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Inorganica Chimica Acta 362 (2009) 811–819 www.elsevier.com/locate/ica
Photoactive trans ammine/amine diazido platinum(IV) complexes Fiona S. Mackay a, Stephen A. Moggach a, Anna Collins a, Simon Parsons a, Peter J. Sadler a,b,* a b
School of Chemistry, University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ, UK Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK Received 30 January 2008; accepted 18 February 2008 Available online 4 March 2008 Dedicated to Professor Bernhard Lippert.
Abstract The synthesis and characterisation of eight new octahedral PtIV complexes of the type trans,trans,trans-[Pt(N3)2(OH)2(NH3)(Am)] where Am = methylamine (2), ethylamine (4), thiazole (6), 2-picoline (8), 3-picoline (10), 4-picoline (12), cyclohexylamine (14), and quinoline (16) are reported, including the X-ray crystal structures of complexes 2, 8, and 14 as well as that of two of the precursor PtII complexes (trans-[Pt(N3)2(NH3)(methylamine)] (1) and trans-[Pt(N3)2(NH3)(cyclohexylamine)] (13)). Irradiation with UVA light rapidly induces loss in intensity of the azide-to-PtIV charge-transfer bands and gives rise to photoreduction of platinum. These complexes have potential for use as photoactivated anticancer agents. Ó 2008 Elsevier B.V. All rights reserved. Keywords: Platinum; Azide; Photochemistry; Crystal structure; Anticancer
1. Introduction Square-planar platinum(II) diam(m)ine complexes such as cisplatin and carboplatin are successful anticancer drugs. However their use is sometimes accompanied by side-effects and by the development of cellular resistance. We are studying relatively inert PtIV complexes which might be non-toxic and capable of activation specifically in cancer cells by the use of (laser) light [1]. Suitable complexes contain intense ligand-to-metal charge-transfer bands. Iodo PtIV complexes were early candidates [2] but these proved to be too readily reduced by glutathione [3], the abundant intracellular tripeptide containing a thiol group. Our recent work [4] has shown that PtIV diazido complexes are much more stable towards reduction by glutathione and interestingly that both cis and trans complexes * Corresponding author. Address: Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK. Tel.: +44 24 76523818; fax: +44 24 76523819. E-mail address:
[email protected] (P.J. Sadler).
0020-1693/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.ica.2008.02.039
can exhibit cancer cell cytotoxicity upon photoactivation [5], with the potential to be much more potent than clinically-used cisplatin under conditions of short treatment times [6]. Moreover their mechanisms of cytotoxicity appear to be novel [7]. The work reported here is part of our investigation into the effect of variations in the amine ligand in trans diazido dihydroxo mixed-ammine/amine PtIV complexes on photoactivation. The synthesis and characterisation of eight new complexes is described (Fig. 1). 2. Experimental 2.1. Materials and instrumentation Silver nitrate, methylamine (40% solution, MeNH2), ethylamine (70% solution, EtNH2), thiazole (tz), 2-picoline (2-pic), 3-picoline (3-pic), 4-picoline (4-pic), cyclohexylamine (cha), acetone-d6, D2O and the platinum standard solution for ICP-OES were purchased from Aldrich. NaN3 and HCl (37%) were from Fisher. K2[PtCl4] from
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H2 OH N N3
H2 OH N N3
Pt
Pt
N3
OH
NH3
N3
2
OH
NH3
4
Spectrometer (Optima 5300 DV) calibrated with standard solutions (0.1–100 ppm). The ultraviolet light source used for photochemical studies was a UV lamp (2 15 W tubes, model VL215 L; Merck Eurolab, Poole, UK) which operates at 365 nm. Samples were irradiated at a distance of 10 cm from the lamp, where the power is 1.5 mW/cm2, this power delivers a dose of 10 J/cm2 over 2 h.
S N
OH Pt
N3
OH
N
N3
N3
2.2. Syntheses
NH3
Caution. No problems were encountered during this work, however heavy metal azides are known to be shock sensitive detonators, therefore it is essential that all platinum azide compounds are handled with care.
Pt
H3C NH3
OH
N3
6
OH
8 H3C
H3C
N
OH
N3
N
Pt N3
OH
NH3
N3
N
NH3
OH
N3
Pt
Pt
14
OH
12
H2 OH N N3
OH
N3
Pt
10
N3
OH
NH3
N3
OH
NH3
2.2.1. trans-[Pt(N3)2(NH3)(methylamine)] (1) trans-[PtCl2(NH3)(methylamine)] (75.9 mg, 0.242 mmol) was suspended in H2O (25 mL) and AgNO3 (1.95 mol equiv., 80.1 mg) added. The reaction was stirred in the dark at 333 K for 24 h then filtered with an inorganic membrane filter (Whatman, Anotop 10, 0.02 lm). NaN3 (0.968 mmol, 63.0 mg) was added and the yellow solution was stirred for 4 h, then reduced to dryness. Ice-cold H2O was added and the product filtered, washed with ethanol and diethyl ether then dried under vacuum. Crystals suitable for X-ray crystal structure determination were grown from H2O at 277 K. Yield: 77.6%. 1H NMR (acetone-d6): d 4.20 (s, NH2, 2H), 3.70 (s, NH3, 3H), 2.45 (t, CH3, 1J(CH3–NH2) 6.5 Hz, 3H).
16
Fig. 1. Structures of some of the complexes synthesized in this study.
Alfa Aesar, NH4Cl from BDH and H2O2 from Sigma. trans-[PtCl2(NH3)(methylamine)], trans-[PtCl2(NH3)(ethylamine)] and trans-[PtCl2(NH3)(cyclohexylamine)] were prepared by the literature method [8]. NMR spectra were recorded at 298 K on a Bruker DMX500 spectrometer (1H: 500.13 MHz). Samples were prepared in acetone-d6 or 90% H2O/10% D2O with 1H chemical shifts referenced internally to dioxane (d 3.764 ppm). All data were processed with XWIN-NMR software (Version 3.6, Bruker, UK Ltd.). Positive ion electrospray mass spectrometry (ESI-MS) was performed on a Platform II Mass Spectrometer (Micromass, Manchester, UK). The capillary voltage was 3.5 V, and the cone voltage typically varied between 5 and 30 V. All samples were prepared in water. Data was acquired and processed with MASS LYNX software (Version 2.5). UV–Vis electronic absorption spectra were recorded on a Varian Cary 300 UV–Vis spectrophotometer in 1 cm path-length cuvettes. All spectra were recorded in water and referenced to solvent alone. Data were processed with Microcal Origin 5.0. The platinum content of aqueous solutions was determined by ICP-OES with a Perkin Elmer Optimal Emission
2.2.2. trans,trans,trans-[Pt(N3)2(OH)2(NH3) (methylamine)] (2) trans-[Pt(N3)2(NH3)(methylamine)] (59.8 mg, 0.183 mmol) was suspended in H2O (20 mL) and H2O2 (0.732 mmol, 0.083 mL) added. After stirring in the dark at 298 K for 1 h the solvent was removed. Ethanol was added to precipitate the product which was filtered, washed sparingly with ice cold water, ethanol and diethyl ether then dried under vacuum. Crystals suitable for X-ray structure determination were grown from water at 298 K. Yield: 81.3%. 1H NMR (90% H2O/10% D2O): d 2.36 (septet, CH3, 3H). ESI-MS: obs. 362.1 m/z, calc. for [PtCN8O2H11]+ 362.2 m/z. UV–Vis: kmax = 286 nm (e = 19,384 M1 cm1). 2.2.3. trans-[Pt(N3)2(NH3)(ethylamine)] (3) trans-[Pt(N3)2(NH3)(ethylamine)] was prepared by the same method as complex 1. Yield: 80.3%. 1H NMR (acetone-d6): d 4.20 (s, 14NH2, 2H), 3.70 (d, 15NH3, 1 15 J( N–1H) 60.0 Hz, 3H), 2.77 (sextet, CH2, 2H), 1.32 (t, CH3, 1J(CH2-CH3) 6.0 Hz, 3H). 2.2.4. trans,trans,trans-[Pt(N3)2(OH)2(NH3) (ethylamine)] (4) trans,trans,trans-[Pt(N3)2(OH)2(NH3)(ethylamine)] was prepared by the same method as complex 2. Yield: 72.7%. ESI-MS: obs. 375.9 m/z, calc. for [PtC2N8O2H13]+
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376.2 m/z. UV–Vis: kmax = 285 nm (16,516 M1 cm1). 1H NMR (90% H2O/10% D2O): 5.71 (s, NH2, 2H), 2.89 (sextet, CH2, 2H), 1.33 (t, CH3, 1J(CH2-CH3) 7.3 Hz, 3H). 2.2.5. trans-[PtCl2(NH3)(thiazole)] Cisplatin (81.8 mg, 0.273 mmol) was suspended in H2O (2 mL) and thiazole (tz, 0.819 mmol, 0.058 mL) added. The reaction was stirred at 343 K for 2 h, brought to reflux, then cooled. HCl (3.276 mmol, 0.273 mL) was added and the solution stirred at 378 K for 6 h. After cooling to room temperature the product was further precipitated by cooling on ice, then filtered, washed with water, ethanol and diethyl ether and dried under vacuum. Yield: 77.3%. 1H NMR (acetone-d6: d 9.53 (dd, H-2, 2J2,4 0.9 Hz, 2J2,5 2.4 Hz, 1H), 8.29 (dd, H-4, 1J4,5 3.7 Hz, 1H), 7.81 (dd, H-5, 1H), 3.81 (s, NH3, 3H). 2.2.6. trans-[Pt(N3)2(NH3)(thiazole)] (5) trans-[Pt(N3)2(NH3)(thiazole)] was prepared by the same method as complex 1 except the reaction was stirred for 24 h after adding NaN3. Yield: 77.4%. 1H NMR (acetone-d6): d 9.42 (dd, H-2, 2J2,4 0.9 Hz, 2J2,5 2.4 Hz, 1H), 8.12 (dd, H-4, 1J4,5 3.7 Hz, 1H), 7.95 (dd, H-5, 1H), 4.07 (s, NH3, 3H). 2.2.7. trans,trans,trans-[Pt(N3)2(OH)2(NH3)(thiazole)] (6) trans-[Pt(N3)2(NH3)(thiazole)] (31.7 mg, 0.083 mmol) was suspended in H2O (200 mL) and H2O2 (30%, 0.332 mmol, 0.034 mL) added. After stirring in the dark at room temperature for 24 h, the volume was reduced to 15 mL and filtered. All solvent was then removed and acetone added to precipitate the product. The yellow solid was collected by filtration, washed sparingly with ice-cold water, ethanol and diethyl ether, and dried under vacuum. Yield: 71.2%. ESI-MS: obs. 415.9 m/z, calc. for [PtC3N8O2H9S]+ 416.3 m/z. UV–Vis: kmax = 289 nm (15,234 M1 cm1), 236 nm (8,630 M1 cm1). 1H NMR (90% H2O/10% D2O): d 9.51 (dd, H-2, 2J2,4 1.0 Hz, 2J2,5 2.4 Hz, 1H), 8.24 (dd, H-4, 1J4,5 3.6 Hz, 1H), 8.04 (dd, H-5, 1H). 2.2.8. trans-[PtCl2(NH3)(2-picoline)] Cisplatin (0.103 g, 0.343 mmol) was suspended in H2O (1 mL) and 2-picoline (1.372 mmol, 0.1277 g) added. The reaction was stirred at 348 K for 2.5 h and then refluxed for 30 min. The solvent was removed and HCl (2.7 M, 1.5 mL) added. The solution was stirred at 378 K for 5 h then cooled to 277 K for 24 h and filtered. The filtrate was returned to heat at 378 K for a further 6 h and then cooled to 277 K and filtered again. The two batches of yellow solid were combined and washed with water, ethanol and diethyl ether and dried under vacuum. Yield: 68.5%. 1 H NMR (acetone-d6): d 8.80 (d, H-6, 1J 5.7 Hz, 1H), 7.78 (td, H-4, 1J 7.7 Hz, 2J 1.5 Hz, 1H), 7.43 (d, H-3, 1J 7.7 Hz, 1H), 7.27 (t, H-5, 1H), 3.68 (s, NH3, 1J(15N–1H) 72.0 Hz, 1H), 3.13(s, CH3, 3H).
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2.2.9. trans-[Pt(N3)2(NH3)(2-picoline)] (7) trans-[PtCl2(NH3)(2-picoline)] (87.3 mg, 0.232 mmol) was suspended in H2O (50 mL) and DMF (0.5 mL). AgNO3 (1.95 mol equiv., 76.9 mg) was added and the reaction stirred in the dark at 333 K for 24 h. All the solvent was removed and the solid redissolved in H2O (50 mL). NaN3 (0.928 mmol, 60.3 mg) was added and the solution stirred for 4 h, the volume was then reduced to 3 mL and the bright yellow solid filtered, washed with water, ethanol and diethyl ether and dried under vacuum. Yield: 90.0%. 1 H NMR (acetone-d6): d 8.95 (d, H-6, 1J 5.9 Hz, 1H), 7.89 (td, H-4, 1J 7.7 Hz, 2J 1.7 Hz, 1H), 7.59 (d, H-3, 1H) 7.42 (t, H-5, 1H), 3.74 (s, NH3, 1J(15N–1H) 72.0 Hz, 3H), 3.20(s, CH3, 3H). 2.2.10. trans,trans,trans-[Pt(N3)2(OH)2(NH3) (2-picoline)] (8) trans,trans,trans-[Pt(N3)2(OH)2(NH3)(2-picoline)] was prepared by the same method as complex 6. Crystals suitable for X-ray structure determination were grown from H2O at 277 K. Yield: 73.4%. ESI-MS: obs. 446.6 m/z, calc. for [PtC6N8O2H12Na]+ 446.2 m/z. UV–Vis: kmax = 292 nm (17,888 M1 cm1), 276 nm (sh, 14,500 M1 cm1). 1H NMR (90% H2O/10% D2O): d 8.66 (d, H-6, 1J 6.4 Hz, 1H), 8.04 (td, H-4, 1J 7.7 Hz, 1H), 7.54 (d, H-3, 1H) 7.51 (t, H-5, 1H), 3.06 (d, CH3, 3H). 2.2.11. trans-[Pt(N3)2(NH3)(3-picoline)] (9) trans-[PtCl2(NH3)(3-picoline)] and trans-[Pt(N3)2(NH3)(3-picoline)] were prepared by the same method as the analogous 2-picoline complexes 9 and 10. Yield: 73.2%. 1H NMR (acetone-d6): d 8.59 (s, H-2, 1H), 8.57 (d, H-6, 1J5,6 5.9 Hz, 1H), 7.88 (d, H-4, 1J4,5 7.9 Hz, 1H), 7.46 (dd, H5, 1H), 3.95 (s, NH3, 3H), 2.42 (s, CH3, 3H). 2.2.12. trans,trans,trans-[Pt(N3)2(OH)2(NH3) (3-picoline)] (10) trans,trans,trans-[Pt(N3)2(OH)2(NH3)(3-picoline)] was prepared by the same method as complex 6. Yield: 81.4%. ESI-MS: obs. 424.0 m/z, calc. for [PtC6N8O2H13]+ 424.2 m/z. UV–Vis: kmax = 289 nm (13,575 M1 cm1). 1 H NMR (90% H2O/10% D2O): d 8.53 (s, H-2, 1H), 8.51 (d, H-6, 1H), 8.07 (d, H-4, 1J4,5 7.9 Hz, 1H), 7.65 (dd, H-5, 1H), 2.50 (s, CH3, 3H). 2.2.13. trans-[Pt(N3)2(NH3)(4-picoline)] (11) trans-[PtCl2(NH3)(4-picoline)] and trans-[Pt(N3)2(NH3)(4-picoline)] were prepared by the same method as the analogous 2-picoline complexes 9 and 10. Yield: 84.2%. 1H NMR (acetone-d6): d 8.57 (d, H-2, H-6, 1J(2,63,5) 6.6 Hz, 2H), 7.41 (d, H-3, H-5, 2H), 3.94 (s, NH3, 3H), 2.46 (s, CH3, 3H). 2.2.14. trans,trans,trans-[Pt(N3)2(OH)2(NH3) (4-picoline)] (12) trans,trans,trans-[Pt(N3)2(OH)2(NH3)(4-picoline)] was prepared by the same method as complex 6. Yield:
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68.2%. ESI-MS: obs. 424.0 m/z, calc. for [PtC6N8O2H13]+ 424.2 m/z. UV–Vis: kmax = 289 nm (14 318 M1 cm1). 1H NMR (90% H2O/10% D2O): d 8.51 (d, H-2, H-6, 1 J(2,63,5) 6.8 Hz, 2H), 7.60 (d, H-3, H-5, 2H), 2.58 (s, CH3, 3H). 2.2.15. trans-[Pt(N3)2(NH3)(cyclohexylamine)] (13) trans-[PtCl2(NH3)(cyclohexylamine)] (7.97 mg, 0.021 mmol) dissolved in DMF (2 mL) was added to a solution of NaN3 (0.044 mmol, 2.87 mg) in methanol. After stirring at 298 K for 2 d the volume was reduced and crystals suitable for X-ray structure determination were grown at 298 K. 1H NMR (acetone-d6): d 4.18 (s, NH2), 3.75 (s, NH3), 2.35 (m, H-1, 1H), 1.76 (m, H-2a,5a, 2H), 1.61 (d, H-3a,5a, 2H), 1.33 (t, H4a, 1H), 1.16 (m, H-2b,3b,5b,6b, 4H), 0.88 (m, H-4b, 1H). a are equatorial, b are axial hydrogens. 2.2.16. trans,trans,trans-[Pt(N3)2(OH)2(NH3) (cyclohexylamine)] (14) trans-[Pt(N3)2(NH3)(cyclohexylamine)] (5.0 mg, 0.013 mmol) was suspended in H2O (2 mL) and H2O2 (0.500 mmol, 51 lL) was added. After stirring at 298 K for 12 h the volume was reduced and crystals suitable for X-ray structure determination were grown at 277 K. ESIMS: obs. 452.1 m/z, calc. for [PtC6N8O2H18Na]+ 452.2 m/z. 1H NMR (90% H2O/10% D2O): 2.94 (m, H-1, 1H), 2.14 (m, H-2a,5a, 2H), 1.76 (d, H-3a,5a, 2H), 1.63 (t, H4a, 1H), 1.35 (m, H-2b,3b,5b,6b, 4H), 1.18 (m, H-4b, 1H). a are equatorial, b are axial hydrogens. 2.2.17. trans-[PtCl2(NH3)(quinoline)] Cisplatin (48.0 mg, 0.16 mmol) was suspended in H2O (2 mL) and quinoline added (0.32 mmol, 37.8 lL). After stirring at 378 K for 1 h a pale yellow solution was present and no precipitate appeared on cooling. HCl (1.92 mmol, 0.16 mL) was added and the solution stirred at 378 K for 5 h, 368 K for 12 h and then 378 K again for 5 h. The reaction was cooled on ice for 1 h and filtered to collect the yellow solid which was washed with water, ethanol and ether and dried under vacuum. Yield: 64.6%. 1H NMR (acetone-d6): d 9.80 (d, H8, 3J7,8 8.8 Hz, 1H), 9.29 (dd, H2, 3J2,3 5.3 Hz, 1H), 8.55 (d, H4, 3 J3,4 8.1 Hz, 1H), 8.06 (d, H5, 3J5,6 8.3 Hz, 1H), 7.96 (dd, H7, 3J6,7 6.8 Hz, 1H), 7.74 (dd, H6, 1H), 7.59 (dd, H3, 1H), 3.86 (br s, NH3, 3H). 2.2.18. trans-[Pt(N3)2(NH3)(quinoline)] (15) trans-[PtCl2(NH3)(quinoline)] (30.6 mg, 0.0743 mmol) and AgNO3 (25.1 mg, 0.148 mmol) were stirred in H2O (30 mL) and DMF (0.3 mL) at 333 K for 12 h. The AgCl precipitate was filtered off with an inorganic membrane filter (Whatman, Anotop 10, 0.02 lm) and NaN3 (48.3 mg, 0.743 mmol) added. After stirring at 298 K for 12 h the pale yellow was collected by filtration, washed with water, ethanol and ether and dried under vacuum. Yield: 81.7%. 1 H NMR (acetone-d6): d 9.82 (d, H8, 3J7,8 8.8 Hz, 1H),
9.43 (dd, H2, 3J2,3 5.3 Hz, 1H), 8.65 (d, H4, 3J3,4 8.1 Hz, 1H), 8.14 (d, H5, 3J5,6 8.3 Hz, 1H), 8.07 (dd, H7, 3J6,7 6.8 Hz, 1H), 7.81 (dd, H6, 1H), 7.73 (dd, H3, 1H), 3.91 (br s, NH3, 3H). 2.2.19. trans,trans,trans[Pt(N3)2(OH)2(NH3)(quinoline)] (16) trans-[Pt(N3)2(NH3)(quinoline)] (12.9 mg, 0.03 mmol) was placed in H2O (30 mL) and H2O2 (40 mol equiv., 124 lL) added. After stirring at 323 K for 5 h, the yellow solution was filtered through an inorganic membrane filter (Whatman, Anotop 10, 0.02 lm) and then the solvent removed. Acetone was added, the solid was collected by filtration and washed with water, ethanol and ether and dried under vacuum. Yield: 68.8%. 1H NMR (D2O): d 9.82 (d, H8, 3J7,8 8.8 Hz, 1H), 9.43 (dd, H2, 3J2,3 5.3 Hz, 1H), 8.65 (d, H4, 3J3,4 8.1 Hz, 1H), 8.14 (d, H5, 3J5,6 8.3 Hz, 1H), 8.07 (dd, H7, 3J6,7 6.8 Hz, 1H), 7.81 (dd, H6, 1H), 7.73 (dd, H3, 1H), 3.91 (br s, NH3, 3H). ESIMS: [M+Na]+ 482.14 m/z. UV–Vis: 233 nm, 294 nm, 316 nm (sh). 2.3. X-ray structure determination Diffraction data were collected with Mo Ka radiation ˚ ) on a Bruker Smart Apex CCD diffractom(k = 0.71073 A eter equipped with an Oxford Cryosystems low-temperature device operating at 150 K. Data were corrected for absorption using the program SADABS [9]. The crystal structures of 1, 8, and 13 were solved by Patterson methods (DIRDIF [10]), and 2 and 14 by direct methods (SHELXS [11] or SIR92 [12]). All structures were refined against F2 using SHELXL [13] or CRYSTALS [14], and the H-atoms placed in geometrically calculated positions. NH3 and CH3 groups in 1, 8, and 13 were treated as rotating rigid groups. In 8, the 2-picoline ligand is disordered by a 180° rotation about the Pt–N bond. Similarity restraints were applied to the geometry of the two part-weight components of the disorder. The occupancies were refined. Only fulloccupancy atoms were refined with anisotropic displacement parameters. Analysis of the poorly-fitting data [15] showed that the crystal of 14 was twinned via a twofold rotation about [1 0 0], the twin law being expressed by the matrix 1 0 1 0 0 C B @ 0:758 1 0 A: 0:878 0 1 The twin scale factor refined to 0.5482(13). 3. Results and discussion Eight novel PtIV diazido complexes, with general structure trans,trans,trans-[Pt(N3)2(OH)2(NH3)(Am)], have been synthesised and fully characterised.
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3.1. Synthesis and characterisation The PtII dichloro complexes (trans-[PtCl2(NH3)(Am)], Am = MeNH2, EtNH2, tz, 2-pic, 3-pic, 4-pic, cha and quin) were all prepared from cisplatin by replacing the chloride ligands with the appropriate Am ligand followed by addition of HCl. Due to the trans effect, the chlorides bind to platinum in a trans position. Conversion of the chloride ligands to azides was generally carried out by removing the chlorides with silver nitrate, and then adding azide in the form of sodium azide, except for complex 13, the reasons for this are discussed later. Hydroxyl ligands were added to the PtII diazido complexes in the axial position by oxidation of aqueous solutions with hydrogen peroxide. trans,trans,trans-[Pt(N3)2(OH)2(NH3)(MeNH2)] (2) and trans,trans,trans-[Pt(N3)2(OH)2(NH3)(EtNH2)] (4) were both prepared in high yields by the same method. Their electronic absorbance spectra closely resemble that of trans,trans,trans-[Pt(N3)2(OH)2(NH3)2] [5]; the kmax for all three complexes is 285–286 nm. The aqueous solubilities of 2 and 4 are significantly increased by the incorporation of the methylamine and ethylamine ligands. The synthesis of trans-[PtCl2(NH3)(tz)] has been described previously [16], however the method described here produced high yields of pure product without the need for recrystallisation. It was necessary to carry out the oxidation of trans-[Pt(N3)2(NH3)(tz)] (5) in a large volume of water, this is due to its aqueous insolubility. The kmax of trans,trans,trans-[Pt(N3)2(OH)2(NH3)(tz)] (6) is shifted slightly towards the visible region, and a separate absorbance due to the internal transitions of the thiazole ring can be seen at 236 nm. The X-ray crystal structures of trans-[PtCl2(tz)2] and trans[PtCl2(NH3)(tz)] have been determined by Farrell et al. [16,17]. In both cases platinum is bound to the nitrogen atom of thiazole. Although PtII is a soft metal centre and is known to have a high affinity for sulphur donors, calculations on the electronic structure of thiazole have shown that the net charge of the thioethertype sulphur is positive [17]. The negative charge resides on the nitrogen and it is therefore a much better donor to platinum. For this reason it is assumed that trans,trans, trans-[Pt(N3)2(OH)2(NH3)(tz)] also has thiazole bound through the nitrogen. trans-[PtCl2(NH3)(2-pic)] was prepared from cisplatin in a similar way to trans-[PtCl2(NH3)(tz)]. The silver nitrate step was carried out with a small amount of DMF added to help solubilise the hydrophobic PtII dichlorido species. In the electronic absorption spectrum, the LMCT (N3 ? Pt) band of trans,trans,trans-[Pt(N3)2(OH)2(NH3)(2-pic)] is at 292 nm, which is at a longer wavelength than any of the other PtIV azide compounds synthesised. Problems were encountered during the synthesis of trans[PtCl2(NH3)(cha)] and oxidation to PtIV was often observed. PtIV–NH protons were detected by 1H NMR spectroscopy in acetone-d6. Oxidation also occurred during conversion of the chloride ligands to azide ligands by the usual silver
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nitrate method, and therefore this reaction was carried out by direct substitution in DMF/methanol instead. 3.2. X-ray crystal structures The X-ray crystal structures of two PtII azide complexes (trans-[Pt(N3)2(NH3)(MeNH2)] (1) and trans-[Pt(N3)2(NH3)(cha)] (13)) were determined. ORTEP structures are depicted in Fig. 2 and crystal structure data can be found in Table 1. The X-ray structure of trans-[PtCl2(MeNH2)2] has been published [18], the bond lengths did not differ significantly from those of transplatin [19], and these am(m)ine bond lengths are also very similar to those of trans-[Pt(N3)2(NH3)(MeNH2)] (1) (Table 2). The geometry of 1 is square-planar and the angles are all very close to 90°. The azide bond lengths compare very well with other platinum azide compounds (PtII and PtIV) [5,20]. The Pt–N(a)– N(b) angles agreed well with the other PtII complexes, but were found to be significantly larger than those of the PtIV compounds (2, 8, and 14, Table 5, Fig. 3). This same difference is seen for the cis-diazido PtII and PtIV structures [20].
Fig. 2. X-ray crystal structures of PtII complexes (a) trans[Pt(N3)2(NH3)(MeNH2)] (1) and (b) trans-[Pt(N3)2(NH3)(cha)] (13) (50% probability ellipsoids).
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Table 1 Crystal structure data for the PtII diazido complexes [Pt(N3)2(NH3)(MeNH2)] (1) and trans-[Pt(N3)2(NH3)(cha)] (13) Empirical formula Formula weight Crystal size (mm) Crystal system Space group ˚) a (A ˚) b (A ˚) c (A a (°) b (°) c (°) Z Dcalc (mg/m3) l (mm1) F(0 0 0) h Range (°) Reflections collected Independent reflections ˚ 3) Volume (A Conventional R wR2
1
13
CH8N8Pt 327.24 0.28 0.16 0.10 monoclinic P21/c 13.4380(2) 7.65630(10) 6.99530(10) 90 96.7290(10) 90 4 3.041 19.572 592 3.05 to 30.35 13043 2117 714.756(17) 0.0197 0.0503
C6H16N8Pt 395.36 0.39 0.37 0.22 monoclinic P21/n 6.12230(10) 21.9394(5) 8.1404(2) 90 98.8660(10) 90 4 2.431 12.972 744 1.86 to 43.18 18880 6296 1080.35(4) 0.0329 0.0710
Table 2 ˚ ), and bond angles (°) for Selected bond lengths (A [Pt(N3)2(NH3)(MeNH2)] (1) and trans-[Pt(N3)2(NH3)(cha)] (13) 1 Pt–N(13) Pt–N(14) N(13)–N(23) N(23)–N(33) N(14)–N(24) N(24)–N(34) Pt–N(11) Pt–N(12) Pt–N(13)–N(23) N(13)–N(23)–N(33) Pt–N(14)–N(24) N(14)–N(24)–N(34) N(11)–Pt–N(12) N(13)–Pt–N(14) N(11)–Pt–N(14) N(14)–Pt–N(12) N(12)–Pt–N(13) N(13)–Pt–N(11) Pt–N(12)–C(22) N(13)–Pt–N(14)– N(24) N(14)–Pt–N(13)– N(23)
trans-
trans-
13 2.030(2) 2.027(2) 1.204(3) 1.152(3) 1.202(3) 1.155(3) 2.050(2) 2.051(2) 124.48(19) 173.80(3) 122.48(19) 174.5(3) 177.55(9) 178.95(9) 90.80(10) 91.61(11) 88.10(10) 89.51(10) 119.67(18) 44.2 149.1
Pt–N(13) Pt–N(12) N(13)–N(23) N(23)–N(33) N(12)–N(22) N(22)–N(32) Pt–N(1) Pt–N(11) Pt–N(13)–N(23) N(13)–N(23)–N(33) Pt–N(12)–N(22) N(12)–N(22)–N(32) N(11)–Pt–N(12) N(12)–Pt–N(1) N(1)–Pt–N(13) N(13)–Pt–(11) N(12)–Pt–N(13) N(11)–Pt–N(1) Pt–N(11)–C(21) N(13)–Pt–N(14)– N(24) N(14)–Pt–N(13)– N(23)
2.039(3) 2.041(3) 1.197(4) 1.150(4) 1.203(4) 1.146(5) 2.052(3) 2.056(2) 121.1(2) 175.7(3) 121.0(2) 174.7(3) 95.69(10) 84.99(11) 94.52(11) 84.80(11) 179.49(11) 178.42(10) 115.74(17) 175.4 2.97
The smaller Pt–N(a)–N(b) angle for PtIV complexes could be a result of intramolecular hydrogen bonding between the axial hydroxide hydrogen and the azide ligand. There is intermolecular hydrogen bonding in complex 1 between the am(m)ine hydrogens and the azide nitrogens. The azide bond lengths and angles of trans[Pt(N3)2(NH3)(cha)] (13) also compare well with other platinum azide structures [20]. However the geometry of 13 is
Table 3 Crystal structure data for the PtIV diazido complexes trans,trans,trans[Pt(N3)2(OH)2(NH3)(MeNH2)] (2), trans,trans,trans-[Pt(N3)2(OH)2(NH3)(2-pic)] (8) and trans,trans,trans-[Pt(N3)2(OH)2(NH3)(cha)] (14) Empirical formula Formula weight Crystal size (mm) Crystal system Space group ˚) a (A ˚) b (A ˚) c (A a (°) b (°) c (°) Z Dcalc (mg/m3) l (mm1) F(0 0 0) h Range (°) Reflections collected Independent reflections ˚ 3) Volume (A Conventional R wR2
2
8
14
CH10N8O2Pt
C6H12N8O2Pt
C6H18N8O2Pt
361.23
423.33
429.35
0.35 0.11 0.10 0.52 0.28 0.12 0.24 0.14 0.12 triclinic
monoclinic
triclinic
P 1 5.0127(2) 5.6360(2) 14.5362(5) 86.981(2) 82.408(2) 82.706(2) 2 2.973
I2/a 12.9666(2) 7.8790(1) 21.5367(4) 90 92.898(1) 90 8 2.559
P 1 5.5050(2) 13.3500(4) 17.8930(6) 75.307(2) 82.238(2) 81.007(2) 4 2.281
17.367 332 2.829 to 30.461 11081
12.778 1584 2.75 to 29.98 15237
11.232 816 1.590 to 30.494 7070
3950
3171
7070
403.51(3) 0.0291
2197.46(6) 0.0191
1250.07(7) 0.0355
0.0738
0.0467
0.0817
Table 4 ˚ ) and angles (°) of complex 13 H-bonding distances (A D–H
d(D–H)
d(H A)
\DHA
d(D A)
A
N1–H N1–H N1–H N11–H N11–H
0.910 0.910 0.910 0.920 0.920
2.289 2.542 2.200 2.598 2.419
150.44 133.98 162.45 156.11 141.81
3.113 3.241 3.079 3.459 3.193
N12a N32b N33c N12d N33e
Symmetry operations: (a) x + 1, y, z + 1; (b) x, y, z 1; (c) x, y, z; (d) x 1, y, z; (e) x, y, z + 1.
distorted from square-planar, the angle between the cyclohexylamine ring and the azide ligand which is orientated towards it (N(12)–N(22)–N(32)) is >95° (Table 2). This distortion is not seen for trans-[PtCl2(NH3)(cha)] where the angles are all 90 ± 1° [21]. The complex is still relatively planar around the platinum centre with angles very close to 180°. The molecules form hydrogen-bonded chains, with interactions occurring between the am(m)ine hydrogens and azide nitrogens (Table 4); similar hydrogen bonds are found in the analogous chloride compound trans[PtCl2(NH3)(cha)] [21]. trans,trans,trans-[Pt(N3)2(OH)2(NH3)(2-pic)] (8) crystallised in an monoclinic crystal system with the space group I2/a (Table 3). The structure is shown in Fig. 3. The azide bond lengths and angles are very similar to the other PtIV
F.S. Mackay et al. / Inorganica Chimica Acta 362 (2009) 811–819
azide compounds (Table 5) [5,6]. The Pt–N(2-pic) bond ˚ ) than that of Pt– length is significantly longer (2.092(5) A ˚ N(py) in compound 4 (2.059(4) A), which is presumably due to steric hindrance caused by the methyl group of 2-picoline. In the crystal structure of trans-[PtIICl2(NH3)(2-pic)], the methyl group lies over the square-plane above the platinum atom [22,23]. The 2-picoline ligand is disordered by a 180° rotation about the Pt–N bond. The system is hydro-
817
gen-bonded to produce ‘‘slabs” of molecules bound either side of the hydrophobic picolines. The centroid–centroid ˚ with separation of the p – p stacked picoline rings is 3.355 A a dihedral angle of 0.00(27)°. trans,trans,trans-[Pt(N3)2(OH)2(NH3)(cha)] (14) crystallised in a triclinic crystal system with the space group P 1 (Table 3), as did complex 2. The structure of 14 is shown in Fig. 3. The azide bond lengths and angles are very
Table 5 ˚ ) and angles (°) of azide ligands in trans,trans,trans-[Pt(N3)2(OH)2(NH3)(MeNH2)] (2), trans,trans,trans-[Pt(N3)2(OH)2(NH3)(2-pic)] (8) Bond lengths (A and trans,trans,trans-[Pt(N3)2(OH)2(NH3)(cha)] (14, 140 ) Pt–N(a1) Pt–N(a2) N(a1)–N(b1) N(b1)–N(c1) N(a2)–N(b2) N(b2)–N(c2) Pt–N(a1)–N(b1) N(a1)–N(b1)–N(c1) Pt–N(a2)–N(b2) N(a2)–N(b2)–N(c2) N(a1)–Pt–N(a2)–N(b2) N(a2)–Pt–N(a1)–N(b1)
2
8
14
140
2.055(3) 2.048(3) 1.228(4) 1.149(4) 1.229(4) 1.133(5) 115.2(2) 175.5(3) 117.2(2) 174.8(4) 131.23 91.44
2.054(2) 2.051(2) 1.212(4) 1.158(4) 1.222(4) 1.141(4) 115.7(2) 175.3(3) 115.3(2) 175.0(3) 114.5 164.4
2.041(7) 2.032(7) 1.224(10) 1.139(11) 1.194(11) 1.148(11) 114.9(5) 175.6(9) 119.0(6) 174.0(9) 119.4 91.2
2.028(7) 2.053(7) 1.190(10) 1.149(11) 1.213(10) 1.142(10) 123.5(6) 174.0(9) 116.5(6) 174.5(9) 104.2 127.0
Fig. 3. X-ray crystal structures of PtIV complexes (a) trans,trans,trans-[Pt(N3)2(OH)2(NH3)(MeNH2)] (2), (b) trans,trans,trans-[Pt(N3)2(OH)2(NH3)(2-pic)] (8), and (c) trans,trans,trans-[Pt(N3)2(OH)2(NH3)(cha)] (14) (50% probability ellipsoids).
818
F.S. Mackay et al. / Inorganica Chimica Acta 362 (2009) 811–819
1.0
1.0
Absorbance
N3
Pt 0.6
N3
NH 3
OH
0.4
2
0.2 0.0 200
300
400
H2 OH N N3
0.8
Absorbance
NH 2
0.8
OH
500
Pt
0.6
N3
OH
0.4
NH3
4
0.2 0.0 200
600
300
400
Wavelength (nm)
500
600
Wavelength (nm)
1.0
1.0
S OH
N
0.8
N3
Pt
0.6
N3
0.4
OH
NH 3
6
0.2 0.0 200
Absorbance
Absorbance
0.8
N 0.6
N3
NH3
8
0.0 300
400
500
600
200
300
400
500
600
Wavelength (nm)
1.2
1.0
1.0
0.8
H3 C H3 C
0.8
N
OH
N3
Absorbance
Absorbance
OH
0.2
Wavelength (nm)
Pt 0.6
N3 0.4
NH 3
OH
N
OH
0.6
N3
Pt 0.4
N3
OH
NH 3
0.2
10
0.2 0.0 200
N3
Pt
H3 C
0.4
OH
12
0.0 300
400
500
600
200
300
Wavelength (nm)
400
500
600
Wavelength (nm)
1.0 1.0
Absorbance
Pt
0.6
N3 0.4
OH
0.2 0.0 200
Absorbance
H2 OH N N3
0.8
NH 3
N
0.8
OH
0.6
N3 0.4
OH
NH3
16
0.2
14
N3
Pt
0.0 300
400
500
600
Wavelength (nm)
200
300
400
500
600
Wavelength (nm)
Fig. 4. Effect of UVA irradiation on the electronic absorption spectra of 50–80 lM aqueous solutions of complexes 2, 4, 6, 8, 10, 12, 14, and 16 showing the decrease in intensity of the azide-to-PtIV charge-transfer band after 0, 1, 5, 15, 30, and 60 min.
similar to the other PtIV azide compounds. The X-ray structure of trans,cis,cis-[Pt(OAc)2Cl2(NH3)(cha)] (JM216) has been determined; it crystallised in a monoclinic crystal system with space group P21/a [24]. The cyclohexylamine bond
lengths and angles of complex 14 compare well with those of JM216, as do the Pt–am(m)ine bond lengths. The geometry of 14 is nearly octahedral with the cyclohexylamine ring adopting a chair conformation. Complex 14 crystallised
F.S. Mackay et al. / Inorganica Chimica Acta 362 (2009) 811–819
with four molecules in the unit cell, two of which were different. Intermolecular hydrogen bonding between the ammonia, hydroxide and azide ligands is present, as for complexes 2 and 8. An NH2 hydrogen and the equatorial ring hydrogen attached to C2 are also involved in intramolecular hydrogen bonding to the azide ligands.
819
plexes 1, 2, 8, 13, and 14. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.ica.2008.02.039. References
3.3. Photochemistry IV
The photoreactions of Pt azide complexes can be followed by UV–Vis spectroscopy. Aqueous solutions (3 mL, 50 lM to 80 lM) were irradiated with UVA light and the spectra recorded after 0, 1, 5, 15, 30, and 60 min (Fig. 4). All complexes have an intense N3 ? Pt ligand-to-metal charge-transfer (LMCT) band between 285 – 295 nm. Upon irradiation, this band decreases indicating loss of the azide ligands [25]. The evolution of a gas, thought to be nitrogen, was clearly visible during these photoreactions. The UV–Vis spectra of the photoreaction of trans,trans, trans-[Pt(N3)2(OH)2(NH3)2] show the appearance of a new peak (253 nm), at a shorter wavelength than the LMCT band (286 nm), after 5 min UVA irradiation [5]. This peak is likely to be due to the monoazide species trans,trans,trans-[Pt(N3)(OH)3(NH3)2] as it decreases upon further irradiation, consistent with loss of the second azide. trans,trans,trans-[Pt(N3)(OH)3(NH3)2] has also been identified as a photoproduct by 2D [1H,15N] HSQC NMR spectroscopy and mass spectrometry [26]. The appearance and subsequent decrease (upon further irradiation) of a new peak at higher energy than the LMCT bands was also seen for complexes 2, 4, and 14. For the thiazole (6), picoline (8, 10 and 12) and quinoline (16) complexes, the new monoazide peak may be masked by intraligand absorbances of the aromatic systems. These complexes all react extremely rapidly upon exposure to UVA light, as can be seen from the large decrease in the N3 ? Pt LMCT band after only 1 min of irradiation (Fig. 4). The absorption bands also extend out into the visible region (>400 nm) which means there is scope for activating these complexes using longer wavelength light (which penetrates more deeply into tissues). Acknowledgements We thank the EPSRC, Scottish Enterprise and EC COST Action D39 for support. We are grateful to Dr. Julie Woods (Dundee) and Professor Patrick Bednarski (Greifswald) for stimulating discussions. Appendix A. Supplementary material CCDC 675566, 675570, 675567, 675568, and 675569 contain the supplementary crystallographic data for com-
[1] P.J. Bednarski, F.S. Mackay, P.J. Sadler, Anticancer Agents Med. Chem. 7 (2007) 75. [2] N.A. Kratochwil, M. Zabel, K.-J. Range, P.J. Bednarski, J. Med. Chem. 39 (1996) 2499. [3] N.A. Kratochwil, Z.J. Guo, P.D. Murdoch, J.A. Parkinson, P.J. Bednarski, P.J. Sadler, J. Am. Chem. Soc. 120 (1998) 8253. [4] N.A. Kratochwil, J.A. Parkinson, P.J. Bednarski, P.J. Sadler, Angew. Chem., Int. Ed. 38 (1999) 1460. [5] F.S. Mackay, J.A. Woods, H. Moseley, J. Ferguson, A. Dawson, S. Parsons, P.J. Sadler, Chem. Eur. J. 12 (2006) 3155. [6] F.S. Mackay, J.A. Woods, P. Heringova´, J. Kaspa´rkova´, A.M. Pizarro, S.A. Moggach, S. Parsons, V. Brabec, P.J. Sadler, Proc. Natl. Acad. Sci. USA 104 (2007) 20743. [7] P.J. Bednarski, R. Gru¨nert, M. Zielzki, A. Wellner, F.S. Mackay, P.J. Sadler, Chem. Biol. 13 (2006) 61. [8] L.R. Kelland, C.F.J. Barnard, I.G. Evans, B.A. Murrer, B.R.C. Theobald, S.B. Wyer, P.M. Goddard, M. Jones, M. Valenti, A. Bryant, P.M. Rogers, K.R. Harrap, J. Med. Chem. 38 (1995) 3016. [9] G.M. Sheldrick, SADABS, University of Go¨ttingen, Go¨ttingen, Germany, 2004. [10] P.T. Beurskens, G. Beurskens, R. de Gelder, S. Garcia-Granda, R.O. Gould, R. Israel, J.M.M. Smits, DIRDIF99 Program System, Crystallography Laboratory, University of Nijmegen, The Netherlands, 1999. [11] G.M. Sheldrick, SHELXS, University of Go¨ttingen, Go¨ttingen, Germany, 1997. [12] A. Altomare, G. Cascarano, G. Giacovazzo, A. Guagliardi, M.C. Burla, G. Polidori, M. Camalli, J. Appl. Crystallogr. 27 (1994) 435. [13] G.M. Sheldrick, SHELXL, University of Go¨ttingen, Go¨ttingen, Germany, 1997. [14] P.W. Betteridge, J.R. Carruthers, R.I. Cooper, K. Prout, D.J. Watkin, J. Appl. Crystallogr. 36 (2003) 1487. [15] R.I. Cooper, R.O. Gould, S. Parsons, D.J. Watkin, J. Appl. Crystallogr. 35 (2002) 168. [16] U. Bierbach, Y. Qu, T.W. Hambley, J. Peroutka, H.L. Nguyen, M. Doedee, N. Farrell, Inorg. Chem. 38 (1999) 3535. [17] M.V. Beusichem, N. Farrell, Inorg. Chem. 31 (1992) 634. [18] J. Arpalahti, B. Lippert, H. Scho¨llhorn, U. Thewalt, Inorg. Chim. Acta 153 (1988) 45. [19] G.H.W. Milburn, M.R. Truter, J. Chem. Soc. A (1966) 1609. [20] P. Mu¨ller, B. Schro¨der, J.A. Parkinson, N.A. Kratochwil, R.A. Coxall, A. Parkin, S. Parsons, P.J. Sadler, Angew. Chem., Int. Ed. 42 (2003) 335. [21] E.G. Talman, W. Bru¨ning, J. Reedijk, A.L. Spek, N. Veldman, Inorg. Chem. 36 (1997) 854. [22] G. McGowan, Ph.D. Thesis, University of Edinburgh, 2005. [23] G. McGowan, S. Parsons, P.J. Sadler, Inorg. Chem. 44 (2005) 7459. [24] S. Neidle, C.F. Snook, Acta Crystallogr. C 51 (1995) 822. [25] H. Knoll, R. Stich, H. Hennig, D.J. Stufkens, Inorg. Chim. Acta 178 (1990) 71. [26] F.S. Mackay, Ph.D. Thesis, University of Edinburgh, 2006.
