Sulfur-containing carboxylic acids: 6.* The syntheses of 3,3′-sulfinyldipropionic and 2,2′-sulfinyldiacetic acids

Article abstract of DOI:10.1023/A:1024416829619

Pure sulfoxides of thiodialiphatic acids were obtained in high yields by oxidation of the corresponding sulfides in organic solvents. 3,3′-Sulfinyldipropionic acid was obtained by the reaction of hydrogen peroxide with thiodipropionic acid in acetone. 2,2′-Sulfinyldiacetic acid was synthesized by the reaction of thiodiglycolic acid with H₂O ₂ in acetone containing acetic acid (26 mol %). Pure 2,2′-sulfinyldiacetic acid was found to be stable in storage rather than labile as reported previously.

Full text of DOI:10.1023/A:1024416829619

958
Russian Chemical Bulletin, International Edition, Vol. 52, No. 4, pp. 958—960, April, 2003
Sulfurꢀcontaining carboxylic acids
6.* The syntheses of 3,3´ꢀsulfinyldipropionic and 2,2´ꢀsulfinyldiacetic acids
T. P. Vasil´eva
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Fax: +7 (095) 135 5085. Eꢀmail: kolomiets@ineos.ac.ru
Pure sulfoxides of thiodialiphatic acids were obtained in high yields by oxidation of the
corresponding sulfides in organic solvents. 3,3´ꢀSulfinyldipropionic acid was obtained by the
reaction of hydrogen peroxide with thiodipropionic acid in acetone. 2,2´ꢀSulfinyldiacetic acid
was synthesized by the reaction of thiodiglycolic acid with H2O2 in acetone containing acetic
acid (26 mol %). Pure 2,2´ꢀsulfinyldiacetic acid was found to be stable in storage rather than
labile as reported previously.
Key words: thiodipropionic acid, thiodiglycolic acid, oxidation, 3,3´ꢀsulfinyldipropionic
acid, 2,2´ꢀsulfinyldiacetic acid, stability.
In continuation of the studies1,2 devoted to sulfurꢀ
Scheme 1
containing carboxylic acids, we investigated oxidation of
3,3´ꢀthiodipropionic (1) and thiodiglycolic (2) acids.
Some sulfoxides (e.g., those containing methyl,3 tertꢀbuꢀ
tyl, vinyl,4 aryl,5 and acylaminoethyl3 radicals) are known
to have pronounced radioprotective properties and be nonꢀ
toxic, as distinct from corresponding sulfides. For this
reason, functionalized sulfoxides, especially carboxylꢀconꢀ
taining ones, can be of interest as intermediates for the
synthesis of new biologically active substances. The goal
of the present work was to select optimum conditions for
the synthesis of sulfinyldialiphatic acids and study the
effects of the solvent and the sulfide structure on the
oxidation course.
Oxidation of sulfurꢀcontaining acids 1 and 2 into the
corresponding sulfoxides, namely, 3,3´ꢀsulfinyldipropꢀ
ionic (3) and 2,2´ꢀsulfinyldiacetic acids (4), has been
poorly studied to date. The known procedures afford imꢀ
pure sulfoxides 3 6,7 and 4.8—12 Thus, the oxidation of
thiodipropionic acid 1 (preꢀneutralized with KOH) with
hydrogen peroxide in water is completed over 24 h to
give, along with sulfoxide 3,7 3,3´ꢀsulfonyldipropionic acid
as a byꢀproduct of its further oxidation. Alternatively,
sulfoxide 3 can be obtained by the reaction of sulfide 1
with H2O2 in acetone for 2 days.6 However, the oxidation
product under these conditions contains a significant adꢀ
mixture of the starting sulfide 1 (MS and TLC data). The
yield and purity of oxidation product 3 were increased by
extending the reaction time to 5 days (Scheme 1).
was not purified, and its purity was not checked. That is
the reason why the literature data on its melting point
show a large discrepancy: from 79—80 °C (with excess
H2O2 in the absence of a solvent)8 and 109 °C (with broꢀ
mine water)12 to 119 °C (with excess H2O2 in water9 or
acetone10) and 119—121 °C (with ozone in water).11 Earꢀ
lier,9 the reaction of excess hydrogen peroxide with sulꢀ
fide 2 in water was reported to be the optimum method for
the synthesis of compound 4 (m.p. 119 °C). When reꢀ
peated by us, the synthesis gave an oxidation product
(m.p. 80—100 °C) containing sulfoxide 4, the starting sulꢀ
fide 2, the corresponding sulfone (2,2´ꢀsulfonyldiacetic
acid (5)), and other admixtures. Obviously, other previꢀ
ous products8—11 were crude sulfoxide 4 containing difꢀ
ferent amounts of compounds 2 and 5. Thus, the oxidaꢀ
tion of sulfide 2 in water affords impure sulfoxide 4. Apꢀ
parently, water provokes side reactions. In addition, the
solvent should be removed to isolate the oxidation prodꢀ
uct, and sulfoxide 4 partly decomposes when heated in
aqueous solutions.9,10 These undesirable effects seemed
to be quite avoidable if acetone is used instead of water as
a solvent. However, it turned out that the oxidation rate
Oxidation of thiodiglycolic acid 2 yielded highly imꢀ
pure products. As a rule, sulfoxide 4 obtained earlier8—12
* For Part 5, see Ref. 1.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 908—910, April, 2003.
1066ꢀ5285/03/5204ꢀ958 $25.00 © 2003 Plenum Publishing Corporation

Sulfinyldialiphatic acids
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 4, April, 2003
959
of thiodiacetic acid 2 in acetone is lower than in water.
Moreover, sulfide 2 is much harder to react with H2O2 in
acetone than thiodipropionic acid 1: under the reaction
conditions for sulfoxide 3 (see Scheme 1), the oxidation
of sulfide 2 was only half completed. A similar tendency
was observed earlier in the oxidation of these acids with
hydrogen peroxide in water; the rate constant for 2 is
much lower (0.003) than for 1 (0.17).7 We found the
optimum conditions for the synthesis of sulfoxide 4 by
oxidation of sulfide 2 with hydrogen peroxide in acetone
containing ∼26 mol % acetic acid (Scheme 2).
The purity of the sulfoxides 3 and 4 obtained was
confirmed by TLC, H NMR, and elemental analysis
data, as well as by a special titrimetric reductive method
developed for sulfoxides.13
1
It is worth noting that the protons of the sulfurꢀbound
methylene group are nonequivalent because of the pyraꢀ
midal structure of the sulfoxide substituent in Sꢀmonoꢀ
1
oxides 3 and 4. In H NMR spectra, they are manifested
as a multiplet (for 3) or a quadruplet AB system (for 4).
Meanwhile their signals appear as singlets at δ 3.13
(DMSOꢀd6) or 3.52 (acetoneꢀd6 14) for the correspondꢀ
ing sulfide 2 and at δ 4.47 (acetoneꢀd614) for sulfone 5.
Thus, it was shown that dialkyl sulfides containing an
electronꢀwithdrawing βꢀ and especially αꢀcarboxy group
are more resistant to oxidation.
Scheme 2
Hence, we developed preparative methods for the seꢀ
lective oxidation of thiodialiphatic acids into sulfoxides
with an easily accessible oxidant, modified the method
for the synthesis of 3,3´ꢀsulfinyldipropionic acid (3), and
obtained for the first time stable sulfinyldiacetic acid (4)
in the individual state.
Under these mild conditions, the oxidation rate is
satisfactory, and no decomposition of 4 or further oxidaꢀ
tion occur. The accelerating effect of AcOH can be exꢀ
plained by the reaction mechanism involving proton transꢀ
fer and the formation of a trimolecular cyclic intermeꢀ
diate (Scheme 3).
Experimental
The starting sulfides, namely, 3,3´ꢀthiodipropionic (1) and
thiodiglycolic (2) acids (Fluka Chemie AG), were used as reꢀ
ceived. Acetone (analytical grade) was not purified. Other, doꢀ
mestic solvents (AcOH, benzene, and ether) were purified by
standard methods. 1H NMR spectra were recorded on a Bruker
AMXꢀ400 instrument with HMDS as the internal standard. The
course of the reaction was monitored and the purity of sulfoxꢀ
ides was checked by TLC on Silufol plates (Czech Republic) in
EtOH—CHCl3 (1 : 3) (A), Me2CO—CHCl3, (1 : 1) (B) and
(3 : 1) (C) (visualization with iodine vapor), as well as by the
titrimetric reductive method as described earlier.13
Scheme 3
Complete oxidation of sulfides into sulfoxides 3 and 4 was
indicated by a negative test with aqueous KI/HCl for peroxide.
Caution! The use of a large excess of H2O2 (> 10—20%) in
the synthesis of compounds 3 and 4 can yield explosive acetone
peroxide! For safety purposes, isolation of sulfoxides 3 and 4
should be preceded by analysis for peroxides and the reaction
mixture should be evacuated at T < 56—60 °C.
R = CH2COOH
3,3´ꢀSulfinyldipropionic acid (3). Aqueous 50.8% H2O2
(1.65 g, 24.7 mmol) was added at 0 °C to a solution of comꢀ
pound 1 (4 g, 22.5 mmol) in 73 mL of Me2CO, and the reaction
mixture was left in a refrigerator for three days. The precipitate
that formed was filtered off and washed with cold acetone and
ether to give compound 3 (0.87 g), m.p. 112—114 °C. The filꢀ
trate containing, along with sulfoxide 3, unreacted H2O2 (test
with KI/H+) and sulfide 1 (TLC/A), was allowed to stand in the
dark at ∼20 °C for the reaction to be completed. Two days later,
the precipitate that formed was separated as described above to
give compound 3 (1.36 g), m.p. 112—114 °C. The mother liquor
was evaporated in vacuo to dryness, and the residue was
washed with ether to give an additional 1.91 g of acid 3, m.p.
111—114 °C. The total yield of sulfoxide 3 was 4.14 g (95%).
The purity of compound 3 was confirmed by TLC (Rf 0.72/A)
and 1H NMR data. Recrystallization of compound 3 from water
Sulfoxide 4 can be purified by soft methods in
Me2CO—C6H6 or MeOH—Et2O systems. Crystallization
from water, which was used to purify propionic analog 3,6
is unsuitable for compound 4. The melting point of pure
compound 4 was found to be 142—143 °C. In the previꢀ
ous studies,8—11 the products obtained were not purified
and hence sulfoxide 4 had lower melting points. Comꢀ
plete decomposition of sulfoxide 4 (m.p. 119 °C) on storꢀ
age at 20 °C within two months9 is mainly due to the
presence of sulfide 2 and sulfone 5. The behavior of its
analog 3 is quite different; for this reason, we studied the
stability of 4 in storage. Like sulfoxide 3, pure compound 4
(m.p. 142—143 °C) was found to be stable at 20 °C for
6.5 months.

960
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 4, April, 2003
T. P. Vasil´eva
(as described earlier6) does not increase the melting point but
results in considerable weight losses and thus seems to be inexꢀ
pedient.
Compound 4 was also synthesized as described earlier8 (exꢀ
cept that the reaction mixture was concentrated at 38—50 °C
(~23 Torr) rather than over H2SO4 in a vacuum desiccator). The
yield of the product was 84%, m.p. 80—100 °C. Along with
sulfoxide 4 (Rf 0.18), the product contained admixtures of the
starting sulfide 2 (Rf 0.56), the corresponding sulfone 5 (Rf 0.41),
and unidentified substances (TLC/B data). Previously,9 comꢀ
pound 4 was obtained in 70% yield (m.p. 119 °C).
Found (%): C, 37.00; H, 5.26; S, 16.48. C6H10O5S. Calcuꢀ
1
lated (%): C, 37.11; H, 5.15; S, 16.49. H NMR (AcOHꢀd4), δ:
2.94 (t, 2 H, CH2CO, J = 6.8 Hz); 3.24 (m, 2 H, CH2SO).
According to the previous method,6 the yield of pure comꢀ
pound 3 with m.p. 112 °C (water) (cf. Refs. 6, 7: m.p. 114 °C)
was only 33%; concentration of the mother liquor gave an addiꢀ
tional amount of product 3 (43%), m.p. 109—112 °C, containꢀ
ing ∼10% sulfide 1 (Rf 0.9/A).
References
2,2´ꢀSulfinyldiacetic acid 4. A. Aqueous 50.8% H2O2 (8.08 g,
0.12 mol) was added at 0 °C to a solution of acid 2 (15 g,
0.1 mol) in 135 mL of Me2CO. The reaction mixture was left in
a refrigerator for three days and then kept (while periodically
stirring without access for light) at ∼20 °C for 26 h and at ∼35 °C
for 2 h. The ratio of 4 : 2 in the resulting solution (in system B)
was ≈ 1 : 1 (TLC data).
B. Aqueous 50.8% H2O2 (8.08 g, 0.12 mol) was added at
0 °C to a solution of acid 2 (15 g, 0.1 mol) in a mixture of
Me2CO (135 mL) and AcOH (1.5 mL, 26 mmol). The reaction
mixture was left in a refrigerator for three days and then at
∼20 °C for two days. The reaction mixture was stirred at
∼35—47 °C until H2O2 disappeared (∼5.5 h) and evaporated
in vacuo to dryness. The residue was washed with Et2O and dried
in vacuo over P2O5 to give a white powder (14.9 g, m.p.
119—124 °C) containing compounds 4 (∼90%), 2 (∼10%), and
sulfone 5 (trace amounts) (TLC/B and 1H NMR/DMSOꢀd6
data). Sulfone 5 as a reference substance for TLC was prepared
according to the known procedure.15 Pure sulfoxide 4 was obꢀ
tained by reprecipitation from hot Me2CO with benzene (yield
72%, m.p. 141—142 °C) or precipitation from a methanolic soꢀ
lution with Et2O (yield 55%, m.p. 142—143 °C) (cf. Refs. 8—10:
Rf 0.1—0.18/B, 0.38—0.44/C).
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1958, 91, 75.
Attempts to recrystallize compound 4 from water (as deꢀ
scribed in Ref. 5 for sulfoxide 3) failed: a sample of 4 (1 g, m.p.
119—124 °C) dissolved in 5 mL of water at 63 °C gave no preꢀ
cipitate upon cooling. Found (%): C, 28.84; H, 3.59; S, 19.27;
reductive equivalent12 (E) 82.5. C4H6O5S. Calculated (%):
C, 28.92; H, 3.61; S, 19.28; E, 83 (M/2). 1H NMR (DMSOꢀd6),
δ: 3.69 (q, 4 H, two overlapping AB systems, CH2SCH2, δA 3.6,
12. E. Larsson, Svensk. Kem. Tids., 1940, 52, 9; Chem. Abstrs.,
1940, 34, 4054.
13. S. Allenmark, Acta Chem. Scand., 1966, 20, 910.
14. M. Brink, Acta Chem. Scand., 1966, 20, 2882.
15. H. Backer, Rec. Trav. Chim. PaysꢀBas, 1953, 72, 119.
Received April 12, 2002;
δ
B 3.78, JAB = 14.7 Hz); 5.21 (br.s, 2 H, 2 COOH).
in revised form August 22, 2002