Di-ionizable calix[4]arene-1,3-crown-4 ligands in 1,3-alternate, cone, and partial-cone conformations: Synthesis and metal ion extractions

Article abstract of DOI:10.1016/j.tet.2012.01.051

Di-ionizable calix[4]arene-1,3-crown-4 compounds locked in 1,3-alternate, cone, and partial-cone conformations are synthesized for evaluation in metal ion separations. The ionizable functions include carboxylic acid and N-(X)sulfonyl carboxamide groups in which the acidity is tuned by variation of the electron-withdrawing ability of X. Similar synthetic routes were employed for preparation of the cone and 1,3-alternate ligand series. A different preparative route utilizing protection and deprotection was required to obtain the partial-cone analogues. Ligand conformations were confirmed by their proton and/or carbon NMR spectra. X-ray diffraction verified an unusual 1,2-alternate conformation in the solid-state for one synthetic intermediate. Effects of ligand conformation and ionizable group variations on competitive solvent extractions of alkali and alkaline earth metal cations from aqueous solutions into chloroform were assessed. Single species solvent extractions of Hg ²⁺ and Pb²⁺ were also performed.

Full text of DOI:10.1016/j.tet.2012.01.051

Tetrahedron 68 (2012) 2233e2244
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Di-ionizable calix[4]arene-1,3-crown-4 ligands in 1,3-alternate, cone, and partial-
cone conformations: synthesis and metal ion extractions
,
Yanfei Yang a, Xiaodan Cao a, David W. Purkiss a, John F. Cannon b, Richard A. Bartsch a
*
a Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409-1061, USA
b Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602-5700, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Di-ionizable calix[4]arene-1,3-crown-4 compounds locked in 1,3-alternate, cone, and partial-cone con-
formations are synthesized for evaluation in metal ion separations. The ionizable functions include
carboxylic acid and N-(X)sulfonyl carboxamide groups in which the acidity is tuned by variation of the
electron-withdrawing ability of X. Similar synthetic routes were employed for preparation of the cone
and 1,3-alternate ligand series. A different preparative route utilizing protection and deprotection was
required to obtain the partial-cone analogues. Ligand conformations were confirmed by their proton
and/or carbon NMR spectra. X-ray diffraction verified an unusual 1,2-alternate conformation in the solid-
state for one synthetic intermediate. Effects of ligand conformation and ionizable group variations on
competitive solvent extractions of alkali and alkaline earth metal cations from aqueous solutions into
chloroform were assessed. Single species solvent extractions of Hg2þ and Pb2þ were also performed.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 5 December 2011
Received in revised form 16 January 2012
Accepted 17 January 2012
Available online 24 January 2012
Keywords:
Calix[4]arenes
Crown ethers
Proton-ionizable groups
Metal ion extractions
1. Introduction
exchange process to form an electroneutral di-ionized cal-
ixcrownedivalent metal ion complex in the organic phase, thereby
In calixareneecrown ethers, also called calixcrowns, a calixar-
ene platform is linked to a polyether unit by connecting two phe-
nolic oxygens of the former with a polyether chain.1e6 More
commonly encountered are calix[4]arene-1,3-crown ethers in
which a calix[4]arene scaffold is bridged by a polyether fragment
connecting two distal phenolic oxygens. The first example of this
ligand family, p-tert-butylcalix[4]arene-1,3-crown-6, was reported
in 1984 by Ungaro and co-workers.7 Metal ion complexation
studies have focused mainly on dialkylated, 1,3-bridged calix[4]
arene-crown ethers, which have been found to exhibit high bind-
ing affinity and selectivity in alkali and alkaline earth metal cation
extractions.8e10 In such calix[4]areneecrown compounds, the
bridging polyether unit may lock the calixarene framework in cone,
1,3-alternate, or partial-cone conformations.1
Of particular interest to our metal ion separations research
program are 1,3-disubstituted calix[4]arene-crown compounds
with pendant acidic groups on the two remaining phenolic oxy-
gens. (The initial example of such a di-ionizable calixcrown com-
pound, a cone p-tert-butylcalix[4]arene-1,3-crown-5 dicarboxylic
acid, was reported by Ungaro and co-workers.)10 Such ligands
provide efficient extraction of divalent metal ions from aqueous
solutions into organic media. The extraction proceeds by an ion-
avoiding the need for concomitant transfer of a hydrophilic anion
from the aqueous phase.
In addition to oxyacetic acid functions, we have employed N-(X)
sulfonyl oxyacetamide groups with X¼methyl, phenyl, p-nitro-
phenyl, and trifluoromethyl groups.11,12 Variation of X is used to
‘tune’ the ligand acidity.13 Also, we have observed that the N-(X)
sulfonyl oxyacetamide groups produce ligands with greater solu-
bility in organic extraction solvents than corresponding carboxylic
acids.
In earlier work, we have evaluated the effect of conformational
variation upon the efficiency and selectivity of alkaline earth metal
ion solvent extractions by di-ionizable p-tert-butylcalix[4]arene-
1,3-crown-6 ligands.14 To probe the effect of shortening the poly-
ether unit, the preparation of di-ionizable p-tert-butylcalix[4]arene-
1,3-crown-4 ligands was proposed. However, synthetic difficulties
arose, which made it impossible to obtain a full set of ligands.15
Further investigation revealed that with removal of the p-tert-
butyl groups the desired series of di-ionizable calix[4]arene-1,3-
crown-4 ligands could be realized. We now report the synthesis
of these new ligands in 1,3-alternate (1aee), cone (2aee), and
partial-cone (3aee) conformations (Fig. 1). Their metal ion com-
plexation properties have been evaluated in competitive solvent
extractions of alkali metal cations and of alkaline earth metal cat-
ions from aqueous solutions into chloroform. Single species solvent
extractions of Hg2þ and Pb2þ were also conducted.
* Corresponding author. Tel.: þ1 806 742 3069; fax: þ1 806 742 1289; e-mail
address: richard.bartsch@ttu.edu (R.A. Bartsch).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.01.051

2234
Y. Yang et al. / Tetrahedron 68 (2012) 2233e2244
O
Y
O
O
Y
Y
Y
a
-OH
O
b -NHSO2Me
c
O
O
-NHSO2Ph
-NHSO2C6H4-4-NO2
O
O
O
d
O
O
O
O
O
O
O
e -NHSO2CF3
O
O
O
O
Y
O
O
O
O
Y
Y
Partial-cone
3a-e
1,3-Alternate
1a-e
Cone
2a-e
Fig. 1. Conformationally locked, di-ionizable calix[4]arene-1,3-crown-4 ligands in 1,3-alternate (1aee), cone (2aee), and partial-cone (3aee) conformations.
2. Results and discussion
d 3.93. These protons in 1bee were singlets. These proton signals all
correlated with single carbon signals at 38 ppm. This verified that
the conformations of 1aee were 1,3-alternate.
2.1. Synthesis of 1,3-alternate di-ionizable calix[4]arene-1,3-
crown-4 ligands
2.2. Synthesis of cone di-ionizable calix[4]arene-1,3-crown-4
ligands
Yamato and Shinkai16 reported the synthesis of calix[4]arene-
1,3-crown-4 in 71% yield by reaction of calix[4]arene with tri-
ethylene glycol ditosylate and Na2CO3 in refluxing MeCN.18 Our
synthesis of the 1,3-alternate calix[4]arene-1,3-crown-4 ligands
(Scheme 1) began with the preparation of calix[4]arene-1,3-crown-
4 (5) from calix[4]arene (4) by this reported method. Then cal-
ixcrown 5 was treated with KH in THF followed by addition of ethyl
bromoacetate to produce diester 6 in 65% yield. Di(carboxylic acid)
1a was realized in 95% yield by hydrolysis of diester 6 with Me4NOH
(TMAOH) in aq THF. Di(carboxylic acid) 1a was converted into the
corresponding di(acid chloride) by reaction with oxalyl chloride in
refluxing benzene. The crude di(acid chloride) was used directly
without further purification. The appropriate, commercially avail-
able sulfonamide was converted into its sodium salt by reaction
with NaH in THF. Then the di(acid chloride) was added and the
reaction was allowed to proceed at room temperature overnight to
give 1bee in 67e85% yields.
The 1,3-alternate conformation for products 1aee was readily
established by their 1H and 13C NMR spectra (Table 1) according to
the ‘De Mendoza’ rule.17 Since the aromatic units are alternately anti
to each other, the differential between the equatorial protons He and
axial protons Ha on the methylene bridge should be minimized. As
a result, a singlet is generally observed in the 1H NMR spectrum.
However, the methylene bridge (ArCH2Ar) protons appeared as an
AB pattern for calix[4]arene-1,3-crown-4 di(carboxylic acid) 1a at
Formation of the di-ionizable calix[4]arene-1,3-crown-4 series
ligands in the cone conformation followed a similar synthetic route
(Scheme 2). Calix[4]arene-1,3-crown-416 (5) was reacted with NaH
and then ethyl bromoacetate in THF to form diester 7 in the cone
conformation as the major product in 50% yield. Di(carboxylic acid)
2a was prepared from 7 in 97% yield by hydrolysis with TMAOH in
refluxing aq THF. By reaction with oxalyl chloride in refluxing
benzene, di(carboxylic acid 2a) was converted into corresponding
di(acid chloride), which was used in the subsequent reaction
without purification. A commercially available sulfonamide was
treated with NaH in THF followed by room temperature reaction of
the corresponding sodium salt with the di(acid chloride) in THF.
Products 2bee were realized in 40e73% yields.
The conformations for 2aee were deduced from their 1H and 13
C
NMR spectra. Selected 1H and 13C NMR chemical shifts are listed in
Table 1. The syn arrangement of all aromatic units of the calix[4]
arene framework makes the equatorial protons He and axial protons
Ha diastereotopic to each other. The methylene bridge (ArCH2Ar)
protons appeared as a pair of widely separated (by at least 1 ppm)
doublets, which is a typical AX pattern for calix[4]arene com-
pounds in the cone conformation. The corresponding carbon sig-
nals were located at 30e31 ppm,17 which further confirms the cone
conformation. The eNH protons in 2bee were located around
O
O
O
O
O
O
a
b
OH
O
OH O
O
O
O
O
OH
OH
OH
OH
O
O
4
5
6
SO2X
SO2X
NH
HN
O
HO
O
O
O
O
OH
O
X
b -Me
c -Ph
O
O
O
O
c
d
d -C6H4-4-NO2
e -CF3
O
O
O
O
O
O
1a
1b-e
Scheme 1. Synthesis of 1,3-alternate di-ionizable calix[4]arene-1,3-crown-4 ligands 1aee. Reagents and conditions: (a) TsO(CH2CH2O)3Ts, Na2CO3, MeCN, reflux; (b) BrCH2CO2Et,
KH, THF, rt; (c) 10% aq NMe4OH, THF, reflux; (d) (i) (COCl)2, C6H6, reflux; (ii) XSO2NH2, NaH, THF, rt.

Y. Yang et al. / Tetrahedron 68 (2012) 2233e2244
2235
Table 1
Table 2
Selected proton and 13C chemical shifts (ppm) for the 1,3-alternate and cone di-
ionizable calix[4]arene-1,3-crown-4 ligands in CDCl3
Reactions of calix[4]arene-1,3-crown-4 (5) with ethyl bromoacetate and 10 equiv of
base under different conditions
Ligand
NH/OH
OCH2C(O)
OCH2C(O)a
ArCH2Ar
ArCH2Ara
Base
Solvent
Reaction conditions
Diester conformation
1a
1b
1c
1d
1e
2a
2b
2c
2d
2e
d
4.14
4.01
3.85
3.81
3.95
4.37
4.33
4.22
4.24
4.40
67.36
70.63
70.52
70.61
70.47
71.53
74.79
73.88
73.83
73.98
3.93 AB pair
3.90 singlet
3.86 singlet
3.88 singlet
3.93 singlet
4.31, 3.22
4.28, 3.24
4.24, 3.15
4.23, 3.18
4.26, 3.26
37.76
37.99
37.99
37.99
38.01
30.43
30.59
30.56
30.57
30.57
NaH
NaH
NaH
NaH
K2CO3
Cs2CO3
t-BuOK
THF
THF
DMF
DMF
THF
THF
THF
rt
Cone
8.14
8.42
8.60
8.50
d
Reflux
rt
70 ꢀC
rt
rt
rt
Coneþpartial-cone (minor)
Coneþpartial-cone (minor)
Coneþpartial-cone (minor)
No reaction
1,3-Alternate
1,3-Alternate
10.88
10.87
11.20
11.61
A partial-cone conformation was anticipated for di-tert-butyl
ester 11, since it would facilitate hydrogen bonding between the
two distal hydroxyl groups. The NMR spectra of 11 in CDCl3 were in
agreement with this expectation. However, the solid-state struc-
ture of 11 as determined by X-ray diffraction revealed that the
compound exists in a 1,2-alternate conformation in the solid-state
(Fig. 2). Solid-state structures of mobile calix[4]arene ligands in 1,2-
alternate conformations are rare with only a few cases reported in
the literature.18,19 As shown by the data in Table 3, the 1,2-alternate
conformation structure for 11 is stabilized by hydrogen bonding of
each phenolic hydroxyl group with an adjacent alkyl aryl ether
oxygen.
a
Chemical shifts for 13C.
11 ppm. A clear downfield shift was observed for these eNH pro-
tons compared to those of 1,3-alternate conformer analogues 1bee.
This downfield shift is rationalized as resulting from the NH pro-
tons in the cone conformers being situated in the deshielding re-
gion of the aromatic units.
2.3. Synthesis of partial-cone di-ionizable calix[4]arene-1,3-
crown-4 ligands
Incorporation of the polyether segment was accomplished by
reaction of 11 with K2CO3 and triethylene glycol ditosylate in MeCN
at reflux to form diester 12 in 45% yield. Calix[4]crown-4 diacid 3a
in the partial-cone conformation was obtained in quantitative yield
from 12 with NaOH in refluxing aq THF. Diacid 3a was converted
into the corresponding di(acid chloride) by reaction with oxalyl
chloride in refluxing benzene. A commercially available sulfon-
amide in THF was treated with NaH to convert it into the sodium
salt. The crude di(acid chloride) was dissolved in THF and reacted
with the sodium salt of the sulfonamide at room temperature to
produce partial-cone products 3bee in low yields of 15e43%.
Partial-cone conformers with two anti-arranged proton-
ionizable groups are less symmetrical than corresponding 1,3-
alternate and cone conformers. The reduced symmetry (from C2v
to Cs) brought extra complexity to the 1H NMR spectra of the
partial-cone conformers (Table 4). The two non-equivalent NeH
protons appeared as two widely separated singlets. One was lo-
In the preparation of cone diester 7 by reaction of calix[4]arene-
1,3-crown-4 (5) with NaH and ethyl bromoacetate in THF, a small
amount of the partial-cone conformer was observed. Subsequent
attempts with various baseesolvent combinations and reaction
temperatures (Table 2) to substantially enhance formation of the
partial-cone conformer diester were unsuccessful.
Therefore, an entirely different synthetic route (Scheme 3) in-
volving a protectionedeprotection strategy was developed for
preparation of the partial-cone conformers. Reaction of calix[4]
arene (4) with K2CO3 and benzyl bromide in MeCN at reflux gave
dibenzyl calix[4]arene 9 in 90% yield. Reaction of 9 with KH and
tert-butyl bromoacetate in THF at room temperature gave dibenzyl
calixarene di-tert-butyl ester 10 in the partial-cone conformation in
55% yield. (The 1,3-alternate conformer was isolated as a minor
product in 25% yield.) Steric repulsion between the benzyl and tert-
butyl groups together with an appropriate metal cation (Kþ in this
case) chelation effect with the calix[4]arene framework were pos-
tulated as key factors in controlling the conformation. The benzyl
protecting groups in 10 were removed by quantitative catalytic
hydrogenolysis with Pd/C in THF/EtOH.
cated downfield at about
d 11e12 and the other around d 6. These
very large chemical shift differences are attributed to different local
magnetic environments for the proton-ionizable groups. In the
a
OH
b
O
O
O
OH O
O
O
O
O
O
O
O
O
O
O
O
O
O
O O
O
O O
OH
HO
5
7
2a
X
b -Me
c -Ph
d -C6H4-4-NO2
e -CF3
c
O
O
O
O
O
O
O
O HN
NH
SO2X
2b-e
SO2X
Scheme 2. Synthesis of cone di-ionizable calix[4]arene-1,3-crown-4 ligands 2aee. Reagents and conditions: (a) BrCH2CO2Et, NaH, THF, rt; (b) 10% aq NMe4OH, THF, reflux; (c) (i)
(COCl)2, C6H6, reflux; (ii) XSO2NH2, NaH, THF, rt.

2236
Y. Yang et al. / Tetrahedron 68 (2012) 2233e2244
O
O -Bu
t
O
O -Bu
t
O
O
a
b
c
OH
OH
O
O
O
Bn
OH
O
O
OH
OH
OH
O
OH
OH
Bn
Bn
Bn
-BuO
O
-BuO
t
O
t
4
9
10
11
SO2X
NH
-BuO
O
O
t
O
HO
O
O
X
b
c
d
e
-Me
O
f
d
e
-Ph
-C6H4-4-NO2
-CF3
O
O
O
O
O
O
O
O
O
O
O
O
O
O
Ot-Bu
O O
OH
O
O
HN
SO2X
12
3a
3b-e
Scheme 3. Synthesis of partial-cone di-ionizable calix[4]arene-1,3-crown-4 ligands 3aee. Reagents and conditions: (a) BnBr, K2CO3, MeCN, reflux; (b) KH, BrCH2CO2-t-Bu, THF, rt;
(c) Pd/C, H2, THF/EtOH, rt; (d) TsO(CH2CH2O)3Ts, K2CO3, MeCN, reflux; (e) NaOH, aq THF, reflux; (f) (i) (COCl)2, C6H6, reflux; (ii) XSO2NH2, NaH, THF, rt.
partial-cone conformers, two distal aromatic units are linked by the
crown ether ring. The other two aromatic units bearing the proton-
ionizable groups are arranged anti to each other. The three syn-
arranged aromatic units cause strong deshielding of the NeH
protons in the syn-arranged proton-ionizable group, while less
deshielding affects the proton-ionizable group linked to the anti-
arranged aromatic unit. This rationalization agrees with the trend
observed for the 1,3-alternate and cone analogues. Based on an
earlier NMR study,20 the proton-ionizable group, that is, syn to the
crown ether ring has its acidic proton appearing relatively down-
field and vice versa. Similar results were observed for the OCH2C(O)
protons and are caused by the same effects. A pair of widely sep-
arated (>1 ppm) doublets (AX pattern) and a pair of closely spaced
doublets (for diacid) or a singlet (for sulfonamides) (AB patterns)
were observed for the methylene bridge (ArCH2Ar) protons. The AX
system correlated with syn-orientated bridge carbons at about
30 ppm and the AB system correlated with anti-orientated bridge
carbons at around 38 ppm. These data confirm the partial-cone
conformations for ligands 3aee.
2.4. Effects of ligand conformation and ionizable group
variation on metal ion extractions
Fig. 2. Solid-state structure of intermediate 11 in a 1,2-alternate conformation.
The effects systematic structural variations in di-ionizable calix
[4]arene-1,3-crown-4 ligands 1aee, 2aee, and 3aee on their metal
ion complexation behavior were probed by extractions from
aqueous solutions into chloroform. The structural variations in-
Table 3
Hydrogen bonds for intermediate 11
ꢀ
ꢀ
ꢀ
ꢀ
DeH/A
O(3)eH(3A)/O(1)#1a
d(DeH) A
d(H/A) A
d(D/A) A
<(DHA)
cluded changing the conformation of the calix[4]arene scaffold
(1,3-alternate, cone, and partial-cone) and varying the identity of
the two pendant acidic groups (carboxylic acid and N-(X)sulfonyl
carboxamides). Competitive solvent extractions of five alkali metal
cation species and of four alkaline earth metal cation moieties were
performed. Single species solvent extractions were conducted with
Hg2þ and Pb2þ. (Calix[4]arenes with two N-(X)sulfonyl oxy-
acetamide groups on the lower rim and analogous calixcrown
compounds are reported to efficiently extract Hg2þ and Pb2þ from
acidic aqueous solutions into chloroform.11,12,14,15) The solvent ex-
traction studies included hard21 alkali and alkaline earth metal
0.82
2.03
2.8233(15)
165.1
a
Symmetry transformations used to generate equivalent atoms: #1 ꢁxþ1, yþ2, z.
Table 4
Selected proton and 13C chemical shifts (ppm) for the partial-cone di-ionizable li-
gands 3aee in CDCl3
Ligand NH/OH
OCH2C(O) OCH2C(O)a ArCH2Ar
ArCH2Arb
3a
3b
3c
3d
3e
d
4.64, 3.16 1.48
4.42, 3.39; 3.99, 3.89 37.76, 30.18
4.39, 3.42; 3.94, 3.90 30.21, 37.37
cations, intermediate Pb2þ, and soft Hg2þ
.
11.48, 6.26 4.63, 2.46 2.17
11.53, 6.39 4.50, 2.28 2.22
11.82, 6.36 4.55, 2.60 1.95
12.20, 6.38 4.71, 2.35 2.36
Since polyether cavities in the calix[4]arene-1,3-crown-4 li-
gands are too small to accommodate even Liþ in nesting complexes,
coordination of the metal cation by the polyether portion of the
ligand should involve perching on one or more of the alkyl aryl
ether oxygens.
4.21, 3.13; 3.83
4.27, 3.24; 3.88, 3.83 30.19, 37.44
4.36, 3.44; 3.92 30.02, 37.40
30.02, 37.24
a
Dd value for the two OCH2C(O) group protons.
b
Chemical shifts for 13C.

Y. Yang et al. / Tetrahedron 68 (2012) 2233e2244
2237
2.4.1. Competitive solvent extraction of alkali metal cations by di-
a
e
200
180
160
140
120
100
80
c
b
d
ionizable calix[4]arene-1,3-crown-4 ligands. Competitive solvent
extractions of aqueous alkali metal cation solutions (10.0 mM each
in Liþ, Naþ, Kþ, Rbþ, and Csþ) by 1.0 mM solutions of di-ionizable
calix[4]arene-1,3-crown-4 ligands 1aee, 2aee, and 3aee in chlo-
roform were performed. The results are presented in Figs. 3e6,
respectively, as plots of metal ion loadings of the organic phase
versus the equilibrium pH of the aqueous phase. Since monovalent
cations were being extracted by di-ionizable ligands, the maximum
metal loading was 200%. In the literature, preferred complexation
of Naþ among the alkali metal cations by calix[4]arene ligands has
often been reported.
60
40
200
e
b
c
d
a
20
180
160
140
120
100
80
0
0
2
4 6 8 10 120 2 4 6 8 10 120 2 4 6 8 10120 2 4 6 8 10 120 2 4 6 8 10 12
pH
Fig. 5. Percent metal loading versus equilibrium pH of the aqueous phase for com-
petitive solvent extraction of alkali metal cations into chloroform by partial-cone di-
ionizable calix[4]arene-1,3-crown-4 ligands (a) 3a, (b) 3b, (c) 3c, (d) 3d, and (e) 3e.
(,¼Liþ, B¼Naþ, 6¼Kþ
,
¼Rbþ, >¼Csþ).
7
b
d
e
a
c
60
100
40
20
80
60
40
20
0
0
0 2 4 6 8 10120 2 4 6 8 10120 2 4 6 8 10120 2 4 6 8 10120 2 4 6 8 1012
pH
Fig. 3. Percent metal loading versus equilibrium pH of the aqueous phase for com-
petitive solvent extractions of alkali metal cations into chloroform by 1,3-alternate di-
ionizable calix[4]arene-1,3-crown-4 ligands (a) 1a, (b) 1b, (c) 1c, (d) 1d, and (e) 1e.
(,¼Liþ, B¼Naþ, 6¼Kþ
,
¼Rbþ, >¼Csþ).
7
200
c
a
e
b
d
180
160
140
120
100
80
0
2
4
6
8 100
2
4
6
8 100
2
4
6
8 100
2
4
6
8 100
2
4 6 8 10
pH
Fig. 6. Percent metal loading versus equilibrium pH of the aqueous phase for com-
petitive solvent extraction of alkaline earth metal cations into chloroform by 1,3-
alternate di-ionizable calix[4]arene-1,3-crown-4 ligands 1aee, (a) 1a, (b) 1b, (c) 1c,
(d) 1d, and (e) 1e. (,¼Mg2þ, B¼Ca2þ, 6¼Sr2þ
,
¼Ba2þ).
7
cations. On the other hand, the N-(X)sulfonyl carboxamide ligands
1bee all showed best extraction of Naþ, nearly negligible extraction
of Liþ, and intermediate extractions of the other alkali metal cations
with little differentiation among Kþ, Rbþ, and Csþ. For 1cee, the
total metal ion loading approaches 200% with 100% loading of Naþ.
This suggests preferred complexation of Naþ at the polyether
binding site followed by non-selective electrostatic binding of Kþ,
Rbþ, and Csþ by an ionized group of the 1:1 complex. This would
minimize repulsion of the two positively charged metal ions.
Fig. 4 presents results for competitive alkali metal cation ex-
traction by cone conformation ligands 2aee, all of which exhibited
high selectivity for Naþ. In the cone conformation, the two ioniz-
able groups may be oriented over the polyether unit forming an
electron-rich pocket for complexation of Naþ. Strong favoring for
1:1 complex formation with Naþ is indicated by the total metal ion
loadings below 100% (compared with a 200% maximum) for all
members of this ligand series. Coordination of a second alkali metal
cation by the 1:1 complex would require dislocation of one of the
ionizable groups complexing the Naþ.
60
40
20
0
0
2 4 6 8 10120 2 4 6 8 10 120 2 4 6 8 10 120 2 4 6 8 10120 2 4 6 8 1012
pH
Fig. 4. Percent metal loading versus equilibrium pH of the aqueous phase for com-
petitive solvent extraction of alkali metal cations into chloroform by the cone di-
ionizable calix[4]arene-1,3-crown-4 ligands (a) 2a, (b) 2b, (c) 2c, (d) 2d, and (e) 2e.
(,¼Liþ, B¼Naþ, 6¼Kþ
,
¼Rbþ, >¼Csþ).
7
Fig. 3 records results for competitive alkali metal cation ex-
tractions by alternate conformation ligands 1aee. In this confor-
mation, the two ionizable side arms are directed away from the
polyether binding site. Di(carboxylic acid) 1a exhibited only very
limited extraction with little selectivity among the alkali metal

2238
Y. Yang et al. / Tetrahedron 68 (2012) 2233e2244
Fig. 5 presents the results from competitive solvent extraction of
d
a
e
b
c
100
80
60
40
20
0
alkali metal cations by partial-cone di-ionizable calix[4]arene-1,3-
crown-4 ligands 3aee. For all five ligands, the cation selectivity
order was Naþ>Csþ with negligible extraction of Liþ, Kþ, and Rbþ.
The total metal loading was very low for di(carboxylic acid) 3a.
When the acidic group was N-(X)sulfonyl acetamide, the extraction
efficiency changed markedly as the
X group was varied
eMe<ePh<eC6H4-4-NO2<eCF3, the trend of side arm acidity for
eC(O)NHSO2X.13 Partial-cone 3e with X¼eCF3 provided the best
combination of extraction selectivity and efficiency for Naþ ex-
traction among ligands 1e3. This is somewhat surprising since in
the partial-cone conformation one acidic side arm may be situated
over the polyether ring, but the other side arm must point away
from the polyether ring.
2.4.2. Competitive solvent extraction of alkaline earth metal cations
by di-ionizable calix[4]arene-1,3-crown-4 ligands. For extraction of
alkaline earth metal cations by di-ionizable calix[4]crown-4 ligands
1aee, 2aee, and 3aee, the two anionic centers formed upon ioni-
zation produce an electroneutral complex with a divalent cation so
the maximum metal ion loading was 100%.
For competitive solvent extractions of aqueous alkaline earth
metal ion (10.0 mM in each) solutions by 1.0 mM solutions of di-
ionizable calix[4]arene-crown-4 ligands 1aee, 2aee, and 3aee in
chloroform, plots of metal ion loading of the organic phase versus
the equilibrium pH of the aqueous phase are presented in Figs. 6e8,
respectively.
0
2
4
6
8 100
2
4
6
8 100
2
4
6
8 100
2
4 6 8 100 2 4 6 8 10
pH
Fig. 8. Percent metal loading versus equilibrium pH of the aqueous phase for com-
petitive solvent extraction of alkaline earth metal cations into chloroform by partial-
cone di-ionizable calix[4]arene-1,3-crown-4 ligands (a) 3a, (b) 3b, (c) 3c, (d) 3d, and
(e) 3e. (,¼Mg2þ, B¼Ca2þ, 6¼Sr2þ
,
¼Ba2þ).
7
methylsulfonyl carboxamide) 2b. The results obtained in the cur-
rent study with the cone di-ionizable calix[4]arene-1,3-crown-4
series 2aee are also quite different than those reported earlier for
cone p-(tert-butyl)calix[4]arene-1,3-crown-4 analogues for which
increasing the side arm acidity enhanced the extraction efficiency
and Ba2þ selectivity.15
In Fig. 8, results for competitive solvent extraction of alkaline
earth metal cations by partial-cone di-ionizable calix[4]arene-1,3-
crown-4 ligands 3aee are displayed. As can be seen, negligible
extraction was observed. This reveals that in alkaline earth cation
extraction by a di-ionizable calix[4]arene-1,3-crown-4 isomer both
ionizable side arms must be available to participate in binding.
e
a
b
c
d
100
80
60
40
20
0
2.4.3. Competitive solvent extraction of Pb2þ by di-ionizable calix[4]
arene-1,3-crown-4 ligands. In the study of Pb2þ extraction, an
aqueous solution containing 1.00 mM Pb2þ was extracted by
0.50 mM solutions of di-ionizable ligands 1aee, 2aee, and 3aee in
chloroform. Plots of Pb2þ loading of the organic phase versus the
equilibrium pH of the aqueous phase are shown in Fig. 9aec,
respectively.
From the data presented in the panels, the relative extraction
efficiencies may be compared in terms of Pb2þ loading of the or-
ganic phase as a function of the aqueous phase pH. Extraction from
a more acidic aqueous solution shows stronger binding. As is
readily evident, the Pb2þ extraction efficiency was highest for the
1,3-alternate series ligands 1aee as a group, intermediate for the
cone series ligands 2aee, and lowest for the partial-cone series li-
gands 3aee. Thus, a conformation with the two ionized side arms
oriented away from polyether region of the ligand is preferred. It
seems reasonable that the divalent metal cation is sandwiched
between the two anionic side arms.
2
4
6
8
100
2
4
6
8 100
2
4
6
pH
8 100
2
4
6
8 100
2
4 6 8 10
Fig. 7. Percent metal loading versus equilibrium pH of the aqueous phase for com-
petitive solvent extraction of alkaline earth metal cations into chloroform by cone di-
ionizable calix[4]arene-1,3-crown-4 ligands (a) 2a, (b) 2b, (c) 2c, (d) 2d, and (e) 2e.
(,¼Mg2þ, B¼Ca2þ, 6¼Sr2þ
,
¼Ba2þ).
7
Fig. 6 displays the results for di-ionizable calix[4]arene-1,3-
crown-4 1,3-alternate conformers 1aee. The total metal ion load-
ings were low for ligands 1a, 1b, and 1e. Ligands 1c and 1d with N-
(X)sulfonyl carboxamide side arms and X¼phenyl and p-nitro-
phenyl, respectively, gave appreciable extraction with selectivity
for Ba2þ. Since the two ionizable groups are directed away from the
polyether ring in the 1,3-alternate conformation, the results sug-
gest coordination of Ba2þ between the two ionized side arms and
For the 1,3-alternate ligands with N-(X)sulfonyl carboxamide
side arms, the Pb2þ extraction efficiency increased as the electron-
withdrawing propensity of X was enhanced eMe, ePh<eC6H4-4-
NO2<eCF3 increasing the acidity to the two side arms. Ligands
1a, 1d, and 1e gave quantitative extraction, whereas ligands 1b and
1c provided maximum extractions of about 70%.
possible interactions with the p-clouds of their aromatic rings.
For the cone series, Pb2þ extraction was observed only with li-
gands 2aec. For the cone ligands with N-(X)sulfonyl carboxamide
side arms, no significant Pb2þ extraction was noted with the
stronger acidifying X groups in 2d and 2e. The reason for the op-
posite effects of X group variation on Pb2þ extraction efficiency for
Fig. 7 presents the alkaline earth metal cation extraction data for
cone di-ionizable calix[4]crown-4 ligands 2aee. In sharp contrast
with the results shown above for the 1,3-alternate isomers 1aee,
highest extraction efficiency with very high Ba2þ selectivity was
observed for the cone di(carboxylic acid) 2a and the di(N-

Y. Yang et al. / Tetrahedron 68 (2012) 2233e2244
2239
very similar. In comparison, extraction levels for most of the N-(X)
sulfonyl carboxamide-containing ligands substantially surpass
those noted for the di(carboxylic acid) ligands. This demonstrates
an important effect of ionizable group identity.
The highest extraction efficiencies were found for ligands 1bee
in the 1,3-alternate conformation. In this conformation, the two
ionized N-(X)sulfonyl carboxamide side arms project away from the
polyether cavity providing an electronegative pocket for complex-
ation of the divalent cation. Noteworthy are the high levels of Hg2þ
extraction obtained from quite acidic aqueous solutions.
100
80
60
40
20
0
a
b
c
The extraction profiles for cone ligands 2bee and partial-cone
ligands 3bee Fig. 10b and c, respectively, are quite similar. Thus
for Hg2þ extraction having the two ionized side arms on the same
side of the polyether unit appears to be of much lesser importance
than it was in extractions of Ba2þ and Pb2þ
.
For the cone ligands 2bee (Fig. 10b), the Hg2þ extraction effi-
ciency decreased as X was varied in the order eCF3>ePh>eC6H4-
4-NO2>eMe. Except for reversed positions for the two aryl groups,
this trend follows the electron-withdrawing ability of X.
For the partial-cone ligands 3bee (Fig. 10c), the extraction effi-
ciency diminished as X was changed in the order eCF3>eC6H4-4-
NO2>ePh>eMe. This ordering mirrors the change in the
electron-withdrawing ability of X.
0
2
4
6
8
0
2
4
pH
6
8
0
2
4
6
8
Fig. 9. Percent metal loading versus equilibrium pH of the aqueous phase for single
species solvent extraction of Pb2þ into chloroform by di-ionizable calix[4]arene-1,3-
crown-4 ligands in three conformations: (a) 1,3-alternate, 1aee, (b) cone, 2aee, and
(c) partial-cone, 3aee. (,¼eCO2H, B¼eC(O)NHSO2CH3, 6¼eC(O)NHSO2C6H5,
¼eC(O)NHSO C H -4-NO , >¼eC(O)NHSO CF ).
7
2
6
4
2
2
3
the 1,3-alternate and cone conformation ligands is not obvious at
this time.
3. Conclusions
With the partial-cone series of ligands having one ionizable
group located near the polyether cavity and the other distant, only
limited Pb2þ extraction efficiencies were found with the most ef-
fective ligands 3a and 3e. Thus, having the two acidic side arms in
close proximity is judged to be a requirement for effective Pb2þ
extraction by the di-ionizable calix[4]arene-1,3-crown-4 ligands.
Synthetic routes are established for three series of di-ionizable
calix[4]arene-1,3-crown-4 structural isomers in 1,3-alternate,
cone, and partial-cone conformations, 1aee, 2aee, and 3aee, re-
spectively. Side arm acidic groups include eCO2H and eC(O)
NHSO2X with variation in the inductive effects of X. In one syn-
thetic sequence, a conformationally unrestricted intermediate is
isolated in an unusual 1,2-alternate conformation as determined by
X-ray diffraction.
2.4.4. Competitive solvent extraction of Hg2þ by di-ionizable calix[4]
arene-1,3-crown-4 ligands. Aqueous nitrate solutions containing
0.25 mM Hg2þ were extracted with 0.25 mM solutions of di-
ionizable calix[4]arene-1,3-crown-4 ligands 1aee, 2aee, and
3aee in chloroform. Plots of Hg2þ loading of the organic phase
versus the equilibrium pH of the aqueous phase are presented in
Fig. 10aec, respectively.
To probe the effect of varying the calix[4]arene scaffold con-
formation on metal ion complexation, solvent extraction of metal
cations from aqueous solutions into chloroform are conducted. This
includes competitive extraction of hard alkali metal cations and
alkaline earth metal cations, intermediate Pb2þ, and soft Hg2þ
.
For ligands with significant extraction of alkali metal cations,
Naþ selectivity is noted. Propensities for extraction of the remain-
ing alkali metal cation species are found to vary depending upon
the calix[4]arene unit conformation in the ligand.
For the di(carboxylic acid)s 1a, 2a, and 3a (squares in Fig. 10aec,
respectively), Hg2þ extraction was low and the three profiles are
Modest extraction of alkaline earth metal cations is observed for
some ligands in the 1,3-alternate and cone conformations. When
effective, the ligands exhibit selectivity for Ba2þ. Isomers with
partial-cone conformations give negligible extraction of alkaline
earth metal cations.
100
a
b
c
80
60
40
20
0
For intermediate Pb2þ, ligands with the calix[4]arene unit in the
1,3-alternate conformation are strong extractants. High levels of
Pb2þ extraction are also observed for some of the cone conforma-
tion ligands. The partial-cone isomers are weak extractants of Pb2þ
.
For soft Hg2þ, the three di(carboxylic acid) ligands exhibit uni-
formly weak extraction behavior. With pendant eC(O)NHSO2X
acidic functions, high extraction efficiency is obtained when the
calix[4]arene unit is in a 1,3-alternate conformation. Lower, but still
substantial Hg2þ, is produced by ligands with eC(O)NHSO2X ion-
izable groups and cone and partial-cone conformations.
High levels of Pb2þ and Hg2þ extractions from acidic solutions
by ligands with eC(O)NHSO2X acidic groups and a 1,3-alternate
conformation are noteworthy.
0
2
4
6
8
0
2
4
pH
6
8
0
2
4
6
8
Previously, we have published results for competitive solvent
extraction of alkaline earth metal cations from aqueous solutions
into chloroform by di-ionizable calix[4]arene-1,3-crown-527 (cone
conformation) and di-ionizable calix[4]arene-1,3-crown-614 (cone,
1,3-alternate, and partial-conformation) ligands. When combined
Fig. 10. Percent metal loading versus equilibrium pH of the aqueous phase for single
species solvent extraction of Hg2þ into chloroform by di-ionizable calix[4]arene-1,3-
crown-4 ligands in three conformations: (a) 1,3-alternate, 1aee, (b) cone, 2aee, and
(c) partial-cone, 3aee. (,¼eCO2H, B¼eC(O)NHSO2CH3, 6¼eC(O)NHSO2C6H5,
¼eC(O)NHSO C H -4-NO , >¼eC(O)NHSO CF ).
7
2
6
4
2
2
3

2240
Y. Yang et al. / Tetrahedron 68 (2012) 2233e2244
with data obtained in the present study, the effects of some sys-
tematic structural variations emerge. Based upon the data obtained
with di-ionizable calix[4]arene-crown-4 and -crown-6 ligands, the
efficiency and selectivity of alkaline earth metal cation extraction
diminish as the conformation of a di-ionizable calix[4]arene-crown
ether is varied in the order of cone>1,3-alternate>partial-cone. For
variation of the crown ring size with cone conformation ligands,
the efficiency and selectivity of alkaline earth metal cation extrac-
tion decreases in the order of crown-6>crown-5>crown-4. Cone
di-ionizable calix[4]arene-1,3-crown-6 compounds give efficient
and selective extraction of Ba2þ. Models show the metal ion posi-
tioned within the polyether cavity with apical coordination by an
ionized group above and below the crown ether ring.
10% aq HCl (25 mL) were added slowly. The organic layer was
separated, washed with water (2ꢂ50 mL), dried over MgSO4, and
evaporated in vacuo. The residue was purified by recrystallization
from MeOH/CH2Cl2 to give 6 (0.86 g, 65%) as a white solid with mp
195 ꢀC. IR (deposit from CH2Cl2 solution on a NaCl plate): 1750 (C]
O) cmꢁ1. 1H NMR (CDCl3):
d
1.15 (t, J¼7.5 Hz, 6H, CH2CH3), 2.97 (t,
J¼5.0 Hz, 4H, OCH2CH2O), 3.18 (s, 4H, OCH2C(O)), 3.36 (s, 4H,
OCH2CH2O), 3.54 (t, J¼5.0 Hz, 4H, OCH2CH2O), 3.86 (d, J¼16.5 Hz,
4H, ArCH2Ar), 4.01 (q, J¼7.0 Hz, 4H, OCH2CH3), 4.20 (d, J¼16.5 Hz,
4H, ArCH2Ar), 6.87 (t, J¼7.5 Hz, 2H, ArH), 6.94 (t, J¼7.5 Hz, 2H, ArH),
7.13 (d, J¼7.5 Hz, 8H, ArH). 13C NMR (CDCl3)
d: 14.0, 38.3, 60.2, 67.8,
68.5, 69.7, 70.0, 122.8, 123.4, 130.2, 133.6, 134.9, 155.8, 156.6, 170.4.
Anal. Calcd for C42H46O10: C, 70.98, H, 6.48%. Found: C, 70.74; H,
6.38%.
4. Experimental
4.1. General
4.2.3. 1,3-Alternate 25,27-Bis(carboxymethoxy)calix[4]arene-1,3-
crown-4 (1a). A mixture of diester 6 (5.00 g, 7.04 mmol), 10% aq
Me4NOH (TMAOH) (200 mL), and THF (200 mL) was refluxed for
24 h. After evaporating the THF in vacuo, 200 mL of 6 N aq HCl was
added to the residue. The aqueous mixture was extracted with
CH2Cl2 (2ꢂ150 mL). The combined organic layers were washed
with water (2ꢂ200 mL) and dried over MgSO4. After evaporation of
the THF in vacuo, di(carboxylic acid) 1a (4.37 g, 95%) was obtained
as a white solid that decomposed at 270 ꢀC without melting. IR
(deposit from CH2Cl2 solution on a NaCl plate): 3418 (OH), 1753
Melting points were determined with a Mel-Temp melting point
apparatus. Infrared (IR) spectra were recorded with a Nicolet IR100
FT-IR spectrometer as deposits from CH2Cl2 solutions on NaCl
plates unless otherwise noted. The catalytic hydrogenolysis re-
action was carried out with a low pressure Parr reaction apparatus.
The 1H and 13C NMR spectra were recorded with a Varian Unity
INOVA 500 MHz FT-NMR (1H 500 MHz and 13C 126 MHz) spec-
trometer in CDCl3 with Me4Si as internal standard unless men-
(C]O) cmꢁ1 1H NMR (CDCl3)
. d: 2.62 (s, 4H, OCH2CH2O), 3.43 (t,
tioned otherwise. Chemical shifts (
d
) are given in parts per million
J¼4.0 Hz, 4H, OCH2CH2O), 3.70 (t, J¼4.0 Hz, 4H, OCH2CH2O), 3.93
(AB pattern, J¼16.5 Hz, J0¼12.0 Hz, 8H, ArCH2Ar), 4.14 (s, 4H,
OCH2C(O)), 6.94 (t, J¼7.5 Hz, 2H, ArH), 7.07 (m, 6H, ArH), 7.17 (d,
downfield from TMS and coupling constants values (J) are in hertz.
Elemental analysis was performed by Desert Analytics Laboratory
(now Columbia Analytical Services) of Tucson, Arizona.
Reagents were purchased 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. Triethylene glycol ditosylate was
prepared according to a published procedure.22
J¼7.5 Hz, 4H, ArH). 13C NMR (CDCl3):
d 37.8, 67.4, 69.0, 69.4, 70.8,
124.4, 124.56, 129.4, 130.2, 133.4, 133.5, 153.7, 156.0, 168.1. Anal.
Calcd for C38H38O10$0.8CH2Cl2: C, 70.75; H, 6.06%. Found: C, 70.82;
H, 5.83%.
4.2.4. General procedure for preparation of 1,3-alternate 25,27-bis[N-
(X)sulfonyl carbamoylmethoxy]calix[4]arene-1,3-crown-4 com-
pounds 1bee. Di(carboxylic acid) 1a (1.50 g, 2.30 mmol) was dried
with a benzene azeotrope before addition of oxalyl chloride (2.92 g,
23.00 mmol) in benzene (100 mL). The solution was refluxed
overnight. After conversion to the di(acid chloride) was confirmed
by a shift of the C]O IR absorption, the benzene was evaporated in
vacuo and the residue was dried under oil pump vacuum for
30 min. The residue was dissolved in freshly distilled THF (20 mL)
and the solution was added to a mixture of the appropriate sul-
fonamide (5.10 mmol) and NaH (0.55 g, 23.00 mmol) in THF (40 mL)
under nitrogen at room temperature. The reaction mixture was
allowed to stir at room temperature for 24 h. The THF was removed
in vacuo and CH2Cl2 (50 mL) and 10% aq HCl (50 mL) were added to
the residue. The organic layer was separated, washed with brine
(2ꢂ50 mL), and then water (2ꢂ50 mL), and dried over MgSO4.
Evaporation of the CH2Cl2 in vacuo gave the crude product, which
was purified by either recrystallization or column chromatography
on silica gel. For the latter, an extra acid wash process was neces-
sary. The eluted product was dissolved in CH2Cl2 (50 mL) and
washed with 6 N aq HCl (100 mL). The organic layer was separated,
washed with water (2ꢂ100 mL), dried over MgSO4, and evaporated
in vacuo to give the final product.
4.2. Ligand synthesis
4.2.1. 25,27-Dihydroxycalix[4]arene-1,3-crown-4 (5).16 A slurry of
calix[4]arene (4) (17.00 g, 0.040 mol) and Na2CO3 (42.40 g,
0.40 mol) in MeCN (2.0 L) was refluxed for 2 h under nitrogen.
Triethylene glycol ditosylate (19.24 g, 0.042 mol) dissolved in MeCN
(200 mL) was added dropwise during a 3-h period. The mixture
was refluxed for 7 days. After evaporation of the MeCN in vacuo,
CH2Cl2 (500 mL) and 10% aq HCl (500 mL) were added to the res-
idue. The organic phase was separated, washed with brine
(2ꢂ250 mL), and then water (2ꢂ250 mL), dried over MgSO4, and
evaporated in vacuo to give the crude product, which was purified
by chromatography on silica gel with CH2Cl2/EtOAc (10:1 to 2:1) as
eluent to give 5 (13.40 g, 69%) as a white solid with mp >400 ꢀC,
(lit.16 mp >400 ꢀC). IR (deposit from CH2Cl2 solution on a NaCl
plate): 3309 (OH) cmꢁ1. 1H NMR (CDCl3):
d
3.39 (d, J¼13.5 Hz, 4H,
ArCH2Ar), 4.02 (s, 4H, OCH2CH2O), 4.18e4.25 (m, 8H, OCH2CH2O),
4.38 (d, J¼13.5 Hz, 4H, ArCH2Ar), 6.59 (t, J¼7.5 Hz, 2H, ArH), 6.82 (t,
J¼7.5 Hz, 2H, ArH), 7.00e7.06 (m, 8H, ArH), 8.75 (s, 2H, OH). 13C
NMR (CDCl3): d 31.8, 69.2, 69.5, 74.6, 119.3, 125.7, 128.2, 128.7, 128.9,
134.5, 152.1, 152.9.
4.2.4.1. 1,3-Alternate
25,27-bis(N-methanesulfonyl
carba-
4.2.2. 1,3-Alternate 25,27-bis(ethoxycarbonylmethoxy)calix[4]arene-
1,3-crown-4 (6). A mixture of 5 (1.00 g, 1.86 mmol) and KH (0.45 g,
11.20 mmol) in THF (50 mL) was stirred under nitrogen at room
temperature for 30 min and BrCH2CO2Et (1.86 g, 11.20 mmol) was
added in one portion. The mixture was stirred at room temperature
for another 24 h. After evaporating the THF in vacuo, the residue
was allowed to cool to room temperature. Then CH2Cl2 (50 mL) and
moylmethoxy)calix[4]arene-1,3-crown-4 (1b). The crude product
was recrystallized from CH2Cl2/MeOH to give a 67% yield of pale
yellow solid with mp 176e180 ꢀC. IR (deposit from CH2Cl2 solution
on a NaCl plate): 3345 (NH), 1719 (C]O) cmꢁ1 1H NMR (CDCl3):
.
d
2.76 (s, 4H, OCH2CH2O), 3.32 (s, 6H, CH3), 3.34 (t, J¼5.0 Hz, 4H,
OCH2CH2O), 3.64 (t, J¼5.0 Hz, 4H, OCH2CH2O), 3.90 (s, 8H,
ArCH2Ar), 4.01 (s, 4H, OCH2C(O)), 6.97 (t, J¼7.5 Hz, 2H, ArH), 7.02 (t,

Y. Yang et al. / Tetrahedron 68 (2012) 2233e2244
2241
J¼7.5 Hz, 2H, ArH), 7.17 (q, J¼4.0 Hz, 8H, ArH), 8.14 (s, 2H, NH). 13
C
ArH), 6.96 (t, J¼7.5 Hz, 2H, ArH), 7.15 (d, J¼7.5 Hz, 4H, ArH). 13C NMR
NMR (CDCl3):
d
38.0, 41.5, 69.1, 70.5, 70.6, 124.0, 124.1, 129.7, 130.8,
(CDCl3): d 14.2, 30.7, 60.8, 70.2, 71.7, 71.82, 73.8, 122.3, 122.6, 127.7,
133.2, 134.2, 155.6, 156.2, 168.5. Anal. Calcd for C40H44N2O12S2: C,
59.40; H, 5.44; N, 3.46%. Found: C, 59.37; H, 5.36; N, 3.11%.
129.2, 132.7, 136.6, 154.4, 158.0, 169.43. Anal. Calcd for C42H46O10: C,
70.98; H, 6.48%. Found: C, 70.90; H, 6.15%.
4.2.4.2. 1,3-Alternate 25,27-bis(N-benzenesulfonyl carbamoylme-
thoxy)calix[4]arene-1,3-crown-4 (1c). The crude product was
chromatographed on silica gel with CH2Cl2/MeOH (250:1 to 25:1
gradient) as eluent to afford in 85% yield a white solid that
decomposed at 265 ꢀC. IR (deposit from CH2Cl2 solution on a NaCl
4.2.6. Cone
25,27-bis(carboxymethoxy)calix[4]arene-1,3-crown-4
(2a). The procedure was the same as that employed for preparation
of 1a from 7. After the reaction, 2a (4.45 g, 97%) was collected as
a white solid with mp 260e262 ꢀC. IR (deposit from CH2Cl2 solution
on a NaCl plate): 3426 (OH), 1745 (C]O) cmꢁ1 1H NMR (CDCl3):
.
plate): 3337 (NH), 1721 (C]O) cmꢁ1. 1H NMR (CDCl3):
d
2.76 (s, 4H,
d
3.22 (d, J¼13.5 Hz, 4H, ArCH2Ar), 3.90 (s, 4H, OCH2CH2O), 4.07 (t,
OCH2CH2O), 3.27 (t, J¼4.5 Hz, 4H, OCH2CH2O), 3.59 (t, J¼4.5 Hz, 4H,
OCH2CH2O), 3.85 (s, 4H, OCH2C(O)), 3.86 (s, 8H, ArCH2Ar), 6.78 (t,
J¼8.0 Hz, 2H, ArH), 6.97e7.02 (m, 6H, ArH), 7.13 (d, J¼7.5 Hz, 4H,
ArH), 7.58e7.61 (m, 4H, ArH), 7.67e7.70 (m, 2H, ArH), 8.14e8.16 (m,
J¼5.5 Hz, 4H, OCH2CH2O), 4.273 (t, J¼5.5 Hz, 4H, OCH2CH2O), 4.32
(d, J¼13.5 Hz, 4H, ArCH2Ar), 4.37 (s, 4H, OCH2C(O)), 6.13 (d,
J¼8.0 Hz, 4H, ArH), 6.28 (t, J¼7.5 Hz, 2H, ArH), 7.00 (t, J¼7.5 Hz, 2H,
ArH), 7.17 (d, J¼7.5 Hz, 4H, ArH). 13C NMR: (CDCl3):
d 30.4, 70.6, 70.8,
4H, ArH), 8.42 (s, 2H, NH). 13C NMR (CDCl3):
d
38.0, 69.0, 69.1, 70.5,
71.5, 74.0, 122.8, 123.4, 128.1, 129.4, 132.4, 136.2, 152.7, 158.1, 170.6.
Anal. Calcd for C38H38O10: C, 69.72; H, 5.81%. Found: C, 69.42; H,
5.76%.
70.5,123.8, 124.3,128.8, 128.9, 129.5,130.6, 133.3,134.1, 134.2, 138.3,
155.4, 156.1, 167.3. Anal. Calcd for C50H48N2O12S2$0.1CH2Cl2: C,
63.91; H, 5.16; N, 2.98%. Found: C, 63.90; H, 5.02; N, 3.06%.
4.2.7. General procedure for the preparation of cone 25,27-bis[N-(X)-
sulfonyl carbamoylmethoxy]calix[4]arene-1,3-crown-4 compounds
2bee. The procedure was the same as that employed for synthe-
sizing compounds 1bee but starting from 2a.
4.2.4.3. 1,3-Alternate 25,27-bis(N-4-nitrobenzenesulfonyl carba-
moylmethoxy)calix[4]arene-1,3-crown-4 (1d). The crude product
was chromatographed on silica gel with CH2Cl2/MeOH (250:1 to
25:1 gradient) as eluent to give in 66% yield a pale yellow solid that
decomposed at 262 ꢀC. IR (deposit from CH2Cl2 solution on a NaCl
4.2.7.1. Cone 25,27-bis(N-methanesulfonyl carbamoylmethoxy)
calix[4]arene-1,3-crown-4 (2b). The crude product was chromato-
graphed on silica gel with CH2Cl2/MeOH (250:1 to 25:1 gradient) as
eluent to produce a 40% yield of white solid with mp 225e227 ꢀC. IR
(deposit from CH2Cl2 solution on a NaCl plate): 3289 (NH), 1716
plate): 3326 (NH), 1732 (C]O) cmꢁ1. 1H NMR (CDCl3):
d 2.83 (s, 4H,
OCH2CH2O), 3.24 (t, J¼4.5 Hz, 4H, OCH2CH2O), 3.59 (t, J¼4.5 Hz, 4H,
OCH2CH2O), 3.81 (s, 4H, OCH2C(O)), 3.88 (s, 8H, ArCH2Ar), 6.80 (t,
J¼7.5 Hz, 2H, ArH), 7.00e7.05 (m, 6H, ArH), 7.16 (d, J¼7.5 Hz, 4H,
ArH), 8.32e8.35 (m, 4H, ArH), 8.41e8.43 (m, 4H, ArH), 8.60 (br s,
(C]O) cmꢁ1. 1H NMR (CDCl3):
d
3.24 (d, J¼13.0 Hz, 4H, ArCH2Ar),
2H, NH). 13C NMR (CDCl3):
d
38.0, 68.9, 69.2, 70.5, 70.6, 124.1, 124.2,
3.41 (s, 6H, CH3), 3.89 (s, 4H, OCH2CH2O), 3.91 (t, J¼5.5 Hz, 4H,
OCH2CH2O), 4.27e4.30 (m, 8H, ArCH2Ar, OCH2CH2O), 4.33 (s, 4H,
OCH2C(O)), 6.03 (d, J¼8.0 Hz, 4H, ArH), 6.25 (t, J¼8.0 Hz, 2H, ArH),
7.01 (t, J¼8.0 Hz, 2H, ArH), 7.18 (d, J¼8.0 Hz, 4H, ArH), 10.88 (s, 2H,
129.6,130.2, 130.8,133.1,134.3, 143.6, 150.9,155.4,156.2,167.6. Anal.
Calcd for C50H46N4O16S2: C, 58.70; H, 4.53; N, 5.48%. Found: C,
59.08; H, 4.53; N, 5.11%.
NH). 13C NMR (CDCl3):
d 30.6, 42.0, 69.4, 70.1, 73.8, 74.8, 122.7, 123.7,
4.2.4.4. 1,3-Alternate 25,27-bis(N-trifluoromethanesulfonyl car-
bamoylmethoxy)calix[4]-arene-1,3-crown-4 (1e). The crude product
was recrystallized from CH2Cl2/MeOH in 82% yield as a white solid
that decomposed at 225 ꢀC. IR (deposit from CH2Cl2 solution on
128.2, 129.6, 132.1, 136.0, 153.3, 158.4, 169.0. Anal. Calcd for
C40H44N2O12S2: C, 59.40; H, 5.44; N, 3.46%. Found: C, 59.76; H, 5.50;
N, 3.73%.
a NaCl plate): 3311 (NH), 1756 (C]O) cmꢁ1. 1H NMR (CDCl3):
d
2.83
4.2.7.2. Cone 25,27-bis(N-benzenesulfonyl carbamoylmethoxy)
calix[4]arene-1,3-crown-4 (2c). The crude product was chromato-
graphed on silica gel with CH2Cl2/MeOH (250:1 to 25:1 gradient) as
eluent to afford a 70% yield of white solid with mp 178e180 ꢀC. IR
(deposit from CH2Cl2 solution on a NaCl plate): 3306 (NH), 1719
(s, 4H, OCH2CH2O), 3.28 (t, J¼4.5 Hz, 4H, OCH2CH2O), 3.63 (t,
J¼4.5 Hz, 4H, OCH2CH2O), 3.94 (d, J¼8.0 Hz, 12H, ArCH2Ar,
OCH2C(O)), 6.96 (t, J¼7.5 Hz, 2H, ArH), 7.04 (t, J¼7.5 Hz, 2H, ArH),
7.13 (d, J¼8.0 Hz, 4H, ArH), 7.18 (d, J¼7.5 Hz, 4H, ArH) 8.50 (s, 2H,
NH). 13C NMR (CDCl3):
d
38.0, 69.1, 68.9, 70.6, 124.3, 124.5, 129.7,
(C]O) cmꢁ1. 1H NMR (CDCl3):
d
3.15 (d, J¼13.0 Hz, 4H, ArCH2Ar),
130.9, 133.2, 134.3, 155.2, 156.3, 166.8. Anal. Calcd for
C40H38N2O12S2F6: C, 52.40; H, 4.15; N, 3.06%. Found: C, 52.31; H,
4.29; N, 3.42%.
4.00e4.02 (m, 8H, OCH2CH2O), 4.22e4.23 (m, 8H, ArCH2Ar,
OCH2C(O)), 4.32 (t, J¼5.5 Hz, 4H, OCH2CH2O), 6.00 (d, J¼8.0 Hz, 4H,
ArH), 6.22 (t, J¼8.0 Hz, 2H, ArH), 7.00 (t, J¼8.0 Hz, 2H, ArH), 7.16 (d,
J¼8.0 Hz, 4H, ArH), 7.59 (t, J¼8.0 Hz, 4H, ArH), 7.67e7.71 (m, 2H,
4.2.5. Cone 25,27-Bis(ethoxycarbonylmethoxy)calix[4]arene-1,3-
crown-4 (7). A mixture of 5 (1.00 g, 1.86 mmol) and NaH (0.27 g,
11.20 mmol) in THF (50 mL) was stirred under nitrogen at room
temperature for 30 min and then BrCH2CO2Et (1.86 g, 11.20 mmol)
was added. The mixture was stirred at room temperature for 24 h.
After evaporating the THF in vacuo, CH2Cl2 (50 mL) and 10% aq HCl
(25 mL) were added slowly to the residue. The organic layer was
separated, washed with water (2ꢂ50 mL), dried over MgSO4, and
evaporated in vacuo. MeOH was added into the oily residue pro-
ducing a precipitate, which was filtered. The crude product was
recrystallized from hexane/EtOAc to give 7 (0.66 g, 50%) as a white
solid with mp 148e150 ꢀC. IR (deposit from CH2Cl2 solution on NaCl
ArH), 8.14e8.16 (m, 4H, ArH), 10.87 (s, 2H, NH). 13C NMR (CDCl3)
d:
30.6, 70.0, 70.4, 73.9, 74.6, 122.7, 123.6, 128.1, 128.5, 129.0, 129.6,
132.1, 134.1, 136.2, 138.8, 153.458, 158.228, 167.5. Anal. Calcd for
C50H48N2O12S2: C, 64.36; H, 5.19; N, 3.00%. Found: C, 64.40; H, 5.37;
N, 3.11%.
4.2.7.3. Cone 25,27-Bis(N-4-nitrobenzenesulfonyl carbamoylme-
thoxy)calix[4]arene-1,3-crown-4 (2d). The crude product was
chromatographed on silica with CH2Cl2/MeOH (250:1 to 25:1 gra-
dient) as eluent to give a 61% yield of pale yellow solid with mp
198e201 ꢀC. IR (deposit from CH2Cl2 solution on a NaCl plate): 3320
(NH), 1719 (C]O) cmꢁ1. 1H NMR (CDCl3):
d
3.18 (d, J¼13.0 Hz, 4H,
plate): 1754 (C]O) cmꢁ1. 1H NMR (CDCl3):
d
1.31 (t, J¼7.0 Hz, 6H,
ArCH2Ar), 4.04 (t, J¼5.0 Hz, 4H, OCH2CH2O), 4.06 (s, 4H, OCH2
-
CH2CH3), 3.21 (d, J¼13.5 Hz, 4H, ArCH2Ar), 3.83 (s, 4H, OCH2CH2O),
4.13e4.20 (m, 8H, OCH2CH2O), 4.25 (q, J¼7.5 Hz, 4H, OCH2CH3),
4.45 (s, 4H, OCH2C(O)), 4.51 (d, J¼13.5 Hz, 4H, ArCH2Ar), 6.15 (d,
J¼7.5 Hz, 4H, ArH), 6.23e6.26 (AB pattern, J¼7.0 Hz, J0¼1.0 Hz, 2H,
CH2O), 4.22e4.24 (m, 8H, ArCH2Ar, OCH2C(O)), 4.36 (t, J¼5.0 Hz, 4H,
OCH2CO), 6.01 (d, J¼8.0 Hz, 4H, ArH), 6.24 (t, J¼8.0 Hz, 2H, ArH),
7.02 (t, J¼8.0 Hz, 2H, ArH), 7.18 (d, J¼8.0 Hz, 4H, ArH), 8.35e8.37 (m,
4H, ArH), 8.42e8.44 (m, 4H, ArH), 11.20 (s, 2H, NH). 13C NMR

2242
Y. Yang et al. / Tetrahedron 68 (2012) 2233e2244
(CDCl3):
d
30.6, 69.6, 70.4, 73.8, 74.8,122.8, 123.8, 124.2,128.2, 129.7,
was removed in vacuo. Diester 11 (3.90 g, quantitative yield) was
obtained as a white solid with mp 195e197 ꢀC. IR (deposit from
CH2Cl2 solution on a NaCl plate): 3407 (OH), 1734 (C]O) cmꢁ1. 1H
130.1, 132.0, 135.9, 144.1, 150.9, 153.3, 158.4, 167.8. Anal. Calcd for
C50H46N4O16S2: C, 58.70; H, 4.53; N, 5.48%. Found: C, 58.75; H, 4.90;
N, 5.09%.
NMR (CDCl3):
d
1.23 (s, 18H, OC(CH3)3), 3.76e3.79 (d, J¼15.5 Hz, 4H,
ArCH2Ar), 3.98 (s, 4H. OCH2C(O)), 4.10e4.13 (d, J¼15.5 Hz, 4H,
ArCH2Ar), 6.70e6.73 (t, J¼7.5 Hz, 2H, ArH), 6.89 (s, 2H, OH),
6.98e7.01 (t, J¼7.5 Hz, 2H, ArH), 7.07e7.08 (d, J¼7.5 Hz, 4H, ArH),
4.2.7.4. Cone
25,27-bis(N-trifluoromethanesulfonyl
carba-
moylmethoxy)calix[4]arene-1,3-crown-4 (2e). The crude product
was chromatographed on silica gel with CH2Cl2/MeOH (250:1 to
25:1 gradient) as eluent to give a 67% yield of a pale yellow solid
with mp 170e174 ꢀC. IR (deposit from CH2Cl2 solution on a NaCl
7.17e7.18 (d, J¼7.5 Hz, 4H, ArH). 13C NMR (CDCl3):
d 27.9, 34.5, 70.8,
82.4, 119.6, 125.1, 127.1, 128.4, 129.0, 133.6, 153.2, 153.3, 167.6. Anal.
Calcd for C40H44
H, 7.13%.
O10$0.3CH2Cl2: C, 74.11; H, 6.90%. Found: C, 74.02;
plate): 3053 (NH), 1753 (C]O) cmꢁ1 1H NMR (CDCl3):
. d 3.26 (d,
J¼13.0 Hz, 4H, ArCH2Ar), 3.88e3.92 (m, 8H, OCH2CH2O), 4.26 (d,
J¼13.0 Hz, 4H, ArCH2Ar), 4.34 (t, J¼3.0 Hz, 4H, OCH2CH2O), 4.40 (s,
4H, OCH2C(O)), 6.04 (d, J¼8.0 Hz, 4H, ArH), 6.27 (t, J¼8.0 Hz, 2H,
ArH), 7.02 (t, J¼8.0 Hz, 2H, ArH), 7.20 (d, J¼8.0 Hz, 4H, ArH). 13C
4.2.11. Partial-cone 26,28-bis(tert-butoxycarbonylmethoxy)calix[4]
arene-1,3-crown-4 (12). A mixture of diester 11 (0.50 g, 0.80 mmol)
and K2CO3 (1.12 g, 8.00 mmol) in MeCN (100 mL) was refluxed for
2 h. To the refluxing mixture, triethylene glycol ditosylate (0.37 g,
0.88 mmol) in MeCN (50 mL) was added dropwise during a 2-h
period. The mixture was refluxed for another 5 days. After evapo-
ration of the MeCN in vacuo, CH2Cl2 (50 mL), and 1 N aq HCl (50 mL)
were added to the residue. The organic layer was separated, washed
with water (2ꢂ100 mL), and dried over MgSO4. A viscous oily
product was obtained after the solvent was removed in vacuo. The
residue was crystallized from hexanes/EtOAc to give 12 (0.28 g,
45%) as colorless crystals with mp 200e202 ꢀC. IR (deposit from
NMR (CDCl3):
d 30.6, 68.3, 70.1, 74.0, 75.1, 120.6, 122.7, 123.9, 128.3,
129.6, 132.0 135.8, 153.5, 158.7, 167.1. Anal. Calcd for
C40H38N2O12S2F6: C, 52.40; H, 4.15; N, 3.06%. Found: C, 52.83; H,
3.82; N, 3.06%.
4.2.8. 25,27-Bis(benzyloxy)-26,28-bis(hydroxy)calix[4]arene (9). A
mixture of calix[4]arene (4) (10.00 g, 23.60 mmol) and K2CO3
(3.90 g, 28.30 mmol) in MeCN (350 mL) was refluxed for 1 h under
nitrogen. Benzyl bromide (8.90 g, 51.90 mmol) was injected all in
once by syringe. The mixture was refluxed for 1 h and poured into
ice water. The precipitate was filtered and recrystallized from
CH2Cl2/MeOH to give 9 (13.80 g, 90%) as white crystals with mp
CH2Cl2 solution on a NaCl plate): 1743 (C]O) cmꢁ1
.
1H NMR
(CDCl3): 1.16 (s, 9H, OC(CH3)3), 1.47 (s, 9H, OC(CH3)3), 1.76 (s, 2H,
d
OCH2C(O)), 3.23e3.27 (m, 2H, OCH2CH2O), 3.35 (d, J¼13.5 Hz, 2H,
224e225 ꢀC (lit.23 mp 219e222 ꢀC); 1H NMR (CDCl3):
d 3.34 (d,
ArCH2Ar), 3.56e3.60 (m, 2H, OCH2CH2O), 3.73 (s, 4H, OCH2CH2O),
J¼13.0 Hz, 4H, ArCH2Ar), 4.31 (d, J¼13.0 Hz, 4H, ArCH2Ar), 5.06 (s,
4H, OCH2Ar), 6.65 (t, J¼8.0 Hz, 2H, ArH), 6.75 (t, J¼8.0 Hz, 2H, ArH),
6.89 (d, J¼8.0 Hz, 4H, ArH), 7.05 (d, J¼8.0 Hz, 4H, ArH), 7.34e7.40
(m, 6H, ArH), 7.64e7.66 (m, 4H, ArH), 7.81 (s, 2H, OH). 13C NMR
3.80e3.86 (m, 4H, OCH2CH2O, ArCH2Ar), 4.00e4.05 (m, 4H, OCH2
-
CH2O, ArCH2Ar), 4.52 (s, 2H, OCH2C(O)), 4.60e4.62 (d, J¼13.0 Hz,
2H, ArCH2Ar), 6.61e6.64 (t, J¼7.5 Hz, 1H, ArH), 6.84e6.93 (m, 4H,
ArH), 7.01e7.06 (m, 3H, ArH), 7.18e7.23 (m, 4H, ArH). 13C NMR
(CDCl3):
129.0, 133.2, 136.8, 151.9, 153.3.
d
31.4, 78.4, 118.9, 125.4, 127.4, 127.9, 128.0, 128.4, 128.7,
(CDCl3):
122.8, 123.7, 123.8, 128.2, 128.7, 130.2, 132.8, 134.0, 134.6, 137.5,
1545.0, 155.8, 155.8, 169.0, 169.3. Anal. Calcd for
C46H54 10$0.6CH2Cl2: C, 68.43; H, 6.80%. Found: C, 68.54; H, 6.53%.
d 28.0, 28.1, 30.3, 36.7, 68.8, 69.0, 70.2, 72.7, 73.0, 80.1, 81.5,
4.2.9. Partial-cone
25,27-bis(benzyloxy)-26,28-bis(tert-butox-
O
ycarbonylmethoxy)calix[4]arene (10). A mixture of
9 (1.30 g,
2.00 mmol) and KH (0.20 g, 4.40 mmol) in freshly distilled THF
(50 mL) was stirred under nitrogen for 2 h at room temperature and
tert-butyl bromoacetate (0.97 g, 5.00 mmol) was added. The mix-
ture was stirred at room temperature for 24 h. After removing the
THF in vacuo, 1 N aq HCl (100 mL) and CH2Cl2 (100 mL) were added
to the residue. The organic layer was separated, washed with water
(2ꢂ100 mL), and dried over MgSO4. After removing the solvent in
vacuo, the residue was chromatographed on silica gel with hexanes/
EtOAc (5:1) as eluent to give diester 10 (0.88 g, 55%) as a white solid
with mp 62 ꢀC. IR (deposit from CH2Cl2 solution on a NaCl plate):
4.2.12. Partial-cone 26,28-bis(carboxymethoxy)calix[4]arene-1,3-
crown-4 (3a). A solution of diester 12 (1.00 g, 1.33 mmol) in THF
(25 mL) mixed with NaOH (0.50 g, 12.50 mmol) in water (25 mL)
was refluxed for 24 h. The THF was removed in vacuo. The residue
was acidified with 1 N aq HCl (100 mL) and extracted with CH2Cl2
(100 mL). The organic layer was separated, washed with water
(2ꢂ100 mL), and dried over MgSO4. After removing the solvent in
vacuo, diacid 3a (0.86 g, quantitative yield) was collected as a white
solid with mp 246 ꢀC. IR (deposit from CH2Cl2 solution on a NaCl
plate): 3066 (OH), 1748 (C]O) cmꢁ1. 1H NMR (CDCl3):
d 3.16 (s, 2H,
1754 (C]O) cmꢁ1. 1H NMR (CDCl3):
d
1.25 (s, 9H, OC(CH3)3), 1.59 (s,
OCH2C(O)), 3.35e3.40 (m, 4H, OCH2CH2O, ArCH2Ar), 3.53e3.57 (m,
2H, OCH2CH2O), 3.65e3.77 (m, 6H, OCH2CH2O), 3.87e4.01 (AB
pattern, J¼33.0 Hz, J0¼18.0 Hz, 4H, OCH2CH2O), 4.03e4.08 (m, 2H,
OCH2CH2O), 4.42 (d, J¼13.0 Hz, 2H, ArCH2Ar), 4.64 (s, 2H,
OCH2C(O)), 6.82 (t, J¼7.5 Hz, 1H, ArH), 6.87e6.93 (m, 4H, ArH), 7.03
(d, J¼7.5 Hz, 2H, ArH), 7.10e7.13 (m, 1H, ArH), 7.18 (d, J¼7.5 Hz, 2H,
9H, OC(CH3)3), 3.12 (d, J¼13.5 Hz, 2H, ArCH2Ar), 3.51 (d, J¼13.5 Hz,
2H, ArCH2Ar), 3.67 (d, J¼13.5 Hz, 2H, ArCH2Ar), 3.98 (s, 2H,
OCH2C(O)), 4.27 (s, 2H, OCH2C(O)), 4.40 (d, J¼13.5 Hz, 2H, ArCH2Ar),
4.74 (d, J¼12.0 Hz, 2H, OCH2Ar), 4.85 (d, J¼12.0 Hz, 2H, OCH2Ar),
6.25 (d, J¼8.0 Hz, 2H, ArH), 6.50 (t, J¼7.5 Hz, 2H, ArH), 6.74 (t,
J¼7.5 Hz,1H, ArH), 6.85 (t, J¼7.5 Hz,1H, ArH), 7.02e7.04 (AB pattern,
J¼7.5 Hz, J0¼1.5 Hz, 4H, ArH), 7.01e7.12 (AB pattern, J¼7.5 Hz,
J0¼1.5 Hz, 2H), 7.33e7.36 (m, 2H, ArH), 7.38e7.41 (m, 4H, ArH),
ArH), 7.23e7.25 (m, 2H, ArH). 13C NMR (CDCl3):
d 30.2, 30.3, 37.8,
65.7, 68.5, 69.5, 71.7, 74.3, 124.3, 124.5, 124.7, 128.7, 128.8, 129.5,
132.2, 133.2, 133.8, 136.4, 153.9, 154.4, 155.1, 168.3, 170.8. Anal. Calcd
for C38H38O10: C, 69.72; H, 5.81%. Found: C, 69.46; H, 6.21%.
7.46e7.47 (d, J¼7.5 Hz, 4H, ArH). 13C NMR (CDCl3):
d 27.9, 28.2, 31.7,
34.8, 68.4, 71.4, 76.4, 80.2, 81.8,121.9,122.0,122.4,127.7,127.9,128.4,
128.5, 129.0, 129.1, 130.5, 132.2, 133.4, 133.8, 134.6. Anal. Calcd for
C54H56O6$0.3CH2Cl2: C, 78.91, H, 6.90%. Found: C, 78.95; H, 6.93%.
4.2.13. General procedure for the preparation of partial-cone 26,28-
bis[N-(X)-sulfonyl
carbamoylmethoxy]calix[4]arene-1,3-crown-4
compounds 3bee. The procedure was the same as that employed for
the preparation of compounds 1bee and 2bee but starting from 3a.
4.2.10. Partial-cone
25,27-bis(hydroxy)-26,28-bis(tert-butox-
ycarbonylmethoxy)calix[4]arene (11). Diester 10 (5.00 g, 6.20 mmol)
was dissolved in freshly distilled THF (50 mL). To the solution, EtOH
(50 mL) and 10% Pd/C were added. Hydrogenolysis was conducted
under H2 (50 psi) for 24 h. After the catalyst was filtered, the solvent
4.2.13.1. Partial-cone
moylmethoxy)calix[4]arene-1,3-crown-4 (3b). The crude product
was chromatographed on silica gel with CH2Cl2/MeOH (250:1 to
26,28-bis(N-methanesulfonyl
carba-

Y. Yang et al. / Tetrahedron 68 (2012) 2233e2244
2243
25:1 gradient) as eluent to give in 26% yield a white solid with mp
129.7, 129.9, 133.2, 133.3, 134.7, 136.7, 154.5, 154.9, 155.2, 164.3,
167.6. Anal. Calcd for C40H38N2O12S2F6: C, 52.40; H, 4.15; N, 3.06%.
Found: C, 52.46; H, 4.38; N, 2.80%.
144e146 ꢀC. IR (deposit from CH2Cl2 solution on a NaCl plate): 3357
(NH), 3296 (NH), 1716 (C]O) cmꢁ1. 1H NMR (CDCl3):
d 2.46 (s, 2H,
OCH2C(O)), 2.92 (s, 3H, CH3), 3.31 (s, 3H, CH3), 3.35e3.39 (m, 2H,
OCH2CH2O), 3.42 (d, J¼13.0 Hz, 2H, ArCH2Ar), 3.62e3.70 (m, 4H,
OCH2CH2O), 3.78e3.86 (m, 4H, OCH2CH2O), 3.92 (AB patterns,
J¼17.0 Hz, J0¼5.5 Hz, 4H, ArCH2Ar), 4.03e4.07 (m, 2H, OCH2CH2O),
4.39 (d, J¼12.0 Hz, 2H, ArCH2Ar), 4.63 (s, 2H, OCH2C(O)), 6.26 (s, 1H,
NH), 6.86e7.25 (m, 12H, ArH), 11.48 (s, 1H, NH). 13C NMR (CDCl3):
4.3. Solid-state structure determination of intermediate 11
Crystals suitable for structure determination of 11 were grown
from deuteriochloroform/hexane. Crystal and intensity data for the
structural study were obtained with a Nicolet R3m/V automated
d
30.2137.4, 41.4, 41.6, 67.5, 68.1, 69.3, 71.8, 76.80,124.0,124.7,124.8,
ꢀ
diffractometer with Mo K
a
radiation (
l
¼0.71073 A). The structure
129.0, 129.3, 129.6, 129.8, 133.2, 133.3, 134.5, 136.8, 155.1, 166.8,
169.8. Anal. Calcd for C40H44N2O10S2$0.1CH2Cl2: C, 58.92; H, 5.45; N,
3.43%. Found: C, 58.84; H, 5.27; N, 3.09%.
was solved and initially refined using programs contained in the
SHELXTL PLUSÒ program package.24 Final refinement and the
structure display were accomplished using the SHELXTL PCÒ pro-
gram package.25 The crystal data and experimental details are listed
in Table 5.
4.2.13.2. Partial-cone
26,28-bis(N-benzenesulfonyl
carba-
moylmethoxy)calix[4]arene-1,3-crown-4 (3c). The crude product
was chromatographed on silica gel with CH2Cl2/MeOH (250:1 to
25:1 gradient) as eluent to afford in 43% yield a pale yellow solid
with mp 148e150 ꢀC. IR (deposit from CH2Cl2 solution on a NaCl
plate): 3345 (NH), 3294 (NH), 1719 (C]O) cmꢁ1. 1H NMR (CDCl3):
Table 5
Crystallographic data for intermediate 11
Formula
C40H44O8
652.75
FW (g molꢁ1
)
d
2.28 (s, 2H, OCH2C(O)), 3.14 (d, J¼12.5 Hz, 2H, ArCH2Ar),
Temperature (K)
Crystal system
Space group
296(2)
Monoclinic
P2(1)/c
12.257(3)
8.9690(18)
16.161(3)
90
105.29(3)
90
1713.8(6)
2
0.087
696
0.34ꢂ0.35ꢂ0.09
2.61e25.38
18,310
3.34e3.37 (m, 2H, OCH2CH2O), 3.59e3.76 (m, 6H, OCH2CH2O),
3.83e3.87 (m, 6H, OCH2CH2O, ArCH2Ar), 4.00e4.04 (m, 2H, OCH2
-
ꢀ
a (A)
CH2O), 4.21 (d, J¼12.5 Hz, 2H, ArCH2Ar), 4.50 (s, 2H, OCH2C(O)), 6.41
(s, 1H, NH), 6.56 (t, J¼8.0 Hz, 2H, ArH), 6.80e6.83 (m, 2H, ArH),
6.89e6.92 (m, 2H, ArH), 6.99 (d, J¼8.0 Hz, 2H, ArH), 7.06e7.12 (m,
2H, ArH), 7.16 (d, J¼7.5 Hz, 2H, ArH), 7.50e7.69 (m, 6H, ArH),
7.85e7.87 (m, 2H, ArH), 8.07e8.09 (m, 2H, ArH), 11.53 (s, 1H, NH).
ꢀ
b (A)
ꢀ
c (A)
a
(ꢀ)
b (ꢀ)
c (ꢀ)
3
ꢀ
Volume (A)
13C NMR (CDCl3):
d 30.0, 37.2, 67.4, 68.2, 69.4, 71.9, 77.0,123.9, 124.7,
Z
m
128.3, 128.4, 128.6, 128.8, 128.8, 129.1, 129.5, 129.7, 133.1, 133.3,
133.7, 133.8, 134.6, 136.6, 138.7, 139.1, 154.6, 154.9, 153.3, 165.4,
168.2. Anal. Calcd for C50H48N2O12S2: C, 64.36; H, 5.19, N, 3.00%.
Found: C, 64.30; H, 5.25; N, 2.73%.
(mmꢁ1
)
F(000)
Crystal size (mm)
(ꢀ)
q
Reflections collected
Reflections observed
Number of parameters
Goodness-of-fit on F2
3149
221
1.033
0.0423
4.2.13.3. Partial-cone 26,28-bis(N-4-nitrobenzenesulfonyl carba-
moylmethoxy)calix[4]-arene-1,3-crown-4 (3d). The crude product
was chromatographed on silica gel with CH2Cl2/MeOH (250:1 to
25:1 gradient) as eluent to provide a 15% yield of a pale yellow solid
with mp 171e173 ꢀC. IR (deposit from CH2Cl2 solution on a NaCl
R (I>2
s
(I))
3
ꢀ
Largest difference peak and hole (e A )
0.390, ꢁ0.342
plate): 3335 (NH), 1736 (C]O) cmꢁ1. 1H NMR (CDCl3):
d 2.60 (s, 2H,
Crystallographic data for compound 11 have been deposited
with CCDC, 12 Union Road, Cambridge CB2 1EZ, UK and are iden-
tified by deposition number CCDC 853897. A copy of this in-
formation can be obtained free of charge on request by e-mail at
deposit@ccdc.cam.ac.uk or at http://www.ccdc.cam.ac.uk.
OCH2C(O)), 3.24 (d, J¼13.0 Hz, 2H, ArCH2Ar), 3.41e3.44 (m, 2H,
OCH2CH2O), 3.60e3.90 (m, 12H, ArCH2Ar, OCH2CH2O), 4.04e4.08
(m, 2H, OCH2CH2O), 4.27 (d, J¼13.0 Hz, 2H, ArCH2Ar), 4.55 (s, 2H,
OCH2C(O)), 6.36 (s, 1H, NH), 6.62 (t, J¼8.0 Hz, 2H, ArH), 6.84e6.85
(m, 2H, ArH), 6.92 (t, J¼8.0 Hz, 1H, ArH), 7.07e7.21 (m, 7H, ArH),
7.98e8.01 (m, 2H, ArH), 8.27e8.29 (m, 2H, ArH), 8.35e8.38 (m, 4H,
4.4. Procedures for metal ion extraction
ArH),11.82 (s,1H, NH). 13C NMR (CDCl3):
d 30.2, 37.4, 67.3, 68.0, 69.5,
71.6, 76.8, 123.8, 124.0, 124.1, 124.7, 124.8, 128.8, 129.3, 129.8, 129.8,
130.0, 133.0, 133.4, 134.4, 136.5, 143.9, 144.5, 150.7, 150.7, 154.5,
154.9, 155.2, 165.7, 168.6. Anal. Calcd for C50H46N4O16S2: C, 58.70; H,
4.53, N, 5.47%. Found: C, 58.85; H, 4.23; N, 5.53%.
Procedures for competitive alkali metal cation extraction,
competitive alkaline earth metal cation extraction, single species
extraction of Hg2þ, and single species extraction of Pb2þ from
aqueous solutions into chloroform have been reported
previously.26
4.2.13.4. Partial-cone
26,28-bis(N-trifluoromethanesulfonyl
carbamoylmethoxy)calix-[4]arene-1,3-crown-4 (3e). The crude
product was chromatographed on silica gel with CH2Cl2/MeOH
(250:1 to 25:1 gradient) as eluent to give a 38% yield of white solid
that decomposed at 235 ꢀC. IR (deposit from CH2Cl2 solution on
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 (gs1) (Grant DE-FG02-90ER1446) for support of
this research.
a NaCl plate): 3324 (NH), 3258 (NH), 1755 (C]O) cmꢁ1 1H NMR
.
(CDCl3):
d 2.35 (s, 2H, OCH2C(O)), 3.40e3.46 (m, 4H, OCH2CH2O,
ArCH2Ar), 3.63e3.67 (m, 2H, OCH2CH2O), 3.72e3.83 (m, 6H,
OCH2CH2O, ArCH2Ar), 3.92 (s, 4H, OCH2CH2O), 4.03e4.07 (m, 2H,
OCH2CH2O), 4.36 (d, J¼13.0 Hz, 2H, ArCH2Ar), 4.71 (s, 2H,
OCH2C(O)), 6.38 (s, 1H, NH), 6.85 (t, J¼8.0 Hz, 1H, ArH), 6.96 (t,
J¼8.0 Hz, 2H, ArH), 7.02e7.13 (m, 5H, ArH), 7.21 (d, J¼8.0 Hz, 2H,
ArH), 7.26e7.29 (m, 2H, ArH), 12.20 (s, 1H, NH). 13C NMR (CDCl3):
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