Preparation of pseudo-arsonolipids: 2-acyloxypropane-1,3-bis(arsonic acids). The crystal structure of 2-hydroxypropane-1,3-bis(arsonic acid)

Article abstract of DOI:10.1016/S0009-3084(02)00030-0

Epihalohydrins react with alkaline arsenite to give in very good yields 2-hydroxypropane-1,3-bis(arsonic acid) (7), a key compound for the synthesis of pseudo-arsonolipids and more complex arsinolipids. Through a series of reduction to -As(SPh)₂, acylation, and oxidation to -AsO₃H₂, pseudo-arsonolipids, i.e. 2-acyloxypropane-1,3-bis(arsonic acids), were obtained. These pseudo-lipids are very sensitive to bases, being de-acylated. The bis(arsonic acid) (7) crystallizes in the orthorombic space group P2₁2₁2₁ with unit cell constants a=6.911(3), b=17.496(8), c=7.002(3) A. Both arsenic atoms are essentially tetrahedral being bound to three oxygens and one carbon. All hydrogen atoms have been located. There is no intramolecular but only intermolecular hydrogen bonding involving all the As=O, As-OH, and C-OH groups. The C-OH group acts as a hydrogen donor to an acidic As-OH, and this As-OH, in turn, acts as a hydrogen donor to an As=O group.

Full text of DOI:10.1016/S0009-3084(02)00030-0

Chemistry and Physics of Lipids
117 (2002) 53–61
www.elsevier.com/locate/chemphyslip
Preparation of pseudo-arsonolipids:
2-acyloxypropane-1,3-bis(arsonic acids). The crystal structure
of 2-hydroxypropane-1,3-bis(arsonic acid)
Aris Terzis a, Panayiotis V. Ioannou b,*
a Institute of Material Science, NCSR ‘‘Democritos’’, 15310 Aghia Paraske6i Attikis, Greece
b Department of Chemistry, Uni6ersity of Patras, Patras, Greece
Received 26 November 2001; received in revised form 27 February 2002; accepted 28 March 2002
Abstract
Epihalohydrins react with alkaline arsenite to give in very good yields 2-hydroxypropane-1,3-bis(arsonic acid) (7),
a key compound for the synthesis of pseudo-arsonolipids and more complex arsinolipids. Through a series of
reduction to ꢀAs(SPh)2, acylation, and oxidation to ꢀAsO3H2, pseudo-arsonolipids, i.e. 2-acyloxypropane-1,3-bis(ar-
sonic acids), were obtained. These pseudo-lipids are very sensitive to bases, being de-acylated. The bis(arsonic acid)
(7) crystallizes in the orthorombic space group P212121 with unit cell constants a=6.911(3), b=17.496(8), c=
,
7.002(3) A. Both arsenic atoms are essentially tetrahedral being bound to three oxygens and one carbon. All hydrogen
atoms have been located. There is no intramolecular but only intermolecular hydrogen bonding involving all the
AsꢁO, AsꢀOH, and CꢀOH groups. The CꢀOH group acts as a hydrogen donor to an acidic AsꢀOH, and this AsꢀOH,
in turn, acts as a hydrogen donor to an AsꢁO group. © 2002 Elsevier Science Ireland Ltd. All rights reserved.
Keywords: Epihalohydrins; The Meyer reaction; Bis(arsonic acids); X-ray diffraction
We asked whether by replacing the phosphorus
atom in 1 with arsenic we will get arsenic-contain-
ing lipids with interesting properties. But such a
replacement cannot be achieved because esters
having an CꢀOꢀAs functionality, e.g. 2, X=O,
are hydrolytically very unstable (Long and Ray,
1973). However, compounds having an CꢀAs
bond are hydrolytically stable and we prepared
the arsonolipids 2, X=CH2 (Serves et al., 1995),
3 (Tsivgoulis et al., 1991; Serves et al., 1993) and
the arsinolipids 4 (Kordalis and Ioannou, 2000)
and 5 (Ioannou, 2002). The arsonolipids 3, so far
studied in more detail, have interesting biophysi-
1. Introduction
Phospholipids, 1, are membrane building
blocks (Eibl, 1984). A few lipids can also have
other biochemical functions, e.g. the simplest
phospholipid, phosphatidic acid (1, R%=H), acts
as a second messenger (Ghosh et al., 1996), and
the platelet-activating factor (Demopoulos et al.,
1979) is an extremely potent chemical mediator.
* Corresponding author. Tel.: +30-61-0997107
E-mail address: ioannou@chemistry.upatras.gr (P.V. Ioan-
nou).
0009-3084/02/$ - see front matter © 2002 Elsevier Science Ireland Ltd. All rights reserved.
PII: S0009-3084(02)00030-0

54
A. Terzis, P.V. Ioannou / Chemistry and Physics of Lipids 117 (2002) 53–61
cal (Serves et al., 1993; Gortzi et al., 2001; Fatouros
et al., 2001) and biochemical (Rogers et al., 1996;
Supuran et al., 1996) properties. Liposomes made
of 3/PC/cholesterol showed a promising selective in
vitro toxicity towards certain cancer cell lines
(Gortzi et al., 2002).
ally distilled (b.p. 140–2 °C/1.8 mmHg). The
impure and the distilled acid had the same mobility
on TLC (CHCl3/MeOH 10:1, Rf 0.46). Dicyclo-
hexylcarbodiimide (DCC) and 4-dimethylamino-
pyridine (DMAP) were from Aldrich.
If the biological activity of the lipids 3 is due to
their As(V), then a molecule having more As(V)
groups might be more potent provided that it can
be incorporated into liposomes. With this thought
in mind we prepared molecules of the type 6 having
the very lipophilic docosanoyl group, and the quite
hydrophilic 2-[2-(2-methoxyethoxy) ethoxy]acetyl
group. In this report we describe the preparation
of these two pseudo-arsonolipids, Scheme 1, and
the crystal structure of their parent bis(arsonic
acid), 2-hydroxypropyl-1,3-bis(arsonic acid), 7, be-
cause its analytical and IR data were puzzling.
2. Experimental
2.1. Materials
Epibromohydrin (Ferak) and epichlorohydrin
(Aldrich) were redistilled. Docosanoic acid
(Aldrich) was used without further purification.
2-[2-(2-methoxyethoxy) ethoxy]acetic acid (Ald-
rich) technical grade (ꢀ50% purity) was fraction-
Scheme 1.

A. Terzis, P.V. Ioannou / Chemistry and Physics of Lipids 117 (2002) 53–61
55
Dichloromethane for acylations was dried over A4
molecular sieves. De-aerated methanol and
petroleum ether were prepared by boiling, stopper-
ing, and cooling to room temperature, r.t. Silica gel
60 H (Merck) was used for TLC.
3354 sharp, s, 3150 broad, w, 2988 sharp, mw, 2932
mw, 2592 broad, w, 2322 broad, m, 1648 broad, m,
1442 m, 1390 m, 1190 broad, ms, 1084 ms, 950 ms,
886 vs, 830 shoulder, ms, 790 vs, 777 vs, 724
1
shoulder, ms, 622 ms. H NMR (D2O), l: 2.88 (d,
J 6.6 Hz, 4H, CH2As), 4.64 (m, 1H, CHOH). 13C
NMR (D2O), l: 44.28 (CH2As), 63.35 (CHOH).
2.2. Methods
TLCs were run on microslides. Visualization was
done with I2 [for 7 and ‘AsO33−’ (Serves et al.,
1993; Tsivgoulis et al., 1998)] and by spraying with
35% sulfuric acid and charring. PhS-containing
compounds gave a characteristic pink and then
purple colour before charring. IR spectra of solid
samples were taken in KBr discs and of oily samples
in NaCl plates on a Perking Elmer, model 16PC,
FT-IR spectrometer, while 1H NMR (at 400 MHz)
and 13C NMR (at 100 MHz) spectra were obtained
on a Bruker, model DPX Avance, spectrometer.
Melting points were taken on an Electrothermal,
model IA9100, apparatus. Elemental analyses were
done by C.N.R.S., Vernaison, France.
2.4. Synthesis of 2-docosanoyloxypropane-1,3-bis
(arsonic acid) (6), R=C21H43
To the bis(arsonic acid) 7 (924 mg, 3 mmol)
suspended in de-aerated methanol (15 ml), thiophe-
nol (2.56 ml, 25.2 mmol) was added under nitrogen
and stirred at r.t. for 3 h. Removal of methanol and
drying in vacuo gave a white solid which was freed
from excess thiophenol and most diphenyl disulfide
by extracting under nitrogen with de-aerated
petroleum ether (2×20 ml) by gently swirling the
flask. Drying in vacuo gave the product 8 (1.972 g,
expected 1.932 g) as an oil contaminated with
diphenyl disulfide. TLC (CHCl3: product Rf 0.62;
PhSSPh Rf ꢀ1). Solubilities, IR and 1H NMR data
of a purer sample have been published (Ioannou,
2002). The product 8 was not stable (TLC analysis)
and therefore it was used without delay.
2.3. Synthesis of 2-hydroxypropane-1,3-bis
(arsonic acid) (7)
To a solution of arsenic trioxide (9.90 g, 50 mmol
As2O3) in 23.1 ml 13 M NaOH (300 mmol),
epibromohydrin (6.85 g, 50 mmol) was added. The
mixture was stirred at r.t. for 3 days, and then at
80 °C for 8 h. The cooled (ice/water) slightly
yellowish viscous solution was slowly acidified by
hydrochloric acid (calculated 41.6 ml 6 M HCl for
250 mmol HO−), transferred to a centrifuge tube
and left at +4 °C overnight to crystallize. The
solid was recrystallized twice from 30 ml boiling
water. Centrifugation and drying in vacuo over
phosphorus pentoxide gave the product 7 (8.88 g,
58%) as a white crystalline solid, pure by TLC
(MeOH/conc. NH3 4:1, Rf 0.55). It is soluble in
ethylene glycol, boiling water, moderately soluble
in water at r.t. and in boiling methanol, sparingly
soluble in methanol at r.t. (ꢀ10 mg per 1 ml
MeOH), and insoluble in boiling acetone or ether.
It foams at ꢀ176 °C and decomposes at 183–
185 °C. Calculated for C3H10O7As2 (Mr 307.95) C
11.70, H 3.27%; found C 10.62, H 3.06%. IR (KBr):
To the impure product 8 [1.792 g, assuming to
contain 3 mmol of the bis(dithioarsonite), 8], do-
cosanoic acid (1.330 g, 3.9 mmol), DMAP (37 mg,
0.3 mmol), and dry dichloromethane (30 ml) were
added, de-aerated, and flushed with nitrogen. A
solution of DCC (772 mg, 3.75 mmol) in dry
dichloromethane (10 ml) was added dropwise,
during 90 min, at r.t., and the system stirred at r.t.
overnight. After 3 h reaction TLC (CHCl3)
showed the presence of product at Rf ꢀ1, the
excess of docosanoic acid at Rf 0.3, traces of
dicyclohexylurea at Rf 0.15, traces of an unknown
impurity at Rf 0.06, and no starting compound 8
at Rf 0.60. The soft solid, obtained after evapora-
tion and drying in vacuo, was suspended in ether
(30 ml) and filtered through celite, washing with
ether (3×4 ml). The filtrate had no dicyclohexy-
lurea and became opalescent [probably by air
oxidation in the presence of moisture of the
ꢀAs(SPh)2 group in 9 to ꢀAsO3H2 (Kamai and
Chadaeva, 1957; Cullen et al., 1984)]. It was

56
A. Terzis, P.V. Ioannou / Chemistry and Physics of Lipids 117 (2002) 53–61
transferred to a centrifuge tube, water (3 ml) and
30% hydrogen peroxide (1.50 ml, 13.6 mmol H2O2)
were added and stirred vigorously at r.t. for 2 h.
The product precipitated as a white solid ab-
sorbing the added water. Centrifugation and wash-
ing the precipitate with boiling ether (1×20 ml)
gave the product (1.796 g, expected 1.893 g) con-
taminated by traces of docosanoic acid and
diphenyl disulfide. The pure product 6, R=
C21H43, (1.446 g, 76%) was obtained by triturating
the solid with boiling ether (5×20 ml). From the
ether extracts more product (74 mg) was isolated.
The product gave trailing spots in acidic solvents:
CHCl3/MeOH/AcOH 4:2:1 and 6:2:1 with Rf 0.32
and 0.40, respectively. It is soluble in DMSO,
CHCl3/MeOH 1:1 and warm methanol, and insol-
uble in chloroform and methanol. M.p.: 178–
180 °C dec. Calculated for C25H52O8As2 (Mr
630.51) C 47.62, H 8.31%; found C 47.69, H
8.42%. IR (KBr): 2914 vs, 2850 vs, 1742 m, 1472
mw, 1152 m, 1014 mw, 908 m, 884 m, 819 m, 786
Section 2.4. Since the product was water soluble,
the ether was syringed off, the oil washed with
ether (1×20 ml) and freeze-dried to give the
impure (by the polyether acid) product. This was
triturated with boiling ether (5×20 ml) to give the
product 6, R=C6H13O6 (1.13 g, expected 1.40 g)
as a white very hygroscopic powder which by
NMR contained ꢀ8% of polyether acid. It is
soluble in water, methanol, and DMSO and insol-
uble in ether, acetone, acetonitrile and ethyl ace-
tate. M.p.: at 92–93 °C froaths and at
162–164 °C the froath melts. Calculated for
C10H22O11As2 (Mr 468.12) containing 8%
polyether acid (C7H14O5, Mr 178.18): C 27.37, H
4.99%. Found C 27.48, H 4.87%. IR (KBr): 3422
m, 2930 s, 1758 s, 1650 ms, 1568 w, 1468 w, 1198
s, 1122 vs, 1098 vs, 902 vs, 867 sh, 770 vs. 1H NMR
(DMSO-d6), l: 2.79 (d, J 5.6 Hz, 4H, CH2As), 3.24
(s, 3H, CH3O), 3.43 (t, J 4.0 Hz, 2H, CH3OCH2),
3.52 (m, CH3OCH2OCH2), 3.60 (t, J 4.0 Hz,
CH2OCH2COO), 3.73 (broad, H2O in DMSO),
4.01 (s, acid CH2COOH impurity), 4.10 (s, 2H,
CH2COO), 5.49 (quintet, J 6.0 Hz, 1H, CH).
Attempts at removing the polyether acid by
dissolving the impure product in methanol and
precipitating by ether were unsuccessful for the
product was now contaminated with ꢀ5% acid
and ꢀ2% methanol.
1
m, 777 m. H NMR (DMSO-d6), l: 0.85 (t, J 6.8
Hz, 3H, CH3), 1.23 (s, 36H, (CH2)18), 1.51 (m, 2H,
CH2CH2COO), 2.27 (t, J 7.2 Hz, 2H, CH2COO),
2.77 (d, J 6.0 Hz, 4H, CH2As), 5.41 (quintet, J 6.2
Hz, 1H, CH). A very strong peak at 3.43–3.44
ppm attributable to water in DMSO (Williams and
Fleming, 1995, p. 162) was seen in various runs.
Attempts at the preparation of the tetralithium
salt of 6 (R=C6H13O3) in methanol using lithium
hydroxide in methanol as in Section 2.5 also
resulted in hydrolysis.
2.5. Attempted synthesis of the tetralithium salt
of 2-docosanoyloxypropane-1,3-bis(arsonic acid)
To a solution of the acid (0.1 mmol) in
methanol, a saturated solution of lithium hydrox-
ide (0.4 mmol) in methanol was added. The solid,
2.7. X-ray crystallographic study of 7
which was obtained had no ester (at 1742 cm−1
)
Colorless, prismatic crystals of 7 suitable for
X-ray analysis were grown from a dilute aqueous
solution. Details of the crystal data and a sum-
mary of collection and refinement parameters for
7 are given in Table 3. The crystal used for data
collection was mounted in capillary. Diffraction
measurements were performed at r.t. on a Crystal
Logic Dual Goniometer diffractometer using
graphite monochromated Mo radiation. Unit cell
dimensions were determined and refined by using
the angular settings of 25 automatically centered
reflections in the 11B2qB23° range. Intensity
data were recorded using a q−2q scan with scan
but an acid (RCOOH) group at 1722 cm−1 and
the ꢀAsO3
group at 844 cm−1. Its H NMR
2−
1
spectrum in D2O showed no RCOOCH proton at
5.41 ppm but a quintet at 4.37 ppm due to
HOꢀCH. The RCOOH was not detected because
it was insoluble in D2O.
2.6. Synthesis of 2-[2-(2 methoxyethoxy)ethoxy]
acetyloxypropane-1,3-bis(arsonic acid) (6),
R=C6H13O3
The reduction of 7 (3 mmol scale), acylation of
8 and oxidation of 9 were done as described in

A. Terzis, P.V. Ioannou / Chemistry and Physics of Lipids 117 (2002) 53–61
57
speed 4.0° min−1 and scan range 2.25°+h1h2 sep-
aration. Three standard reflections showed less
than 3% variation and no decay. Lorenz polariza-
tion and c-scan absorption corrections were ap-
plied using Crystal Logic software.
The structure was solved by direct methods
using SHELXS-86 (Sheldrick, 1986) and refined
by full-matrix least-squares techniques on F2 with
SHELXL-93 (Sheldrick, 1993). All non-hydrogen
atoms were refined anisotropically. All hydrogen
atoms were located by difference maps and
refined isotropically. The largest shift/esd in the
final cycle was 0.054.
because bromide is a better leaving group than
chloride. The reaction is best conducted first at
RT till all the oily epihalohydrins disappear,
probably due to faster attack of the nucleophile at
the epoxide carbon (Serves et al., 1994a,b) and
then at 80 °C to complete the displacement of the
halide. The bis(arsonic acid) 7 crystallized from
water as anhydrous, as did the propane-1,3-bis(ar-
sonic acid) (Ellerman et al., 1986), and it is worth
noting that both acids have the same melting
points (183–185 °C). The %C in 7 was lower than
expected and could not be explained by the pres-
ence of impurities. This was one reason for deter-
mining its structure by X-ray analysis.
2.8. Supplementary material
The reduction 7“8 was done in order to con-
vert the acid to a dichloromethane soluble com-
pound to facilitate the acylation which follows.
We used this technique for the preparation of 3
(Serves et al., 1993), 4 (Kordalis and Ioannou,
2000) and 5 (Ioannou, 2002). The complete re-
moval of diphenyl disulfide from the product 8, in
this case, was not imperative because the disulfide
does not interfere with the acylation which fol-
lows. If desired, the most efficient removal of
diphenyl disulfide was found to be by petroleum
ether extractions (Ioannou, 2002). The bis(-
dithioarsonites) 8 and 9, like some other aliphatic
dithioarsonites (Kamai and Chadaeva, 1957; Cul-
len et al., 1984), are unstable in the presence of
dioxygen and moisture. Therefore, 8 was used
immediatelly. For the acylation of 8 we used an
excess of fatty acid over both 8 and DCC. The
reasons are: (a) the fatty anhydride can react to a
certain extent with the dithioarsonite (Kamai and
Chadaeva, 1957):
Crystallographic data (excluding structure fac-
tors) for the structure in this paper have been
deposited with the Cambridge Crystallographic
Data Centre as Supplementary publication no.
CCDC 179737. Copies of the data can be ob-
tained, free of charge, on application to the Direc-
tor, CCDC, 12 Union Road, Cambridge CB2
1EZ, UK (fax: +44-1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk).
3. Results and discussion
3.1. Preparations
For the preparation of 7 from epihalohydrins,
the reaction requires 5NaOH Scheme 1 and not
6NaOH (per one molecule of As2O3 to give
2‘Na3AsO3’) because one molecule of NaOH is
produced during the ring opening reaction. How-
ever, we used 6NaOH because the excess NaOH
R%As(SPh)2+2(RCO)2O
helps in increasing the concentration of the reac-
“R%As(OCOR)2+2RCOSPh
(2)
3−
tive nucleophile, AsO3
(Serves et al., 1994a) in
the Meyer reaction (Meyer, 1883):
and (b) if excess DCC over fatty acid is used, it
cannot be easily removed from the product 6,
while all dicyclohexylurea can be filtered off espe-
cially from etheral suspensions.
The docosanoyl 6 could easily be purified by
extracting the docosanoic acid with ether. How-
ever, this method did not work well with the
polyether 6. When both 6 in methanol were
treated with methanolic lithium hydroxide (1:4
RX+‘Na3AsO3’“RAsO3Na2+NaX
(1)
A larger excess of sodium hydroxide or con-
ducting the reaction at 70 °C lowered the yield of
7 because more glycerol and/or 2,3-dihydroxy-
propylarsonic acid were produced (TLC estima-
tion). Epibromohydrin gave more product than
epichlorohydrin because it is less volatile and

58
A. Terzis, P.V. Ioannou / Chemistry and Physics of Lipids 117 (2002) 53–61
2900–2300 and at 900 cm−1, respectively. The
splitting (790 and 777 cm−1) observed for 7, in
KBr or in Nujol, can be attributed to asymmetri-
cal and symmetrical stretching vibrations of the
AsꢀOH bond because there is only one AsꢀOH
,
bond length (1.69–1.71 A), Table 1.
The w(AsꢁO) of the C15, C17–C20 alkylarsonic
acids is found at 905 cm−1 (McBreatry et al.,
1968) while in the shorter ones (C4–C14, C16) is at
940 cm−1 (McBreatry et al., 1968; Dietze, 1971).
The w(AsꢁO) of the lipids 6 is at ꢀ900 cm−1
indicating strong hydrogen bonding, as strong as
the long chain alkylarsonic acids.
In the 1H NMR spectra, the CH2As in 2,3-dihy-
droxypropylarsonic (Tsivgoulis et al., 1991), pro-
pane-1,3-bis(arsonic acid) (Ellerman et al., 1986),
and 7 in D2O resonate at 2.60, 2.70 and 3.00 ppm,
respectively, indicating that 7 is least ionized.
Table 1
,
Bond lengths (A) and angles (°) for compound 7
Fig. 1. Molecular structure of 7. Hydrogen atoms attached to
C(1) and C(3) have been omitted. Open bonds indicate hydro-
gen bonds; oxygen atoms from neighboring molecules are also
shown to emphasize the hydrogen bond scheme.
As(1)ꢀO(3)
As(1)ꢀO(2)
As(1)ꢀO(1)
As(1)ꢀC(1)
As(2)ꢀO(6)
As(2)ꢀO(4)
As(2)ꢀO(5)
As(2)ꢀC(3)
O(7)ꢀC(2)
C(1)ꢀC(2)
C(2)ꢀC(3)
1.654(5)
1.694(4)
1.695(5)
1.911(8)
1.650(5)
1.703(5)
1.708(5)
1.905(7)
1.416(8)
1.513(9)
1.533(9)
mol/mol) the tetralithium salt of 7 and free fatty
or polyether acids were obtained, instead of the
tetralithium salts of 6, indicating intramolecular
assistance to hydrolysis (see also Ramirez et al.,
1976).
O(3)ꢀAs(1)ꢀO(2)
O(3)ꢀAs(1)ꢀO(1)
O(2)ꢀAs(1)ꢀO(1)
O(3)ꢀAs(1)ꢀC(1)
O(2)ꢀAs(1)ꢀC(1)
O(1)ꢀAs(1)ꢀC(1)
O(6)ꢀAs(2)ꢀO(4)
O(6)ꢀAs(2)ꢀO(5)
O(4)ꢀAs(2)ꢀO(5)
O(6)ꢀAs(2)ꢀC(3)
O(4)ꢀAs(2)ꢀC(3)
O(5)ꢀAs(2)ꢀC(3)
C(2)ꢀC(1)ꢀAs(1)
O(7)ꢀC(2)ꢀC(1)
O(7)ꢀC(2)ꢀC(3)
C(1)ꢀC(2)ꢀC(3)
C(2)ꢀC(3)ꢀAs(2)
111.0(3)
112.0(3)
98.8(3)
3.2. Spectra
111.2(3)
114.7(3)
108.7(3)
111.4(3)
112.6(3)
101.7(3)
115.0(3)
108.5(3)
106.6(3)
112.2(5)
112.0(6)
110.9(5)
109.4(6)
110.9(5)
The IR spectrum of 7 in KBr in the CꢀOH
region shows a strong, sharp peak at 3354 cm−1
indicative of an intramolecular single bridge hy-
drogen bonding (Williams and Fleming, 1995, p.
41). Since 7, Fig. 1, has only intermolecular hy-
drogen bonds, this peak is due to hydrogen bond-
ing CꢀOH…OHꢀAs (Section 3.3). In 7 and in the
related propane-1,3-bis(arsonic acid) (Ellerman et
al., 1986) the AsOꢀH and AsꢁO groups are in-
volved in strong hydrogen bonding as indicated
by the position of their vibrations in the region

A. Terzis, P.V. Ioannou / Chemistry and Physics of Lipids 117 (2002) 53–61
59
Table 2
Hydrogen bonds (A and °) for compound 7
,
DꢀH…A
d(DꢀH)
d(H…A)
d(D…A)
B(DHA)
O(1)ꢀHO1…O(3)a
O(2)ꢀHO2…O(6)b
O(4)ꢀHO4…O(3)c
O(5)ꢀHO5…O(6)d
O(7)ꢀHO7…O(1)b
0.89(10)
1.00(8)
0.832(5)
0.61(9)
1.65(10)
1.66(8)
1.754(5)
2.09(9)
2.523(7)
2.615(7)
2.582(7)
2.656(8)
2.797(7)
166(9)
157(7)
173.7(4)
155(10)
167(9)
0.82(11)
1.99(11)
Symmetry transformations used to generate equivalent atoms.
a x+1/2, −y+1/2, −z+2.
b x−1/2, −y+1/2, −z+1.
c −x, y+1/2, −z+3/2.
d −x+1/2, −y+1, z−1/2.
This, coupled with a large downfield resonance of
the CHꢀOH proton (4.75 vs 4.10 ppm in 2,3-dihy-
droxypropylarsonic acid) probably indicates ei-
ther protonation, CHꢀOH2+, or very strong
hydrogen bonding by the flanking ꢀAsO3H2
groups.
As(2)ꢀC(3)ꢀC(2)ꢀC(1) −174.8°, indicate a nearly
planar molecular AsC3As backbone in 7.
The coordination around each arsenic atom in
7 is essentially tetrahedral as indicated by the
interatomic angles given in Table 1. However, the
HO(2)ꢀAs(1)ꢀO(1)H angle is only 98.8°, probably
because it has to accommodate the H(7) which
hydrogen-bonds to O(1), i.e. the As(1)O3 group
has five while the As(2)O3 group has four hydro-
gen bonds.
3.3. Crystal structure of
2-hydroxypropane-1,3-bis(arsonic acid) (7)
In the solid bis(arsonic acid) 7 the hydrogen
bonding, Fig. 1 and Table 2, results in a complex
three dimensional association. All hydrogen
bonds deviate from linearity by 6–25°. In pro-
pane-1,3-diphosphonic acid each PꢁO participates
in two hydrogen bonds (Gebert et al., 1977) and
in propane-1,3-bis(arsonic acid) it is proposed
that each AsꢁO is involved in two hydrogen
bonds (Ellerman et al., 1986). In our 7 each AsꢁO
oxygen also participates in two hydrogen bonds
with two different AsꢀOH groups from neighbor-
ing molecules. These hydrogen bonds are quite
The molecular structure of 7 is shown in Fig. 1.
Crystal data, data collection, and structure refine-
ment details are shown in Table 3, bond distances
and angles are collected in Table 1, while hydro-
gen bonding distances and angles are depicted in
Table 2.
Overall, the AsꢀC, AsꢀOH, and AsꢁO bond
lengths in 7 and in other arsonic and arsinic acids,
either aliphatic or aromatic, which have been
studied, do not show great variations, falling in
the regions of 1.88–1.92, 1.70–1.74, and 1.61–
,
,
1.67 A, respectively (aromatic arsonic: Doak and
short, lying in the range of 2.52–2.66 A, and
Freedman, 1970; Marx et al., 1996; aliphatic ar-
sonic: Smith et al., 1971; Falvello et al., 1977;
Kamiya et al., 1983; aliphatic arsinic: Trotter and
Zobel, 1965; Smith et al., 1969; Goedken et al.,
1993). In general, the bond lengths are AsꢀOH\
AsꢁO, with the exception of the dimeric dimethy-
therefore are strong. No intramolecular hydrogen
bonding of the AsꢁO with the CꢀOH group,
which would give a six-membered ring, was ob-
served. The CꢀOH group is then hydrogen-
bonded to the oxygen of an AsꢀOH group of
another molecule which acts as an acceptor. This
,
A
larsinic acid where AsꢀOH$AsꢁO=1.62
(Trotter and Zobel, 1965).
The torsion angles: As(1)ꢀC(1)ꢀC(2)ꢀC(3)
176.5°, As(1)ꢀC(1)ꢀC(3)ꢀAs(2) 2.5°, and
,
hydrogen bond is significantly longer (2.80 A)
than the other bonds and, therefore, weaker and
is responsible for the sharp peak observed at 3356
cm−1 in the IR spectrum of 7.

60
A. Terzis, P.V. Ioannou / Chemistry and Physics of Lipids 117 (2002) 53–61
York, pp. 53–54.
Table 3
Eibl, H., 1984. Phospholipids as functional constituents of
biomembranes. Angew. Chem. Int. Ed. Engl. 23, 257–271.
Ellerman, J., Brehm, L., Lindner, E., Hiller, W., Fawzi, R.,
Dickert, F.L., Waidhas, M., 1986. Chemistry of polyfunc-
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derived from 1,3-bis(di-iodoarsino)propane with mono-
cyclic, tricyclic, and straight-chain structures; X-ray crystal
Crystal data, data collection and structure refinement details
for compound 7
Parameter
Formula
M
C3H10As2O7
307.95
structure
of
2,8,13,14-tetraoxa-1,3,7,9-tetra-arsatricy-
Crystal habit
Crystal colour
Crystal size (mm)
Crystal system
Space group
Prism
clo[7.3.1.13,7]tetradecane. J. Chem. Soc. Dalton Trans.,
997–1001.
Colourless
0.10×0.30×0.50
Orthorombic
P212121
Falvello, L., Jones, P.G., Kennard, O., Sheldrick, G.M., 1977.
Dicyclohexylammonium arsonomethylphosphonate. Acta
Cryst. B33, 3207–3209.
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Stuart, M.C.A., Brisson, A., Ioannou, P.V., 2001. Prepara-
tion and properties of arsonolipid containing liposomes.
Chem. Phys. Lipids 109, 75–89.
Gebert, E., Reis, A.H. Jr., Druyan, M.E., Peterson, S.W.,
Mason, G.W., Peppard, D.F., 1977. Structure investiga-
tions of methylenediphosphonic acids. 2. The molecular
and crystal structure of propane-1,3-diphosphonic acid. J.
Phys. Chem. 81, 471–475.
Ghosh, S., Strum, J.C., Sciorra, V.A., Daniel, L., Bell, R.M.,
1996. Raf-1 kinase possesses distinct binding domains for
phosphatidylserine and phosphatidic acid. J. Biol. Chem.
271, 8472–8480.
Goedken, V.L., Brough, L.F., Rees, W.S. Jr., 1993. Aspects of
the chemistry of vinylarsenic compounds. The preparation
of divinylarsinic acid, tetravinyldiarsine oxide, and te-
travinyldiarsine, and the X-ray crystal structure of the
helical divinylarsinic acid. J. Organometal. Chem. 449,
125–130.
Gortzi, O., Klepetsanis, P., Antimisiaris, S.G., Ioannou, P.V.,
2001. Capability of arsonolipids to transport divalent
cations: a pressman cell study. Chem. Phys. Lipids 112,
21–29.
Gortzi, O., Papadimitriou, E., Kontoyannis, C.G., An-
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Lipids 117, 7.
,
a (A)
6.911(3)
17.496(8)
7.002(3)
,
b (A)
,
c (A)
Z
4
3
,
V (A )
846.6(6)
2.416
7.894
600
Dcalc (g cm−3
)
v (Mo Ka) (mm−1
F(000)
)
q range for data collection (°)
Index ranges
2.33–25.00
−80h08, 00k020,
00l08
Reflections collected
1667
Independent reflections
1496 (Rint=0.0536)
Observed reflections [I \2| (I)] 1455
Maximum and minimum
transmission
1.00 and 0.28
Parameters refined
145
1.073
GoF on F2
Final R indices [I\2| (I)]
R1a=0.0443,
wR2b=0.1090
R1a=0.0454,
wR2b=0.1102
1/[|2 (Fo2)+(0.0894P)2
+0.2641P]
0.978, −0.752
0.31(3)
Final R indices (all data)
Weighing scheme, wc
−3
,
Residual (e A
)
Absolute structure parameter
a R1=S(ꢀFoꢀ−ꢀFcꢀ)/SꢀFoꢀ.
1
b wR2={[Sw(Fo2−Fc2)2]/S[w(Fo2)2]}2.
c P=(max(Fo2, 0)+2Fc2)/3.
Kamai, G., Chadaeva, N.A., 1957. Alkyl esters of ethylth-
ioarsinous [ethylthiolarsonous] acid. Proc. Acad. Sci.
USSR 115, 717–719.
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