Azomacrocyclic derivatives of imidazole: synthesis, structure, and metal ion complexation properties

Article abstract of DOI:10.1016/j.tet.2007.03.095

New azocrown ethers comprising imidazoles in the macrocycle have been synthesized. Imidazole, 2-methyl-, 4-methyl-, and 4-phenylimidazole were incorporated to form macrocyclic units by coupling with the appropriate bis-diazonium salts. The syntheses were?

Full text of DOI:10.1016/j.tet.2007.03.095

Tetrahedron 63 (2007) 4414–4421
Azomacrocyclic derivatives of imidazole: synthesis, structure,
and metal ion complexation properties
a
b
a
Ewa Wagner-Wysiecka,a, Marzena Jamrogiewicz, Marina S. Fonari and J. F. Biernat
*
ꢀ
aDepartment of Chemical Technology, Gdansk University of Technology, Narutowicza 11/12, 80-952 Gdanꢀsk, Poland
bInstitute of Applied Physics, Academy of Sciences, Kishinev, Republic of Moldova
Received 21 December 2006; revised 26 February 2007; accepted 15 March 2007
Available online 18 March 2007
Abstract—New azocrown ethers comprising imidazoles in the macrocycle have been synthesized. Imidazole, 2-methyl-, 4-methyl-, and
4-phenylimidazole were incorporated to form macrocyclic units by coupling with the appropriate bis-diazonium salts. The syntheses
were performed under high dilution conditions. The X-ray structure of a water adduct of the 21-membered crown ether derivative of 4-methyl-
imidazole 8 has been solved. Metal cation binding was investigated with the use of UV–vis spectroscopy in acetonitrile, methanol, and
methanol–water mixtures. The obtained chromoionophores were tested as ion-carriers in ion-selective membrane electrodes.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
known that the imidazole residue of histidine plays a crucial
role in zinc(II) and copper(II) metalloproteins, where com-
plexes of 2:1 (ligand:metal) stoichiometry are formed.7 In
this paper, we present the synthesis of new imidazole deriv-
atives of different macrocycle size and study their metal ion
complexation.
Since Pedersen’s discovery,1 crown ethers have been inten-
sively investigated macrocyclic compounds due to facile
synthesis and almost infinite possibilities of chemical modi-
fications. Crown ethers equipped with chromogenic resi-
due(s) enable visual or colorimetric examination of metal
cation complexation, in particular alkali metal cations, which
formerly could not be determined with the use of ‘classical’
complexing reagents. Furthermore, in the case of macrocy-
clic reagents, the complexation process is controlled by the
proper fit of cavity and ion radius. Previously, we presented
a series of chromogenic crown ethers bearing two azo units
and phenol,2 pyrrole3,4 or imidazole3 residues, all forming
inherent parts of the macrocycle. Macrocycles with azole
residue were expected to show rather increased susceptibility
to bind softer cations. In fact, the recently described pyrrole
derivatives 1–44 (Scheme 1a) selectively transport and bind
Pb2+ amongst Co2+, Ni2+, Cu2+, and Zn2+ cations. Lead(II)
selectivity was also found for ion-selective membrane elec-
trodes doped with the above pyrrole macrocycles.
2. Results and discussion
2.1. Synthesis
The title azocrown ethers were obtained by coupling imid-
azoles with the respective bis-diazonium salts (Scheme 1b
and c), analogously to previously described procedures.3 The
coupling reaction was carried out in water under high dilu-
tion conditions at a pH of about 10 (NaOH). Imidazole or its
derivatives substituted in position 2 or 4 were used as starting
materials to obtain macrocycles with azo groups in positions
4 and 5, or in positions 2 and 5 of imidazole moiety, respec-
tively. Consequently, compounds of different lipophilicity
and with different orientation of imidazole residue versus
macrocycle were obtained. By changing the length of oligo-
oxyethylene chain in bis-diazonium salts 17-, 18-, 20-,
and 21-membered chromoionophores (compounds 6–12,
18, and 19) were obtained. The extracted products were pu-
rified by column chromatography. The highest yield (55%)
was found for compound 6. Macrocycles 18 and 19 with
ethyl substituents in benzene rings were obtained by multi-
step reaction shown in Scheme 1c. The starting 3-ethylphe-
nol was nitrated to give 13, which in turn was alkylated with
1,5-dichloro-3-oxapentane or 1,8-dichloro-3,6-dioxaoctane
to produce dinitropodands 14 or 15, which were reduced
More recently,3 we reported the synthesis of analogous 18-
membered chromogenic imidazole derivative (5, Scheme 1).
This compound selectively binds sodium cations among
alkali metal cations in acetonitrile. However, the type and
location of donor atoms in the macrocycle should favor com-
plexation of 3d block metal cations.5,6 It is, for example,
Keywords: Azomacrocyclic ligands; Imidazole; Synthesis; Metal com-
plexes; X-ray structure.
* Corresponding author. Tel.: +48 58 347 2359; fax: +48 58 347 1949;
e-mail: fonia@chem.pg.gda.pl
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.095

E. Wagner-Wysiecka et al. / Tetrahedron 63 (2007) 4414–4421
4415
X
O
O
(a)
O
O
O
O
O
N
N
N
N
N
N
N
N
H
N
H
N
2. X = CH2CH2
3. X = 1,2-phenylene
4. X = 2,3-naphthylene
1
n
n
(b)
O
yield
O
O
O
5*. n = 1,
6. n = 2,
7. n = 1,
8. n = 2,
9. n = 1,
10. n = 2,
R = H
R = H
42 %
55 %
35 %
45 %
O
O
R = Me
R = Me
N
N
N
N
NH2
H2N
H
N
R = Phe 35 %
R = Phe 30 %
H
N
NaNO2
HCl
N
N
R
R
n
n
O
O
O
O
+
pH~10
O
O
11. n = 1
12. n = 2
25 %
20 %
H
N
_
Cl
_
Cl
+
CH3
[
N2
N ]
2
N
N
N
N
N
NH
CH3
N
n
n
O
(c)
O
Et
OH
Et
O
O
Et
N2H4, Pd/C
EtOH
HNO3
Et
OH
Cl
Cl
AcOH, CHCl3
K2CO3, DMF
NO2
O2N
NO2
13, 46%
14. n = 1, 62%
15. n = 2, 51%
n
n
O
O
O
Et
Et
O
O
Et
Et
O
1. NaNO2, HCl
NH2
16. n = 1
17. n = 2
H2N
NH
N
N
N
N
pH~10
2.
N
H
N
yield
18. n = 1, 43%
19. n = 2, 46%
quantitative yield
N
Scheme 1. Synthesis of azocrown ethers with imidazole residue. *Compound 5 was obtained previously.3
to diamino compounds 16 and 17. The diamines were con-
verted into bis-diazonium salts and coupled with imidazole
as described above.
for metal cation complexation studies. Binding of alkali,
alkaline earth, transition, and lead(II) cations was studied
spectrophotometrically in three different solvents: aceto-
nitrile, methanol, and mixed methanol–water (4:1, v/v) sys-
tem. In all systems no significant changes in absorption
spectra were found in the presence of lithium, sodium, potas-
sium, and magnesium cations.
2.2. X-ray structure
A single crystal of compound 8$H2O was obtained by crys-
tallization from acetone. In the solid state 8 exists in the form
of an internal hydrate stabilized by hydrogen bonds. There
are two independent molecules in the crystal lattice
(Fig. 1, left and right structures). The molecule (right) shows
disorder of one oxyethylene residue (denoted as A and B).
In acetonitrile and methanol, the original orange-red color of
the ligand changes to yellow on titration with Ca2+, Sr2+ or
Ba2+ salts, whereas titration with Co2+, Cu2+, Ni2+, Zn2+,
and Pb2+ changes it to purple-violet. The respective spectral
changes of 8 during titration are shown in Supplementary
data.
2.3. Metal cation complexation in solution—UV–vis
spectroscopy
The stoichiometry of the formed complexes was determined
from Job’s and/or molar ratio plots (not shown here) in cases
where complex absorption band does not overlap bands of
21-Membered 4-methylimidazole azocrown ether 8 (Scheme
1), as a representative of this class of compounds, was used

4416
E. Wagner-Wysiecka et al. / Tetrahedron 63 (2007) 4414–4421
Figure 1. Structure of 8$H2O: non-disordered form (left) and molecule with one disordered oxyethylene residue denoted as A and B (right) with hydrogen bonds
created by internal water molecule.
in acetonitrile it was only about 25 nm with a less distinctive
complex band (cf. Supplementary data).
Table 1. Stoichiometry and values of stability constants (log b) of com-
plexes in acetonitrile at 25ꢀ0.5 ꢁC for 8
Ion
Ca2+ Sr2+ Ba2+ Zn2+ Pb2+ Co2+ Cu2+ Ni2+
The stoichiometry of the formed complexes and the values
of their stability constant were determined as for acetonitrile
solutions. The results are listed in Table 2.
[L:M] 1:1
1:1
1:1
1:1
2:1
5.17
3.80
1:1
2:1
5.38
3.87 9.02
1:1
2:1
6.64
4.55
2:1
2:1
log b1 4.19
log b2
4.32 4.81
9.31
The spectroscopic experiments show that in methanol the
number of species under equilibrium is reduced comparing
acetonitrile. In most cases only one complex is formed:
1:1 for barium and zinc, and 2:1 (L:M) for lead and copper.
Cobalt and nickel ions appear not to be completely com-
plexed within the time scale of the initial spectrophotometric
titration; thus no reasonable values of stability constants
could be obtained. On the other hand, complexation in
acetonitrile occurs rapidly. This is in contrast with the earlier
described zinc(II), cobalt(II) or nickel(II) complexation by
pyrrole azocrowns.4
free ligand. Stability constant values for 1:1 and 2:1 ligand:
metal (L:M) complexes were calculated using Dynafit7 pro-
gram. The obtained results are listed in Table 1.
For alkaline earth cations the best fit was found for 1:1 stoi-
chiometry, whereas for cobalt(II) and nickel(II) the most
probable stoichiometry is 2:1 (L:M). On the other hand,
for lead(II), copper(II), and zinc(II) the best fit was obtained
for systems where two complexes exist: 1:1 and 2:1 (L:M).
Preliminary studies of compound 8 in aqueous methanol
showed increase of ligand absorption coefficient compared
to solutions in pure methanol and in acetonitrile. Further
titrations were performed in water–methanol system (4:1,
v/v), which was found to be the most favorable (cf. Supple-
mentary data). Table 3 compares the absorption coefficients
in the above systems.
Analogous titrations of 8 with alkaline earth metal cations
were performed also in methanol, however, only in the
case of barium ions changes in absorption spectra were suf-
ficient to estimate stoichiometry and the value of stability
constant (Table 2). Details of these experiments are shown
in Supplementary data.
Contrary to acetonitrile solutions, changes of absorption
spectra in methanol are more spectacular for Co2+, Cu2+,
Ni2+, Zn2+, and Pb2+ cations. In methanol, isosbestic points
are better pronounced than in acetonitrile; they are also fol-
lowed by larger spectral shifts. In most cases a bathochromic
shift of about 50 nm was noticed. In methanol the largest
shift, 65 nm, was found for the lead(II) complex, whereas
In water containing solvent system both lead(II) and cop-
per(II) cations formed complexes of 1:1 stoichiometry
with log b equal to 4.75 and 5.51, respectively. The spectral
shift for the copper complex is 55 nm and for lead is 61 nm
(Fig. 2).
Diversity of spectral changes upon complexation of alkaline
earth cations on one, and the remaining studied cations on
Table 2. Stoichiometry and values of stability constants of complexes in
methanol at 25ꢀ0.5 ꢁC for 8
Ion
Ca2+ Sr2+ Ba2+ Zn2+ Pb2+ Co2+ Cu2+ Ni2+
Table 3. Molar absorption coefficients for compound 8 at lmax¼492 nm
Solvent
a
a
[L:M]
log b
1:1
4.00
1:1
5.61
2:1 nd
7.67 nd
2:1
7.48
nd
nd
3max (ꢂ104)
—
—
Acetonitrile
Methanol
Methanol–water (4:1)
1.97
2.27
2.67
nd, Not determined due to slow kinetics.
Insufficient changes in absorption spectra do not allow determination
stoichiometry and the value of stability constants.
a

E. Wagner-Wysiecka et al. / Tetrahedron 63 (2007) 4414–4421
4417
(a)
(b)
1,4
1,2
1,0
0,8
0,6
0,4
0,2
0,0
1,6
1,4
1,2
1,0
0,8
0,6
0,4
0,2
0,0
300
400
500
600
700
300
400
500
600
700
wavelength [nm]
wavelength [nm]
Figure 2. Changes in absorption spectra upon titration of ligand 8 with metal perchlorates: (a) copper (cL¼6.98ꢂ10ꢃ5 mol dmꢃ3, cM¼1.87ꢂ10ꢃ3 mol dmꢃ3
)
and (b) lead (cL¼6.98ꢂ10ꢃ5 mol dmꢃ3, cM¼1.42ꢂ10ꢃ3 mol dmꢃ3) in methanol–water (4:1). The initial spectrum is that of the starting ligand and the final
corresponds to the complexed form (see Section 4).
the other side could be ascribed to the different stoichio-
metries of the formed compounds. However, taking into ac-
count HSBA theory, it is also possible that binding of
particular ions involves different parts of ligand molecule.
To distinguish between these possibilities, the complexation
Unfortunately, attempts to obtain metal complexes in form
suitable for X-ray investigations that may confirm the above
statement, failed.
2.4. Ion-selective electrodes
1
was studied by H NMR spectroscopy. To better visualize
the role of imidazole ring in complexation, in this experi-
ment 21-membered azocrown 6 with an unsubstituted imid-
azole moiety (Scheme 1b) was used. Complexes with barium
and lead(II) perchlorates were obtained using equimolar
amounts of components in acetonitrile. The solvent was
evaporated and the spectra were registered in d-acetone.
Differences in chemical shifts of particular protons of
‘free’ ligand and of its respective complexes are listed in
Table 4.
Electrodes based on pyrrole crown ethers4 (Fig. 1a) are
lead(II) selective. We carried out series of experiments to
test electrodes doped with imidazole derivatives. General
information on preparing electrodes and measurements are
described in detail in Section 4. From preliminary studies,
60% molar amount of lipophilic salt in relation to ionophore
was found to be most favorable.
Compound 5 was an inefficient ionophore as it readily leaked
to the aqueous solution in the presence of Pb2+ ions. In gen-
eral, electrodes based on smaller 17- and 18-membered ring
ionophores showed very short lifetimes (less than 24 h),
which makes their application limited. Better properties were
found for electrodes doped with the larger, 21-membered
ion-carriers. Among them, the electrode based on compound
19 possesses the best properties; however, the range of linear
response is rather narrow. Parameters of constructed elec-
trodes are listed in Table 5. The respective values of the
selectivity coefficients are summarized in Figure 3.
For the barium complex all OCH2 signals are shifted more
than the lead(II) complex. On the other hand, for the lead
complex aromatic signals are more shifted, especially the
C–H proton of the imidazole ring. These results indicate
that in both cases the contribution of different parts of the
ligand to the complex formation is not identical. This could
explain different trends of spectral changes upon com-
plexation of alkaline earth metal cations and other studied
metal ions.
Table 4. Shifts+Dd [ppm] in 1H NMR spectra for compound 6 and for its barium or lead(II) complexes in d-acetone
C
C'
B
B'
O
O
A
A'
1'
4'
1
4
O
O
2
3
2'
3'
N
N
N
N
H
N
N
5
Complex of 6 with
A,A0
0.26
0.25
w0.2
B,B0
0.33
0.33
w0.28
C,C0
0.28
1,10
2,20
3,30
4,40
5
Ba2+
0.15
0.14
0.14
0.15
0.13
0.12
0.22
0.21
w0.09
0.00
0.01
0.04
0.06
0.44
Pb2+
0.21
w0.15
w0.12
0.72

4418
E. Wagner-Wysiecka et al. / Tetrahedron 63 (2007) 4414–4421
Table 5. Linear responses and slopes for electrodes based on compound 11, 6, 8, 19, and for blank electrode
Ionophore
11
6
8
19
Blank
Linear response range
Slope [mV/dec]
ꢃ5.0 to ꢃ2.5
ꢃ5.0 to ꢃ3.0
ꢃ5.5 to ꢃ2.5
ꢃ4.5 to ꢃ3.0
ꢃ4.5 to ꢃ1.5
30.7
37.5
35.6
25.6
21.8
a UNICAM UV 300 apparatus. Mass spectra were taken on
AMD-604 apparatus and IR spectra were recorded on Gen-
esis II FTIR (Mattson) instrument. The mp (ꢁC) are uncor-
rected. Potentiometric measurements were done using 654
pH-meter (METROHM). As reference OP-08201 Ag/AgCl
electrode (Radelkis) was used. For all solutions deionized
water was used.
8
H
K
7
6
5
4
3
2
NH4
Cu
Na
H
H
Pb
Pb
Pb
Pb
H
Zn
Ba
NH4
NH4
Cd
1
0
NH4
Cd
Pb
H
Na
Cu
K
Na
K
NH4
Cu
Cd
Zn
Co
K
Ca
Sr
K
4.2. Synthesis
-1
-2
-3
-4
-5
-6
-7
Cu
Na
Zn
Ni
Co
Zn
Mg
i
N
Ba
Co
Cd
Synthesis of macrocyclic compounds was carried out analo-
gously to described earlier procedures.2,3
Ba
Co
Co
Cd
Ni
Ba
Mg
Ca
Na
Ba
Ni
Cu
Ni
Ca
Mg
Sr
Ca
Sr
Ca
Sr
Sr
Two solutions were prepared:
Mg
Zn
Mg
Solution A. To a suspension of 1,5-bis-(2-aminophenoxy)-3-
oxapentane, 1,8-bis-(2-aminophenoxy)-3,6-dioxaoctane,2,9
1,5-bis-(2-amino-5-ethylphenoxy)-3-oxapentane or 1,8-bis-
(2-amino-5-ethylphenoxy)-3,6-dioxaoctane (2 mmol) in
40 cm3 water, 1 cm3 concd hydrochloric acid was added.
The clear solution was diazotized with sodium nitrite
(0.28 g, 4 mmol) dissolved in 2 cm3 cold water.
11
6
8
19
Blank
Electrode number
pot
Figure 3. Selectivity coefficients ðlogK Þ for membrane electrodes doped
Pb;X
with compound 11, 6, 8 or 19 and blank electrode. Number of electrode
corresponds to number of ionophore (Scheme 1).
3. Conclusions
SolutionB. Imidazole, 2-methyl-, 4-methyl-or 4-phenylimid-
azole (2 mmol), and sodium hydroxide (0.2 g, 5 mmol) were
dissolved in 40 cm3 water. To the solution containing 4-phe-
nylimidazole 2 cm3 ethanol was added.
Azomacrocycles of different sizes were obtained with rela-
tively high yield (up to 55%) by coupling imidazole with
the respective bis-diazonium salts. In the solid state azo-
crown 8 existsin the form of an internal hydrate. The chromo-
genic compounds form complexes with alkaline earth metal
cations and with Co2+, Ni2+, Cu2+, Zn2+, and Pb2+. The stoi-
chiometry of the formed complexes, values of stability con-
stants, and spectral shifts are solvent dependent. The best
shape of the spectra and highest peak separations were found
in methanol–water (4:1) mixtures. Due to the selectivity of
complex formation, the 21-membered crown ether 8 could
be used as a spectrophotometric reagent for identification
and determination of Cu2+ and Pb2+ in solution. The advan-
tage is that it may be used in water containing system, impor-
tant from an analytical point of view. Electrodes with
membranes doped with macrocyclic derivatives of imidazole
are lead(II) selective, however, taking into account other
available ionophores, often with better properties,8 the appli-
cation of the presented here crown ethers is rather limited.
Ice-cold solutions A and B were added dropwise with the
same rate during 45 min to a vigorously stirred cold
(10 ꢁC) water (600 cm3) alkalized with NaOH to pH w10.
Then stirring was continued overnight. During the first 3 h
the temperature was maintained at 10 ꢁC, and then was
kept at room temperature for 12 h. The reaction mixture
was adjusted to pH w6 with acetic acid and extracted with
chloroform. The combined extracts were evaporated under
reduced pressure and the respective crowns were isolated
by column chromatography on silica gel using solvent mix-
tures of increasing polarity (methylene chloride, acetone,
and methanol).
Azocrown 5: 18-membered derivative of imidazole was
described in reference.3
4.2.1. Azocrown 6: 21-membered derivative of imidazole.
Orange-red solid crystallized from acetone; mp 161–163 ꢁC.
TLC, Rfw0.8 (CH2Cl2–methanol 15:2). 1H NMR dH (ppm):
8.15 (1H, s, ArH); 7.95 (1H, d, J¼8.3 Hz, ArH); 7.80 (1H, d,
J¼7.8 Hz, ArH); 7.50–7.35 (2H, m, ArH); 7.10–7.00 (4H,
m, ArH); 4.35–4.25 (4H, m, ArOCH2); 4.00–3.90 (4H, m,
ArOCH2CH2); 3.80 (4H, s, central OCH2CH2O). 13C NMR
dC (ppm): 68.5; 68.6; 69.5; 69.5; 70.8; 70.8; 113.6; 113.8;
116.7; 117.0; 121.6; 132.8; 134.4; 137.0; 142.3; 142.5;
146.3; 156.0; 156.7; 157.5. IR nmax (film): 3476; 1588; 1279;
1233; 1153; 1118; 1087; 1044; 756 cmꢃ1. HRMS (EI):
found [M]+¼422.1698; C21H22N6O4 requires 422.1703.
4. Experimental
4.1. General
All materials and solvents were of analytical reagent grade.
For TLC experiments aluminum plates covered with silica
1
gel 60 F254 (Merck) were used. H and 13C NMR spectra
(in CDCl3 or d-acetone as indicated) were recorded on
Varian instrument at 500 or 125 MHz, respectively. NMR
studies of barium and lead complexes of azocrown 6 were
performed in acetone. UV–vis spectra were recorded on

E. Wagner-Wysiecka et al. / Tetrahedron 63 (2007) 4414–4421
4419
1H NMR of crown ether 6 and its barium and lead(II) com-
plexes in d6-acetone; dH (ppm) is as follows:
128.9; 129.0; 133.0; 133.4; 135.3; 142.2; 142.8; 143.6;
154.7; 157.4; 158.3. IR nmax (film): 3554; 3502; 1587;
1300; 1274; 2222; 1158; 1062; 936; 758 cmꢃ1. HRMS (EI):
found [M]+¼454.1749; C25H22N6O3 requires 454.1753.
4.2.1.1. Crown 6. 8.12 (1H, s); 7.85 (1H, dd, J1¼1.5 Hz,
J2¼8.3 Hz, ArH); 7.79 (1H, dd, J1¼1.5 Hz, J2¼8.3 Hz,
ArH); 7.60 (1H, t, J¼8.3 Hz, ArH); 7.51 (1H, t, J¼8.7 Hz,
ArH); 7.33 (1H, d, J¼8.3 Hz, ArH); 7.28 (1H, d,
J¼8.7 Hz, ArH); 7.14–7.08 (2H, m); 4.41 (2H, t,
J¼4.4 Hz, ArOCH2); 4.39 (2H, t, J¼4.4 Hz, ArOCH2);
3.99 (2H, t, J¼4.4 Hz, ArOCH2CH2); 3.96 (2H, t,
J¼4.4 Hz, ArOCH2CH2); 3.82 (4H, s, central OCH2CH2O).
4.2.5. Azocrown 10: 21-membered derivative of 4-phe-
nylimidazole. Dark brownish-red solid from methylene
chloride–acetone, magenta dilute solution in acetone; mp
1
193–195 ꢁC. TLC, Rf w0.85 (CH2Cl2–methanol 15:2). H
NMR dH (ppm): 8.56–8.48 (2H, m, ArH); 8.10 (1H, d,
J¼7.8 Hz, ArH); 7.84 (1H, d, J¼7.8 Hz, ArH); 7.56–7.50
(2H, m, ArH); 7.49–7.36 (3H, m, ArH); 7.18–7.10 (4H, m,
ArH); 4.35–4.32 (4H, m, ArOCH2); 4.00–3.90 (4H, m, Ar-
OCH2CH2); 3.75 (4H, s, central OCH2CH2O). 13C NMR
dC (ppm): 29.6; 68.5; 68.5; 69.5; 70.8; 70.8; 113.6; 113.7;
117.2; 117.3; 121.7; 121.7; 128.7; 128.9; 129.2; 132.6;
134.6; 142.3; 142.5; 143.1; 156.7; 157.6. IR nmax (film):
3603; 1586; 1492; 1447; 1276; 1227; 1164; 1132; 1105;
1062; 940; 759 cmꢃ1. HRMS (EI): found [M]+¼498.2017;
C20H22N6O3 requires 498.2016.
4.2.1.2. Crown 6DBa(ClO4)2. 8.56 (1H, s); 7.85 (1H, d,
J¼7.8 Hz, ArH); 7.80 (1H, d, J¼7.8 Hz, ArH); 7.73 (1H,
t, J¼7.3 Hz, ArH); 7.63 (1H, t, J¼7.3 Hz, ArH); 7.48 (1H,
d, J¼8.3 Hz, ArH); 7.42 (1H, d, J¼8.3 Hz, ArH); 7.22–
7.17 (2H, m, ArH); 4.67 (2H, t, J¼3.9 Hz, ArOCH2);
4.64 (2H, t, J¼3.9 Hz, ArOCH2); 4.32 (2H, t, J¼3.9 Hz,
ArOCH2CH2); 4.29 (2H, t, J¼3.9 Hz, ArOCH2CH2); 4.10
(4H, s, central OCH2CH2O).
4.2.1.3. Crown 6DPb(ClO4)2. 8.82 (1H, s); 7.87 (1H, d,
J¼8.3 Hz, ArH); 7.83 (1H, d, J¼8.3 Hz, ArH); 7.79 (1H, t,
J¼7.3 Hz, ArH); 7.70 (1H, t, J¼8.3 Hz, ArH); 7.47–7.42
(2H, m, ArH); 7.26–7.20 (2H, m, ArH); 4.60 (4H, s, Ar-
OCH2); 4.25 (4H, s, ArOCH2CH2); 4.02 (4H, s, central
OCH2CH2O).
4.2.6. Azocrown 11: 17-membered derivative of 2-methyl-
imidazole. Brownish-red solid; mp 193–195 ꢁC. TLC, Rf
w0.45 (CH2Cl2–methanol 15:2). H NMR dH (ppm): 7.82
1
(2H, d, J¼7.8 Hz, ArH); 7.32–7.27 (2H, t, J¼7.3 Hz, ArH);
7.12–7.08 (2H, t, J¼7.3 Hz, ArH); 6.99 (2H, d, J¼8.3 Hz,
ArH); 4.25–4.15 (4H, m, ArOCH2); 4.00–3.85 (4H, m,
ArOCH2CH2); 2.60 (3H, s, CH3). 13C NMR dC (ppm):
15.0; 69.2; 70.0; 114.2; 121.4; 131.2; 131.6; 143.2;
147.5; 149.7. IR nmax (film): 3152; 1593; 1529; 1280;
1250; 1160; 1141; 1119; 1064; 940; 755 cmꢃ1. HRMS
(ESI): found [M+H]+¼393.1691; C20H20N6O3 requires
392.1691.
4.2.2. Azocrown 7: 18-membered derivative of 4-methyl-
imidazole. Deep red solid; mp 185–187 ꢁC. TLC, Rf w0.6
(CH2Cl2–methanol 15:2). H NMR dH (ppm): 8.00–7.80
1
(2H, m, ArH); 7.55–7.35 (2H, m, ArH); 7.20–7.05 (4H, m,
ArH); 4.35–4.30 (4H, m, ArOCH2); 4.10–3.95 (4H, m, Ar-
OCH2CH2); 2.75 (3H, s, CH3). 13C NMR dC (ppm): 12.7;
71.1; 71.3; 116.1; 116.5; 117.9; 123.0; 123.1; 133.2; 135.5,
142.7; 142.9; 157.3; 158.4. IR nmax (film): 3442; 1591; 1547;
1264; 1134; 1055; 1012; 754; 616 cmꢃ1. HRMS (EI): found
[M]+¼392.1587; C20H20N6O3 requires 392.1597.
4.2.7. Azocrown 12: 20-membered derivative of 2-methyl-
imidazole. Dark brownish-red solid; mp 135–138 ꢁC.
TLC, Rf w0.5 (CH2Cl2–methanol 15:2). 1H NMR dH
(ppm): 7.53 (2H, d, J¼7.3 Hz, ArH); 7.34 (2H, t,
J¼8.3 Hz, ArH); 7.06 (2H, d, J¼8.3 Hz, ArH); 7.01 (2H, t,
J¼7.8 Hz, ArH); 4.34–4.26 (4H, m, ArOCH2); 3.64–3.58
(4H, m, ArOCH2CH2); 3.32 (4H, s, central OCH2CH2O);
2.6 (3H, s, CH3). 13C NMR dC (ppm): 14.9; 70.5; 71.2;
117.5; 120.0; 122.0; 132.0; 145.2; 146.9; 155.5. IR nmax
(film): 3466; 1589; 1504; 1283; 1244; 1227; 1111; 1042;
941; 754 cmꢃ1. HRMS (ESI): found [M+H]+¼437.1962;
C22H24N6O4 requires 436.1962.
4.2.3. Azocrown 8: 21-membered derivative of 4-methyl-
imidazole. Dark red solid crystallized from acetone; mp
1
162–166 ꢁC. TLC, Rf w0.75 (CH2Cl2–methanol 15:2). H
NMR dH (ppm): 7.95 (1H, d, J¼8.3 Hz, ArH); 7.84 (1H, d,
J¼7.8 Hz, ArH); 7.44 (1H, t, J¼7.3 Hz, ArH); 7.35 (1H, t,
J¼7.4 Hz, ArH); 7.06–7.00 (4H, m, ArH); 4.38–4.28 (4H,
m, ArOCH2); 4.00–3.90 (4H, m, ArOCH2CH2); 3.79 (4H,
s, central OCH2CH2O); 2.80 (3H, s CH3). 13C NMR dC
(ppm): 13.2; 68.7; 68.7; 69.6; 69.7; 70.8; 70.9; 113.7;
113.9; 116.7; 117.0; 121.6; 121.7; 132.0; 134.1; 142.5;
142.7; 143.0; 147.6; 155.1; 156.4; 157.5. IR nmax (film):
3478, 1584, 1538, 1350, 1304, 1275, 1242, 1221, 1197,
4.2.8. 5-Ethyl-2-nitro-phenol (13). To a solution of 3-ethyl-
phenol (7.32 g, 60 mmol) in a mixture of 500 cm3 chloro-
form and 80 cm3 glacial acetic acid, concd nitric acid
(4.60 cm3) in acetic acid (80 cm3) was added dropwise
with stirring at room temperature. Stirring was continued
for 4 h. The mixture was diluted with water. The organic
layer was separated and washed with sodium bicarbonate
solution and evaporated. The residue was chromatographed
on column using methylene chloride–petroleum ether (1:2)
mixture as an eluent. The first fraction contains yellow
oily product. 1H NMR dH (ppm): 10.7 (1H, s, ArOH);
8.02 (1H, d, J¼8.7 Hz, ArH); 7.02 (1H, d, J¼1.9 Hz,
ArH); 6.86 (1H, dd, J¼1.9 Hz, J¼8.7 Hz, ArH); 2.70
(2H, q, J¼7.6 Hz, ArCH2); 1.30 (3H, t, J¼7.5 Hz,
ArCH2CH3). MS (EI): found [M]+¼167; C8H9NO3 requires
167.
1156, 1105, 954, 757 cmꢃ1
. HRMS (ESI): found
[M]+¼436.1956; C22H25N6O4 requires 436.1956.
4.2.4. Azocrown 9: 18-membered derivative of 4-phenyl-
imidazole. Dark red-violet solid; mp 186–190 ꢁC. TLC, Rf
1
w0.6 (CH2Cl2–methanol 15:2). H NMR dH (ppm): 8.58–
8.55 (2H, m, ArH); 8.10 (1H, dd, J1¼6.4 Hz, J2¼1.5 Hz,
ArH); 7.94–7.90 (1H, dd, J1¼6.8Hz, J2¼1.5Hz, ArH);
7.58–7.50 (3H, m, ArH); 7.49–7.42 (2H, m, ArH); 7.20–
7.10 (4H, m, ArH); 4.50–4.48 (4H, m, ArOCH2); 4.15–
4.00 (4H, m, ArOCH2CH2). 13C NMR dC (ppm): 70.2;
71.0; 71.2; 116.3; 116.5; 116.6; 116.7; 122.6; 128.5;

4420
E. Wagner-Wysiecka et al. / Tetrahedron 63 (2007) 4414–4421
4.2.9. 1,5-Bis-(5-ethyl-2-nitrophenoxy)-3-oxapentane
(14). A mixture of 5-ethyl-2-nitrophenol 13 (6.1 g,
40 mmol), anhydrous potassium bicarbonate (7.2 g,
52 mmol), and 1,5-dichloro-3-oxapentane (1.42 cm3) in
DMF (26 cm3) was heated at 140 ꢁC for 8 h. To the cooled
mixture, water was added and the product was extracted
with chloroform and purified on a short column using
methylene chloride–petroleum ether (1:1) mixture as an
eluent. Yield of yellow oily product is 62%.
J¼7.6 Hz, ArCH2); 1.25 (6H, t, J¼6.6 Hz, ArCH2CH3).
HRMS (EI): found [M]+¼388.4850; C22H32N2O4 requires
388.4842.
4.2.14. Azocrown 18: 18-membered derivative of imid-
azole. Pale-red solid; mp 220–222 ꢁC. TLC, Rf w0.7
(CH2Cl2–methanol 15:2). H NMR dH (ppm): 8.02 (1H, s,
1
ArH); 7.88 (1H, d, J¼7.8 Hz, ArH); 7.74 (1H, d,
J¼8.3 Hz, ArH); 7.35 (1H, d, J1¼8.3 Hz, ArH); 6.98–6.84
(3H, m, ArH); 4.45–4.35 (4H, m, ArOCH2); 4.05–3.95
(4H, m, ArOCH2CH2); 2.75–2.62 (4H, m, ArCH2); 1.32–
1.28 (4H, m, ArCH2CH3). IR nmax (film): 2965; 2929;
2873; 1598; 1454; 1435; 1238; 1162; 1116; 1059; 952;
856; 753 cmꢃ1. HRMS (EI): found [M]+¼434.2057;
C23H26N6O3 requires 434.2066.
1H NMR dH (ppm): 7.92–7.80 (2H, d, J¼1.7 Hz, ArH);
7.62–7.48 (2H, dd, J¼1.7 Hz, J¼8.3 Hz, ArH); 7.34–7.10
(2H, d, J¼8.3 Hz, ArH); 4.36–4.28 (4H, m, ArOCH2);
4.10–3.98 (4H, m, ArOCH2CH2); 2.73 (4H, q, J¼7.6 Hz,
ArCH2); 1.28 (6H, t, J¼7.5 Hz, ArCH2CH3). IR nmax
(film): 2968; 2939; 2876; 1606; 1589; 1551; 1425; 1348;
1282; 1262; 1178; 1138; 1092; 1046; 946; 878; 838 cmꢃ1
.
4.2.15. Azocrown 19: 21-membered derivative of imid-
azole. Red solid; mp 164–165 ꢁC. TLC, Rf w0.8 (CH2Cl2–
methanol 15:2). H NMR dH (ppm): 8.14 (1H, s ArH);
HRMS (EI): found [M]+¼404.1589; C20H24N2O7 requires
1
404.1584.
7.97 (1H, d, J¼8.3 Hz, ArH); 7.73 (1H, d, J¼7.8 Hz,
ArH); 6.92–6.84 (4H, m, ArH); 4.40–4.28 (4H, m, Ar-
OCH2); 4.00–3.90 (4H, m, ArOCH2CH2); 3.84–3.76 (4H,
s, central OCH2CH2O); 2.75–2.62 (4H, m, ArCH2); 1.32–
1.28 (6H, m, ArCH2CH3). IR nmax (film): 2963; 2927;
2899; 1598; 1576; 1454; 1431; 1280; 1246; 1233; 1168;
1116; 1103; 1055; 955; 848; 836 cmꢃ1. HRMS (EI): found
[M]+¼478.2336; C21H22N6O4 requires 478.2329.
4.2.10. 1,8-Bis-(5-ethyl-2-nitrophenoxy)-3,6-dioxaoctane
(15). This compound was obtained analogously to com-
pound (14) using 1,8-dichloro-3,6-dioxaoctane instead of
1,5-dichloro-3-oxapentane. Yield of yellow solid is 51%;
mp 78–80 ꢁC. 1H NMR dH (ppm): 7.80–7.72 (2H, d,
J¼1.8 Hz, ArH); 7.50–7.42 (2H, dd, J¼1.9 Hz, J¼7.9 Hz,
ArH); 7.28–7.14 (2H, d, J¼8.1 Hz, ArH); 4.32–4.24 (4H,
m, ArOCH2); 4.00–3.92 (4H, m, ArOCH2CH2); 3.82–3.74
(4H, m, central OCH2CH2O); 2.69 (4H, q, J¼7.6 Hz,
ArCH2); 1.26 (6H, t, J¼6.6 Hz, ArCH2CH3). IR nmax
(film): 2967; 2934; 2875; 1606; 1590; 1529; 1515; 1454;
1426; 1351; 1282; 1263; 1178; 1128; 1092; 1047; 949;
878; 838 cmꢃ1. HRMS (EI): found [M]+¼448.4289;
C22H28N2O8 requires 448.4286.
4.3. X-ray studies
All measurements were performed on a Kuma KM4CCD
k-axis diffractometer with graphite-monochromated Mo
Ka radiation. The data were corrected for Lorentz and polar-
ization effects. No absorption correction was applied. Data
reduction and analysis were carried out with the Kuma
Diffraction (Wroc1aw) programs.
4.2.11. Reduction of dinitro compounds 14 and 15 to
amines 16 and 17. To a solution of the respective dinitro
compound (2 mmol) in methanol, Pd–C was added as cata-
lyst. To the warm (50 ꢁC) reaction mixture first portion of
80% hydrazine (0.5 cm3) was added. After 1 h hydrazine
was added in next three portions of 0.5 cm3 each in 1 h inter-
vals. Reduction progress was monitored by TLC (methylene
chloride–acetone 20:1). After about 5 h (no substrate in
reaction mixture), the catalyst was filtered off and the filtrate
was evaporated under reduced pressure until first amine
crystals appear. Products were allowed to crystallize over-
night at 5 ꢁC. Pure products were obtained with 97–99%
yield.
The structure was solved by direct methods10 and refined
using SHELXL.11 The refinement was based on F2 for all
reflections with exception of those with very negative F2.
The F20>2s(F20) criterion was used only for calculation of
R factors. Some hydrogen atoms were located from a differ-
ential map and refined isotropically. The remaining hydro-
gen atoms were located in idealized averaged geometrical
positions, allowed to ride at the heavy atoms. Additionally,
disorder in the polyether linker in one of the macrocyclic
molecules with occupation factors, 0.645(1) and 0.355(1),
was solved.
4.2.12. 1,5-Bis-(2-amino-5-ethylphenoxy)-3-oxapentane
4.4. UV–vis spectroscopy
1
(16). H NMR dH (ppm): 6.98 (2H, d, J¼7.6 Hz, ArH);
6.68 (2H, d, J¼6.2 Hz, ArH); 6.44 (2H, d, J¼8.3 Hz,
ArH); 4.30–4.20 (4H, m, ArOCH2); 4.08–3.96 (4H, m,
ArOCH2CH2); 3.70 (4H, s, ArNH2); 2.70 (4H, q,
J¼7.6 Hz, ArCH2); 1.25 (6H, t, J¼6.6 Hz, ArCH2CH3).
HRMS (EI): found [M]+¼334.4379; C20H28N2O3 requires
334.4366.
The complexation studies were performed using UV–vis
spectroscopy in acetonitrile, methanol, and methanol–water
(4:1, v/v) solvent mixture. In all titration experiments ligand
concentration was about 10ꢃ5 mol dmꢃ3. Starting volume of
titrated ligand: 3 cm3. All metal perchlorates were used at
concentration of about 10ꢃ2 mol dmꢃ3. Titration step:
0.01 cm3. The values of appropriate stability constants were
calculated using Dynafit7 program. For systems where
complex absorption band do not overlap ligand band the
stoichiometry of formed compounds was additionally esti-
mated using molar ratio and/or continuous variation
methods.12
4.2.13. 1,8-Bis-(2-amino-5-ethylphenoxy)-3,6-dioxaoct-
ane (17). 1H NMR dH (ppm): 6.94 (2H, d, J¼7.8 Hz,
ArH); 6.76–6.54 (4H, m, ArH); 4.30–4.20 (4H, m, Ar-
OCH2); 4.00–3.94 (4H, m, ArOCH2CH2); 3.84–3.76 (4H,
m, central OCH2CH2O); 3.73 (4H, s, ArNH2); 2.70 (4H, q,

E. Wagner-Wysiecka et al. / Tetrahedron 63 (2007) 4414–4421
4421
4.5. Membrane electrodes and potentiometric
measurements
Supplementary data
Electronic supplementary material associated with this arti-
cle contains additional X-ray data, absorption spectra, and
spectroscopic titration experiments with metal perchlorates
in different solvents. Supplementary data associated with
this article can be found in the online version, at
doi:10.1016/j.tet.2007.03.095.
The preparation of membrane for ion-selective electrodes
was described earlier in details.13 In 1 cm3 of freshly
distilled THF 2 mg of ionophore, 50 mg PCV, 0.1 cm3 of
2-nitrophenyl-octyl ether, and potassium tetrakis(4-chloro-
phenyl)borate were dissolved. The following amounts of
lipophilic salts (% mol in relation to the ionophore):
100, 80, 70, 60, and 50 were used for membrane preparation.
Membranes were incorporated onto Ag/AgCl electrode
bodies with 5ꢂ10ꢃ3 mol dmꢃ3 PbCl2 as an internal electro-
lyte. The selectivity coefficients were determined using the
separate solution method14 employing metal nitrate
solutions of 10ꢃ2 activity at pH 5.0ꢀ0.1 (adjusted with
HNO3).
References and notes
1. Pedersen, C. J. J. Am. Chem. Soc. 1967, 89, 7017–7036.
2. Wagner-Wysiecka, E.; Skwierawska, A.; Kravtsov, V. Ch.;
Biernat, J. F. J. Supramol. Chem. 2001, 1, 77–85.
3. Wagner-Wysiecka, E.; Luboch, E.; Kowalczyk, M.; Biernat,
J. F. Tetrahedron 2003, 59, 4415–4420.
Electrodes were conditioned in 10ꢃ2 mol dmꢃ3 Pb(NO3)2
solution for 24 h, then soaked for 1 h in water (pH 5.0 from
HNO3) before taking measurements.
4. Luboch, E.; Wagner-Wysiecka, E.; Fainerman-Melnikova, M.;
Lindoy, L. F.; Biernat, J. F. Supramol. Chem. 2006, 18,
593–601.
5. Pearson, R. G. J. Chem. Educ. 1968, 45, 643–648.
6. Hay, B. P.; Hancock, R. D. Coord. Chem. Rev. 2001, 212, 61–78.
Supplementary data: It is deposited with the Cambridge
Crystallographic Data Centre with supplementary publica-
tion number CCDC 623703 (CCDC, 12 Union Road, Cam-
bridge CB2 1EZ, UK; e-mail: deposit@ccdc.cam.ac.uk).
ꢁ
7. Kuzmic, P. Anal. Biochem. 1996, 237, 260–273; http://
www.biokin.com.
8. cf. B
€uhlmann, P.; Pretch, E.; Bakker, E. Chem. Rev. 1998, 98,
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9. Skwierawska, A.; Inerowicz, H. D.; Biernat, J. F. Tetrahedron
Lett. 1998, 39, 3057–3060.
Acknowledgements
10. Sheldrick, G. M. Acta Crystallogr. 1990, A46, 467–473.
11. Sheldrick, G. M. SHELXL93. Program for the Refinement
Financial support from the Polish State Committee for
Scientific Research, Grant no. 3TO9A15127 is kindly ac-
knowledged. The authors thank Ewa Kowalska, Maria
€
of Crystal Structures; University of Gottingen: Gottingen,
€
Germany, 1993.
_
Zernicka, and Tomasz Rzymowski for remarkable experi-
12. Job, P. Ann. Chim. Phys. 1928, 9, 113–203.
13. Luboch, E.; Biernat, J. F.; Muszalska, E.; Bilewicz, R.
Supramol. Chem. 1995, 5, 201–210.
mental contributions. The X-ray measurements were under-
taken in the Crystallographic Unit of the Physical Chemistry
Laboratory at the Chemistry Department of the University of
Warsaw.
€
14. Umezawa, Y.; Buhlmann, P.; Umezawa, K.; Thoda, K.;
Amemiya, S. Pure Appl. Chem. 2000, 72, 1851–2028.