[Hydroxy(aryl)methylene]diphosphonic acids, a class of drugs in bone pathology treatments, crystallize as head-to-head dimers

Article abstract of DOI:10.1107/S0108270102012386

Two [hydroxy(aryl)methylene]diphosphonic acids have been crystallized as dimers. The first compound, [hydroxy(phenyl)methylene]diphosphonic acid monohydrate, C₇H₁₀O₇P₂·H₂O, crystallizes in the non-cen

Full text of DOI:10.1107/S0108270102012386

organic compounds
Acta Crystallographica Section C
Crystal Structure
Communications
are very dif®cult to crystallize as free dehydrated acids and
only one example has been reported for the crystal structure
of an anhydrous hydroxybisphosphonic compound (Ohanes-
sian et al., 1997). These acids are more easily crystallized as
mono salts of sodium or potassium (Sylvestre et al., 2001), or
better, dimethylammonium salts using the vapour-diffusion
technique (Neuman et al., 2002). When crystals are obtained,
they generally include solvent, and give well characterized
solvates, as is the case for the two title compounds, (IIIa) and
(IIIb).
ISSN 0108-2701
[Hydroxy(aryl)methylene]diphos-
phonic acids, a class of drugs in
bone pathology treatments, crystallize
as head-to-head dimers
Marc Lecouvey, Carole Barbey, Alda Navaza, Alain
Â
Neuman and Thierry Prange*
Â
Chimie Structurale et Spectroscopie Biomoleculaire (UMR 7033-CNRS),
74 rue M. Cachin, 93017 Bobigny Cedex, France
Correspondence e-mail: prange@lure.u-psud.fr
Received 10 June 2002
Accepted 10 July 2002
Online 31 July 2002
Two [hydroxy(aryl)methylene]diphosphonic acids have been
crystallized as dimers. The ®rst compound, [hydroxy(phenyl)-
methylene]diphosphonic acid monohydrate, C7H10O7P2ÁH2O,
crystallizes in the non-centrosymmetric space group P21, with
the two enantiomers related by a non-crystallographic centre
of inversion, while the second compound, [hydroxy(4-nitro-
phenyl)methylene]diphosphonic acid tetrahydrofuran disol-
vate, C7H9NO9P2Á2C4H8O, crystallizes in the centrosymmetric
space group P21/c and uses the centre of symmetry to form the
same dimer.
Although (IIIa) is a racemic monohydrate, it crystallizes in
the non-centrosymmetric space group P21 with the two (+)-
and ( )enantiomers facing each other, building a tight dimer
around a local non-crystallographic centre of symmetry at
(x, y, z) = (0.609, 0.255, 0.354). The content of the asymmetric
unit corresponds to two molecules of (IIIa) and two molecules
of water. The centrosymmetry is only broken by the hydration
network.
Comment
Phosphonic acids are usually diprotonated in their free acid
form. In (IIIa), the phosphonic H atoms are observed, but
those of the two solvate water molecules are not (Fig. 1); these
are probably in a disordered exchange within the hydrogen-
Bisphosphonates belong to a relatively new class of drugs
developed for the treatment of various pathologies in bone
(Fleisch, 1999), and also for the treatment of cancer (Mundy,
1999; Brown & Coleman, 2002). We have previously described
a one-pot method for the synthesis of aromatic 1-hydroxy-
methane-1,1-bisphosphonic acid compounds (Lecouvey et al.,
2001). The aim of this paper is to analyze the structure of two
new 1-hydroxymethane-1,1-bisphosphonic acids, namely
hydroxy(phenyl)methylene]diphosphonic acid monohydrate,
(IIIa), and [hydroxy(4-nitrophenyl)methylene]diphosphonic
acid tetrahydrofuran disolvate, (IIIb), with an aromatic ring
attached to the functional C atom. These structures were also
investigated to con®rm the presence of the bisphosphonic acid
group, because of a possible phosphono±phosphate rearran-
gement as a by-product of the synthesis, as previously
mentioned by Fitch & Moedritzer (1962) and Kanaan &
Burgada (1988).
Hydroxy bisphosphonic acids are compounds with super-
acid properties, and they are able to complex with a large
number of cations. As such, they have been widely investi-
gated as detoxifying agents in heavy-metal poisoning and also
as carrier molecules for 99mTc delivery in scintillography. They
Figure 1
A view of the dimer of (IIIa) (asymmetric unit), showing the atom-
labelling scheme. Displacement ellipsoids are drawn at the 50%
probability level and H atoms are shown as small spheres of arbitrary
radii.
Acta Cryst. (2002). C58, o521±o524
DOI: 10.1107/S0108270102012386
# 2002 International Union of Crystallography o521

organic compounds
Ê
bond network. Nevertheless, atom O1W is 3.02 A from
symmetry-related atom O2W and is certainly hydrogen
bonded to it.
and c directions. Firstly, dimers are connected side-by-side,
building in®nite ribbons along the c direction (Fig. 2), and
secondly, these ribbons are crosslinked perpendicularly (along
a) through their O2/O10 and O20/O1 atoms. The most signi®-
cant distances are given in Table 2.
Details of the four hydrogen bonds responsible for the
pairing are given in Table 2. In addition, in®nite inter-
molecular hydrogen-bond networks are present along the a
The crystals of (IIIb) are less stable than those of (IIIa),
with a tendency to bleach and turn to powder upon standing in
air at room temperature. The present data were therefore
recorded at 132 K. The structure is a tetrahydrofuran disolvate
which crystallizes in the P21/c space group (Fig. 3). The bis-
hydroxyphosphonate molecules also form strong dimers,
linked by four hydrogen bonds, as in (IIIa). However, the local
centre of inversion in the dimer corresponds to a crystal-
lographic centre of symmetry of the space group. All the
phosphonic acid H atoms were located in difference maps. The
hydrogen-bond network in (IIIb) also involves dimers,
building ꢀ-sheet-like ribbons (Fig. 4) similar to those observed
in (IIIa) but running along the b axis. The two solvated
tetrahydrofuran molecules form part of the network through
their ring O atoms (Fig. 3). They connect locally those
phosphonate O atoms that are not involved in the pairing (O2
and O6; Table 4). In a similar way, molecules of water connect
the dimers in (IIIa). However, the tetrahydrofuran molecules
are more bulky than the water molecules and ®ll more space
between the ribbons, preventing them from coming close
enough for crosslinking. This leads to weaker crystal cohesion
in the direction perpendicular to the ribbons.
Figure 2
The hydrogen bonding between dimers of (IIIa), viewed along the c axis.
Only H atoms involved in the bonding are shown and the solvate water
molecules have been omitted for clarity.
Figure 3
Figure 4
A view of the asymmetric unit of (IIIb), showing the atom-labelling
scheme. Displacement ellipsoids are drawn at the 50% probability level
and H atoms are shown as small spheres of arbitrary radii.
The supramolecular arrangement of (IIIb) dimers along the b direction;
tetrahydrofuran solvate molecules have been omitted for clarity. Atoms
labelled with an asterisk (*) are at symmetry position (1 x, 1 y, 1 z).
ꢀ
o522 Marc Lecouvey et al.
C7H10O7P2ÁH2O and C7H9NO9P2Á2C4H8O
Acta Cryst. (2002). C58, o521±o524

organic compounds
Table 2
Hydrogen-bonding geometry (A, ) for (IIIa).
Experimental
ꢁ
Ê
The syntheses of the title compounds were based on the addition of
two equivalents of tris(trimethylsilyl)phosphite to the corresponding
acid chlorides, (I), to yield the tetrakis(trimethylsilyl) ester of 1-aryl-
1-trimethylsiloxymethane-1,1-bisphosphonic acid, (II) (not isolated).
Direct methanolysis afforded the title substituted [hydroxy(aryl)-
methylene]diphosphonic acids, (IIIa) with aryl = phenyl and (IIIb)
with aryl = 4-nitrophenyl, in nearly quantitative yields (see Scheme).
Compound (IIIa) was obtained as a white powder in 91% yield, and
was crystallized by slow evaporation of a solution in a mixture of
ethanol and water (90:10) at room temperature. Spectroscopic
analysis, 31P NMR (D2O, ꢁ, p.p.m.): 16.0 (s); 1H NMR (D2O, ꢁ, p.p.m.):
DÐHÁ Á ÁA
DÐH
HÁ Á ÁA
DÁ Á ÁA
DÐHÁ Á ÁA
i
O2ÐH21Á Á ÁO10
0.82
0.82
0.82
0.82
0.82
0.82
0.82
0.82
0.82
0.82
0.82
1.92
1.80
1.78
1.75
1.84
1.83
1.83
1.80
2.07
2.36
2.12
2.583 (9)
2.602 (9)
2.592 (9)
2.549 (9)
2.647 (9)
2.637 (9)
2.609 (9)
2.594 (9)
2.805 (9)
2.894 (10)
2.789 (9)
137
164
169
165
169
167
160
163
149
123
138
O20ÐH2PÁ Á ÁO1ii
O3ÐH31Á Á ÁO40
O30ÐH3PÁ Á ÁO4
O5ÐH51Á Á ÁO10
O50ÐH5PÁ Á ÁO1
O6ÐH61Á Á ÁO2W
O60ÐH6PÁ Á ÁO1W
O7ÐH71Á Á ÁO4iii
O7ÐH71Á Á ÁO3
iv
O70ÐH72Á Á ÁO40
7.08±7.13 (m, 4H, C6H5), 7.46 (t, J = 5 Hz, 1H, C6H5); 13C NMR
3
Symmetry codes: (i) 1 ‡ x; y; z; (ii) x 1; y; z; (iii) x; y; z 1; (iv) x; y; 1 ‡ z.
1
(D2O, ꢁ, p.p.m.): 78.76 (t, J = 145.75 Hz, COH), 128.9, 130.8, 131.2,
138.6 (C6H5). Compound (IIIb) was obtained as a yellow powder in
85% yield, and was crystallized by slow evaporation of a solution in
tetrahydrofuran at room temperature. Spectroscopic analysis,
31P NMR (D2O, ꢁ, p.p.m.): 15.3 (s); 1H NMR (D2O, ꢁ, p.p.m.): 7.89 (d,
Compound (IIIb)
Crystal data
3
3
2H, J = 8.5 Hz, C6H4), 8.15 (d, 2H, J = 8.5 Hz, C6H4); 13C NMR
3
C7H9NO9P2Á2C4H8O
Dx = 1.474 Mg m
Mo Kꢂ radiation
Cell parameters from 78
re¯ections
1
(D2O, ꢁ, p.p.m.): 75.28 (t, J = 149 Hz, COH), 124.67, 128.15, 146.13,
148.35 (C6H4).
Mr = 457.30
Monoclinic, P21=c
Ê
a = 14.0005 (9) A
ꢃ = 8±40ꢁ
ꢄ = 0.27 mm
T = 132 (1) K
Ê
b = 6.0243 (2) A
1
Ê
c = 24.4427 (6) A
Compound (IIIa)
ꢀ = 91.903 (3)ꢁ
V = 2060.44 (16) A
Z = 4
3
Ê
Plate, pale yellow
0.20 Â 0.20 Â 0.05 mm
Crystal data
3
C7H10O7P2ÁH2O
Dx = 1.668 Mg m
Cu Kꢂ radiation
Cell parameters from 25
re¯ections
Data collection
Mr = 286.10
Monoclinic, P21
Nonius KappaCCD area-detector
diffractometer
' and ! scans
3734 measured re¯ections
3734 independent re¯ections
2986 re¯ections with I > 2ꢅ(I)
ꢃmax = 25.5ꢁ
Ê
a = 8.42 (2) A
ꢃ = 8±25ꢁ
ꢄ = 3.81 mm
T = 293 (2) K
Ê
b = 23.05 (1) A
h = 0 ! 16
1
Ê
c = 5.91 (2) A
k = 0 ! 7
ꢀ = 97.7 (2)ꢁ
V = 1137 (6) A
Z = 4
l = 29 ! 29
3
Ê
Rod-shaped prism, colourless
0.5 Â 0.2 Â 0.2 mm
Re®nement
Re®nement on F2
R[F2 > 2ꢅ(F2)] = 0.045
wR(F2) = 0.096
S = 1.02
3734 re¯ections
w = 1/[ꢅ2(Fo2) + (0.025P)2
+ 2.62P]
Data collection
where P = (Fo2 + 2Fc2)/3
(Á/ꢅ)max = 0.046
Philips PW1100 diffractometer
ꢃ/2ꢃ scans
3430 measured re¯ections
3430 independent re¯ections
2875 re¯ections with I > 2ꢅ(I)
ꢃmax = 65.8ꢁ
k = 23 ! 24
l = 0 ! 6
3
Ê
Áꢆmax = 0.39 e A
3 standard re¯ections
every 130 re¯ections
frequency: 120 min
intensity decay: 3%
3
Ê
0.37 e A
329 parameters
All H-atom parameters re®ned
Áꢆmin
Extinction correction: SHELXL97
=
Extinction coef®cient: 0.0017 (6)
h = 9 ! 9
Re®nement
For compound (IIIa), all H atoms apart from four (on the O1W
and O2W solvent water molecules) were located in difference Fourier
Re®nement on F2
R[F2 > 2ꢅ(F2)] = 0.040
wR(F2) = 0.096
S = 1.12
3430 re¯ections
w = 1/[ꢅ2(Fo2) + (0.0356P)2
+ 1.8431P]
Table 3
Selected interatomic distances (A) for (IIIb).
Ê
where P = (Fo2 + 2Fc2)/3
(Á/ꢅ)max = 0.098
3
Ê
P1ÐO1
P1ÐO2
P1ÐO3
P1ÐC1
1.5034 (17)
1.5637 (18)
1.5553 (18)
1.889 (2)
P2ÐO4
P2ÐO5
P2ÐO6
P2ÐC1
1.5044 (16)
1.5615 (17)
1.5881 (18)
1.870 (2)
Áꢆmax = 0.27 e A
3
Ê
0.29 e A
311 parameters
H-atom parameters constrained
Áꢆmin
=
Table 4
Hydrogen-bonding geometry (A, ) for (IIIb).
ꢁ
Table 1
Selected interatomic distances (A) for (IIIa).
Ê
Ê
DÐHÁ Á ÁA
DÐH
HÁ Á ÁA
DÁ Á ÁA
DÐHÁ Á ÁA
P1ÐO1
P1ÐO2
P1ÐO3
P1ÐC1
P2ÐO4
P2ÐO5
P2ÐO6
P2ÐC1
1.502 (6)
1.554 (5)
1.539 (6)
1.824 (5)
1.497 (7)
1.552 (6)
1.558 (4)
1.840 (7)
P10ÐO10
P10ÐO20
P10ÐO30
P10ÐC10
P20ÐO40
P20ÐO50
P20ÐO60
P20ÐC10
1.520 (7)
1.511 (5)
1.527 (6)
1.866 (5)
1.478 (7)
1.547 (6)
1.561 (4)
1.836 (7)
O2ÐH21Á Á ÁO12
O3ÐH31Á Á ÁO4i
O5ÐH51Á Á ÁO1i
O6ÐH61Á Á ÁO11
O7ÐH71Á Á ÁO4ii
O7ÐH71Á Á ÁO3
0.87 (4)
0.80 (4)
0.94 (4)
0.84 (4)
0.86 (4)
0.86 (4)
1.73 (3)
1.85 (3)
1.63 (3)
1.74 (3)
2.21 (3)
2.51 (3)
2.594 (3)
2.645 (3)
2.564 (3)
2.579 (3)
2.981 (3)
2.993 (3)
173 (3)
175 (4)
171 (4)
174 (4)
150 (3)
117 (3)
Symmetry codes: (i) 1 x; 1 y; 1 z; (ii) x; 1 ‡ y; z.
ꢀ
Acta Cryst. (2002). C58, o521±o524
Marc Lecouvey et al.
C7H10O7P2ÁH2O and C7H9NO9P2Á2C4H8O o523

organic compounds
maps. They were placed in geometrically idealized positions and were
constrained to ride on their parent atoms, with CÐH = 0.93 and OÐ
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ꢀ
o524 Marc Lecouvey et al.
C7H10O7P2ÁH2O and C7H9NO9P2Á2C4H8O
Acta Cryst. (2002). C58, o521±o524