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Acta Cryst. (2009). E65, o288-o289    [ doi:10.1107/S1600536809000907 ]

Hydronium (3-oxo-1-phosphono-1,3-dihydroisobenzofuran-1-yl)phosphonate

C. Barbey, P. Retailleau, E. Guénin and N. Dupont

Abstract top

In the title compound, H3O+·C8H7O8P2-, the anions form inversion dimmers by way of pairs of O-H...O hydrogen bonds involving the phosphonic functions and via the hydronium cation. Further O-H...O links involving the hydronium cation play a prominant part in the cohesion of the crystal structure by building bridges between bisphosphonate pairs, forming infinite ribbons along the b-axis direction and by cross-linking these ribbons perpendicularly along the a-axis direction, forming an infinite three-dimensional hydrogen-bond network. The benzene ring and the C=O atoms of the furan ring are disordered over two sets of positions of equal occupancy.

Comment top

The title compound, C8H8O8P2, belongs to the bisphosphonate family (or 1-hydroxymethylene-1,1-bisphosphonic acids or HMBPs). These compounds are synthetic structural analogues of pyrophosphate and are characterized by an enzymatically stable P—C—P group instead of the P—O—P. They are known to have a wide range of applications. They are clinically used in treatement of various bone diseases, such as Pagets disease, osteoporosis, tumor osteolysis or hypercalcemia of malignancy (Heymann et al., 2004; Rodan & Martin, 2000). They are known to induce inhibition of breast and prostate cancer cell proliferation and more recently to inhibit angiogenesis in vitro and in vivo (Fournier et al., 2002; Hamma-Kourbali et al., 2003; Wood et al., 2002). In addition, HMBPs have also activity against several trypanosomatid and apicomplexan parasites (Martin et al., 2001; Martin et al., 2002; Sanders et al., 2003). HMBPs are usually obtained from two different synthetic methods (Lecouvey & Leroux, 2000). Unfortunately, these methods are not always suitable for fragile, aromatic or functionalized substrates. Recently we developed a new method of HMBP synthesis from silylated phosphite and acid chlorides (Lecouvey et al., 2003a,b; Monteil et al., 2005) (or acid anhydrides (Guénin et al., 2004)) that gave an easy access to the obtaining of aromatic and functionalized HMBPs. Using phthalic anhydride as a substrate, a new and original cyclic bisphosphonate was described (Guénin et al., 2004). The cyclic structure of this compound was provided indirectly by IR measurements and further opening of the cycle in basic media. Here we undoubtly proved this cyclic structure, the hydroxy function being part of a lactone. This compound presents a real biological interest as it could act as a prodrug. The hydroxy function which is essential to the HMBP biological properties is in this particular case totally hidden, but could be reformed in the cell by esterase activity. Such acyloxymethyl bis(phosphonate) prodrugs have already been described and the protection shown to be reversible (Vachal et al., 2006).

Bisphosphonate are compounds with super-acid properties, and they easily crystallize as mono salts of sodium or potassium (Sylvestre et al., 2001) or as well characterized solvates (Lecouvey et al., 2002) where crystals generally include water.

The asymetric unit of the title compound is built up from one deprotonated HMBP anion and a H3O+ cation (Fig. 1) which are linked through OW—H···O hydrogen bonds (Table 1). The crystal structure consists of hydrophilic layers that enclose the hydronium cation and bisphosphonate function where molecules linked by pair and less hydrophilic layers made of aromatic rings attached to the cyclic bisphosphonate structure.

Related literature top

For the pharmacological applications of bisphosphonates, see Heymann et al. (2004); Rodan & Martin (2000); Fournier et al. (2002); Hamma-Kourbali et al. (2003); Wood et al. (2002); Martin et al. (2001, 2002); Sanders et al. (2003). For general background, see Lecouvey et al. (2003a,b); Monteil et al. (2005); Guénin et al. (2004); Lecouvey & Leroux (2000); Vachal et al. (2006). For related structures, see Sylvestre et al. (2001); Lecouvey et al. (2002).

Experimental top

Synthesis of (3-Oxo-1-phosphono-1,3-dihydro-isobenzofuran-1-yl) -phosphonic acid] was done according to the published procedure (Guénin et al., 2004, compound 3 h). Briefly two equivalents of tris(trimethylsilyl)phosphite were added under N2 to phtalic anhydride in freshly distilled THF at room temperature. The resulting mixture was then heated at 50°C for 12 h. After evaopration of volatile fractions methanol was added to the residue. After 1 h stirring and methanol evaporation the title compound was washed several times with dimethyl ether. Crystallization was done by slow evaporation at room temperature from a concentrated methanol/ water (9/1) solution to give colorless crystal with max. size 0.3 mm, suitable for diffraction.

Refinement top

All H atoms attached to C or O atoms were fixed geometrically and treated as riding with C—H = 0.93 Å (aromatic) or 0.96 Å (methylene) and O—H = 0.82 Å (hydoxyl) with Uiso(H) = 1.2Ueq(C) (aromatic) and 1.5Ueq(O) for others. Owing to the fact that each of the P2—O22 and P2—O23 bonds seems to be a mixture of single and double bonds and that solvent molecule was 3 times hydrogen donor, the solvent molecule was refined as H3O+ and the bisphoshonate as the basic form. H atoms of the hydronium were located in difference Fourier syntheses and initially refined using restraints (O-H= 0.93 (1)Å) with Uiso(H) = 1.5Ueq(O). In the last stage of refinement they were treated as riding on the parent O atom.

Disorder of the cyclic structure was modeled with two different positions per disordered atom with occupation factors of 0.5. The two disordered part were refined using the tools, PART and SAME, available in SHELXL-97 (Sheldrick, 2008).

Computing details top

Data collection: COLLECT (Hooft, 1998); cell refinement: HKL (Otwinowski & Minor, 1997); data reduction: HKL (Otwinowski & Minor, 1997); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEP-3 for Windows (Farrugia, 1997); software used to prepare material for publication: WinGX (Farrugia, 1999) and CrystalBuilder (Welter, 2006).

Figures top
[Figure 1] Fig. 1. Molecular View of the title compound. Displacement ellipsoids are drawn at the 30% probability level. H atoms are represented as small spheres of arbitrary radii.
Hydronium (3-oxo-1-phosphono-1,3-dihydroisobenzofuran-1-yl)phosphonate top
Crystal data top
H3O+·C8H7O8P2−F(000) = 1280
Mr = 312.10Dx = 1.716 Mg m−3
Monoclinic, C2/cMo Kα radiation, λ = 0.71069 Å
Hall symbol: -C 2ycCell parameters from 2338 reflections
a = 26.2271 (9) Åθ = 0.4–25.4°
b = 7.2913 (3) ŵ = 0.40 mm−1
c = 15.2621 (6) ÅT = 293 K
β = 124.103 (2)°Parallelepipedic, colourless
V = 2416.66 (16) Å30.30 × 0.10 × 0.10 mm
Z = 8
Data collection top
Nonius KappaCCD
diffractometer		1627 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tubeRint = 0.071
graphiteθmax = 25.4°, θmin = 3.0°
Detector resolution: 9 pixels mm-1h = −31→30
φ and ω scansk = −8→8
14205 measured reflectionsl = −18→17
2139 independent reflections
Refinement top
Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.045Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.126H-atom parameters constrained
S = 1.05 w = 1/[σ2(Fo2) + (0.0625P)2 + 4.0148P]
where P = (Fo2 + 2Fc2)/3
2139 reflections(Δ/σ)max = 0.001
229 parametersΔρmax = 0.33 e Å−3
21 restraintsΔρmin = −0.37 e Å−3
Crystal data top
H3O+·C8H7O8P2−V = 2416.66 (16) Å3
Mr = 312.10Z = 8
Monoclinic, C2/cMo Kα radiation
a = 26.2271 (9) ŵ = 0.40 mm−1
b = 7.2913 (3) ÅT = 293 K
c = 15.2621 (6) Å0.30 × 0.10 × 0.10 mm
β = 124.103 (2)°
Data collection top
Nonius KappaCCD
diffractometer		1627 reflections with I > 2σ(I)
14205 measured reflectionsRint = 0.071
2139 independent reflectionsθmax = 25.4°
Refinement top
R[F2 > 2σ(F2)] = 0.045H-atom parameters constrained
wR(F2) = 0.126Δρmax = 0.33 e Å−3
S = 1.05Δρmin = −0.37 e Å−3
2139 reflectionsAbsolute structure: ?
229 parametersFlack parameter: ?
21 restraintsRogers parameter: ?
Special details top

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

Refinement. Refinement of F2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The threshold expression of F2 > σ(F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/UeqOcc. (<1)
P10.81092 (4)0.03803 (12)0.41201 (6)0.0268 (3)
O110.79680 (10)−0.0117 (3)0.49420 (18)0.0338 (6)
H110.76150.01910.47210.051*
O120.75192 (9)0.0932 (3)0.30772 (17)0.0338 (6)
H120.75280.05410.25820.051*
O130.84830 (10)−0.1086 (3)0.40406 (18)0.0339 (6)
P20.82143 (3)0.45428 (11)0.46825 (6)0.0250 (3)
O230.80619 (9)0.4158 (3)0.54732 (17)0.0316 (5)
O220.76507 (9)0.5004 (3)0.36019 (17)0.0323 (6)
O210.87289 (10)0.5997 (3)0.50941 (18)0.0339 (6)
H210.86050.68560.46760.051*
C10.85893 (13)0.2462 (4)0.4606 (2)0.0252 (7)
O10.90991 (9)0.2067 (3)0.57008 (15)0.0329 (6)
C2A0.9660 (4)0.2436 (17)0.5830 (7)0.030 (3)0.50
O2A1.0134 (4)0.2317 (14)0.6679 (7)0.058 (3)0.50
C3A0.9536 (4)0.2866 (17)0.4802 (7)0.032 (3)0.50
C40.89030 (14)0.2748 (5)0.4041 (2)0.0295 (7)
C50.86705 (16)0.3115 (5)0.2986 (3)0.0373 (8)
H50.82500.30670.24670.045*
C6A0.9093 (5)0.356 (2)0.2737 (11)0.037 (4)0.50
H6A0.89470.38900.20460.045*0.50
C7A0.9732 (6)0.3515 (19)0.3495 (10)0.056 (4)0.50
H7A1.00030.37360.32960.068*0.50
C8A0.9952 (5)0.3150 (15)0.4523 (9)0.050 (3)0.50
H8A1.03740.30920.50320.060*0.50
C2B0.9639 (5)0.1751 (16)0.5743 (9)0.038 (4)0.50
O2B1.0105 (4)0.1345 (12)0.6576 (8)0.053 (2)0.50
C3B0.9517 (4)0.2220 (17)0.4728 (8)0.030 (3)0.50
C6B0.9075 (6)0.297 (3)0.2668 (12)0.045 (5)0.50
H6B0.89220.30940.19550.055*0.50
C7B0.9703 (6)0.264 (2)0.3393 (11)0.062 (5)0.50
H7B0.99710.27230.31770.074*0.50
C8B0.9926 (5)0.2211 (16)0.4419 (10)0.052 (3)0.50
H8B1.03390.19180.48970.062*0.50
O1W0.85750 (13)−0.1636 (4)0.2188 (2)0.0646 (9)
H1W0.8473−0.16390.26900.097*
H2W0.8410−0.25450.16540.097*
H3W0.9009−0.15440.25750.097*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
P10.0238 (4)0.0260 (5)0.0315 (5)0.0011 (3)0.0160 (4)0.0003 (3)
O110.0267 (12)0.0395 (14)0.0395 (13)0.0046 (10)0.0212 (11)0.0068 (11)
O120.0250 (11)0.0408 (14)0.0277 (11)0.0002 (10)0.0099 (10)−0.0051 (10)
O130.0351 (12)0.0286 (13)0.0461 (14)0.0040 (10)0.0277 (12)−0.0010 (10)
P20.0219 (4)0.0269 (5)0.0268 (4)−0.0013 (3)0.0141 (4)0.0004 (3)
O230.0298 (11)0.0380 (13)0.0329 (12)0.0034 (10)0.0211 (11)0.0044 (10)
O220.0224 (11)0.0385 (14)0.0311 (12)0.0041 (10)0.0120 (10)0.0051 (10)
O210.0259 (11)0.0296 (13)0.0391 (13)−0.0050 (10)0.0138 (11)0.0014 (10)
C10.0174 (14)0.0338 (18)0.0203 (14)0.0011 (13)0.0081 (13)0.0012 (12)
O10.0210 (11)0.0494 (15)0.0257 (11)0.0043 (10)0.0116 (10)0.0059 (10)
C2A0.012 (4)0.046 (9)0.026 (5)0.000 (4)0.007 (4)−0.008 (4)
O2A0.022 (4)0.111 (8)0.032 (4)−0.004 (5)0.009 (3)−0.001 (5)
C3A0.024 (4)0.033 (9)0.038 (5)−0.008 (4)0.016 (4)−0.005 (4)
C40.0237 (16)0.0341 (19)0.0338 (16)0.0004 (14)0.0180 (15)0.0002 (14)
C50.0329 (18)0.046 (2)0.0331 (18)0.0081 (16)0.0186 (16)0.0073 (16)
C6A0.046 (6)0.032 (11)0.039 (5)0.008 (5)0.027 (5)0.006 (5)
C7A0.050 (6)0.086 (12)0.057 (6)−0.004 (7)0.045 (6)0.005 (7)
C8A0.032 (5)0.074 (9)0.048 (5)−0.016 (6)0.026 (4)−0.010 (6)
C2B0.033 (6)0.035 (8)0.043 (6)−0.005 (4)0.019 (5)−0.010 (5)
O2B0.020 (3)0.083 (7)0.038 (4)0.008 (4)0.005 (3)−0.002 (5)
C3B0.024 (4)0.028 (8)0.039 (5)−0.006 (4)0.019 (4)−0.009 (4)
C6B0.073 (8)0.036 (12)0.053 (7)0.017 (6)0.051 (7)0.014 (6)
C7B0.050 (7)0.091 (12)0.070 (8)0.011 (7)0.049 (7)0.024 (8)
C8B0.029 (5)0.074 (9)0.061 (6)−0.001 (6)0.030 (5)0.007 (7)
O1W0.0470 (16)0.081 (2)0.0599 (18)0.0001 (16)0.0266 (15)−0.0147 (16)
Geometric parameters (Å, °) top
P1—O131.501 (2)C4—C3B1.395 (9)
P1—O121.526 (2)C5—C6A1.397 (11)
P1—O111.537 (2)C5—C6B1.397 (11)
P1—C11.842 (3)C5—H50.9300
O11—H110.8200C6A—C7A1.405 (11)
O12—H120.8200C6A—H6A0.9300
P2—O231.495 (2)C7A—C8A1.360 (11)
P2—O221.511 (2)C7A—H7A0.9300
P2—O211.546 (2)C8A—H8A0.9300
P2—C11.847 (3)C2B—O2B1.207 (10)
O21—H210.8200C2B—C3B1.437 (11)
C1—O11.469 (3)C3B—C8B1.393 (10)
C1—C41.503 (4)C6B—C7B1.396 (12)
O1—C2A1.397 (9)C6B—H6B0.9300
O1—C2B1.399 (10)C7B—C8B1.366 (11)
C2A—O2A1.193 (9)C7B—H7B0.9300
C2A—C3A1.447 (10)C8B—H8B0.9300
C3A—C8A1.390 (10)O1W—H1W0.9423
C3A—C41.397 (9)O1W—H2W0.9469
C4—C51.391 (4)O1W—H3W0.9450
O13—P1—O12115.47 (13)C3A—C4—C1108.0 (5)
O13—P1—O11111.42 (13)C4—C5—C6A117.4 (6)
O12—P1—O11110.24 (12)C4—C5—C6B117.6 (7)
O13—P1—C1106.83 (13)C6A—C5—C6B18.0 (14)
O12—P1—C1105.50 (13)C4—C5—H5121.3
O11—P1—C1106.80 (13)C6A—C5—H5121.3
P1—O11—H11109.5C6B—C5—H5118.0
P1—O12—H12109.5C5—C6A—C7A122.2 (10)
O23—P2—O22112.47 (12)C5—C6A—H6A118.9
O23—P2—O21111.60 (13)C7A—C6A—H6A118.9
O22—P2—O21112.81 (13)C8A—C7A—C6A119.5 (11)
O23—P2—C1106.84 (13)C8A—C7A—H7A120.3
O22—P2—C1110.08 (13)C6A—C7A—H7A120.3
O21—P2—C1102.39 (13)C7A—C8A—C3A119.0 (10)
P2—O21—H21109.5C7A—C8A—H8A120.5
O1—C1—C4103.8 (2)C3A—C8A—H8A120.5
O1—C1—P1106.1 (2)O2B—C2B—O1119.4 (10)
C4—C1—P1110.7 (2)O2B—C2B—C3B132.5 (10)
O1—C1—P2105.48 (18)O1—C2B—C3B107.6 (8)
C4—C1—P2113.9 (2)C8B—C3B—C4122.0 (8)
P1—C1—P2115.74 (15)C8B—C3B—C2B128.0 (9)
C2A—O1—C2B21.1 (7)C4—C3B—C2B110.0 (7)
C2A—O1—C1109.7 (4)C7B—C6B—C5121.7 (11)
C2B—O1—C1109.7 (5)C7B—C6B—H6B119.2
O2A—C2A—O1120.8 (9)C5—C6B—H6B119.2
O2A—C2A—C3A131.1 (9)C8B—C7B—C6B120.3 (11)
O1—C2A—C3A108.1 (7)C8B—C7B—H7B119.9
C8A—C3A—C4121.7 (8)C6B—C7B—H7B119.9
C8A—C3A—C2A128.8 (9)C7B—C8B—C3B118.1 (10)
C4—C3A—C2A109.1 (7)C7B—C8B—H8B120.9
C5—C4—C3B119.7 (5)C3B—C8B—H8B120.9
C5—C4—C3A119.7 (5)H1W—O1W—H2W119.8
C3B—C4—C3A19.8 (8)H1W—O1W—H3W106.4
C5—C4—C1131.7 (3)H2W—O1W—H3W113.4
C3B—C4—C1107.6 (5)
Hydrogen-bond geometry (Å, °) top
D—H···AD—HH···AD···AD—H···A
O11—H11···O23i0.821.692.504 (3)168
O12—H12···O22ii0.821.642.438 (3)164
O21—H21···O13iii0.821.722.522 (3)167
O1W—H1W···O130.942.092.996 (4)162
O1W—H2W···O23iv0.951.902.845 (4)174
O1W—H3W···O2Bv0.941.932.875 (10)177
O1W—H3W···O2Av0.941.952.853 (9)159
Symmetry codes: (i) −x+3/2, −y+1/2, −z+1; (ii) −x+3/2, y−1/2, −z+1/2; (iii) x, y+1, z; (iv) x, −y, z−1/2; (v) −x+2, −y, −z+1.
Table 1
Hydrogen-bond geometry (Å, °) top
D—H···AD—HH···AD···AD—H···A
O11—H11···O23i0.821.692.504 (3)168
O12—H12···O22ii0.821.642.438 (3)164
O21—H21···O13iii0.821.722.522 (3)167
O1W—H1W···O130.942.092.996 (4)162
O1W—H2W···O23iv0.951.902.845 (4)174
O1W—H3W···O2Bv0.941.932.875 (10)177
O1W—H3W···O2Av0.941.952.853 (9)159
Symmetry codes: (i) −x+3/2, −y+1/2, −z+1; (ii) −x+3/2, y−1/2, −z+1/2; (iii) x, y+1, z; (iv) x, −y, z−1/2; (v) −x+2, −y, −z+1.
Acknowledgements top

The authors thank Dr Jana Sopkova de Oliveira Santos, CERMN, Université de Caen Basse-Normandie, for help during the data processing, and acknowledge Professor Marc Lecouvey for his advice.

references
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