On C-As bond formation: Preparation of aliphatic arsonic acids

Article abstract of DOI:10.1080/10426500210237

A review of the attempts to create a C-As bond in aliphatic arsonic acids using a variety of As(III) nucleophiles and carbon electrophiles is presented together with our additional efforts on this subject. The results suggest that the Meyer reaction canno

Full text of DOI:10.1080/10426500210237

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On C--As Bond Formation: Preparation of Aliphatic
Arsonic Acids
Panayiotis V. Ioannou a
a Department of Chemistry, University of Patras, Patras, Greece
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Phosphorus, Sulfur and Silicon, 2002, 177:1–14
C
Copyright 2002 Taylor & Francis
1042-6507/02 $12.00 + .00
ON C AS BOND FORMATION: PREPARATION
OF ALIPHATIC ARSONIC ACIDS
Panayiotis V. Ioannou
Department of Chemistry, University of Patras, Patras, Greece
(Received June 12 2001.)
A review of the attempts to create a C As bond in aliphatic arsonic acids
using a variety of As(III) nucleophiles and carbon electrophiles is pre-
sented together with our additional efforts on this subject. The results
suggest that the Meyer reaction cannot be realized by bulky As(III) nu-
cleophiles or substrate electrophiles most likely from inability to attain
the SN2 transition state. The reaction cannot be run in organic solvents
but works in aqueous or aqueous/alcoholic alkaline arsenite solutions,
and the main challenge is to render a lipophilic substrate water solu-
ble. Such a substrate is the -halocarboxylic acid due to its hydrophilic
CHXCOO part which after conversion to CH(AsO3H2)COOH and
decarboxylation, yields the aliphatic arsonic acid. The mechanisms for
these two reactions have been studied and the conditions for optimal
yields have been found. Thus a new, and most likely a widely applicable,
strategy for the preparation of aliphatic arsonic acids is now available.
Keywords: 2-arsonocarboxylic acids; -halocarboxylic acids; arsenites;
arsonic acids; decarboxylation; Meyer reaction
INTRODUCTION
For the preparation of aliphatic arsonic acids there exists two method-
ologically general methods:1
1. A carbanion displaces a good leaving group attached to a suitable
As(III) compound. The other two groups must also be labile when
the new As(III) is transformed to As(V) in arsonic acid. This is the
case with Grignard reagents as shown in Eq. 1:2
H2O2,H2O
¨
¨
(Et2N)2 As Cl + RMgX → R As(NEt2)2
> RAsO3H2 (1)
Address correspondence to Panayiotis V. Ioannou, Department of Chemistry, Univer-
sity of Patras, Patras, Greece.
1

2
P. V. Ioannou
However, aliphatic Grignard reagents cannot be prepared when the
R contains OH, NH2, >C O, COOR 0 etc. groups.3
2. Using the lone electron pair on the arsenic in the As(III) compounds
to attack an electrophilic carbon as shown in Eq. 2:
work-u>p RAsO3H2
(2)
solvent
→As: + R Y
> →As+
R
TABLE I Arsenic Nucleophiles and Carbon Electrophiles Tested for
Creation of a C As Bond in Aliphatic Arsonic Acids Under Various
Conditions (Those in Italics are Reported Herein)
Nucleophile
Electrophile
Solvent
Catalyst
(RO)3As:
1 RX
7 H2O
BuAsO3H2
(RS)3 As:
Na3AsO3
2 RO-SO2-Me
8 H2O/MeOH
neutral
3
9 MeOH
anionic
cationic
(amsylate)
EtOH
DMSO
4
10 H2O/monoglyme
Ag3AsO3
5
6
H2O/diglyme
H2O/triglyme
b
(Me4N)3AsO3
11 H2O/THF
H2O/HOCH2CH2OH
12
13
14
15
16
Na3AsO3 means an aqueous alkaline arsenite solution prepared using the stoich-
iometry: 1/2As2O3 + 3NaOH → Na3AsO3 + 3/2 H2O. Actually the Na3AsO3 is in trace
amounts in such solutions.14
b(Me4N )3AsO3 means a methanolic solution prepared using the stoichiometry:
1/2As2O3 + 3Me4NOH → (Me4N)3AsO3 + 3/2H2O. The solution should also contain
(Me4N)2HAsO3, (Me4N)H2AsO3, and Me4NOH due to hydrolysis of (Me4N)3AsO3.

Arsonic Acids
3
Then, a range of As(III) compounds, electrophiles and solvents can
be used, as shown in Table I.
Trialkyl arsenites, (1) do not react with alkyl halides.4 In fact, the ar-
sonic acid ester on heating reverts back to the trialkyl arsenite5 (retro-
Arbuzov reaction6), as seen in Eq. 3:
0
(RO)3 As + R0
X
R
As(O)(OR)2 + RX
(3)
*
)
The trialkyl4 and triphenyl7 trithioarsenites (2) did not give the Ar-
buzov type reaction (3) with alkyl halides. Likewise, we found that
the (PhS)3As with the amsylate 9 in dichloromethane gave As2O3 and
PhSSPh without consuming the substrate.8 These experiments demon-
strated that the lone electron pair on arsenic in 1 and 2 was chemically
inactive.
Aqueous alkaline arsenite, symbolized Na3AsO3, 3 (Table I), reacts
with alkyl halides to give the arsonic acid, the Meyer reaction.9 It works
12
with a variety of short chain alkyl halides,10
but with lipophilic
ones, such as butyl bromide, shows an induction period13 of 100 h
the cause of which still remains unknown. Addition of a cosolvent, usu-
ally methanol, accelerates the reaction presumably by increasing the
solubility of the alkyl halide.13 The mechanism of the Meyer reaction
3
was found14 to be SN2 and the nucleophile is the bulky trianion, AsO3
,
the dianion HAsO23 not having an appreciable activity. The concentra-
3
tion of AsO3 increases in concentrated aqueous arsenite solutions or
in the presence of excess sodium hydroxide.15 In practice a little excess
of base is preferable.16
The complex 4 although in the solid state has a stereochemically
active lone electron pair17 it was chemically unreactive against 1-
bromooctane in benzene solution, probably for steric reasons, while with
9 or 10 gave the monooctyl ether of catechol.8
Therefore, if one wishes to prepare an aliphatic arsonic acid one has
3
to use the AsO3 nucleophile and modify the electrophilic substrate
and the reaction solvent.
A lipophilic substrate like an alkyl halide can be made somewhat
hydrophilic, at least near the electrophilic carbon, by converting it to
mesylate, 8, amsylate, 9, or [3]betylate, 10. However, these substrates
under the Meyer conditions gave the parent alcohol, ROH, implying
3
attack of HO and not of AsO3 most likely for steric reasons.8
The Meyer reaction of Na3AsO3 is not restricted to alkyl halides but
other substrates, like ethylene oxide, 11,18,19 and rac, R or S glycidols,
12,20,21 can be used to prepare specific arsonic acids.

4
P. V. Ioannou
When vicinal to a halide leaving group there is a hydrophilic group,
then the Meyer reaction with Na3AsO3 will be facilitated. Moreover,
if this group can be removed under mild conditions, then a valuable
strategy for the preparation of arsonic acids will be available.
A hydrophilic, nonremovable, group is the OH one. Thus, the
24
substrates 13, 14, and 15 give 2-hydroxyethylarsonic,22
2,3-
dihydroxypropylarsonic,16, 25 and 3-arsono-2-hydroxy-2-(hydroxyme-
thyl)propionic26 acids, respectively. Mechanistically, these substrates
react mainly by first being converted to their epoxides,16,23,26 and to a
lesser degree by direct displacement of the halide.14
The substrate 16 contains the very hydrophilic COO group, which
will either render the whole molecule soluble or bring the halide into
contact with the aqueous alkaline arsenite phase and will also facilitate
the displacement of the halide. Once the geminal arsonocarboxylic acid
has been prepared it can be decarboxylated,27 because the AsO3H2
group is somewhat electron withdrawing, thus giving the aliphatic ar-
sonic acid. This represents a method of wider scope for the preparation
of aliphatic arsonic acids and it was first described for the preparation
of the arsonomethyl analogue of AMP.28
In this article we report on the mainly disappointing results in
achieving the Meyer reaction with the lipophilic 1-bromopentane, 1-
bromooctane and 1-bromododecane by the nucleophiles 3, 5, and 6 in
various solvents, in the presence of various catalysts and by using son-
ication. Because of the low yields obtained during the synthesis of the
arsonomethyl analogue of the AMP28 we prepared 2-arsonohexanoic
acid and decarboxylated it to pentylarsonic acid in order to optimize
the reaction conditions.
RESULTS AND DISCUSSION
Silver orthoarsenite suspended in DMSO in the presence of
1-bromooctane did not give any octylarsonic acid. Similarly,
(Me4N)3AsO3 in methanol and various alkyl bromides at RT did not
give alkylarsonic acids probably because it was in the nonnucleophilic14
2
HAsO3 form.
The Meyer reaction has also been run in mixed solvents:
H2O/MeOH,13 H2O/EtOH9,11,12,29 and H2O/glycerol30,31 to assist the
dissolution of the alkyl halide in the aqueous alkaline arsenite phase,
but still the reactions were slow, for example, 356 h refluxing for the
preparation of 2-methylpropylarsonic acid in 42% yield.12 We tried as
cosolvents THF, ethylene glycol, and mono-, di-, and triglyme in such
proportions as to give a one phase solution with the aqueous alkaline
arsenite. From these systems only the H2O/monoglyme showed some

Arsonic Acids
5
promise but the reaction was still quite slow with the 1-bromooctane :
50% reaction after 6 days at 60 C.
It was reported32,33 that upon addition of butylarsonate to the sys-
tem butyl bromide and Na3AsO3, the rate of the reaction, at 91 C,
increased giving 60% of the product after an unspecified period of time.
We used neutral, anionic and cationic compounds as catalysts for the
Meyer reaction with 1-bromooctane but without any success. There-
fore, the origin of the induction period noted by Pietsch13 is still an
open question. Sonication as a means of bringing the aqueous alkaline
arsenite and lipophilic alkyl halide into close contact was also tried but
without success.
In order to optimize the reaction conditions for the transformation28
RCHCOOH → RCHCOOH → RCH2AsO3H2
(4)
|
|
Br
AsO3H2
we prepared 2-bromohexanoic acid by the Hell-Volhard-Zelinskii
method.34 This procedure gives impure product35 and the fatty acid
contaminant can only be removed by repeated distillations.36 More-
over, the aggressive reagents and conditions used in this method
may not be tolerated by many substances if one wishes to pre-
pare their arsonic acids. However, there are milder ways to cre-
ate the CHBrCOOH functionality such as from an alcohol via
28
its aldehyde using Ph3P CBrCOOCMe3 or an alkyl halide using
(EtO2C)2CHNHAc.37
A classical example of conversion of a 2-halocarboxylic acid into a
2-arsonocarboxylic acid is in the preparation of arsonoacetic acid.38
This preparation is unique for its rapidity and high yields, which im-
ply that side reactions, for example path b in Scheme 1, did not take
place. In the case of a secondary halide, which is known to react only
slightly in the Meyer reaction,11 the possible routes leading to product
and by-products are shown in Scheme 1. Therefore, the yield of the con-
version into 2-arsonocarboxylic acid will depend on the relative quan-
tities of substrate/Na3AsO3/NaOH, their concentrations and reaction
temperature.
Adams et al.28 using excess of Na3AsO3 and even larger excess
NaOH at 2.5 M concentration obtained 20% of their 2-arsonocarboxylic
acid after 24 h at 40 C. At RT sodium 2-bromohexanoate with stoi-
chiometric amount of Na3AsO3 or with 100% excess of both Na3AsO3
and NaOH at 13 M concentration gave traces of 2-hexanoic acid, the
main by-product being 2-hydroxyhexanoic acid. This acid is produced
in greater amounts when the system becomes warm during the addition

6
P. V. Ioannou
SCHEME 1
of the substrate to the alkaline arsenite. We have observed faster at-
3
tack by HO than by AsO3 at higher reaction temperatures in other
Meyer reactions.39 Best yields of 2-arsonohexanoic acid are obtained
with excess Na3AsO3, in the presence of NaOH and in concentrated
solutions all these factors leading to increased concentration of the ac-
3
tive nucleophile,14 AsO3
.
There are only three reports in the literature on the decarboxylation
(under different conditions) of arsenic containing molecules. By heating
arsonoacetic acid and ethylene glycol (1:2 molar ratio) at 140 C for
10 min, Englund40 isolated the lead methylarsonate in 70% yield.
Adams et al.28 also decarboxylated this acid in 1-propanol by azeotropic
removal of the water of esterification of the As(O)(OH)2 group. The
arsenic acid, [hydroxy(phenyl)arsinyl]acetic acid, Ph As(O)(OH)
CH2COOH, was decarboxylated in 85% yield in benzene/1-butanol
by azeotropic removal of the water of esterification of the >As(O)OH
group.41 Finally, Adams et al.28 decarboxylated in 50% yield the pre-
cursor of the arsonomethyl analogue of AMP in DMSO/1-propanol by
azeotropic distillation of the water produced. Since the decarboxylation
will be the last reaction in this novel preparation of arsonic acids and in
view of the not quantitative yields reported, we studied the conditions
of decarboxylation of 2-arsonohexanoic acid. A suggestion as to what
happens during the decarboxylation is shown in Scheme 2.
Since salts of phenylmalonic acid42 and arsonic acids28 do not decar-
boxylate, a free COOH must be present for intramolecular hydrogen
transfer to one of the arsenic oxygens to take place.28 An esterified,
AsO(OR0)2, group must also be present. If the reaction is run in water

7

8
P. V. Ioannou
either no reaction takes place after 3 h at 100 C (this work) or slow
C As bond cleavage takes place.28
Decarboxylation of 2-arsonohexanoic acid in the presence of ethylene
glycol in 1:1, 1:2 or 1:2.5 molar ratios by thermal removal of the water of
esterification at 130–140 C (oil bath temperature) could not be effected.
Partial esterification of the COOH group was observed and As2O3 was
produced via the retro-Arbuzov reaction5,6 shown in Scheme 2.
When the decarboxylation was done in DMSO/1-propanol at 110 C
without removal of the water of esterification, only 20% of pentylar-
sonic acid was obtained. Esterification of the COOH group took place
and As2O3 was also produced. Decarboxylation in 1-propanol with re-
moval of the water of esterification at oil bath temperature of 160 C was
accompanied by 37% C As bond fission. At the same time some esteri-
fication of the COOH group took place. The yield of the pentylarsonic
acid was 38%.
In an attempt to avoid the ester, COOR0, formation we tried the
decarboxylation in t-butanol. Since t-butanol does not form an easily
separable azeotrope with water, we slowly distilled the solvent at 130 C.
A 20% C As bond fission and some esterification were observed, the
decarboxylation was incomplete, and the pentylarsonic acid could not
be isolated.
Because of the esterification, COOR0 could not be avoided, we there-
fore focused on the problem of C As bond fission which occurs via the
retro-Arbuzov reaction. The temperature at which an ester of an ali-
phatic arsonic acid starts isomerizing depends on both alkyl groups: R0
and R of Eq. 3, ranging from 115 to 282 C.5 Evidently, the 1-propyl and
t-butyl esters of 2-arsonohexanoic acid start isomerizing in the region of
110 C. The water of esterification then, before being removed as an
azeotrope, reacted with the ester of the arsenious acid giving the observ-
ed opalescence due to As2O3 produced (Scheme 2). Therefore, the de-
carboxylation has to be done at as low a temperature as possible. The
benzene/water azeotrope contains 8.9% water and boils at 69 C.43 The
esterification of an arsonic acid is best done with 100% excess alcohol44
and for our purpose the best candidate41 is 1-butanol (b.p. 118 C) for it
will remain in the benzene phase during the azeotropic removal of the
water. Using these conditions we noticed that very small amounts of
As2O3 were produced at 75 C oil bath temperature. Keeping the tem-
perature at 115 C during the azeotropic removal of water the yield of
the product was >66% and the As2O3 could not be isolated. Since some
esterification to COOBu was observed and C As bond cleavage was
minute, then the major by-product should be the RCH(AsO3H2)COOBu.
Summarizing the results on the series of reactions (Eq. 4), for the
preparation of arsonic acids, the first reaction must be run at low

Arsonic Acids
9
temperature and with excess NaOH and Na3AsO3. Most of the latter
is recovered as As2O3. The second reaction must be run at as low
temperatures as possible to minimize the C As bond cleavage via
the retro-Arbuzov reaction. It seems that ester, COOR, formation
cannot be avoided. Under our conditions the overall yield of Eq. 4 is
30–50%.
The IR spectrum of pentylarsonic acid resembles the published2,45
1
spectra and has the (As O) at 938 cm and the (As OH) at 776
1
cm flanked by two much smaller peaks at 882 and 730 cm 1. How-
ever, in the spectrum of 2-arsonohexanoic acid these peaks are moved to
1
890 and 784 cm 1. Since the (C O) is at 1712 cm implying dimeric,
COOH HOOC , association, then the AsO3H2 group should be in-
volved in much stronger hydrogen bonding with an AsO3H2 group of
another molecule. While in the anhydrous dilithium methylarsonate
2
the AsO3 group absorbs46 at 862 and 845 cm 1, in the trilithium
2
salt of 2-arsonhexanoic acid the AsO3 group absorbs at 898 and 820
cm 1, probably because it is affected by the geminal COO group.
EXPERIMENTAL
1-Bromopentane was from Aldrich (Athens, Greece). 1-Bromooctane
(b.p. 106 C, 15 mm Hg) and 1-bromododecane (b.p. 104–6 C, 0.8 mm
Hg) were prepared form 1-octanol and 1-dodecanol by the HBr + H2SO4
and red P/Br2 methods, respectively.47 2-Bromohexanoic acid (b.p. 98 C,
1.5 mm Hg) contaminated by 9% hexanoic acid was prepared accord-
ing to the literature.34 The yellow silver orthoarsenite, Ag3AsO3, was
prepared by adding a dilute solution of Na3AsO3 into an aqueous so-
lution of silver nitrate in 1:3 molar ratio (m.p. 150 C dec; lit.43 150 C
dec). It is soluble in acetic acid and it gives a yellow suspension in
DMSO and in DMF. Tetramethylammonium hydroxide 25% by weight
in methanol from Aldrich was used to prepare methanolic solutions
of (Me4N)3AsO3 (Table I). Aliquat 336 (methyltrioctylammonium chlo-
ride) was a generous gift of Henkel (Kankakee, IL). Ethylene glycol,
ethylene glycol dimethyl ether (monoglyme), di- and triethylene gly-
col dimethyl ether (diglyme and triglyme), and sodium silicate solu-
tion (extra pure) were from Merck. Silica gel Si60 (Serva; Heidelberg,
Germany) was used for column chromatography and silica gel H (Merck)
for thin layer chromatography. Methanol, absolute ethanol, 1-propanol,
1-butanol, t-butanol, benzene, and DMSO were stored over A4 molec-
ular sieves. Thin layer chromatography (TLC) was run on microslides,
always using appropriate standards. Visualization was effected first by
3
,8
iodine vapours (for hexanoic acid, 2-bromohexanoic acid, and AsO3
)
followed by spraying with 35% H2SO4 and charring. Arsenic(III) oxide

10
P. V. Ioannou
was detected by IR (sharp peak at 802 cm 1).48 Arsenic(III) was deter-
mined titrimetrically in buffered, with NaHCO3, solution with standard
iodine solution.49 A Soniprep 150 sonicator (MSE) was used. IR spectra
1
were obtained on a Perkin-Elmer model 16PC FT-IR spectrometer. H
NMR spectra were run on a Brucker DPX Avance (400 MHz) spectrom-
eter. Elemental analyses were done by CNRS, Vernaison, France.
Syntheses of Compounds
2-Arsonohexanoic Acid, CH3[CH2]3CH(AsO3H2)COOH
To arsenic(III) oxide (990 mg, 5 mmol As2O3) dissolved in 13 M
NaOH (3.1 ml, 40 mmol NaOH) was added at RT, dropwise (during 1 h)
2-bromohexanoic acid (975 mg, 5 mmol). During the addition, the tem-
perature did not rise and a gel was formed. After stirring at RT for
2 days a clear viscous solution was formed and on further stirring for
2 days a semigel was formed. TLC (MeOH/conc. NH3 4:1) showed traces
of the starting acid (Rf 0.80), Na3AsO3 (Rf 0.53), the product (Rf 0.32)
and an unknown impurity at Rf 0.05. The system was neutralized with
6 M HCl (calculated for 35 mmol HO :5.8 ml) and centrifugation gave
As2O3 (255 mg). The solution was extracted with ether (3
20 ml),
separating the phases by centrifugation. The aqueous phase contained
As2O3 and 2-hydroxyhexanoic acid. The ether phase gave an oil (1.23 g)
which was chromatographed (silica gel, 12 g, in ether). Elution with
Et2O (100 ml) gave 2-hexenoic acid (traces), hexanoic acid ( 80 mg), 2-
bromohexanoic acid ( 20 mg), and 2-hydroxyhexanoic acid ( 250 mg).
These impurities on TLC (Et2O/petroleum ether 1:1) had Rf : 0.88, 0.76,
0.76, and 0.38 respectively, and their quantities were calculated from
1
the H NMR spectrum of the mixture. Then, elution with methanol
(75 ml) gave the methanol-contaminated product (834 mg, 70%) as a
very viscous-to-glassy oil, purity >90%, soluble in water, methanol and
DMSO and insoluble in chloroform. IR (neat): 3318 broad s, 2960 vs,
2872 s, 1714 vs, 1642 shoulder m, 1460 m, 1382 w, 1330 m, 1298 s,
1266 s, 1246 s, 1190 s, 1112 m, 1016 m, 890 vs, 784 vs, 675 w. 1H NMR
(D2O), : 0.76 (t, J 6.8 Hz, 3 H, CH ), 1.23 (multiplet, 2 H, CH3CH ),
3
2
1.31 (multiplet, 2 H, CH3CH2CH ), 1.92 (multiplet, 2 H, CH CH), 3.21
2
2
(s, MeOH), 3.60 (double doublet, J + JBX 14 Hz, 1 H, CH), 3.69 (s,
AX
0.26 H, impurity). For elemental analyses a sample was converted into
its trilithium salt.
Trilithium Salt of 2-Arsonohexanoic Acid,
CH3[CH2 ]3CH(AsO3Li2 ) COOLi
To a saturated solution of lithium hydroxide in methanol ( 3 ml),
a solution of 2-arsonohexanoic acid (95 mg, 0.4 mmol) in methanol

Arsonic Acids
11
was added. The voluminous precipitate was centrifuged, washed with
methanol (2 2 ml), and dried in vacuo over phosphorus pentoxide to
give the product (90 mg, 86%) as a white, hard solid. At 275 C the
product turns light brown and does not melt until up to 300 C. Found:
C 26.23, H 4.33%; calculated for C6H10O5AsLi3; 0.2CH3OH: C 26.34,
H 4.55%. IR (KBr): 3420 m, 2958 s, 2930 m, 2864 m, 1582 vs, 1467 m,
1462 m, 1398 vs, 1164 w, 1100 w, 898 vs, 820 vs, 728 w. 1H NMR (D2O),
: 0.76 (t, J 6.0 Hz, 3 H, CH ), 1.19 (m, 4 H, CH2CH2CH3), 1.68 and
3
1.80 (multiplets, 2 H, CH2CH), 2.69 (double doublet, JAX + JBX 15.2 Hz,
1 H, CH), 3.23 (s, 2% MeOH).
The MeOH could not be completely removed after 10 h drying at
100 C, 2 mm Hg.
Decarboxylation of 2-Arsonohexanoic Acid
to Pentylarsonic Acid
In DMSO/1-Propanol
2-Arsonohexanoic acid (360 mg, 1.5 mmol) dissolved in DMSO
(2 ml) and 1-propanol (2 ml) was refluxed for 2 h (oil bath temperature
110 C) at which point the solution became opalescent due to As2O3.
TLC (MeOH/conc. NH3 4:1) showed traces of 2-arsonohexanoic acid (Rf
0.35), the product (Rf 0.61), and by-products (see Scheme 2), (Rf 0.95).
Water (0.5 ml) was added, the propanol and water evaporated (rotary,
50 C), and most of the DMSO removed in vacuo (oil bath at 90 C, 4
mm Hg). To the oil, water (4 ml) was added, boiled, and, on cooling
to RT 48 mg of a solid (As2O3 and product, by IR), precipitated. The
supernatant on cooling at 4 C overnight gave the product (55 mg,
19%), m.p. 162 C (lit.2 163–165 C), insoluble in chloroform and water
at RT, soluble in DMSO and warm water. IR (KBr): 4132 broad w,
3420, broad w, 2965 s, 2870 ms, 2740 broad m, 1460 w, 1198 m, 938
1
s, 776 vs. H NMR (DMSO d6), : 0.86 (t, J 7.2 Hz, 3 H, CH3), 1.30
and 1.37 (multiplets, 4 H, CH2CH2CH3), 1.63 (quintet, J 7.6 Hz,
2 H, CH2CH2As), 2.15 (t, J 7.6 Hz, 2 H, CH2As), 3.81 (broad s, 2 H,
AsO3H2). The final supernatant after evaporation and drying gave an
1
oil which had by IR: DMSO and molecules with COOR (1734 cm
)
and AsO3H2 (952, 910 and 776 cm 1) groups.
In 1-Propanol
2-Arsonohexanoic acid (1.376 g, 5.73 mmol) was dissolved in dry 1-
propanol (25 ml) in a two-neck 100 ml round bottom flask connected
to an insulated 15 cm Dufton condenser having on top an insulated
sloping Claisen stillhead, and immersed into a silicone oil bath. Af-
ter 15 min the oil temperature reached 145 C and the solution became

12
P. V. Ioannou
opalescent due to As2O3. After 90 min the azeotrope had distilled (88 C)
the oil temperature being 160 C. After 4 h refluxing TLC showed no
starting diacid present, and the solution cooled to RT. Water (1 ml) was
added, the propanol/water evaporated (rotary, 50 C) and the residue
dried in vacuo. The solid (1.383 g) was extracted with warm methanol
(3 3 ml) leaving As2O3 (by IR) (190 mg, corresponding to 34% C As
bond cleavage). The methanol extracts gave a solid which recrystallized
from boiling acetone (4 ml), filtering traces of As2O3 through a cotton
plugged Pasteur pipette. The crystallized product (407 mg) was impure
(by TLC). From the supernatant 92 mg impure product was obtained
after evaporation and trituration with ether (5 ml). The ether gave
416 mg of an oil which by TLC contained some product. Its IR spec-
trum showed a COOR (1730 cm 1) and a COOH (1720 cm 1) group.
The presence of the ester COOR group was verified in the complex
1H NMR (triplet at 4.14 ppm, J 6.3 Hz, COOCH2CH2CH3). The im-
pure products were combined and triturated with acetone (10 ml) and
ether (5 ml) to give pure product (420 g, 38%), m.p. 162–164 C. Data:
as in case DMSO/1-propanol.
In 1-Butanol/Benzene
2-Arsonohexanoic acid (1.668 g, 6.95 mmol), dry 1-butanol (2.6 ml,
27.8 mmol), and dry benzene (25 ml) were placed in a two-neck 100 ml
round bottom flask connected to an insulated Dean-Stark trap and im-
mersed in an oil bath. When the oil temperature (after 5 min heating)
reached 75 C, the solution became very slightly opalescent and when
the temperature reached 105 C, it became slightly opalescent and re-
mained so until the end of the heating (5 h). Water production seems
to have ended after 2 h of distillation. The progress of the decarboxy-
lation was followed by TLC (as in DMSO/1-propanol) and at the end
traces of starting material and by-products could be seen. After cooling
to RT the slightly opalescent solution could not be clarified by filtra-
tion through a cotton plugged Pasteur pipette. To the filtrate, water
(1 ml) was added, evaporated, and briefly dried in vacuo to give a bu-
tanol smelling semisolid (3.07 g, expected 1.362 g). Ether (10 ml) was
added and warmed to extract the impurities. The still impure solid
product was triturated with boiling acetone (3 ml) and, after cooling
to RT, centrifugation gave the product (775 mg, 57%), m.p. 161–164 C.
Spectra as in DMSO/1-propanol. The ether and acetone extracts were
combined and evaporated. Trituration of the residue with boiling ether
(5 ml) gave more product (121 mg, 9%), m.p. 161–163 C. The ether phase
gave a butanol smelling oil (420 mg) which by IR had an ester group
at 1730 cm 1 and by TLC it contained nearly equal amounts of product
and by-products.

Arsonic Acids
13
ACKNOWLEDGMENTS
It is our pleasure to thank Dr. H. B. F. Dixon (University of Cambridge)
for his valuable comments on an early draft of this paper and for very
constructive discussions on the reactions of Eq. 4 which he and his
group conceived as a novel method of wider scope for the preparation
of aliphatic arsonic acids.
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