Synthesis, extraction, and transport properties of dibenzo-18-crown-6 modified with the fragments of 2-amino-1,3,4-thiadiazol and kojic acid

Article abstract of DOI:10.1134/S1070363208100174

New heterocyclic derivatives of dibenzo-18-crown-6 (DB18C6), the products of coupling of kojic acid (5-hydroxy-2-hydroxymethyl-γ-pyrone) with 4′-DB18C6-yldiazonium chloride, 4′,4″-and 4′,5′- DB18C6-diyldiazonium dichlorides and products of heterocyclization of DB18C6 mono-and dicarboxylic acids with thiosemicarbazide are prepared. Their structures are studied by the methods of ¹H NMR and IR spectroscopy. Polyphosphoric acid is found to be the best agent for the heterocyclization of thiosemicarbazide with DB18C6 carboxylic derivatives. It is proven that the parent substrates, the DB18C6 mono or dicarboxylic acids, serve as phase transfer catalysts for the heterocyclization reaction. Extraction and transport properties of the obtained compounds in respect of potassium, sodium and ammonium picrates are explored.

Full text of DOI:10.1134/S1070363208100174

ISSN 1070-3632, Russian Journal of General Chemistry, 2008, Vol. 78, No. 10, pp. 1924–1928. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © D.V. Kuznetsov, A.A. Kuznetsova, Sh.A. Kadirova, R.V. Reshetnikova, A.K. Tashmukhamedova, 2008, published in Zhurnal
Obshchei Khimii, 2008, Vol. 78, No. 10, pp. 1689–1693.
Synthesis, Extraction, and Transport Properties
of Dibenzo-18-crown-6 Modified with the Fragments
of 2-Amino-1,3,4-thiadiazol and Kojic Acid
D. V. Kuznetsov, A. A. Kuznetsova, Sh. A. Kadirova,
R. V. Reshetnikova, and A. K. Tashmukhamedova
Mirzo Ulugbek National University of Uzbekistan, Chemical Faculty, Tashkent, 700174 Uzbekistan
e-mail: 17091982@mail.ru
Received April 26, 2007
Abstract―New heterocyclic derivatives of dibenzo-18-crown-6 (DB18C6), the products of coupling of kojic
acid (5-hydroxy-2-hydroxymethyl-γ-pyrone) with 4'-DB18C6-yldiazonium chloride, 4',4''- and 4',5''-DB18C6-
diyldiazonium dichlorides and products of heterocyclization of DB18C6 mono- and dicarboxylic acids with
1
thiosemicarbazide are prepared. Their structures are studied by the methods of H NMR and IR spectroscopy.
Polyphosphoric acid is found to be the best agent for the heterocyclization of thiosemicarbazide with DB18C6
carboxylic derivatives. It is proven that the parent substrates, the DB18C6 mono or dicarboxylic acids, serve as
phase transfer catalysts for the heterocyclization reaction. Extraction and transport properties of the obtained
compounds in respect of potassium, sodium and ammonium picrates are explored.
DOI: 10.1134/S1070363208100174
This communication concerns continuation of our
investigation on the modification of dibenzo-18-
crown-6 (DB18C6) with natural compounds [1–5].
Here we represent the synthesis of several new
hterocyclic derivatives, the products of coupling of
kojic acid (5-hydroxy-2-hydroxymethyl-γ-pyrone)
with 4'-DB18C6-yldiazonium chloride and 4',4''- and
pesticides [8]. Kojic acid is a natural heterocyclic
compound produced by many species of the genus of
Aspergilus, some species of Penicillum and some of
acetic bacteria [9]. It reveals antibiotic, bactericide and
fungicide actions. The benzocrown ethers being
synthetic functional analogs of natural antibiotics such
as valinomycin and others reveal ionophoric properties
[10]. Modifying of benzocrown ethers with the
fragments of 2-amino-1,3,4-thiadiazole and kojic acid
is expected to allow joining biological activity of these
heterocycles with ionophoric activity of the
macrocyclic fragment. Synthesis of the DB18C6
derivatives modified with kojic acid has been describd
[11]. Below are shown structures of these derivatives.
4
',5''-DB18C6-diyldiazonium dichlorides, and the pro-
ducts of heterocyclization of DB18C6 mono- and
dicarboxylic acids with thiosemicarbazide.
As is known, 1,3,4-thiadiazoles and their deriva-
tives possess biological activity of wide spectrum [6]
and are applied as medicine preparations [7] and
OH
O
O
N N
O
O
O
O
R1
O
R2
CH OH
O
2
OH
OH
N N
O
N N
O
1
2
1
2
1
2
I: R = R = H; II: R = H, R =
; III: R =
, R = H.
O
O
CH OH
CH OH
2
2
1924

SYNTHESIS, EXTRACTION, AND TRANSPORT PROPERTIES
1925
In literature have been described the methods for
the synthesis of aminothiadiazole derivatives from
aromatic acids by their heterocyclization with thio-
semicarbazide in the medium of trifluoroacetic acid
[12] and from aliphatic acids in polyphosphoric acid
under the conditions of phase transfer catalysis [13].
3
N
2
4
N
5
O
C
O
S
O
O
O
O
O
O
O
O
O
HO
H
2
N
C
NH
NH
2
H N
S
1
2
CF COOH or
3
polyphosphoric acid
O
O
IV
VI
O
C
O
O
O
O
O
H
HO
OH
C
O
O
V
N
N
O
S
O
O
O
H
H N
S
2
H N
C
NH
NH2
2
S
NH2
O
CF COOH or
3
polyphosphoric acid
O
N
N
VII
We synthesizes the DB18C6 2-amino-1,3,4-
thiadiazole derivatives by analogy with the data of [12,
3]. We found that the best agent for the hetero-
cyclization of thiosemicarbazide with DB18C6
carboxylic derivatives is polyphosphoric acid. In the
case of application of trifluoroacetic acid,
decomposition of reaction mixture requires much
higher pH value than in the case of polyphosphoric
acid. The high рН of reaction mixture leads to
destruction of the heterocyclic aminothiadiazole
fragment resulting in formation of colloid sulfur, and
yield is lower (Table 1).
1
Structure of the obtained compounds was
1
evidenced by the methods of H NMR and IR
spectroscopy. The protons of aromatic nuclei of 4'-[5-
(
2-amino-1,3,4-thiadiazolyl)]dibenzo-18-crown-6 ap-
pears as a multiplet in the region of 6.80–7.10 ppm, the
protons of macrocyclic fragment induce two multiplets
in the regions of 3.98–4.24 ppm (α-ОСН ) and 3.70–
2
Table 1. Results of heterocyclization of DB18C6 mono- and dicarboxylic acids with thiosemicarbazide
Substrate–reagent
Yield,
%
Substrate
Cyclization agent
Reaction product
mp, °С
mole ratio
VI
4
4
4
4
'-DB18C6-carboxylic acid
CF
CF
3
3
COOH
COOH
1:1
40
2
138–141
261–263
137–138
260–262
VII
VI
',4''(5'')-DB18C6-dicarboxylic acid
'-DB18C6-carboxylic acid
1:2.2
1:1
Polyphosphoric acid
Polyphosphoric acid
64
52
VII
',4''(5'')-DB18C6-dicarboxylic acid
1:2.2
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 10 2008

1
926
KUZNETSOV et al.
3
.94 ppm (β-ОСН ), two protons of amino group of
metals [14, 15] and a macrocyclic fragment capable of
binding alkali metal cations. Thus, these compounds
are promising dual ionophores.
2
thiadiazole are visualized as a signal at 2.48 ppm. The
protons of aromatic rings of 4',4''(5'')-di-[5-(2-amino-
1
,3,4-thiadiazolyl)]dibenzo-18-crown-6 induce a multi-
It was interesting to study effect of the fragments of
-amino-1,3,4-thiadiazole and kojic acid on the extrac-
plet at 6.80–7.10 ppm, the protons of macrocylic
fragment induce two multiplets in the regions of 4.01–
4
2
tion and ionophoric properties of the macrocycle. We
explored extraction of potassium, sodium and ammo-
nium picrates from aqueous medium into the crown-
containig sorbents by analogy with [17, 18]. The
crown-containing sorbent are solidified low-melting
mixtures of extraction agents I–III, VI, and VII with
paraffin as a diluting agent. Concentration of solution
before and after extraction was measured by
spectrophotometry at λ 315 nm, by analogy with [19].
.24 ppm (α-ОСН ) and 3.65–4.02 ppm (β-ОСН ), 4
2
2
protons of amino group give a signal at 1.20 ppm.
In the IR spectrum of 4'-[5-(2-amino-1,3,4-thiadi-
azolyl)]dibenzo-18-crown-6 the symmetrical and anti-
symmetrical vibrations of the aminothiadiazole
fragment NH group appear at 3062, 3035 cm ,
vibrations of aromatic С–Н bond characteristic of
–
1
2
–
1
1,2,4-substitution induce two bands, at 933 and 810 cm .
The extraction coefficient (K ) was calculated by the
formula:
ext
Symmetrical and antisymmetrical vibrations of
amino group of 4',4''(5'')-di-[5-(2-amino-1,3,4-thiadia-
zolyl)]dibenzo-18-crown-6 appear as band at 3076 and
1 2 1
Kext = [(D – D )/D ]×100%.
–1
2
923 cm , the bands characteristic of vibrations of С–
Here D and D are values of optical density of
1
2
Н bonds of 1,2,4-substituted aromatic rings occur at
aqueous solution of the salt before and after extraction.
The extraction percent was measured after noticeable
change in the color of the parent solutions of picrates
–1
8
75 and 765 cm .
It should be noted that the syntheses of thiadiazoles
(
after 2 days).
in the medium of polyphosphoric acid described in
literature have been carried out under the conditions of
phase transfer catalysis [13]. Considering our results
on the syntheses of the new derivatives we assume that
on our case the role of phase transfer catalyst plays
parent substrate IV or V.
The transport properties were explored with an
improvised membrane made of the same crown-
containing sorbent as the used for extraction. The
transported potassium, sodium or ammonium picrate
percent was also obtained by spectrophotometry and
calculated as [D /D ]×100% where D and D are
2
1
1
2
To proof this assumption we carried out a series of
syntheses in the polyphosphoric acid medium of 2-
amino-1,3,4-thiadiazole derivatives not containing
DB18C6 in their structures, namely, 2-amino-5-
methyl-1,3,4-thiadiazole (VIII) and 2-amino-5-phenyl-
optical densities of aqueous solutions with initial
concentration of salt and with the concentration after
passing the solution through the crown-containing
sorbent.
1
,3,4-thiadiazole (IX).
From Table 2 is seen that all the compounds display
higher extraction power toward the sodium picrate.
Notable that all the studied compounds display
mutually resembling extraction characteristics,
therefore we conclude preliminary that the fragments
of 2-amino-1,3,4-thiadiazole and kojic acid are not
involved to this process and not affect perceptibly the
crown ether conformation.
N
N
N
N
CH3
S
NH2
S
NH2
VIII
IX
The products yields were 1.2 and 24%,
respectively, but by adding a catalytic amount of
DB18C6 to the reaction mixture we succeeded in
improving yield by the factor almost 40 for VIII and
over 3-fold for IX. Thus, these experiments confirmed
our assumption absolutely.
Examination of transport properties shows that the
crown-containing sorbents based on compounds II and
+
III are selective toward K ion. Compounds II and VI
+
are very badly transporting Na ion, and for compound
+
4
I the same true in respect of NH ion. Note that the
The new obtained compounds are interesting be-
cause their structures include fragments of kojic acid
I–III or 2-amino-1,3,4-thiadiazole VI, VII possessing
ability of formation of the complexes with d-series
same is observed even after 150 days.
Comparing the results obtained in the study of
extraction and transport we conclude preliminary that
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 10 2008

SYNTHESIS, EXTRACTION, AND TRANSPORT PROPERTIES
1927
Table 2. Results of the study of extraction and transport properties of the obtained compounds
Extraction, % (after 2 days)
Transfer, % (after 2 days)
Transfer, % (after 150 days)
Comp.
no.
+
+
+
4
+
+
+
4
+
+
+
4
Na
K
NH
Na
K
NH
Na
K
NH
I
64.2
64.2
51.5
77
24.3
7.5
7.8
15.7
3.8
–
–
–
–
–
–
5.9
11.7
–
–
–
–
–
–
46.3
9.4
47.0
52.9
56.5
29.4
23.5
9.0
45.5
43.2
31.8
38.6
II
III
VI
VII
24.3
15.9
15.9
56.2
3.7
15.7
7.8
64.2
–
43.7
sodium picrate forms more stable complex with
compounds II and VI.
cooled to room temperature and a solution of ammonia
was added. The precipitate dropped was filtered off,
washed several times with hot ethanol and dried in air.
1
EXPERIMENTAL
Yield of product was 0.01 g (2%), mp 261–263°С. H
NMR spectrum, δ, ppm: 6.80–7.10 m (6Н, ArH),
Synthesis of 4'-[5-(2-amino-1,3,4-thiadiazolyl)]
dibenzo-18-crown-6 (VI). a. To 1.5 ml of trifluoro-
acetic acid at continuous mechanical stirring was
added 0.50 g of 4'-DB18C6-carboxylic acid. Tempera-
ture in bath was elevated to 50°С, and 0.11 g of
thiosemicarbazide was added. Reaction was conducted
for 7 h. Then the reaction mixture was cooled to room
temperature and solution of ammonia was added. The
precipitate formed was filtered off, washed several
4.01–4.24 m (8Н, α-ОСН ), 3.65–4.02 m (8Н, β-
2
–1
ОСН ), 1.20 s (4Н, NH ); IR spectrum, ν, cm : 3076,
2
2
2923 (symmetrical and antisymmetrical vibrations of
NH group), 875, 765 (1,2,4-substituted aromatic ring).
2
b. 0.50 g of 4',4''(5'')-DB18C6-dicarboxylic acid
was dissolved in 2.50 g of polyphosphoric acid at 25–
30°С at mechanical stirring. Then 0.20 g of thio-
semicarbazide was added . Stir was continued for 8 h,
and then the reaction mixture was cooled and
decomposed with 10 ml of cold water. The precipitate
dropped was filtered off and washed with water to
neutral reaction, then several times with a solution of
ammonia, and dried at 50°С in a dryer. The product
yield was 0.32 g (52%), mp 260–262°С.
times with hot ethanol and dried in air. Yield 0.22 g
1
(
40%), mp 138–141°С. H NMR spectrum, δ, ppm:
6
3
.80–7.10 m (7Н, ArH), 3.98–4.24 m (8Н, α-ОСН2),
.70–3.94 m (8Н, β-ОСН ), 2.48 s (2Н, NH ); IR
2
2
–
1
spectrum, ν, cm : 3062, 3035 (symmetrical and
unsymmetrical vibrations of NH group), 933, 810
2
(
1,2,4-substituted aromatic ring).
General procedure for preparation of crown-
containing sorbents. A compound under study I–III,
VI, VII was taken for preparation of melt with
paraffin, considered conventionally as a solvent, to
achieve concentration 10 mol l . Then the mixture
was grinded in a stamp with adding some liquid
nitrogen to obtain monotonically colored melt. Then
necessary, the last operation was repeated.
b. 0.50 g of 4'-DB18C6-carboxylic acid was
dissolved in 2.50 g of polyphosphoric acid at 25–30°С
with mechanical stirring. Then 0.12 g of thiosemi-
carbazide was added. Stir was continued for 8 h, and
then the reaction mixture was cooled and decomposed
with 10 ml of cold water. The mass dropped was
filtered off and washed with water to neutral reaction
and then several times washed with a solution of
ammonia and dried at 50°С in a dryer. Yield of pro-
duct 0.36 g (64%), mp 137–138°С.
–
3
–1
General procedure for extraction of alkali metal
picrates with the crown-containig sorbents based
on compounds I–III, VI, and VII. 1.22 g of
powdered crown-containing sorbent (corresponding to
2 ml of conventional solution) was immersed into 5 ml
of aqueous solution of corresponding metal picrate.
The mixture was carefully stirred to remove air
bubbles from the crown-containing sorbent surface and
left for 2 days. Then 0.1 ml of aqueous layer was taken
and diluted with distilled water to 3 ml volume, and
Synthesis of 4',4''(5'')-di[5-(2-amino-1,3,4-thia-
diazolyl)]dibenzo-18-crown-6 (VII). a. In 0.38 ml of
trifluoroacetic acid at continuous mechanical stirring
was dissolved 0.30 g of 4',4''(5'')-DB18C6-dicarboxy-
lic acid, then temperature in bath was elevated to 50°С
and 0.13 g of thiosemicarbazide was added. Reaction
was conducted for 7 h. Then the reaction mixture was
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 10 2008

1
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KUZNETSOV et al.
optical density of the obtained solution at the
frequency 315 nm was measured.
6. Elderfeld, R., Geterotsiklicheskie soedineniya (Hetero-
cyclic Compounds), Moscow: Mir, 1965, vol. 7, p. 448.
7
. Rubtsov, M.V. and Baichikov, A.G., Sinteticheskie
General procedure for the study of transport of
alkali metal picrates through the paraffin
membrane modified with a compound I–III, VI, or
VII. The membrane was prepared as follows: to a glass
khimiko-farmatsevticheskie
Chemical-Pharmaceutical
Meditsina, 1971.
preparaty
Preparations),
(Syntheic
Moscow:
8
9
. Mel’nikov, N.N., Pestitsidy. Khimiya, tekhnologiya and
primenenie (Pesticides: Cemistry, Technology, and
Application), Moscow: Khimiya, 1987.
–
3
–1
cylinder 2 cm diameter was placed 3 ml of 10 mol l
aqueous solution of respective picrate and 0.3 g of the
examined crown-containing sorbent. The mixture was
heated on a water bath to complete melting of the
paraffin substance that floated up to the surface of the
picrate solution. After cooling to room temperature the
crown-containing sorbent solidified in the form of
dense hermetical membrane 0.2 mm thickness
. Shemyakin, M.M. and Khokhlov, A.S., Khimiya anti-
bioticheskikh veshchestv (Chemistry of Antibiotic
Substances), Moscow: Goskhimizdat, 1953.
1
0. Ovchinnikov, Yu.A., Ivanov, V.T., and Shkrob, A.M.,
Membranno-aktivnye kompleksony (Membrane-Active
Compexones), Moscow: Nauka, 1974.
(
working diameter 14 mm). Then above the membrane
1
1
1. Kuznetsov, D.V., Andreev, S.A., and Tashmukha-
was poured 3 ml of distilled water and transport was
monitored. After 2 days a sample from the distilled
water layer was analyzed according to above described
procedure.
medova, A.K., Khim. Prirod. Soed., 2006, no. 5, p. 415.
2. Eremin, K.I., Golovanov, A.V., Krutikov, V.I., and Lav-
rent’ev, A.N., Zh. Obshch. Khim., 1997, vol. 67, no. 1,
p. 144.
1
1
3. Song, J., US Pat. 2.799 683, 1957, C.A., 1958, 52446c.
4. Beelik, A., Adv. Carbohydr. Chem., 1956, vol. 48,
no. 11, p. 145.
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