The oxidation of trialkyl trithioarsenites, (RS)3As, by octasulfur/triethylamine and dioxygen

Article abstract of DOI:10.1080/104265091001092

Trialkyl trithioarsenites, (RS)₃ As, bearing terminal carboxy (-COOH) or carboxylate (-COO^-Na⁺) or zwitterionic (-CH(NH₃⁺)COO^-) groups were studied for their ability to be oxidized by octasulfur, S₈, and by dioxygen. The carboxy-bearing trithioarsenites are not oxidized by S₈ to the corresponding As(V) esters, (RS)₃As=S, probably because they cannot open the octasulfur ring, but they react with S₈ in the presence of triethylamine, which acts as an activator of S₈. The carboxylate-bearing trithioarsenites, however, do react under drastic conditions with S₈. In both cases colored insoluble solids were obtained which could not be characterized. The carboxy-bearing trithioarsenites are oxidized by air in a hydrocarbon chain-length depended manner, while the carboxylate-bearing trithioarsenites are not, if at all, oxidized by air to arsenic(III) oxide, As₂O₃, and disulfide, RSSR. The zwitterion-bearing tris(penicillamine), tris(cysteine), and tris(glutathione) trithioarsenites are air oxidized slower than their corresponding parent thiols and this may be of biochemical significance. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/104265091001092

Phosphorus, Sulfur, and Silicon, 181:413–425, 2006
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265091001092
The Oxidation of Trialkyl Trithioarsenites, (RS) As,
3
by Octasulfur/Triethylamine and Dioxygen
Gerasimos M. Tsivgoulis
Theano C. Fotopoulou
Panayiotis V. Ioannou
Department of Chemistry, University of Patras, Patras, Greece
Trialkyl trithioarsenites, (RS) As, bearing terminal carboxy ( COOH) or carboxy-
3
−
+
+
−
late ( COO Na ) or zwitterionic ( CH(NH )COO ) groups were studied for
3
their ability to be oxidized by octasulfur, S , and by dioxygen. The carboxy-bearing
trithioarsenites are not oxidized by S to the corresponding As(V) esters, (RS) As=S,
probably because they cannot open the octasulfur ring, but they react with S in
the presence of triethylamine, which acts as an activator of S8. The carboxylate-
8
8
3
8
bearing trithioarsenites, however, do react under drastic conditions with S . In both
8
cases colored insoluble solids were obtained which could not be characterized. The
carboxy-bearing trithioarsenites are oxidized by air in a hydrocarbon chain-length
depended manner, while the carboxylate-bearing trithioarsenites are not, if at all,
oxidized by air to arsenic(III) oxide, As O , and disulfide, RSSR. The zwitterion-
2
3
bearing tris(penicillamine), tris(cysteine), and tris(glutathione) trithioarsenites are
air oxidized slower than their corresponding parent thiols and this may be of bio-
chemical significance.
Keywords Activation; binding; dioxygen; octasulfur; trialkyl trithioarsenites
INTRODUCTION
Inorganic arsenic can enter into a cell either as arsenate or as arsen-
ite. Whichever the mechanism of the entry, once inside arsenate can
1
mimic the reactions of phosphate or it can be reduced to arsenite by
2
arsenate reductase (E.C.1.20.4.1) or biological thiols, e.g., cysteine or
3
−5
glutathione
according to Eq. (1):
H3AsO4 + 5RSH → (RS)3As + RSSR + 4H2O .
(1)
Received February 22, 2005; accepted February 22, 2005.
We thank Dr. D. Vachliotis of the Centre of Instrumental Analyses, University of
Patras, for the elemental analyses and NMR spectra and Dr. H.B.F. Dixon (University of
Cambridge) for stimulating discussions.
Address correspondence to Panayiotis V. Ioannou, Univeristy of Patras, Department
of Chemistry, Patras, Greece. E-mail: ioannou@chemistry.upatras.gr
413

4
14
G. M. Tsivgoulis et al.
Similarly, arsenite inside a cell can react with these thiols according to
Eq. (2):
H3AsO3 + 3RSH → (RS)3As + 3H2O.
(2)
The fate of these trialkyl trithioarsenites, when formed inside a cell,
has not been studied, except that the eukaryote S. cerevisiae pumps
As(III) probably as As(glutathione)3 into a vacuole thus detoxifying
6
the arsenite. The same ester was found to be transported out of
7
hepatocytes by MRP2/cMOAT and into bile in rats. As(glutathione)3
8,9
10
has been found to be an inhibitor of yeast and S. cerevisiae glu-
tathione reductase (E.C. 1.8.1.7), yeast and bovine glutathione per-
10
oxidase (E.C. 1.11.1.9), and equine glutathione S-transferase (E.C.
1
0
2
1
(
.5.1.18), while As(cysteine)3 inhibits thioredoxine reductase (E.C.
1
1
.8.1.9). The inhibition may or may not involve transthiolation
1
2
Eq.(3)), e.g. the transfer of As(III) to a dithiol or to closely spaced-
SH (cysteine) groups on an enzyme which may form such a dithiol.
ꢀ
ꢀ
(
RS)3As + 3R SH ꢀꢁ (R S)3As + 3RSH.
Conceivably, trialkyl trithioarsenites can be oxidized by dioxygen. It
(3)
1
3
is known that certain liquid aliphatic trithioarsenites, e.g., (EtS)3As,
1
3,14
14
(
n-PrS)3As,
spheric oxygen (65% As2O3 is produced when air is bubbled through
n-BuS)3As for 2 h). However, the oily ester As(SCH2CH2OH)3 is “fairly
and (n-BuS)3As, are very sensitive towards atmo-
14
(
1
5
stable” (p. 827) towards air oxidation. The stability of the biologically
relevant As(cysteine)3 and As(glutathione)3 towards dioxygen has not
been studied but their close analogue, Me-As(cysteine)2, is unstable
under aerobic conditions.16
It was found that aromatic trithioarsenites, (ArS)3As, are oxidized
by dioxygen to As2O3 and disulfides according to Eq. (4):
2
(ArS)3As + 3/2O2 → As2O3 + 3ArSSAr,
and the extent of the oxidation depends on the solvent, the nature of Ar
substituted phenyl, 2-pyridyl or 2-pyridyl N-oxide), the nature of the
(4)
(
17
13
para substituent, and the nature of E in (PhE)3As (SeꢁS).
The action of other oxidizing elements on trithioarsenites has not
been studied much. Thus, alcoholic iodine decomposed (PhS)3As to its
1
8
19,20
disulfide and octasulfur in boiling carbon disulfide was said
to oxi-
2
1
dize (p-MePhS)3As to (p-MePhS)3As S. However, we showed that the
As(III) in this and other aromatic trithioarsenites is not nucleophilic to-
wards octasulfur and such As(V) esters cannot be produced by reacting
trithioarsenites with octasulfur. Moreover, it was found that As2O3
and ArSSAr were produced during the attempted oxidations by octasul-
fur, obviously according to Eq. (4). When the octasulfur ring was opened
2
1

Air Oxidation of Trialkyl Trithioarsenites
415
in the presence of 10–20 mol% triethylamine, the esters (ArS)3As gave
colored, insoluble solids always accompanied by As2O3.
In this article we describe our results on the reaction of the aliphatic
trithioarsenites 1–3, 5, and 6 with octasulfur in the absence and in the
presence of triethylamine, as an activator of octasulfur, and on the air
oxidation of aliphatic trithioarsenites bearing carboxy, 1–4, carboxylate,
5
–8, and zwitterionic, 9–11, groups.
RESULTS AND DISCUSSION
Preparation and Properties of the Trithioarsenites 1–11
The preparation of the esters (RS)3As is usually done by reacting the liq-
uid and water-sensitive AsCl3 with the sodium salt of a thiol, the latter
1
3,14
being prepared from the thiol and sodium metal.
The use of the solid
and easily handled As2O3 for the preparation of As(SCH2COOH)3 in wa-
ter was reported in 190422 and we developed the method in order to pre-
pare a wide variety of aromatic and aliphatic trithioarsenites in water,
5
5
methanol, or ethanol solvent with very satisfactory yields. Previously,
and 6 have been prepared by reacting As2O3 with HSCH2COONa in
5
water or the “Na3AsO3” with the HSCH2CH2COOH in water. Now, the
compounds 5–8 have been prepared by neutralizing 1–4 with an equiv-
alent amount of NaOH. An excess of NaOH should be avoided because
5
,23
the trithioarsenites are not stable in alkaline solutions.
The trithioarsenites 4, 7, and 8 could not be studied because of their
low solubilities.

4
16
G. M. Tsivgoulis et al.
Reaction of the Trithioarsenites 1–3, 5, and 6 with Octasulfur
As in the case of aromatic trithioarsenites,21 the acidic esters 1–3 did not
react with octasulfur in chloroform/methanol solutions, indicating that
the As(III) is not nucleophilic enough to open the octasulfur ring. The
reaction can, however, be effected by a catalytic amount (∼20 mol%) of
triethylamine, which reacts with an acidic sulfur-containing impurity
2
4a
(
e.g., H2S, SO2), found even in recrystallized octasulfur,
giving an
anion which, in turn, opens the octasulfur ring giving Impurity-S-S-
−
S6-S . The basic environment of the carboxylate-bearing 5 and 6 in
water is sufficient to open the octasulfur ring presumably by activating
−
the previously mentioned impurity, or by direct reaction of HO on S8,
2
−
2− 24b
which is known to give a variety of products, e.g., S and SO
.
3
−
The penultimate sulfur shown in bold, Impurity-S-S-S6-S , can now
be attacked by the As(III) of the esters 1–3, 5, and 6 in a manner anal-
2
5
ogous to that postulated for the dithioarsonites, Ar-As(SPh)2 and the
aromatic trithioarsenites, (ArS)3As21 to give colored precipitates. The
precipitates were insoluble in all common organic solvents and aque-
ous hydrochloric acid and were decomposed by aqueous sodium hydrox-
ide. Those obtained from 1–3 contained less triethylamine compared to
2
1
those obtained from the aromatic trithioarsenites. From the color and
the solubilities, the orange solids may be mixtures of As4S6 (orange) and
oligomeric (?) As4S4 rings having RS-groups.
While the solids obtained from the aromatic trithioarsenites in
chloroform always contained As2O3 produced at the beginning of the
2
1
reaction, the aliphatic trithioarsenites 1–3, 5, and 6 dissolved in
nondeaerated solvents reacted with octasulfur producing traces only
of As2O3 (Table I). Control experiments (dissolution of 5 or 6 and
10% As2O3 in water, evaporation and drying) showed that As2O3 was
clearly detectable by IR, implying that it was not converted to, e.g.,
NaH2AsO3/NaAsO2, by the alkaline environment. Thus, the aromatic
trithioarsenites studied21 seems to be more vulnerable to As2O3 produc-
tion than the aliphatic ones during the S8/Et3N treatment. The mech-
anism of the As2O3 production has not been elucidated.
Air Oxidation of the Trithioarsenites 1–3, 5–7, and 9–11
The polar esters 1–11 are grouped in three classes: acidic 1–4, basic
5
–8, and zwitterionic 9–11. From Table II it is clear that the acidic 1–3
are oxidized by air much faster than the other two classes and moreover
the oxidative decomposition to As2O3 and, presumably, disulfide is di-
minished with the chain length of the carboxy thiol.

Air Oxidation of Trialkyl Trithioarsenites
417
TABLE I Conditions for the Reaction of Some Aliphatic Thioesters,
RS) As, (0.2 mmol) With Octasulfur (0.6 mmol Sulfur Atoms) and
(
3
Some Characteristics of the Obtained Insoluble, Orange Solids.
N.D. = Not Detected by IR
Solvent
RS/Et3N, RS content,
temperature,
Et3N, Time, Weight,
molar
ratio
% by
weight
Ester
◦
As2O3
N.D.a
C
mol%
h
mg
1
CHCl3/MeOH 1:1
5
CHCl3/MeOH 1:1
5
CHCl3/MeOH 1:1
5
H2O
00
H2O
00
20
24
26
1:0.5
1:0.7
1:0.6
—
11
8
2
2
3
5
6
20
20
0
24
24
9
25
22
21
10
N.D.b
N.D.a
N.D.c
N.D.c
2
13
1
2
1
0
9
—
2
1
a
Traces of As2O3 were detected in the supernatant.
b
c
<10% As2O3 was detected in the supernatant.
As2O3 was not detected in the supernatant.
TABLE II Percent of Oxidative Decomposition of Some Trialkyl
Trithioarsenites, (RS) As, When Stirred in Air at R.T., and Air
3
Oxidation of Some Parent Thiols Under the Same Conditions.
N.D. = Not Detected by IR
%
oxidative decomposition from
As2O3 in
RSSR
from
RSH, %
Molarity
M
Time precipitated
supernatant
(by IR)
Ester
Solvent
days
As2O3
1
CHCl3/MeOH
0.17
0.17
0.17
4
40
N.D.
N.D.
∼ 7
−
−
−
1
:1
CHCl3/MeOH
:1
CHCl3/MeOH
:1
2
3
4
4
32
22
1
1
5
6
7
9
0
1
H2O
H2O
H2O
H2O
H2O
H2O
0.06
0.06
0.06
3
3
3
7
7
7
N.D.
N.D.
N.D.
0
0
0
∼ 10
−
−
−
b
N.D.
a
b
N.D.
c
0.01
<5
0
<2
41
d
1
1
0.004a
0.025
24
13
e
a
Light suspension.
b
−1
Very weak peak at ∼840 cm (NaAsO2 ?).
c
0.35 M.
d
0.40 M.
e0.08 M.

4
18
G. M. Tsivgoulis et al.
The basic 5–7 in water are autoxidized very slowly, if at all (Table II).
Only in the case of 5 did we detected As2O3, while an extremely weak
−
1
peak at ∼840 cm , which can be attributed to NaAsO2 (which, when
2
6
−1
pure, exhibits strong, sharp peaks at 831 and 848 cm ), was seen in
the IR spectra of the air oxidized 6 and 7. Control experiments (e.g, an
aqueous solution of 7 containing As2O3 was freeze dried) showed that
a 10% As2O3 can be seen in the solid state IR spectrum.
The rates of air oxidation of D-penicillamine, L-cysteine, and re-
duced glutathione28 have a maximum at pH ∼ 7.5 and are slow at acidic
and not so slow at alkaline pH. We found that unbuffered aqueous so-
lutions of DL-penicillamine (pH ∼ 5), cysteine (pH ∼ 6), and reduced
glutathione (pH ∼ 4) after 7 days stirring in air were oxidized to their
disulfides to an extent of 41, 24, and 13%, respectively (Table II).
A dilute solution of 9 in water was oxidized by air after 7 days stirring
2
7
28
(
Table II), giving apart from As2O3 (detected by IR), disulfide, and free
1
DL-penicillamine, detected by H NMR. However, no reliable percent-
ages of oxidative decomposition could be obtained from the H NMR
1
spectrum because 9 is sparingly soluble whereas penicillamine and its
disulfide are soluble in water. From the IR spectrum a <5% oxidative
decomposition was estimated (Table II).
An unbuffered suspension of 10 in water did not produce (IR analysis)
any As2O3 after stirring in air for 7 days, while an unbuffered aqueous
solution of 11, stirred in air, produced <2% As2O3 (by IR) and 14%
1
oxidized glutathione by ( H NMR). The latter value is similar to that
obtained from the air oxidation of free reduced glutathione.
Recently, we have studied the air oxidation of aromatic trithioarsen-
ites, (ArS)3As, to As2O3 and ArSSAr, and we found that with electron-
donating para substituted phenyl groups the autoxidation in nonpo-
lar solvents was slow while with electron-withdrawing groups, e.g.,
1
7
chloro and nitro, the autoxidation was much faster. These results
were explained by assuming binding of triplet dioxygen to As(III),
2
9,30
the binding being more favorable with contracted
4d orbitals of
˙
As(III), to give a diradical, (ArS)3A s˙ O O, or a cyclic arsenadioxi-
rane, (ArS)3As(O2), intermediate.17 Any of these intermediates can give
the As(V) esters (ArS)3As O which by expelling a disulfide, ArSSAr,
are reduced to [ArS As O]. The latter, then, oxidatively gives As2O3
and more ArSSAr. Compounds of the type [RS As O], e.g., [(arsenate
reductase)-cys-S As O], was postulated to hydrolytically give (arsen-
ate reductase)-cys SH and H3AsO3. The enzyme prevents the oxida-
tion of cystein to cysteine, while in our case such an inhibition is not
possible and a disulfide, ArSSAr, is produced. In solvents containing
methanol, the rate of the air oxidation generally increased probably be-
31
+
−
17
cause a zwitterion (ArS)3As -O O was formed, which, by hydrogen

Air Oxidation of Trialkyl Trithioarsenites
419
bonding with methanol, was more easily attacked32 by another (ArS)3As
to produce two molecules of (ArS)3As O. In moist solvents the wa-
ter accelerates the air oxidation of some aromatic trithioarsenites
probably because a pentacoordinated arsenic(V) intermediate, (ArS)3
(
HO)As OOH, is formed.
The other route of air oxidation of the trithioarsenites is the
“hydrolysis-oxidation” one, in which stepwise hydrolysis (Eq. (5)) leads
to As(OH)3 and thiol:
H2O
ꢀ
ꢁ
H2O
ꢀ
ꢁ
H2O
(
RS)3As
(RS)2As OH
SR As(OH)2
ꢀ
ꢁ
As(OH)3. (5)
RSH
RSH
RSH
The arsenous acid dehydrates to As4O6 while the thiol is oxidized by
dioxygen to its disulfide:
2RSH + 1/2O2 → RSSR + H2O.
(6)
This route, if followed at all, should be a minor one for aromatic
trithioarsenites because thiols in a neutral environment are not au-
3
3
toxidized to their disulfides in the absence of radical initiators. The
autoxidation of thiols takes place in alkaline media because it is the
−
anion RS which reacts with O2 in the rate determining step, and it is
faster in nonprotic than in protic solvents.34
The nonpolar liquid aliphatic trithioarsenites, mentioned in the in-
1
3,14
troduction, e.g., (RS)3As, R = Et, n-Pr, n-Bu,
are sensitive to air
1
4
oxidation giving As2O3 and presumably RSSR. Their autoxidation
cannot be explained by the “hydrolysis-oxidation” route and, there-
fore, can go only by a diradical, (RS)3As O O or a arsenadioxi-
rane, (RS)3As(O2), intermediate. The hydroxyl-bearing liquid ester,
As(SCH2CH2OH)3, is “fairly stable” to air oxidation and its autoxi-
dation can proceed via an intermediate analogous to 12.
.
.
1
5
A likely explanation of the oxidative decomposition of 1 is based on
the formation of the hydroperoxy intermediate 12 having a 5-membered
and an 8-membered structure. Nucleophilic attack by As(III) of another
1
on the hydroperoxy oxygen (see also ref. 32) will afford two (RS)3As O
molecules, which will decompose to As2O3 and RSSR as described above.
The size of the ring system for 2 and 3 can explain the diminished rates
of their air oxidation (Table II). The alternative “hydrolysis-oxidation”
route cannot a priori be excluded, but the protic solvent and the absence
of base to give the mercaptide ion34 point towards a very slow autoxi-
dation of the carboxy-bearing free thiols generated by Eq. (5).
The very small decomposition of the water-soluble 5 and 6 can be
explained by the prevention of attack by As(III) of another 5 or 6 at the

4
20
G. M. Tsivgoulis et al.
negatively charged hydroperoxy oxygen as shown in 13. The probable
micellar structure of 7 in water makes the detailed understanding of
its unreactivity more difficult.
The detection of free DL-penicillamine during the air oxidation of
9
implies that detachment of the penicillamine molecule had taken
place according to Eq. (5). Then, the facile air oxidation of the penicil-
lamine will give its disulfide. Overall, therefore, the data indicate that
the binding of penicillamine to As(III) protects it from oxidation, and
the air oxidation of 9 most likely proceeds via the “hydrolysis-oxidation”
route. A very dilute suspension of 10 in water is not autoxidized, prob-
ably meaning that hydrolysis according to Eq. (5) does not take place
and that the O2 cannot coordinate to As(III) in 10. This maybe due to
+
+
hydrogen bonding of the NH3 group to As(III) as shown in 14. Then,
O2 cannot displace the NH3 group, and therefore oxidative decom-
position can not take place. The finding that aqueous solutions of 11
in air produce As2O3 and GSSG imply that 11 in water is most likely
autoxidized by the “hydrolysis-oxidation” route and the intermediates,
e.g., (GS)2As OH, are not hydrolysed to As(OH)3.
Summarizing, the rate of oxidation of the biochemically interesting
thiols in unbuffered aqueous solutions is penicillamine > cysteine >
glutathione, and their trithioarsenites are air oxidized at a slower rate
probably by the “hydrolysis-oxidation” route. Therefore, 9–11 them-
selves do not produce reactive oxygen species probably because the
dioxygen binding is not favored.

Air Oxidation of Trialkyl Trithioarsenites
421
EXPERIMENTAL
1-mercaptoundecanoic acid and 16-mercaptohexadecanoic acid were
from Aldrich and were used without further purification. L-glutathione
reduced form) was from Serva. The trialkyl trithioarsenites 1, 2, 5, 6,
1
(
5
and 9–11 were prepared according to Ioannou and colleaques. Octasul-
3
5
fur was recrystallized from carbon disulfide. AR grade solvents and
solutions were deaerated by boiling, flushing with nitrogen, stoppering,
and cooling to r.t.
Arsenic(III) oxide was detected by IR (sharp peak at 802–804 cm 1).26
−
IR spectra were obtained on a Perkin-Elmer model 16PC FT-IR spec-
1
13
trometer. H (400 MHz) and C (100 MHz) NMR spectra were run on a
Bruker DPX Advance spectrometer. Elemental analyses were obtained
through the Center of Instrumental Analyses, University of Patras,
Patras, Greece.
Preparation of the Trithioarsenites 3, 4, 7, and 8
Tris(10-carboxydecyl) trithioarsenite, 3
A suspension of 11-mercaptoundecanoic acid (1.308 g, 6 mmol) and
arsenic(III) oxide (198 mg, 1 mmol As2O3) in deaerated methanol
(
10 mL) was stirred at r.t. for 2 days. Centrifugation and washing with
methanol (1 × 1.5 mL) gave the product, 3, (1.334 g, 92%) as a white
solid, insoluble in MeOH, Me2CO, Et2O, and petroleum ether (peth)
◦
and sparingly soluble in CHCl3 and CS2. M.p. 85–87 C. Calculated for
C33H63O6S3As (Mr726.94): C, 54.52; H, 8.74; S,13.23%; found; C, 54.10;
H, 8.72; S, 13.53% IR (KBr): 3434 w, broad, 2916 vs, 2850 s, 1700 s,
1470 mw, 1432 mw, 1288 mw, 1256 w, 1230 w, 1106 w, 938 w, 720 w, 682 w.
Tris(15-carboxypentadecyl) trithioarsenite, 4
A suspension of 16-mercaptohexadecanoic acid (433 mg, 1.5 mmol)
and arsenic (III) oxide (50 mg, 0.25 mmol As2O3) in deaerated methanol
(
10 mL) was stirred at r.t. for 2 days. Centrifugation and washing with
methanol (1 × 1.5 mL) gave the product, 4, (428 mg, 91%) as a white
solid, insolube in MeOH, Me2CO, CHCl3 peth, and p and sparingly
◦
soluble in CS2. M.p. 96–98 C. Calculated for C48H93O6S3As (Mr 937.33):
C, 61.50; H, 10.00; S, 10.26%; found: C, 61.84; H, 10.20; S, 10.36% IR
(
KBr): 3432 w, broad, 2918 vs, 2850 s, 1700 m, 1470 mw, 1436 w, 1292
w, 1254 w, 1216 w, 948 w, 718 w, 670 w.
Trisodium Salt of tris(carboxymethyl) trithioarsenite, 5
To a solution of the acid 1.1/2H2O (209 mg, 0.6 mmol) in methanol
5 mL) a solution of sodium hydroxide (72 mg, 1.8 mmol) in methanol
(

4
22
G. M. Tsivgoulis et al.
(
1 mL) was added and stirred at r.t. for 4 h. Centrifugation and washing
with methanol (1 × 1.5 mL) gave the salt 5 (210 mg, 85%), m.p. 240–
◦
5
◦
2
41 C dec. (lit. 238–240 C dec). IR (KBr): same as in ref. 5.
Trisodium Salt of tris(α-carboxyethyl) trithioarsenite, 6
To a solution of the acid 2 (195 mg, 0.5 mmol) in methanol (5 mL), a
solution of sodium hydroxide (60 mg, 1.5 mmol) in methanol (1 mL) was
added and stirred at r.t. for 1 h. The solution was concentrated until
opalescence, warmed, transferred to a centrifuge tube and the product
precipitated by adding acetone (6 mL). Washing with acetone (1 × 2 mL)
◦
5
◦
and drying gave the salt 6 (234 mg, 92%), m. p. 212 C dec. (lit. 210 C
dec.) IR (KBr): same as in ref. 5.
Trisodium Salt of tris(10-carboxydecyl) trithioarsenite, 7
To a suspension of 3 (145 mg, 0.2 mmol) in methanol (5 mL) a solution
of sodium hydroxide (24 mg, 0.6 mmol) in methanol (5 mL) was added
and stirred at r.t. for 2 days. Concentration to a small volume, centrifu-
gation of the fluffy solid, and washing with methanol (1 × 1.5 mL) gave
◦
the product 7 as a white solid, (137 mg, 86%). M.p. 254–259 C dec.
It is insoluble in peth, CS2, CHCl3 Et2O, Me2CO, and slightly soluble
in MeOH and H2O. Calculated for C33H60O6S3AsNa3 (Mr 792.89): C,
49.98; H, 7.63%; found; C, 49.70; H 7.60%. IR (KBr): 3422 mw, broad,
2918 s, 2848 vs, 1560 vs, 1470 m, 1442 m, 1422 m, 1300 w, 924 w, 718 w,
698 w.
Trisodium Salt of tris(15-carboxypentadecyl) trithioarsenite, 8
To a suspension of 4 (188 mg, 0.2 mmol) in methanol (5 mL) a so-
lution of sodium hydroxide (24 mg, 0.6 mmol) in methanol (5 mL)
was added and stirred at r.t. for 2 days. Centrifugation of the fluffy
solid gave the product 8 as a white powder (194 mg, 96%), insoluble in
◦
MeOH, Me2CO, CHCl3, and H2O. M.p. 257–264 C. dec. Calculated for
C48H90O6S3AsNa3 (Mr 1003.28): C, 57.50; H, 9.04%; found: C 57.27; H,
9
1
.19%. IR (KBr): 3422 mw, broad, 2918 vs, 2850 vs, 1560 vs, 1468 m,
440 ms, 1420 ms, 1300 w, 1260 w, 924 w, 718 mw.
Reaction of the Trithioarsenites 1–3 with S /Et N
8
3
A solution of 2 (98 mg, 0.25 mmol) and octasulfur (8 mg, 0.25 mmol
sulfur atoms) in chloroform/methanol 1:1 (6 mL) was stirred in air at
r.t. Octasulfur was always detected by TLC (silica gel, petroleum ether,
Rf 0.80) and the solution gradually deposited a solid. After 24 h, cen-
trifugation gave 9 mg of a yellowish solid, which, by IR, was octasulfur
contaminated by traces of 2 and As2O3.

Air Oxidation of Trialkyl Trithioarsenites
423
To a solution of 1, 2, or 3 (0.2 mmol) in chloroform/methanol 1:1
5 mL), octasulfur (19 mg, 0.6 mmol sulfur atoms) was suspended.
(
Triethylamine (6 µl, 0.04 mmol, 20 mol%) was added and the solu-
tion was stirred at r.t. for 24 h. A white suspension was formed which
in ∼1.5 h became yellow and in ∼2 h an orange solid formed. Cen-
trifugation gave the orange solid, which was insoluble in all solvents
and decomposed by aqueous sodium hydroxide. To weighed samples
of the solids containing known amounts of benzylarsonic acid (as in-
ternal standard), D2O and solid NaOH were added, and the decol-
1
orized solutions were analyzed by H NMR. The results are shown in
Table I. Evaporation of the chloroform/methanol supernatant gave a
solid, which was examined for As2O3 by IR. Data are also shown in
Table I.
Reaction of the Trithioarsenites 5, 6 with S8
To 5 or 6 (0.2 mmol) dissolved in water (1.5 mL) in a centrifuge
tube, octasulfur (0.6 mmol sulfur atoms) was added and stirred in an
◦
oil bath at 110 C for 9 h. After cooling at r.t., centrifugation, wash-
ing with water (1.5 mL), acetone (1.5 mL), and carbon disulfide (1.5
mL) gave an orange solid insoluble in all solvents and decomposing
in aqueous sodium hydroxide. The percentage of the RS groups in
1
the solid was determined by H NMR, as previously mentioned. The
◦
supernatants were combined, evaporated (rotary 50 C), and dried to
a solid which was examined, by IR, for As2O3. Data are shown in
Table I.
Air Oxidation of the Trithioarsenites 1–3
A solution of 1, 2, or 3 (0.5 mmol) in chloroform/methanol 1:1 (3 mL),
was stirred in air for 4 days at r.t., and the solvent was replenished
from time to time. The solution was evaporated and dried. An ad-
dition of acetone (3 mL) and centrifugation left pure As2O3 (by IR)
from which the oxidative decomposition of the esters was calculated
(
Table II).
Air Oxidation of the Trithioarsenites 5–7
The ester 5 or 6 (0.25 mmol) dissolved (while 7 gave a light suspen-
sion) in water (4 mL) and was stirred at r.t. for 3 days. Then, acetone
(
40 mL) was added and centrifuged. The solid and the supernatant, af-
ter evaporation and drying, were analyzed by IR for As2O3. The results
are shown in Table II.

4
24
G. M. Tsivgoulis et al.
When a 0.01 M aqueous solution of 7 was stirred at r.t. for 24 h an
opalescence developed in 10 min and gradually a white solid formed.
Freeze drying and IR (KBr) examination revealed that about half the
COONa groups have been protonated by (CO2 + H2O) giving the water
insoluble 3. As2O3 was not present in the solid.
Relative Rates of Air Oxidation of the Trithioarsenites 9–11
and Their Parent Thiols
A 0.01 M solution of 9 in water was stirred in air for 7 days. Evaporation
◦
1
(
rotary, 50 C) and drying gave a solid which, by IR, had <5% As2O3. H
NMR of a saturated solution of the solid in D2O showed the presence of
2
7,36
disulfide and peaks due to free DL-penicillamine.
A 0.35 M solution
of DL-penicillamine in water was air oxidized to its disulfide to an extent
1
of 25% in 3 days and 41% in 7 days ( H NMR analysis).
The ester 10 (10 mg) was suspended in water (6 mL) and stirred in
air for 7 days. Evaporation and drying gave a white solid which, by IR,
did not contain As2O3. A 0.4 M solution of cysteine in water stirred in
air precipitated cystine corresponding to a 10% oxidation in 3 days and
a 24% oxidation in 7 days.
A solution of 11 (25 mg) in water (1 mL) was stirred in air for 7 days.
Evaporation and drying gave a solid which, by IR, contained <2%
1
13
As2O3. The H and C NMR spectra of the solid in D2O showed the
3
,4,7
presence of 11
and 14% of glutathione disulfide. A 0.08 M solution
of reduced glutathione in water that was stirred in air for 7 days was
1
oxidized to glutathione disulfide to an extent of 13% ( H NMR analysis).
Control experiments (solutions or emulsions of 9–11 and 10% by
weight As2O3 were freezed-dried) showed that As2O3 was very clearly
seen in their IR spectra.
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