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Syntheses, X-ray Diffraction Study and Characterisations of Metal Complexes of

Clodronic Acid and Its Symmetrical Dianhydride Derivatives

Susan Kunnas-Hiltunen

Department of Chemistry

University of Eastern Finland Finland

Joensuu 2010

Susan Kunnas-Hiltunen Department of Chemistry, University of Eastern Finland, Joensuu Campus P.O. Box 111, FI-80101 Joensuu, Finland Supervisors Prof. Markku Ahlgrén Prof. Matti Haukka Referees Prof. Reijo Sillanpää, University of Jyväskylä Prof. Risto Laitinen, University of Oulu Opponent Assoc. Prof. John C. Plakatouras, University of Ioannia To be presented with the permission of the Faculty of Science and Forestry of the University of Eastern Finland for public criticism in Auditorium F100, Yliopistokatu 7, Joensuu, on April 23rd, 2010 at 12 o´clock noon. Copyright © 2010 Susan Kunnas-Hiltunen ISBN 978-952-61-0081-4 ISBN 978-952-61-0082-1 (PDF) Joensuun yliopistopaino Joensuu 2010

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ABSTRACT Bisphosphonates are the most important pharmaceuticals, after vitamin D, for the treatment of diseases affecting bone tissue, for example in osteoporosis, bone metastases, hypercalcaemia and Paget’s disease, due to their high propensity to bone mineral hydroxyapatite. They are, however, highly hydrophilic compounds due to their ionisable phosphonic acid groups, and they also form metal complexes with other metal cations in the body, with the result that their absorption is very low. The clodronic dianhydrides are the first-reported bioreversible prodrugs of clodronate to have the potential to improve the oral bioavailability of clodronate. They are more lipophilic than the parent clodronate and hydrolyse entzymatically to clodronate in human serum. In addition, the strong binding of metal cations, both on surfaces or in solutions, makes the bisphosphonates important compounds in non-medical applications, such as ion exchange, sorption, gas storage and catalysts for inorganic and organic synthesis. The discovery of fascinating structures of different dimensionalities and porous structures has confirmed that the metal bisphosphonates should be regarded as important building blocks in crystal engineering. This thesis deals with the synthesis of a new clodronic dianhydride and with the alkaline, alkaline earth metal, first series transition metal and zinc complexes of clodronate and its dianhydride derivatives. These compounds were prepared by using the gel, solution and vapour diffusion crystallisation methods, and the crystals formed were characterised by means of single-crystal X-ray diffraction, elemental analyses and FT-IR. The thermal behaviour of the transition metal and zinc complexes was also studied by means of thermogravimetric analyses (TGA). Most of the clodronate metal complexes were formed by hydrolysis of the clodronic dianhydride ligands, and most of them were also prepared by using the clodronate as a starting material. An interesting finding was that the diacetyl and dipropanoyl derivatives of clodronate were swiftly hydrolysed to the crystalline trisodium clodronate, while the longer hydrolysis time of dibenzoyl derivative of clodronate, resulting from the resonance stabilisation of dibenzoyl moieties, resulted mainly in non-hydrolysed metal complexes. Under these circumstances, the absorption in the body may not be increased by using diacetyl or dipropanoyl derivatives of clodronate as prodrugs. The esterification of the clodronate did not prevent the formation of 2D polymeric structures through coordinative or hydrogen bonding between the monomeric and dimeric units and chains. In addition, the sizes of the ester moieties and the ionic radii of the metal cations controlled the coordination. The metal clodronates, in turn, formed all of the 3D structures through additional Na+ cations or by a 3D hydrogen bond network. The isostructural Co(II), Ni(II) and Zn(II) complexes of clodronic acid also possessed 2-3D water clusters between the structural units.

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LIST OF ORIGINAL PUBLICATIONS This dissertation is a summary of the following original publications I, III-V and submitted manuscript II. I Kontturi, M., Kunnas-Hiltunen, S., Vepsäläinen, J. J., Ahlgrén, M., X-ray

diffraction study of polymeric Mg complexes of clodronic acid, Solid State Sciences, 2006, 8, 1098-1102.

II Kunnas-Hiltunen, S., Haukka, M., Vepsäläinen, J., Ahlgrén, M., Alkaline and

Alkaline Earth Metal Complexes of Dianhydride Derivatives of Clodronate and Their Hydrolysis Products, submitted for publication.

III Kunnas-Hiltunen, S., Matilainen, M., Vepsäläinen, J. J., Ahlgrén, M., X-ray

diffraction study of bisphosphonate metal complexes: Mg, Sr and Ba complexes of (dichloromethylene)bisphosphonic acid P, P’-dibenzoyl anhydride, Polyhedron, 2009, 28, 200-204.

IV Kunnas-Hiltunen, S., Laurila, E., Haukka, M., Vepsäläinen, J., Ahlgrén, M.,

Organic-Inorganic Hybrid Materials: Syntheses, X-ray diffraction Study and Characterisations of Manganese, Cobalt and Copper Complexes of Modified Bis(phosphonates), Z. Anorg. Allg. Chem., 2010, 636, in press.

V Kunnas-Hiltunen, S., Haukka, M., Vepsäläinen, J., Ahlgrén, M., Syntheses, X-

ray Diffraction Study and Characterisations of Ni and Zn Complexes of Clodronic acid and Its Dibenzoyl derivative, Eur. J. Inorg. Chem., 2009, 5335-5345.

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CONTENTS ABSTRACT 3 LIST OF ORIGINAL PUBLICATIONS 4 CONTENTS 5 ABBREVIATIONS 6 1. INTRODUCTION 7 1.1. BISPHOSPHONATES AS PHARMACEUTICALS 71.2. BISPHOSPHONATES IN SOLID STATE CHEMISTRY 81.2.1. METAL COMPLEXES OF GEMINAL BISPHOSPHONATES 91.2.2. METAL COMPLEXES OF ALKYLENE- AND ARYLBISPHOSPHONATES 161.2.3. METAL COMPLEXES OF IMINO- AND ALKYL/ARYL-IMINOBIS(METHYLENEPHOSPHONATES) 191.2.4. METAL COMPLEXES OF CARBOXYLATE-BISPHOSPHONATES 201.2.5. METAL COMPLEXES OF METHYLENEBISPHOSPHONATE ESTER DERIVATIVES 22 2. AIMS OF THE STUDY 23 3. EXPERIMENTAL 243.1. CLODRONIC DIANHYDRIDE LIGANDS 243.1.1. SYNTHESIS OF Na2L2 253.2. METAL COMPLEXES 253.2.1. CRYSTALLISATION OF METAL COMPLEXES 263.3. CHARACTERISATION 29 4. RESULTS AND DISCUSSION 344.1. COORDINATION CHEMISTRY 344.1.1. METAL COORDINATION 354.1.2. BONDING MODES OF THE LIGANDS 364.1.3. EFFECTS OF METAL AND ESTER MOIETIES ON STRUCTURE FORMATION 394.2. INTERMOLECULAR INTERACTIONS AND CRYSTAL-PACKING 41 5. CONCLUSIONS 47 ACKNOWLEDGEMENTS 48 REFERENCES 50

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ABBREVIATIONS AAS atomic absorption spectroscopy aebpH4 (1-aminoethylidene)-1,1-bisphosphonic acid ahbbpH4 (4-amino-1-hydroxy-1,1-butanylidene)bisphosphonic

acid ahpbpH4 (3-ammonium-1-hydroxypropylidene)-1,1-bisphosphonic

acid BP bisphosphonate bpmaH5 N,N-bis(phosphonomethyl)aminoacetic acid Cl2mbpH4 (dichloromethylene)bisphosphonic acid CN coordination number 1D one-dimensional 2D two-dimensional 3D three-dimensional DMF dimethylformamide EA elemental analysis en ethylenediamine EtOH ethanol FT-IR Fourier transform infrared G gel crystallisation method hebpH4 (1-hydroxyethylidene)-1,1-bisphosphonic acid hpebpH4 (1-hydroxy-2-(3-pyridyl)-ethylidene)bisphosphonic acid ibmpH4 iminobis(methylenephosphonic) acid imhebpH4 (2-(1-imidazole)-1-hydroxyl-1,1´-ethylidene)-

bisphosphonic acid L ligand M metal MBP methylene bisphosphonate Me methyl MS metal salt Na2Clo disodium clodronate NMR nuclear magnetic resonance Ph phenyl S solution crystallisation method TGA thermogravimetric analysis TMOS tetramethoxysilane V vapour diffusion crystallisation method XRD X-ray diffraction

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1. INTRODUCTION

This thesis summarises the two starting points for structural studies of metal complexes of clodronic acid and its symmetrical dianhydride derivatives among the chemical group of the bisphosphonates. Of particular interest are the alkaline, alkaline earth metal, first series transition metal and zinc complexes of the modified bisphosphonate ligands with alkyl/aryl groups, functional groups, and/or ester moieties, and their effect on the structure formation and packing.

1.1. BISPHOSPHONATES AS PHARMACEUTICALS Geminal bisphosphonates (BPs), which are the stable analogues of pyrophosphate, are a class of drugs used as anticancer agents, for the treatment of diseases affecting bone tissue and in inhibiting the mineralisation of soft tissues, such as Paget’s disease, hypercalcaemia and osteoporosis (Figure 1a-b). BPs have a high ability to bind metal cations, especially calcium in hydroxyapatite crystals, inhibiting their growth, aggregation and dissolution. The weak point, however, is that they also bind other metal cations in the human body and form high molecular weight metal complexes which are relatively insoluble and precipitate easily, and the adsorption to the bone is reduced.1-9 Added to this, the methylenebisphosphonates (MBPs), for example clodronate [Cl2mbpH2]2- in Figure 1c, are highly hydrophilic compounds due to their ionisable phosphonic acid groups, and hence their absorption from the gastrointestinal tract is very low, their oral bioavailability being 1-3%1. Under these circumstances, the required drug dose may be very high and side-effects may appear.4b-c Improving their absorption in the human body can be achieved by adding bioactive moieties (R1, R2) to the geminal carbon atom of MBPs (H2O3P-(R1)C(R2)-PO3H2), as has been done, for example, with etidronate (R1 = OH, R2 = CH3), pamidronate (R1 = OH, R2 = CH2CH2NH2), risedronate (R1 = OH, R2 = CH2-C5H4N) and zoledronate (R1 = OH, R2 = CH2-C3H3N2). These groups also possess coordinating moieties, which further enhance the adsorption to the bone minerals.1-3, 4a, 5-9 However, the metal complexation was not reduced. Partly as a result of the complicated chemistry of the BPs, very little attention has been paid to the prodrug approach, where the phosphonic acid groups are masked so that the compound formed is more hydrophopic and will release the parent clodronate after the absorption by undergoing chemical and/or enzymatic hydrolysis.10-

12 Partial esterification of the clodronate with the hydrophopic alkyl and aryl groups has led either to excessively unstable compounds or to compounds which do not release the parent clodronate, and thus these compounds do not fulfil the criteria for a prodrug.13-14 The clodronic dianhydrides are the first-reported bioreversible prodrugs of clodronate with the potential to improve the oral bioavailability of clodronate. They are

8 more lipophilic than the parent clodronate and hydrolyse entzymatically to clodronate in human serum.15

a b c Figure 1. General structures of a) geminal BPs (R1 = H, Cl, OH and R2 = Cl, CH3, amine, alkyl chain with heterocyclic amine etc.), b) pyrophosphate and c) clodronate. The importance of studying the coordination properties of the dianhydride derivatives of clodronate arises from this pharmaceutical background, since their complexation properties provide important information for understanding the mechanism of their action. Their indirect structural characterisation, for example by computational chemistry, is time-consuming because of the large molecules, and pure chemical and/or analytical methods do not provide adequate information to provide an understanding of the structure-property relations. In studying the structural features of clodronate and its dianhydride derivatives, which are/can be effective drugs for bone diseases, the critical information is provided by their crystalline nature. The alkaline and alkaline earth metal complexes are of particular interest, since the s-block elements of the periodic table make important contributions in our body and other biological systems, and hence can act as model crystalline compounds. These metals can also be found on the surface of bone mineral, where the MBP drugs encounter the Ca2+ cations, both in solution and on the bone mineral surfaces, and form metal complexes.4a, d

1.2. BISPHOSPHONATES IN SOLID STATE CHEMISTRY The strong binding of metal cations, both on a surface (interface) or in solutions (complex formation), also make the BPs important compounds in non-medical applications. BPs and other polyphosphates have been widely used as complexing agents in the textile, fertilizer and oil industries for over a hundred years. In addition, BPs inhibit the precipitation of calcium salts and have been used as “water softeners”.

9 They can act as corrosion inhibitors by forming stable chelating compounds with multivalent iron, copper, and zinc cations. They can dissolve the oxidized materials on the surface of such metals.2-3,4e At the present time, the focus of the use of the BPs is also in crystal engineering and in the field of solid state chemistry and inorganic open framework materials. The discovery of fascinating structures with different dimensionalities has created an exponential growth in the class of metal BPs. Hybrid organic-inorganic compounds, such as the metal phosphonates and carboxylates, have organic polyfunctional ligands as linkers between the inorganic coordinating moieties. The inorganic parts, with their numerous potential donor-oxygen atoms, are capable of forming structure-strengthening chelate rings with metal cations. In addition, the chain between the phosphonate and carboxylate groups can be modified with alkyl, aryl or amine groups to increase the distance of the coordinating moieties (H2O3P-R-PO3H2 / HO2C-R-CO2H, R = alkyl, aryl or amine group), thus increasing their dimensionality and possibly also their porousness. Other structure-directing agents may include the degree of protonation/deprotonation and the presence of other cations, anions or neutral molecules in the starting mixture.16-19 The chemists have moved on from the ordinary phosphate and phosphonate crystal structures to a point where their interest is in manipulating and designing structures by using supramolecular assembly for special purposes. This is achieved with the assistance of the tools of crystal engineering, i.e. the network approach, to simplify complex crystal structures and to mimic the functional properties of natural clays and zeolites.20-22 The layered structures and 3D porous solids with thermally and chemically stabile voids can be found in applications such as ion exchangers, sorbents, sensors, hosts for intercalation of guest molecules and gas storage. Structures can also be built up layer by layer to produce stable thin films. In addition, the target applications of the metal phosphonates have included proton conductors, magnetic materials, nonlinear optic materials, photochemically active materials and catalysts for inorganic and organic synthesis.16-22

1.2.1. METAL COMPLEXES OF GEMINAL BISPHOSPHONATES The metal complex structures of halogenated MBPs other than clodronate have not been published. The first disodium and calcium clodronates were characterised in the early 1980s with the intention of studying the crystal structures of bone growth regulators.23 Twenty years later, the clodronate metal complexes were introduced as possible open framework structures for applications. Clodronate adopts the mono-, bis- and tetra-chelating bonding modes. With the divalent alkaline earth metal24-26, Zn2+ and Cd2+ 27 cations it forms polymeric structures, chains, double chains and layers, which can be extended to 2-3D structures by coordination bonds of Na+ and/or by hydrogen bonds of water molecules. The channels between the layers may be filled with crystal water or NO3

- anions.24-27 Chlorine atoms were involved in the coordination only

10 once27, and they generally pointed towards each other, facing into the channels formed within the network.24-27 When the geminal R2 group is increased in size, the metal complex structures confront steric hindrance, and hence the packing arrangement displays at clearer division within the hydrophilic and hydrophopic areas. This may be important in the self-assembly of the metal BP structures.

Etidronate ((1-hydroxyethylidene)-1,1-bisphosphonic acid, hebpH4) has remained the most significant compound in non-medical applications since as early as the year 1897.4e Many research results focusing on the metal complexes of the etidronate have been published28, but all of the structures, with the exception of a few, are transition metal complexes. The mono- and disodium etidronates are 2D structures, where the etidronate chelates Na+ ions in bidentate and in tridentate fashion in both compounds. The hydroxyl group of the middle-carbon atom permits the tridentate coordination mode.28a-b The same kind of bonding modes can also be seen in the K+, NH4

+ and Ba2+ complexes of etidronate, which form polymeric chain structures28c-d The etidronate ligand in a Mg(II) complex, in turn, is in mono-chelating bonding mode, and the structure is monomeric.28e In the research into the structural features of the first series transition metal and zinc complexes of etidronate, it has been common to use organic templates such as NH4

+ and [NH3(CH2)2-6NH3]2+ as charge-compensating cations to create 3D open framework structures28f-q or to introduce chirality into structures28f. In addition, the alkaline metals Na+, K+, Cs+ may coordinate with the metal phosphonate oxygen atoms and hence increase the dimensionality. Generally, the crystal-packing and charge-compensating effects are major determinants of cation incorporation into the solid lattice.29 In mono-chelating or bis-chelating and bridging modes with Mn(II), Fe(II,III), Ni(II), Cu(II), and Zn(II) the etidronate forms anionic chains which are extended to a 3D open hydrogen bond network, where the diammonium alkane cations and/or lattice water molecules are located in the channels between the chains balancing the overall charge of the structures.28f-l It has been observed that the cations with larger sizes [NH3(CH2)2-6NH3]2+ favour 2D anionic layers, whereas the smaller cation (NH4

+) directs the formation of an anionic chain.28j In Mn(II), Zn(II) and Fe(II) complexes with [NH3(CH2)2-6NH3]2+, where the etidronate acts as both a bidentate and tridentate chelating and bridging ligand, the ladder-like double chains are formed with strong hydrogen bonding, and the diammonium alkane cations and lattice water molecules are located in the channels of these 3D supramolecular assemblies (Figure 2a). The double chains are formed when the metal cations settle against each other, while the hydrophopic methyl group points towards the interlayer section or inside the channel. The coordination of the hydroxyl group does not greatly affect the direction of the methyl group.28f,k-l Many studies of the Cu(II) complexes where the etidronate ligand is

11 in bis-chelating and bridging bonding modes have been published.28m-p In these structures the ladder-chains may form the 2D layer structure by means of 4,4´-bipyridine or 4,4´-azobispyridine as a linker between the chains.28m The diammonium alkane cations and/or lattice water molecules may also be located between the 2D sheets by hydrogen bonding.28n-o These alternating anionic and cationic sheets are represented in Figure 2b. In the case of pyrazine (C4H4N2) as a template molecule, 2D planes, constructed of the double chains linked by {CuO4} units, are further connected by pyrazine bridges to a 3D open framework structure.28p The 4,4´-bipyridine can also connect the mixed valence Cu(I,II) phosphonate units into a layer-like structure, which is further extended to a 3D network by hydrogen bonding and π−π stacking interactions.28n The etidronate also binds Co(II) in a bidentate and tridentate fashion and forms a multinuclear compound28r and a 2D plane structure28s.

a

b

Figure 2. a) An example of an arrangement of the Mn(hebpH2)2 double-chains with the 1,4-diammoniumbutane cations and lattice water molecules in the channels.28f b) A representation of alternating anionic {Cu3(hebp)2}n

2n- sheets and cationic sheets of diamines and lattice water molecules (for clarity all of the hydrogen atoms have been omitted).28o (The carbon atoms are represented as grey spheres, hydrogen atoms as pale grey spheres, oxygen atoms as red spheres, phosphorus atoms as pink spheres, nitrogen atoms as violet spheres and metal cations as blue spheres.)

12 Because of the coexistence of one amino group and two phosphonate groups in (1-aminoethylidene)-1,1-bisphosphonic acid (aebpH4), aebpH4 is expected to exhibit zwitterionic (cationic and anionic) properties (Figure 3).

Figure 3. The coordination modes of (1-aminoethylidene)-1,1-bisphosphonic acid: a) aebpH4, b) aebpH3

-, c ) aebpH22-, d) aebpH3- and e) aebp4-.

AebpH4 forms 1D and 2D structures with Ca(II) and Sr(II) cations, respectively. The zwitterionic aebpH3- ligands coordinate the Ca2+ cations monodentately and aebpH3-

/aebpH22- ligands are coordinated bidentately, whereas in the Sr(II) complex the

aebpH22- is not in a zwitterion form and acts as a tris-chelating and bridging ligand

through phosphonate oxygen atoms.30a The zwitterion aebp ligand exists in two modes when coordinating Co2+, in bis-chelating bridging aebpH2

2- and mono-chelating aebpH3

- modes, and forms a 2D layer structure which is extended into 3D through hydrogen bonding.30b In research into the divalent Co(II), Ni(II), Cu(II) and Zn(II) complexes of aebpH3

-; 1,10-phenanthroline; 2,2´-bipyridine and 4,4´-bipyridine molecules are used as second ligands attached bidentately to the metal, while the zwitterionic aebpH3

- ligand is in mono-chelating mode. All of these structures form 3D

supramolecular structures through hydrogen bonding and through strong aromatic face-to-face π−π stacking interactions.30c-e The aebp4- ligand uses its amino group for coordination only in the Cu(II) and Zn(II) complexes. The aebp4- ligand tris-chelates the Cu2+ to the ladder-like chains, and bis-chelates the Zn2+ cations.30f-g In the Cu(II) complex, the double chains are connected by {CuO4} units, and the planes formed are further linked by 4,4´-bipyridine molecules to a 3D structure.30f In the Zn(II) complex the Zn(aebp)2

6- anions and ethylenediamine cations are connected through hydrogen bonds and form channels in which lie the hydrogen-bonded water cluster tapes (Figure 4).30g

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Figure 4. A 3D arrangement of the (enH2)3[Zn(aebp)2].6H2O complex, where the hydrogen-bonded water cluster tapes are formed along the crystallographic a-axis.30g (The carbon atoms are represented as grey spheres, hydrogen atoms as pale grey spheres, oxygen atoms as red spheres, phosphorus atoms as pink spheres, nitrogen atoms as violet spheres and Zn(II) cations as blue spheres.)

The pamidronate, (3-ammonium-1-hydroxypropylidene)-1,1-bisphosphonic acid (ahpbpH4), with Na(I) and Zn(II) shows the trans carbon chain conformation, which separates the positively charged nitrogen atom from the negative phosphonate groups.31a-b In a disodium complex, the ahpbpH2

2- ligand simultaneously adopts two different chelating modes: a tris-chelating mode through the phosphonate and hydroxyl groups, and a mono-chelating mode through the phosphonate groups.31a In addition, the pamidronate acts as a bridging ligand. In the Zn(II) salt of pamidronate, in turn, the zwitterion ahpbpH3

- chelates the Zn2+ in bidentate fashion.31b Both of these structures form 1D columns through hydrogen bonding.31a-b In preceding structures and in the Ca(II) complex of ahpbpH3

-, the carbon chain conformations are different. In a Ca(II) complex, the pamidronate adopts a twisted conformation, which permits the intermolecular N-H...O hydrogen bond. The ahpbpH3

- acts with Ca2+ as a mono-chelating and bridging ligand, and forms a 3D hydrogen bond network.31c The same bonding mode of zwitterion ahpbpH3

- is also found in the Ni(II) complex of pamidronate, which forms a dinuclear Ni(II) cluster.31d The pamidronate (ahpbpH2

2-) coordinates Mn2+ and Co2+ by means of tetra-chelating and bridging modes and bis-chelates Cu2+, and forms double-chain structures, where the alkylamines and hydroxyl groups of the geminal carbon atom point to the inter-chain section.31d-e By bis-chelating the Zn(II) through phosphonate and hydroxyl groups and by bridging the Zn2+ cations,

14 the zwitterionic ahpbpH2

2- ligand forms a grid-like structure, while the same mode of zwitterion ahpbpH3- with tetra-chelation of Cu(II) leads to a unique 3D pillared layer structure.31d

In the Na(I), Ca(II), Mn(II) and Co(II) complexes of the alendronate, (4-amino-1-hydroxy-1,1-butanylidene)bisphosphonic acid (ahbbpH4), as expected, the negatively charged part of the zwitterion ahpbpH3

-/ahpbpH22- ligands chelate the metal cations,

while the positive end of the ligand is stretched in the opposite direction.32a-c The alendronate acts as a mono-chelating and bridging ahpbpH3

- ligand with Ca(II) and forms a 1D hydrogen bonded column structure.32a In bis- and tris-chelating bonding through phosphonate and hydroxyl groups, the molecular Na(I) complex of ahpbpH3

-

and double chains of Mn(II) and Co(II) complexes of ahpbpH22- all form a 3D

hydrogen bonded network through NH3+ groups, phosphonate oxygen atoms and

crystal water.32b-c An exception to this is a Co(II) complex of ahpbpH22-, in which the

NH3+ group bends in the direction of the central dinuclear core to form an intra-

molecular hydrogen bond (Figure 5).32d

Figure 5. A polyhedral illustration of the Co2(ahbbpH2)4 complex, where the NH3+

group is bending towards the hydrophilic part of the structure.32d (PCO3 tetrahedrons in green, CoO6 octahedrons in blue, carbon atoms as grey spheres, hydrogen atoms as pale grey spheres, oxygen atoms as red spheres and nitrogen atoms as violet spheres.)

BPs with an amine chain of -(CH2)4-5NH2 in the middle-carbon atom follow the same pattern as has been found with previous BPs in the arrangement of their geminal functional groups. The mixed valence Fe(II,III) complex of [(H3N(CH2)4)(OH)C(PO3)2]3- is a 2D plane structure, where the ligand is a tetra-chelating and bridging ligand, and forms a 3D supramolecular network through the hydrogen bonding of NH3

+ group and crystal water molecules (Figure 6a).33 The few structures of [H3N(CH2)5)(OH)C(PO3H)2]- are mononuclear Co(II) and Zn(II) complexes with a mono-chelating ligand and a dinuclear Mn(II) complex with a mono-chelating and bridging ligand.32d

15 The risedronate, (1-hydroxy-2-(3-pyridyl)-ethylidene)bisphosphonic acid (hpebpH4), in a zwitterion mode ahpbpH3

- mono-chelates or tris-chelates and bridges the Na(I) and K(I) atoms with phosphonate oxygen atoms and forms a 3D hydrogen bond network.34a-b The ahpbpH2

2- ligand bis-chelates and bridges the Co2+ cations and forms double chains, which form a 3D network through π−π contacts and hydrogen bonding (Figure 6b).34c

a

b

Figure 6. a) The 3D structure of the Fe(II,III) complex of [(H3N(CH2)4)(OH)C(PO3)2]3-

.33 (The carbon atoms are represented as grey spheres, hydrogen atoms as pale grey spheres, oxygen atoms as red spheres, phosphorus atoms as pink spheres, nitrogen atoms as violet spheres and Fe(II,III) cations as blue spheres.) b) A polyhedral packing picture of Co(II) complex of ahpbpH2

2- showing the aromatic π−π contacts.34c (PCO3 tetrahedrons in green, CoO6 octahedrons in blue, carbon atoms as grey spheres, hydrogen atoms as pale grey spheres, oxygen atoms as red spheres and nitrogen atoms as violet spheres.)

The zoledronate (2-(1-imidazole)-1-hydroxyl-1,1´-ethylidene)bisphosphonic acid (imhebpH4), in turn, forms tightly bound 2D layer structures with K(I) in a tris-chelating zwitterion bonding mode imhebpH3

-, and with Co(II) and Ni(II) in bis- and

16 tris-chelating and bridging bonding modes of imhebpH-.35a-b The mono-chelating bonding mode of zwitterion imhebpH3

- with Co(II), Ni(II) and Zn(II) leads to mononuclear structures, which form 3D hydrogen bond networks.35b-c The hydrophopic aromatic side chains of the risedronate and zoledronate extend outwards on both sides of the chains/layers and may engage in close π−π stacking contacts with their neighbouring counterparts.34c, 35a-b

1.2.2. METAL COMPLEXES OF ALKYLENE- AND ARYLBISPHOS-PHONATES

Ethylenebisphosphonates are used as linkers between the first series transition metal/zinc-bisphosphonate planes to form pillared 3D frameworks.36 The ligand can be in bridging36a-d,g or mono-chelating36g/bis-chelating36a, or in both bonding modes36g while creating 3D structures. The focus is no longer on the properties of the phosphonate oxygen atoms of the ligands but the ligands are treated as if they were building blocks of the structures. The alkylenebisphosphonates are thought of as linear tethers, and the metal oxide clusters are described as nodal units. In addition, Na+, K+, NH4

+, MoO3, NH2(CH2)2NH2; 1,10-phenanthroline, tetra-2-pyridylpyrazine and bipyridimine, commonly used in structure formation, are simplified to become secondary metal/linear binucleating ligand sub units.36e-f,h These groups may only be decorating the 1D chains, as is the case with the Mn(II) complex of ethylidenebisphosphonate with 1,10-phenantroline36a and some Co(II)/Ni(II)-organonitrogen/oxomolybdate-organobisphosphonates36e-f, but generally they contribute the structures to form higher dimensionalities and potentially open frameworks.36a,c,e-h The length of the alkyl chain, however, does not correlate with the dimensionality formed. The 2D planes are formed of both, [O3P(CH2)2-3PO3]4- with Ni(II)36f and [O3P(CH2)9PO3]4- with Co(II)36e, by oxomolybdate-organobisphosphonate chains linked through tetranuclear Co(II)/Ni(II)-organonitrogen cationic subunits. In addition, in a Zn(II) complex of (propylene)bisphosphonic acid, the [NH3(CH2)2NH3]2+ cations fill the void space between the layers and interrupt the layers in their formation of a 3D framework.36g The 3D structures are formed of bimetallic Co(II)/Ni(II)/Cu(II)-molybdophosphonate layers linked through the (CH2)3-6-tethers of bisphosphonate36e-f,h and also through the Co-O-Mo bonding, which leads to a densely packed profile36e. In addition, a 3D sandwich-like framework may form when, for example, K-Cl lamellae link the Zn-O-P hybrid double layers (Figure 7a).36g The open 3D frameworks of Co(II)/Ni(II)-organonitrogen/oxomolybdate-organobisphosphonate36e,h, are formed in the same way as the corresponding 3D structures, but the attachment points are staggered in the Co(II) complex and have been increased by a unique binuclear Ni(II)-

17 organonitrogen cationic rod in the Ni(II) complex.36e,h The channel size in the Co(II) complex is 21.6 Å x 14.6 Å x 10.6 Å, which is consistent with the 28.6% accessible volume per unit cell of crystal water (Figure 7b).36e In addition, the Zn(II) complexes of ethylene- and propylenebisphosphonic acid with NH4

+ and/or [NH3(CH2)2NH3]2+, possess 8- and 12-membered channels.36g

a

b

Figure 7. a) The 3D arrangement where K-Cl lamellae link the Zn-O-P hybrid double layers.36g (PCO3 tetrahedrons in green, ZnO3Cl tetrahedrons in blue, potassium cations as pink spheres, chlorine atoms as green spheres, carbon atoms as grey spheres, hydrogen atoms as pale grey spheres and oxygen atoms as red spheres.) b) A packing picture of Co(II)-organonitrogen/oxomolybdate-organobisphosphonate with large cavities.36e (PCO3 tetrahedrons in green, CoO3N3 octahedrons in yellow, MoO6 octahedrons in blue, carbon atoms as grey spheres, hydrogen atoms as pale grey spheres, oxygen atoms as red spheres and nitrogen atoms as violet spheres.)

18 The alkylenebisphosphonates form 1-3D structures, which indicate that the predictability of structures is still elusive due to the complexity of hydrothermal conditions, such as pH and temperature, and, the diversity of linkage modes. However, at the present moment, 3D frameworks are more common than 2D structures.36e-g,h

The aryl bisphosphonates, such as phenylenebisphosphonic acid (C6H4(PO3H2)2) (and its dihydroxy derivative), p-xylylenebisphosphonic acid (C6H4(CH2PO3H2)2) and 4-(4´-phosphonophenoxy)phenyl phosphonic acid (O(C6H4-PO3H2)2) mainly form 3D pillared layer structures with Co(II), Ni(II), Cu(II) and Zn(II), where the aryl groups connect the inorganic metal phosphonate layers (Figure 8).37a-f The exceptions are the 2D Zn(II) complex of biphenylylenebisphosphonic acid [O3P(C6H4)2PO3]2- and the V(IV) complex of p-xylylenebisphosphonic acid.37f-g Microporosity can be found in the Zn(II) complex of 1,4-dihydroxy-2,5-benzenebisphosphonate, which has DMF molecules in its pores37b and also in the Co(II) complex of p-xylylenebisphosphonic acid, which is stable up to 500oC and may undergo a reversible dehydration/rehydration process driven by temperature.37d

Figure 8. A polyhedral representation of the Co(II) complex of p-xylylene-bisphosphonic acid.37c (PCO3 tetrahedrons in green, CoO6 octahedrons in blue, carbon atoms as grey spheres, hydrogen atoms as pale grey spheres and oxygen atoms as red spheres.)

19 1.2.3. METAL COMPLEXES OF IMINO- AND ALKYL/ARYL-IMINO-

BIS(METHYLENEPHOSPHONATES) The iminobis(methylenephosphonic) acids (ibmpH4) contain a CH2-NH-CH2-chain between the phosphonate groups. The nitrogen atom may coordinate the metal ions or behave in zwitterionic form as a hydrogen bond donor atom in metal complexes. This ligand leads to 1-3D structures with Ba(II), Mn(II), Co(II) and Cu(II) polyhedrons.38 In the 1D Cu(II) chains, the ibmpH2

2- ligand bis-chelates the metal cation through nitrogen and phosphonate oxygen atoms and is also a bridging ligand.38a In Co(II) complexes the zwitterionic ibmpH2

2-/ibmpH4 ligands bridge the Co(II) octahedrons to

2D structures with cavities or crystal water molecules in the middle of the interlayer space.38a-b The 3D structures are formed either of the interconnection of the Mn(II)/Co(II) octahedrons bridged by the ibmpH2

2-/ibmpH3- ligands, respectively, or by using 4,4´-bipyridine as a second metal linker, which connects the Cu(II)-ibmp layers to a pillared layer structures.38a,c The open 3D frameworks can be observed in the Ba(II) and Cu(II) complexes38d-f, where in the Ba(II) complex the tetra-chelating and bridging zwitterion ibmpH3- ligand coats the inner wall of pores sized 3.6 x 4 Å.38d

The alkyl iminobis(methylenephosphonates) with methyl-, butyl- and cyclo-hexyl groups attached to the nitrogen atom act with the metal cations in the same way as do the ibmpHn

(4-n)- (n = 1-4) ligands without the alkyl group, but all of the alkyl- and aryl groups are oriented towards the inter chain/layer space.39 The tridentately bridging zwitterionic methyl-ibmpH2

2- ligand leads to a double chain structure with Zn2+, and is further connected to a 2D structure by hydrogen bonding between the NH groups, lattice water molecules and phosphonate oxygen atoms.39a The zwitterionic ibmpH3- ligand with methyl and cyclo-hexyl groups act as tetra- and hexadentate metal linkers, respectively, in Zn(II) complexes, forming 2D layer structures.39b-c In the Mn(II) complex of zwitterionic methyl-ibmpH3

-, the ligand also forms a 2D structure by mono-chelating and bridging the metal cations, but hydrogen bonds are formed between the layers and the overall structure is 3D.39b When the cyclo-hexyl group is added to the nitrogen atom, also a 2D Mn(II) complex39d and a porous 3D framework with Zn(II) complex of cyclo-hexyl-ibmpH3-,39e are formed. The porous Zn(II) structure possesses 40 atom rings 16.3 x 9.8 Å in size39e (Figure 9). The zwitterionic phenylmethan-ibmpH2

2-/ibmpH3- and p-xylylmethan-ibmpH2

2- form covalently coordinated and hydrogen bonded 2D structures with Mn(II).39f The pyridin-3-ylmethyl-ibmpH3

- and pyridine-4-ylmethyl-ibmpH22- ligands form 2D layer and double

layer structures with Co(II), respectively, by the coordination of phosphonate oxygen, imino nitrogen, and pyridyl nitrogen atoms. The Co(II) complex of pyridin-3-ylmethyl-ibmpH3

- is extended into a 3D network through the hydrogen bonding of crystal water molecules between the layers.39g In addition, the benzimidazol-2-ylmethyl has been added to the ibmp ligands, and it forms 1D chains with Mn(II), Fe(II), Co(II) and

20 Cu(II) by tetra-chelating the metal cations through phosphonate oxygen, imino nitrogen, and imidazole nitrogen atoms. These chains are further connected through aromatic stacking of the benzimidazole rings and hydrogen bonds to 3D supramolecular arrangements.39h

Figure 9. A packing picture of the Zn(II) complex of cyclo-hexyl-ibmpH3- showing the holes in the structure.39e (The carbon atoms are represented as grey spheres, hydrogen atoms as pale grey spheres, oxygen atoms as red spheres, phosphorus atoms as pink spheres, nitrogen atoms as violet spheres and Zn(II) cations as blue spheres.)

1.2.4. METAL COMPLEXES OF CARBOXYLATE-BISPHOS-PHONATES

Various carboxylate groups have also been attached to the nitrogen atom of ibmp, and hence the ligand has nine donor atoms for coordination or deprotonated/protonated acceptor/donor atoms for hydrogen bonding. The carboxylate ligand is bent when it coordinates metal cations40a-d, but when it is not coordinated, it is oriented perpendicular to the layers pointing towards the adjacent layer and may act as a donor/acceptor of hydrogen bonding40e-i. With the tetradentate chelating N,N-bis(phosphonomethyl)aminoacetic acid, HO2CCH2N(CH2PO3H2)2 (bpmaH5), the Ni(II) forms [Ni(bpmaH2)(H2O)2]- anions which are interlinked via H-bonds to a 2D structure.40a The same bonding mode is found in the Co(II) complex, which is a polymeric chain structure with a 3D hydrogen bond network.40b When, in addition, the ligand bridges the Zn2+ cations, a 3D framework is formed.40c The secondary metal linkers; 4,4´-bipyridine molecules, are also introduced into the Co(II) and Zn(II) complexes of bpmaH2

3-/bpma5-, respectively. The Co(II) complex possesses a 2D layer

21 structure which has interstitial water molecules, and hence the overall dimensionality is 3D through its hydrogen bonds. In the Zn(II) complex, in turn, the 4,4´-bipyridines connect the Zn(II)-phosphonate layers to a 3D pillared layered structure (Figure 10).40d Figure 10. The polyhedral representations of the Zn(II) complex of bpma5-, where the 4,4´-bipyridines connect the layers40d. For clarity all of the hydrogen atoms of the crystal water molecules have been omitted. (PCO3 tetrahedrons in green, Zn(II) polyhedrons in blue, carbon atoms as grey spheres, hydrogen atoms as pale grey spheres and oxygen atoms as red spheres.) The layered Co(II) complexes of [HO2C(CH2)3NH(CH2PO3H)2]-, [HO2C-C6H4-CH2N(CH2PO3)2]4- and [HO2C-C6H4-CH2N(CH2PO3H)2]2- and Zn(II) complex of [HO2C-C6H4-CH2NH(CH2PO3)2H]2-

form 3D supramolecular networks through the hydrogen bonding of the carboxylic groups and phosphonate oxygen atoms, and in the case of the Zn(II) complex, through its crystal water molecules.40e-g With the [HO2C-C6H4-CH2NH(CH2PO3)2H]2- and [HO2C-C6H4-CH2NH(CH2PO3H)2]-, the Ca(II) forms 1-2D metal complexes which have 2D hydrogen bond networks.40h The 4,4´-bipyridine molecules join the adjacent Co3[HO2C-C6H4-CH2N(CH2PO3)2H]2

3- layers to a 3D pillared layer structure.40i An interesting ligand is a squarato derivative of ibmp (C4HO3-N(CH2PO3H2)2), which has a four-membered aromatic rigid ring that may adopt various coordination modes with its three oxygen atoms. With Mn(II) it forms 1D chains, but with Cu(I), the squarato-phosphonate ligands are linkers between the Cu(I)-4,4´-bipyridine-chains, and the 2D structure is extended into a 3D arrangement through hydrogen bonding between the chains (Figure 11).40j

22

Figure 11. The polyhedral representation of the Cu(I)-4,4´-bipyridine-chains, which are joined by the squarato-phosphonate ligands.40j (PCO3 tetrahedrons in green, Cu(I) cations as blue spheres, carbon atoms as grey spheres, hydrogen atoms as pale grey spheres, oxygen atoms as red spheres and nitrogen atoms as violet spheres.)

1.2.5. METAL COMPLEXES OF METHYLENEBISPHOSPHONATE ESTER DERIVATIVES

MBP ester derivatives have not been widely studied as metal complexing agents. Solvent exctraction properties of tetramethyl and tetraethyl esters of bisphosphonates with f-block metal cations have been examined41a-d, and tetraisopropyl esters have been used in the study of the stannylmethylated diphosphorylmethanes41e-f and bismuth phosphonate phases41g. In addition, a dimeric neutral Lewis base complex of lithium chloride with a tetraisopropylester derivative of bisphosphonate41h and the Cu(II) complex of the same ligand with perchlorate anion41j have also been reported.

The mono- and diester derivatives of clodronate have been studied at the University of Joensuu. There are relatively few metal complexes resulting from the mono ester derivatives of clodronate, but monoethyl- and phenyl derivatives of clodronic acid with Ca(II)42a, Ba(II)42b and Cd(II)42c form 2D structures, of which the Ca(II) complex of monoethyl derivative is extended to a 3D structure through hydrogen bonds, and the Cd(II) complex of monophenyl derivative form layers which are held together by weak π-π-interactions. In these structures, the ethyl and phenyl ester derivatives of

23 clodronate mono-, bis- and tris-chelate and bridge the metal ions.42a-c The diester derivatives of clodronate also act in a chelating manner and bridge the metal ions, forming dimeric complexes with Ca(II) and Sr(II)42d, a tetrameric complex with Ca(II)42e, a hexameric and wheel-like structure with Cu(II)42f and polymeric chains with Mg(II), Ba(II) and Zn(II),27, 42d-g some of which form 1D and 2D structures through hydrogen bonding. The 2D structures are formed with Zn(II) and Sr(II), where in the Zn(II) structure, the Zn(II)-phosphonate layers are connected by Na+ cations.42f-g

2. AIMS OF THE STUDY

Our research group has studied the crystallisation and coordinating properties of the metal complexes of clodronate and its partial ester derivatives, and this study represents an extension of the earlier work. The results of the previous studies, the background of the potential prodrugs of clodronate and the functionality of the compounds as being interesting building blocks in crystal engineering have motivated the whole research process from the very start, and continue to do so. Our first aim was to synthesise a new dianhydride ligand with the intention of completing the series of previously synthesised clodronic dianhydrides15. In addition, it was our intention to crystallise and characterise the alkaline and alkaline earth metal complexes of the clodronic dianhydrides in order to understand the hydrolysis and coordinating behaviour of these ligands, both as pharmaceuticals and also as ligands of coordination chemistry. The crystallisation of the ligands and possible hydrolysis products was obviously also one of our aims.

In the course of our earlier work the transition metal complexes of clodronic acid had not been prepared, and thus our second aim was to crystallise and characterise the first series transition metal and zinc complexes by using both clodronate and its dianhydride derivatives as ligands. The focus of our research was to study the effect of the dianhydride groups on the bonding of the ligand and on the dimensionalities of the formed structures in comparison with the corresponding structures of clodronate. In addition, although some of the transition metals are toxic, the first series transition metal complexes are good model structures, since the ionic radii of the metal cations are comparable in size to those of the alkaline earth metal complexes. Thus, it was suspected that the transition metal complexes might also provide important information in support of research into BPs as pharmaceutical products.

24

3. EXPERIMENTAL

3.1. CLODRONIC DIANHYDRIDE LIGANDS The symmetrical clodronic dianhydride ligands L12--L52-; P, P’-diacetyl- ; P, P’-dipropanoyl- ; P, P’-dibenzoyl- ; P, P’-dibutyroyl- and P, P’-dipivaloyl-(dichloromethylene)bisphosphonates used in this study are represented in Figure 12. The clodronate [Cl2C(PO3H)2]2-, also used as a ligand in this study, has been represented in Figure 1. Our attempts to crystallise metal complexes of the ligands L42-

-L52- or their hydrolysis products have been unsuccessful. Disodium salts of clodronic dianhydrides are stable in solid form, but in phosphate buffer solution the Na2L1 molecule hydrolyses completely in 45 min at pH 2 and in 15.2 h at pH 7.4, whereas the Na2L3 molecule hydrolyses completely in 11.9 days at pH 2 and in 9.8 days at pH 7.4.15 The hydrolysis time of Na2L2, synthesised during this study, has not been defined. Na2L1-Na2L3 possess a lower water solubility than disodium clodronate15, and the solubility decreases in the order Na2L1 > Na2L2 > Na2L4 > Na2L5 > Na2L3. This means that Na2L1-Na2L5 are soluble in water at room temperature, but the water solution of L32- has to be warmed to 40oC to gain complete solubility. Figure 12. Schematic representations of clodronic dianhydrides (L12--L52-) used as ligands in this study.

25 3.1.1. SYNTHESIS OF Na2L2 The synthesis of the starting material, anhydrous tetrasodium clodronate, for the synthesis of Na2L2, has been reported earlier.43 Na2L2 was prepared following the synthetic method devised by Ahlmark et al.15 The synthetic route for Na2L2 is represented in Scheme 1. Scheme 1. A representation of the synthetic route of Na2L2. The anhydrous tetrasodium clodronate (5.0 g, 15.0 mmol) was heated in an oil bath with an excess of propionic acid anhydride (50.0 ml, 338.0 mmol) at 90-100oC for 120 h. The shorter or longer heating time resulted in a mixture of starting materials and mono- and dianhydrides. The mixture was chilled to 5oC and allowed to stand overnight in the cold. The following day, the mixture was filtered, washed several times with ether and dried to give Na2L2 as a white solid (2.8g, 46%). 3.2. METAL COMPLEXES Fifteen new alkaline and alkaline earth metal, first series transition metal and zinc complexes of clodronic acid and its dianhydride derivatives (1a-b, 1d-3h) were prepared. All metal complexes are presented in Table 1. Of particular noteworthiness here are the metal complexes of clodronate. All of the metal complexes, except the Co(II) complex, are formed as a hydrolysis product of the L12--L32- ligands during their crystallisations. Most of these compounds can also be prepared by using clodronate as a starting material for the ligand. The Co(II), Ni(II) and Zn(II) complexes of clodronic acid (1e-g) are isostructural, while the Ni(II) and Zn(II) complexes of L32- (3g-h) are isomorphous structures. Attempts to prepare metal complexes of the L22- ligand were unsuccessful, but L12- and L22- both formed the first crystalline hydrolysis product of these clodronic dianhydrides, compound 1a. All of these metal complexes were characterised by single-crystal X-ray diffraction.

26 Table 1. The metal complexes 1a-3h prepared during this study.

Ligand in the metal complex

M+/2+ Starting material ligands Formula of the metal complex Publ.

Clo2-

Na+ Mg2+

Ca2+ Sr2+ Co2+ Ni2+ Zn2+

Na2L1, Na2L2 Na2L1, Na2L2, Na2Clo Na2L1-Na2L3, Na2Clo23-24 Na2L1 Na2Clo Na2Clo, Na2L3 Na2L3

[Na3{Cl2C(PO3)2}(H2O)4]n [NaMg(Cl2CP2O6H)(H2O)5]n [{Ca2(Cl2C(PO3)2)(H2O)6}. 4.5H2O]n [{Sr2(Cl2C(PO3)2)(H2O)4}. H2O]n [{Co2(Cl2C(PO3)2)(H2O)7}. 4H2O] [{Ni2(Cl2C(PO3)2)(H2O)7}. 4H2O] [{Zn2(Cl2C(PO3)2)(H2O)7}. 6H2O]

1a 1b 1c 1d 1e 1f 1g

II I , II II, III 23-24 II IV V V

L12-

Ba2+ Na2L1 [Ba{Cl2C(PO2O(C(O)Me))2}(H2O)3]n 2a II

L32-

K+ Mg2+

Sr2+

Ba2+

Mn2+ Co2+ Ni2+

Zn2+

Na2L3 Na2L3 Na2L3 Na2L3 Na2L3 Na2L3 Na2L3 Na2L3

[K2{Cl2C(PO2O(C(O)C6H5))2}O]n [Mg{[Cl2C(PO2O(C(O)C6H5))2](H2O)5}. H2O] [Sr2{[Cl2C(PO2O(C(O)C6H5))2]2(H2O)9}. H2O]n [Ba{Cl2C(PO2O(C(O)C6H5))2}(H2O)2]n [Mn{Cl2C(PO2O(C(O)C6H5))2}(H2O)3] [Co{Cl2C(PO2O(C(O)C6H5))2(H2O)5}. 2H2O-{Cl2C(PO2O(C(O)C6H5))2}{Co(H2O)6}] [{Na2Ni3(Cl2C(PO2O(C(O)C6H5))2)(H2O)20)}-{Cl2C(PO2O(C(O)C6H5))2}]n [{Na2Zn3(Cl2C(PO2O(C(O)C6H5))2)(H2O)20)}-{Cl2C(PO2O(C(O)C6H5))2}]n

3a 3b 3c 3d 3e 3f 3g 3h

II III III III IV IV V V

Na2Clo = disodium clodronate, Clo2- = clodronate 3.2.1. CRYSTALLISATION OF METAL COMPLEXES The chemistry of clodronate and its dianhydride derivatives, like that of other BPs, is very challenging. In addition, the clodronic dianhydrides are soluble only in water, hydrolyse during the previously mentioned time range, and cannot withstand heating to high temperatures while in solution. This delimits the crystallisation methods. The hydrothermal and solvothermal crystallisation methods generally used to obtain the metal complexes of bisphosphonates are too harsh for the derivatives of clodronate. Under these circumstances, the metal complex formation has to take place swiftly enough and the reaction conditions have to be optimised. The crystals of the L12--L32- metal complexes had to form in the course of only a few days otherwise the hydrolysis product formed instead. The solution crystallisation method, which includes a temperature difference (from room temperature to cold) has proved promising for the dianhydride ligands owing to its ease and rapidity. The gel or vapour diffusion crystallisation methods, in their turn, are highly effective for controlling the rate of the diffusion and precipitation processes, but the reactions themselves can take time and the amount of crystals is limited. It is for this reason that the metal complexes of clodronic acid prepared by using either Na2L1-Na2L3 or disodium clodronate as starting material for the ligand are crystallised by the gel or vapour diffusion

27 crystallisation methods, while most of the metal complexes of L32- are crystallised by the solution crystallisation method. For example, to obtain the Ni(II) and Zn(II) complexes of L32-, 3g-h, and its hydrolysis products, 1f-1g, we intentionally prepared them by using the solution and gel crystallisation methods, respectively. However, if the ligand reacted with the metal swiftly enough, as was the case with compounds 2a and 3b-d, the gel crystallisation method produced good quality crystals with perfectly shaped faces. In the gel, the crystals may be formed without any outer mechanical disturbance, almost as if without gravity, in the course of from one day to a few months, once the precipitant is added.

Illustrations of the gel and vapour diffusion crystallisation methods are presented in Figure 13, and the crystallisation conditions of the prepared metal complexes 1a-3h are shown in Table 2. In the gel crystallisation method A, the solutions of the ligand and the metal salt in water were shaken with tetramethoxysilane (TMOS) to form a gel. In the case of L32-, the L32- solution was warmed to 40oC in a water bath before being mixed with TMOS to achieve a better dissolution of the L32-. After the completion of the gel formation, organic precipitant was added above the gel. In the case of gel crystallisation method B, a carefully weighed amount of the ligand was dissolved in water, the TMOS was added and the two-phase system was shaken until homogeneous. After the gel had formed, a metal salt solution (1 ml) was placed above the gel, and after two weeks it was replaced by precipitant. In the vapour diffusion method, the water solutions of the ligand and the metal salt were mixed together and placed in a small vessel, the opening of which was provided with parafilm with pinched holes. The vessel was placed in a larger glass tube containing precipitant and then the system was sealed. The solution crystallisation method included mixing the ligand and metal salt water solutions with the precipitant in a particular certain ratio, and then allowing the solution to stand in the cold until crystals were formed.

Figure 13. Illustrations of the gel crystallisation methods A and B and the vapour crystallisation method.

28 Table 2. Syntheses of compounds 1a-3h.a

Method / starting material ligand

nL mmol

VH2O ml

pHL nMS mmol

VH2O ml

pHMS pH of the gel (G) / Solution

(S)

Final pHb

Precipitant

1a GA/Na2L1 GA/Na2L2

0.4022 0.0312

0.9 0.9

5.12 5.03

- -

- -

- -

6.46 6.25

5.17 6.38

EtOH EtOH

1b GA/Na2L1 GA/Na2L2 GA/Na2Clo

0.010 0.0050 0.11

0.45 0.45 0.45

4.7c 6.87 3.9c

0.010 0.0050 0.22

0.45 0.45 0.45

5.1c 5.42 4.5c

4.2c 4.98 2.5c

- 4.62

-

acetone 1:1 acetone-water

EtOH 1c GA/Na2L1

V/Na2L1 GA/Na2L2 GA/Na2L3

0.0054 0.0027 0.0050 0.0013

0.45 0.25 0.45 0.45

4.99 -

6.87 4.08

0.0054 0.0027 0.0050 0.0026

0.45 0.25 0.45 0.45

4.79 -

5.51 5.40

4.51 -

5.30 4.10

4.29

5.20 4.75

acetone EtOH (1 ml)

acetone acetone

1d GA/Na2L1 V/Na2L1

0.0054 0.0027

0.45 0.25

4.97 -

0.0054 0.0027

0.45 0.25

5.48 -

4.69 -

4.32 -

1:1 acetone-water EtOH (1ml)

1e GB/Na2Clo 0.087 0.9 3.45 6.0 1.0 2.70 3.51 2.42 acetone 1f GB/Na2Clod

GA/Na2L3 0.088 0.0040

0.8 0.45

3.42 4.00

0.005 0.0040

1.0 0.45

2.80 5.24

3.49 3.53

1.11 2.69

acetone acetone

1g GA/Na2L3 0.010 0.45 4.00 0.020 0.45 5.20 3.40 1.98 acetone 2a GA/Na2L1 0.013 0.45 5.05 0.013 0.45 5.78 4.98 4.73 acetone 3a S/Na2L3 0.010 1.0 3.74 0.010 1.0 4.81 4.38 4.35 acetone (1ml) 3b GA/Na2L3

S/Na2L3 0.010 0.050

0.45 2.0

4.01 -

0.010 0.050

0.45 0.50

5.17 -

3.92 -

4.00 -

EtOH acetone (2 ml)

3c GA/Na2L3e 0.0019 0.45 4.00 0.0019 0.45 4.95 3.95 4.60 1:1 acetone-water 3d GA/Na2L3 0.0010 0.45 4.05 0.0010 0.45 5.00 3.90 4.69 EtOH 3e S/Na2L3 0.030 1.0 3.75 0.030 1.0 4.94 3.51 3.14 acetone (1ml) 3f S/Na2L3 0.030 1.0 3.74 0.030 1.0 4.49 3.30 3.22 acetone (1ml) 3g S/Na2L3 0.030 1.0 3.76 0.030 1.0 4.87 4.08 3.84 acetone (1ml) 3h S/Na2L3 0.089 2.5 3.74 0.178 1.0 4.55 3.67 3.63 acetone (2ml)

a The density of the gel was 10% v/v. The pH values of the syntheses were measured using a Schott pH-Meter CG 840 with a Hamilton cheese electrode. b The final pH of the gel/solution was measured after the crystals were formed. c The pH values of the syntheses were measured using pH-indicator strips. d The density of the gel was 20% v/v. e An additional 20% TMOS-layer (0.225 ml) was placed above the gel before the precipitant was added. L = ligand, MS = metal salt, GA = gel method A, GB = gel method B, S = solution method, V = vapour diffusion method.

The disodium clodronate itself had been crystallised previously23, but the crystallisation of the dianhydride derivatives, Na2L1 and Na2L2, produced the hydrolysis product 1a in both cases. The Na2L3 molecule, in turn, did not form crystalline structure(s). Ligands L12--L22- also formed alkaline earth metal complexes of clodronic acid by hydrolysis, while the L32- ligand did not form hydrolysis products as much as did L12--L22-, due to the resonance stabilization of the benzoyl moieties. The hydrolysis products of the Ca(II) complexes of the dianhydride derivatives of clodronate are also worth mentioning here. The clodronate forms four different Ca(II) structures by gel and evaporation crystallisation methods, depending on the pH23-24. However, the L12--L32- ligands all formed the same Ca(II) complex form of the clodronate, 1c, by hydrolysis with various crystallisation methods and within a pH range 4.3-5.2 in a systematic way. A similar observation can be made regarding the formation of structure 1b 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

29 clodronate and its dianhydride derivatives compete with each other in the process of the metal complex formation. The clodronate shows the higher affinity to the metal cations compared to the clodronic dianhydrides L12--L22- exactly according to the prodrug principle.

3.3. CHARACTERISATION The synthesised Na2L2 was characterised by means of 1H and 31P NMR spectroscopy in D2O. The side-products from the synthesis of Na2L2 when the reaction time had not been optimised were easily observed by 31P NMR spectroscopy. The unequivalent phosphorus atoms in the non-symmetrical mono- and di- and also possibly tri-P,P´-ester derivatives and starting materials gave rise to two separate doublets with equal 2JPP coupling values.44 The symmetrical dianhydride ester derivative, Na2L2 in turn, gave only a single line in decoupled 31P spectra, and hence the quartet and triplet in the 1H NMR spectrum and its high solubility in water confirmed the structure (Figure 14). In addition, all of the ligands were characterised by elemental analyses, FT-IR spectroscopy and by the means of thermogravimetric analyses (TGA).

a b

Figure 14. a) The 1H NMR spectrum, and b) the 31P NMR spectrum for Na2L2.

The crystals of 1a-3h were separated under the microscope and characterised by Nonius Kappa CCD diffractometer, elemental analysis (EA), atomic absorption spectrometry (AAS) and FT-IR spectroscopy. In addition, the thermal behaviour of the transition metal and zinc compounds 1e-f and 3e-h was studied by means of thermogravimetric analyses (TGA). Powder X-ray diffraction (XRD) data for the final products of the TGA were collected with a Bruker Advance D8 diffractometer by using Cu Kα radiation (λ = 1.5406 Å) in the 2θ range of 5-100o with a step size of 0.05o and a counting time of 3s per step. The EA and AAS were used to confirm the elemental

30 composition (%) and purity of the compounds, while the bonding behaviour of the ligands in metal complexes was examined using the IR spectra. The yields of the crystallisation tests varied and so obtaining a sufficient number of samples for the other characterisation techniques was not easy. In addition, the attempt to produce powder material from compounds 1a-3h was challenging. The hydrolysis of the water-soluble clodronic dianhydride ligand produced mixtures of the metal complexes of clodronic acid and its dianhydride derivative. Of the two phosphonate groups, the clodronate, in turn, possesses high coordination flexibility and diverse structural properties. As a result, it also produced powder mixtures easily. Thus, with this we were able to perform all of the characterisation analyses from the crystals obtained in the additional crystallisations. It should also be noted that, the samples were pure and the crystallisation methods were reproducible. The solution crystallisation method produced larger amounts of crystals that were also more easily separable than the gel and vapour crystallisation methods. As expected, the crystals of the transition metal and zinc complexes were more stable and bigger in size than those obtained from the alkaline and alkaline earth metal complexes of clodronic acid and its dianhydride derivatives.

The IR spectra of complexes 1a-3h were recorded using the KBr pellet technique. These assignments are based on the published values for similar compounds and IR tables.45 Structural differences in Na2L1-Na2L3 and structures 1a-3h are readily observed. The characteristic IR regions for the clodronic dianhydrides Na2L1-Na2L3 and their metal complexes 2a-3h were observed at 1770-700 cm-1 and the characteristic region for clodronic acid metal complexes 1a-g was observed at 1240-760 cm-1. The clodronic acid framework absorptions for the Na2L1-Na2L3 and 1a-3h compounds were at 1330-915 cm-1, which can be attributed to the stretching vibrations of the phosphonate PO3 groups, i.e. at 890-760 cm-1, which can be attributed to the asymmetric and symmetric ν(P-C-P) vibrations, and at 810-675cm-1 due to the asymmetric and symmetric ν(CCl2) vibrations. The ν(P=O) stretching vibrations of Na2L1-Na2L3 and compounds 2a-3h occurred at 1330-1270 cm-1, while the corresponding ν(P=O) stretching vibrations of the metal clodronate compounds 1a-g occurred at 1240-1130 cm-1. Hence, the ν(P=O) absorptions are approximately 35-200 cm-1 at a higher wavenumber in the spectra of Na2L1-Na2L3 and 2a-3h, compared with the spectra of the metal clodronates, owing to the ester moieties attached to the phosphonate groups. In addition, in the spectra of structures 1a-2a and 3b-h there can be seen broad bands of ν(H2O) at around 3600-3400 cm-1 and weaker absorptions of δ(H-O-H) in the region of 1650-1590 cm-1 owing to the coordinated and crystal water molecules in the structures. These bands are missing from the spectra of 3a and Na2L1-Na2L3. The stretching frequency of the O-H bonds of the water cluster patterns observed in the range 3420-3440 cm-1 in the spectra of compounds 1e-g are also

31 noteworthy. The same frequencies of ice appear at 3220 cm-1 and of liquid water at 3490 cm-1 and 3280 cm-1.46 This confirms that the O…O distances of the water clusters of compounds 1e-g can be compared to liquid water O…O distances. In addition, the dianhydride groups display absorptions due to the ν(C=O), ν(C-O(-P)) and ν(C-C) vibrations appearing at 1770-1690 cm-1, at 1180-1115 cm-1 and at 1115-1100 cm-1. The alkyl groups of Na2L1-Na2L2 and compound 2a displayed bands at around 2940-2880 cm-1 and 1470-1370 cm-1 due to the asymmetric and symmetricν(C-H) and d(C-H) vibrations, respectively. For compounds Na2L3 and 3a-h, the aromatic ring ν(C=C) vibrations occurred at about 1605 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 3075-2570 cm-1 region. The absorptions for the monosubstituted aromatic ring, resulting from the out-of-plane C-H vibrations, were at ca. 750 cm-1 and 700 cm-1. The IR spectra of Co(II) complex of clodronic acid and Ni(II) complex of L32- are represented in Figure 15.

a

b

Figure 15. FT-IR spectra of a) the Co(II) complex of clodronic acid 1e, and b) the Ni(II) complex of L32- 3g.

32 The thermal behavior of the Na2L1-Na2L3 and the first series transition metal and zinc complexes 1e-f and 3e-h was studied under N2 gas flow. Definite TG analysis in the case of compound 1g could not be performed, since the sample quantity was limited. The thermal behaviour of the Co(II) and Ni(II) complexes of clodronic acid 1e-f followed the same pattern as was previously observed with the clodronate metal complexes (Figure 16). The decomposition process took place in three steps at about 50-150oC, 150-350oC and 350-800oC owing to the evaporation of the crystal water and coordinated water and also, finally, as a result of the loss of chlorine atoms, respectively. The middle-carbon atom was not released. The loss of the crystal water and coordinated water led to a complete breakdown of the 3D structures, since these lattices were held together by hydrogen bonds, which are essential for the stability of the overall structures.

Figure 16. The TGA curve for the Ni(II) complex of clodronic acid 1f.

The TGA diagrams of Na2L1-Na2L3, in turn, demonstrated two overlapped steps at about 50-800oC that were attributable to the release of chlorine atoms and the dianhydride moieties. The decomposition process of 3e-g took place in three overlapped weight-loss steps, while for 3h the decomposition required four steps (Figure 17). The first weight-loss step occurred at about 50-200oC for 3e-g and at 100-230oC for 3e as a result of the release of aqua ligands. The TGA diagram for the Mn(II) complex of L32-, 3e, indicated that the compound is stable up to 100oC, probably as a result of the structure-strengthening chelate rings in the structure. The second weight-loss was observed at about 230-300oC for 3e, 200-250oC for 3f, and 200-455oC for 3g-h and was attributable to the release of chlorine atoms, while the third step occurred at about 300-800oC for 3e, 250-800oC for 3f, 455-900oC for 3g, and 455-775oC for 3h owing to the release of the benzoyl groups of the ligands and lattice ligands. The fourth

33 weight-loss step for compound 3h was observed at about 775-800oC, and was attributable to the release of the middle-carbon atom. This final step was not observed for the isomorphous form of 3g, even though it was heated to 900oC during the TG analyses. In addition, complexes 3e-f were heated to 900oC, but the decomposition processes ended at 800oC. The black final products of TGA were multiphase, displaying an identifiable crystalline phase of metal phosphates for Na2L1- Na2L3 (Na2P3O10) and compounds 1f (NiPO4), 3e (MnP4O11) and 3g-h (NaNi(PO3)3 and NaZn(PO4), respectively). The identifiable phases of the black final products of compounds 1e and 3f could not be definitely identified by means of powder X-ray diffractometry, since these Co(II) complexes created a strong fluorescence background. However, the calculable final products are Co(PO3)2 for 1e and Co2C9OH5(PO3)4 for 3f.

Figure 17. The TGA curve for the Ni(II) complex of L32- 3g.

34

4. RESULTS AND DISCUSSION

4.1. COORDINATION CHEMISTRY

In this section, the coordination properties of clodronate and its dianhydride derivatives are compared with each other and also with the metal complexes of similar structures that had been previously prepared. A closer look at the bonding modes and structure formation behaviour of the ligands reveals the versatility of the coordination structures of diverse clodronic acid derivatives. The overall structural comparison of the new structures prepared and characterised during this study is summarised in Table 3. Table 3. A summary of the structural features of the new metal bisphosphonates prepared and characterised in this study.

M+/2+ / L2- CN ionic radii47

The role of the L The overall dimension of the structure

Bridging Chelating 1a Na+ / Clo2- Na1 6

Na2 6 Na3 6

1.02 X X 3D formed by coordination bonds

1b Mg2+, Na+ / Clo2- Mg1 6 Na1 6

0.72 1.02

X X 3D formed by coordination bonds

1d Sr2+ / Clo2- Sr1 7 Sr2 8

1.21 1.26

X X 3D formed by hydrogen bonds between the planes

1e Co2+ / Clo2- Co1 6 Co2 6

0.745 X X 3D formed by hydrogen bonds between the dinuclear units

1f Ni2+ / Clo2- Ni1 6 Ni2 6

0.69 X X 3D formed by hydrogen bonds between the dinuclear units

1g Zn2+ / Clo2- Zn1 6 0.74 X X 3D formed by hydrogen bonds between the dimeric units

2a Ba2+ / L12- Ba1 10 1.52 X X 2D formed by hydrogen bonds between the chains

3a K+ / L32- K1 7 K2 6

1.46 1.38

X X 2D formed by coordination bonds

3b Mg2+ / L32- Mg1 6 0.72 2D formed by hydrogen bonds between the monomeric units

3c Sr2+ / L32- Sr1 9 Sr2 8

1.31 1.26

X X 2D formed by hydrogen bonds between the chains

3d Ba2+ / L32- Ba1 8 1.42 X X 2D formed by hydrogen bonds between the chains

3e Mn2+ / L32- Mn1 6 0.83 X X 2D formed by hydrogen bonds between the dimeric units

3f Co2+ / L32- Co1 6 Co2 6

0.745 2D formed by hydrogen bonds between the monomeric units

3g Ni2+, Na+ / L32- Ni1 6 Ni2 6 Na1 6

0.69

1.02

X 2D formed by hydrogen bonds between the chains

3h Zn2+, Na+ / L32- Zn1 6 Zn2 6 Na1 6

0.74

1.02

X 2D formed by hydrogen bonds between the chains

L = ligand, M = metal, CN = coordination number

35 4.1.1. METAL COORDINATION

The coordination numbers and geometries of the metal cations are dependent on the size of the ionic radii. The ionic radii and the M-O bond distances of the Mn2+, Co2+, Ni2+ and Zn2+ are comparable in size to those of the Mg2+ (and Ca2+) cations (See Tables 3 and 4). The alkaline earth metal ions are smaller and less polarisable than the alkaline metal ions. Despite the essentially ionic nature of K+ and Na+ cations, in some organometallic compounds, the M-O bonds have a slight covalent nature. The charge-per-radius values of alkaline earth metals are 3.1 (Mg2+), 2.0 (Ca2+), 1.8 (Sr2+) and 1.5 (Ba2+), and hence the magnesium has a tendency to covalent bond formation, while the charge-per-radius value of barium indicates a strong ionic bonding. The chemistry of covalently bound Zn2+ cations resembles the chemistry of Mg2+, but the polarizing ability of Zn2+ is larger.

Table 4. A summary of the M-O bond distances in 1a-b and 1d-3h compared with those reported in the literature (CCDC Structural Database48).

a The Na-Cl distance is omitted. M = metal, CN = coordination number, BSA = bicapped square antiprism, BTP = bicapped trigonal prism, DOD = dodecahedron, OC = octahedron, PBP = pentagonal bipyramid, SA = square antiprism, TP = trigonal prism, TTP = tricapped trigonal prism.

The M-O bond distances of complexes 1a-b and 1d-3h are in good agreement with those given in the literature48. Only in 1a is a unique Na-Cl(C) coordination bond, which is 0.65 Å longer than the average Na-O bond distance of 1a. According to the CCDC Structural database48 there are only a few structures with a Na-Cl(C) interaction, the differences in their distance ranging between 0.59-0.91 Å compared with the Na-O coordination bonds of these structures. In addition, in 3a the K-O bond distances of the six-coordinated K+ cation vary between 2.684-3.302 Å, with two relatively long K-O bonds. In terms of the CCDC Structural Database48, however, the K-O(-P) bond length range is 2.22-3.33 Å. The most common coordination numbers for Sr2+ and Ba2+ are 6-8 and 5-10, respectively. In 1d and 3c, Sr2+ has coordination numbers 7-9, and in 2a and 3d, Ba2+ has coordination numbers 8 and 10. As expected for Mg2+, Zn2+ and all the first series transition elements, they form complexes with

M+/2+ CN Geom. Compounds M-O bond distances (Å) Literature Min. Max. Average Average (Å)48 Na+ 6 OC 1aa, 1b, 3g, 3h 2.315(2) 2.806(2) 2.44 ± 0.09 2.42 ± 0.11 K+ 6

7 TP

PBP 3a 3a

2.684(2) 2.703(2)

3.302(2) 2.834(2)

2.86 ± 0.23 2.77 ± 0.05

2.80 ± 0.12 2.82 ± 0.12

Mg2+ 6 OC 1b, 3b 2.010(2) 2.139(2) 2.06 ± 0.04 2.07 ± 0.05 Sr2+ 7

8 9

PBP DOD, BTP

TTP

1d 1d, 3c

3c

2.457(2) 2.530(7) 2.055(3)

2.678(2) 2.724(2) 3.049(5)

2.56 ± 0.08 2.64 ± 0.06 2.57 ± 0.32

2.57 ± 0.06 2.63 ± 0.11 2.67 ± 0.08

Ba2+ 8 10

SA BSA

3d 2a

2.682(2) 2.683(2)

2.850(2) 3.029(2)

2.80 ± 0.05 2.86 ± 0.11

2.80 ± 0.09 2.87 ± 0.12

Mn2+ 6 OC 3e 2.1170(14) 2.2347(14) 2.18 ± 0.05 2.07 ± 0.16 Co2+ 6 OC 1e, 3f 2.018(2) 2.2232(2) 2.10 ± 0.06 2.09 ± 0.08 Ni2+ 6 OC 1f, 3g 2.011(2) 2.165(2) 2.07 ± 0.04 2.06 ± 0.05 Zn2+ 6 OC 1g, 3h 1.9917(12) 2.4732(11) 2.11 ± 0.10 2.11 ± 0.09

36 clodronate and its derivatives with the most common coordination number six in octahedral geometry.

4.1.2. BONDING MODES OF THE LIGANDS The bonding modes of etidronate, clodronate and its partial ester derivatives and other geminal bisphosphonates have been discussed in the preceding sections. They possess various chelating and bridging bonding modes with metal cations but, typically, they all form four- to six-membered chelate rings, and often in bis-chelating and bridging bonding modes. In addition, the phosphonate oxygen atoms act as di- and triatomic bridges. The mean P-O bond lengths for clodronate, etidronate, pamidronate and alendronate are in the range 1.50-1.52 Å, and the corresponding values for pendant or protonated oxygen atoms are in the range 1.52-1.54 Å.48 In this study the clodronate presented itself in four bonding modes A1-A4, which are illustrated in Scheme 2. The bonding modes of the clodronic dianhydride ligands L12- and L32- are represented in Schemes 3-4.

Scheme 2. Representations of the bonding modes A1-A4 of clodronate that have found in this study. The 3D polymeric structure 1a holds the new bonding mode A1, where the clodronate ligand forms two five-membered and two six-membered chelate rings. Clodronate acts as a hexadentate ligand, since the chlorine atom also participates in the metal coordination. Two of the phosphonate oxygen atoms are diatomic bridges and one is a triatomic bridge, while the two coordinate the metal cations in a monodentate manner, with an average P-O bond length of 1.524 Å. The bis-chelating and bridging bonding mode A2 is found in 1b and in its isomorphous form, the Zn(II) complex of clodronate27. The average P-O distance of this bonding mode is 1.520 Å. The 2D polymeric structure 1d follows the bonding mode of A3, where clodronate forms one

37 four- and two six-membered chelate rings with metal cations. In addition four of its phosphonate oxygen atoms are diatomic bridges between the metal cations. In this bonding mode, the average P-O bond distance is 1.518 Å. The bis-chelating bonding mode A4 is a feature of the dinuclear compounds 1e-f and dimeric compound 1g. A similar coordination of metal cations can be found with several metal complexes of the medronate49, etidronate28f, m-n, P, P-diethyl42d, P-piperidinyl-P´-methyl42f and P-pyrrodinyl-P´-methyl42g derivatives of clodronate. In A3 for 1e-f and g, the average P-O bond length is 1.520 Å.

Only one metal complex of L12-, a polymeric chain structure 2a, could be successfully prepared, and its bonding mode B1 is illustrated in Scheme 3. This bonding mode shows how the ligand L12- also coordinates to the metal cations by means of the carbonyl oxygen atom of its acetyl moiety, leaving the nearest phosphonate group without coordinative bonds. The other phosphonate group, however, coordinates with its two available phosphonate oxygen atoms to the metal cations both in a monodentate manner and also by acting as diatomic bridges by chelating the same metal cation. The average P-O bond distances of the substituted oxygen atoms, 1.648 Å, are clearly longer than those of the coordinated or non-coordinated oxygen atoms, 1.482 Å.

Scheme 3. The bonding mode B1 of the L12- ligand. The bonding mode C1 of the L32- ligand shows how flexible in terms of coordination the dibenzoyl derivative of clodronic acid can be if the metal is suitably sized, as in the case of compound 3a, which has K+ as a metal cation. The L32- ligand forms five six-membered chelate rings that have all of the donor atoms, four phosphonate oxygen and two carbonyl oxygen atoms, coordinated to the metal cations. In addition, the carbonyl oxygen acts as a diatomic bridge and coordinates another metal cation. The monomeric

38 compounds 3b and 3f hold the bonding mode C2, where the L32- ligand coordinates the metal cation monodentately. This simple bonding has never occurred previously in the case of the medronate, etidronate, clodronate or its partial ester derivatives, since the polyfunctional ligand generally uses at least two of its donor oxygen atoms to coordinate the metal cations. It has, however, been previously found in the Ca2+ complex of aebpH3- ligand.30a The other unusual bonding modes are the C3 of 3c and the C4 of isomorphous structures 3g-h, where the L32- coordinates the metal cations bidentately, with phosphonate oxygen atoms or with phosphonate and carbonyl oxygen atoms, respectively, without forming chelate rings. The C3 bonding mode has also been observed previously only in the Zn(II) complex of the P, P´-diisopropyl ester derivative of clodronate27 and in the Mn(II) complex of ethylidenebisphosphonate with 1,10-phenantroline36a. Hence, it is likely that the additional template ligand and the sizes of the diester groups provide steric hindrance to the structure and direct the coordination in conjunction with the metal cation. In addition, the third exception to the chelating and bridging diester derivatives of clodronate is the tridentately bridging Cd(II) complex of the P, P-diphenyl derivative of clodronate42c. In the bonding mode C5 of 3e the ligand forms a typical six-membered chelate ring through the phosphonate oxygen atoms of the different phosphonate groups and, in addition, it bridges the second metal cation monodentately with one phosphonate oxygen atom. The various metal complexes of etidronate28f-h,l,q, aebp30b, pamidronate31d, alendronate32a, [H3N(CH2)5)(OH)C(PO3H)2]-32d, and, P, P-diethyl42d, 50, P-piperidinyl-P´-methyl42f and P-morpholinyl-P´-methyl42g,51 derivatives of clodronate possess the similar coordination mode C5. Compound 3d follows the C6 bonding mode and has three six-membered chelate rings formed by L32-. The phosphonate oxygen atoms are again in bis-chelating bonding mode, but the third chelate ring is formed between the phosphonate oxygen and carbonyl oxygen atoms. As in the case of the P-O distances of L12-, L22- also displays the difference in the P-O bond lengths between the substituted and coordinated/non-coordinated phosphonate oxygen atoms. The average P-O distance of the substituted oxygen atoms is 1.637 Å, while the corresponding distance of the coordinated/non-coordinated oxygen atoms is 1.479 Å.

39 Scheme 4. The bonding modes C1-C6 of the L32- ligand. 4.1.3. EFFECTS OF METAL AND ESTER MOIETIES ON

STRUCTURE FORMATION

The clodronate and its monoester and diester derivatives, with the exception of the two previously mentioned diester derivative structures27, 42c, tend to chelate and bridge metal cations with ionic radii of 0.74(Zn2+)-1.42(Ba2+)47 to molecular and polymeric structures, which may form 2-3D structures through hydrogen or coordinative bonding. This is also the case with the Sr(II) complex of clodronate, 1d. In addition, a 3D structure of clodronate metal complexes may be formed by coordination bonds when Na+ participates in structure formation by pillaring the chains and layers together, as in the Na(I) and Mg(II)/Na(I) complexes of clodronate, 1a-b. Exceptions to this are the

40 monomeric Sr(II) complex of clodronate25, dinuclear Co(II) and Ni(II) complexes, 1e-f, and the dimeric Zn(II) complex, 1g, of clodronate. These structures, the 1e-g of which are isostructural, form an extended 3D hydrogen bond network through coordinated and lattice water molecules.

In structures 3b and 3f, with hexa-coordinated Mg2+ (ionic radii 0.72 Å47) and Co2+ (ionic radii 0.745 Å47), it was an interesting finding that the polyfunctional ligand L32- has bound the metal cations only monodentately. In 3f, L32- does not even chelate and/or bridge the two Co2+ cations, although the lattice L32- ligand and the [Co(H2O)6]2+ cation participate in forming the crystal structure. Generally, the L32- ligand tends to chelate and/or bridge the metal cations, as can be seen in Scheme 4 and Table 3, and therefore the size of the ionic radii of the metal cation may have an effect on structure formation in this particular case. With hexa-coordinated Ni2+ (ionic radii 0.69 Å47) and Zn2+ (ionic radii 0.74 Å47) in compounds 3g-h, the L32- ligand bonds metal cations in a monodentate fashion but also bridges them to the hexa-coordinated Na+ (ionic radii 1.02 Å47) atom, forming polymeric chains. In the K+ complex, 3a, and the Sr2+, Ba2+ and Mn2+ complexes, 3c-e, where the metal cation has ionic radii in the range of 0.83-1.46 Å (Table 3), the L32- ligand both chelates and bridges the metal cations, and forms a dimeric structure 3e and polymeric structures 3a and 3c-d. In addition, the compound 2a is polymeric, where the L12- ligand both chelates and bridges the Ba2+ cations. In consequence, this may indicate that the L12- and L32- ligands could both chelate and bridge metal cations with ionic radii > 0.80 Å and that way increase the dimensionality, but otherwise they would act in a monodentate or bidentate manner without forming chelate rings.

Evidently, the two bulky groups attached to the phosphonate oxygen atoms by esterification diminish the metal complexation and reduce the dimensionality of the formed structures, as these compounds as prodrugs of clodronate should do. This does not, however, prevent the formation of 2D polymeric structures, which might in this case result from the geometry and coordination flexibility of the L12- and L32- ligands. In the metal complexes of L12- and L32- the R-O-P-C-P-O-R framework has made room for the other four phosphonate oxygen and two carbonyl oxygen atoms of the ester groups to coordinate to the metal cations by reducing the (R-)O-P-C angles to about 95-110o, while the average O-P-C angle of clodronate metal complexes is approximately 102-110o. In addition, the P-C-P angles of the metal complexes of L12- and L32- are 109-114o, while the corresponding angles of structures 1a-g and the previously reported metal clodronates23-27 are 114-119o. The size difference between the acetyl and benzoyl groups does not, however, affect the size of the (R-)O-P-C nor P-C-P angles.

41 4.2. INTERMOLECULAR INTERACTIONS AND CRYSTAL-

PACKING

The observation that dimensionality depends on the length of the organic unit, the number of donor atoms and the degree of protonation of the phosphonate groups has guided the research into the bisphosphonate ligands.16 In addition, the presence of other cations, anions or neutral molecules in the starting mixture may have an effect on the dimensionality. When, for example, organic templates, Na+ or crystal water participate in structure formation, they can connect the adjacent molecules, chains or layers to higher dimensionalities via coordinative bonds or hydrogen bonds, respectively.52 In addition, they can act as clathrated guest molecules, occupying the open cavities in crystal structures.53 Accordingly, the metal bisphosphonates can produce microporous or mesoporous material with specifically defined cavities and high chemical and thermal stability.53-54 Among the space filling molecules, small water clusters have been widely studied both theoretically and experimentally. Water is a very important factor in many biological and chemical systems, and its structural and binding properties may provide insights into the bulk properties of water. Water molecules are especially attracted to s-block ions, and the structuring the water clusters is also significant in the designing of new metal-organic framework structures.46, 55 In the case of the bisphosphonates, water molecules are able to form four hydrogen bonds in tetrahedral fashion, at least with water-water or water-phosphonate oxygen contacts. The simplest water cluster patterns have been classified, but the hydrogen bond networks can be extremely complex.

The hydrolysis products of Na2L1-Na2L2, the trisodium clodronate 1a, and the Mg(II)/Na(I) complex of clodronic acid 1b, show how the Na+ ions participate in structure formation and the 3D structures are formed by coordination bonds. In 1a, the dense sodium clodronate planes are pillared by two NaO6 octahedrons, sharing two µ-H2O bridges with each other (Figure 18a). The planes are constructed by NaO6

octahedrons organised in the hydrophilic inner section of the plane, covered by bridging and chelating clodronate ligands. In compound 1b, in turn, the Mg(II) clodronate chains are connected by NaO6 octahedrons in a 3D arrangement. The Sr(II) clodronate, 1d, is a 2D polymeric compound, but the planes are connected to a 3D structure by hydrogen bonding. The clodronate, with a hydrophilic frame, also allows the lattice water molecules to place themselves between the layers and form hydrogen bonds in the third dimension, but there are no porous spaces in the structure, even if the lattice water molecules were to be removed (Figure 18b). 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 SrO7 and SrO8 polyhedrons form chains, which the bridging and chelating clodronate connects together with the help of µ-H2O

42 ligands. Intra- and intermolecular hydrogen bonds in structures 1a-d involve all of the aqua ligands and lattice water molecules as donors and also the phosphonate oxygen atoms, lattice aqua ligands and chlorine atoms as acceptors.

a

b

Figure 18. Polyhedral packing pictures of a) trisodium clodronate 1a, and b) the Sr(II) complex of clodronate 1d. (PCO3 tetrahedrons in green, NaO6 and SrO7/SrO8

polyhedrons in blue, carbon atoms as grey spheres, hydrogen atoms as pale grey spheres, oxygen atoms as red spheres and chlorine atoms as green spheres.)

The isostructural Co(II), Ni(II) and Zn(II) clodronates, 1e-g, all have voids where water clusters are trapped by hydrogen bonds. Crystal water molecules surround the inorganic parts of the dinuclear motifs of 1e-f, which are organised in zig-zag mode. Compound 1g, in turn, has more crystal water molecules, which surround the whole dimeric Zn(II) clodronate units. In 1e-f the coordinated water and crystal water molecules form infinite hydrogen bonded tapes. In the tapes of 1e, the (H2O)10 rings are joined together by two cyclic water molecules in the rings (Figure 19a), while the tapes of 1f consist of cyclic hexamers connected by two acyclic water molecules. The average O…O distance in the water clusters of 1e-f are 2.813 Å and 2.824 Å,

43 respectively, and they are longer than the corresponding value in ice Ih (2.759 Å46), although they can be compared to the O…O distance of liquid water (2.854 Å46). These hydrogen bonded tapes are extended to the 3D hydrogen bond network when the phosphonate oxygen atoms serve as hydrogen bond acceptors. The water cluster pattern of 1g is three-dimensional. The polyhedral (H2O)18 rings surround the highly hydrophilic Zn(II) clodronate units, and the phosphonate oxygen atoms complete the 3D polyhedral hydrogen bond pattern (Figure 19b). Water clusters tend to grow in size within the hexameric and higher membered water rings as the hydrophilicity of the solute molecules increases.55a This tendency can also be seen in structures 1e-g. The average O…O distance of the (H2O)18 ring is 2.756 Å, which is slightly shorter than the corresponding values of ice (2.759 Å46) and liquid water (2.854 Å46).

a

b

Figure 19. A close view of the hydrogen bonding of a) the 1D (H2O)10 water cluster tape of compound 1e; and b) the 3D (H2O)18 water cluster rings of compound 1g. (PCO3 tetrahedrons in grey, hydrogen atoms as pale grey spheres, oxygen atoms as grey spheres, hydrogen bond interactions as grey and black dashed lines.)

44 Since the significant proportions of structures 1e-g are formed by lattice water molecules between the large hydrophilic areas, with all water molecules being found and refined during the structural refinement process and, in addition, experimentally observed by FT-IR and TGA, the space that the crystal water accommodates was also undoubtedly involved. The water in the crystallisation in structures 1e-g was removed to determine the void spaces using PLATON software SOLV56. Although SOLV56 was originally used principally in the study of organic structures, it has also been proved to be a good tool for determing the volumes of voids in microporous inorganic crystals.56 In reality, however, the crystal structures of 1e-g will collapse after the crystal water is removed, since the 3D lattice has been constructed by the hydrogen bonds. Although structures 1e-g are isostructural, the packing modes are different, and the total potential solvent area volumes were 158.8, 286.6 and 460.0 Å3, respectively, i.e. 9.1% of the total unit cell volume for 1e, 16.8% for 1f and 23.2% for 1g. These values indicate that the slightly different packing of the crystal water has an influence on the size of the space that the water molecules accommodate. In addition, the solvent-accessible void space of compound 1e does not penetrate the structure continuously, as in the case of compounds 1f-g, but the crystal water is blocked inside the structure. These values may be compared, for example, with the expected volume of 40 Å3 for hydrogen bonded H2O-molecule. The space-filling illustrations of the blocked solvent accessible void spaces of 1e and the whole structure penetrating voids of 1g, made by means of the PLATON software CAVITY56, are presented in Figure 20.

a b

Figure 20. The space-filling illustrations of solvent accessible voids of a) compound 1e and b) compound 1g. (Unoccupied space as white space-filling, metal cations as black spheres, phosphorus and chlorine atoms as grey spheres and oxygen atoms as pale grey spheres.)

45 All the metal complexes of the L12- and L32- ligands form 2D structures through coordinative bonds (3a) or hydrogen bonding between crystal water, coordinated water and phosphonate oxygen atoms (2a, 3b-h). The monomeric Mg(II) and Co(II) complexes of L32-, 3b and 3f place themselves with inorganic MO6 octahedrons against each other, forming 2D hydrogen bonds between the aqua ligands and lattice water molecules, while the hydrophopic benzoyl groups and chlorine atoms point towards the interlayer section. The Co(II) complex also has lattice [Co(H2O6)]2+ octahedrons and lattice L32- ligands to support the layered arrangement. The dimeric Mn(II) complex of L32-, 3e, is formed by two MnO6 octahedrons sharing three corners of two PCO3 tetrahedrons of L32-. The dimeric units are arranged in a similar way to that of the preceding structures, with their inter-layer space between the 2D layers filled with hydrophopic moieties of the ligands.

The majority of the metal clodronic dianhydride compounds are polymeric chains. The Sr(II) and Ba(II) complexes of L32-, 3c-d, and the Ba(II) complex of L12-, 2a (Figure 21), are formed, as had been expected, in relation to the polyfunctional clodronic dianhydride ligands. The metal cations form chains by sharing µ-H2O ligands and phosphonate and carbonyl oxygen atoms of the bridging and chelating L12- and L32- ligands. In addition, their aqua ligands form hydrogen bonds between the chains to form the inner hydrophilic core of the layers. Structure 2a is a good example of the function of the clodronic dianhydride ligand as an extended linker, with the carbonyl oxygen atoms also functioning as coordinating units. If the ester groups were longer and had terminal coordinating groups, the porosity of the structure could be increased. In addition, such chains could also be added to the geminal carbon atom, and thus the structure could be extended into the third dimension, as is the case with the other geminal bisphosphonates. This procedure would also permit the formation of hydrogen bonds between the layers. The isomorphous Ni(II) and Zn(II) complexes, 3g-h, are not exceptions to the packing mode of clodronic dianhydrides, but the metal chains are formed by the NaO6 and MO6 octahedrons by their sharing two µ-H2O ligands. The L32- ligands are simultaneously bonded monodentately to the metal chain and to the M(H2O)5 polyhedrons. In addition, the metal chain is supported by additional lattice L32- ligands. As can be seen, hydrogen bonds are significant in the stabilisation of the crystal structures and in developing the dimensionality of the metal clodronic dianhydride compounds. The K(I) complex of L32-, 3a, is, however, the only compound which has no coordinated or crystal water molecules in its structure, even though it has been crystallised from a water solution. KO6 and KO7 polyhedrons have formed the typical 2D plane structure by sharing the phosphonate and carbonyl oxygen atoms of the chelating and bridging L32- ligand and µ-O ligands. In addition, the K(I) complexes of the BPs are less common, since the alkaline metal cations are generally considered to be spectator ions in crystal structures.

46 a

b

Figure 21. Packing pictures of the Ba(II) complexes of a) L12-, 2a, and b) L32-, 3d. (PCO3 tetrahedrons in green, BaO10/BaO8 polyhedrons in blue, carbon atoms as grey spheres, hydrogen atoms as pale grey spheres, oxygen atoms as red spheres and chlorine atoms as green spheres.)

The clodronic acid metal complexes may benefit from the Na+ ions participating in the formation of the crystal structure, but the acetyl and benzoyl groups of the L12- and L32- ligands hinder any increase in the dimensionality. Since compounds 2a and 3a-h are oriented in the packing scheme so that the bulky organic groups lie against each other, hydrogen bonding in that direction is not possible. At most, therefore, the L12--L32- ligands can form 2D structures with or without hydrogen bonding. This leads to dense packing modes with no solvent-accessible voids. The clodronic acid ligand, in turn, can form a 3D hydrogen bond network, since this ligand is more hydrophilic and flexible by coordination. In those structures, lattice water molecules can also place themselves between the layers.

47

5. CONCLUSIONS

The new clodronic dianhydride Na2L2 and fifteen new alkaline and alkaline earth metal, first series transition metal and zinc complexes of clodronic acid and its dianhydride derivatives were prepared and characterised. Most of the clodronate metal complexes were formed by hydrolysis of the clodronic dianhydride ligands L12- and L22-, and most of them were also prepared by using the clodronate as a starting material. The interesting finding was that the clodronic dianhydrides Na2L1 and Na2L2 swiftly hydrolysed to the crystalline trisodium clodronate, while the longer hydrolysis time of Na2L3, due to the resonance stabilisation of the dibenzoyl moieties, resulted mainly in non-hydrolysed metal complexes. Under these circumstances their absorption into the body may not be increased by using Na2L1-Na2L2 as prodrugs.

The clodronate also demonstrated experimentally its higher propensity towards the metal cations, compared with the clodronic dianhydrides, in precise accordance with the prodrug principle. In addition, the two hydrophopic ester moieties reduced the dimensionality of the metal complexes formed. Esterification did not, however, prevent the formation of 2D polymeric structures which resulted from the coordination flexibility of the O-P-C-P-O framework of the L12- and L32- ligands. The ligands also took advantage of the additional carbonyl oxygen atoms of the dianhydride groups in coordination to the metal cations. In addition, the ionic radii of the metal cations and the sizes of the diester groups directed the coordination by applying steric hindrance to the structures. These facts led to clearer hydrophilic and hydrophopic areas in the packing of the structures.

All of the metal complexes of clodronic dianhydrides L12- and L32- formed 2D structures, through coordinative or hydrogen bonding between the monomeric and dimeric units, and chains. These layer structures had all the hydrophilic inner core and hydrophopic outer surfaces, and in some cases the additional lattice ligands, [M(H2O)6]2+ cations and crystal water supported the 2D structures. As expected, the orientation of the phosphonate and carbonyl oxygen atoms and the bulky ester moieties hinder hydrogen bond formation in the third dimension. The metal clodronates, in turn, all formed 3D structures through additional Na+ cations or within a 3D hydrogen bond network. The isostructural Co(II), Ni(II) and Zn(II) complexes of clodronic acid also possessed 2-3D water clusters between their structural units, which were found and refined during the structural refinement process and observed experimentally by means of FT-IR and TGA. The heating of the structures, however, led to a complete breakdown of the lattices when the strongly cohesive hydrogen bonded coordinated and the crystal water molecules were released.

48

ACKNOWLEDGEMENTS

This work was carried out within the Inorganic Materials Chemistry Graduate Program (EMTKO) at the Department of Chemistry, University of Joensuu/University of Eastern Finland, in 2004-2010. Financial support provided by the University of Joensuu/University of Eastern Finland, Department of Chemistry, Faculty of Science and EMTKO is gratefully acknowledged.

I express my deepest gratitude to my supervisor, Professor Markku Ahlgrén, for introducing me to inorganic chemistry and to the fascinating world of the metal bisphosphonates. I have also appreciated his support in the final stages of my work, when he provided me with so much motivation. I am also extremely grateful to Professor Matti Haukka for all of his support, encouragement, and guidance in X-ray crystallography and coordination chemistry. His door has always been open for my questions. I should like especially to thank him both for our numerous fruitful discussions and for the opportunity to participate in conferences in Oulu and Christchurch, and in summer schools in Siena and Helsinki.

Sincere thanks are also due to Professor Jouko Vepsäläinen, Kuopio Campus, for his excellent co-operation and for providing me with the bisphosphonate ligands, and to Dr Sirpa Peräniemi for all the help and guidance that she provided in the early stage of my studies. I am also very grateful to Tarja Virrantalo for all the help she gave in the lab and in carrying out the elemental analyses. She has always been the person I could depend on, and talk to about everything, both in professional terms and also about life in general. In addition, I should also like to thank Päivi Inkinen, Ritva Romppainen and Taina Nivajärvi for the measurements that they provided, Dr John A. Stotesbury for improving the language of the original publications (II and IV) and of this thesis, and Dr Kathleen Ahonen for improving the language of the original publications I, III and V. And I should like to thank to our Coordination Chemistry Group and the entire staff of the Department of Chemistry for creating such a pleasant working environment.

I am indebted to Dr Mervi Matilainen and Elina Laurila for our fruitful co-operation and discussions. Thank you, Elina, for the encouragement and all of your help in my professional life, and for being such good company on our professional trips to Italy and New Zealand. Our office at the university has always been full of women’s energy. And to my most recent room-mates, Heli Eronen, thank you for your friendship and support, and Tero Alanen: I have really enjoyed our banter. I would also like to thank my neighbouring room-mate Dr Larisa Oresmaa for encouraging and advising me throughout the writing of this doctoral thesis.

49 On the actual day of the public defence of my doctoral thesis we shall be celebrating not simply my achievements, but also, our life, family, love and friendship. Thank you, Sanna, for the support, fun weekends and trips abroad. Thank you, Karoliina, for the unbelievable discussions and music sessions. Thank you, Maija-Liisa, for being my personal motivator and friend, and thank you, Maija, for being such a good friend and introducing me to heavy music. Thank you, Aila and Martti, for always being there for me and for being such a great help. This thesis is dedicated to my family, my mother Eeva and brother Jouni and my late father, grandfather and grandmother, who all supported and encouraged me from the very beginning, no matter what. Although I sometimes thought of giving up, you always kept me moving forward. Matti, my dear, we have been engaged for ten years and married five years this year, so you have walked by my side throughout my studies at the university. Your understanding, love and support have given me the strength and freedom to achieve everything that I want in my life.

Joensuu, April 2010 Susan Kunnas-Hiltunen

50

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