New quaternary ammonium salts and metal complexes of organylheteroacetic acids with diaza-18-crown-6 ether

Article abstract of DOI:10.1134/S1070363210050269

Quaternary ammonium salts 2(RCH₂COO)^-. (2H·DACE)⁺ were synthesized in up to 98% yield by the reaction of biologically active organylheteroacetic acids (OHA) RCH₂COOH with diaza-18-crown-6 ether (DACE). Pleiades Publishing, Ltd., 2010.

Full text of DOI:10.1134/S1070363210050269

ISSN 1070-3632, Russian Journal of General Chemistry, 2010, Vol. 80, No. 5, pp. 1007–1010. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © S.N. Adamovich, A.N. Mirskova, R.G. Mirskov, O.M. Perminova, N.N. Chipanina, T.N. Aksamentova, M.G. Voronkov, 2010,
published in Zhurnal Obshchei Khimii, 2010, Vol. 80, No. 5, pp. 837–840.
New Quaternary Ammonium Salts and Metal Complexes
of Organylheteroacetic Acids with Diaza-18-crown-6 Ether
S. N. Adamovicha, A. N. Mirskovaa, R. G. Mirskova, O. M. Perminovab,
N. N. Chipaninaa, T. N. Aksamentovaa, and M. G. Voronkova
a Favorskii Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences,
ul. Favorskogo 1, Irkutsk, 664033 Russia
e-mail: mir@irioch.irk.ru
b Research Institute of Clinical Immunology, Siberian Branch,
Russian Academy of Medical Sciences, Novosibirsk, Russia
Received January 12, 2010
Abstract―Quaternary ammonium salts 2(RCH2COO)–.(2Н.DACE)+ were synthesized in up to 98% yield by
the reaction of biologically active organylheteroacetic acids (OHA) RCH2COOH with diaza-18-crown-6 ether
(DACE).
DOI: 10.1134/S1070363210050269
Complexes of crown ethers with protic acids and
their metal salts attract the attention of researchers not
only due to their specific molecular and stereo-
electronic structure but also due to the possibility of
their practical use [1, 2]. Complexation with crown
ethers increases physiological activity of a number of
chemical compounds. Apparently, this is related with
the ability of the formed complexes to pass through the
cell and hemato-organic barriers. In particular, specific
complexing properties of crown ethers allow their use
for the design of new drugs. Among them are cardio-
and neurotropic drugs possessing cancerostatic, cation
transport effect and affecting the vegetative nervous
system. On their basis biocides, antimicrobial, anti-
parasite and other drugs were prepared [1, 2].
Paramagnetic complexes of lanthanides with crown
ethers can be used as nanodimensional thermosensors
for in vivo nuclear magnetic resonance tomography,
cartography of body temperature and diagnostics of
diseases [3].
Earlier we have shown that tris(2-hydroxyethyl)-
ammonium salts of organylheteroacetic acids (OHA),
[RYCH2COO]–·[NH(CH2CH2OH)]3+ (R = Ar, Het; Y =
O, S, SO2), belonging to 2,8,9-trihydroprotatranes [4],
is a new class of biologically active compounds, pro-
mising for design of adaptogens, immunomodulators,
drugs with antitumor and protecting effect from the
UHF radiation, stimulators of protein biosynthesis,
regulators of microorganisms and plants growth [5–11].
In a search for new immunoactive compounds we
have synthesized the earlier unknown quaternary
ammonium salts I–VI by the reaction of OHA with
diaza-18-crown-6 ether (DACE) in the ratio of 2:1 and
in the yield up to 98%:
O
O
_
_
diaza-18-crown-6
+
+
2 RCH2COOH
RCH2COO NH2
H2N OOCCH2R
O
O
S
S
I_V: R = o-CH3 C6H4O (I), p-Cl_C6H4S (II), p-ClC6H4SO2 (III),
_
SO
(IV),
(V),
2 (VI).
N
N
N
H
C6H5
C6H5
1007

1008
ADAMOVICH et al.
The biogenic metal (Na, K, Zn) salts of OHA form
with DACE complex compounds VII–XI:
atom forms coordination bonds with oxygen atoms of
DACE. This is reflected in the decrease of the С–О–С
stretching vibration bands of DACE in the spectrum of
complex X to 1108, 1058 and 1040 cm–1. A narrow
band ν(NH) at 3334 cm–1 belonging to free NH groups
in the spectrum of DACE remains intact in the
spectrum of its complex X pointing to the absence of
coordination interaction of the metal with nitrogen
atoms. Earlier we have shown that vibration
frequencies ν(СОО–) 1633 and 1558 cm–1 and their
difference Δν 75 cm–1 in the IR spectrum of (о-
СН3С6Н4ОСН2СОО)2Zn are indicative of the presence
of bidentate bonds of the metal with carboxylate anion
[13]. Apparently, similar bands are present in complex
X since the values of ν(СОО–) are equal to 1636,
1568 cm–1 and Δν is 68 cm–1. The bands of the О→Zn
stretching vibrations in the spectrum of X appear at
460, 380, and 285 cm–1. Therefore, the data of IR
spectroscopy and elemental analysis suggest that the
zinc atom in complex X is coordinated to four oxygen
atoms of DACE, lying in one plane, and to oxygen
atoms of the two СОО– groups of the carboxylate
anions in the axial position.
O
O
HN
NH + (RCH2COO)nM
O
O
_
[O(O)CCH2R]n
O
O
O
+ M
NH
HN
O
VII_XI
R = о-ОН–С6Н4О, М = K (VII); R = p-Сl–С6Н4SО2, М =
Na (VIII); R = p-Сl–С6Н4SO2, М = K (IX), R = о-СН3–
С6Н4О, М = Zn (X); R =
n = 1, 2.
,
М = Na (XI),
S
N
H
Screening of immunoactive properties of com-
pounds I–IV was performed by their ability to affect
the in vitro spontaneous and mitogen (concanavalin A,
Con A, Sigma) induced proliferation of splenocytes of
mice (antiproliferative properties). Proliferative activity
of cells was judged by their ability to incorporate H3-
thymidine into the DNA of the dividing cells.
The synthesized compounds I–XI are fine-
crystalline colorless compounds. Compounds I–VI
have clear melting points, whereas compounds VII–XI
melt in the interval of 5–10°С that may be indicative
of their liquid-crystal structure (similar to [12]).
The experiments were carried out on healthy
sexually mature hybrid mice of both sexes
(CBA×C57BL/6)F1 (CBF1), 8–10 week age, with a
body mass of 18–20 g. The results were treated by the
non-parametric Wilcoxon-Mann-Whitney test U. The
highest immunosuppressing activity was found for
compounds II and IV in dose of 30–300 μg ml–1. By
the ability to suppress the in vitro spontaneous (II,
72%, IV, 54%) and Con A-induced (II, 99%, IV, 39%)
proliferation of cells in dose of 300 μg ml–1 these
compounds can be considered as immunosuppressants.
The results of the present work are indicative of advis-
ability of more detailed examination of immunoactive
properties of these and related compounds.
The composition and structure of compounds I–XI
1
is proved by the data of elemental analysis, Н, 13С
NMR and IR spectroscopy. In the IR spectra of I–VI
wide absorption bands ν(NH2+) are observed in the
range 2800–2200 cm–1. The bands of the stretching
vibrations of the О–С–О fragments of the starting
DACE are shifted to high frequencies from 1120,
1100, and 1067 to 1150–1090 cm–1 in I–VI. Similar
shift of the ν(С–О–С) vibration bands is observed in
the spectra of VII–IX. The bands of the asymmetric
and symmetric stretching vibrations of the carboxylate
group СОО– in OHA in the spectra of compounds I–
XI appear in the range 1580–1350 cm–1. The values of
the main frequencies in the spectra of I–XI slightly
differ from those determined by us earlier for the
triethanolammonium salts of OHA [4]. The bands of
the symmetric and asymmetric vibrations of the SO2
group in III, VI, VIII, and IX are equal to 1164 and
1323 cm–1, respectively. We have examined the IR
spectra of X in more detail. In molecule X, the zinc
EXPERIMENTAL
IR spectra were recorded on a Varian 3100 FT-IR
75 spectrophotometer. NMR spectra were registered
1
on a Bruker DPX 400 spectrometer (400 MHz for H
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 5 2010

NEW QUATERNARY AMMONIUM SALTS AND METAL COMPLEXES
1009
and 100 MHz for 13С) in D2O or CD3OD. OHA and
their metal salts were synthesized and purified by
procedures [13-15].
ОСН2), 2.49 t (8Н, NСН2). 13С NMR (D2O): 170.80
(С=О), 146.05 (С6Н4О), 130.56–130.50 (С6Н4), 70.43
(ОСН2), 69.38 (ОСН2СН2О), 48.27 (NCH2). Found,
%: С 44.62; Н 5.69; K 7.01. С20Н32О8N2ClSK.
Calculated, %: С 44.86; Н 5.98; К 7.28.
Complex I. To the solution of о-СН3С6Н4О·
СН2СООН (3.32 g, 0.02 mol) in 10 ml of МеОН the
solution of DACE (2.62 g, 0.01 mol) in 10 ml of
MeOH was added dropwise, and the mixture was
stirred for 12 h at room temperature. The solvent was
removed in a vacuum, the solid residue was thoroughly
washed with ether and dried in a vacuum to give
colorless powder (5.63 g, 98%) with mp 118°С,
Metal complexes VII, VIII, X, XI were prepared
similarly. Compound VII. Yield 80%. Tdecomp 230–
240°С. Compound VIII. Yield 82%, mp 170–180°С.
Compound X. Yield 79%, mp 120–130°С. Com-
pound XI. Yield 74%, mp 95–100°С.
1
ACKNOWLEDGMENTS
readily soluble in water, alcohol. Н NMR (D2O):
7.11–6.68 m (4Н, С6Н4), 4.37 s (4Н, СН2СОО), 3.63–
3.56 m (16Н, ОСН2), 3.15 t (8Н, NСН2), 2.13 s (3Н,
СН3). 13С NMR (D2O): 176.80 (С=О), 156.04
(С6Н4О), 140.87–111.56 (С6Н4), 69.42(ОСН2), 66.99
(СН2СОО), 65.29 (ОСН2СН2О), 47.31 (NСН2), 15.53
(С6Н4-СН3).
This work was performed with a financial support
from the Council on Grants of the President of the
Russian Federation (grant no. NSh-255.2008.3).
REFERENCES
Complexes II–V were prepared similarly. Com-
pound II. Yield 89%, mp 113°С. Compound III.
Yield 93%, mp 122°С. Compound IV. Yield 88%, mp
60оС. Compound V. Yield 89%, mp 144°С.
1. Bogatskii, A.V., Nazarov, E.I., and Golovenko, N.Ya.,
Zh. Vses. Khim. Ob–va, 1985, vol. 30, no. 5, p. 593.
2. Hiraoka, M., Crown Compounds, Their Characteristics
and Applications, Tokyo, 1982.
Complex VI was prepared similarly from
suspension of 0.02 mol of 1-benzylindol-3-ylsul-
fonylacetic acid [prepared by oxidation of 1-benzyl-
indol-3-ylsulfanylacetic acid with hydrogen peroxide
3. Babailov, S.P. and Mordvintseva, A.V., Abstracts of
Papers, Konf. “Meditsinskaya genomika i proteo-
mika” (Conf. “Medical Genomic and Proteomic”),
Novosibirsk, 2009, p. 83.
1
in acetic acid, mp 164–166°С; Н NMR (СD3OD):
4. Voronkov, M.G., Albanov, A.I., Aksamentova, T.N.,
Adamovich, S.N., Chipanina, N.N., Mirskov, R.G.,
Kochina, T.A., Vrazhnov, D.V., and Litvinov, M.Yu.,
Zh. Obshch. Khim., 2009, vol. 79, no. 11, p. 1817.
8.00–7.23 m (10Н, С14Н10N), 5.46 s (2Н, NCH2С6Н5),
4.22 s (2Н, СН2SО2). 13С NMR (СD3OD): 164.98
(С=О), 135.04–119.85 (С14Н10N), 110.95 (СН2SО2),
61.08 (NСН2С6Н5)] in 20 ml of acetone and 0.01 mol
of DACE in 25 ml of acetone at 22°С for 3 h. Yield
5. Sof’ina, Z.P., Voronkov, M.G., D’yakov, V.M., Seme-
nova, N.V., Platonova, A.T., Peretolchina, N.M.,
Lesnaya, N.A., and Smetankina, O.Z., Khim.-Farm. Zh.,
1978, vol. 12, no. 4, p. 74.
1
89%. mp 165°С, soluble in water, alcohol. Н NMR
(D2O): 7.75–7.15 m (10Н, С14Н10N), 5.34 s (2Н,
NCH2С6Н5), 4.09 s (2Н, СН2SО2), 3.60–3.55 m (16Н,
ОСН2), 3.11 t (8Н, NСН2). 13С NMR (D2O): 176.38
(С=О), 137.56–119.01 (С14Н10N), 110.09 (СН2SО2),
69.21 (ОСН2), 66.99 (ОСН2 СН2О), 62.29
(NСН2С6Н5), 46.46 (NСН2).
6. Voronkov, M.G., Rasulov M.M., Khim.-Farm. Zh.,
2007, vol. 41, no. 1, p. 3.
7. Voronkov, M.G., Kolesnikova, O.P., Rasulov, M.M.,
and Mirskova, A.N., Khim.-Farm. Zh., 2007, vol. 41,
no. 5, p. 13.
8. Mirskova, A.N., Levkovskaya, G.G., Mirskov, R.G.,
and Voronkov, M.G., Zh. Org. Khim., 2008, vol. 44,
no. 10, p. 1501.
Metal complex IX. To suspension of р-СlС6Н4SО2·
СН2СООK (2.72 g, 0.01 mol) in 10 ml of МеОН the
solution of DACE (2.62 g, 0.01 mol) in 10 ml of
methanol was added dropwise, the reaction mixture
was stirred at reflux for 8 h until it became homo-
geneous. The solvent was removed in a vacuum, the
solid residue was crystallized from hot benzene to
obtain colorless crystals (5.07 g, 95%) with mp 88–95°С,
soluble in water, alcohol. 1Н NMR (D2O): 7.49–7.28 m
(4Н, С6Н4), 4.03 s (3Н, СН2СОО), 3.27–3.22 m (16Н,
9. Shabanov, P.D., Ganapol’skii, V.P., Zarubina, I.V.,
Zhumasheva, A.B., and Elistratova, А.А., Neironauki,
2006, vol. 3, no. 5, p. 43.
10. Kolesnikova, O.P., Mirskova, A.N., Adamovich, S.N.,
Mirskov, R.G., Kudaeva, O.T., and Voronkov, M.G.,
Dokl. Akad. Nauk, 2009, vol. 425, p. 556.
11. Voronkov, M.G., Sofronov, G.A., Starchenko, D.A.,
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 5 2010

1010
ADAMOVICH et al.
Adamovich, S.N., and Mirskova, A.N., Dokl. Akad.
Mirskov, R.G., Mirskova, A.N., and Voronkov, M.G.,
Nauk, 2009, vol. 428, p. 125.
Zh. Obshch. Khim., 2008, vol. 78, no. 9, p. 1523.
12. Zabirov, N.G., Pozdeev, O.K., Shcherbakova, V.A., Shumilo-
va, T.N., Gil’manova, G.Kh., and Cherkasov, R.A.,
Khim.-Farm. Zh., 1990, vol. 24, no. 9, p. 51.
14. Mirskova, A.N., Levkovskaya, G.G., Guseva, S.A., and
Kryukova, Yu.I., Zh. Org. Khim., 1984, vol. 20, no. 3,
p. 602.
13. Adamovich, S.N., Kuznetsova, G.A., Chipanina, N.N.,
Aksamentova, T.N., Kashik, T.V., Zykova, E.V.,
15. Levkovskaya, G.G., Rudyakova, E.V., and Mirsko-
va, A.N., Zh. Org. Khim., 2002, vol. 38, no. 11, p. 1697.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 5 2010