Preparation of 2-picolylarsonic acid and its reductive cleavage by ascorbic acid/iodine and by thiophenol

Article abstract of DOI:10.1080/10426500214875

Contrary to dialkylaminoethyl halides, 2-picolyl chloride reacts with alkaline arsenite to give nearly quantitative yields 2-picolylarsonic acid. This acid is decomposed by ascorbic acid in the presence of catalytic amounts of iodine to 2-picoline and arsenious acid, most likely by hydride transfer from the ascorbic acid. Thiophenol decomposes this arsonic acid very quickly to 2-picoline, diphenyl disulfide and triphenyl trithioarsenite. In this case a proton from the thiophenol is transferred to the incipient 2-picolyl carbanion.

Full text of DOI:10.1080/10426500214875

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Preparation of 2-Picolylarsonic Acid and its Reductive
Cleavage by Ascorbic Acid/Iodine and by Thiophenol
a
a
b
Panayiotis V. Ioannou , Pantelis A. Afroudakis & Michael G. Siskos
a
University of Patras , Patras, Greece
b
University of Ioannina , Ioannina, Greece
Published online: 27 Oct 2010.
To cite this article: Panayiotis V. Ioannou , Pantelis A. Afroudakis & Michael G. Siskos (2002) Preparation of 2-Picolylarsonic
Acid and its Reductive Cleavage by Ascorbic Acid/Iodine and by Thiophenol, Phosphorus, Sulfur, and Silicon and the Related
Elements, 177:12, 2773-2783, DOI: 10.1080/10426500214875
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Phosphorus, Sulfur and Silicon, 2002, Vol. 177:2773–2783
Copyright �C 2002 Taylor & Francis
1
042-6507/02 $12.00 + .00
DOI: 10.1080/10426500290146767
PREPARATION OF 2-PICOLYLARSONIC ACID AND
ITS REDUCTIVE CLEAVAGE BY ASCORBIC
ACID/IODINE AND BY THIOPHENOL
a
a
Panayiotis V. Ioannou, Pantelis A. Afroudakis,
b
and Michael G. Siskos
University of Patras, Patras, Greece and University
of Ioannina, Ioannina, Greeceb
a
(
Received April 4, 2002)
Contrary to dialkylaminoethyl halides, 2-picolyl chloride reacts with al-
kaline arsenite to give nearly quantitative yields 2-picolylarsonic acid.
This acid is decomposed by ascorbic acid in the presence of catalytic
amounts of iodine to 2-picoline and arsenious acid, most likely by hy-
dride transfer from the ascorbic acid. Thiophenol decomposes this ar-
sonic acid very quickly to 2-picoline, diphenyl disulfide and triphenyl
trithioarsenite. In this case a proton from the thiophenol is transferred
to the incipient 2-picolyl carbanion.
Keywords: 2-Picolyl chloride; arsonic acids; ascorbic acid; di-
alkylaminoethyl halides; picolylarsonic acid; the Meyer reaction;
thiophenol
INTRODUCTION
In the past years we developed methods for the synthesis of arso-
nolipids,1 1, and arsinolipids, 2, which are nonisosteric analogues of
the phospholipids phosphatidic acid and phosphatidyldiglyceride (bis-
phosphatidic acid) respectively. Isosteric arsenic analogues of phospho-
lipids, that is, those containing a C O As group, cannot be prepared
–3
4
5
6
because the As OR group is hydrolytically very unstable. Isosteric
6
7
analogues, 3, have been prepared but in low overall yields.
We thank Professor S. G. Antimisiaris (Department of Pharmacy, University of Patras)
for checking the activity of 2-picolylarsonic acid against the cells reported herein.
Address correspondence to Panayiotis V. Ioannou, Department of Chemistry, Univer-
sity of Patras, Patras, Greece. E-mail: ioannou@chemistry.upatras.gr
2
773

2
774
P. V. Ioannou et al.
FORMULA 1
3
The arsonolipids 1 form liposomes as phospholipids do, but due to
different size and polarity of the AsO3H2 group they are disc-like, and
8
one of these lipids forms tubules. Biochemically, the arsonolipids 1 are
9
substrates (the R but not the S isomers) for phospholipase A2 and are
potent inhibitors of carbonic anhydrase, isozyme II.10
Another difference between As(V) and P(V) is that the former can
be very easily reduced by thiols to “thioarsenites” (vide infra). In fact
the therapeutic importance of arsonic acids against protozoal infec-
11,12
tions is due to their reaction with sulfhydryl enzymes.
This re-
duction is shown by arsonolipids 1, and the dithioarsonites obtained
are inhibitors of carbonic anhydrase, isozymes I and II.1 Therefore,
arsonolipid-containing liposomes should have biological activity and
this recently was shown by demonstrating a selective toxicity towards
3
1
4
certain cancer cell lines.
Extending the range of arsinolipids, which can be prepared, we fo-
cused on the nonisosteric analogues of phosphatidylethanolamine and
phosphatidylcholine, 4. One strategy for the preparation of 4 is to re-
act 2-chloroethylamine or 2-chlorotrimethylammonium chloride with
1
5
alkaline arsenite (the Meyer reaction ) to get the compounds 5. These
will be reduced to their arsenoso compound, (Y CH2CH2 AsO)x, with
ascorbic acid/iodine or triphenylphosphine/iodine16 and then following
4
the series of reactions described in Kordalis and Ioannou the arsino-
lipids 4 will be obtained.
FORMULA 2

Preparation of 2-Picolylarsonic Acid and its Reductive Cleavage
2775
However, 2-chloroethyldiethylamine or 2-bromoethyldiethylamine
and methyl-2-chloroethyldiethylammonium chloride do not react with
1
7
alkaline arsenite. The first substrate was largely unattacked and
small amounts of diethylaminoethanol and of an unsaturated amine
were detected. Hypothesizing that unreactivity of the above substrates
is due to the tetrahedral nitrogen atom causing steric hindrance in
the approach of the bulk nucleophile,1 :AsO3 , to the electrophilic car-
bon, we tried the Meyer reaction with 2-picolyl chloride in which the
nitrogen is trigonally hybridized. In this communication we describe
the facile synthesis of 2-picolylarsonic acid and its reductive decom-
position by triphenylphosphine/iodine, by ascorbic acid/iodine and by
thiophenol.
8
3�
RESULTS AND DISCUSSION
The nearly quantitative conversion of 2-picolyl chloride into 2-
picolylarsonic acid using the Meyer reaction is in sharp contrast to
inability17 of 2-chloroethyldiethylamine to afford any arsonic acid under
the same conditions. A possible explanation is as follows. It is known1
that in dilute aqueous solutions dialkylaminoethyl chlorides are in equi-
librium with their aziridinium cations which then react with various
nucleophiles by ring opening. The Meyer reaction with epoxides as sub-
9
1
8
strates was found to follow SN2 kinetics and the nucleophile was the
trianion AsO3 which is present in minute amounts in the alkaline
�
3
3�
arsenite solutions. Since AsO3 opens the epoxide ring it is expected
that it should open the aziridinium ring much more easily. That it does
not, probably is due to the very small concentrations of these reactants
under the Meyer reaction conditions. The reason why the AsO3 nu-
�
3
cleophile does not attack the dialkylaminoethyl chloride (or bromide)
may be due to steric hindrance by the tetrahedral nitrogen to the ap-
2
0
3�
proach of the bulky, hydrated, tetrahedral, :AsO3 to the electrophilic
carbon. A similar explanation can be given for the inertness of methyl-2-
1
7
21
chloroethyldiethylammonium chloride and 1,2-dibromoethane un-
der the Meyer conditions. The reaction of methyl tosylate with alkaline
1
7
arsenite was sluggish, but it gave methylarsonic acid in the presence
of iodide22 most likely via methyl iodide. We also found that aliphatic
23
3�
mesylates, amsylates, and [3]betylates do not react with AsO3 but
with the HO , which is present in the system, attributing the negative
�
results to steric hindrance. It seems, therefore, that the bulkiness of
the �-substituent exerts a significant effect in the Meyer reaction. In
the case of 2-picolyl chloride the nitrogen, being trigonally hybridized,
3
3
�
leaves room for the AsO to attack at the �-carbon.

2
776
P. V. Ioannou et al.
The solid state IR spectrum of 2-picolylarsonic acid shows an N H
�
1
stretching vibration at 2332 cm and therefore it is a zwitterion. Con-
�
1
� 1
sequently, the �(As O) moved to 904 cm compared to 940 cm in
2
4
simple aliphatic arsonic acids, while the �(As OH) remained at the
�
1
1
same position, 786 cm . The H-NMR spectrum of 2-picolylarsonic acid
in D2O showed the CH2 protons at 3.91 ppm, nearly at the same position
(
3.96 ppm) with the CH2 protons of benzylarsonic acid in D2O.
The reduction of arsonic acids to arsonous acids, RAs(OH)2, or ar-
senoso compounds, (RAsO)x, is usually effected by catalytic amounts of
16
I2 and a coreductant, such as SO2, Ph3P, or ascorbic acid. The core-
ductant reduces the I2 to HI thereby being oxidized. The HI is then
the actual reducing agent of the AsO3H2 group, being oxidized to
I2. Before being reduced, the AsO3H2 group must be converted to an
+
+
+
As (OH)2OY species, either by H or by Ph3P OMe, and then the
�
+
16
I adds to As to give a pentacoordinated intermediate.
In the absence of iodine, equimolar amount of triphenylphosphine
did not attack, as expected, the substrate 2-picolylarsonic acid. In its
presence it reacted but very slowly indicating that the nitrogen on the
substrate poisons the system. Since triphenylphosphine oxide was de-
tected by TLC, then the 2-picolylarsenoso compound must have been
1
6
1
formed and it was detected by H-NMR [(ArCH2AsO)x : 3.46 ppm com-
pared to (PhCH2AsO)x: 3.50 ppm ]. Its amount was small. Thus, the
1
6
main route that has been followed was the attack of a nucleophile (most
16
probably the Ph3P) on the �-carbon of the intermediate with the ex-
�
pulsion of H2AsO which was isolated as As2O3.
3
Since the system PhP3/I2 causes extensive C As bond cleavage when
the bond is weak, we tried the milder system ascorbic acid/iodine.
Ascorbic acid gave dehydroascorbic acid (by TLC) in the presence but
not in the absence of iodine. The only product that we were able to isolate
1
was impure 2-picoline. The impurity from the H-NMR spectrum was
the 2-picolylarsenoso compound. Only traces of arsenic(III) oxide were
precipitated in experiments designed to isolate it. Clearly, the ascorbic
acid/iodine system decomposed the arsonic acid. Since in the presence
of hydrochloric acid, instead of hydro iodic acid, no reaction took place,
it seems that the hydro iodic acid is required to activate the AsO3H2
group, as in the case of 2-arsonohexanoic acid.25 When the polarity of the
solvent increased (methanol/water 1:1 and water) then the decomposi-
tion was greatly inhibited. This indicates that the activated complex is
less polar than the reactants. A plausible activated complex is shown
in Scheme 1. In this, as in the case of 2-arsonohexanoic acid,2 ascor-
bic acid reduces the substrate most likely by hydride transfer because
we did not detect the ascorbic acid radical by ESR. The zwitterionic
form of the 2-picolylarsonic acid would help the hydride transfer by
5

Preparation of 2-Picolylarsonic Acid and its Reductive Cleavage
2777
SCHEME 1 Proposed activated complex for the C-As bond fission of 2-picolyl-
arsonic acid by ascorbic acid.
hydrogen-bonding to the OH group on C-2 thus forming a six-
�
membered ring in the activated complex and the As O would abstract
the proton from the acidic OH group on C-3. The resulting I As(OH)2
will solvolyze to MeO As(OH)2 and HI. The latter will start another
activation cycle faster than being oxidized by ascorbic acid.
This is a third example in which it is suggested that ascorbic acid
may act as a hydride donor instead of a two one-electron reductant;
26
the other cases being the reduction of 2,6-dichloroindophenol and 2-
2
5
arsonohexanoic acid.
A still milder reducing agent for the AsO3H2 and AsO2H groups
0
27
is a thiol, which gives a dithioarsonite, R-As(SR )2, or thioarsinite,
0
28
R2As-SR respectively. We used these functionalities en route to the
preparation of 1 and 2. More recently, the RAs(SR )2 was exploited as
a precursor of the nucleophile RAsO for the construction of more com-
plex arsinolipids. Therefore we tried the reduction of 2-picolylarsonic
acid with thiophenol in an attempt to achieve the preparation of a
close analogue of 4. However, the reduction followed equation (1) (Ar =
3
,4
0
2
�
2
2
9
2
-pyridyl):
Ar CH2 AsO3H2 + 5PhSH → Ar CH3 + PhSSPh + (PhS)3As + 3H2O
1)
(
0
For the reduction of arsonic acids by thiols to RAs(SR )2 the mecha-
0
11
nisms proposed involve an R-As(SR )4 intermediate or an R-As(OH)2
0
27,30
16
one via R-As(OH)2(SR )2,
and we proposed a concerted addition of
a thiol to the As O group of the substrate. A plausible mechanism

2
778
P. V. Ioannou et al.
SCHEME 2 Proposed mechanism for the reductive decompositions of 2-
picolylarsonic acid by thio phenol(Ar = 2-pyridyl).
for the reaction (1) is shown in Scheme 2. Thiophenol attacks the
As O of the unionized 2-picolylarsonic acid because the reaction is
favoured when the reagents are unionized,31 eventually giving the
2
-picolylarsonous acid. Evidence for this was obtained by analyzing

Preparation of 2-Picolylarsonic Acid and its Reductive Cleavage
2779
by TLC the supernatant and the oil which was formed 5 min after
mixing of the reactants. The oil and the supernatant, when devel-
oped in Et2O/petr. ether 1:5, showed the presence of both PhSSPh and
(
PhS)3As and of a compound which charred at Rf � 0. When developed in
MeOH/conc. NH3 4:1 they showed no charred 2-picolylarsonic acid at Rf
.50 but a spot at Rf 0.60 due to “(NH4)3AsO3” and a charred compound
at Rf � 0.90. The charred compound should be the 2-picolylarsonous
0
3
3
�
acid and the AsO should have been formed by basic hydrolysis of
(
PhS)xAs(OH)3� x during the development. Normally the arsonous acids
2
7
32
are further reduced to dithioarsonites with a concerted mechanism
shown in Scheme 1. However, in our case, because of the resonance and
inductive effects of the nitrogen in the ring, the CH2 group is forced to
withdraw electronic charge from the less electronegative As(III) (com-
pared to As(V) in 2-picolylarsonic acid) and therefore the proton of the
thiol is attracted to the partially negatively charged CH2 group instead
to the OH group. These effects also made possible the stabilization
and, therefore, the detection of 2-picolylarsonous acid, while, when the
reduction gives the dithioarsonite, the intermediate arsonous acid re-
31
acts with the thiol faster than being formed [see also Serves et al.,
von D o¨ llen,33 Scott et al ].
34
EXPERIMENTAL
2
-Picolyl chloride hydrochloride and triphenylphosphine were from
Aldrich, while ascorbic acid and thiophenol from Merck. Methanol
was not dried over molecular sieves because wet methanol should be
used for reductions with ascorbic acid/iodine.35 De-aerated solutions
were prepared by boiling, stoppering, and cooling to room tempera-
ture (r.t.). Silica gel H (Merck) was used for thin-layer chromatography
(
TLC). TLC was run on microslides using, where possible, appropriate
standards. Visualization was effected first by iodine vapour (for triph-
enylphosphine, triphenylphosphine oxide, 2-picoline and “AsO3
�
”
23
fol-
3
lowed by spraying with 35% sulfuric acid and charring. PhS-containing
molecules gave a pink, then a purple and finally a very faint black spot,
while 2-picolylarsonic acid gave a characteristic green spot before be-
3
�
ing charred. Arsenic(III) oxide was detected as “AsO ” on TLC and
3
3
6
� 1
confirmed by IR (sharp peak at 802 cm ). IR spectra were taken
1
on a Perkin-Elmer model 16PC FT-IR spectrometer. H-NMR spectra
were run on a Brucker DPX Avance (400 Mz) spectrometer. Electron
spin resonance (ESR) measurements at r.t. were taken on a Varian
E-109 spectrometer. Elemental analyses were done by CNRS,
Vernaison, France.

2
780
P. V. Ioannou et al.
Synthesis of 2-Picolylarsonic Acid
To a solution of arsenic(III) oxide (2.970 g, 15 mmol As2O3) dissolved
in 9.2 ml 13 M aqueous sodium hydroxide (120 mmol NaOH), solid
2
-picolyl chloride hydrochloride (4.920 g, 30 mmol) was added portion-
wise, over 2 h, at r.t. The color changed from light orange to brown and
sodium chloride precipitated. The system was stirred at r.t. for 3 days
and then at 100 C for 6 h. TLC (MeOH/conc. NH3 4:1) showed that the
�
reaction was over in � 2 days, the product having Rf 0.50. The cooled
(
ice-water) system was neutralized with 12 M hydrochloric acid (cal-
�
culated for 60 mmol HO : 5 ml), whereupon the product and sodium
chloride precipitated. After centrifugation the product was extracted
with boiling methanol (5 � 30 ml). The dark red methanolic extracts
were concentrated to � 20 ml and centrifuged to give a colored product.
This was triturated with acetone (6 ml) leaving the product (4.227 g,
�
6
5%) as a very pale brownish solid. M.p.: at 165 C turns orange/red and
�
at 166–167 C melts to an orange oil. It is soluble in water and in boiling
methanol and insoluble in acetone, acetonitrile, chloroform, and ethyl
acetate. Calculated for C6H8NO3As : C 33.20, H 3.71%. Found C 33.37,
H 3.70%. IR (KBr) : 3440 broad w, 2972 m, 2930 w, 2724 broad w, 2332
broad m, 1598 s, 1572 w, 1480 w, 1440 w, 1310 w, 1254 w, 1192 w, 1086 w,
1
1
3
8
058 w, 1020 w, 904 s, 786 vs, 748 m, 638 w, 470 m. H-NMR (D2O), � :
.91 (s, 2H, CH2), 7.78 (t, J 6.6 Hz, 1H, H-5), 7.83 (d, J 8.0 Hz, 1H, H-3),
.34 (t, J 7.8 Hz, 1H, H-4), 8.59 (d, J 6.4 Hz, 1H, H-6).
The dark red methanol supernatant and the light orange acetone
extract were combined and evaporated to give 1.96 g brown solid. This
was dissolved in boiling methanol (5 ml); acetone (3 ml) was added and
left at r.t. to crystallize. Centrifugation gave slightly impure product
�
(
1.342 g, 21%), m.p. 163–165 C. The supernantant, by TLC, contained
�
100 mg of product.
The 2-picolylarsonic acid, dissolved in water, was inactive against
human leukaemia cells (HL-60) and healthy human umbilical vein en-
dothelian cells (HUVEC).
Reduction of 2-Picolylarsonic Acid
With Triphenylphosphine/Iodine
2
-Picolylarsonic acid (109 mg, 0.5 mmol) was dissolved by boiling in
methanol (3 ml), stoppered and cooled to r.t. Triphenylphosphine (131
mg, 0.5 mmol) was added under nitrogen and the system stirred at r.t.
for 3 h. TLC (Et2O) showed no triphenylphosphine oxide at Rf 0.16.
Iodine (4 mg, 3 mol%) was then added and the system stirred at r.t.
for 30 h. The starting acid dissolved after 5 h and the triphenylphos-
phine after 24 h. Evaporation and drying in vacuo gave a brownish

Preparation of 2-Picolylarsonic Acid and its Reductive Cleavage
2781
solid (233 mg) which was extracted with ether (3 � 3 ml) (to remove
triphenylphosphine oxide and triphenylphosphine which did not react)
and then with chloroform (3 � 3 ml). In the extracts we detected by
1
H-NMR 2-picolylarsenoso compound [singlet at 3.46 ppm which can be
attributed16 to (ArCH2AsO)x]. The solid was extracted with methanol
(
1 � 2 ml) leaving As2O3 (32 mg), corresponding to 64% C As bond
fission. Evaporation of the methanol gave impure 2-picolylarsonic acid
(
30 mg, 28% recovery).
When 0.75 mmol triphenylphosphine was used, then after 3 days
stirring, triphenylphosphine (33 mg) was recovered as methanol insol-
uble, and arsenic(III) oxide (39 mg) was isolated, corresponding to 77%
C As bond fission. We did not recover 2-picolylarsonic acid.
With Ascorbic Acid/Iodine
2
-Picolylarsonic acid (0.4340 g, 2 mmol) was suspended in de-aerated
methanol (12 ml) and flushed with nitrogen. Ascorbic acid (0.423 g, 2.4
mmol) was added and the system stirred at r.t. for 2 h. No reaction took
place (as judged from TLC). Iodine (16 mg, 3 mol%) was then added
and the system stirred at r.t. for 5 h. A clear solution was obtained after
�
4 h. TLC (Et2O/Me2CO 1:1) showed only the dehydroarscorbic acid
and the excess of ascorbic acid while in MeOH/conc. NH3 4:1 no starting
acid was detected. Concentrated hydrochloric acid (4 drops, >2 mmol
HCl) was added and the solution evaporated and dried in vacuo to give
an orange-brown solid. It was dissolved in 2 ml of saturated sodium
carbonate, saturated with sodium chloride, and extracted with ether
(
2
3 � 5 ml). The ether extracts were dried (Na2SO4), evaporated (rotary,
�
0 C) and the residue dried with a hair drier to give a smelly oil (TLC :
CHCl3, Rf 0.20; ether/petr. ether 1:5, Rf 0.08; petr. ether, Rf 0.0) which
was slightly impure 2-picoline (88 mg, 45%). Its IR spectrum was similar
to that of pure 2-picoline and no peak due to �(As O) of (ArCH2AsO)x in
�
1
1
the region 700–800 cm was present. Its H NMR spectrum in CDCl3
was the same with that of pure 2-picoline but contained a singlet at
3
1
6
.46 ppm which can be attributed to (ArCH2AsO)x. From the aqueous
phase we could not isolate any arsenic(III) oxide.
When the reaction was run in methanol/water 1:1 or in water as sol-
vents in the absence of iodine, no decomposition was found by TLC after
2
h. Addition of iodine (3 mol%) and stirring under nitrogen for 22 h the
arsonic acid was still present and small amounts and traces of 2-picoline
were detected (by TLC) in methanol/water and water, respectively.
For the detection of ascorbic free radical, solutions of the reactants in
de-aerated methanol and in methanol/water 1:1 were prepared under
argon. No ESR signal was detected in the absence and in the presence
of iodine (3 mol%) 15 and 90 min after the addition of iodine.

2
782
P. V. Ioannou et al.
When instead of I2, methanolic hydrogen chloride (5 mol%) was used,
no reaction took place in methanol after 24 h stirring at r.t.
With Thiophenol
2
-Picolylarsonic acid (108 mg, 0.5 mmol) was dissolved in boiling
methanol (2 ml), stoppered and cooled to r.t. Thiophenol (0.26 ml, 2.5
mmol) was added and the solution stirred at r.t. After 5 min an oil
precipitated which after 3 min became solid. More solid deposited af-
terward. After 2 h the system was transferred to a centrifuge tube,
centrifuged and washed with methanol (2 � 1.5 ml). The solid (244 mg)
was (PhS)3As contaminated by PhSSPh (by TLC : petroleum ether, Rf
0
.12 and 0.40 respectively). Most PhSSPh was extracted by trituration
with petroleum ether (1 � 1.5 ml) leaving impure (PhS)3As (175 mg,
�
31
�
1
expected 201 mg), m.p. 88–90 C (lit. 93–95 C). Its IR and H-NMR
3
1
spectra were similar to pure (PhS)3As. The methanol supernatant,
smelling 2-picoline, contained (by TLC) PhSSPh, a small amount of
(
PhS)3As, and 2-picoline. It was acidified with methanolic hydrochlo-
ric acid (0.5 mmol HCl), evaporated and dried to give a white solid
147 mg). Trituration with warm petroleum ether (2 � 1.5 ml) left the
-picoline hydrochloride (55 mg, expected 65 mg) as an off-white very
(
2
1
hygroscopic solid. H-NMR (D2O), � : 2.69 (d, J 3.6 Hz, 3H, CH3),
7
4
.77 (m, 2H, (H-3) + (H-5) 8.36 (quartet, 1H, J 4 Hz, H-4), 8.50 (t, J
Hz, 1H, H-6). Finally, all the petroleum ether extracts were pooled,
evaporated, and dried to give PhSSPh [contaminated with (PhS)3As]
�
37
�
(
152 mg, expected 109 mg), m.p. 55–57 C (lit. 61–62 C). Its IR and
1
H MR spectra resemble those of pure diphenyl disulfide.
REFERENCES
[
[
[
1] G. M. Tsivgoulis, D. N. Sotiropoulos, and P. V. Ioannou, Phosphorus, Sulfur, and
Silicon, 57, 189 (1991).
2] G. M. Tsivgoulis, D. N. Sotiropoulos, and P. V. Ioannou, Phosphorus, Sulfur, and
Silicon, 63, 329 (1991).
3] S. V. Serves, D. N. Sotiropoulos, P. V. Ioannou, and M. K. Jain, Phosphorus, Sulfur,
and Silicon, 81, 181 (1993).
[
[
[
[
4] N. L. Kordalis and P. V. Ioannou, Appl. Organometal. Chem., 14, 273 (2000).
5] R. Engel, Chem. Rev., 77, 349 (1977).
6] J. W. Long and W. J. Ray, Biochemistry, 12, 3932 (1973).
7] S. V. Serves, D. N. Sotiropoulos, and P. V. Ioannou, Phosphorus, Sulfur, and Silicon,
1
06, 75 (1995).
[
[
8] D. Fatouros, O. Gortzi, P. Klepetsanis, S. G. Antimisiaris, M. C. A. Stuart, A. Brisson,
and P. V. Ioannou, Chem. Phys. Lipids, 109, 75 (2001).
9] J. Rogers, B.-Z. Yu, S. V. Serves, G. M. Tsivgoulis, D. N. Sotiropoulos, P. V. Ioannou,
and M. K. Jain, Biochemistry, 35, 9375 (1996).
[
10] C. T. Supuran, S. V. Serves, and P. V. Ioannou, J. Inorg. Biochem., 62, 207 (1996).

Preparation of 2-Picolylarsonic Acid and its Reductive Cleavage
2783
[
[
11] A. Cohen, H. King, and W. I. Strangeways, J. Chem. Soc., 3043 (1931).
12] L. S. Goodman and A. Gilman, The Pharmacological Basis of Therapeutics
Macmillan, New York, 1975), 5th ed., pp. 924–928.
(
[
13] D. Timotheatou, P. V. Ioannou, A. Scozzafava, F. Briganti, and C. T. Supuran, Metal-
Based Drugs, 3, 263 (1996).
[
14] O. Gortzi, E. Papadimitriou, C. G. Kontoyannis, S. G. Antimisiaris, and P. V. Ioannou,
Pharmaceutical Res., 19, 79 (2002).
[
[
[
[
15] G. Meyer, Ber. Dtsch. Chem. Ges., 16, 1439 (1883).
16] P. V. Ioannou, Appl. Organometal. Chem., 14, 261 (2000).
17] G. A. C. Gough and H. King, J. Chem. Soc., 2426 (1928).
18] S. V. Serves, D. N. Sotiropoulos, P. V. Ioannou, and H. B. F. Dixon, Phosphorus,
Sulfur, and Silicon, 90, 103 (1994).
[19] B. Cohen, E. R. Van Artsdalen, and J. Harris, J. Am. Chem. Soc., 74, 1878 (1952).
[20] T. M. Loehr and R. A. Plane, Inorg. Chem., 7, 1708 (1968).
[21] A. J. Quick and R. Adams, J. Am. Chem. Soc., 44, 805 (1922).
[22] M. Nagazawa, T. Hamazaki, and I. Okuda, Jap. Pat. No. 6764 (1963); Chem. Abst.,
5
9, 11567b (1963).
[
23] G. M. Tsivgoulis, D. N. Sotiropoulos, and P. V. Ioannou, Phosphorus, Sulfur, and
Silicon, 81, 181 (1998).
[
[
[
[
[
24] U. Dietze, J. Prakt. Chem., 313, 889 (1971).
25] P. V. Ioannou and M. G. Siskos, Appl. Organometal. Chem., 15, 511 (2001).
26] T. S. Rao, N. R. Kale, and S. P. Dalvi, React. Kinet. Catal. Lett., 34, 179 (1987).
27] H. J. Barber, J. Chem. Soc., 1020 (1929).
28] N. A. Chadaeva, G. K. Kamai, and G. M. Usacheva, J. Gen. Chem. USSR, 36, 718
(1966).
[
[
[
29] P. V. Ioannou, Chem. Phys. Lipids, 117(7) (2002).
30] W. R. Cullen, B. C. McBride, and J. Reglinski, J. Inorg. Biochem., 21, 179 (1984).
31] S. V. Serves, Y. C. Charalambidis, D. N. Sotiropoulos, and P. V. Ioannou, Phosphorus,
Sulfur, and Silicon, 105, 109 (1995).
[
32] N. A. Chadaeva, K. A. Mamakov, R. R. Shagidullin, and G. K. Kamai, J. Gen. Chem.
USSR, 43, 825 (1973).
[
[
33] A. von D o¨ llen and H. Strasdeit, Eur. J. Inorg. Chem., 61 (1998).
34] N. Scott, K. M. Hatlelid, N. E. Mackenzie, and D. E. Carter, Chem. Res. Toxicol., 6,
1
02 (1993).
[
35] R. W. Herbert, F. L. Hirst, E. G. V. Persival, R. J. W. Raynolds, and F. Smith,
J. Chem. Soc., 1270 (1933).
[
[
36] F. A. Miller and C. H. Wilkins, Anal. Chem., 24, 1253 (1952).
37] R. C. Weast, CRC Handbook of Chemistry and Physics (CRC Press, Boca Raton, FL,
1
985), 65th ed.