Enlarging the size of calix[4]arene-crowns-6 to improve Cs +/K+ selectivity: A theoretical and experimental study

Article abstract of DOI:10.1016/j.tet.2004.06.058

Ab initio calculations in the gas-phase indicate that the substitution of an ethylene with a propylene moiety in the polyether bridge of 1,3-di-iso-propoxycalix[4]arene-crowns-6 could result in an enhanced Cs ⁺/K⁺ selectivity which i

Full text of DOI:10.1016/j.tet.2004.06.058

Tetrahedron 60 (2004) 7869–7876
Enlarging the size of calix[4]arene-crowns-6 to improve
Cs1/K1 selectivity: a theoretical and experimental studyq
a
a
b
,
Alessandro Casnati,a Nicola Della Ca’, Francesco Sansone, Franco Ugozzoli
,
*
*
and Rocco Ungaroa
a
`
Dipartimento di Chimica Organica e Industriale, Universita di Parma, Parco Area delle Scienze 17/A, I-43100 Parma, Italy
`
Dipartimento di Chimica Generale ed Inorganica, Chimica Analitica, Chimica Fisica, Universita di Parma,
b
Parco Area delle Scienze 17/A, I-43100 Parma, Italy
Received 15 April 2004; revised 13 May 2004; accepted 11 June 2004
Available online 28 July 2004
Abstract—Ab initio calculations in the gas-phase indicate that the substitution of an ethylene with a propylene moiety in the polyether
bridge of 1,3-di-iso-propoxycalix[4]arene-crowns-6 could result in an enhanced Csþ/Kþ selectivity which is of particular interest in nuclear
waste treatment. We therefore synthesised two novel calix[4]arene-crown-6 compounds (1 and 2) having a propylene moiety in their
structure and for this named calix[4]arene-propylene-crown-6. The structures of compounds 1 and 2 were elucidated by NMR in solution and
for 1 also by X-ray diffraction studies in the solid state. Association constants (Ka) in CHCl3 of the two novel calix-crowns were measured
and pointed out a plateau selectivity towards alkali metal ions which was not predicted by molecular modelling calculations. These results
indicate the important role played by the solvent molecules and counter-anions in binding for this class of ionophores.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
compound for the selective extraction of cesium from acidic
radioactive waste where sodium is present at high
concentration (5–7 M) while cesium is only present in
trace amounts (1024–1026 M). Other authors10–12 have
slightly modified the calix-crown-6 structure in order to
enhance the cesium selectivity. Compound Ia is still one of
the ionophores having the highest Csþ/Naþ selectivity (aCs/
Calix[4]arene-crown ethers or calix[4]crowns are among
the most widely studied class of synthetic ionophores.1,2
They show binding properties for alkali metal ions strongly
dependent on the number of oxygen atoms in the ether
bridge and on the conformation of the calixarene skeleton.
In the last 20 years, we synthesised a large number of these
macrobicyclic ionophores and showed that cation binding
involves not only ether oxygen atoms but also the calixarene
aromatic nuclei providing experimental evidence for the
operation of cation/p interactions.3 As expected from the
size complementarity, 1,3-calix[4]crowns-4 are selective
for sodium ion,4 1,3-calix[4]crowns-55,6 for potassium and
the 1,3-calix[4]crowns-6 for cesium.7 Usually, the confor-
mationally mobile derivatives are much less efficient and
selective than the more preorganized receptors fixed in the
1,3-alternate conformation. The high Csþ/Naþ selectivity
exhibited by the 1,3-dialkoxy-calix[4]crowns-6 in the 1,3-
alternate conformation (I) prompted us8,9 to use this class of
¼28,500) in extraction and its application in the removal
Na
of cesium from radioactive fuel reprocessing waste is
currently under study.9 The substitution of ethylene
moieties Y or X with benzo units allowed us also to
develop the calix[4]-monobenzo- (Ib) and dibenzo- (Ic)
crown-613–15 compounds where the Csþ/Naþ selectivity is
even slightly increased (aCs/Na¼34,000 and 31,000,
respectively). However, all these compounds suffer from
an aCs/K at least two orders of magnitude lower than the aCs/
selectivity, which might be a drawback in the case of
Na
some basic radioactive waste where Kþ concentration can
reach values around 1 M. Ring-enlarged crown-ethers,
(3mþn)-crown-m, also known as crown ethers of low
symmetry,16 usually show decreased cation binding ability
in comparison to the corresponding symmetric crown
ethers, but sometimes enhanced selectivity.17 For example,
the potassium selectivity of 18-crown-6 is shifted to
rubidium and cesium for less symmetric 20-crown-6 and
22-crown-6, respectively. Therefore, in the present work,
we modified the structure of calix[4]crown-6 (Ia) and
calix[4]dibenzocrown-6 (Ic) enlarging the crown ether
q Supplementary data associated with this article can be found in the online
version, at doi: 10.1016/j.tet.2004.06.058
Keywords: Calixarenes; Ring-enlarged crown-ethers; Cesium selectivity;
Alkali metal ions; Semiempirical calculations; Calix-crowns.
*
Corresponding authors. Tel.: þ39-521-905458; fax: þ39-521-905472
(A.C.), tel.: þ39-521-905417; fax: þ39-521-905557 (F.U.);
e-mail addresses: casnati@unipr.it; ugoz@unipr.it
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.06.058

7870
A. Casnati et al. / Tetrahedron 60 (2004) 7869–7876
bridge by the introduction of a propylene unit in the Y
position and thus obtaining compounds 1 and 2.
Table 1. Dihedral angles t (8) between the reference plane (R) anþd the
planes through the phenolic rings in the calculated structures of þ1,71·K and
1·Csþ in the gas-phase and in the solid state structure of Ia·Cs
t
1(gas)
1·Kþ
1·Csþ
Ia·Csþ
R–A
R–B
R–C
R–D
86.99
257.07
87.27
99.99
262.3
101.83
255.65
101.26
258.74
103.02
248.87
103.3(3)
257.5(2)
105.9(2)
246.3(2)
271.44
Table 2. Dihedral angles u (8) between opposite phenolic rings
u
1(gas)
1·Kþ
1·Csþ
Ia·Csþ
A–C
B–D
5.81
3.71
22.06
21.82
24.28
38.81
29.2(3)
36.2(2)
least-squares plane between the four CH2 bridging groups
according to standard rules for calixarenes)18 and the
opposite rings are almost parallel (Tables 1 and 2). This
conformation of the calix forces the crown to adopt an
elliptical shape with the major axis orthogonal to the pseudo
C2 axis (see Fig. 1). In a second step of calculations, the
geometries of 1·Kþ and 1·Csþ (Fig. 2(a) and (b),
respectively) have been obtained by geometry optimisation
at the HF/3-21G level. As an initial guess for geometry
optimisation the structure of each complex was built-up
from that of 1 (optimised in the gas-phase) by placing the
metal cation in the barycentre of the six oxygen atoms of the
crown. The final structures of 1·Kþ and 1·Csþ, optimised
without geometrical constraints, are shown in Figure 2.
2. Results and discussion
2.1. Modeling studies
We first investigated the structural and electronic factors
which influence the binding properties of ligand 1 by using
ab initio calculations in the gas-phase. In order to find the
equilibrium geometries of the 1·Kþ and 1·Csþ cationic
complexes we also preliminarily modelled the structure of
the ligand 1 in the gas-phase which was obtained in two
steps: (i) the structure of the minimum energy conformer
was calculated with semiempirical methods at the PM3
level; (ii) the geometry of the minimum energy conformer
was further minimized at the HF/3-21G level. The final
equilibrium geometry of the isolated molecule 1 is shown in
Figure 1. In the gas-phase the calix[4]arene moiety shows a
pseudo C2v symmetry where all the aromatic rings are
almost orthogonal to the reference plane R (the weighted
Figureþ2. Optimisþed geometries of the cationic complexes in the gas-phase.
(a) 1·K , (b) 1·Cs .
The calix[4]arene basket undergoes a significant confor-
mational reorganization upon complexation. The strong
variations of the dihedral angles t and u reported in Tables 1
and 2 indicate that the opposite phenolic units are forced to
rotate towards the exterior of the macrocycle to favour the
binding of the metal ion and that the rotations increase as the
size of the cation increases.
The analysis of the interatomic Mþ2O distances, summar-
ized in Table 3, shows that the Kþ ion is tetracoordinated to
Figure 1. Optimised geometry of the ligand 1 at the HF/3-21G level in the
gas-phase.

A. Casnati et al. / Tetrahedron 60 (2004) 7869–7876
7871
þ
þ
Table 3. M · · ·O interatomic distances (A) in the 1·K and 1·Csþ
compþlexes calculated in the gas-phase and in the solid state structure of
Ia·Cs
the two calix[4]arene-propylene-crown-6 compounds 1 and
2 in order to experimentally determine their binding
properties.
˚
1·Kþ
1·Csþ
Ia·Csþ
2.2. Synthesis and structure of the ligands
Mþþ· · ·O1A
Mþ· · ·O1C
Mþ· · ·O1
Mþ· · ·O2
Mþ· · ·O3
M · · ·O4
2.64
2.65
2.89
4.44
4.55
2.71
3.15
3.00
3.09
3.43
3.13
3.23
3.189(5)
3.188(5)
3.245(6)
3.475(7)
3.276(9)
3.100(5)
Ditosylate 7 was prepared starting from propylene glycol 3
and diethylene glycol monotrityloxy monotosylate 4,20
in 40% overall yield through a protection–deprotection
strategy (Scheme 1).
O1A, O1C, O1 and O4, whereas the two oxygen atoms O2
þ
cooordination sphere of the potassium ion.
˚
and O3 with K 2O.4.4 A are excluded from the
þ
2.72 A) and are shorter than those found in the X-ray
˚
The K 2O bond distances range from 2.64 to 2.89 A (av.
˚
structure of the partial cone di-isopropoxy-p-tert-butyl-
calix[4]arene-crown-5·KPic (Pic¼picrate),19 (from
˚
˚
2.748(8) to 3.015(10) A av. 2.872 (9) A) and in the cone
di-ethoxy-p-tert-butylcalix[4]arene-crown-5·KPic19 (from
2.76(1) to 2.87(1) A av. 2.81(1) A). On the contrary in 1·Cs
the cesium ion is hexacoordinated: the Csþ2O bond
distances range from 3.0 to 3.43 A (av. 3.172 A) and are
slightly shorter than those in the X-ray structure of the
1,3-alternate di-iso-propoxycalix[4]arene-crown-6·CsPic
Ia·Csþ previously reported by us7 (from 3.100(5) to
þ
˚
˚
Scheme 1.
˚
˚
After coupling of the glycol 3 with 2.2 equiv. of the
diethylene glycol monotosylate 4, the resulting trityloxy
derivative 5 was deprotected with HCl to give the diol 6.
The latter was reacted with tosyl chloride (TsCl) and
triethylamine in dichloromethane using a catalytic amount
of dimethylamino pyridine (DMAP). Ditosylate 11 was
obtained by reaction (Scheme 2) of 1,3-dibromopropane
with 2 equiv. of 2-(2-hydroxyethoxy)phenol (9)15 with NaH
in DMF. Under these conditions alkylation of the catechol
free hydroxy group was mainly obtained and compound 10
could be isolated in 53% yield. Subsequent reaction of 10
with tosyl chloride (TsCl) and triethylamine in dichloro-
methane gave 11 in 61% yield.
˚
˚
3.475(7) A av. 3.245(7) A). It is also of some interest to
compare the optimised molecular geometry of 1·Csþ with
the X-ray structure6 of the Ia·Csþ to highlight how the
substitution of the ethylene moiety with a propylene unit
influences the binding ability of the ligand. In the two
structures, shown in Figure 3, the calix[4]arene confor-
mation is quite similar with small differences in the dihedral
angles t (see Table 1). The crown conformation is almost
identical at least from O1A to O1 and from O1C to O4.
Then, along the chain from O1 to O4 the conformational
differences are more relevant, as expected. It is however
surprising that the increase in size of the crown length in
1·Csþ does not increase the Csþ2O bond distances but, on
the contrary, a small but not negligible shortening of them
˚
(av. 3.172 vs. 3.245(8) A) is observed.
Therefore these data, which show a relevant difference in
the coordination numbers of the two metal ions suggesting a
high Csþ/Kþ selectivity, which prompted us to synthesise
Scheme 2.
For the final cyclization reaction we followed the classical
conditions reported for calix[4]crown-6 and reacted 1,3-di-
i-propoxycalix[4]arene (8) with a slight excess (1.2 equiv.)
of the appropriate ditosylate 7 or 11 and an excess of
Cs2CO3 in dry acetonitrile. After quenching, extraction and
purification by column chromatography, calix[4]arene-
propylene-crown-6 compounds 1 and 2 were obtained in
54 and 59% yield, respectively. The identity of the two
calix[4]crowns were characterised using NMR and mass
Figure 3. Molecular structure of the cationic complexes (a) Ia·Csþ (solid
state), (b) 1·Csþ (gas-phase).

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A. Casnati et al. / Tetrahedron 60 (2004) 7869–7876
The calix[4]arene is blocked in the 1,3-alternate confor-
mation in a pseudo C2v symmetry. The polyether crown
moiety shows an elliptical shape with its minor axis
orthogonal to the pseudo C2 axis. The dihedral angles t
between opposite phenolic rings are: A–C 42.06(8)8 and
B–D 35.05(8)8. The whole conformation of the calix[4]-
arene basket is unequivocally described by the dihedral
angles t and by the conformational parameters21 reported
in Table 4 leading to the symbolic representation C1
þþ,22,þþ,22.
The values of the pairs f and x, together with the t values
clearly indicate that the distortion of the 1,3-alternate
structure from an ideal C2v symmetry is very small.
Probably due to packing forces, this solid state structure
slightly differs from the calculated one (Fig. 1) both in the
shape of the calixarene basket and in the conformation of
the crown. In the gas-phase, in fact, the calix[4]arene moiety
shows also a pseudo C2v symmetry but the phenolic rings
are almost orthogonal to the reference plane R and the
opposite rings are almost parallel in pairs (Tables 1 and 2).
This conformation of the calix forces the crown to adopt an
elliptical shape with the major axis orthogonal to the pseudo
C2 axis (see Fig. 1).
2.3. Complexation studies
In order to evaluate the binding properties of ligands 1-2 in
comparison with calix[4]arene-crown-6 Ia and -dibenzo-
crown-6 Ic we determined the association constants (log Ka)
with alkali picrates in chloroform, using Cram’s method22,23
(Table 5 and Fig. 5).
Figure 4. ORTEP view of the molecular structure of the ligand 1. Thermal
ellipsoids at 20% probability. Hydrogen atoms have been omitted for
clarity.
spectrometry. In particular the 1,3-alternate structure was
confirmed by the presence of an AB system for the
methylene bridge at dH¼3.75–3.82 and a triplet at
dC¼38.5 in the NMR spectra. Isolation of a single crystal
of compound 1 allowed us to solve its X-ray diffraction
structure. The molecular geometry of 1 in the solid state is
shown in Figure 4.
The data show, in general, a strong decrease in cation
binding properties of propylene-crown-6 (1 and 2) in
comparison with calix[4]crown-6 (Ia and Ic). This effect
is more significant for larger cations (Csþ.Rbþ.Kþ) and
Table 4. Conformational parameters f, x (8) and dihedral angles t (8)
between the least-squares reference plane (R) and the least-squares planes
through the phenolic rings in the solid state structure of 1
Conformational parameters (8)
Dihedral angles (8)
f
x
t
A–B
B–C
C–D
D–A
128.5(3)
130.6(3)
R–A
111.18(6)
252.24(6)
110.87(6)
252.71(7)
2129.5(3)
130.4(3)
2129.2(3)
2130.7(3)
127.6(3)
2131.4(3)
R–B
R–C
R–D
Figure 5. Binding free energies (2DG8, kJ/mol) of complexes of
calixcrowns-6 with alkali metal picrates in CHCl3 saturated with water at
22 8C.
Table 5. Association constants (Ka)a and binding free energies (2DG8, kJ/mol) of complexes of calixcrowns-6 with alkali metal picrates in CHCl3 saturated
with water at 22 8C
Ligand
log Ka
Naþ
2DG8 (kJ/mol)
Naþ
aCs/K
(DDG8)
Kþ
Rbþ
Csþ
Kþ
Rbþ
Csþ
Ia7
Ic15
1
5.2
,5
,5
6.4
7.8
6.1
6.4
7.9
8.9
6.8
6.9
8.8
9.0
7.2
6.6
29.2
,29.0
,29.0
,29.0
36.8
44.8
35.3
36.8
44.6
51.1
39.1
39.5
49.4
51.7
41.6
37.7
12.6
6.9
6.3
1.2
2
,5
a
Errors ,10%.

A. Casnati et al. / Tetrahedron 60 (2004) 7869–7876
7873
in the dibenzo-crown-6 derivative 2. The stability of the
cesium complex drops by 14.0 kJ/mol with the introduction
of the propylene moiety in the dibenzo-crown-6 series,
while it decreases only by 7.8 kJ/mol when no benzo units
are present in the crown bridge. This causes a plateau
selectivity of calix-dibenzo-propylene-crown-6 (2) which
indeed shows only a very weak preference for Rbþ.
Moreover, while in calixcrowns-6 (I) the stabilities of the
complexes remarkably rise with the introduction of two
benzo units, in propylene-crown-6 there are only minor
differences between propylene-dibenzo-crown-6 (2) and
-propylene-crown-6 (1). In conclusion, the substitution of an
ethylene with a propylene moiety in the bridge of calix-
crown-6 compounds decreases both the efficiency and
selectivity of cesium complexation in contrast to what was
predicted by ab initio calculations. The origin of such a
discrepancy should be ascribed to the fact that, in the
modeling, effects due to solvation and interaction with the
counter-anion are not taken into account.
(M2C6H5), 493 (M2C19H15). Anal Calcd for C49H52O6: C,
79.86; H, 7.11. Found: C, 80.02; H, 7.19.
3.1.2. 2-(2-{3-[2-(2-Hydroxy-ethoxy)-ethoxy]-propoxy}-
ethoxy)-ethanol (6). A sample of compound 5 (3.3 g,
4.5 mmol) was dissolved at room temperature in 100 mL of
a 1:1 mixture of CH2Cl2 and CH3OH and then 0.5 mL of a
12 M HCl solution were added. After 3 h the reaction was
cooled to 0 8C, 50 mL of a 5% NaHCO3 solution were
slowly added (CAUTION!) and the solution was stirred for
30 min. Then the solvent was distilled off under reduced
pressure and the residue extracted with 100 mL of CH2Cl2
and 100 mL of 1 M HCl. Water was removed under
vacuum from the aqueous layer and the solid residue
extracted twice with MeOH (2£30 mL). After removal of
methanol pure product 6 was isolated as an oil (1.05 g,
1
93%). H NMR (CD3OD): d 3.70–3.50 (m, 20H, OCH2),
1.85 (quin, J¼6.3 Hz, 2H, CH2CH2CH2); 13C NMR
(CD3OD): d 72.5, 70.24, 70.16, 68.2 (CH2CH2CH2), 61.1
(CH2OH), 29.8 (CH2CH2CH2); MS m/z: 253.0 (Mþ1).
Anal Calcd for C11H24O6: C, 52.36; H, 9.59. Found: C,
52.41; H, 9.63.
3. Experimental
3.1. Synthesis
3.1.3. 2-(2-{3-[2-(2-Tosyloxy-ethoxy)-ethoxy]-propoxy}-
ethoxy)-ethanol (7). Compound 6 (1.0 g, 4.0 mmol) was
dissolved in dry CH2Cl2 (50 mL) at room temperature and
under nitrogen atmosphere. The stirred solution was cooled
at 0 8C and tosyl chloride (1.86 g, 9.8 mmol), dry triethyl-
amine (1.8 mL), and a catalytic amount of dimethylamino-
pyridine (DMAP) were slowly added. After 20 h the solvent
was removed under reduced pressure and the residue was
extracted with 100 mL of CH2Cl2 and 100 mL of 1 M HCl.
The organic layer was washed twice with water (2£100 mL)
and the solvent distilled off to give compound 7 (57%) as
oil; 1H NMR (CDCl3): d 7.79 (d, J¼8.4 Hz, 4H, TsH), 7.34
(d, J¼8.4 Hz, 4H, TsH), 4.15 (t, J¼4.8 Hz, 4H, CH2OTs),
3.68 (t, J¼4.8 Hz, 4H, OCH2CH2OTs), 3.59–3.55
(m, 4H, OCH2CH2OCH2CH2OTs), 3.52–3.48 (m, 8H,
CH2OCH2CH2CH2OCH2), 2.44 (s, 6H, TsCH3), 1.82
(quin, J¼6.5 Hz, 2H, CH2CH2CH2; 13C NMR (CDCl3): d
144.7, 133.0 (Ar), 129.7, 127.9 (ArH), 70.6, 70.0, 69.1, 68.6,
68.1 (OCH2), 29.8 (CH2CH2CH2), 21.5 (CH3); MS m/z: 561
(Mþ1). Anal Calcd for C25H36O10S2: C, 53.55; H, 6.47.
Found: C, 53.60; H, 6.45.
Materials and methods. Most of the solvents and all
reagents were obtained from commercial supplies and
used without further purification. DMF was freshly distilled
˚
and stored over 4 A molecular sieves while acetonitrile for
˚
synthesis was dried over 3 A molecular sieves. Proton and
carbon nuclear magnetic resonance spectra (1H NMR and
13C NMR) were recorded on a Bruker AC300 and Bruker
300 Avance spectrometers of the Centro Interdipartimentale
of the Parma University. Chemical shifts are reported as d
values in ppm from TMS (d 0.0) as internal standard.
Analytical thin-layer chromatography was carried out on
silica gel plates (SiO2, Merk 60 F254). Mass spectra were
performed with FINNIGAN MAT SSQ 710 (CI, CH4).
Melting points were obtained in a nitrogen-sealed capillary
on an Electrothermal Apparatus. Diethylene glycol mono-
trityloxy monotosylate (4),20 2-(2-hydroxyethoxy)phenol
(9)15 and 25,27-di-iso-propoxycalix[4]arene (8)7 were
synthesised according to the literature.
3.1.1. 2-(2-{3-[2-(2-Trityloxy-ethoxy)-ethoxy]-propoxy}-
ethoxy)-ethanol (5). A sample of propylene glycol 3
(0.46 g, 6.0 mmol) in dry THF (20 mL) was added to a
suspension of KOH (1.30 g, 23 mmol) in dry THF (30 mL)
at reflux under nitrogen atmosphere; the mixture was stirred
for 1 h. Then compound 4 (6.7 g, 13.3 mmol) in dry THF
(20 mL) was added and the reaction mixture stirred for 2
days. After cooling, the solvent was distilled off and the
residue extracted with 50 mL of CH2Cl2 and 50 mL of
water; the organic solvent was removed under reduced
pressure. The pure product 5 was obtained by column
chromatography (SiO2 CH2Cl2/hexane/ethyl acetate 3:8:1)
as an oil (3.30 g, 74%); 1H NMR (CDCl3): d 7.44–7.41 (m,
12H, ArH meta), 7.32–7.22 (m, 18H, ArH ortho and para),
3.69–3.55 (m, 16H, OCH2CH2O), 3.16 (t, J¼6.2 Hz,
4H, OCH2CH2CH2O), 1.90 (quin, J¼6.2 Hz, 2H,
OCH2CH2CH2O); 13C NMR (CDCl3): d 144.1 (Ar),
128.7, 127.6, 126.8 (ArH), 86.5 (C(C6H5)3), 70.7, 70.6,
70.2, 68.3, 63.3 (OCH2), 30.0 (CH2CH2CH2); MS m/z: 660
3.1.4. Glycol 10. A mixture of compound 9 (5.3 g,
34.4 mmol) and NaH (0.83 g, 34.4 mmol) in dry DMF
(100 mL) was stirred at room temperature for 30 min. Then
a solution of 1,3-dibromopropane (9) (3.5 g, 17.2 mmol)
dissolved in dry DMF (50 mL) was added dropwise and the
mixture stirred at room temperature for 24 h. After removal
of DMF under vaccum, the residue was dissolved in
dichloromethane and washed with water (CAUTION!).
The organic layer was dried over sodium sulfate and the
solvent evaporated under reduced pressure. The pure
product 10 (3.2 g, 53%) was obtained by crystallization
from ethanol/water (1:1); mp 87–88 8C; 1H NMR (CDCl3):
d 7.00–6.89 (m, 8H, ArH), 4.30 (t, J¼5.7 Hz, 4H,
OCH2CH2CH2O), 4.08 (t, J¼4.2 Hz, 4H, ArOCH2CH2OH),
3.90 (t, J¼4.2 Hz, 4H, ArOCH2CH2OH), 2.23 (quin, J¼
5.7 Hz, 2H, OCH2CH2CH2O); 13C NMR (CDCl3): d 149.3,
148.4 (Ar), 122.2, 121.6, 115.7, 114.4 (ArH), 71.1, 66.5
(ArOCH2), 61.2 (CH2OH), 29.0 (CH2CH2CH2); MS m/z:

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A. Casnati et al. / Tetrahedron 60 (2004) 7869–7876
348.15 (Mþ). Anal. Calcd for C19H24O6: C, 65.50; H, 6.94.
Found: C, 65.45; H, 6.85.
lisation from methanol; yield¼59%; mp 83–85 8C; 1H
NMR (CDCl3): d 7.04–6.93 (m, 12H, ArH), 6.86 (d, J¼
7.4 Hz, 4H, ArH meta), 6.81 (t, J¼7.4 Hz, 2H, ArH para),
6.65 (t, J¼7.4 Hz, 2H, ArH para), 4.28 (t, J¼6.2 Hz, 4H,
CH2CH2CH2), 4.20 (ept, J¼6.0 Hz, 2H, CH(CH3)2), 3.82
(d, J¼15.9 Hz, 4H, ArCH2Ar), 3.74 (d, J¼15.9 Hz, 4H,
ArCH2Ar), 3.67 (t, J¼6.4 Hz, 4H, ArOCH2CH2OArOCH2),
3.44 (t, J¼6.4 Hz, 4H, ArOCH2CH2OArOCH2), 2.32 (quin,
J¼6.2 Hz, 2H, CH2CH2CH2), 0.88 (d, J¼6.0 Hz, 12H,
CH(CH3)2). 13C NMR (CDCl3): d 156.2, 154.8 (Ar ipso),
150.5, 149.7 (Bn), 134.5, 133.7 (Ar ortho), 130.2, 129.5 (Ar
meta), 123.0, 121.98, 121.97, 121.92 (ArH para and BnH),
119.9, 117.0 (BnH), 70.5, 69.9, 68.0, 67.1 (OCH2), 38.9
(ArCH2Ar), 30.1 (CH2CH2CH2), 21.7 (CH3); MS m/z: 820.1
(Mþ). Anal. Calcd for C53H56O8: C, 77.53; H, 6.87. Found:
C, 77.58; H, 6.93.
3.1.5. Ditosylate 11. A mixture of compound 10 (2.5 g,
7.2 mmol) and triethylammine (3 mL, 21 mmol) in dichloro-
methane (50 mL) was stirred at room temperature. To this
solution were added tosyl chloride (3.2 g, 16.8 mmol) and a
catalytic amount of 4-dimethylaminopyridine DMAP. After
heating at reflux for 24 h the mixture was cooled at room
temperature and extracted with 60 mL of 1 M HCl. The
organic layer was dried over sodium sulfate and the solvent
evaporated under vacuum. The residue was purified by
column chromatography (SiO2 Et2O/hexane 7:3) to afford
compound 11 as white solid (2.9 g, 61%); mp 79–83 8C; 1H
NMR (CDCl3): d 7.78 (d, J¼8.3 Hz, 4H, TsH), 7.29 (d,
J¼8.3 Hz, 4H, TsH), 6.94–6.91 (m, 4H, ArH), 6.87–6.79
(m, 4H, ArH), 4.31 (t, J¼4.2 Hz, 4H, TsOCH2CH2O),
4.19–4.15 (m, 8H, CH2OArOCH2), 2.41 (s, 6H, TsCH3),
2.25 (quin, J¼6.2 Hz, 2H, CH2CH2CH2); 13C NMR
(CDCl3): d 149.4, 147.9, 144.8, 132.9 (Ar), 129.8, 127.9,
122.7, 121.2, 116.1, 114.4 (ArH), 68.2, 67.3, 65.7 (OCH2),
29.3 (CH2CH2CH2), 21.5 (CH3). MS m/z: 656.6 (Mþ). Anal.
Calcd for C33H36O10S2: C, 60.35; H, 5.52. Found: C, 60.44;
H, 5.46.
3.3. X-ray crystallographic studies of 1
Crystal data and the most significant parameters for the
structure refinement of 1 are reported in Table 6. A single
transparent crystal was mounted on a glass fibre and
protected from air by a thin film of perfluoric oil.
Table 6. Crystallographic data and experimental details for 1a
3.2. General procedure for the synthesis of calix-crown-6
(1 and 2)
Crystal data
Empirical formula
Formula weight
Crystal size [mm]
Crystal system
Space group
C45H56O8
724.933
0.4£0.3£0.4
Triclinic
P-1
10.962(5)
17.945(5)
11.009(5)
104.06(2)
91.34(2)
76.09(2)
2038(2)
2
25,27-Di-iso-propoxycalix[4]arene 8 (2 mmol) was dis-
solved in CH3CN (300 mL) and an excess of Cs2CO3
(2.60 g, 8 mmol) and of the appropriate glycol di-p-
toluenesulfonate (2.5 mmol) added under a nitrogen atmo-
sphere. The reaction mixture was refluxed for 24 h. Then
CH3CN was removed under reduced pressure and the
residue extracted with 70 mL of CH2Cl2 and 70 mL of 10%
HCl. The organic phase was separated, washed twice with
water (2£100 mL) and the solvent distilled off. The pure
compounds were isolated as described below.
˚
a (A)
˚
b (A)
˚
c (A)
a (8)
b (8)
g (8)
3
˚
V (A )
Z
r (Calcd) (g/cm3)
F(000)
Data collection
1.182
780
3.2.1. Calix[4]arene-propylene-crown-6 (1). Calix-crown-
6 1 was obtained after purification on a silica gel column
using ethyl acetate/hexane (2:3) as eluent; yield¼54%; mp
T (K)
Index range
295
212#h#12,220#k#19, 0#l#19
6757
1
Reflections collected
Independent reflections
Observed reflections
Structure refinement
Data/restraints/parameters
Goodness-of-fit on F2a
Final R indices (obs. data)a
R indices (all data)
216–218 8C; H NMR (CDCl3): d 7.07 (d, J¼7.4 Hz, 4H,
6374(Rint¼0.016)
ArH meta), 7.01 (d, J¼7.4 Hz, 4H, ArH meta), 6.79
(t, J¼7.4 Hz, 2H, ArH para), 6.78 (t, J¼7.4 Hz, 2H, ArH
para), 4.22 (ept, J¼6.1 Hz, 2H, CH(CH3)2), 3.81 (d,
J¼15.6 Hz, 4H, ArCH2Ar), 3.74 (d, J¼15.6 Hz, 4H,
ArCH2Ar), 3.67 (t, J¼5.8 Hz, 4H, OCH2CH2CH2O), 3.63
(t, J¼4.8 Hz, 4H, ArOCH2CH2OCH2CH2O), 3.54–3.49 (m,
8H, ArOCH2CH2 and ArOCH2CH2OCH2CH2O), 3.31 (t,
J¼5.8 Hz, 4H, ArOCH2CH2), 1.86 (quin, J¼5.8 Hz, 2H,
4262 [F0$4s(F0)]
6374/0/488
1.161
R1¼0.056, wR2¼0.178
R1¼0.0832, wR2¼0.164
0.53, 20.43
P
3
˚
Largest diff. peak and hole (e/A )
P
P
P
R1¼ kF0l2lFck/ lF0l, wR2¼[ w(F202Fc2)2/ wF04]1/2. Goodness-of-fit¼
a
P
[
number of parameters.
w(F202F2c)2/(n2p)]1/2, where n is the number of reflections and p the
OCH2CH2CH2O), 0.92 (d, J¼6.1 Hz, 12H, CH(CH3)2); 13
C
NMR (CDCl3): d 156.6, 154.7 (Ar ipso), 134.4, 133.4 (Ar
ortho), 130.0, 129.6 (ArH meta), 121.8, 121.4 (ArH para),
70.7 (CH(CH3)2), 70.4, 70.2, 69.8, 69.2, 66.9 (OCH2), 38.5
(ArCH2Ar), 30.1 (CH2CH2CH2), 21.8 (CH(CH3)2). MS m/z:
724.5 (Mþ). Anal Calcd for C45H56O8: C, 74.56; H, 7.79.
Found: C, 74.63; H, 7.71.
The X-ray measurements were performed at room tempera-
ture on a Philips PW1100 diffractometer using graphite
˚
monochromated Mo Ka radiation (l¼0.71073 A). The cell
parameters were obtained from a least-squares fitting on 25
Iu,x,f reflections found in a random search on the reciprocal
lattice in the range 16#u#208. One standard reflection,
collected every 100 to monitor crystal decay and instru-
mental linearity, showed a linear decay of almost 10%. The
intensities were corrected for Lorentz and polarization but
not for absorption. The structure was solved by Direct
3.2.2. Calix[4]arene-propylene-dibenzocrown-6 (2).
Calix-benzocrown-6 2 was obtained after column chroma-
tography on silica gel using first CH2Cl2/hexane (1:1) and
then ethyl acetate/methanol (95:5) as eluent and crystal-

A. Casnati et al. / Tetrahedron 60 (2004) 7869–7876
7875
Methods using SIR9224 and refined by full-matrix least-
squares methods on F2 using SHELXL-97.25 All non-
hydrogen atoms were refined with anisotropic atomic
displacement parameters. The hydrogen atoms were placed
at their calculated positions with the geometrical constraint
Fanni, S.; Schwing, M. J.; Egberink, R. J. M.; de Jong, F.;
Reinhoudt, D. N. J. Am. Chem. Soc. 1995, 117, 2767–2777.
8. Hill, C.; Dozol, J. F.; Lamare, V.; Rouquette, H.; Eymard, S.;
Tournois, B.; Vicens, J.; Asfari, Z.; Bressot, C.; Ungaro, R.;
Casnati, A. J. Inclusion Phenom. Mol. Recognit. Chem. 1994,
19, 399–408.
˚
C–H 0.96 A and refined ‘riding’ on their parent carbon
atoms. The structure has also been tested in the monoclinic
9. Dozol, J.-F.; Lamare, V.; Simon, N.; Ungaro, R.; Casnati, A.
Extraction of cesium by calix[4]arene crown-6: from synthesis
to process. In Calixarene Molecules for Separation; Lumetta,
G. J., Rogers, R. D., Gopalan, A. S., Eds.; American Chemical
Society, 2000; pp 12–25 Washington.
˚
system (a¼15.716, b¼15.353, c¼17.945 A, b¼109.038),
space group C2/c, however the refinement was unsuccesful.
Geometrical calculations were obtained by PARST97.26
Crystallographic data (excluding structure factors) for the
structure reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre: CCDC deposition
number 232991.
10. Sachleben, R. A.; Bonnesen, P. V.; Descazeaud, T.;
Haverlock, T. J.; Urvoas, A.; Moyer, B. A. Solvent Extr. Ion
Exch. 1999, 17, 1445–1459.
11. Sachleben, R. A.; Urvoas, A.; Bryan, J. C.; Haverlock, T. J.;
Hay, B. P.; Moyer, B. A. Chem. Commun. 1999, 1751–1752.
12. Bonnesen, P. V.; Haverlock, T. J.; Engle, N. L.; Sachleben,
R. A.; Moyer, B. A. Development process chemistry for the
removal of cesium from acidic nuclear waste by calix[4]arene-
crown-6 ethers. In Calixarene Molecules for Separation;
Lumetta, G. J., Rogers, R. D., Gopalan, A. S., Eds.; American
Chemical Society, 2000; pp 26–44 Washington.
3.4. Computational methods
All the calculations were executed on a Pentium IV PC
(2.5 MHz). The semiempirical calculations at the PM3
level were performed with SPARTAN 02.27 The ab initio
calculations at the HF level were carried out using
GAUSSIAN03 in the G03W suite.28 Molecular symmetry
was disabled in all calculations. The basis set for cesium
was taken from literature.29
13. Lamare, V.; Dozol, J. F.; Ugozzoli, F.; Casnati, A.; Ungaro, R.
Eur. J. Org. Chem. 1998, 1559–1568.
14. Casnati, A.; Giunta, F.; Sansone, F.; Ungaro, R.; Montalti, M.;
Prodi, L.; Zaccheroni, N. Supramol. Chem. 2001, 13,
419–434.
4. Supplementary data available
15. Casnati, A.; Sansone, F.; Dozol, J. F.; Rouquette, H.; Arnaud,
N. F.; Byrne, D.; Fuangswasdi, S.; Schwing-Weill, M. J.;
Ungaro, R. J. Inclusion Phenom. Macromol. Chem. 2001, 41,
193–200.
Cartesian coordinates of HF/3-21Gp p optimized structures
of all compounds reported in this work and the .cif file of
the X-ray crystal structure of ligand 1 are available on-line
as Supplementary Data.
16. Ouchi, M.; Hakushi, T.; Inoue, Y. Complexation by crown
ethers of low symmetry. In Cation Binding by Macrocycles;
Inoue, Y., Gokel, G. W., Eds.; Marcel Dekker: New York,
1990; pp 549–579.
Acknowledgements
17. Ouchi, M.; Inoue, Y.; Kanzaki, T.; Hakushi, T. J. Org. Chem.
1984, 49, 1408–1412.
18. Perrin, M.; Oehler, D. In Calixarenes, a Versatile Class of
We thank MIUR (COFIN2003 Project: ‘Supramolecular
Devices’) and EU (CALIXPART Project FIKW-CT2000-
¨
Macrocyclic Compounds; Vicens, J., Bohmer, V., Eds.;
`
00088) for financial support. The Centro Interfacolta
Kluwer Academic: Dordrecht, 1991; pp 65–85.
19. Ugozzoli, F.; Ori, O.; Casnati, A.; Pochini, A.; Ungaro, R.;
Reinhoudt, D. N. Supramol. Chem. 1995, 5, 179–184.
20. Fischer, C.; Sarti, G.; Casnati, A.; Carrettoni, B.; Manet, I.;
Schuurman, R.; Guardigli, M.; Sabbatini, N.; Ungaro, R.
Chem. Eur. J. 2000, 6, 1026–1034.
di Misure (CIM) of the University of Parma is also
acknowledged for the use of NMR and Mass facilities.
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