Synthesis and spectroscopic properties of new bis-tetrazoles

Article abstract of DOI:10.1007/s10847-012-0219-4

Syntheses of N,N′-phenyltetrazole podands link with aliphatic chains containing oxygen, nitrogen and sulphur atoms, are described. The complexing properties of these compounds towards metal cations (Fe²⁺, Cu ²⁺, Zn²⁺, Co²⁺, Ni²⁺) were investigated by absorption and infrared spectroscopy. The UV-Vis titrations were performed to estimate the stability constant values of the respective complexes with Cu²⁺ ion. Changes in UV-Vis absorption spectra and IR spectra of compound 6 under various concentrations of Cu²⁺ ion in methanol suggest formation of very unstable complex. The structure of ligand 2 has been deduced by X-ray crystallography. The Author(s) 2012.

Full text of DOI:10.1007/s10847-012-0219-4

J Incl Phenom Macrocycl Chem
DOI 10.1007/s10847-012-0219-4
ORIGINAL ARTICLE
Synthesis and spectroscopic properties of new bis-tetrazoles
•
Agnieszka Pazik Anna Skwierawska
Received: 19 December 2011 / Accepted: 10 July 2012
Ó The Author(s) 2012. This article is published with open access at Springerlink.com
Abstract Syntheses of N,N0-phenyltetrazole podands link
with aliphatic chains containing oxygen, nitrogen and
sulphur atoms, are described. The complexing properties of
complexes with metals and halogens. They have wide
applications as corrosion inhibitors [1], analytical reagents,
high-energy materials [2, 3] and component of ionic liquid
and gas generating compositions [4]. Tetrazoles play
important role in coordination chemistry as ligands [5], in
medicinal chemistry as metabolically stable substitutes for
carboxylic acids. However, tetrazoles themselves exhibit
no pharmacological activity; many of their derivatives
possess interesting biological (anti-hypertensive, anti-
allergic and antibiotic) activities [6]. In recent years, par-
ticular attention has been directed to mono- or bidentate
tetrazole ligands as molecular hosts in generating supra-
molecular arrays and functionalized poly-tetrazoles such as
sensors.
these compounds towards metal cations (Fe2?, Cu2?, Zn2?
,
Co2?, Ni2?) were investigated by absorption and infrared
spectroscopy. The UV–Vis titrations were performed to
estimate the stability constant values of the respective
complexes with Cu2? ion. Changes in UV–Vis absorption
spectra and IR spectra of compound 6 under various con-
centrations of Cu2? ion in methanol suggest formation of
very unstable complex. The structure of ligand 2 has been
deduced by X-ray crystallography.
Keywords Tetrazole ꢀ X-ray ꢀ IR ꢀ UV–Vis
Methods of synthesis monosubstituted tetrazoles, which
include 1-, 2- and 5-monosubstituted tetrazoles, were the
main subject of various studies. The choice of synthetic
methods of 1-substituted tetrazoles is limited. One of the
most known methods of synthesis 1-substituted tetrazoles
is cycloaddition of isocyanides to hydrazoic acid. This
method was improved replacing hydrazoic acid by a more
effective reagent, trimethylsilyl azide (Me3SiN3) [7].
Another method involves the reaction of amines with ethyl
orthoformate and sodium azide in glacial acetic acid.
Aromatic, aliphatic and heteroaromatic amines can be used
for preparation of tetrazoles and bis-tetrazole derivatives.
2-Substituted tetrazoles are usually synthesized by alkyl-
ation or acylation of tetrazole and that reactions are char-
acterized by low selectivity and poor yield. 5-Substituted
tetrazoles can be prepared in several ways; the commonest
method of synthesis involves the cycloaddition of nitriles
to azides. The reaction is general and is widely used in the
synthesis of tetrazoles derivatives in the design of new
drugs containing a tetrazole ring. Nitriles possessing vari-
ous functional groups and dinitriles can be used as initial
Introduction
Numerous proposals have been made over a considerable
period for the production of the synthetic tetrazoles from
nitriles, amines and amides. The tetrazole function is
metabolically stable and this feature and a close resem-
blance between the acidic character of the tetrazole group
and the carboxylic group has inspired syntheses of poten-
tial therapeutic agents. Due to the possibility of deproto-
nation, protonation and alkylation amongst other reactions,
the properties of tetrazoles can be considerably varied and
result in numerous possible derivatives. The tetrazole ring
is resistant to the action of acids, bases and reducing
agents. Tetrazolate anions have dual reactivity, form stable
A. Pazik (&) ꢀ A. Skwierawska
Department of Chemical Technology, Chemical Faculty, Gdansk
´
University of Technology, 80-233 Gdansk, Poland
e-mail: mikaga20@wp.pl
123

J Incl Phenom Macrocycl Chem
compounds. Interesting is synthesis of substituted tetra-
zoles in multistep reaction of aldehydes with iodine in
aqueous ammonia, followed by addition of sodium azide in
the presence of Lewis acids (e.g., ZnCl2 or ZnBr2) [8] in
the mixture of water, ammonium chloride and N,N-
dimethylformamide. In classical synthesis of tetrazoles,
hydrazoic acid or sodium azide reacts with imidoyl chlo-
ride intermediate which is formed in reaction of amide with
phosphorus(V) chloride [9]. Noteworthy is one-step con-
version of secondary monoamides to tetrazoles under
Mitsunobu reaction conditions with azides, especially with
tributyl- or trimethylsilyl azide which are safe and soluble
in organic solvents [10, 11]. An alternate method employs
trifluoromethanesulfonic anhydride and sodium azide for
imidoyl derivatives preparation, and thus is converted to
tetrazoles [12]. It is commonly known that application of
this methodology to the bisamides is impractical because of
poor yield and low solubility of this type of compounds in
the typical Mitsunobu reaction medium (e.g., anhydrous
THF or dichloromethane).
The purpose of this work was synthesis of new bis-
tetrazoles containing chains with different heteroatoms.
The structures of new compounds are presented in Fig. 1.
Influence of ligands chemical structure on cation metal
complexation was studied by means of IR and UV–Vis
spectroscopy.
Results and discussion
Synthesis
Bis-tetrazole compounds 1–7 which possess in their
structure aromatic rings linked by chains with heteroatoms,
CH3
Fig. 1 General formula of the
macrocycles
O
S
N
O
n = 0, 1, 2
O
N
O
N
O
N
O
N
O
N
O
N
O
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
1-3
4
5
O
N
S
N
S
N
S
N
S
N
N
N
N
N
N
N
N
N
N
N
N
N
6
7
n
Scheme 1 Synthesis of bis-
[2-(1H-tetrazo-1-yl)phenoxy]-
ethane derivatives
n
O
O
n
OH
O
O
O
O
O
H2N-NH2
Pd/C, i-PrOH
Cl
Cl
K2CO3, DMF
NO2
NO2
O2N
NH2
H2N
n
O
O
O
NaN3, HC(OEt)3
AcOH
1
2
3
n = 0 (99 %)
n = 1 (98.5 %)
n = 2 (97 %)
N
N
N
N
N
N
N
N
1-3
123

J Incl Phenom Macrocycl Chem
such as oxygen, nitrogen and sulphur were synthesized.
Compounds 1–3 were obtained in three-stage reaction:
alkylation of 2-nitrophenol, reduction of bis-nitroderiva-
tives follow by heterocyclic ring formation (Scheme 1).
The same procedure was applied in synthesis of com-
pounds 4 and 5, but well established reduction with hydra-
zine at presence of Pd/C catalyst was found ineffective and
SnCl2 in hydrochloric acid solution was used (Scheme 2).
Ph
(a)
N
OH
SO2Cl
Ph
N
Ph
N
O
O
NO2
C5 H5
N
, DMF
K2CO3
OH
OH
OTs
OTs
NO2
O2N
CH3
Ph
N
Ph
N
O
N
O
O
O
SnCl 2.2H 2
HCl / EtOH
O
NaN3, HC(OEt)3
AcOH
N
NH2
H2N
N
N
N
N
N
N
90.6 %
4
Ts
(b)
N
OH
SO2Cl
H
N
Ts
O
O
NO2
C5 H5N
N
K2CO3, DMF
OH
OH
OTs
OTs
NO2
O2N
CH3
Ts
Ts
N
N
O
O
O
O
SnCl2.H2
O
NaN3, HC(OEt)3
AcOH
HCl/EtOH
N
N
N
NH2
H2N
N
N
N
N
N
46%
5
Scheme 2 Synthesis of bis-[2-(1H-tetrazo-1-yl)phenoxy)-3-azapentane derivatives
Ph
Ph
(a)
N
N
Ph
N
SH
K2CO3, DMF
S
S
S
S
N
NaN3, HC(OEt)3
AcOH
HCl/MeOH
OTs
OTs
NH2
NH2
H2N
N
.2HCl
N
N
N
N
N
N
45%
6
O
O
(b)
SH
S
S
S
S
K2CO3, DMF
HCl/MeOH
NaN3, HC(OEt)3
AcOH
O
Cl
Cl
NH2
NH2
H2N
N
N
N
.2HCl
N
N
N
N
N
65%
7
Scheme 3 a Synthesis of bis-[2-(1H-tetrazo-1-yl)phenyl(thio)]-3-phenylazapentane, b synthesis of bis-[2-(1H-tetrazo-1-yl)phenyl(thio)]-3-
oxapentane
123

J Incl Phenom Macrocycl Chem
1
Fig. 2 a H NMR spectra of 6
in CDCl3, b 1H NMR spectra of
1,5-bis[2-aminophenyl(thio)]-3-
phenylazapentane
hydrochlochloride in d-MeOH
1
Ligands contain sulphur atoms were obtained in two
step reactions: selective alkylation of 2-aminotiobenzene
and amine groups transformation into tetrazole rings (see
Scheme 3).
mention that in tetrazoles’ H NMR spectra characteristic
C–H signal at 8.99–9.77 ppm is observed. As a compari-
son, two 1H NMR spectra of 1,5-bis[2-aminophenyl(thio)]-
3-phenylazapentane and 1,5-bis[2-(1H-tetrazol-1-yl)phe-
nyl(thio)]-3-phenylazapentane (6) are presented in a Fig. 2.
Singlet at 8.90 ppm corresponds to two C–H tetrazole
protons of compound 6.
In all cases tetrazole residues were obtained in reaction
of amines with ethyl orthoformate and sodium azide in
glacial acetic acid. The reaction occurs under mild condi-
tions and the yield of products is very high. The best yield
over 97 % was obtained in case of compounds 1–3. Final
products (1–5) were purified by crystallization. The com-
pounds are white (1–3) or brown (4) solids. The oil com-
pounds 6–7 were purified by column chromatography.
The infrared spectroscopy is excellent technique to
study the progress of cyclization reaction. IR Spectra of
reagents show typical amine and azide bands at ca. 3400
and ca. 2060 cm-1, respectively, which are decreased
adequately to tetrazole rings formation. It is worth to
X-ray structural analysis of the 1,5-bis[2-(1H-tetrazol-
1-yl)phenoxy]-3-oxapentane (2)
Experimental data were collected on the KM4 j-geometry
diffractometer equipped with Sapphire 2 CCD detector
(Oxford Diffraction). Enhanced Mo Ka1 X-ray radiation
source with a graphite monochromator was used. Mea-
surements were carried out in four x-scan runs—scan
width 0.758, exposure time 300 s per frame was rather long
Fig. 3 Molecular structure of 2, displacement ellipsoids drawn at
50 % probability level
Fig. 4 Stacking interactions in crystals off compound 2 in vicinity of
inversion centre
123

J Incl Phenom Macrocycl Chem
due to weak diffracting power of all the specimen. Deter-
mination of the unit cell and data collection was carried out
at room temperature, i.e., 293(2) K. All preliminary cal-
culations were performed using CrysAlis RED and Cry-
sAlis CCD software package (Oxford Diffraction, 2010).
The structure was solved by direct methods. Refinement
was made against all reflections by the full-matrix least
squares procedure based on F2. All of the non-hydrogen
atoms were refined with anisotropic thermal parameters.
Hydrogen atoms were refined as riding with isotropic
U values fixed as 1.2 times Ueq of the respective pivot
atom. Due to low value of absorption no correction was
applied. The calculations were carried out using the
SHELX-97 (G. Sheldrick, 1997) program package, run
under WinGX 1.70.00 (L. Farrugia, 1999) Windows shell
program.
Table 1 Crystal data and structure refinement for podand 2
Compound
2
Empirical formula
Formula weight
Temperature
C
18H18N8O3
394.40
297(2) K
˚
0.71073 A
Wavelength
Crystal system, space group Monoclinic, P21/c
˚
Unit cell dimensions
a = 15.0902(17) A, a = 908
˚
b = 16.7301(18) A, b = 99.260(10)8
˚
c = 7.7390(8) A, c = 908
3
˚
1928.3(4) A
Volume
Z, calculated density
Absorption coefficient
F(000)
4, 1.359 Mg/m3
0.098 mm-1
824
Crystal size
0.06 9 0.08 9 0.54 mm
2.74–26.008
h range for data collection
Limiting indices
Compound 2 crystallizes in monoclinic space group
P21/c with four molecules in the unit cell. Molecular
structure together with the atom labeling scheme is shown
in Fig. 3. The system of rings is not flat. Dihedral angle
between mean planes defined by skeletal atoms of C1–C6
phenyl ring and N1–N4–C7 tetrazole ring is equal to
24.888, and between C12 and C17 phenyl ring and N5–N8–
C18 tetrazole ring is even wider 36.038.
No classical hydrogen bonds can be found in the
structure of podand 2. Only one stronger stacking interac-
tion can be found in the structure, namely between N1–N4–
C7 tetrazole ring and C1–C6 phenyl ring from the neighbor
molecule related by the inversion centre located at (0 1/2
1/2) (symmetry code: -x, 1 - y, 1 - z). The distance of
-18 B h B 18, -13 B k B 20,
-5 B l B 9
Reflections collected/unique 7,039/3,796 [Rint = 0.0322]
Completeness to h = 26.00
Refinement method
99.9 %
Full-matrix least squares on F2
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I [ 2r(I)]
R indices (all data)
3,796/0/262
0.844
R1 = 0.0380, wR2 = 0.0652
R1 = 0.1206, wR2 = 0.0786
0.115 and -0.111 e A-3
Largest difference peak
and hole
have more degrees of freedom during complex formation.
In further studies other electron donating atoms such as
nitrogen (compounds 4 and 5) and sulfur (compounds 6 and
7) were introduced into molecule structure. That modifi-
cation should improve selective recognition of transition
and heavy metal cations.
˚
centers of gravity of the two rings is equal to 3.922 A, all
the other rings have centers at mutual distances greater than
˚
4 A. In fact two of such interactions, related by the
inversion center are operating (see Fig. 4). Summary of
crystal data and details on data collection of 2 and structure
refinement are given in Table 1.
UV–Vis Absorption spectra of ligands 1–7 show three
maxima just about 210, 240 and 280 nm in methanol
solution. Calculated value of extinction coefficients are
summarized in Table 2.
Spectrophotometric studies of the metal cation
complexation
In spectroscopic studies chlorides were used in methanol
solution. Any absorbance change in spectra of 1–7 was
observed in case of Li?, Na?, K?, Sr2?, Mg2?, and Ca2?
chlorides. We expected ligands 1–3 response, because of
In recent years the number of publications and patents
describing the structure and physicochemical properties of
ligands including in their structure tetrazole heterocyclic
fragment has grown intensely. This is due to the wide range
of practical applications of these compounds. The high
physiological activity and low toxicity of tetrazoles makes
it possible to regard their metal complexes as substances of
versatile biochemical and pharmaceutical destination.
Complex stability depends on ligands structure, essentially
position and type of electron donating atoms. Compounds
1–3 consist of two 1-N-phenyltetrazole residues linked by
polyether chain. Ligand 1 in comparison to 2 and 3 forms
the most rigged system. More flexible its analogues 1–2
Table 2 The absorption maxima (kmax) and corresponding extinction
coefficients of new bis-tetrazole in MeOH at 298 K
Compound
kmax (nm)
e (M-1cm-1
)
1
2
3
6
7
209
209
210
205
206
62,000
59,454
58,433
47,520
58,200
123

J Incl Phenom Macrocycl Chem
1,2
1,0
0,8
0,6
0,4
0,2
0,0
the presence of oxygen atoms which are hard bases
according to HSAB theory. In next experiments Fe2?
,
Co2?, Zn2?, Ni2? and Cu2? chlorides were used. Figure 5
presents spectral absorbance changes of 1–3 upon addition
of tenfold access of an appropriate salt. Bis-tetrazoles
exhibit increase of all maxima upon addition of ferrous(II)
chloride. In the presence of copper(II) chloride diminishing
of maximum at 210 nm is only observed for 1. Zinc(II) and
nickel(II) chlorides do not influence on ligands absorbance.
It is worth to note that only ligand 3 shows positive
response to cobalt(II) chloride. In the spectrum all main
absorption bands are strengthened. Further spectroscopic
titration of compounds 1–3 with ferrous(II), copper(II) and
cobalt(II) chlorides show continuous increase of the main
bands that makes determination of complexation constants
impossible. As an example ligand 2 titration with cop-
per(II) solution is shown in the Fig. 5d.
200
250
300
350
400
wavelength [nm]
Fig. 6 UV–Vis titration of 1,5-bis[2-(1H-tetrazol-1-yl)phenyl(thio)]-
3-phenylazapentane (c = 2.5 9 10-5 mol dm-3
with copper(II)
chloride (c = 10-4 mol dm-3, titration step 0.01 ml)
)
1,0
(a)
(b)
O
O
O
1,6
1,4
1,2
1,0
0,8
0,6
0,4
0,2
0,0
L
L
0,9
0,8
0,7
0,6
0,5
0,4
0,3
0,2
0,1
0,0
L+Fe2+
L+Cu2+
L+Zn2+
L+Co2+
L+Ni2+
O
O
L+Fe2+
L+Ni2+
L+Zn2+
L+Co2+
L+Cu2+
N
N
L=
N
N
N
N
N
N
N
N
N
N
N
N
N
N
250
300
350
250
300
350
L
wavelength [nm]
wavelength [nm]
1,4
1,2
1,0
0,8
0,6
0,4
0,2
0,0
(d)
(c)
1,6
1,4
1,2
1,0
0,8
0,6
0,4
0,2
0,0
O
O
L+Cu2+
L+Fe2+
L+Zn2+
L+Co2+
L+Ni2+
O
N
O
N
L=
N
N
N
N
N
N
250
300
350
210
240
270
300
330
wavelength [nm]
wavelength [nm]
Fig. 5 The changes in UV–Vis spectra in the presence of metal
chloride (tenfold excess) for compounds a 1 (c = 2 9 10-5 mol
d UV–Vis titration of 2 (c = 2.5 9 10-5 mol dm-3) with copper(II)
chloride (c = 10-4 mol dm-3, titration step 0.01 ml) in methanol at
298 K
dm-3); b 2 (c = 2.5 9 10-5 mol dm-3); c 3 (c = 2 9 10-5 mol dm-3
)
123

J Incl Phenom Macrocycl Chem
Fig. 7 IR spectra (film) of pure ligand 6 (a) compared with its complex with copper(II) (b)
(Fig. 6), increase in Cu2? concentration caused continuous
raise of absorbance maxima at 258 nm. The gradual addi-
tion of Cu2? causes also the change of color from colorless
to yellow. However after few minutes yellow color disap-
pears that may suggest formation of very unstable complex.
Plot of absorbance versus Cu2?: 6 ratio showed graduate
increase of the absorbance band at 258 nm.
In order to confirm complexation of 6 with Cu2? ion,
series of IR spectra of the ligand 6 in the presence of
copper(II) chloride have been recorded within the range of
3500–500 cm-1. We took ligand and the copper(II) chlo-
ride and dissolved separately in a small amount of chlo-
roform and methanol, respectively. The solutions were
combined, stirred, solvent was removed and residue was
dried in vacuum. Result solid was dissolved in dry CH2Cl2
and obtained solution was used for film preparation char-
acterized with IR spectroscopy as shown in Fig. 7.
Figure 7 shows the characteristic down-shifts of the
tetrazoles C–H stretching vibration at 3129 cm-1 copper(II)
coordination. The symmetry of ligand is observed in IR
spectroscopy with one large signal deriving from two tet-
razoles C–H stretching vibration. A reference spectrum was
taken from pure ligand. Figure 8 compares the C–H tetra-
zole stretching vibrations of pure ligand with the vibrations
observed of the new complex in MIR spectroscopy. Com-
plexation can be observed in the loss of stretching vibration
Fig. 8 MIR spectra (film) of compound 6 (upper spectrum) and its
complex
Very similar pattern of spectroscopic changes in
absorption spectra may suggest that polyether chain is not
engaged in complex. Another possible explanation is that
complex is formed inside of a ligand cavity. Further
nitrogen and sulfur atoms were introduce to ligands
structure to enhance affinity between ligand and metal
cation. This modification do not improved selective rec-
ognition of transition or heavy metal cations by ligands.
Compounds 4–7 were titrated with Fe2?, Co2?, Zn2?, Ni2?
and Cu2? chlorides in methanol solution. Very similar
results were obtained, with one exception. Compound 6
titrated with copper(II) chloride in methanol solution
at 3129 and the new signals can be found below 3000 cm-1
.
The occurrences of the peaks of the pure ligand at
3065 cm-1 prove incomplete complexation.
In the preliminary experiments we investigate the spec-
troscopic characterization of the ligand 2 and its complex
with ferrous(II) and ferrous(III) chloride. FT–IR Spectra of
the ligand and the complexes have been taken within the
range of 3500–500 cm-1. The spectra are depicted in Fig. 9.
The range between 1700 and 500 cm-1 is particular inter-
esting for us. The bands at 1508, 1473, 1454, 1129 cm-1 are
due to combinations of bond stretching vibrations typical for
123

J Incl Phenom Macrocycl Chem
Fig. 9 a Mid range FT-IR spectrum (film) of the ligand 2 b ligand with FeCl2 c ligand with FeCl3
123

J Incl Phenom Macrocycl Chem
coordinated tetrazole rings (Fig. 9a). The band at 1602 cm-1
is due to stretching vibration of the C=C bond from phenyl
rings. The absorption of at 754 cm-1 is typical for bond
angle deformation of the substitution tetrazole rings in the
phenyl ring. After complexation up-shift of 40 cm-1 can be
observed in the spectrum of the complexation attempt with
iron(II) and small up-shift of 3 cm-1 for iron(III). The strong
absorption at 1602 cm-1 is shifted to the 1642 cm-1. The
coordination of the tetrazole N-atom to the iron(II) can be
observed through strong force constants of the neighboring
bonds from phenyl rings. No changes in the intensities of
absorption characteristic for polyether chain can confirm our
earlier hypothesis that it is not engaged in complex.
15 mmol) was dissolved in 10 ml glacial acetic acid and
was stirred and heated at 90 °C for 9–10 h. It was subse-
quently cooled to room temperature and the resulting
solution was poured into 50 ml of water and the precipitate
was filtered off. The crude product (1–5) was purified by
recrystallization using distilled water. Compounds 6 and 7
were purified by column chromatography on silica gel. As
an eluent, methylene chloride (at the beginning) and then a
mixture of methylene chloride–methanol (50:1) was used.
1,2-Bis[2-(1H-tetrazol-1-yl)phenoxy]ethane (1)
Yield 99 % (1.73 g), white solid, mp 215–216 °C. 1H
NMR (500 MHz, d-DMSO): d = 4.35 (s, 4H, CH2), 7.04
(d, J = 8.31 Hz, 2H, Ar), 7.10 (m, 2H, Ar), 7.41 (m, 2H,
Ar), 7.62 (d, J = 7.33 Hz, 2H, Ar), 8.95 (s, 2H, tetrazole)
ppm. IR (KBr): 3137, 3090, 2962, 2900, 1510, 1489, 1473,
Conclusion
A novel group of bis-tetrazole containing aromatic units
and aliphatic chains with sulphur, nitrogen and oxygen
atoms was synthesized. The bis-tetrazole was synthesized
by using amines and ethyl orthoformate, sodium azide in
glacial acetic acid. It was found that the yield of the
products is polyether’s chains occurrence dependent. The
X-ray structure of compound 2 was reported. Complexing
properties of compounds 1–7 have been studied by spec-
trophotometric titration and IR.
1397, 1288, 1252, 1171, 1133, 1085, 1036, 746 cm-1
.
Anal. calcd. for C16H14N8O2: C 54.85, H 4.03, N 31.98.
Found: C 54.91, H 4.08, N 31.87.
1,5-Bis[2-(1H-tetrazol-1-yl)phenoxy]-3-oxapentane (2)
Yield 98.5 % (1.94 g), white solid, mp 85–88 °C. 1H NMR
(500 MHz, CDCl3): d = 3.81 (t, J = 4.4 Hz, 4H, CH2),
4.27 (t, J = 4.39 Hz, 4H, CH2), 7.15 (m, 4H, Ar), 7.46 (m,
2H, Ar), 7.82 (d, J = 6.35 Hz, 2H, Ar), 9.34 (s, 2H, tet-
razole) ppm. IR (KBr): 3127, 3069, 2952, 2891, 1512,
1473, 1453, 1399, 1297, 1253, 1175, 1142, 1132, 1084,
745 cm-1. Anal. calcd. for C18H18N8O3: C 54.82, H 4.60,
N 28.41. Found: C 54.78, H 4.54, N 28.37.
Experimental section
All materials and solvents were of analytical reagent grade.
Thin layer chromatographies (TLC) were performed on
aluminium plates covered with Silica gel 60 F254 (Merck).
1H NMR spectra were taken on Varian instrument at 200
and 500 MHz. IR spectra were recorded on Genesis II
FTIR (Mattson) instrument. UV–Vis measurements were
carried with the use of UNICAM UV 300 Series spectro-
photometer. Elemental analyses were obtained on EAGER
200 apparatus. The melting points were uncorrected. All
measurements were performed out at room temperature.
1,8-Bis[2-(1H-tetrazol-1-yl)phenoxy]-3,6-dioxaoctane (3)
Yield 97 % (2.12 g), white solid, mp 110–112 °C. 1H
NMR (500 MHz, d-DMSO): d = 3.71 (m, 6H, CH2), 4.25
(m, 6H, CH2), 7.16 (m, 2H, Ar), 7.32 (d, J = 7.69 Hz, 2H,
Ar), 7.50 (m, 2H, Ar), 7.67 (d, J = 6.31 Hz, 2H, Ar), 9.71
(s, 2H, tetrazole) ppm. IR (KBr): 3150, 3073, 2948, 2888,
1507, 1470, 1448, 1394, 1294, 1256, 1166, 1131, 1100,
750 cm-1. Anal. calcd. for C20H22N8O4: C 54.79, H 5.06,
N 25.56. Found: C 54.73, H 5.12, N 25.48.
Syntheses
The starting diamines: 1,2-bis(2-aminophenoxy)ethane, 1,5-
bis(2-aminophenoxy)-3-oxapentane, 1,5-bis[2-aminophenyl
(thio)]-3-oxapentane hydrochloride and 1,8-bis(2-amino-
phenoxy)-3,6-dioxaoctane were synthesized as described
earlier in literature [13–16].
1,5-Bis[2-(1H-tetrazol-1-yl)phenoxy]-3-phenylazapentane
(4)
1
Yield 90.6 % (0.25 g), brown solid, mp 146–148 °C. H
NMR (500 MHz, d-DMSO): d = 3.58 (m, 4H, CH2), 4.15
(m, 4H, CH2), 6.61 (m, 4H, Ar), 7.12 (m, 2H, Ar), 7.29
(d, J = 8.06 Hz, 2H, Ar), 7.55 (t, J = 7.69 Hz, 3H, Ar),
7.66 (d, J = 7.69 Hz, 2H, Ar), 9.77 (s, 2H, tetrazole) ppm.
IR (KBr): 3147, 3081, 2935, 2883, 1599, 1510, 1473, 1453,
1289, 1251, 1165, 1128, 1088, 751 cm-1. Anal. calcd. for
General procedure for synthesis the bis-tetrazoles
A mixture of respective diamine (5 mmol), sodium azide
(0.78 g, 12 mmol) and triethyl orthoformate (2.49 ml,
123

J Incl Phenom Macrocycl Chem
C24H23N9O2: C 61.39, H 4.94, N 26.85. Found: C 61.47, H
4.99, N 26.93.
(500 MHz, CDCl3): d = 2.43 (s, 6H, CH3), 3.57 (t, J =
6.19 Hz, 4H, CH2), 4.11 (t, J = 6.02 Hz, 4H, CH2), 6.51
(d, J = 8.06 Hz, 2H, Ar), 6.74 (t, J = 7.32 Hz, 1H, Ar),
7.15 (t, J = 8.3 Hz, 1H, Ar), 7.26 (d, J = 7.61 Hz, 5H,
Ar), 7.71 (d, J = 8.3 Hz, 4H, Ar) ppm. IR (KBr): 2958,
1925, 1598, 1505, 1579, 1230, 1150, 1096, 965, 889, 851,
1,5-Bis[2-(1H-tetrazol-1-yl)phenoxy]-3-
(4-toluenesulfonyl)azapentane (5)
1
Yield 46 % (0.075 g), brown solid, mp 103–108 °C. H
819, 778, 747, 665, 554, 502 cm-1
.
NMR (500 MHz, d-DMSO): d = 2.37 (s, 3H, CH3), 3.65
(m, 4H, CH2), 4.14 (m, 4H, CH2), 6.88 (m, 4H, Ar), 7.39
(d, J = 8.06 Hz, 2H, Ar), 7.76 (d, J = 8.06 Hz, 2H, Ar),
8.06 (m, 4H, Ar), 8.88 (s, 2H, tetrazole) ppm. IR (KBr):
3135, 3078, 2975, 2881, 1539, 1463, 1453, 1330, 1289,
1251, 1185, 1158, 1088, 1043, 970, 894, 740, 694, 650,
548 cm-1. Anal. calcd. for C25H25N9O4S: C 54.83, H 4.60,
N 23.02, S 5.86. Found: C 54.79, H 4.68, N 23.13, S 5.91.
1,5-Bis(2-nitrophenoxy)-3-phenylazapentane
A mixture of 2-nitrophenol (1.11 g, 8 mmol), 1,5-di
(4-toluenesulfonyloxy)-3-phenylazapentane (1.95 g, 4 mmol)
and anhydrous potassium carbonate (1.1 g) in N,N-dimeth-
ylformamide (5 ml) was heated at 100 °C for 8 h. After 8 h
TLC (eluent, petroleum ether–diethyl ether, 1:2 v/v) con-
firmed that the starting material had completely been used.
The mixture was then diluted with water; the precipitate was
separated, washed with water, dried and next recrystallized
from propan-2-ol. Yield 1.67 g (99 %) of pale yellow solid,
1,5-Bis[2-(1H-tetrazol-1-yl)phenyl(thio)]-3-
phenylazapentane (6)
1
Yield 45 % (0.45 g) of yellow oil. TLC (methylene chlo-
ride–methanol, 30:1). 1H NMR (500 MHz, CDCl3):
d = 2.86 (t, J = 6.84 Hz, 4H, CH2), 3.29 (t, J = 7.32 Hz,
4H, CH2), 7.17 (t, J = 7.32 Hz, 3H, Ar), 7.45 (m, 5H, Ar),
7.53 (m, 3H, Ar), 7.57 (d, J = 7.32 Hz, 2H, Ar), 8.90
(s, 2H, tetrazole) ppm. IR (film): 3129, 3096, 3065, 3010,
2927, 1693, 1596, 1496, 1462, 1356, 1279, 1200, 1052,
1045, 997, 874, 754 cm-1. Anal. calcd. for C24H23N9S2: C
57.46, H 4.62, N 25.13. Found: C 57.39, H 4.57, N 25.28.
mp 111–113 °C. H NMR (200 MHz, CDCl3): d = 4.02 (t,
J = 5.08 Hz, 4H, CH2), 4.31 (t, J = 5.06 Hz, 4H, CH2), 6.76
(m, 3H, Ar), 7.00 (m, 3H, Ar), 7.26 (t, J = 8.01 Hz, 3H, Ar),
7.48 (m, 2H, Ar), 7.82 (m, 2H, Ar) ppm. IR (KBr): 2930,
2882, 1608, 1510, 1347, 1272, 1252, 1195, 1168, 1038, 902,
849, 740, 694, 696, 611 cm-1
.
1,5-Bis(2-aminophenoxy)-3-phenylazapentane
1,5-Bis(2-nitrophenoxy)-3-phenylazapentane (0.42 g, 1 mmol)
was suspended in 3.2 ml of ethanol/concentrated hydro-
chloric acid. To reaction mixture, SnCl.22H2O (2.03 g,
9 mmol) in 2.5 ml concentrated hydrochloric acid was
added dropwise over a period of 30 min. The mixture was
refluxed for 8 h with reaction progress control by TLC
(diethyl ether). After cooling the reaction mixture was
diluted with water and extracted with methylene chloride.
The extract was dried with MgSO4 and evaporated under
reduced pressure. Pure product, beige–yellow oil, 0.26 g
(71 %) was recrystallized from propan-2-ol. 1H NMR
(200 MHz, CDCl3): d = 3.91 (t, J = 5.86 Hz, 4H, CH2),
4.21 (t, J = 5.86 Hz, 4H, CH2), 6.73 (m, 6H, Ar), 6.80 (t,
J = 7.32 Hz, 3H, Ar), 6.86 (d, J = 7.81 Hz, 2H, Ar), 7.26
(t, J = 7.31 Hz, 2H, Ar) ppm. IR (film): 3450, 2930, 2880,
1598, 1507, 1453, 1347, 1312, 1272, 1252, 1190, 1163,
1,5-Bis[2-(1H-tetrazol-1-yl)phenyl(thio)]-3-oxapentane (7)
1
Yield 65 % (0.26 g) of yellow oil. H NMR (500 MHz,
CDCl3): d = 2.89 (t, J = 5.86 Hz, 4H, CH2), 3.41 (t, J =
6.35 Hz, 4H, CH2), 7.46 (m, 4H, Ar), 7.54 (t, J = 6.84 Hz,
2H, Ar), 7.65 (d, J = 7.82 Hz, 2H, Ar), 9.05 (s, 2H, tet-
razole) ppm. IR (film): 3137, 3080, 2945, 2555, 1584,
1526, 1474, 1146, 1163, 1297, 1143, 1087, 1007, 761,
467 cm-1. Anal. calcd. for C18H18N8OS2: C 50.69, H 4.25,
N 26.27, S 15.03. Found: C 50.73, H 4.32, N 26.19, S
15.14.
Synthesis of substrates
1,5-Di(4-toluenesulfonyloxy)-3-phenylazapentane
1035, 900, 849, 740, 694, 696 cm-1
.
N-Phenyldiethanolamine (7.25 g, 40 mmol) was suspended
in 100 ml pyridine and cooled with ice at 0 °C. To stirring
mixture, three portions of 4-toluenesulfonyl chloride
(30.64 g, 160 mmol) were added over a period of 30 min.
The mixture was allowed to stay at 5 °C for 24 h. After ice
addition, crude product was precipitated. Pure product was
obtained by crystallized from petroleum ether. Yield
1,5-Di(4-toluenesulfonyloxy)-3-
(4-toluenesulfonyl)azapentane
Diethanolamine (3.83 ml, 40 mmol) was suspended in
60 ml pyridine and cooled with ice at 0 °C. To stirring
mixture, three portions of 4-toluenesulfonyl chloride
1
18.05 g (92 %) of white solid, mp 91–93 °C. H NMR
123

J Incl Phenom Macrocycl Chem
1,5-Bis[2-aminophenyl(thio)]-3-phenylazapentane
hydrochlochloride
(45.86 g, 240 mmol) were added over a period of 30 min.
The mixture was allowed to stay at 5 °C for 24 h. After ice
addition, crude product was precipitated. Pure product was
obtained by crystallized from benzene. Yield 9.0 g
(39.6 %) of green solid, mp 95–98 °C. 1H NMR
(200 MHz, d-DMSO): d = 2.37 (s, 3H, CH3), 2.42 (s, 6H,
CH3), 3.28 (t, J = 5.85 Hz, 4H, CH2), 3.99 (t, J =
5.86 Hz, 4H, CH2), 7.35 (d, J = 7.81 Hz, 2H), 7.48 (d, J =
7.81 Hz, 4H), 7.56 (d, J = 8.3 Hz, 2H), 7.72 (d,
J = 8.3 Hz, 4H) ppm. IR (KBr): 2953, 1936, 1597, 1494,
1453, 1357, 1307, 1197, 1097, 1089, 859, 815, 738, 654,
2-Aminothiophenol (1.07 ml, 10 mmol), 1,5-di(4-toluene-
sulfonyl)oxy-3-phenylazapentane (2.44 g, 5 mmol) and
anhydrous potassium carbonate (1.38 g) in dimethylform-
amide (10 ml) were heated for 24 h at 100 °C. The solvent
was removed under reduced pressure and the crude product
was diluted with water and extracted with methylene
chloride. The extract was dried with MgSO4 and evapo-
rated under reduced pressure. Bisamine was then dissolved
in methanol and concentrated hydrochloric acid (0.32 ml)
to provide red solid of 1,5-bis[2-aminophenyl(thio)]-3-
phenylazapentane hydrochloride (2.32 g, 98 %), mp
168–171 °C. 1H NMR (500 MHz, d-MeOH): d = 3.11
(m, 4H, CH2), 3.68 (m, 4H, CH2), 7.02 (m, 3H, Ar), 7.31
(t, J = 7.63 Hz, 3H, Ar), 7.43 (m, 5H, Ar), 7.66
(d, J = 7.63 Hz, 2H, Ar) ppm. IR (KBr): 3420, 2827,
2580, 2547, 1972, 1599, 1555, 1503, 1494, 1444, 1280,
517 cm-1
.
1,5-Bis(2-nitrophenoxy)-3-(4-toluenesulfonyl)azapentane
A mixture of 2-nitrophenol (2.22 g, 16 mmol), 1,5-di
(4-toluenesulfonyloxy)-3-(4-toluenesulfonyl)azapentane
(4.5 g, 8 mmol) and anhydrous potassium carbonate
(2.21 g) in dimethylformamide (10 ml) was heated at
100 °C for 8 h. The mixture was then diluted with water;
the precipitate was separated, washed with water, dried and
next recrystallized from propan-2-ol. Yield 3.96 g (99 %)
1214, 1182, 1141, 759, 691, 452 cm-1
.
1,5-Bis[2-aminophenyl(thio)]-3-oxapentane hydrochloride
1
of pale beige solid, mp 117–119 °C. H NMR (200 MHz,
A mixture of 2-aminothiophenol (2.14 ml, 20 mmol), 1,5-
dichloro-3-oxapentane (1.17 ml, 10 mmol) and anhydrous
potassium carbonate (2.76 g) in 10 ml of dimethylform-
amide was heated for 24 h at 80 °C. The reaction progress
was monitored by TLC using mixture of petroleum ether–
ethyl acetate (4:1 v/v) as a mobile phase. The reaction
mixture was cooled to room temperature and extracted with
methylene chloride (2 9 20 ml) and water (20 ml). The
organic phase was dried over MgSO4 and concentrated
under reduced pressure. Pure product was obtained with the
use of column chromatography with the same mixture of
solvents as TLC. The product was subsequently dissolved
in methanol and concentrated hydrochloric acid to give
white solid of 1,5-bis(2-aminophenylsulfide)-3-oxapentane
CDCl3): d = 2.31 (s, 3H, CH3), 3.87 (t, J = 5.37 Hz, 4H,
CH2), 4.31 (t, J = 5.37 Hz, 4H), 7.02 (m, 4H), 7.15 (d, J =
7.81 Hz, 2H), 7.52 (t, J = 8.3 Hz, 2H), 7.68 (d, J =
8.3 Hz, 2H), 7.82 (d, J = 6.35 Hz, 2 H) ppm. IR (KBr):
2966, 2882, 1608, 1523, 1486, 1356, 1335, 1280, 1257,
1156, 1088, 1048, 1014, 967, 895, 748, 716, 696, 641,
547 cm-1
.
1,5-Bis(2-aminophenoxy)-3-(4-toluenesulfonyl)azapentane
1,5-Bis(2-nitrophenoxy)-3-(4-toluenosulfonylo)azapentan
(0.25 g, 0.5 mmol) was suspended in 1.6 ml of ethanol/
concentrated hydrochloric acid. To reaction mixture,
SnCl2ꢀ2H2O (1 g, 4.5 mmol) in 1.25 ml concentrated
hydrochloric acid was added dropwise over a period of
30 min. The mixture was refluxed for 6 h with reaction
progress control by TLC (methylene chloride–methanol,
10:1). After cooling the reaction mixture was diluted with
water and extracted with methylene chloride. The extract
was dried with MgSO4 and evaporated under reduced
pressure. Pure product, beige–yellow oil, 0.176 g (71 %)
1
hydrochloride, mp 197–199 °C. Yield 2.75 g (70 %). H
NMR (200 MHz, CDCl3): d = 2.9 (t, J = 6.0 Hz, 4H,
CH2), 3.41 (t, J = 6.05 Hz, 4H, CH2), 6.18–7.12 (m, 8H,
Ar). IR (KRr): 3437, 2900, 2560, 1992, 1584, 1556, 1526,
1474, 1446, 1297, 1097, 1007, 757, 467 cm-1. The syn-
thesis was performed analogously to the synthesis com-
pounds described in literature.
1
was recrystallized from propan-2-ol. H NMR (200 MHz,
Spectrophotometric studies of metal cation complexation
CDCl3): d = 2.40 (s, 3H, CH3), 3.70 (t, J = 5.37 Hz,
4H, CH2), 4.14 (t, J = 5.37 Hz, 4H, CH2), 6.64 (m, 2H,
Ar), 6.86 (m, 6H, Ar), 7.35 (d, J = 7.32 Hz, 2H, Ar),
7.26 (d, J = 7.81 Hz, 2H, Ar) ppm. IR (film): 3434,
2976, 2880, 1618, 1527, 1453, 1335, 1322, 1287, 1255,
1187, 1159, 1085, 1044, 970, 894, 740, 694, 656,
UV–Vis titration was carried out by addition of metal
chloride to the bis-tetrazole solution. Titrations were car-
ried out in 1 cm path length quartz cuvette keeping con-
stant volume of the ligand solution (2 ml). Titration step
0.01 ml.
550 cm-1
.
123

J Incl Phenom Macrocycl Chem
6. Rostom, S.A.F., Ashour, H.M.A., Abd El Razik, H.A., Abd El
Fattah, H., El-Din, N.N.: Azole antimicrobial pharmacophre-
based tetrazoles: synthesis and biological evaluation as potential
antimicrobial and anticonvulsant agents. Bioorg. Med. Chem. 17,
2410–2422 (2009)
7. Jin, T., Kamijo, S., Yamamoto, Y.: Synthesis of 1-substituted
tetrazoles via the acid-catalyzed [3?2] cycloaddition between
isocyanides and trimethylsilyl azide. Tetrahedron Lett. 45,
9435–9437 (2004)
8. Shie, J.-J., Fang, J.-M.: Direct conversion of aldehydes to amides,
tetrazoles, and triazines in aqueous media by one-pot tandem
reactions. J. Org. Chem. 68, 1158–1160 (2002)
9. Yu, K.L., Johnson, R.L.: Synthesis and chemical properties of
tetrazole peptide analogs. J. Org. Chem. 52, 2051–2059 (1987)
10. Bliznets, I.V., Vasilev, A.A., Shorshnev, S.V., Stepanov, A.E.,
Lukyanov, S.M.: Microwave-assisted synthesis of sterically hin-
dered 3-(5-tetrazolyl)pyridines. Tetrahedron Lett. 45, 2571–2573
(2004)
Supplementary material
Complete crystallographic data of structure have been
deposited with the Cambridge Crystallographic Data Cen-
tre, CCDC Nos. 859174. Copies of this information may be
obtained free of charge from The Director, CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (fax: ?44-1223-
3336-033, e-mail:deposit@ccdc.cam.ac.uk).
Acknowledgments Financial support of this work from Gdansk
University of Technology, grant No. BW 014694/038, BW
014694/039 is kindly acknowledged.
Open Access This article is distributed under the terms of the
Creative Commons Attribution License which permits any use, dis-
tribution, and reproduction in any medium, provided the original
author(s) and the source are credited.
11. Duncia, J.V., Pierce, M.E., Santella, J.B.: Tree synthetic routes to
a sterically hindered tetrazole. A new one-step mild conversion of
an amide into a tetrazole. J. Org. Chem. 56, 2395–2400 (1991)
12. Thomas, E.W.: The conversion of secondary amides to tetrazoles
with trifluoromethanesulfonic anhydride and sodium azide. Syn-
thesis 8, 767–768 (1993)
References
13. Kumar, S., Bhalla, V., Singh, H., Singh, H.: Synthetic ionophores
part 19: synthesis and ionophore character of 2-aminothiophenol
based silver selective acyclic and cyclic receptors. Tetrahedron
54, 5575–5586 (1998)
1. Zucchi, F., Trabanelli, G., Fonsati, M.: Tetrazole derivatives as
corrosion inhibitors for copper in chloride solutions. Corros.
Sci.38, 2019–2029 (1996)
´
14. Holl, J.: Macrocycles synthetiques. I. Action du sodium sur les o,
o’-polymethylenedioxy-bis-(benzylidene-anilines). Helv. Chim.
2. Xue, H., Gao, Y., Twamley, B., Shreeve, J.M.: New energetic
salts based on nitrogen-containing heterocycles. Chem. Mat. 17,
191–198 (2005)
´
`
`
Acta 41, 1783–1792 (1958)
15. Tasker, P.A., Fleischer, E.B.: Iron(II), cobalt(II), nickel(II), and
zinc-(II) complexes of a series of new macrocyclic hexadentate
ligands. J. Am. Chem. Soc. 92, 7072 (1970)
3. Klapotke, T.M., Mayer, P., Schulz, A., Weigand, J.J.: 1,5-Dia-
mino-4-methyltetrazolium dinitramide. J. Am. Chem. Soc. 127,
2032–2033 (2005)
16. Dutasta, J.P., Simon, P.: Synthesis of novel crown derivatives
incorporating a diasminophosphine group in a polyether macro-
cycle. Tetrahedron Lett. 28(31), 3577–3580 (1987)
4. Ogihara, W., Yashizawa, M., Ohno, H.: Novel ionic liquids
composed of only azole ions. Chem. Lett. 33, 1022–1023 (2004)
5. Aromi, G., Barrios, L.A., Roubeau, O., Gamez, P.: Triazoles and
tetrazoles: prime ligands to generate remarkable coordination
materials. Coord. Chem. Rev. 255, 485–546 (2011)
123