DALTON COMMUNICATION J. Chem. Soc., Dalton Trans., 1999, 663–666 663 Synthesis and characterisation of the first organotin complex of piroxicam. An extended network system via non-hydrogen, hydrogen bonding linkages and C–H ? ? ?� contacts Sotiris K. Hadjikakou,a Mavroudis A. Demertzis,a John R. Miller b and Dimitra Kovala-Demertzi a* a Inorganic and Analytical Chemistry, Department of Chemistry, University of Ioannina, 45100 Ioannina, Greece. E-mail: dkovala@cc.uoi.gr b Department of Biological and Chemical Sciences, University of Essex, Wivenhoe Park, Colchester, UK CO4 3SQ Received 7th January 1999, Accepted 18th January 1999 The organotin complex, [SnBu2(pir)]n, of the potent and widely used anti-inflammatory drug piroxicam, H2pir, was obtained and a crystal structure determination showed that in this complex the ligand is doubly deprotonated at the oxygen and amide nitrogen atoms.There are two similar molecules in the asymmetric unit. The isolated molecules of Sn(1) or Sn(2) are arranged in polymers in a head to tail fashion with a stacking of alternate parallel chains. Extended networks of Sn–O–Sn, C–H ? ? ? O and C– H? ? ?� contacts lead to aggregation and a supramolecular assembly.Real concentration protonation constants for the zwitterionic form (pyridyl group) and the protonated piroxicam (enolic group) were determined spectrophotometrically in pure aqueous solutions of constant ionic strength. It is the first example where piroxicam is proved to act as a doubly deprotonated tridentate ligand.Piroxicam [4-hydroxy-2-methyl-3-(2-pyridyl carbamoyl)-2H- 1,2-benzothiazine 1,1-dioxide], H2pir, is a potent and extensively used non-steroidal anti-inflammatory (NSDA), anti-arthritic drug with a long biological half-life,1a which acts by inhibiting enzymes involved in the biosynthesis of prostaglandins. To date, piroxicam is among the top ten NSDAs on the market.1 The drug, with four donor atoms and several possible isomers,1 is known to react as a monodentate ligand through the pyridyl nitrogen towards platinum(II) and as a singly deprotonated bidentate chelate ligand, through the pyridyl nitrogen and the amide oxygen, towards copper(II) and cadmium(II).2 Iron(II), cobalt(II), nickel(II) and zinc(II) almost certainly behave similarly to cadmium(II).2 Organotin(IV) compounds form an important series of compounds and have been receiving increasing attention in recent years, not only because of their intrinsic interest, but also owing to the importance of tin-based anti-tumour drugs.3,4 We have developed 5 an interest in the coordination chemistry and anti-inflammatory properties of nonsteroidal anti-inflammatory drugs, and report here the interaction of SnBu2Cl2 with piroxicam (H2pir) † and the crystal structure of the complex [SnBu2(pir)]n.‡ There are two similar molecules in the asymmetric unit.[SnBu2(pir)]n has 1 : 1 Sn : pir stoichiometry and the doubly deprotonated ligand, pir, is coordinated as a tridentate ligand via the enolic oxygen O(1), the amide N(2) and pyridyl N(1) nitrogen atoms.The molecular structure is shown in Fig. 1 which includes some selected bond parameters. The very long Sn–N(pyridyl) bonds are readily explic- Fig. 1 An ORTEP representation of [SnBu2(pir)]n with the atom numbering scheme. Selected bond lengths (Å) [data from the second molecule are in square brackets]; Sn–O 2.083(3) [2.074(2)]; Sn–N(pyridyl) 2.427(3) [2.478(3)]; Sn–N(amide) 2.135(3) [2.176(3)]; Sn(1)–C(16) 2.119(5) [2.120(4)]; Sn(1)– C(20) 2.119(5) [1.238(4)]; C(8)–O(1) 1.313(4) [1.321(4)]; C(6)–O(2) 1.229(5) [1.238(4)]; N(2)–C(5) 1.389(5) [1.388(4)]; N(2)–C(6) 1.375(5) [1.354(4)].664 J.Chem. Soc., Dalton Trans., 1999, 663–666 Table 1 Inter-hydrogen bonding, non-hydrogen intermolecular interactions and C–H ? ? ?p interactions in [SnBu2(pir)]n in Å and degrees. Cg = ring centroid a Donor (D) C(1) C(20) C(36) C(38) C(43) Sn(1) Sn(2) Sn(2) Sn(2) Ha H(1) H(20B) H(36) H(38B) H(43A) Acceptor (A) b O(3)i O(3)i O(3)ii O(4)i O(8)iii O(2)i O(6)iii N(6)iii C(29)iii D? ? ?A 3.238(5) 3.402(5) 3.291(5) 3.521(5) 3.354(5) 3.019(4) 2.611(2) 3.598(3) 3.535(4) H? ? ?A 2.5195 2.4895 2.5278 2.4927 2.4145 D–H? ? ?A 132.55 145.95 137.49 169.18 149.72 C(16)–H(16A) ? ? ? Cg(1) C(21)–H(21A) ? ? ? Cg(1) C(40)–H(40A) ? ? ? Cg(2) C(40)–H(40B) ? ? ? Cg(2) C(44)–H(44B) ? ? ? Cg(2) C(2)–H(2) ? ? ? Cg(3) C(35)–H(35) ? ? ? Cg(4) H? ? ? Cg 2.772 2.760 3.355 2.697 2.438 3.283 2.818 X? ? ? Cg 2.897 3.315 3.151 3.151 3.170 4.059 3.666 C–H? ? ? Cg 86.34 113.51 69.83 106.37 126.58 140.27 113.51 a Cg(1) and Cg(2) are the centroids of the four-membered rings Sn(1)–N(1)–C(5)–N(2) and Sn(2)–N(4)–C(28)–N(5) respectively; Cg(3) and Cg(4) are the six-membered rings N(4)–C(24)–C(25)–C(26)–C(27)–C(28) and C(9)–C(10)–C(11)–C(12)–C(13)–C(14) respectively.b Symmetry operations; i, 1/2 2 x, 1/2 1 y, 1/2 2 z; ii, 1 2 x, 2y, 1 2 z; iii, 3/2 2 x, 21/2 1 y, 1/2 2 z.able in terms of ring strain eVects in the four-membered chelate ring and as a result of the low degree of covalent character of the Sn–N(pyridyl) bond. According to Crow et al.,6c diorganotins with Sn–N bonds longer than 2.39 Å are associated with antitumour activity. On this basis, [SnBu2(pir)]n should be active. Analysis of the shape determining angles using the approach of Reedijk and coworkers 7 yields t ((a 2 b)/60) values of 0.01 and 0.13 for Sn(1) and Sn(2) respectively (t = 0.0 and 1.0 for SPY and TBPY geometries respectively).The metal coordination geometry is therefore described as SPY with the N(2) and N(5) occupying the apical positions for Sn(1) and Sn(2) respectively. The donors N(2) and N(5) are chosen as apices by the simple criterion that neither should be any of the four donor atoms which define the two largest angles, a and b.7 The coordinated part of the ligand is made of three rings, one heterocyclic (I) and two chelates (II and III).The dihedral angles between the planes of the rings I and II, II and III and I and III are 1.5(2), 3.1(2), 4.4(2) and 3.2(2), 5.2(1), 8.0(2)8 for Sn(1) and Sn(2) respectively, indicating that the ligand as a whole deviates from planarity, the largest deviations arising Fig. 2 Packing diagram of the complex [SnBu2(pir)]n viewed along the b axis of the unit cell, showing intra- and inter-molecular hydrogen bonds.from the expected puckering of the sulfonamide rings which contain the pyramidal saturated N atoms, N(3) and N(6). The plane (I) of the first molecule Sn(1) is tilted by 77.92(19)8 with respect to the plane (I) of the second one Sn(2). The di-anionic, tridentate ligand has a EZZ configuration about the bonds C(5)–N(2), N(2)–C(6) and C(6)–C(7) and the corresponding bonds in molecule (2). This type of ligand configuration was found in the ethanolamine salt of piroxicam1b and diVers from the ZZZ isomer only by a 1808 rotation of the pyridyl ring providing an additional internal hydrogen bond of piroxicam.A molecular mechanics analysis 2c showed that the ZZZ con- figuration is more stable than the EZZ one, the deprotonation of amide nitrogen being one of the principal eVects which favour EZZ. The negative charge of the deprotonated amide is delocalized over the three atom fragment C(6)–N(2)–C(5). This is confirmed by an elongation of the C(6)–N(2) bond to 1.375(5) Å and an elongation of the N(2)–C(5) bond to 1.389(5) Å.The bond distances of the five-atom fragment O(1)–C(8)– C(7)–C(6)–O(2) are consistent with the neutral isomer of piroxicam.1c Large thermal parameters are observed in the last two C atoms of the butyl chains; this is considered to arise from disorder in the conformation. Molecules of the same numbering, related by the 21 symmetry axis, are joined into chains by intermolecular bonds between tin and the neighbouring ketonic oxygen atom, with distances Sn(1) ? ? ? O(2)i 3.019(4) and Sn(2) ? ? ? O(6)ii611(2) Å respectively.The range of intermolecular distances, Sn ? ? ?O of 2.61–3.02 Å have been confidently reported for intramolecular bonds, indicate Sn–O bonding.6b Other close interactions, which may cross-link the chains and ensure crystal cohesion, include the possibility of C–H ? ? ? O and C–H ? ? ?p hydrogen bonds.8a These interactions are listed in Table 1 and are shown in the packing diagram in Fig. 2. The isolated molecules of Sn(1) or Sn(2) are arranged in polymers in a head to tail fashion with a stacking of alternate parallel chains. Crystal cohesion is ensured by the hydrogen bonds in and between the two chains. The monomers of Sn(1) are linked through intermolecular hydrogen bonds of C–H? ? ? O type,8a O(3)axial ? ? ? H–C(1) and O(3)axial ? ? ? H– C(20), while the monomers of Sn(2) are linked through O(8)axial ? ? ? H–C(43).Each polymer Sn(1)n is hydrogen bonded to two neighbouring chains of Sn(2)n by C(36)– H? ? ? O(3)axial and C(38)–H ? ? ? O(4)eq respectively, leading to the formation of corrugated layers which are directed along the ac diagonal of the unit cell. Further, C–H ? ? ?p interactions 8b and intramolecular bonds stabilize this structure.J. Chem. Soc., Dalton Trans., 1999, 663–666 665 Although it is remarkable that there are so many contacts, and of so many diVerent types, the interactions themselves are consistent with known guidelines for hydrogen bond formation. 8c In this case molecular recognition of the hydrogen bonds leads to aggregation and a supramolecular assembly. The concentration protonation constants of piroxicam, Ka1 and Ka2, were determined§ and the 95% confidence limits of their logarithms were found to be equal to 5.61 ± 0.01 and 1.97 ± 0.01 (n = 7) with relative standard deviations 0.16% and 0.64%, respectively. The low solubility of piroxicam and its low Ka2 value is the reason for using spectrophotometry to find the protonation constants of the molecule.In aqueous solutions with pH values between 1 and 12 only three independent species of piroxicam (Hpir2, H2pir and H3pir1) become visible as shown by the absorption spectra in Fig. 3. Acknowledgements D. K. D. thanks HELP EPE for the generous gift of piroxicam and J. R. M. acknowledges the use of the EPSRC’s Chemical Database Service at Daresbury.Notes and references † A suspension of H2pir (0.166 g, 0.5 mmol) in methanol (6 cm3) was treated with a standard aqueous 0.1 mol dm23 KOH solution (1 cm3, 1.0 mmol). The resulting colourless solution was stirred while a solution of SnBu2Cl2 (0.152 g, 0.5 mmol) in methanol (6 cm3) was added to give a colourless solution. A quantity of distilled water was added (10 cm3) and the reaction mixture was stirred for 15 min. The white powder was filtered oV, washed with 2–3 ml of cold distilled water and dried in vacuo over silica gel.Crystals of [SnBu2(pir)]n suitable for X-ray analysis were obtained by slow evaporation of a fresh MeOH–MeCN solution. Anal. Calc. for SnC23H29N3O4S: C, 49.14; H, 5.19; O, 11.38; N, 7.47; S, 5.70. Found: C, 49.95; H, 5.00; O, 11.40; N, 7.94; S, 5.66%. IR (–CO– NH–) n(C]] O) 1590s, n(C]] N) 1522s, n(SO2)as 1340s, n(SO2)sym 1180s. Fig. 3 (a) Absorption spectra for piroxicam at 25 8C in the high pH region, where the species Hpir2 (lmax = 356 nm) and H2pir (lmax = 361 nm) are present; (b) absorption spectra for piroxicam at 25 8C in the low pH region, where the species H2pir (lmax = 361 nm) and H3pir1 (lmax = 335 nm) are present.‡ Crystal data for C23H29N3O4SSn: M = 562.28, monoclinic, space group P21/n (no. 14), a = 19.696(7), b = 12.650(3), c = 21.066(7) Å, b = 106.010(10)8, U = 5045(5) Å3, Z = 8, T = 291 K, Dc = 1.480 g cm23, crystal dimensions 0.30 × 0.41 × 0.89, F(000) = 2296, Mo-Ka radiation, l = 0.71073 Å, m(Mo-Ka) = 1.13 mm21. 10854 unique reflections were measured (Rint = 0.013), 8169 observed (Fo > 3.0s(Fo)) with R and Rw 0.037 and 0.050 respectively. CCDC reference number 186/1319. See http://www.rsc.org/suppdata/dt/1999/663/ for crystallographic files in .cif format. § Aqueous piroxicam solutions of constant ionic strength were used to determine protonation constants. All solutions were prepared using distilled water obtained from a borosilicate autostill (Jencons Ltd.). 5 × 1025 M working piroxicam solutions having diVerent hydrogen ion concentrations and constant ionic strength (m = 0.1) were then prepared using standard HCl or KOH and KCl solutions; all measurements were made at 25 8C and the absorption spectra were collected in the range 240–440 nm. A rearrangement9 of the well known equation Ka1 = [H3O1] e(H2pir) 2 eo eo 2 e(Hpir2) (1) or Ka2 = [H3O1] e(H3pir1) 2 eo eo 2 e(H2pir) (2) (where eo, e(H2pir) and e(H3pir1) are the molar absorption coeYcients of the observed solution, negative ionized, molecular and positive charged species, respectively) in the form of eo = e(H2pir) 2 Ka1 eo 2 e(Hpir2) [H3O1] (3) or eo = e(H3pir1) 2 Ka2 eo 2 e(H2pir) [H3O1] (4) was used to determine Ka1 and e(Hpir2) values from (3) as well as Ka2 and e(H3pir1) values from (4). The e(Hpir2) value can be securely obtained from the absorption spectra of piroxicam that completely coincide with each other with pH > 8.By making use of eqn.(1) and (2) only relatively low errors accompany the e(H2pir) and Ka1, but much larger errors result for the e(H3pir1) and Ka2 values, that have to be determined in very strongly acid solutions. 1 (a) G. A. Ando and J. G. Lombardino, Eur. J. Reumatol. Inflam., 1983, 6, 3; (b) J. Bordner, P. D. Hammen and E. B. Whipple, J. Am. Chem. Soc., 1989, 111, 6572; (c) J. Bordner, J. A. Richards, P. Weeks and E .B. Whipple, Acta Crystallogr., Sect. C, 1984, 40, 989. 2 (a) R.Cini, J. Chem. Soc., Dalton Trans., 1996, 111; (b) D. Di Leo, F. Berrettini and R. Cini, J. Chem. Soc., Dalton Trans., 1998, 1993; (c) R. Cini, R. Basosi, A. Donati, C. Rossi, L. Sabadini, L. Rollo, S. Lorenzini, R. Gelli and R. Marcolongo, Met. Bas. Drugs, 1995, 2, 43; (d ) R. Cini, G. Giorgi, A. Cinquantini, C. Rossi and M. Sabat, Inorg. Chem., 1990, 29, 5197. 3 (a) C. J. Evans and S. Karpel, Organotin Compounds in Modern Technology, J. Organomet. Chem. Library vol. 16, Elsevier, New York, 1985; (b) A. J. Crow, in Metal-Based Antitumour Drugs, ed. M. Gielen, Freund, London, 1989, vol. 1, pp. 103–149. 4 (a) P. Tauridou, U. Russo, G. Valle and D. Kovala-Demertzi, J. Organomet. Chem., 1993, 44, C16; (b) D. Kovala-Demertzi, P. Tauridou, J. M. Tsangaris and A. Moukarika, Main Group Met. Chem., 1993, 16, 315; (c) P. Tauridou, U. Russo, D. Marton, G. Valle and D. Kovala-Demertzi, Inorg. Chim. Acta, 1995, 231, 139; (d ) D. Kovala- Demertzi, P. Tauridou, A.Moukarika, J. M. Tsangaris, C. P. Raptopoulou and A. Terzis, J. Chem. Soc., Dalton Trans., 1995, 123; (e) D. Kovala-Demertzi, P. Tauridou, U. Russo and M. Gielen, Inorg. Chim. Acta, 1995, 239, 177; ( f ) N. Kourkoumelis, A. Hatzidimitriou and D. Kovala-Demertzi, J. Organomet. Chem., 1996, 514, 163. 5 (a) D. Kovala-Demertzi, A. Theodorou, M. A. Demertzis, C. Raptopoulou and A. Terzis, J. Inorg. Biochem., 1997, 6, 151; (b) D. Kovala-Demertzi, D. Mentzafos and A. Terzis, Polyhedron, 1993, 11, 1361; (c) D. Kovala-Demertzi, S. K. Hadjikakou, M. A. Demertzis and Y. Deligiannakis, J. Inorg. Biochem., 1998, 69, 223; (d) M. Konstandinidou, A. Kourounakis, M. Yiangou, L. Hadjipetrou, D. Kovala-Demertzi, S. K. Hadjikakou and M. A. Demertzis, J. Inorg. Biochem., 1998, 70, 63. 6 (a) K. C. Molloy, T. G. Purcell, K. Quill and I. W. Nowell, J. Organomet. Chem., 1984, 267, 237; (b) A. R. Forrester, S. J. Garden, R. A. Howie and J. L. Wardell, J. Chem. Soc., Dalton Trans.,666 J. Chem. Soc., Dalton Trans., 1999, 663–666 1992, 2615; (c) A. J. Crow, P. J. Smith, C. J. Cardin, H. E. Parge and F. E. Smith, Canc. Lett., 1984, 24, 45. 7 A. Addison, R. T. Nageswara, J. Reedijk, J. Van Rijn and G. C. Verschoor, J. Chem. Soc., Dalton Trans., 1984, 1349. 8 (a) T. Steiner, B. Lutz, J. van der Maas, A. M. M. Schreurs, J. Kroon and M. Tamm, Chem. Commun., 1998, 171; (b) T. Steiner, M. Tamm, A. Grzegorzewski, N. Schulte, N. Veldman, A. M. M. Schreurs, J. Kroon, J. van der Maas and B. Lutz, J. Chem. Soc., Perkin Trans. 2, 1996, 2441; (c) M. C. Etter, Acc. Chem. Res., 1990, 23, 120; G. R. Desiraju, Acc. Chem. Res., 1991, 24, 290. 9 R.W. Ramette, Chemical Equilibrium and Analysis, Addison-Wesley Publishing Company, London, 1981, p. 432. Communication 9/00227H