Synthetic receptors based on calix[4]arene functionalized at the lower rim in molecular recognition of dicarboxylic, α-hydroxycarboxylic, and α-amino acids

Article abstract of DOI:10.1023/B:RUCB.0000042270.26330.cb

New calix[4]arenes, di- and tetrasubstituted at the lower rim, with different functional groups were synthesized. They were studied as carriers of a series of dicarboxylic and α-hydroxycarboxylic acids through a liquid impregnated membrane. The calix[4]arenes under study are capable of molecular recognition of oxalic acid in the series of structurally similar dicarboxylic and α-hydroxycarboxylic acids. The regularities found make it possible to change purposefully the receptor ability of 1,3-disubstituted calix[4]arenes by variation of the nature of substituents.

Full text of DOI:10.1023/B:RUCB.0000042270.26330.cb

1172
Russian Chemical Bulletin, International Edition, Vol. 53, No. 6, pp. 1172—1180, June, 2004
Synthetic receptors based on calix[4]arene functionalized at the lower rim
in molecular recognition of dicarboxylic, αꢀhydroxycarboxylic,
and αꢀamino acids ✾
I. I. Stoikov,ꢀ L. I. Gafiullina, D. Sh. Ibragimova, I. S. Antipin, and A. I. Konovalov
Kazan State University,
18 ul. Kremlevskaya, 420008 Kazan, Russian Federation.
Fax: +7 (843 2) 31 5416. Eꢀmail: Ivan.Stoikov@ksu.ru
New calix[4]arenes, diꢀ and tetrasubstituted at the lower rim, with different functional
groups were synthesized. They were studied as carriers of a series of dicarboxylic and
αꢀhydroxycarboxylic acids through a liquid impregnated membrane. The calix[4]arenes under
study are capable of molecular recognition of oxalic acid in the series of structurally similar
dicarboxylic and αꢀhydroxycarboxylic acids. The regularities found make it possible to change
purposefully the receptor ability of 1,3ꢀdisubstituted calix[4]arenes by variation of the nature of
substituents.
Key words: calix[4]arene, thiacalix[4]arene, membrane transport, dicarboxylic acids,
αꢀhydroxycarboxylic acids, carboxylate anions, synthetic receptors, molecular recognition.
Processes of specific recognition, transformations,
transport, and regulation in biological systems are based
on intermolecular interactions.1 Principles of molecular
recognition have intensely been used recently for the creꢀ
ation of different artificial systems. One of the vigorously
developing directions is the synthesis of relatively small
receptor molecules capable of highly selective binding
with substrates of a certain type.2,3
It should specially be mentioned that molecular recꢀ
ognition of carboxylic acids is a complex problem, which
is more difficult than recognition of cations. At least threeꢀ
point binding of a "guest" molecule by a receptor seems to
be principal for recognition of these substrates.4 Carrier
molecules for biologically significant polyfunctional subꢀ
strates, such as peptides, nucleosides, and dicarboxylic,
αꢀhydroxy, and αꢀamino acids, should fulfill several reꢀ
quirements.5 First, receptor molecules should contain sevꢀ
eral coordination sites complementary to a substrate molꢀ
ecule. Second, they should be rather lipophilic. Finally, a
compromise between the stability of a complex formed in
the membrane phase and the high ionꢀexchange rate at
the interface is necessary.
calixarene fragment has a sufficient conformational rigidꢀ
ity and can provide a required orientation of binding sites
in the space. Nonꢀtoxicity of calixarenes in combination
with the complexing ability provides their promising use
in pharmacology to stabilize and prolong the effect of
medicines and decrease their side effect and to create new
convenient medicinal forms.6
We have previously shown7 that the calix[4]arenes disꢀ
tally disubstituted at the lower rim can bind carboxylic
acids and the nature of substituents has a noticeable effect
on complexation.
The use of the functionalized calix[4]arenes as moꢀ
lecular carriers through the lipophilic membrane made it
possible to study the influence of the number and nature
of substituents at the lower rim, heteroatoms included in
the lateral substituents or directly in the macrocycle, on
the ability to molecular recognition of dicarboxylic,
αꢀhydroxy, and αꢀamino acids.
Experimental
1
H NMR spectra were recorded on a Varian XLꢀ300 instruꢀ
Macrocyclic compounds, such as cyclodextrins and
calixarenes, are used as a platform for the creation of
receptors of dicarboxylic, αꢀhydroxycarboxylic, and
αꢀamino acids. Functionalization of phenol groups,
aromatic rings, and bridging fragments in the starting
calix[4]arenes, i.e., [14]ꢀmetacyclophanes, by the correꢀ
sponding organic and organoelement substituents deterꢀ
mines a high receptor ability of "host" molecules. The
ment (300 MHz) using CDCl3 as a solvent. Mass spectra were
obtained on an MXꢀ1310 mass spectrometer. Electroconductivity
of solutions was measured with a WTW inoLab Cond Level 1
conductometric detector.
D,LꢀMandelic, glycolic, D,Lꢀtartaric, D,Lꢀglutamic, oxalic,
malonic, and succinic acids (all reagent grade) and sodium acꢀ
etate (reagent grade) were used. Quantumꢀmechanical calculaꢀ
tions of the complexes were carried out by the MM+ molecular
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1125—1133, June, 2004.
1066ꢀ5285/04/5306ꢀ1172 © 2004 Plenum Publishing Corporation

Synthetic receptors based on calix[4]arenes
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 6, June, 2004
1173
mechanics and semiempirical PM3 methods included in the
MOPAC 7.00 program package.
18 H each, CMe3); 1.36—1.10 (m, 24 H, CH2(CH2)6Me); 3.38
3
3
(dt, 4 H, NHCH2(CH2)6Me, JH,H = 5.2 Hz, JH,H = 6.7 Hz);
2
5,11,17,23ꢀTetraꢀtertꢀbutylꢀ25,27ꢀdihydroxyꢀ26,28ꢀ
bis(Nꢀbenzoylaminoethoxy)calix[4]arene (1). A mixture of
5,11,17,23ꢀtetraꢀtertꢀbutylꢀ25,27ꢀdihydroxyꢀ26,28ꢀbis(aminoꢀ
ethoxy)calix[4]arene8 (4.00 g, 5.78 mmol), benzoic anhydride
(2.61 g, 11.56 mmol), and benzene (30 mL) was refluxed for 2 h.
Then the solvent was removed in vacuo, and the dry residue was
dispersed in a saturated aqueous solution of NaHCO3 (150 mL)
for 30 min, filtered off, and washed with water (3×50 mL). The
residue dried above P2O5 was dissolved in a minimum amount of
CH2Cl2 and precipitated with hexane. The white precipitate was
dried in vacuo (0.01 Torr) at 100 °С for 12 h. The yield was
2.70 g (59%), m.p. 135—136 °С. Found (%): С, 78.91; Н, 7.98;
N, 2.95. C62H74N2O6. Calculated (%): С, 78.95; Н, 7.91;
3.43 (d, 4 H, ArCH2(eq)Ar, JH,H = 13.2 Hz); 4.12 (d, 4 H,
ArCH2(ax)Ar, 2JH,H = 13.2 Hz); 4.56 (s, 4 H, O—CH2C(O)NH);
6.94, 7.08 (both s, 4 H each, ArH); 7.86 (s, 2 H, OH); 8.84 (t,
3
2 H, N—H, JH,H = 5.2 Hz). Found: m/z 986.7121 [M]+.
C64H94N2O6. Calculated: M = 986.7112.
5,11,17,23ꢀTetraꢀtertꢀbutylꢀ25,27ꢀdihydroxyꢀ26,28ꢀ
bis(pyridinꢀ4ꢀylmethoxy)calix[4]arene (4).
A mixture of
5,11,17,23ꢀtetraꢀtertꢀbutylꢀ25,26,27,28ꢀtetrahydroxyꢀ
calix[4]arene (1.00 g, 1.54 mmol), anhydrous K2CO3 (3.14 g,
22.72 mmol), and anhydrous NaI (1.15 g, 7.67 mmol) in MeCN
(150 mL) was refluxed with stirring under argon for 30 min.
Then a solution of 4ꢀchloromethylpyridine hydrochloride (0.54 g,
3.24 mol) in anhydrous MeOH (30 mL) was added to the reacꢀ
tion mixture for 2 h, after which the mixture was refluxed with
stirring for 20 h. Then the reaction mixture cooled to 50 °С was
filtered, the residue was washed with MeCN (2×30 mL), and the
solvent was removed from the combined extracts. The dry resiꢀ
due was dispersed in water (150 mL) for 30 min, washed with
water until the filtrate stopped coloring, and recrystallized from
a mixture of Et2O (50 mL) and MeCN (15 mL). The white
needleꢀlike precipitate was dried for 12 h in vacuo (0.01 Torr)
at 100 °С. The yield was 0.79 g (62%), m.p. 108—109 °С.
Found (%): С, 79.37; Н, 8.15; N, 3.41. С56Н66N2О4. Calcuꢀ
1
N, 2.97. H NMR (CDCl3), δ: 1.12, 1.23 (both s, 18 H each,
2
CMe3); 3.39 (d, 4 H, ArCH2(eq)Ar, JH,H = 14.1 Hz); 3.62 (dt,
3
3
4 H, СН23—N, JH,H = 4.5 Hz, JH,H = 4.9 Hz); 4.03 (t, 4 H,
2
O—СН2, JH,H = 4.5 Hz); 4.18 (d, 4 H, ArCH2(ax)Ar, JH,H
=
14.1 Hz); 7.02, 7.07 (both s, 4 H each, ArH); 7.31 (dd, 4 H,
3
3
ArH, JH,H = 7.4 Hz, JH,H = 7.1 Hz); 7.43 (tt, 2 H, ArH,
3JH,H = 7.4 Hz, JH,H = 1.3 Hz); 7.95 (dd, 4 H, ArH, JH,H
7.1 Hz, JH,H = 1.3 Hz); 8.21 (t, 2 H, N—H, JH,H = 4.9 Hz);
8.39 (s, 2 H, OH). Found: m/z 942.5551 [M]+. C62H74N2O6.
Calculated: M = 942.5547.
=
4
3
4
3
1
5,17ꢀDiꢀtertꢀbutylꢀ11,23ꢀdinitroꢀ25,27ꢀdihydroxyꢀ26,28ꢀ
bis(Nꢀbenzoylaminoethoxy)calix[4]arene (2). A mixture of
5,11,17,23ꢀtetraꢀtertꢀbutylꢀ25,27ꢀdihydroxyꢀ26,28ꢀbis(Nꢀbenꢀ
zoylaminoethoxy)calix[4]arene (1) (0.47 g, 0.5 mmol), CH2Cl2
(50 mL), glacial AcOH (2.9 mL, 50 mmol), and 65% HNO3
(5 mL, 8.0 mmol) was stirred for 30 min at ~20 °C and then
poured into water (50 mL). The organic layer was twice
washed with water and dried with MgSO4. The solvent was
removed in vacuo, and the residue was recrystallized from a
CH2Cl2—hexane mixture. The yield was 0.11 g (28%), m.p.
135 °C. Found (%): С, 70.39; Н, 6.15; N, 6.12. C54H56N4O10.
lated (%): С, 80.93; Н, 8.00; N, 3.37. H NMR (CDCl3), δ:
0.93, 1.30 (both s, 18 H each, CMe3); 3.33 (d, 4 H, ArCH2(eq)Ar,
2JH,H = 13.4 Hz); 4.25 (d, 4 H, ArCH2(ax)Ar, 2JH,H = 13.4 Hz);
5.07 (s, 4 H, O—CH2Pyr); 6.79 (s, 4 H, ArH); 6.97 (s, 2 H,
OH); 7.07 (s, 4 H, ArH); 7.64, 8.63 (both d, 4 H each, C5H4N,
3JH,H = 6.1 Hz). Found: m/z 830.5028 [M]+. С56Н66N2О4. Calꢀ
culated: M = 830.5023.
5,11,17,23ꢀTetraꢀtertꢀbutylꢀ25,27ꢀdihydroxyꢀ26,28ꢀ
bis(pentafluorophenylmethoxy)calix[4]arene (5). A mixture
of
5,11,17,23ꢀtetraꢀtertꢀbutylꢀ25,26,27,28ꢀtetrahydroxyꢀ
calix[4]arene (1.0 g, 1.54 mmol), the appropriate alkyl bromide
(3.24 mmol), and anhydrous K2CO3 (1.7 g, 13.9 mmol) in MeCN
(30 mL) was refluxed with stirring for 12 h. Then the solvent was
removed, and the dry residue was treated with a 5 М solution of
HCl (10 mL) and CHCl3 (50 mL). The organic phase was sepaꢀ
rated, triply washed with water (30 mL), and dried above moꢀ
lecular sieves 4 Å. After the solvent was removed, the residue
was recrystallized from a CHCl3—MeOH mixture. The yield
was 1.33 g (85.5%), m.p. 222 °С. Found (%): С, 68.73; Н, 5.85.
С58Н58F10О4. Calculated (%): С, 69.04; Н, 5.79. 1H NMR
(CDCl3), δ: 0.94, 1.30 (both s, 18 H each, CMe3); 3.28 (d, 4 H,
Calculated (%): С, 70.42; Н, 6.13; N, 6.08. 1H NMR (CDCl3),
2
δ: 1.01 (s, 18 H, CMe3); 3.49 (d, 4 H, ArCH2(eq)Ar, JH,H
=
=
3
3
13.4 Hz); 3.82 (dt, 4 H, СН2—N, JH,H = 4.8 Hz, JH,H
3
5.5 Hz); 4.12 (t, 4 H, O—СН2, JH,H = 4.8 Hz); 4.18 (d, 4 H,
ArCH2(ax)Ar, JH,H = 13.4 Hz); 6.90, 7.30 (both m, 4 H each,
2
ArH); 7.44 (m, 2 H, ArH); 7.69 (t, 2 H, N—H, 3JH,H = 5.5 Hz);
7.86 (d, 4 H, ArH, 3JH,H = 7.5 Hz); 8.04 (s, 4 H, ArH); 8.94 (s,
2 H, OH). Found: m/z 920.4001 [M]+. C54H56N4O10. Calcuꢀ
lated: M = 920.3996.
5,11,17,23ꢀTetraꢀtertꢀbutylꢀ25,27ꢀdihydroxyꢀ26,28ꢀbis(Nꢀ
octylaminocarbonylmethoxy)calix[4]arene (3). A mixture of
5,11,17,23ꢀtetraꢀtertꢀbutylꢀ25,27ꢀdihydroxyꢀ26,28ꢀbis(ethoxyꢀ
carbonylmethoxy)calix[4]arene7 (6) (1.58 g, 2.16 mmol),
nꢀoctylamine (9.5 mL, 57.5 mmol), and NH4Cl (0.16 g,
2.96 mmol) was stirred with refluxing for 2.5 h. Then volatiles
were distilled off in vacuo, and the residue was washed with
water (2×10 mL) and 1 M HCl (3×10 mL). The reaction mixture
was separated by flash chromatography on silica gel L 5—40 µm
(30 g) using successive elution with 10ꢀmL portions of
CHCl3—PriOH (2 : 1, 1 : 1, 1 : 2) mixtures. The solvent was
removed in vacuo. The residue as a colorless glassy mixture was
dried in vacuo (0.001 Torr) at 100 °С for 12 h. The yield was 1.10 g
(60%). Found (%): С, 77.37; Н, 9.85; N, 2.51. C64H94N2O6.
Calculated (%): C, 77.80; H, 9.59; N, 2.84. 1H NMR (CDCl3),
2
ArCH2(eq)Ar, JH,H = 13.09 Hz); 4.22 (d, 4 H, ArCH2(ax)Ar,
2JH,H = 13.09 Hz); 5.09 (s, 4 H, O—CH2); 6.39 (s, 2 H, OH);
6.75, 7.06 (both s, 4 H each, ArH). Found: m/z 1008.4179 [M]+.
С58Н58F10О4. Calculated: M = 1008.4175.
5,11,17,23ꢀTetraꢀtertꢀbutylꢀ25,26,27,28ꢀtetrakis(2ꢀoxoꢀ
propꢀ1ꢀyloxy)calix[4]arene (8). A mixture of 5,11,17,23ꢀtetraꢀ
tertꢀbutylꢀ25,26,27,28ꢀtetrahydroxycalix[4]arene
(1
g,
1.54 mmol) and K2CO3 (1.26 g, 9.25 mmol) in MeCN (70 mL)
was refluxed with stirring for 1 h. Then bromoacetone (0.8 mL,
9.25 mmol) was added with vigorous stirring. The reaction mixꢀ
ture was stirred for 9.5 h at the boiling temperature of the solvent
and filtered through the Celite layer 1.5 cm thick. The precipiꢀ
tate was washed with CHCl3 (3×20 mL), and the solvent was
removed under a reduced pressure. 1 M HCl (20 mL) and CHCl3
(30 mL) were added to the residue, and the mixture was exꢀ
3
δ: 0.84 (t, 6 H, Me(CH2)7, JH,H = 6.9 Hz); 1.05, 1.27 (both s,

1174
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 6, June, 2004
Stoikov et al.
tracted for 30 min. The organic layer was separated and dried
with MgSO4, and the solvent was removed. The dry residue was
recrystallized from a CHCl3—EtOH mixture, and a white crysꢀ
talline substance was obtained. The yield was 1.21 g (90%), m.p.
216—217 °С (Ref. 9: m.p. 204—207 °С). Found (%): С, 77.30;
H, 8.18. C56H72O8. Calculated (%): С, 77.03; Н, 8.31. 1Н NMR
(CDCl3), δ: 1.07 (s, 36 Н, CMe3); 2.21 (s, 12 Н, Me); 3.18 (d,
2
4 H, ArCH2(eq)Ar, JH,H = 13 Hz); 4.81 (d, 4 H, ArCH2(ax)Ar,
2JH,H = 13 Hz); 4.88 (s, 8 Н, O—CH2); 6.80 (s, 8 Н,
ArH). Found: m/z 872.5223 [M]+. C56H72O8. Calculated:
M = 872.5227.
5,11,17,23ꢀTetraꢀtertꢀbutylꢀ25,27ꢀdihydroxyꢀ26,28ꢀ
bis(ethoxycarbonylmethoxy)calix[4]arene7 (6), 5,11,17,23ꢀ
tetraꢀtertꢀbutylꢀ25,26,27,28ꢀtetrakis(ethoxycarbonylꢀ
methoxy)calix[4]arene10 (7), and 5,11,17,23ꢀtetraꢀtertꢀbutylꢀ
25,26,27,28ꢀtetrakis(ethoxycarbonylmethoxy)ꢀ2,8,14,20ꢀtetraꢀ
thiacalix[4]arene11 (9) in the cone conformation were syntheꢀ
sized according to previously described procedures.7,10,11
Experiments on membrane transfer. Transfer rates of subꢀ
strates through liquid impregnated membranes were measured
in a glass vertical diffuse cell, whose temperature was mainꢀ
tained constant, with a movable cylinder.12 The Millipore Type
FA porous Teflon filters (thickness 1 µm, pore size 100 nm,
porosity 85%) served as hydrophobic matrices. They were reinꢀ
forced with a capron mesh and impregnated with the liquid
matrix. The ratio of volumes of the feeding and receiving phases
was 5 : 1, which provided the equal levels of solutions to elimiꢀ
nate osmotic acid transfer. Experiments on mass transfer were
carried out under normal conditions (25 °C). A liquid memꢀ
brane was a 0.05 М solution of carriers 1—9 in an organic solꢀ
vent or a pure solvent (оꢀnitrophenyl octyl ether).
Procedure of experiments on membrane transfer. The startꢀ
ing solution of a substrate was placed in the external vessel with
a constant temperature, and the internal vessel was filled with
bidistilled water. Source and receiving solutions were magnetiꢀ
cally stirred. The concentrations of substances were determined
from the conductance of the solutions. The calibrating plots
were reproduced three times. Experiments on membrane transꢀ
fer were triply reproduced under the same conditions. The error
of determination of the mass transfer flux ji was 10%.
Fig. 1. Models assumed for binding of organic acids by
calix[4]arenes 1,3ꢀdisubstituted at the lower rim: comꢀ
plexes A and B.
forms,2—7 we proposed two models (A and B, Fig. 1) for
molecular recognition of dicarboxylic, αꢀhydroxy, and
αꢀamino acids by 1,3ꢀdisubstituted calix[4]arenes. The
basic distinction of these schemes is the different orientaꢀ
tion of a substrate with respect to the "host" molecule,
namely, interaction of the "docking" (A) or "tweezers" (B)
type. In the first model (see Fig. 1, A), an acid is recogꢀ
nized simultaneously by the phenylic hydroxyls of the
macrocycle and functional groups of the lateral substituꢀ
ents (R). In another scheme (see Fig. 1, B), the R subꢀ
stituents at the lower rim of calix[4]arene operate as a
"tweezers" or a "twoꢀhanded" podand, performing the
ditopic interaction of binding sites of the "host" with both
functions of the "guest." We chose mꢀcyclophanes 1—9 to
accomplish both types of interaction ("docking" and
"tweezers").
Compounds 1—9, which are calix[4]arene and thiaꢀ
calix[4]arene derivatives, were synthesized to vary such
characteristics as the lipophilicity, acidꢀbase properties of
phenol groups, number of fragments at the lower rim (diꢀ
and tetrasubstituted), nature of functional groups of subꢀ
stituents, macrocycle size (on going from calixarene to its
thia analog), sequence of atoms in the amide groups, and
distance between the amide and hydroxy groups of the
macrocycle.
UV experiments on complexation. Electronic absorption specꢀ
tra were recorded on a Perkin—Elmer Lambdaꢀ35 spectrometer
(l = 1 cm). The molar absorption coefficient of calix[4]arene 4
(ε = 5526.3 mol–1 L cm–1 in CH2Cl2) was measured at the waveꢀ
length λ
= 259.03 nm. Solutions of carboxylic acids, which
max
were used as substrates, in CH2Cl2 do not absorb in this spectral
region.13
The reaction of benzoic anhydride with
5,11,17,23ꢀtetraꢀtertꢀbutylꢀ25,27ꢀdihydroxyꢀ26,28ꢀ
bis(aminoethoxy)calix[4]arene8 in benzene gives comꢀ
pound 1. Product 2 was synthesized by the nitration of
macrocycle 1 with nitric acid at room temperature.16 The
selective alkylation17 of pꢀtertꢀbutylcalix[4]arene and
pꢀtertꢀbutylthiacalix[4]arene with the corresponding haloꢀ
derivatives resulted in a series of compounds 4—9 in the
cone conformation18 in 60—90% yields. Diamide 3 was
obtained by heating of 6 with excess amine. The composiꢀ
tions and the structures of the synthesized compounds
Procedure of experiments on measuring the stability conꢀ
stant.14 A solution of receptor 4 in CH2Cl2 with a concentration
of 1•10–4 mol L–1 was added to 1000ꢀfold excess of carboxylic
acid, and the solution was magnetically stirred for 4 h. Then the
solution was filtered to remove uncomplexed acid. Electronic
absorption spectra of the starting solution of macrocycle 4 and
the complexes were recorded, as well as solutions of the comꢀ
plexes diluted by 1.25, 1.43, 1.67, 2.00, 2.50, 3.33, 5.00, and
10.00 times. The results were processed as described previously.15
Results and Discussion
1
Based on analysis of approaches to design of synthetic
were confirmed by the data of Н NMR spectroscopy,
receptors of carboxylic acids using mꢀcyclophane platꢀ
mass spectrometry, and elemental analysis. The cone conꢀ

Synthetic receptors based on calix[4]arenes
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 6, June, 2004
1175
substrates 10—17 (glutamic acid (10), sodium acetate (11),
and tartaric (12), oxalic (13), glycolic (14), malonic (15),
succinic (16), and mandelic (17) acids) are presented in
Table 1.
Liquid membranes were 0.05 М solutions of comꢀ
pounds 1—9 in oꢀnitrophenyl octyl ether impregnated in
pores of Teflon filters.12 The membrane extractions of
glutamic acid 10 and sodium acetate 11 were studied to
estimate the influence of the carboxylate functions on the
mass transfer of carboxylic acids by the carriers studied.
The initial concentration of substrates 10—17 in the source
Comꢀ
pound
X
R1
R2
R3
phase was 0.1 mol L–1
.
1
2
3
4
5
6
7
8
9
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
S
But
NO2
But
But
But
But
But
But
But
CH2CH2NHꢀC(O)ꢀPh
CH2CH2NHC(O)Ph
CH2C(O)NH(CH2)7Me
4ꢀCH2Pyr
H
H
H
H
H
H
The fluxes (ji) through the membrane were calculated
from the initial linear regions of the time plot of the
concentration of the transferred substance in the receivꢀ
ing phase. Table 1 also contains the fluxes of the "blank"
experiment (j0) in which the membrane was the pure solꢀ
vent, оꢀnitrophenyl octyl ether. The incorporation of carriꢀ
ers 1—9 into the membrane phase gives different enhanceꢀ
ment factors for transfer (ε = ji/j0) of substrates 10—17
through the liquid impregnated membranes (Fig. 2). It
should be noted that there was no dependence between
logP of the "guest" (P is the partition constant of acids in
the twoꢀphase octanol—water system, which characterꢀ
izes lipophilicity) and the enhancement factors for the
studied acids (Table 2). Insignificant enhancement facꢀ
tors are observed in the case of the most lipophilic subꢀ
stance among the substrates studied (mandelic acid).
To study the ability of calix[4]arene to bind carboxylic
acids only due to the interaction with two hydroxy groups
at the lower rim, we synthesized mꢀcyclophane 5 with two
pentafluorophenyl groups, which cannot bind substrates
10—17 because of the electronꢀdeficient character of the
substituents and their inability to manifest either protonꢀ
donor or protonꢀacceptor properties. The incorporation
of 5 into the membrane phase did not change the transfer
rates of all substrates under investigation. Therefore, inꢀ
teractions of the substrates only with the hydroxy groups
CH2C6F5
CH2C(O)OEt
CH2C(O)OEt
CH2C(O)Me
CH2C(O)OEt
CH2C(O)Me
CH2C(O)OEt
CH2C(O)OEt
formation18 for compounds 1—8 was established from
signals of the bridging methylene protons of the macroꢀ
cycles appeared as a spin AB system in the Н NMR
spectra.
1
To estimate a possibility of formation of different types
of complexes, we calculated the models proposed for bindꢀ
ing of organic acids by 1,3ꢀdisubstituted calix[4]arenes by
the molecular mechanics (MM+) and semiempirical PM3
methods (see Fig. 1). Simulation of the complexes of mꢀ
cyclophanes 1—9 with the substrates showed that both
the first (A) and second types of binding (see Fig. 1, B) are
possible for interaction with different substrates.
The complexing ability of synthesized mꢀcyclophanes
1—9 with respect to some carboxylic acids was studied by
the membrane extraction method. We carried out experiꢀ
ments on induced (by calix[4]arenes 1—9) transport of
dicarboxylic, αꢀhydroxy, and αꢀamino acids through liꢀ
pophilic liquid membranes. The flux values measured for
Table 1. Mass transfer fluxes (ji/kmol m–2 s–1) of substrates 10—17 through the liquid impregnated membrane (25 °С)a
Subꢀ
ji
strate
b
j0
1
2
3
4
5
6
7
8
9
10 2.8•10–12 2.8•10–12 3.5•10–11 2.8•10–12 2.8•10–12 2.8•10–12 3.2•10–11 2.8•10–12 2.8•10–12 2.8•10–12
11 1.3•10–11 1.3•10–11 1.3•10–11 1.8•10–10 2.8•10–12 1.3•10–11 3.0•10–10 1.3•10–11 1.3•10–11 1.3•10–11
12 4.4•10–12 2.2•10–10 1.7•10–11 4.4•10–12 4.6•10–12 4.4•10–12 4.4•10–12 4.4•10–12 4.9•10–12 2.3•10–11
13 5.0•10–12 1.7•10–11 5.0•10–12 1.2•10–11 1.4•10–9
5.0•10–12 5.0•10–12 5.0•10–12 3.0•10–10 7.7•10–10
14 9.4•10–12 5.3•10–11 9.4•10–12 4.2•10–11 5.0•10–11 9.4•10–12 3.6•10–11 9.4•10–12 2.0•10–11 4.3•10–11
15 2.9•10–11 1.9•10–10 6.7•10–11 2.9•10–11 9.9•10–11 2.9•10–11 2.8•10–11 2.9•10–11 6.3•10–11 1.5•10–10
16 1.3•10–11 4.4•10–11 1.3•10–11 3.0•10–11 1.4•10–11 1.3•10–11 1.4•10–11 1.3•10–11 1.3•10–11 5.5•10–11
17 1.5•10–9
3.5•10–9
1.5•10–9
4.1•10–9
2.8•10–12 1.5•10–9
4.8•10–9
1.5•10–9
1.5•10–9
3.3•10–10
a The error in determination of the mass transfer fluxes is 10%. Surface area of the membrane S = 9.616 cm2.
b The flux of acid through the membrane containing no carrier (kmol m–2 s–1).

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Stoikov et al.
A
1.3
1.2
1.1
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
2
ε
3
4
200
150
100
50
5
9
8
6
7
6
1
5
4
3
10
11
2
1
12
13
14
15
16
Organic acids
17
Fig. 2. Enhancement factors of flux for several organic subꢀ
strates 10—17 through the liquid impregnated membrane conꢀ
taining carriers 1—9.
260
280
300
310 ν/nm
Fig. 3. UV spectra of solutions of calix[4]arene 4 (1) and its 1 : 1
complexes with some organic acids: oxalic (2), malonic (3),
glycolic (4), tartaric (5), and succinic (6).
Table 2. Acid equilibrium constants and lipophilicity of subꢀ
strates 10—17
Substrate
pKa
logP
changes in the UV spectrum of calix[4]arene 4 upon inꢀ
teraction with several acids are caused by the involvement
of a lone electron pair of the nitrogen atom (by the change
in the hybridization of the sp2ꢀhybrid orbital)13 in the
interaction with the carboxy group of the substrate. The
changes in the absorption spectra of calix[4]arene 4 in
the presence of several organic acids are presented in
Fig. 3. The absorption intensity decreases in the series
oxalic > malonic > glycolic > tartaric, succinic acids,
which is related to weakening of the interaction between
the substrate and receptor. The fluxes of the acids through
the membrane decrease in the same sequence, i.e., the
stability of the complexes and transport properties change
in parallel. This dependence indicates that the extraction
of acids from the aqueous phase to the lipophilic organic
membrane is the limiting step of mass transfer.
The stability constants of the complexes with
calix[4]arene 4 formed in CH2Cl2 were determined for
oxalic and glycolic acids by the dilution method14:
(1.2 0.15)•105 and (2.8 0.4)•104 mol L–1, respectively.
According to the published data,5 the stability constant
obtained for acid 13 ranges within the magnitudes charꢀ
acteristic of efficient carriers in the dynamic transfer proꢀ
cess of substances though the liquid membrane. In fact,
the histogram (see Fig. 2) shows that 1,3ꢀdisubstituted
calix[4]arene 4 with the pyridine fragments was found to
be the most efficient and selective carrier. It transfers the
strongest acid (oxalic) with a flux enhancement factor
Glutamic acid (10)
Sodium acetate (11)
Tartaric acid (12)
Oxalic acid (13)
Glycolic acid (14)
Malonic acid (15)
Succinic acid (16)
Mandelic acid (17)
4.33
—
–4.6
–4.24
–1.96
–1.88
–1.02
–0.49
–0.47
0.64
3.03
1.25
3.83
2.85
4.21
3.37
at the lower rim of 1,3ꢀdisubstituted calix[4]arene are
insufficient for binding and extraction of hydrophilic carbꢀ
oxylic acids into the lipophilic membrane phase.
It was of interest to study macrocycles with nitrogenꢀ
containing functional fragments (amide (1—3) and pyriꢀ
dine (4)), because the most part of presently known modꢀ
els of receptors for organic acids are nitrogenꢀcontaining
compounds.2,3
The complexing ability of carrier 4 with the pyridine
fragments at the lower rim was preliminarily studied by
UV spectroscopy in CH2Cl2 (Fig. 3). The absorption specꢀ
trum of mꢀcyclophane 4 is a superposition of the absorpꢀ
tion spectra of the benzene rings of the macrocycle and
monosubstituted pyridine. The binding of organic acids
10—17 by calix[4]arene 4 was shown to be accompanied
by an increase in the intensity of the absorption bands of
the receptor (n→πꢀtransition) with maxima at 259 and
263 nm and the hypsochromic shift of the bands. The

Synthetic receptors based on calix[4]arenes
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 6, June, 2004
1177
are bound with the amide groups. The distance between
the lateral binding sites of macrocycle 1 corresponds to
the substrate length, and the carboxy groups of compound
13 form hydrogen bonds with the amide substituents of
the receptor (see Fig. 5). When a complex of type A
is formed (see Fig. 1), only the amide fragments of
calix[4]arene and only one carboxy group of the acid can
be involved in binding due to discrepancy between the
interaction sites of receptor 1 and acid 13. According to
the simulation results, this structure is less favorable than
the preceding one. It is most likely that the sharp increase
in the oxalic acid flux (almost 50ꢀfold) is related precisely
to the formation of a complex of type B.
a
Malonic acid (15) (ε = 7) is the next substance in
efficiency of transfer by mꢀcyclophane 1 through the liqꢀ
uid membrane. In the case of malonic acid, the calculaꢀ
tions showed that one carboxy group of this substrate can
be involved in hydrogen bonding with the hydroxy groups
of calix[4]arene, while the second carboxy group can form
hydrogen bonds with both amide fragments. It should be
noted that the interaction of both carboxy groups of sucꢀ
cinic acid (16) with "host" 1 via both A and B types is
hindered for steric reasons (ε = 3). Therefore, when bindꢀ
ing occurs via the "docking" type (see Fig. 1, A), the
interaction with malonic acid is the most efficient. Thus,
molecular simulation showed that the formation of a comꢀ
plex by substrate binding via the "tweezers" type (see
Fig. 1, B) is possible only for oxalic acid, and complexes
can be formed via the "docking" type (A) with an increase
in the length of dicarboxylic acid.
b
Fig. 4. Results of PM3 simulation of the 5,11,17,23ꢀtetraꢀ
tertꢀbutylꢀ25,27ꢀdihydroxyꢀ26,28ꢀbis(pyridinꢀ4ꢀylmethoxy)caꢀ
lix[4]arene complexes with oxalic (a) and glycolic (b) acids.
To confirm the binding scheme A for carrier 1, we
synthesized calix[4]arene 2 containing nitro groups at the
upper rim of the macrocycle in order to change the acidꢀ
base properties of phenol groups. The incorporation of
compound 2 into the membrane phase changes the
fluxes substantially compared to those for carrier 1. For
mꢀcyclophane 2, the enhancement factors of transfer for
substrates 11—17 turned out to be close to unity, i.e., the
carrier exerts no effect on mass transfer. This can be exꢀ
plained by the fact that the hydroxy functions of comꢀ
pound 1 are involved in substrate binding (i.e., scheme A
takes place) as proton acceptors rather than proton doꢀ
nors. At the same time, an increase in the acidity of the
phenol groups in 2 increased the flux of glutamic acid
(10) by 25 times, which is related to the enhancement of
interaction with the carboxylate group. It is most likely
that the carboxylate function binds to the acidic phenol
groups as proton donors, and the ammonia and carboxy
groups of the acid are bound to the amide fragments of
calix[4]arene via scheme A.
of 277, while for the next substrate (glycolic acid) the flux
enhancement factor is only 5.
The results of simulation of oxalic acid—calix[4]arene
4 complex are presented in Fig. 4. Both carboxyl groups of
the substrate can form hydrogen bonds with the nitrogen
atoms of the pyridine ring. Although this type of bonding
(see Fig. 1, B) is also possible for malonic and succinic
acids, the results of membrane extraction indicate that the
geometric complementarity of the binding sites and
strength of the acids are primary in the case. Oxalic acid,
being the strongest, conformationally more rigid, and more
preorganized, is more efficiently transferred.
The selectivities of macrocycles 1—3, which bear the
amide function at the lower rim, differ substantially. The
incorporation of carrier 1 into the membrane increases
the fluxes for all substrates studied. In the case of oxalic
acid (13) (see Fig. 2), the transfer rate 50ꢀfold increased,
while those for hydroxycarboxylic (glycolic (14) and manꢀ
delic (17)), dicarboxylic (malonic (15), and succinic (16))
acids increased only by at most 7 times. This agrees well
with the results of molecular simulation (Fig. 5), because
a complex of type B (see Fig. 1) can be formed only in the
case of oxalic acid when both carboxy groups of the acid
The influence of the sequence of atoms in the lateral
amide fragments in 1,3ꢀdisubstituted calix[4]arenes on
the complementarity to substrates 10—17 was studied for
macrocycle 3. We synthesized mꢀcyclophane 3 with a
different sequence of atoms in the amide groups and a

1178
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 6, June, 2004
Stoikov et al.
Fig. 5. Results of PM3 simulation of the 5,11,17,23ꢀtetraꢀtertꢀbutylꢀ25,27ꢀdihydroxyꢀ26,28ꢀbis(Nꢀbenzoylaminoethoxy)calix[4]arene
complexes with malonic and oxalic acids.
shorter distance between the amide and hydroxy groups
of the macrocycle. It turned out that diamide 3 with the
shortest spacer and different orientation of the amide fragꢀ
ments does not accelerate the transfer of the substrates
under study through the lipophilic liquid membrane, exꢀ
cept for sodium acetate, i.e., it is efficient for binding of
the carboxylate function. It should be noted that we have
previously shown7 that calix[4]arene 6 containing the proꢀ
tonꢀacceptor (ester) groups at the lower rim manifested a
capability of transferring substrates containing the carꢀ
boxylate function, viz., glutamic acid and sodium acetate.
To understand the mechanism of transfer of sodium acꢀ
etate, it is important to answer the question how the transꢀ
fer of substrate 11 through the lipophilic membrane by
synthetic receptor 6 occurs: due to the interaction with
the acid anion or metal cation? The fact favoring the
interaction of calix[4]arene 6 exactly with the acetate anꢀ
ion is the absence of its influence on the flux of sodium
bromide through the membrane,7 although the lipoꢀ
philicities (logP) of the Br– and MeCO2– anions are close.

Synthetic receptors based on calix[4]arenes
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 6, June, 2004
1179
Additional experiments were carried out to study a
possibility of involvement of sodium cations in the transꢀ
fer of the substrates under investigation by calix[4]arenes
through the lipophilic membrane. It is well known that,
unlike the 1,3ꢀdisubstituted derivatives, calix[4]arenes
tetrafunctionalized at the lower rims (tetraesters, tetraꢀ
ketones) are more efficient and selective receptors for
alkali metal cations.6,19 As compared to tetraesters, tetraꢀ
ketones based on calix[4]arenes are stronger extragents of
Na+.19—21 Therefore, it was of interest to study the transꢀ
fer of both sodium acetate 11 and substrates 10, 12—17 by
tetraether 7 and tetraketone 8.
Our experiments on membrane extraction demonꢀ
strated the complete absence of any effect of calix[4]arenes
7 and 8 on the transfer of compound 11 through the
lipophilic membrane. This additionally indicates that the
transfer of compound 11 by macrocycles 2 and 6 is caused
by binding of the carboxylate group of the substrate with
the receptor. Thus, it can be concluded that 1,3ꢀdisubstiꢀ
tuted calix[4]arenes containing the OCH2C(O)XAlk fragꢀ
ment (X = O or NH) at the lower rim are capable of
molecular recognition of the carboxylate group.
The study of tetraether 7 and tetraketone 8 as carriers
showed the fundamental difference in their transport propꢀ
erties in the case of transfer of carboxylic acids under
study. Compound 7 turned out to be inactive as a carrier
of substrates 12—17, i.e., the macrocycle does not bind
these organic acids. At the same time, the incorporation
of compound 8 into the liquid membrane almost 60ꢀfold
increases the oxalic acid flux, and a high selectivity is
observed. The enhancement factors of flux for other subꢀ
strates do not exceed 2.3. Taking into account that the
energy of formation of a hydrogen bond between acetone
and the hydroxy group of the ROH compound is someꢀ
what higher than that of hydrogen bond formation beꢀ
tween the hydroxy group of ROH and ethyl acetate
(–∆G25 °C 1.8 and 1.4 kcal mol–1, respectively),21 we can
assert that the high energy of hydrogen bond formaꢀ
tion between the hydroxy groups of the substrates and
the substituents of calixarene 8 makes a certain contriꢀ
bution to complexation. However, such an insignificant
increase in the protonꢀacceptor ability of the carbonyl
group cannot induce a sharp change in the transfer propꢀ
erties of tetraketone 8 compared to tetraether 7. It can be
assumed that the mutual steric repulsion of the methyl
groups in compound 8 allows the protonꢀacceptor carboꢀ
nyl groups of acid 13, which is the smallest in size, to
interact. All these factors result in the appearance of the
transport capability of carrier 8. It is most likely that an
increase in the size of the pseudoꢀcavity, formed by four
carbonyl groups on going from 7 to 8, favors binding of
oxalic acid.
lengths13 from 1.54 Å (C—C) to 1.77 Å (C—S) increases
the macrocycle size. To confirm the basic influence of
exactly the distance between the carbonyl groups on the
complementarity of calix[4]arenes, tetrasubstituted at the
lower rim, to oxalic acid, we synthesized tetraester based
on pꢀtertꢀbutylcalix[4]arene (compound 9).
The replacement of the methylene bridges in carrier 7
by sulfur atoms (carrier 9) increases the size of the pseudoꢀ
cavity formed by four ester fragments. As a result, thiaꢀ
calix[4]arene 9 is capable of efficient and selective transꢀ
fer of oxalic acid (enhancement factor of flux is 154).
Thus, the kinetic study of mass transfer of the subꢀ
strates by 1,3ꢀdisubstituted calix[4]arenes through the liqꢀ
uid impregnated membranes showed that the interaction
of the substrates only with the hydroxy groups at the lower
rim of calix[4]arene is insufficient for binding carboxylic
acids. Variation of the nature of substituents in the lateral
fragments of 1,3ꢀdisubstituted calix[4]arenes makes it posꢀ
sible to construct selective receptors for compounds conꢀ
taining both the carboxyl and carboxylate functions. The
basic difference in transfer properties of synthetic recepꢀ
tors based on the calix[4]arene platform and its thia anaꢀ
log was shown for the calix[4]arenes tetrasubstituted at
the lower rim as an example.
This work was financially supported by the Ministry of
Education of the Russian Federation (Grant PD 02ꢀ1.3ꢀ
95), the Russian Foundation for Basic Research (Project
Nos. 03ꢀ03ꢀ96185 and 04ꢀ03ꢀ32178), and the Joint Proꢀ
gram of the U.S. Civilian Research and Development
Foundation (CRDF) and the Ministry of Education of
the Russian Federation in the framework of the proꢀ
gram "Research and Higher Education" (BRHE, Grant
RECꢀ007).
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Received April 27, 2004