Synthesis, structure, and antimicrobial activity of (carboxyalkyl)dimethylsulfonium halides

Article abstract of DOI:10.1134/S107036321709002X

Reactions of a series of ω-halocarboxylic acids (2-bromo-, 2-chloroethanoic, 3-bromo- and 3-chloropropanoic) with dimethyl sulfide resulted in the formation of stable (carboxylalkyl)dimethylsulfonium bromides and chlorides. Composition and structure of the salts obtained were established by a complex of chemical, physical and physicochemical methods. The sulfonium salts obtained showed high antibacterial and antimycotic activities with respect to the pathogenic microflora of humans and animals.

Full text of DOI:10.1134/S107036321709002X

ISSN 1070-3632, Russian Journal of General Chemistry, 2017, Vol. 87, No. 9, pp. 1903–1907. © Pleiades Publishing, Ltd., 2017.
Original Russian Text © Yu.V. Bakhtiyarova, D.I. Bakhtiyarov, K.A. Ivshin, I.V. Galkina, I.I. Krasnyuk, A.V. Gerasimov, O.N. Kataeva, V.I. Galkin, 2017,
published in Zhurnal Obshchei Khimii, 2017, Vol. 87, No. 9, pp. 1419–1423.
Dedicated to V. F. Mironov on His 60th Anniversary
Synthesis, Structure, and Antimicrobial Activity
of (Carboxyalkyl)dimethylsulfonium Halides
Yu. V. Bakhtiyarovaa, D. I. Bakhtiyarova, K. A. Ivshina, I. V. Galkinaa,
I. I. Krasnyukb, A. V. Gerasimova, O. N. Kataevaa, and V. I. Galkina*
a Kazan (Volga region) Federal University, ul. Kremlevskaya 18, Kazan, Tatarstan, 420008 Russia
*e-mail: vig54@mail.ru
b Sechenov First Moscow State Medical University, Moscow, Russia
Received June 26, 2017
Abstract—Reactions of a series of ω-halocarboxylic acids (2-bromo-, 2-chloroethanoic, 3-bromo- and 3-chloro-
propanoic) with dimethyl sulfide resulted in the formation of stable (carboxylalkyl)dimethylsulfonium
bromides and chlorides. Composition and structure of the salts obtained were established by a complex of
chemical, physical and physicochemical methods. The sulfonium salts obtained showed high antibacterial and
antimycotic activities with respect to the pathogenic microflora of humans and animals.
Keywords: dimethyl sulfide, 2-bromoacetic acid, 3-chloropropanoic acid, (carboxylalkyl)dimethylsulfonium
halides, biological activity
DOI: 10.1134/S107036321709002X
A large number of carboxylate organoelemental
betaines based on phosphorus, arsenic, sulfur, nitrogen,
silicon and antimony is known [1–9]. These com-
pounds are widely used as medications. The most
known and studied carboxylate betaine is glycine, which
is a part of many proteins and plays an important role
in biological processes [10]. Arsenobetain can be
isolated from the most seafood [11–13]. Ме2S+CH2COO–
and Ме2S+(CH2)2COO– are produced by various types
of photosynthesizing organisms, including algae,
phytoplankton, cyanobacteria, and some higher plants
[10, 14, 15].
treatment of the corresponding onium salts with
solutions of alkali or silver oxide [1, 9, 15–19]. One of
the first and most complete studies in this direction
concerns the reactions of triphenylphosphine with
ω-chlorocarboxylic acids (Scheme 1) [1]. The
treatment of phosphonium salts (n = 2, 3) with aqueous
sodium hydrogen carbonate resulted in the formation
of phosphabetaines (Scheme 2).
The Denny–Smith method used for the preparation
of carboxylate phosphabetaines is based on the
dehydrohalogenation of the corresponding onium salts
[9, 17, 20–22]. Previously we have reported on the
synthesis of new phosphonium salts 1–7 (Scheme 3)
[19].
The most common method for the synthesis of car-
boxylate organoelemental betaines is based on the
Scheme 1.
_
+
[Ph3P__(CH2)nCOOH] Cl
Ph3P + Cl(CH2)nCOOH
n = 1, 2, 3.
Scheme 2.
NaHCO3
_
+
[Ph2P__(CH2)nCOOH] Cl_
Ph3P(CH2)nCOO
+
_NaCl
n = 2, 3.
1903

1904
BAKHTIYAROVA et al.
Scheme 3.
_
+
[Ph3P(CH2)nCOOH] Hlg
Ph3P + Hlg(CH2)nCOOH
1_7
n = 1, 2, 3, 4, Hlg = Cl (1–4); n = 1, 2, 3, Hlg = Br (5–7).
Scheme 4.
H3C
H3C
O
O
S
+
Hlg
(CH2)n
S
(CH2)n
C
C
Hlg
H3C
CH3
OH
OH
8_11
n = 1, 2, Hlg = Cl (8, 10); n = 1, 2, Hlg = Br (9, 11).
Here we studied the features of the synthesis of
sulfonium salts based on the corresponding carboxylic
acids: 2-chloro- and 2-bromoacetic, 3-chloro- and
3-bromopropanoic acids and dimethyl sulfide, as well
the composition and structure of the resulting compounds
by a complex of various methods like IR and NMR
spectroscopy, elemental and X-ray diffraction analysis,
and combined TG-DSC method.
up to 80%. It is worth noting that in the reactions with
chlorocarboxylic acids, the yield of the target salts 8
and 10 was substantially less than in the case of
bromocarboxylic acids. An increase in the reaction
time to 14 days did not significantly affect the product
yield. Obviously, all these reactions proceed according
to the classical mechanism of nucleophilic substitution
SN2.
A new series of sulfonium salts 8–11 was obtained
by reacting dimethyl sulfide with the corresponding
halocarboxylic acids (Scheme 4).
Structure of all synthesized sulfonium salts was
proved by a complex of spectral methods. Thus, in the
IR spectrum of salt 11, the stretching vibrations of the
carboxyl (1725 cm–1), C–S (635 cm–1) and O–H (2500–
3000 cm–1) groups were clearly recorded. In the 13C
NMR spectra of compounds 8–11 there was one signal
in the range of 165–175 ppm, which corresponds to the
carbon of the carboxy group. In the range of 40–
45 ppm there were the signals of methylene carbon
atoms. The signals of methyl groups were recorded at
20–25 ppm. The 1H NMR spectra contained the signals
of all groups of the protons.
It should be noted that the sulfonium salt 10 has
been obtained earlier in 1977 [23] in order to compare
the betaine extracted from the leaves of Spartina
anglica with that synthesized from dimethyl sulfide
and trichloropropanoic acid. However, convincing data
confirming the structure of this sulfonium salt were not
provided. Yoo et al. [15] also synthesized sulfonium
salt 8 to prepare the corresponding betaine, and they
succeeded in isolating the crystals and performed X-
ray diffraction analysis. However, even in this work,
there are no physicochemical characteristics of the salt
8, since the aim was the subsequent synthesis of the
corresponding betaine on its base.
Yields, melting points, and IR spectroscopy data of
the obtained sulfonium salts 8–11 are given in Table 1;
the data of elemental analysis are presented in Table 2.
All sulfonium salts obtained gave a positive result to
the Beilstein test.
In the present work, the synthesis of the corres-
ponding sulfonium salts was carried out at room
temperature by mixing chloro- and bromocarboxylic
acids with a 3-fold excess of dimethyl sulfide in aceto-
nitrile or ethyl acetate. In different reactions, their
duration and the products yields differed markedly.
Thus, the reaction of dimethyl sulfide with 2-bromo-
acetic acid resulted in the formation of sulfonium salt 9
within 30 min with the yield of 89%, although for the
other three reactions the product yield ranged from 60
Crystal structure of (carboxymethyl)dimethylsul-
fonium bromide 9 was further confirmed by X-ray
diffraction analysis (see figure). Thermal stability of
compound 9 was studied by a combined method of
thermogravimetry and differential scanning calorimetry
coupled with a quadrupole mass spectrometry (TG-
DSC-MS). The data obtained confirmed high thermal
stability of salt 9. The derivatogram showed pro-
nounced endo effect of fusion with complete
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 9 2017

SYNTHESIS, STRUCTURE, AND ANTIMICROBIAL ACTIVITY
1905
Table 1. Yields, melting points, and IR spectroscopy data for sulfonium salts 8–11
ν, cm–1
Yield,
%
Comp. no.
Salt
mp, °C
C=O
1712
1702
1707
1725
O–H
C–S
640
623
627
635
8
9
[(CH3)2S+CH2COOH]Cl–
[(CH3)2S+CH2COOH]Br–
[(CH3)2S+СН2CH2COOH]Cl–
[(CH3)2S+CH2CH2COOH]Br–
2500–3100
2400–3300
2450–3200
2500–3070
141
148
135
115
80
89
60
71
10
11
Table 2. Elemental analysis data for sulfonium salts 8–11
Found, %
Comp. no.
Calculated, %
Formula
C
H
C
H
8
9
31.07
23.43
35.48
28.10
5.50
4.34
6.19
5.34
С4Н9ClO2S
С4Н9BrO2S
С5Н11ClO2S
С5Н11BrO2S
30.67
23.88
35.19
27.91
5.75
4.48
6.45
5.11
10
11
decomposition with a maximum at 148.4°C. In the
temperature range from 40 to 120°C, the mass loss was
not observed, which indicates the stability of this com-
pound in this temperature range.
analyzer STA 449C Jupiter (Netzsch, Germany)
coupled with a quadrupole mass spectrometer QMS
403C Aeolos (Netzsch, Germany); the heating rate of
the sample was 10 deg/min in an argon atmosphere.
The obtained compounds 8–11 were tested for
biological activity against pathogenic and conditio-
nally pathogenic microflora of humans and animals:
Staphylococcus aureus, Escherichia coli, Bacillus
cereus, Pseudomonas aeruginosa, Salmonella p.B. and
Candida albicans. Among them, compounds 9 and 11
were highly selective for Staphylococcus aureus and
Candida albicans strains, respectively. These compounds
are advisable to recommend for further study as drugs.
(Carboxymethyl)dimethylsulfonium chloride (8).
A solution of 0.99 g (15.9 mmol) of dimethylsulfide in
3 mL of acetonitrile was added with stirring to a
solution of 0.5 g (5.3 mmol) of 2-chloroacetic acid in
5 mL of the same solvent at room temperature. After
the reaction completion, colorless crystals were filtered
off, washed repeatedly with diethyl ether and dried in a
vacuum. Yield 0.663 g (79.86%), mp 141°C. IR
In conclusion, the studied reactions of dimethyl
sulfide and halocarboxylic acids make it possible to
obtain the corresponding tertiary sulfonium salts and
carboxylate sulfabetaines on their basis, which opens
wide opportunities for the synthesis of new
biologically active substances.
EXPERIMENTAL
1H and 13C NMR spectra were recorded on a Bruker
Avance-400 instrument. Chemical shifts were
determined relative to external standards in D2O. IR
spectra were registered on an IR Prestige-21
instrument in the range of 400–3700 cm–1 in mineral
oil or liquid film between KBr plates. Thermal stability
was studied using a synchronous microthermal
Crystal structure of (carboxymethyl)dimethylsulfonium
bromide 9.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 9 2017

1906
BAKHTIYAROVA et al.
spectrum, ν, cm–1: 640 m (C–S), 1712 s (C=O), 3100–
solution) [27] and SHELXL-2014 (refinement of the
structure by the least squares method) software [28].
1
2500 w (OH). H NMR spectrum (D2O), δ, ppm: 2.79
s [6H, (CH3)2S], 4.23 s (2H, SCH2). 13C NMR spec-
trum (D2O), δC, ppm: 24.82 and 24.79 [(CH3)2S], 45.74
(CH2), 167.07 (COOH). Found, %: C 31.07; H 5.50.
C4H9O2SCl. Calculated, %: C 30.67; H 5.75.
Crystals of compound 9 are monoclinic, C4H9O2SBr,
crystal size 0.422×0.469×0.593 mm3, M 201.08 g/mol,
space group P21/n, Z 4, a 7.3809(11), b 7.5985(11),
c 14.303(2) Å, β 101.911(5)°, V 784.9(2) Å3, dcalc
1.702 g/cm3, μ 5.427 mm–1; 18451 reflections
(±9, ±10, ±19) were collected within the limits of
θ from 2.90 to 28.30°. There were 1933 independent
(Rint 0.0384) and 1734 observed reflections with
[I ≥ 2σ(I)]; 79 refinement parameters: R1 0.0352, wR2
0.1341, maximum residual electron density 0.371
(–1.165) e/Å3. The crystallographic data were deposited
at the Cambridge Crystallographic Data Centre (CCDC
1548063).
(Carboxymethyl) dimethylsulfonium bromide (9)
was prepared similarly from 0.5 g (3.6 mmol) of
2-bromoacetic acid and 0.67 g (10.8 mmol) of dimethyl
sulfide; the reaction mixture was stirred at room
temperature for a week. Yield 0.644 g (89.03%),
colorless crystals, mp 148°C. IR spectrum, ν, cm–1:
1
635 m (C–S), 1725 s (C=O), 3070–2500 w (OH). H
NMR spectrum (D2O), δ, ppm: 2.86 s [6H, (CH3)2S],
4.72 s (2H, SCH2). 13C NMR spectrum (D2O), δC,
ppm: 24.84 and 24.86 [(CH3)2S], 45.90 (CH2), 166.89
(COOH). Found, %: C 23.43; H 4.34. C4H9O2SBr.
Calculated, %: C 23.88; H 4.48.
ACKNOWLEDGMENTS
This work was carried out at the expense of
subsidies allocated within the framework of state
support of Kazan (Volga region) Federal University
and the Sechenov First Moscow State Medical
University in order to enhance their competitiveness
among the world’s leading scientific and educational
centers.
(2-Carboxyethyl)dimethylsulfonium chloride (10)
was prepared similarly from 0.5 g (4.6 mmol) 3-chloro-
propanoic acid and 0.86 g (13.8 mmol) of dimethyl
sulfide; the reaction mixture was stirred at room
temperature for a week. Yield 0.470 g (59.71%), mp
135°C. IR spectrum, ν, cm–1: 627 m (C–S), 1707 s
(C=O), 3300–2450 w (OH). 1H NMR spectrum (D2O),
δ, ppm: 2.88 s [6H, (CH3)2S], 2.94 t (2H, CH2COOH,
REFERENCES
3
3JHH = 6.8 Hz), 3.47 t (2H, SCH2, JHH = 6.9 Hz). 13C
1. Denney, D.B. and Smith, L.C., J. Org. Chem., 1962,
NMR spectrum (D2O), δC, ppm: 25.64 [(CH3)2S],
29.12 (CH2COOH), 39.31 (SCH2), 174.10 (COOH).
Found, %: C 35.48; H 6.19. C5H11O2SCl. Calculated,
%: C 35.19; H 6.45.
vol. 27, p. 3404. doi 10.1021/jo01057a005
2. Galkin, V.I., Bakhtiyarova, Yu.V., Polezhaeva, N.A.,
Galkina, I.V., Cherkasov, R.A., Krivolapov, D.B.,
Gubaidullin, A.T., and Litvinov, I.A., Russ. J. Gen.
Chem., 2002, vol. 72, no. 3, p. 384. doi 10.1023/
A:1015487416152
3. Galkin, V.I., Bakhtiyarova, Yu.V., Sagdieva, R.I.,
Galkina, I.V., and Cherkasov, R.A., Heteroatom Chem.,
2006, no. 6, p. 557. doi 10.1002/hc.20276
(2-Carboxyethyl)dimethylsulfonium bromide (11)
was prepared similarly from 0.5 g (3.3 mmol) of
3-bromopropanoic acid and 0.61 g (9.9 mmol) of
dimethylsulfide; the reaction mixture was stirred at
room temperature for 2 days. Yield 0.501 g (71.27%),
mp 115°C. IR spectrum, ν, cm–1: 623 m (C–S), 1702 s
(C=O), 3200–2400 w (OH). 1H NMR spectrum (D2O),
δ, ppm: 2.86 s [6H, (CH3)2S], 2.91 t (2H, CH2COOH,
4. Gamayurova, V.S., Mysh’yak v ekologii i biologii
(Arsenic in Ecology and Biology), Moscow: Nauka, 1993.
5. Jung-Hwa Yoo, E., Feketeovґa, L., Khairallah, G.N.,
White, J. M., and O’Hair, R.A.J., Org. Biomol. Chem.,
2011, vol. 9, p. 2751. doi 10.1039/c0ob00770f
6. Szafran, M., Dega-Szafran, Z., Nowak-Wydra, B., and
Pietrzak, M., J. Mol. Struct., 2001, vol. 563–564, p. 555.
doi 10.1016/S0022-2860(01)00497-5
7. Zemlyansky, N.N., Borisova, L.V., Shestakova, A.K.,
and Ustynyuk, Yu.A., Russ. Chem. Bull., 1993, vol. 42,
no. 12, p. 2056.
8. Zemlyansky, N.N., Borisova, L.V., Shestakova, A.K.,
and Ustynyuk, Yu.A., Russ. Chem. Bull., 2000, vol. 49,
no. 5, p. 920.
3
3JHH = 6.8 Hz), 3.46 t (2H, SCH2, JHH = 6.9 Hz). 13C
NMR spectrum (D2O), δC, ppm: 25.16 [(CH3)2S],
28.55 (CH2COOH), 38.74 (SCH2), 173.73 (COOH).
Found, %: C 28.10; H 5.34. C5H11O2SBr. Calculated,
%: C 27.91; H 5.11.
X-ray diffraction study was carried out on a
Bruker AXS Kappa APEX Duo diffractometer using
MoKα- radiation (λ 0.71073 Å) at 293(2) K by means
of APEX2 [24], SAINT [25], SADABS (accounting
for extinction) [26], SHELXS 97 (the structure
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 9 2017

SYNTHESIS, STRUCTURE, AND ANTIMICROBIAL ACTIVITY
1907
9. Balazs, G., Balazs, L., Breunig, H.J., and Lork, E., Appl.
Organomet. Chem., 2002, vol. 16, p. 155. doi 10.1002/
aoc.255
10. Gorham, J., Amino Acids and their Derivatives in
Higher Plants, Cambridge: Cambridge Academ., 1995,
p. 173.
11. Edmonds, J.S., Francesconi, K.A., Cannon, J.R.,
Raston, C.L., Skelton, B.W., and White, A.H.,
Tetrahedron Lett., 1977, vol. 18, p. 1543. doi 10.1016/
S0040-4039(01)93098-9
Galkina, I.V., Russ. J. Gen. Chem., 2015, vol. 85, no. 9,
p. 2058. doi 10.1134/S1070363215090078
19. Romanov, S.R., Aksunova, A.F., Islamov, D.R., Dob-
rynin, A.B., Krivolapov, D.B., Kataeva, O.N., Bakhti-
yarova, Yu.V., Gnezdilov, O.I., Galkina, I.V., and
Galkin, V.I., Phosphorus, Sulfur, Silicon, Relat. Elem.,
2016, vol. 191, nos. 11–12, p. 1637. doi 10.1080/
10426507.2016.1223661
20. Hudson, R.F. and Chopard, P.A., Helv. Chim. Acta,
1963, vol. 46, p. 2178. doi 10.1002/hlca.19630460638
12. Kaise, N., Watanake, Sh., and Jtoh, K., Talanta, 1985,
21. Li, S.L. and Mak, T.C.W., J. Chem. Crystallogr., 1997,
vol. 14, no. 9, p. 1327. doi 10.1016/0045-6535(85)90153-5
vol. 27, p. 91. doi 10.1007/BF02575901
13. Bhattacharya, P., Welch, A.H., Stollenwerk, K.G.,
McLaughlin, M.J., Bundschuh, J., and Panaullah, G.,
Sci. Total Environ., 2007, vol. 379, no. 2–3, p. 1090. doi
10.1016/j.scitotenv.2007.02.037
22. Aly, A.A.M. and Schmidbaur, H., Z. Naturforsch. B,
1991, vol. 46, p. 775. doi 10.1515/znb-1991-0612
23. Larner, F., Hamelin, J., and Stewart, G.R., Phyto-
chemistry, 1977, vol. 16, p. 2019. doi 10.1016/0031-
9422(77)80117-9
14. Gebser, B. and Pohnert, G., Mar. Drugs, 2013, vol. 11,
no. 6, p. 2168.
24. Bruker. APEX2 Software Suite for Crystallographic
15. Yoo, E.J.H., Feketeova, L., Khairallah, G.N., White, J.M.,
and O’Hair, R.A.J., Org. Biomol. Chem., 2011, vol. 9,
p. 2751. doi 10.1039/c0ob00770f
16. Gamayurova, V.S., Shulaeva, M.M., Sysoeva, M.A.,
and Khalitov, F.G., Zh. Obshch. Him., 1997, vol. 67,
no. 8, p. 1294.
17. Galkin, V.I., Bakhtiyarova, Yu.V., Polezhayeva, N.A.,
Shaikhutdinova, R.A., Klochkov, V.V., and Cherka-
sov, R.A., Zh. Obshch. Khim., 1998, vol. 68, no. 7,
p. 1104.
Programs, Bruker AXS, Inc., Madison, WI, USA, 2009.
25. Bruker. Area detector control and integration software.
Version 5.x. SMART and SAINT, Madison, Wisconsin
(USA), Bruker Analytical X-ray Instruments Inc., 1996.
26. Sheldrick, G.M., SADABS. Program for absorption
corrections, University of Goettingen, Germany, 1996.
27. Sheldrick, G.M., Acta Crystallogr. (A), 2008, vol. 64,
p. 112. doi 10.1107/S0108767307043930
28. Sheldrick, G.M., Acta Crystallogr. (C), 2015, vol. 71,
p. 3. doi 10.1107/S2053229614024218
18. Bakhtiyarova, Yu.V., Aksunova, A.F., Galkin, V.I., and
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 9 2017