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

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
The title compound, C 8 H 8 O 8 P 2 , 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 H 3 O + 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.

Experimental
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 N 2 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 supplementary materials sup-2 temperature from a concentrated methanol/ water (9/1) solution to give colorless crystal with max. size 0.3 mm, suitable for diffraction.

Refinement
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 U iso (H) = 1.2U eq (C) (aromatic) and 1.5U eq (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 H 3 O + 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 U iso (H) = 1.5U eq (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). Fig. 1

Special details
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.