
eluent, yield 52%, white solid, mp 262–265 C. mmax(film)/cm−1
3104 cm−1 (N–H); 1737, 1731 cm−1 (C O). dH 10.95 (2 H, s,
=
NH), 8.27 (4 H, m, PhH), 8.21 (4 H, m, PhH), 6.95 (4 H, s,
ArH), 6.37 (4 H, s, ArH), 5.07 (4 H, s, OCH2CO), 4.38 (4 H,
d, J 12.8, ArCH2Ar), 3.90 (8 H, q, OCH2CH2O), 3.81 (12 H,
m, OCH2CH2O), 3.08 (4 H, d, J 13.1, ArCH2Ar), 1.26 (18 H, s,
C(CH3)3), 0.77 (18 H, s, C(CH3)3). dC 169.08, 152.35, 151.73,
150.46, 145.72, 145.04, 144.53, 134.96, 131.29, 129.88, 125.73,
124.73, 123.82, 73.92, 70.46, 70.39, 70.22, 69.85, 69.40, 33.94,
33.53, 32.03, 31.54, 30.98. Found: C, 62.96; H, 6.58; N, 4.12%.
C70H86O18N4S2 requires C, 62.95; H, 6.49; N, 4.19%.
Cone 5,11,17,23-tetrakis(1,1-dimethylethyl)-25,27-bis[N -
(trifluoromethanesulfonyl)carbamoyl]calix[4]arene-crown-6 (1e).
Chromatography on silica gel with EtOAc–hexanes (1 : 5) as
Partial cone 5,11,17,23-tetrakis(1,1-dimethylethyl)-25,27-bis-
[N-(benzenesulfonyl)carbamoyl]calix[4]arene-crown-6 (2c). Re-
crystallization from CH2Cl2–MeOH, yield 90%, white solid,
◦
◦
eluent, yield 68%, white solid, mp 203–206 C. mmax(film)/cm−1
mp 165–168 C. mmax(film)/cm−1 3300–2800 cm−1 (N–H); 1742,
2800–3200 cm−1 (N–H); 1770 cm−1 (C O). dH 10.97 (2 H, s,
1723 cm−1 (C O). dH 11.00 (1 H, s, NH), 8.52 (1 H, s, NH),
=
=
NH), 7.09 (4 H, s, ArH), 6.45 (4 H, s, ArH), 5.23 (4 H, s,
OCH2CO), 4.51 (4 H, d, J 12.9, ArCH2Ar), 3.84–3.93 (20 H,
m, OCH2CH2O), 3.23 (4 H, d, J 12.9, ArCH2Ar), 1.33 (18 H, s,
C(CH3)3), 0.81 (18 H, s, C(CH3)3). dC 168.08, 152.46, 151.45,
145.82, 145.01, 135.07, 131.48, 125.85, 124.71, 73.33, 70.35,
70.08, 69.84, 68.55, 34.04, 33.57, 32.03, 31.59, 31.00. Found:
C, 58.86; H, 6.09; N, 2.51%. C60H78O14N2S2F6 requires C, 58.62;
H, 6.39; N, 2.28%.
8.07 (2 H, m, PhH), 7.83 (2 H, m, PhH), 7.58 (1 H, m, PhH),
7.52 (1 H, m, PhH), 7.45 (2 H, m, PhH), 7.36 (2 H, m, PhH),
7.17 (2 H, s, ArH), 7.02 (2 H, d, ArH), 6.85 (2 H, d, ArH),
6.75 (2 H, s, ArH), 4.53 (2 H, s, OCH2CO), 4.27 (2 H, d,
J 12.4, ArCH2Ar), 3.76–3.94 (8 H, m, OCH2CH2O, ArCH2Ar),
3.70 (4 H, m, OCH2CH2O), 3.61 (4 H, m, OCH2CH2O), 3.55
(2 H, m, OCH2CH2O), 3.47 (2 H, m, OCH2CH2O), 3.32–3.42
(4 H, m, OCH2CH2O), 2.90 (2 H, d, J 12.4, ArCH2Ar),
1.47 (2 H, s, OCH2CO), 1.40 (9 H, s, C(CH3)3), 1.09 (18 H, s,
C(CH3)3), 1.01 (9 H, s, C(CH3)3). dC 168.73, 164.44, 152.16,
152.01, 151.68, 146.62, 145.70, 145.40, 139.26, 138.46, 136.87,
133.65, 133.36, 133.29, 131.89, 131.80, 128.49, 128.47, 128.42,
128.33, 126.55, 126.13, 125.86, 125.52, 75.60, 71.64, 70.85, 70.32,
70.04, 69.64, 68.26, 38.16, 34.08, 33.82, 33.81, 31.61, 31.1,
30.98, 30.46. Found: C, 67.74; H, 7.17; N, 2.29%. C70H88O14N2S2
requires C, 67.50; H, 7.12; N, 2.25%.
Partial cone 5,11,17,23-tetrakis(1,1-dimethylethyl)-25,27-bis-
(carboxymethoxy)calix[4]arene-crown-6 (2a). A mixture of 5
(8.43 g, 9.91 mmol), THF (250 mL) and KH (2.50 g, 35%
dispersion in mineral oil, 21.80 mmol) was stirred under
nitrogen at room temperature for 1 h. Ethyl bromoacetate
(4.98 g, 29.82 mmol) in THF (50 mL) was added slowly. The
reaction mixture was stirred at room temperature for 12 h
and then quenched with a small amount of water. The THF
was evaporated in vacuo. To the residue was added 95% EtOH
(200 mL), NaOH (2.29 g, 57.25 mmol) and H2O (30 mL) and
the solution was refluxed for 24 h. The EtOH was evaporated
in vacuo and the resulting aqueous mixture was cooled in an
Partial cone 5,11,17,23-tetrakis(1,1-dimethylethyl)-25,27-
bis[N-(p-nitrobenzenesulfonyl)carbamoyl]calix[4]arene-crown-6
(2d). Recrystallization from CH2Cl2–MeOH, yield 46%, light
yellow solid, mp 289–291 ◦C. mmax(film)/cm−1 3300–2800 cm−1
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 6 7 6 – 1 6 8 4
1 6 8 1

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(N–H); 1743, 1727 cm−1 (C O). dH 11.26 (1 H, s, NH), 8.61
dC 169.64, 154.08, 153.39, 146.70, 146.19, 132.92, 132.26, 126.77,
126.54, 71.45, 70.66, 70.64, 70.25, 69.31, 68.55, 41.25, 38.72,
34.11, 34.06, 31.46, 31.22. Found: C, 64.58; H, 7.73; N, 2.61%.
C60H84O14N2S2 requires C, 64.26; H, 7.55; N, 2.50%.
=
(1 H, s, NH), 8.25–8.33 (4 H, m, PhH), 8.18–8.25 (2 H, m,
PhH), 8.00–8.06 (2 H, m, PhH), 7.19 (2 H, s, ArH), 7.04 (2 H,
d, ArH), 6.84 (2 H, d, ArH), 6.76 (2 H, s, ArH), 4.56 (2 H, s,
OCH2CO), 4.29 (2 H, d, J 12.3, ArCH2Ar), 3.77–3.92 (8 H,
m, ArCH2Ar, OCH2CH2O), 3.74 (4 H, m, OCH2CH2O), 3.59
(6 H, m, OCH2CH2O), 3.49 (2 H, m, OCH2CH2O), 3.30–3.42
(4 H, m, OCH2CH2O), 2.94 (2 H, d, J 12.4, ArCH2Ar), 1.44
(2 H, s, OCH2CO), 1.41 (9 H, s, C(CH3)3), 1.07 (18 H, s,
C(CH3)3), 1.01 (9 H, s, C(CH3)3). dC 169.12, 164.84, 151.95,
151.92, 151.70, 146.93, 146.07, 145.81, 144.77, 143.86, 137.02,
133.78, 131.92, 131.86, 130.11, 129.97, 126.70, 126.25, 125.82,
125.62, 123.67, 123.61, 75.51, 71.62, 70.87, 70.33, 70.12, 69.67,
68.16, 38.28, 34.19, 33.89, 33.87, 31.67, 31.07, 30.98, 30.56.
Found: C, 63.23; H, 6.69; N, 4.29%. C70H86O18N4S2 requires C,
62.95; H, 6.49; N, 4.19%.
1,3-Alternate 5,11,17,23-tetrakis(1,1-dimethylethyl)-25,27-bis-
[N -(benzenesulfonyl)carbamoyl]calix[4]arene-crown-6 (3c).
Chromatography on silica gel with CH2Cl2-MeOH (50:1) as
◦
eluent, yield 78%, white solid, mp 264–267 C. mmax(film)/cm−1
3345 cm−1 (N–H); 1726, 1711 cm−1 (C O). dH 9.20 (2 H, s, NH),
=
8.01 (4 H, m, PhH), 7.60 (2 H, m, PhH), 7.49 (4 H, m, PhH),
7.08 (4 H, s, ArH), 7.03 (4 H, s, ArH), 3.92 (8 H, t, ArCH2Ar),
3.57 (4 H, s, OCH2CH2O), 3.52 (8 H, m, OCH2CH2O), 3.42
(4 H, m, OCH2CH2O), 3.16 (4 H, s, OCH2CO), 2.69 (4 H, t,
OCH2CH2O), 1.33 (18 H, s, C(CH3)3), 1.11 (18 H, s, C(CH3)3).
dC 168.62, 153.91, 153.28, 146.88, 146.02, 138.61, 133.77, 133.09,
132.47, 128.94, 128.33, 126.82, 126.68, 71.47, 71.08, 70.72, 70.29,
69.16, 68.64, 38.83, 34.06, 33.94, 31.48, 31.07. Found: C, 67.75;
H, 7.28; N, 2.46%. C70H88O14N2S2 requires C, 67.50; H, 7.12; N,
2.25%.
Partial cone 5,11,17,23-tetrakis(1,1-dimethylethyl)-25,27-bis-
[N -(trifluoromethanesulfonyl)carbamoyl]calix[4]arene-crown-6
(2e). Recrystallization from CH2Cl2–MeOH, yield 66%,
white solid, mp 214–216 ◦C. mmax(film)/cm−1 3300–2800 cm−1
1,3-Alternate 5,11,17,23-tetrakis(1,1-dimethylethyl)-25,27-bis-
[N-(p-nitrobenzenesulfonyl)carbamoyl]calix[4]arene-crown-6 (3d).
Recrystallization fr◦om CH2Cl2–MeOH, yield 63%, light yellow
solid, mp 273–275 C. mmax(film)/cm−1 3300–2800 cm−1 (N–H);
(N–H); 1773, 1750 cm−1 (C O). dH 11.47 (1 H, bs, NH),
=
8.64 (1 H, s, NH), 7.24 (2 H, d, ArH), 7.22 (2 H, s, ArH), 6.96
(2 H, s, ArH), 6.92 (2 H, d, ArH), 4.76 (2 H, s, OCH2CO),
4.52 (2 H, d, J 12.4, ArCH2Ar), 3.81–4.00 (8 H, m, ArCH2Ar,
OCH2CH2O), 3.71–3.81 (4 H, m, OCH2CH2O), 3.42–3.71
(12 H, m, OCH2CH2O), 3.28 (2 H, d, J 12.3, ArCH2Ar), 1.60
(2 H, s, OCH2CO), 1.41 (9 H, s, C(CH3)3), 1.22 (18 H, s,
C(CH3)3), 1.12 (9 H, s, C(CH3)3). dC 168.71, 162.90, 151.91,
151.60, 151.45, 147.47, 146.68, 146.21, 137.50, 134.09, 131.96,
131.79, 126.81, 126.59, 125.93, 125.68, 76.12, 71.51, 71.01,
70.58, 70.03, 69.58, 68.28, 38.46, 34.23, 34.06, 34.02, 31.65,
31.15, 31.03, 30.59. Found: C, 58.62; H, 6.48; N, 2.25%.
C60H78O14N2S2F6 requires C, 58.62; H, 6.39; N, 2.28%.
1727, 1714 cm−1 (C O). dH 9.43 (2 H, s, NH), 8.34 (4 H, m, PhH),
=
8.23 (4 H, m, PhH), 7.11 (4 H, s, ArH), 7.02 (4 H, s, ArH), 3.88
(4 H, d, J 17.0, ArCH2Ar), 3.94 (4 H, d, J 17.0, ArCH2Ar),
3.57 (4 H, s, OCH2CH2O), 3.52 (8 H, m, OCH2CH2O), 3.42
(4 H, m, OCH2CH2O), 3.21 (4 H, bs, OCH2CO), 2.70 (4 H, m,
OCH2CH2O), 1.34 (18 H, s, C(CH3)3), 1.13 (18 H, s, C(CH3)3).
dC 169.10, 153.97, 153.31, 150.76, 146.92, 146.51, 143.97, 133.24,
132.53, 129.77, 126.87, 126.73, 124.27, 71.50, 71.19, 70.73, 70.35,
69.43, 68.53, 38.70, 34.11, 33.98, 31.46, 31.01. Found: C, 62.96;
H, 6.63; N, 4.25%. C70H86O18N4S2 requires C, 62.95; H, 6.49; N,
4.19%.
1,3-Alternate 5,11,17,23-tetrakis(1,1-dimethylethyl)-25,27-bis-
(carboxymethoxy)calix[4]arene-crown-6 (3a). A mixture of
diester 8 (6.09 g, 5.55 mmol), NaOH (1.78 g, 44.4 mmol),
EtOH (100 mL) and water (30 mL) was refluxed for 12 h.
The EtOH was evaporated in vacuo and the resulting aqueous
solution was cooled in an ice-bath and acidified with 6 N HCl.
The solution was extracted with CH2Cl2 (2 × 100 mL). The
combined organic extracts were washed with water (2 × 50 mL)
and dried over MgSO4. After evaporation of the CH2Cl2 in
vacu◦o, 3a was obtained (5.21 g, 97%) as a white solid, mp 265–
1,3-Alternate 5,11,17,23-tetrakis(1,1-dimethylethyl)-25,27-bis-
[N -(trifluoromethanesulfonyl)carbamoyl]calix[4]arene-crown-6
(3e). Chromatography on silica gel with CH2Cl2–EtOAc
(50 : 1) as eluent, yield 52%, white solid, mp 232–234 ◦C.
mmax(film)/cm−1 3300–2800 cm−1 (N–H); 1760 cm−1 (C O).
=
dH 9.35 (2 H, bs, NH), 7.12, 7.10 (8 H, s, ArH), 3.98 (8
H, q, ArCH2Ar), 3.58 (4 H, s, OCH2CH2O), 3.53 (8 H, m,
OCH2CH2O), 3.45 (8 H, m, OCH2CH2O, OCH2CO), 2.74 (4 H,
m, OCH2CH2O), 1.35 (18 H, s, C(CH3)3), 1.25 (18 H, s,
C(CH3)3). dC 167.54, 153.99, 152.75, 147.07, 146.53, 133.16,
132.59, 126.83, 71.46, 70.76, 70.38, 69.12, 68.72, 38.84, 34.11,
33.99, 31.47, 31.02. Found: C, 58.98; H, 6.58; N, 2.32%.
C60H78O14N2S2F6 requires C, 58.62; H, 6.39; N, 2.28%.
268 C. mmax(film)/cm−1 3416 (CO2H), 1760 (C O). dH 7.67 (2
=
H, bs, COOH), 7.10 (4 H, s, ArH), 7.03 (4 H, s, ArH), 4.07
(4 H, s, OCH2CO), 3.96 (4 H, d, J 16.9, ArCH2Ar), 3.90 (4
H, d, J 16.9, ArCH2Ar), 3.55 (4 H, s, OCH2CH2O), 3.50 (8
H, s, OCH2CH2O), 3.34 (4 H, t, OCH2CH2O), 3.03 (4 H, t,
OCH2CH2O), 1.35 (18 H, s, C(CH3)3), 1.23 (18 H, s, C(CH3)3).
dC 169.27, 169.24, 153.63, 151.98, 146.60, 146.31, 146.30, 132.75,
132.42, 126.20, 126.09, 71.19, 71.09, 70.98, 70.03, 68.41, 67.26,
38.61, 34.10, 33.86, 31.54, 31.16. Found: C, 72.17; H, 7.94%.
C58H78O12 requires C, 72.02; H, 8.13%.
5,11,17,23-Tetrakis(1,1-dimethylethyl)-25,27-dihydroxycalix-
[4]arene-crown-6 (5). Under nitrogen,
a solution of p-
tert-butylcalix[4]arene (4·toluene) (5.00 g, 6.75 mmol),
pentaethylene glycol ditosylate (4.18 g, 7.64 mmol) and K2CO3
(1.06 g, 7.64 mmol) in MeCN (300 mL) was refluxed for 24 h.
The mixture was filtered and the MeCN was evaporated in
vacuo. To the residue CH2Cl2 (200 mL) and water (100 mL) was
added. The organic phase was separated and washed with 10%
aqueous HCl (50 mL) and twice with water, dried over MgSO4
and evaporated in vacuo to give the crude product, which was
purified by chromatography on silica gel with EtOAc–hexanes
(1 : 5) as eluent to give 5 (4.71 g, 82%) as a white solid, mp
229–231 ◦C, ref. 9 236–237 ◦C. mmax(film)/cm−1 3405 (OH).
dH 7.06 (4 H, s, ArH), 6.98 (2 H, s, OH), 6.73 (4 H, s, ArH),
4.35 (2 H, d, J 13.1, ArCH2Ar), 4.10 (4 H, m, OCH2CH2O),
4.00 (4 H, m, OCH2CH2O), 3.93 (4 H, m, OCH2CH2O),
3.84 (4 H, m, OCH2CH2O), 3.76 (4 H, s, OCH2CH2O), 3.28
(2 H, d, J 13.1, ArCH2Ar), 1.31 (18 H, s, C(CH3)3), 0.91
(18 H, s, C(CH3)3). dC 150.65, 149.92, 146.73, 141.19, 132.36,
127.79, 125.40, 124.96, 76.26, 71.67, 71.05, 70.10, 69.93, 33.82,
General procedure for preparation of 1,3-alternate 5,11,17,23-
tetrakis(1,1-dimethylethyl)-25,27-bis[N-(X-sulfonyl)carbamoyl]-
calix[4]arene-crown-6 compounds 3b–e. The procedure
followed that utilized for the cone isomers 1b–e.
1,3-Alternate 5,11,17,23-tetrakis(1,1-dimethylethyl)-25,27-bis-
[N -(methanesulfonyl)carbamoyl]calix[4]arene-crown-6 (3b).
Chromatography on silica gel with CH2Cl2–MeOH (20 : 1) as
◦
eluent, yield 77%, white solid, mp 278–280 C. mmax(film)/cm−1
3200 cm−1 (N–H); 1706 cm−1 (C O). dH 8.81 (2 H, s, NH), 7.12
=
(4 H, s, ArH), 7.11 (4 H, s, ArH), 3.93–4.00 (8 H, t, ArCH2Ar),
3.54 (4 H, s, OCH2CO), 3.50–3.54 (12 H, m, OCH2CH2O), 3.43
(4 H, m, OCH2CH2O), 3.16 (6 H, s, CH3SO2), 2.69 (4 H, m,
OCH2CH2O), 1.35 (18 H, s, C(CH3)3), 1.27 (18 H, s, C(CH3)3).
1 6 8 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 6 7 6 – 1 6 8 4

View Article Online
33.79, 31.70, 31.28, 30.95. Found: C, 76.15; H, 8.81%. C54H74O8
requires C, 76.20; H, 8.76%.
Extraction procedure
An aqueous solution of the alkaline earth metal chlorides with
hydroxides for pH adjustment (for 1e, 2e and 3e, 0.10 M HCl
was utilized for pH adjustment) (2.0 mL, 10.0 M in each
alkaline earth metal cation species) and 2.0 mL of 1.0 mM
ligand in chloroform in a metal-free, capped, polypropylene,
15 mL centrifuge tube was vortexed with a Glas-Col Multi-
Pulse Vortexer for 10 min at room temperature. The tube was
centrifuged for 10 min for phase separation with a Becton-
Cone 5,11,17,23-tetrakis(1,1-dimethylethyl)-25,27-bis[(ethoxy-
carbonylmethoxy]calix[4]arene-crown-6 (6). A mixture of 5
(4.89 g, 5.75 mmol), THF (250 mL) and NaH (0.96 g,
28.76 mmol) was stirred under nitrogen at room temperature
for 30 min. Ethyl bromoacetate (5.76 g, 34.49 mmol) in THF
(50 mL) was added slowly. The mixture was stirred at room
temperature for 12 h and quenched with a small amount of
water (added dropwise). The THF was evaporated in vacuo and
CH2Cl2 (200 mL) and 10% HCl (50 mL) were added to the
residue. The organic layer was washed with water (50 mL) twice,
dried over MgSO4 and evaporated in vacuo. The residue was
purified by chromatography on alumina with EtOAc–hexanes
(1 : 5) as eluent to give 6 (4.83 g. 82%) as a white solid, mp 152–
R
Dickinson Clay Adams Brandꢀ Centrifuge. 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 alkaline earth metal cation concentrations in the aqueous
phase from stripping were determined with a Dionex DX-120
Ion Chromatograph with a CS12A column. The pH of the
aqueous phase from the initial extraction step was determined
with a Fisher Accumet AR25 pH meter with a Corning 476157
combination pH electrode.
154 ◦C. mmax(film)/cm−1 1760, 1735 cm−1 (C O). dH 7.01 (4 H, s,
=
ArH), 6.55 (4 H, s, ArH), 4.59 (4 H, s, OCH2CO), 4.52 (4 H,
d, J 12.6, ArCH2Ar), 4.24 (8 H, m, OCH2(CH3), OCH2CH2O),
4.15 (4 H, t, OCH2CH2O), 3.74–3.82 (8 H, m, OCH2CH2O),
3.73 (4 H, s, OCH2CH2O), 3.16 (4 H, d, J 12.8, ArCH2Ar),
1.27–1.32 (6 H, m, (OCH2)CH3), 1.25 (18 H, s, C(CH3)3), 0.89
(18 H, s, C(CH3)3). dC 169.86, 167.23, 154.28, 152.18, 144.98,
144.78, 134.87, 132.23, 125.44, 124.88, 72.72, 71.93, 70.98, 70.75,
70.52, 69.93, 62.32, 60.65, 33.98, 33.64, 31.61, 31.26, 31.14,
25.93, 14.23, 13.99. Found: C, 72.14; H, 8.14%. C62H86O12·0.1
CH2Cl2 requires C, 72.29; H, 8.14%.
Acknowledgements
This research was supported by the Division of Chemical
Sciences, Geosciences and Biosciences of the Office of Basic
Energy Sciences of the U. S. Department of Energy (Grant DE-
FG02-90ER14416). We thank the National Science Foundation
for Grant CHE-9808436 that was used to purchase the Varian
Unity INOVA NMR spectrometer.
5,11,17,23-Tetrakis(1,1-dimethylethyl)-25,27-bis(p-tert-butoxy-
carbonylmethoxy)calix[4]arene (7). A solution of 4·toluene
(10.00 g, 13.50 mmol) and K2CO3 (2.10 g, 15.20 mmol) in
MeCN (150 mL) was heated to reflux for 0.5 h and tert-butyl
bromoacetate (6.14 g, 31.48 mmol) was added dropwise. The
mixture was refluxed for 24 h. The MeCN was removed in
vacuo and CH2Cl2 (300 mL) and water (100 mL) were added to
the residue. The organic layer was separated and washed with
10% HCl (100 mL) and twice with water (100 mL), dried over
MgSO4 and evaporated in vacuo. Chromatography on silica gel
with CH2Cl2–EtOAc (15 : 1) as eluent gave 7 (10.42 g, 88%)
as a white solid, mp 180–182 ◦C. mmax(film)/cm−1 3438 cm−1
References
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=
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(tert-butoxycarbonylmethoxy)calix[4]arene-crown-6 (8). A so-
lution of 7 (10.00 g, 11.40 mmol), pentaethylene glycol ditosylate
(6.83 g, 12.48 mmol), Cs2CO3 (5.57 g, 17.10 mmol) and MeCN
(600 mL) was refluxed for 24 h. The MeCN was evaporated in
vacuo and CH2Cl2 (300 mL) and water (100 mL) were added to
the residue. The organic layer was separated and washed with
10% HCl (100 mL) and twice with water (100 mL) and dried
over MgSO4. The solvent was evaporated in vacuo to give the
crude product, which was purified by chromatography (alumina
with CH2Cl2–EtOAc, 50 : 1, as eluent) to give 8 (7.01 g, 57%) as
a white solid, mp 182–185 ◦C. mmax(film)/cm−1 1756, 1727 cm−1
=
(C O); dH 7.14 (4 H, s, ArH), 7.04 (4 H, s, ArH), 4.08 (4 H,
d, J 15.9, ArCH2Ar), 3.84 (4 H, s, OCH2CO), 3.83 (4 H, d,
J 16.0, ArCH2Ar), 3.53–3.60 (12 H, m, OCH2CH2O), 3.02
(4 H, t, OCH2CH2O), 2.89 (4 H, t, OCH2CH2O), 1.36 (18 H, s,
C(CH3)3), 1.33 (18 H, s, C(CH3)3), 1.24 (18 H, s, C(CH3)3); dC
169.23, 154.42, 153.76, 144.24, 143.80, 133.23, 133.16, 127.30,
126.35, 80.69, 77.26, 77.00, 76.75, 71.48, 71.11, 70.80, 70.76,
69.00, 68.95, 38.62, 33.90, 33.76, 31.55, 31.38, 27.97. Found: C,
73.56; H, 8.68%. C66H94O12 requires C, 73.44; H, 8.78%.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 6 7 6 – 1 6 8 4
1 6 8 3

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1 6 8 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 6 7 6 – 1 6 8 4