Novel biscalix[4]arene-based anion receptors

Article abstract of DOI:10.1016/S0040-4020(02)00799-8

Novel biscalix[4]arene derivatives where two calixarene units are connected via one or two ureido bridges on the upper rim has been prepared. These compounds represent well preorganised cavities with interesting complexation abilities towards anions. The structure of bis-ureido derivative was proved by X-ray crystallography.

Full text of DOI:10.1016/S0040-4020(02)00799-8

Tetrahedron 58 (2002) 7207–7211
Novel biscalix[4]arene-based anion receptors
a
Vaclav Stastny, Pavel Lhotak, Veronika Michlova, Ivan Stibor and Jan Sykora
a
a
a
b
,
*
*
´
´
´
a
´
Department of Organic Chemistry, Institute of Chemical Technology, Technicka 5, 166 28 Prague 6, Czech Republic
Department of Solid State Chemistry, Institute of Chemical Technology, Technicka 5, 166 28 Prague 6, Czech Republic
b
´
Received 22 April 2002; revised 12 June 2002; accepted 4 July 2002
Abstract—Novel biscalix[4]arene derivatives where two calixarene units are connected via one or two ureido bridges on the upper rim has
been prepared. These compounds represent well preorganised cavities with interesting complexation abilities towards anions. The structure
of bis-ureido derivative was proved by X-ray crystallography. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
anions (halogenides, carboxylates). Our results indicate that
the anions are caught by cooperative interactions of both
units (compound 1). The bridging of these molecules with
an appropriate spacer should lead to receptors with
enhanced rigidity (preorganisation) and possibly, to novel
complexation properties (selectivity). In this paper we
report the synthesis and properties of novel cage compounds
based on the bis-calix[4]arenes, possessing preorganised
amide or urea moieties in the molecules.
Calix[4]arenes1,2 represent macrocyclic compounds widely
used in supramolecular chemistry for the construction of
various receptors for the complexation of charged or neutral
molecules. Their unique three-dimensional structures with
almost unlimited derivatisation abilities and a tuneable
shape of the molecules make calixarenes ideal candidates
for building blocks and/or molecular scaffolds in the design
of new more sophisticated molecules.
2. Results and discussion
2.1. Synthesis
The synthesis of bis-calixarenes 6 and 10 was accomplished
according to Scheme 1. Starting tetrapropoxycalix[4]arene
2 was mononitrated (product 3, 45% yield)7 using 100%
HNO3 in dichloromethane/acetic acid mixture and subse-
quently reduced by SnCl2 in ethanol8 to give amino
derivative 4 in 87% yield. Similar reaction conditions led
to 5,17-diaminocalix[4]arene 8 in 26% overall yield. Amino
derivatives 4 and 8 were transformed into corresponding
isocyanates 5 and 9 by refluxing with triphosgene8 in
toluene. Both compounds were obtained in quantitative
yields and due to their alleged instability were used in the
next step without further purification. The condensation of
aminoderivative 4 with 1 equiv. of isocyanate 5 was carried
out in dichloromethane solution at room temperature. Bis-
calixarene 6 was obtained in 61% yield after purification by
preparative TLC. Analogously, the reaction between
difunctional starting compounds 8 and 9 was carried under
high dilution conditions by the simultaneous addition of
both agents to the big volume of solvent (CH2Cl2). This
method gave cage derivative 10 in 15% yield. Monoamine 4
was also used for the condensation with 1,4-phenylene
diisocyanate to form bis-calixarene 11 with two potential
complexation sites for anions.
Whereas cation complexation has been extensively studied
for a long time, the recognition of anions3 by synthetic
receptors based on the calixarenes still remains relatively
unexplored. Thus, introduction of activated amides4 into the
upper rim of calixarene derivatives, preorganised in the
cone conformation, led to the receptors interacting with
anions by hydrogen bonds. Other moieties frequently used
for anion recognition are urea and thiourea units.5 As we
showed in our previous paper,6 cone or 1,3-alternate
conformers bearing two urea functions on the upper rim
exhibit an interesting complexation ability towards selected
Keywords: calixarenes; anion receptors; NMR titration; macrocycles.
*
Corresponding authors. Tel.: þ420-2-2435-4280; fax: þ420-2-2435-
4288; e-mail: lhotakp@vscht.cz
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00799-8

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V. Stastny et al. / Tetrahedron 58 (2002) 7207–7211
Scheme 1. (a) 100% HNO3/CH2Cl2–CH3COOH, rt (45%); (b) SnCl2·2H2O, ethanol, reflux (87%); (c) triphosgene/toluene, reflux (quant.); (d) CH2Cl2 (61%);
(e) 100% HNO3/CH2Cl2–CH3COOH, rt (30%); (f) SnCl2·2H2O, ethanol, reflux (88%); (g) triphosgene/toluene, reflux (quant.); (h) CH2Cl2/high dilution, rt
(15%), (i) 1,4-phenylene diisocyanate/CH2Cl2, rt 84%).
To evaluate the importance of urea units for the anion
binding, derivative 17 bearing two amidic instead of urea
functions was prepared according to Scheme 2 in yield 10%
under high dilution conditions. Dicarboxylic acid 16 was
obtained by the oxidation of corresponding dialdehyde 15
using known procedure.9
2708C) did not show any significant changes. More HB-
competitive solvent (CDCl3/CD3CN¼4:1 v/v) results in the
sharpening of signals, thus supporting the assumption that
this phenomenon is caused by intermolecular aggregation
based on the HB interactions between urea units. Indeed, the
spectrum measured in CDCl3/DMSO-d6¼4:1 v/v mixture
reflects the high proposed symmetry of this cage derivative:
two sets of propyl signals, two doublets of the CH2 bridging
group with typical geminal splitting (J¼13 Hz) and one
singlet for the urea NH groups (6.39 ppm). Corresponding
1H NMR spectra of bis-calixarenes 6, 11 and 17 do not
The 1H NMR spectrum of derivative 10 in CDCl3 consists of
very broad signals indicating some additional chemical
exchange. The shape of signals is concentration dependent,
1
on the other hand, dynamic H NMR methods (þ30 to

V. Stastny et al. / Tetrahedron 58 (2002) 7207–7211
7209
Scheme 2. (a) Br2/CHCl3, rt (95%); (b) PrI/NaH, DMF, rt (87%); (c) (i) BuLi/THF, 2788C; (ii) DMF; (iii) water (56%); (d) NaClO3/sulfanilic acid, rt (75%);
(e) (i) (COCl)2/CCl4, reflux, (ii) 8, CH2Cl2/high dilution, rt (10%).
exhibit similar solvent-dependent behaviour and show
typical splitting pattern of monosubstituted and disubsti-
tuted calix[4]arenes, respectively.
It clearly shows much better preorganisation of bis-
calixarene receptor 10 where the cooperative effect of
both ureido units is possible. On the other hand, similar
derivative 17, with two amidic functions, does not exhibit
any complexation ability towards selected anions (halides,
benzoate). Obviously, urea functions are much better anion
binding fragments than simple amides, in agreement with
our previous finding.6
2.2. Complexation study
The complexation ability of compounds 6, 10, and 17 was
measured by standard 1H NMR titration experiments (Table
1) in a CHCl3/DMSO-d6¼4:1 v/v mixture (to avoid the
self-aggregation of 10) using a constant calixarene concen-
tration (0.5–1.0 mM) and increasing concentrations of the
appropriate anions to obtain different anion/calix ratios
(0.1–20). The plot of induced chemical shifts versus anion
concentration gave typical titration curves corresponding to
the formation of a 1:1 complex. The proposed stoichiometry
of the complexation was also confirmed by the measuring of
Job plots. The appropriate complexation constant was
calculated using original non-linear regression curve-fitting
program.10
Very interesting size-recognition ability was observed in
case of halides. While chloride is complexed by both
receptors (54 mol21 l for 10, 19 mol21 l for 6), other
halides (F2, Br2 and I2) cause only negligible changes
of chemical shifts (less than 10 Hz) as a consequence of
unsuitable size complementarity of receptors and anions.
Similar behaviour (size-dependent recognition of spheri-
cal halides) was found in case of biscalixarene 11
(KCl¼790 mol21 l, KBr¼445 mol21 l, KI¼62 mol21 l).
The ligand 11 was designed to complex two anions at
both anion binding positions (urea units), however, the
Job plot procedure unambiguously confirmed the exclu-
sive formation of only 1:1 complexes with halides or
The addition of C6H5COO2NBuþ4 to the solution of 10
(10:1 ratio) leads to high down-field shift of urea –NH–
signals (550 Hz) indicating strong interactions with anion.
The association constant for benzoate K (734 mol21 l) is
almost 20 times higher that that of derivative 6 (43 mol21 l).
Table 1. Complexation constants Kc of receptors 6, 10, 11 and 17 towards
selected anions (1H NMR, CDCl3/DMSO-d6¼4:1 v/v, 258C, 300 MHz)
Anion
K
C (mol21 l)
6
10
11a
17
b
Cl2
19^3
c
54^5
c
790^295
445^32
62^14
–
–
–
–
b
Br2
–
–
c
c
b
I2
Benzoate
–
43^4
–
734^144
b
1280^735
a
Measured in CDCl3.
No changes in NMR observed.
Small induced chemical shifts (,10 Hz).
Figure 1. Job’s plot for 11/Buþ4 Cl2 system (300 MHz, CDCl3, C11
CCl2¼2 mmol l21).
þ
b
c

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V. Stastny et al. / Tetrahedron 58 (2002) 7207–7211
for 1 h. Evaporation of the solvent gave the crude product
which was purified by the preparative TLC (silica gel,
chloroform/ethyl acetate 100:1) to yield 190 mg of bridged
compound 6 (61%) as a white solid. Mp: .3508C (ethyl
1
acetate). H NMR (CDCl3, 300 MHz) d: 6.65–6.75 (m,
12H, H-arom), 6.40–6.50 (m, 6H, H-arom), 6.33 (s, 4H,
H-arom), 5.65 (s, 2H, NH), 4.46 (d, 4H, J¼13.2 Hz, Ar–
CH2–Ar, ax.), 4.42 (d, 4H, J¼13.7 Hz, Ar–CH2–Ar, ax.),
3.82 (m, 16H, –O–CH2–CH2–), 3.16 (d, 4H, J¼13.2 Hz,
Ar–CH2–Ar, eq.), 3.12 (d, 4H, J¼13.2 Hz, Ar–CH2–Ar,
eq.), 1.90 (m, 16H, –CH2–CH3), 0.99 (m, 24H, –CH2–
CH3). EA calcd for C81H96N2O9: C, 78.35; H, 7.79; N, 2.26;
Found: C, 78.02; H, 7; N, 2.19. FAB MS m/z (rel. int.)
1241.6 [M]þ (100).
Figure 2. ORTEP drawing of the X-ray structure of 10.
3.1.2. Synthesis of derivative 10. The solutions of
diaminocalix[4]arene 8 (100 mg, 0.16 mmol) and diiso-
cyanate 9 (108 mg, 0.16 mmol) each in 50 ml of dry CH2Cl2
were simultaneously added under stirring, over 17 h
(syringe pump), into 500 ml of dry CH2Cl2 (high dilution
conditions) under nitrogen atmosphere at room temperature.
The mixture was stirred for an additional 7 h and then
evaporated to dryness. The crude product was purified by
preparative TLC (silica gel, chloroform/acetone 50:1) to
yield 30 mg of white crystals of the double bridged
compound 10 (15%) as a white solid. Mp: .3508C (ethyl
acetate). 1H NMR (CDCl3/DMSO-d6 4:1, 300 MHz) d: 7.15
(d, 8H, J¼7.69 Hz, H-arom), 6.93 (t, 4H, J¼7.14 Hz,
H-arom), 6.39 (s, 4H, N–H), 5.82 (s, 8H, H-arom), 4.38 (d,
4H, J¼13.2 Hz, Ar–CH2–Ar, ax.), 3.99 and 3.59 (2£t, 16H,
J¼7.14 Hz, –O–CH2–CH2–), 3.09 (d, 4H, J¼13.4 Hz,
Ar–CH2–Ar, eq.), 1.84 (m, 16H, –O–CH2–CH2–CH3),
1.01 and 0.86 (2£t, 24H, J¼7.14 Hz, –CH2–CH3). EA
calcd for C82H96N4O10: C, 75.90; H, 7.46; N, 4.32; Found:
C, 75.39; H, 7.08; N, 4.12. FAB MS m/z (rel. int.) 1297.3
[M]þ (100).
benzoate (Fig. 1). This fact is rather unexpected and the
possible explanation may lie in the repulsive interactions
between two negatively charged sites in close proximity
(particularly in such a non-polar solvent).
2.3. X-Ray study
The structure of 10 was unequivocally proven by X-ray
crystallography (Fig. 2). Suitable single crystals (mono-
clinic system, space group P21/a) were grown from ethyl
acetate and they were air-sensitive. Consequently, all
operations were carried out in a sealed glass capillary.
Both calixarene subunits adopt the pinched cone confor-
mation with two opposite aromatic rings pointing out of the
cavity and the other two (bearing ureido functions) tilted
towards each other. The angles between the main plane
defined by the four CH2 groups and the individual aromatic
units are approx. 138, 75, 139 and 818, respectively. Both
–NH– groups of ureido units are distorted outside from the
cavity what enables the strong hydrogen bonding (H…O
˚
distance: 2.19 and 2.28 A) of the ethyl acetate carbonyl
atom (crystallisation solvent) thus forming the 1:2 (10/
EtOAc) complex.
3.1.3. Synthesis of derivative 11. A solution of p-phenylene
diisocyanate (12 mg, 0.075 mmol) in 30 ml of dry dichloro-
methane was added dropwise over 0.5 h into the solution of
monoamine 4 (100 mg, 0.16 mmol) in 10 ml of dry CH2Cl2.
The reaction mixture was then stirred for 8 h under nitrogen
atmosphere and the solvent was evaporated at reduced
pressure. The crude residue was purified by preparative TLC
(chloroform/acetone 50:1) to yield 87 mg of product 11
(84% yield) as a white solid. Mp: 2588C (CHCl3–MeOH).
1H NMR (CDCl3, 300 MHz) d: 6.97 (s, 4H, H-arom), 6.80–
6.63 (m, 6H, H-arom), 6.21 (br s, 16H, H-arom), 4.35 (d,
8H, Ar–CH2–Ar, ax., J¼13.5 Hz), 3.86 (m, 8H, –O–
CH2–CH2–), 3.65 (m, 8H, –O–CH2–CH2–), 3.06 (d, 4H,
Ar–CH2–Ar, eq., J¼13.2 Hz), 3.04 (d, 4H, Ar–CH2–Ar,
eq., J¼13.5 Hz), 1.84 (m, 16H, –CH2–CH3), 0.97 and 0.85
(2t, 24H, J¼7.4 Hz). EA calcd for C88H102N4O10: C, 76.83;
H, 7.47; N, 4.07; Found: C, 76.25; H, 7.19; N, 3.85.
MALDI-TOF MS m/z (rel. int.) 1377 [MþH]þ (100), 1399
[MþNa]þ (79).
3. Experimental
3.1. General
Melting points are uncorrected and were determined using a
Boetius Block apparatus. 1H NMR spectra were recorded on
a Varian Gemini 300 and a Bruker AMX3 400 spectro-
meters using tetramethyl silane as an internal standard. FAB
MS were measured on ZAB-EQ VG Analytical spectro-
1
meter. H NMR titrations were performed with tetrabutyl-
ammonium salts of corresponding anions that were dried
and stored in evacuated dessicator on P2O5. Dichloro-
methane and CCl4 used for the reaction were dried with
CaH2 and stored over molecular sieves.
Compounds 3,7 7,7 4,8 5,8 8,8 9,8 13,11 14,11 159 and 169
were prepared according to known procedures.
3.1.4. Synthesis of derivative 17. A mixture of diacid 16
(60 mg, 0.088 mmol) and (COCl)2 (76 ml; 0.88 mmol) in
5 ml of anhydrous CCl4 was stirred under reflux for 3 h.
The solvent was distilled off, the residue was dissolved in
anhydrous CCl4 (5 ml) and the solvent was again evaporated
under reduced pressure. This procedure was repeated twice
3.1.1. Synthesis of derivative 6. Calix[4]arene 4 (148 mg,
0.25 mmol) was added to the solution of monoisocyanate 5
(158 mg, 0.25 mmol) in 20 ml of dry CH2Cl2. The reaction
mixture was then stirred under nitrogen at room temperature

V. Stastny et al. / Tetrahedron 58 (2002) 7207–7211
7211
to remove all traces of oxalyl chloride. The resulting solid
References
1. For books on calixarenes see (a) Calixarenes 2001. Asfari, Z.,
¨
Bohmer, V., Harrowfield, J., Vicens, J., Eds.; Kluwer
(acyl chloride) was then dried in a high vacuum for 1 h.
A solution of the above-obtained acyl chloride (63 mg,
0.088 mmol) in dry dichloromethane (50 ml) and a solution
of diaminocalix[4]arene 8 (55 mg, 0.088 mmol) in 50 ml of
CH2Cl2 were simultaneously added under stirring during 6 h
(syringe pump) into 500 ml of dry CH2Cl2 (high dilution
conditions) at room temperature under nitrogen atmosphere.
The mixture was then stirred for an additional 12 h and
evaporated to dryness. The residue was purified by
preparative TLC (silica gel, chloroform) to yield 10 mg of
product 17 (10%) as a white solid. Mp: .3008C (ethyl
Academic: Dordrecht, 2001. (b) Gutsche, C. D. Calixarenes
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¨
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1
acetate). H NMR (CDCl3, 300 MHz) d: 7.39 (s, 2H, NH),
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¨
S. Chem. Rev. 1997, 97, 1713–1734. (b) Bohmer, V. Angew.
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4H, H-arom), 6.19 (s, 4H, H-arom), 4.42 (m, 8H, Ar–CH2–
Ar, ax.), 4.07 (m, 8H, –O–CH2–CH2–), 3.61 (m, 8H,
–O–CH2–CH2–), 3.16 (m, 4H, Ar–CH2–Ar, eq.), 1.81–
2.04 (m, 16H, –CH2–CH3), 1.08 (m, 12H, –CH2–CH3),
0.89 (m, 12H, –CH2–CH3). EA calcd for C82H94N2O10: C,
77.69; H, 7.47; N, 2.21; Found: C, 77.15; H, 7.27; N, 2.09.
FAB MS m/z (rel. int.) 1267.6 [M]þ (100).
´
Chem., Int. Ed. Engl. 1995, 34, 713–745. (c) Lhotak, P.;
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3.2. Crystallographic study
X-Ray data for C41H48O5N2·C4H8O2 M¼736.95 g/mol,
monoclinic system, space group P21/a, a¼19.42(2),
˚
b¼10.54(1), c¼20.00(1) A, b¼111.05(6), Z¼4, V¼
3
4205(6) A , Dc¼1.16 g cm23, m (Cu Ka)¼0.62 mm21
,
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˚
crystal dimensions of 0.8£0.4£0.4 mm. The crystal for
data collection was mounted in a glass capillary with mother
liquor to prevent desolvation during the analysis. Data were
measured at 293 K on an Enraf-Nonius CAD4
diffractometer with graphite monochromated Cu Ka
radiation. The structure was solved by direct methods.12
All heavy atoms were refined anisotropically. The whole
structure was refined by full matrix least-squares on F
values13 to final R¼0.0947 and Rw¼0.0742 using 3386
independent reflections (umax¼608). Urea –NH– hydrogen
atoms were found from difference Fourier maps and their
positions were refined, the other hydrogen atoms were
located from expected geometry and were not refined. Psi
scan was used for the absorption correction. Crystal-
lographic data (excluding structure factors) for the struc-
tures in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
numbers CCDC 172007. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: þ44-1223-336033 or
e-mail: deposit@ccdc.cam.ac.uk].
´ ´
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constants were calculated using the computer program
OPIUM (Kyvala M.), freely available at internet address:
http://www.natur.cuni.cz/~kyvala/opium.html.
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Acknowledgments
We thank the Grant Agency of the Czech Republic for
financial support for this work (GA 104/00/1722 and
203/00/1011).
13. Watkin, D. J.; Prout, C. K.; Carruthers, R. J.; Betteridge, P.
CRYSTALS Issue 10. Chemical Crystallography Laboratory:
Oxford, UK, 1996.