Alkaline and alkaline earth metal complexes of

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Alkaline and alkaline earth metal complexes of dianhydride derivatives of clodronate and their hydrolysis products† Susan Kunnas-Hiltunen,*a Matti Haukka,a Jouko Vepsäläinenb and Markku Ahlgréna Received 4th February 2010, Accepted 13th April 2010 First published as an Advance Article on the web 7th May 2010 DOI: 10.1039/c002403a Alkaline and alkaline earth metal complexes of P,P¢-diacetyl- (L12- ); new P,P¢-dipropanoyl- (L22- ) and P,P¢-dibenzoyl(dichloromethylene)bisphosphonates (L32- ) and their hydrolysis products were prepared and characterized using the single-crystal X-ray diffraction technique and spectroscopy, with the intention of studying the hydrolysis and coordinating properties of these potential prodrugs of clodronate. Na2 L1 and Na2 L2 formed the first crystalline hydrolysis product of these dianhydrides, 3D polymeric trisodium clodronate, [Na3 {Cl2 C(PO3 )2 }(H2 O)4 ]n (1). The other metal complexes prepared comprised the polymeric Ba2+ complex of L12- ligand [Ba{Cl2 C(PO2 O(C(O)Me))2 }(H2 O)3 ]n (2); the new Sr2+ complex of clodronic acid [{Sr2 (Cl2 C(PO3 )2 )(H2 O)4 }·H2 O]n (3), and the K+ complex of the L32ligand [{K2 Cl2 C(PO2 O(C(O)C6 H5 ))2 }O]n (4). In addition, these L12- –L32- ligands have formed the same, previously published [NaMgCl2 CP2 O6 H)(H2 O)5 ]n (5) and [{Ca2 (Cl2 C(PO3 )2 )(H2 O)6 }·4.5H2 O]n (6) by using the hydrolysis method in a systematic way. This study revealed that the Na2 L1 and Na2 L2 hydrolyze quite fast to structure 1 or form hydrolyzed metal complexes of clodronic acid, and hence the absorption in the body may not be increased by the use of Na2 L1-Na2 L2 as prodrugs. Na2 L3, in turn, has a longer hydrolysis time and generally forms crystalline polymeric metal complexes without undergoing hydrolyzation. In addition, the masking of the two phosphonic acid groups by esterification to form clodronic dianhydrides does not prevent the formation of 2D polymeric metal complexes, which methylenebisphosphonates form as drugs on the hydroxyapatite surface of bone. Clodronate, however, is able to extend the dimensionality to 3D by coordination or hydrogen bonding.

Introduction Bisphosphonates, stable analogs of naturally occurring pyrophosphate (P–O–P), have a high affinity to bone mineral hydroxyapatite, preventing the crystal growth, aggregation and dissolution of calcium phosphate crystals. This gives them an important and effective function as drugs in the treatment of diseases affecting bone tissue and in inhibiting the mineralization of soft tissues, for example in osteoporosis, bone metastases, hypercalcaemia and Paget’s disease of bone. The P–C–P backbone of these geminal bisphosphonates, with flexible phosphonate groups by coordination and possible side chains in the middle carbon atom between the phosphonate groups (H2 O3 P-(R1)C(R2)-PO3 H2 , R1 = H, Cl, OH and R2 = Cl, CH3 , amine, alkyl chain with heterocyclic amine etc.), permit many variations of binding calcium and other divalent metal cations while forming a layered structure on the hydroxyapatite surface of bone.1 These properties have also made bisphosphonates, especially those with a modified carbon chain length (H2 O3 P-R-PO3 H2 , R = alkyl or aryl), interesting building blocks in the field of crystal engineering and a Department of Chemistry, Joensuu Campus, University of Eastern Finland, P.O. Box 111, 80101, Joensuu, Finland. E-mail: Susan.KunnasHiltunen@uef.fi; Fax: +358 13 251 3390; Tel: +358 13 251 3377 b Department of Biosciences, Kuopio Campus, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland † Electronic supplementary information (ESI) available: 1 H and 31 P NMR spectra for Na2 L2. IR spectra for ligand Na2 L2 and compounds 1–4. CCDC reference numbers 764807–764810. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c002403a

5310 | Dalton Trans., 2010, 39, 5310–5318

coordination chemistry.2 Depending on the donor atoms and their orientation in the bisphosphonate ligand, various constructions are accessible with metal cations. In addition, the degree of protonation/deprotonation and the presence of other cations, anions or neutral molecules in the starting mixture may have an effect on the dimensionality.3 In addition to the 1D,3a,4 2D5 and 3D bisphosphonate metal complexes,6,3b–d 3D microporous and mesoporous bisphosphonate frameworks have also been prepared with chemically and thermally stable voids.7 Thus, bisphosphonates are capable of forming networks with various dimensions via coordinative and hydrogen bonds, and also have versatile applications in the field of solid state chemistry, for example, in the sorption of organic molecules, as catalysts for inorganic and organic synthesis and in gas storage.2 Disodium clodronate, disodium (dichloromethylene)bisphosphonate tetrahydrate, has a well-documented history.1 The absorption of clodronate and other geminal methylenebisphosphonates from the gastrointestinal tract is very low (< 3%1a ) due to their very low lipophilicity and high ionization at physiological pH values. In addition, they form non-absorbable complexes with divalent metal cations in the body that further reduce the absorption process. One solution to this problem may be the use of prodrug approach, where the hydrophilic phosphonic acid groups are masked so that the compound formed is more hydrophopic and will release the parent moiety, in this case clodronate, after absorption by undergoing chemical and/or enzymatic hydrolysis.8 The partial esterification of clodronate has led either to excessively unstable This journal is © The Royal Society of Chemistry 2010

compounds or to compounds that do not release the parent clodronate, and thus these compounds do not fulfil the criteria of a prodrug.9 The dianhydride derivatives of clodronic acid are the first reported bioreversible prodrugs of clodronate that have the potential to improve the oral bioavailability of clodronate.10 However, very little attention has been paid to the prodrug approach, at least partly as a result of the complicated chemistry of the bisphosphonates. In the present study we focus on the binding and hydrolysis properties of the symmetrical dianhydride derivatives of clodronate with alkaline and alkaline earth metals, since the s-block elements of the periodic table make important contributions to our bodies and other biological systems. These metals can also be found on the surface of bone mineral, where the methylenebisphosphonate drugs encounter Ca2+ ions and form metal complexes. Thus, their complexation properties provide important information for understanding the mechanism of their action. Studying structural features of clodronate and its dianhydride derivatives, which are/may be effective drugs for the bone diceases, the critical knowledge is their crystalline nature. Clodronate [Cl2 C(PO3 H)2 ]2- and its dianhydride derivatives, P,P¢-diacetyl- (L12- ); P,P¢-dipropanoyl(L22- ) and P,P¢-dibenzoyl(dichloromethylene)bisphosphonates (L32- ), which are used as ligands in this study, are presented in Scheme 1. The synthesis of a new Na2 L2, the chemical and hydrolysis properties of the clodronate and the L12- –L32alkaline and alkaline earth metal complexes are discussed together with the crystallization methods and results of X-ray diffraction and IR studies. The metal complexes consist of the following: the first hydrolysis product of these dianhydrides, [Na3 {Cl2 C(PO3 )2 }(H2 O)4 ]n (1); the Ba2+ complex of L12- ligand [Ba{Cl2 C(PO2 O(C(O)Me))2 }(H2 O)3 ]n (2); the new Sr2+ complex of clodronic acid [Sr2 {(Cl2 C(PO3 )2 )(H2 O)4 }·H2 O]n (3), and the K+ complex of the L32- ligand [K2 {Cl2 C(PO2 O(C(O)C6 H5 ))2 }O]n (4). In addition, these L12- –L32- ligands have formed previously published alkaline earth metal complexes of (5) and clodronic acid: [NaMgCl2 CP2 O6 H)(H2 O)5 ]n 11 [{Ca2 (Cl2 C(PO3 )2 )(H2 O)6 }·4.5H2 O]n 12 (6) by use of the hydrolysis method in a systematic way. We have also previously published the alkaline earth metal complexes of the L32- ligand,13 and various divalent transition metal complexes of clodronic acid14 and the L32- ligand in order to study the properties of solid materials.14a–b

Results and discussion Syntheses The chemistry of clodronate and its dianhydride derivatives, as that of the other bisphosphonates, as well, is very challenging. In general, the bisphosphonate metal complexes are crystallized under hydrothermal conditions,3–6 but structures 1–6 were crystallized by each of the gel, liquid and gas-liquid crystallization methods. The clodronate forms metal complexes easily with its six donor oxygen atoms and various metal clodronate forms can be formed under different reaction conditions.11,12 The symmetrical dianhydride derivatives of clodronate, at least Na2 L3, also form metal complexes quite readily via their four phosphonate oxygen and two carbonyl oxygen atoms, but the crystallization time plays a significant role in the crystallization methods because of the This journal is © The Royal Society of Chemistry 2010

Scheme 1 Schematic representation of the clodronate [Cl2 C(PO3 H)2 ]2and its dianhydride derivatives L12- –L32- .

hydrolysis. The clodronic dianhydrides are stable in solid form, but in phosphate buffer solution the Na2 L1 hydrolyzes in 45 min (at pH 2) and in 15.2 h (at pH 7.4), whereas the Na2 L3 ligand hydrolyzes in 11.9 d (pH 2) and 9.8 d (pH 7.4).10 Under these circumstances, the formation of the metal complex has to proceed fast enough and the reaction conditions have to be thoroughly optimized. The liquid crystallization method has proved to be promising for the dianhydride ligands owing to its ease and rapidity. The gel crystallization method, in turn, is highly effective for controlling the rate of diffusion and precipitation processes, but the reaction itself can take time and the quantity of crystals is limited. If the ligand reacts with the metal cation swiftly enough, as is the case with structure 2 and the metal complexes of L32- ,13 the gel crystallization method produces good-quality crystals. An interesting finding is that the clodronic dianhydrides also form metal complexes by hydrolyzation, and the clodronic acid metal complexes thus formed are the same even though the starting material ligands the dianhydride derivatives vary. Most of the clodronic acid metal complexes that are formed can also be synthesized by using clodronate as starting material for the ligand, and hence this study complements the study of clodronic acid metal complexes. The summary of the alkaline and alkaline earth metal complexes of clodronate and its symmetrical dianhydride derivatives that are formed are presented in Table 1. The clodronate itself has been crystallized previously,15 but crystallization of the dianhydride derivatives Na2 L1 and Na2 L2 produce the hydrolysis product 1 in both cases. The Na2 L3, in turn, did not form crystalline structure(s). The ligands L12- –L22- also form alkaline earth metal complexes of clodronic acid by hydrolysis, while the L32- ligand does not form hydrolysis products as much as do L12- –L22- , due to the resonance stabilization of benzoyl moieties10 The hydrolysis products of the Ca2+ complexes of the dianhydride derivatives of clodronate are also worth mentioning here. The clodronate forms four different Ca(II) structures by gel and evaporation crystallization methods, depending on the pH.12,15 However, the L12- –L32- ligands all form the same Ca(II) complex form of the clodronate, 6, by hydrolysis with various crystallization Dalton Trans., 2010, 39, 5310–5318 | 5311

Table 1 Summary of the crystallizations of alkaline and alkaline earth metal complexes of clodronate [Cl2 C(PO3 H)2 ]2- and L12- –L32Metal

Clodronate

L1

L2

L3

(Na+ )

15

Hydrolyzed to 1

Hydrolyzed to 1

—

K+ Mg2+

— 511 [{Mg(H2 O)6 }{Mg(Cl2 CP2 O6 )(H2 O)}·7H2 O]n 11 612 [Ca{Cl2 C(PO3 )2 }(H2 O)5 ]12 [{Ca2 Na0.5 (Cl2 C(PO3 )2 )(H2 O)8 }Cl0.5 ·2H2 O]n 12 [{Ca5 ((Cl2 C(PO3 )2 )2 )(H2 O)15 }(NO3 )2 ·1.5H2 O]n 12 [Sr{Cl2 C(PO3 H)2 }(H2 O)5 ]16 [Ba3 {(Cl2 CP2 O6 H)(H2 O)4 }·H2 O]n 17

— Hydrolyzed to 5

— Hydrolyzed to 5

4 [Mg{[Cl2 C(PO2 O(C(O)C6 H5 ))2 ](H2 O)5 }·H2 O]13

Hydrolyzed to 6

Hydrolyzed to 6

Hydrolyzed to 6

Hydrolyzed to 3 2

— —

[Sr2 {[Cl2 C(PO2 O(C(O)C6 H5 ))2 ]2 (H2 O)9 }·H2 O]n 13 [Ba{Cl2 C(PO2 O(C(O)C6 H5 ))2 }(H2 O)2 ]n 13

Ca2+

Sr2+ Ba2+

methods and within a pH range of 4.3-5.2 in a systematic way. A similar observation can be made with the formation of structure 5 from the clodronate and ligands L12- –L22- . Here we can see how the ligands L12- –L32- start to hydrolyse immediately in water solution, and how the clodronate and its dianhydride derivatives compete with each other of the metal complex formation in the solution. The clodronate shows the higher affinity to the metal cations compared to the clodronic dianhydrides exactly according to the prodrug principle. Spectroscopic properties The characteristic IR region and bands of the ligand material Na2 L3 and its alkaline earth metal and transition metal complexes have been reported previously.13,14a–b In addition to the earlier results, these assignments are based on the published values for similar compounds and IR tables.18 The structural differences of Na2 L2 and structures 1–4 can be readily observed. The characteristic IR regions for the Na2 L2, the Na(I) and Sr(II) complexes of clodronic acid, 1 and 3, the Ba(II) complex of L12- , 2, and the K(I) complex of L32- , 4, were observed at 1764–676 cm-1 . The clodronic acid framework absorptions for the Na2 L2 and 1– 4 compounds were at 1285–920 cm-1 , which can be attributed to the stretching vibrations of the phosphonate PO3 groups; at 855–760 cm-1 , which can be attributed to the asymmetric and symmetric n(P–C–P) vibrations, and at 765–675 cm-1 , due to the asymmetric and symmetric n(CCl2 ) vibrations. The n(P=O) stretching vibrations of the Na2 L2 and structures 1–4 occurred at 1287, 1241, 1271, 1146, and 1273 cm-1 , respectively. Thus, the n(P=O) absorptions are approximately 35–140 cm-1 at a higher wavenumber in the spectra of Na2 L2, 2 and 4, due to the ester moieties attached to the phosphonate groups. In addition, in the spectra of structures 1–3 there can be seen broad bands of n(H2 O) around 3600–3400 cm-1 and weaker absorptions of d(H– O–H) in the region of 1630–1590 cm-1 , owing to the coordinated and crystal water molecules in the structures. In the spectra of Na2 L2 and structures 2 and 4 there are also broad bands at around 3500 cm-1 that could be attributed to the n(C=O) overtone of the propanoyl, acetyl, and benzoyl moieties of the ligands, respectively. In addition, the dianhydride groups display absorptions resulting from the n(C=O) and n(C–O(–P)) vibrations appearing at 1765–1725 cm-1 , and at 1290–1115 cm-1 . The alkyl groups of the ligand material Na2 L2 and structure 2 displayed bands at around 2940–2880 cm-1 and 1471–1370 cm-1 as a result of the asymmetric and symmetricn(C–H) and d(C–H) vibrations, 5312 | Dalton Trans., 2010, 39, 5310–5318

respectively. For structure 4, the aromatic ring n(C=C) vibrations occurred at 1602 cm-1 , 1588 cm-1 , 1494 cm-1 , and 1452 cm-1 , and the stretching vibrations of the ring C–H bonds appeared as a series of bands in the 3070–2855 cm-1 region. The absorptions for the monosubstituted aromatic ring, resulting from the out-ofplane C–H vibrations, were at ca. 750 cm-1 and 700 cm-1 . Crystal structures Our previous studies of the metal complexes of L32- ligand indicated the formation of 2D structures of clodronic dianhydride metal complexes via the hydrogen bonding of coordinated and crystal water.13,14a–b Water molecules are especially attracted to s-block ions, and they are very important factors in the designing of metal–organic frameworks. Generally, the metal complexes of clodronic acid form polymeric structures, chains and layers, which can be extended to 2–3D structures by coordination and/or hydrogen bonds.11–12,16,17 In this study, the metal complexes of the hydrolysis products of the clodronic dianhydrides follow the same pattern. Evidently, the two bulky groups attached to the phosphonate oxygen atoms by esterification diminish the metal complexation and reduce the dimensionality of the structures thus formed, as these compounds as prodrugs of clodronate are expected to do. This esterification does not, however, prevent the formation of 2D polymeric structures, since the R-O12-P1-C1-P2O22-R framework makes room for the other four phosphonate oxygen atoms and two carbonyl oxygen atoms of the ester groups to coordinate with the metal cations by reducing the (R–)O12– P–C angles to approximately 96–97◦ , while the average O–P–C angle of the clodronate metal complexes is approximately 106◦ (Table 2). In addition, the P1–C1–P2 angles of structures 2 and 4 are 110–112◦ , while the corresponding angles of structures 1 and 3 are 118–119◦ . The size difference between the acetyl and benzoyl groups does not, however, affect the size of the (R-)O12P-C angle. This geometry trend can also be seen in the previously reported metal complexes of the clodronate and its dianhydride derivatives.13,14a–b The crystal structure of 1 is a 3D structure constructed of planes pillared by two Na1O6 octahedrons which share two mH2 O bridges with each other (see Fig. 1 and Fig. 2). In addition, the Na1O6 octahedron shares a corner with PCO3 tetrahedron and a m-H2 O bridge with an adjacent Na3O6 octahedron (-x, -y, 2 - z), completing the coordination sphere with two aqua ligands. The dense planes consist of Na2O6 and Na3O6 octahedrons chelated and bridged by clodronate. The Na2O6 octahedron shares corners This journal is © The Royal Society of Chemistry 2010

˚ ) and angles (◦ ) for structures 1–4 Table 2 Selected bond distances (A

P1–O11 P1–O12 P1–O13 P2–O21 P2–O22 P2–O23 P1–C1 P2–C1 O11–P1–C1 O12–P1–C1 O13–P1–C1 O21–P2–C1 O22–P2–C1 O23–P2–C1 P1–C1–P2

1

2

3

4

1.498(2) 1.510(2) 1.574(2) 1.512(2) 1.513(2) 1.537(2) 1.864(3) 1.861(3) 106.49(12) 107.85(12) 102.55(11) 106.99(12) 106.03(12) 104.11(12) 118.98(15)

1.483(2) 1.656(2) — 1.480(2) 1.639(2) — 1.859(3) 1.863(3) 109.16(7) 96.63(12) — 109.25(7) 96.55(12) — 111.6(2)

1.512(2) 1.515(2) 1.529(2) 1.513(2) 1.523(2) 1.518(2) 1.868(3) 1.870(3) 105.96(13) 106.62(12) 103.60(12) 105.98(12) 105.02(13) 105.63(12) 117.6(2)

1.479(2) 1.642(2) 1.478(2) 1.478(2) 1.648(2) 1.485(2) 1.857(3) 1.859(3) 107.99(13) 96.45(12) 109.05(13) 108.45(13) 97.18(12) 107.97(13) 109.6(2) Fig. 2

A polyhedral representation of structure 1 in the bc plane.

only a few structures with a Na–Cl(C) interaction, the differences ˚ compared with the in their distance ranging between 0.59–0.91 A Na–O coordination bonds of these structures. In addition, only a few M–Cl(C) interactions with transition metals and only one with the Cd clodronate14c have been reported earlier. The intra- and intermolecular hydrogen bonds in structure 1 are formed between the aqua ligands, phosphonate oxygen atoms and Cl2 atoms. Structure 2 may be described as a 2D polymeric plane where Ba2+ cation chains are linked by L12- ligands (see Fig. 3 and Fig. 4). Each ten-coordinated Ba2+ cation shares two faces with adjacent BaO10 polyhedrons through four m-H2 O bridges, and with four mono-atomic phosphonate oxygen bridges by sharing an edge with a PCO3 tetrahedron. In addition, the adjacent L12- ligand coordinates the Ba2+ cation monodentately with carbonyl oxygen, and the coordination sphere of the Ba2+ cation is completed with ˚ . This one aqua ligand. The average Ba–O bond length is 2.583 A structure is a good example of the functioning of the clodronic dianhydride ligand as an extended linker, and also of the carbonyl oxygen atoms functioning as coordinating units. If the ester groups were to be made longer and have terminal coordinating groups,

Fig. 1 Atom labelling scheme and 50% thermal ellipsoids for [Na3 {Cl2 C(PO3 )2 }(H2 O)5 ] (1).

with both PCO3 tetrahedrons forming a six-membered chelate ring. In addition, the other corner or phosphonate oxygen acts as a monoatomic bridge to the Na3O6 octahedron, while the other phosphonate oxygen connects the Na2O6 octahedron with adjacent Na2O6 and Na3O6 octahedrons. The preceding NaO6 octahedrons are also coordinated by the adjacent clodronate (1 + x, y, z), and hence these Na+ cations are connected to each other via two monoatomic phosphonate bridges. In addition, the Na3O6 octahedron forms two m-H2 O bridges to the adjacent Na3O6 octahedron (1 - x, 1 - y, 2 - z), and the sixth coordination site of the Na2 atom is occupied with the Cl1 atom of the adjacent clodronate ligand (1 + x, y, z). The average Na1–O, Na2–O and Na3–O ˚ , respectively, coordination bonds are 2.465, 2.379 and 2.477 A ˚ longer than the average and the Na2–Cl1(C) distance is 0.71 A Na2–O distance. According to the CCDC database19 there are This journal is © The Royal Society of Chemistry 2010

Fig. 3 Atom labelling scheme and 50% thermal ellipsoids for [Ba{Cl2 C(PO2 O(C(O)Me))2 }(H2 O)3 ]n (2).

Dalton Trans., 2010, 39, 5310–5318 | 5313

Fig. 4 A polyhedral representation of structure 2 in the ac plane, showing the L12- ligands as linkers between the metal chains.

the porosity of the structure might also increase. In addition, such chains could also be added to the middle-carbon atom, and thus the structure could be extended into a third dimension. This procedure would also permit the formation of hydrogen bonds between the layers. In the present situation, in structure 1, the intra- and intermolecular hydrogen bonds are formed between the aqua ligands and phosphonate oxygen atoms within the layers. Structure 3 is also a 2D polymeric compound, but the planes are connected to a 3D structure by hydrogen bonding (see Fig. 5 and Fig. 6). The clodronate, with its less hydrophobic frame and with no bulky ester groups, permit the lattice water molecules to place themselves between the layers and form hydrogen bonds also in the third dimension. However, the 2D plane is dense due to the short clodronate backbone and the high propensity of the polydentate phosphonate groups to coordinate the metal cations. The clodronate acts here as a pentadentate ligand by chelating and bridging the seven-coordinated Sr12+ and eightcoordinated Sr22+ cations. Four phosphonate oxygen atoms of the PCO3 tetrahedrons act as monoatomic bridges between the Sr12+ and Sr22+ cations, the fifth phosphonate oxygen atom coordinates the Sr12+ cation monodentately, leaving the sixth phosphonate oxygen atom deprotonated. In addition, the Sr12+ and Sr22+ cations are also connected with a m-H2 O bridge, and, moreover, the

Fig. 5 Atom labelling scheme and 50% thermal ellipsoids for [Sr2 {(Cl2 C(PO3 )2 )(H2 O)5 }·H2 O]n (3).

5314 | Dalton Trans., 2010, 39, 5310–5318

Fig. 6 A polyhedral representation of structure 3 in bc plane, showing the interlayer section.

coordination sphere of Sr22+ cation is completed with two aqua ligands. The average Sr1–O and Sr2–O bond distances are 2.559 ˚ , respectively. The intra- and intermolecular hydrogen and 2.644 A bonds involve all of the aqua ligands and lattice water molecules as donors and the phosphonate oxygen atoms, lattice aqua ligands and Cl1 ligands as acceptors. Structure 4 is an exception to the previous metal complexes of the bisphosphonates. First of all, the K+ complexes of the bisphosphonates are less common, since the alkaline metals are generally considered to be spectator ions in crystal structures. In addition, structure 4 does not contain any water molecules, even though the crystals were formed in water solution. Structure 4 is a 2D plane structure constructed by coordination bonds (Fig. 7 and Fig. 8). The plane consists of chains where the L32- ligand acts as a chelating and bridging ligand. The L32- ligand is coordinated with the seven-coordinated K1+ cation monodentately via carbonyl oxygen. The K1+ cation is also chelated by its two adjacent L32ligands via phosphonate oxygen and carbonyl oxygen atoms. The carbonyl oxygen atom of the monodentately coordinated L32ligand and the carbonyl oxygen atom of the other chelating ligand are both monoatomic bridges to the adjacent K1+ cation (-x, 1 - y, 1 - z). In addition, the K1+ cation is connected to another adjacent K1+ cation (-1 - x, 1 - y, 1 - z) via two oxygen bridges. The sixcoordinated K2+ cation, in turn, forms a distorted trigonal prism

Fig. 7 Atom labelling scheme and 50% thermal ellipsoids for [K2 {Cl2 C(PO2 O(C(O)C6 H5 ))2 }O] (4).

This journal is © The Royal Society of Chemistry 2010

and H were carried out using EA 1110 CHNS–O, CarloErba 1106, and VarioMICRO V1.7.0 CHN Mode analyzers where clodronate and EDTA served as standards. The percentage values of Na+ , K+ , Mg2+ , Ca2+ , Sr2+ and Ba2+ were determined using a Varian 220 atomic absorption spectrophotometer. The infrared spectra were recorded on a Nicolet Magna-IRTM spectrometer 750 using the KBr pellet technique. A synthesis of Na2 Cl2 C[PO3 (C(O)CH2 CH3 )]2 (Na2 L2)

Fig. 8 A polyhedral representation of structure 4.

core by sharing six phosphonate oxygen atoms of three chelating L32- ligands. In addition, it shares a face with an adjacent K2+ cation (1 - x, -y, 1 - z). These four phosphonate oxygen atoms of the L32- ligands also bridge the K2+ cation to the adjacent K1+ ˚ , while the K2– cations. The average K1–O bond distance is 2.774 A ˚ , with two relatively O bond distances vary between 2.684-3.302 A long K–O bonds. In terms of the CCDC Structural Database,19 ˚. however, the K–O(–P) bond length range is 2.22–3.33 A

Experimental General considerations All of the reagents used for the synthesis and characterization of compounds 1–6 were of analytical reagent grade, and the water (Milli-Q Plus system) was ultrapure grade. The synthesis and characterization of P,P¢-diacetyl(dichloromethylene)bisphosphonate disodium salt Na2 Cl2 C[PO3 (C(O)CH3 )]2 (Na2 L1); P,P¢-dibenzoyl(dichloromethylene)bisphosphonate disodium salt Na2 Cl2 C[PO3 (C(O)C6 H5 )]2 (Na2 L3) and the starting material, tetrasodium clodronate, for the synthesis of P,P¢dipropanoyl-(dichloromethylene)bisphosphonate disodium salt Na2 Cl2 C[PO3 (C(O)CH2 CH3 )]2 (Na2 L2) have been reported earlier.10,20 1 H and 31 P NMR spectra were recorded on a Bruker AM 400 spectrometer operating at 400.1 and 162.0 MHz, respectively. TSP was used as an internal standard for 1 H measurement, and 85% H3 PO4 was used as an external standard for 31 P measurement. All J values are given in Hz. Compounds 1–3 and 5–6 were prepared by the gel crystallization method, compound 4 by the liquid crystallization method, and, in addition, compounds 3 and 6 were also prepared by the gas-liquid diffusion crystallization method. The initial and final pH values of the syntheses were measured using a Schott pH-Meter CG 840 with a Hamilton cheese electrode. Single crystals of 1–6 were selected for structural determination on a Nonius Kappa CCD diffractometer. Elemental analyses for C This journal is © The Royal Society of Chemistry 2010

Na2 L2 was prepared following the recognized method for clodronic dianhydrides.10 Anhydrous tetrasodium clodronate (5.0 g, 15.0 mmol) and propionic acid anhydride (50.0 mL, 338.0 mmol) were heated in an oil bath at 90–100 ◦ C for 120 h. The mixture was chilled to 5 ◦ C and allowed to stand overnight in the cold. The mixture was filtered, washed several times with ether, and dried to yield Na2 L2 as a white solid (2.8 g, 46%). (Found: C 21.85, H 2.85. Calcd. for C7 H10 Cl2 Na2 O8 P2 : C 20.97, H 2.51%). d H (400 MHz; D2 O; TSP) 2.53 (2H, kv, 3 J HH 7.5, CH 2 CH3 ), 1.12 (3H, t, 3 J HH 7.5, CH2 CH 3 ); d P (400 MHz; D2 O; 85% H3 PO4 ) 2.77 (s). n max /cm-1 : 2993 m (CH), 2946 m (CH), 2923 m (CH), 2880 w (CH), 1764 vs (C=O), 1417 m (CH), 1357 m (CH), 1287 vs (P=O, CO), 1194 m (COP), 1139 vs (CO), 1014 m (C–C), 988 s (POC), 939 w (POC), 853 vs (PCP), 809 m (CH2 ), 769 m (PCP), 743 m (CCl), 676 m (CCl). A synthesis of [Na3 {Cl2 C(PO3 )2 }(H2 O)4 ]n (1) Compound 1 was synthesized using the gel crystallization method for both the Na2 L1 and Na2 L2 compounds. The hydrolysis rate of the Na2 L1 for the clodronate has been described earlier,10 but the hydrolysis product of the clodronic dianhydrides had never been previously crystallised. 1 was prepared from the starting material Na2 L1 by mixing the water solution of Na2 L1 (0.4022 mmol/0.9 mL, pH 5.12) with TMOS (0.1 mL). Once the gel (pH 6.46) was formed, ethanol was added as a precipitant above the gel. Colourless block crystals were formed in the gel (pH 5.17) in two days. 1 was also formed by mixing the water solution of the Na2 L2 (0.0312 mmol/0.9 mL, pH 5.03) with TMOS (0.1 mL). After the formation of the gel (pH 6.25), ethanol was added, and in a week, colourless block crystals were formed above the gel (pH 6.38). (Found: C 3.16, H 2.56, Na 18.58. Calcd. for C2 H18 Na6 O20 P4 Cl4 : C 3.14, H 2.37, Na 18.01%.) n max /cm-1 : 1744 vs (dPO), 1241 vs (P=O), 1014 s (PO), 920 s (PO), 842 vs (PCP), 759 s (PCP), 759 s (CCl). A synthesis of [Ba{Cl2 C(PO2 O(C(O)Me))2 }(H2 O)3 ]n (2) 2 was prepared by mixing the water solutions of Na2 L1 (0.013 mmol/0.45 mL, pH 5.05) and Ba(NO3 )2 (0.013 mmol/0.45 mL, pH 5.78) with TMOS (0.1 mL). Once the gel (pH 4.98) had been formed, acetone was added above the gel. Colourless plate crystals were formed in the gel (pH 4.73) in one day. (Found: C 11.11, H 2.14, Ba 26.40. Calcd for C5 H12 BaCl2 O11 P2 : C 11.59, H 2.33, Ba 26.50%.) n max /cm-1 : 2936 w (CH), 1769 m (C=O), 1747 m (C=O), 1602 m (C=C), 1420 w (CH), 1369 m (CH), 1271 s (P=O), 1240 m (CO), 1115 m (CO, C–C), 1086 w (PO), 1060 w (PO), 1016 m (POC), 916 m (POC), 853 m (PCP), 767 m (PCP, CCl), 751 m (CCl). Dalton Trans., 2010, 39, 5310–5318 | 5315

A synthesis of [Sr2 {(Cl2 C(PO3 )2 )(H2 O)4 }·H2 O]n (3) 3 was prepared by mixing the water solutions of Na2 L1 (0.0054 mmol/0.45 mL, pH 4.97) and Sr(NO3 )2 (0.0054 mmol/0.45 mL, pH 5.48) with TMOS (0.1 mL). After the gel (pH 4.69) was formed, 1 : 1 acetone/water solution was added above the gel as a precipitant. Colourless plate crystals were formed in the gel (pH 4.32) in few days. In addition, 3 was formed by gas-liquid diffusion. The water solutions of Na2 L1 (0.0027 mmol/0.25 mL) and SrCl2 ·6H2 O (0.0027 mmol/0.25 mL) were mixed together and placed in a small vessel, the opening provided with parafilm with pinched holes. The vessel was placed in a larger vessel containing ethanol (1 mL), and then the system was sealed. Plate crystals again formed in the course of a few days. (Found: C 2.82, H 2.45, Sr 34.14. Calcd for CH10 Cl2 O11 P2 Sr2 : C 2.37, H 1.99, Sr 34.62%.) n max /cm-1 : 1643 m (d P–O ), 1146 m (P=O), 1079 s (PO), 959 m (PO), 851 m (PCP), 763 m (PCP), 763 m (CCl). A synthesis of [K2 {Cl2 C(PO2 O(C(O)C6 H5 ))2 }O]n (4) The water solutions of Na2 L3 (0.010 mmol, 1 cm3 , pH 3.74) and KNO3 (0.010 mmol, 1 cm3 , pH 4.81) were compounded and mixed with acetone (1 cm3 ). The solution (pH 4.38) was allowed to stand in the cold and the colourless plate crystals formed in a single day (solution pH 4.35). (Found: C 33.20, H 2.04, K 13.87. Calcd for C15 H10 Cl2 K2 O9 P2 : C 33.04, H 1.85, K 14.34%.) n max /cm-1 : 1727 m and 1704 m (C=O), 1602 w (C=C), 1588 w (C=C), 1494 w (C=C), 1452 m (C=C), 1273 s (P=O, C–O), 1182 w (COP), 1133 m (C–O), 1108 m (C–C), 1090 m (PO), 1068 m (PO), 1025 m (POC), 1003 m (POC), 841 m (PCP), 765 sh (CCl), 764 m (PCP, CH), 698 m (CH), 679 m (CCl). Synthesis of [NaMg(Cl2 CP2 O6 H)(H2 O)5 ]n (5) The preparation of 5 from the clodronate and Na2 L1 ligand has been reported earlier,11 but it was also formed from Na2 L2 with Mg2+ , using the hydrolysis method. The water solutions of Na2 L2 (0.0050 mmol/0.45 mL, pH 6.87) and Mg(NO3 )2 · 2H2 O (0.0050 mmol/0.45 mL, pH 5.42) were mixed together and TMOS (0.1 mL) was added to form a gel (pH 4.98). Once the gel had formed, an acetone-water 1 : 1 solution was placed above the gel as a precipitant. Colourless, needle-like crystals of 5 formed above the gel (pH 4.62) in the course of a month. (Found: C 2.77, H 3.03, Mg 6.20, Na 5.90. Calcd for CH11 Cl2 MgNaO11 P2 : C 3.17, H 2.92, Mg 6.40, Na 6.10%.) A synthesis of [{Ca2 (Cl2 C(PO3 )2 )(H2 O)6 }·4.5H2 O]n (6) Preparation of 6 from the clodronate and the ligand Na2 L3 has been described earlier,12–13,15 but now it was formed by hydrolysis from the Na2 L1 and Na2 L2 clodronate derivatives in various ways. In gel crystallization using the starting material Na2 L1 the water solutions of Na2 L1 (0.0054 mmol/0.45 mL, pH 4.99) and CaCl2 ·2H2 O (0.0054 mmol/0.45 mL, pH 4.79) were mixed together with TMOS (0.1 mL). After the gel had formed (pH 4.51), acetone was added above the gel. In the course of approximately two weeks, colourless and plank-like crystals were formed above the gel (pH 4.29). Using the starting material Na2 L2, in turn, the water solutions of Na2 L2 (0.0050 mmol/0.45 mL pH 6.87) and CaCl2 ·2H2 O (0.0050 mmol/0.45 mL, pH 5.51) were mixed 5316 | Dalton Trans., 2010, 39, 5310–5318

together with TMOS (0.1 mL). After the gel had formed (pH 5.30), ethanol was added above the gel. Within three days, colourless and needle-like crystals formed above the gel (pH 5.20). Compound 6 was also synthesized by means of gas-liquid diffusion. The water solutions of Na2 L1 (0.0027 mmol/0.25 mL) and CaCl2 ·2H2 O (0.0027 mmol/0.25 mL) were mixed together and placed in a small vessel, the opening provided in the form of parafilm with pinched holes. The vessel was placed in a larger glass tube containing acetone (1 ml), and then the system was sealed. Colourless stick crystals formed within a day or two. (Found: C 2.37, H 3.87, Ca 15.60. Calcd for CH21 Cl2 Ca2 O16.5 P2 (510.18): C 2.35, H 4.15, Ca 15.70%.) X-Ray crystallographic study The crystals of 1–4 were immersed in cryo-oil, mounted in a Nylon loop, and the X-ray diffraction data were collected by means of a Nonius KappaCCD diffractometer using MoKa radiation (l = ˚ ). A Denzo-Scalepack21 program package was used for 0.71073 A cell refinements and data reductions. The structures were solved by direct methods, using SHELXS-9722 for structures 1–3 and SIR200423 for structure 4, with a WinGX24 graphical user interface. A semi-empirical absorption correction was applied to the data of structures 2–3: XPREP25 and structure 4: SADABS.26 Structural refinements were carried out using SHELXL-97.22 Structure 4 was refined with two twin components (twin matrices [0.998 0.002 0.002 0.999 -0.999 0.001 0.500 0.001 -0.999] and [1.000 0.000 0.000 0.993 -1.000 0.000 0.486 0.000 -1.000]). The BASF values were refined to 0.02 and 0.05, respectively. In structures 1–3 all of the H2 O hydrogen atoms were located on the difference Fourier map and constrained to ride on their parent atom, with U iso = 1.5. Other hydrogen atoms in structures 2 and 4 were positioned geometrically and were also constrained to ride on their parent ˚ and U iso = 1.5·U eq atoms, in structure 2 with C–H = 0.98 A ˚ and U iso = (parent atom) and in structure 4 with C–H = 0.95 A 1.2 ¥ U eq (parent atom). The crystallographic details have been summarized in Table 3. The atomic positional parameters, full tables of bond lengths and angles, and hydrogen bonds are available in the ESI.†

Conclusions The hydrolysis and binding properties of the first potential prodrugs of clodronate, the clodronic dianhydrides have been studied by crystallizing them with alkaline and alkaline earth metals. In addition, a new clodronic dianhydride Na2 L2 was synthesized. Like clodronate, its dianhydride derivatives L12- and L32- form 2D polymeric compounds with alkaline and alkaline earth metals, but clodronate is also able to form hydrogen bonding in a third dimension. The orientation of the phosphonate oxygen atoms and bulky ester groups of clodronic dianhydrides hinder the formation of 3D structures, but the 2D structures with structurestrengthening chelate rings are formed as a result of the flexible C–P–O-R framework, which provides space for the coordination of the other phosphonate oxygen atoms. In addition, the clodronic dianhydrides Na2 L1-Na2 L2 hydrolyze to 3D crystalline trisodium clodronate, and form other metal complexes of clodronic acid by hydrolysis relatively fast, and hence the absorption in the body may not be increased by using Na2 L1-Na2 L2 as prodrugs. The This journal is © The Royal Society of Chemistry 2010

Table 3 Summary of crystallographic data for structures 1–4

Empirical formula Formula weight T/K Crystal system Space group ˚ a/A ˚ b/A ˚ c/A a/◦ b/◦ g /◦ ˚3 V /A Z rc /g cm-3 m(MoKa)/mm-1 GOF on F 2 Rint R1 b (I ≥ 2s) wR2 c (I ≥ 2s) a

Unmerged data. b R1 =

1

2

3

4

CH10 Cl2 Na3 O11 P2 399.90 293(2) Triclinic P1¯ 6.0326(12) 9.693(2) 11.510(2) 93.31(3) 91.63(3) 103.42(3) 653.0(2) 2 1.947 0.888 0.940 0.0475 0.0377 0.0936

C5 H12 BaCl2 O11 P2 518.33 120(2) Monoclinic C2/m 15.7725(5) 7.5324(2) 14.5010(4) 90.00 118.240(2) 90.00 1517.73(8) 4 2.268 3.228 1.122 0.0252 0.0183 0.0415 - F c 2 )2 ]/ [w(F o 2 )2 ]]1/2 .

CH10 Cl2 O11 P2 Sr2 506.17 120(2) Monoclinic P21 /c 5.7600(2) 12.1202(3) 18.0234(6) 90.00 95.303(2) 90.00 1252.87(7) 4 2.683 9.243 1.090 0.0422 0.0231 0.0581

C15 H10 Cl2 K2 O9 P2 545.27 100(2) Triclinic P1¯ 6.7201(2) 10.4562(5) 16.0580(8) 72.827(2) 84.164(3) 71.395(3) 1021.67(8) 2 1.772 0.929 1.041 0.095a 0.0433 0.0963

F o | - |F c /R |F o |. c wR2 = [

[w(F o 2

clodronate shows the higher affinity to the metal cations compared to the clodronic dianhydrides exactly according to the prodrug principle. An exception to this is structure 2, the polymeric Ba(II) complex of the ligand L12- . This shows that if the dianhydride ligand coordinates the reactive metal cation sufficiently fast, that is, if the reaction conditions are optimized, stable metal complexes of L12- –L22- can be formed. Na2 L3, in turn, requires a longer hydrolysis time and generally forms crystalline polymeric metal complexes without hydrolyzing. These new findings concerning the coordination properties of the dianhydride derivatives of a clodronate and their hydrolysis products, the metal complexes of clodronate, show the versatility of the coordination structures of diverse clodronic acid derivatives, and thus provides important information in support of research into bisphosphonates as pharmaceutical products.

4

5

6

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