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Synthesis and structural properties of ylidenemalonatoplatinum(II) complexes
Po/yhedron Vol. 13, No. 9, pp. 1397-1403, 1994 copyright 0 1994 Elswier science Ltd Printed in Great Britain. All rights Icgcnrcd 0277-5387194 S7.00+0.00
Pergamon 0277%5387(93)EOO5H
SYNTHESIS AND STRUCTURAL PROPERTIES OF YLIDENEMALONATOPLATINUM@) COMPLEXES SUNG SIL LEE and MOO JIN JUN Department of Chemistry, Yonsei University, Seoul 120-749, Korea and KWAN MOOK KIM, OK-SANG JUNG* and YOUN SO0 SOHN*
Inorganic Chemistry Laboratory, Korea Institute of Science and Technology, Seoul 130-650, Korea (Received 28 September
1993 ; accepted 16 November 1993)
Abstract-New
platinum(I1) complexes A2Pt(OOC)2C=CR2 (1, A2 = 3-aminohexahydroazepine, R2 = -(CHJ5- ; 2, A2 = 3-aminohexahydroazepine, R = CH3 ; 3, A2 = 3-aminohexahydroazepine, R2 = -SCH2CH2S- ; 4, A = cyclopropylamine, R2 = -SCH2CH2 S-) have been prepared and characterized. The molecular structures of the representative complexes 1 *2H20 and 4. C3H7N0 were determined by X-ray analysis. The platinum atoms for 1. 2H20 and 4 * C3H7N0 achieve a typical square planar arrangement with each nitrogen atom in cis position. For 1 *2H20 an unusually short c=C bond [1.298(18) A] has been observed in contrast to the corresponding bond [1.374(g)& in 4 - C3H7N0. The spectroscopic and physicochemical data disclose that these platinum complexes are stable and their molecular structures are retained in aqueous solution.
cis-Diaminedichloroplatinum(I1) is one of the most effective oncolytic agents against cancers of the testes, ovaries, bladder and neck.‘” However, its usefulness is limited due to severe toxicities such as nephrotoxicity, nausea/vomiting, and myelosuppression along with development of resistance in the tumor cell.“’ Accordingly, a great number of analogues have been synthesized and screened for better anticancer agents.g-12 In order to overcome the drawbacks a new series of ylidenemalonatoplatinum(I1) complexes that contain nitrogen donor coligands has been synthesized and screened in our laboratory. I3914In a continuing effort to extend the chemistry of the platinum complexes, the structural features for an interesting family of ylidenemalonatoplatinum(II) are discussed based on the crystal structures together with physicochemical properties.
EXPERIMENTAL
Elemental analyses were performed by the Advanced Analysis Centre at KIST. The infrared spectra in the 4000 - 4OOcrn region were measured as KBr pellets on a MIDAC model 101025 FT-IR spectrophotometer. ‘H- and 13C-NMR spectra were recorded on a Varian Gemini-300 NMR spectrometer relative to SiMe, as an external standard or dioxane as an internal standard. Conductivities in aqueous solution were determined on a Fisher YSI Model 32 Conductance Meter. Potassium tetrachloroplatinate(II) was purchased from Kojima, and diethyl isopropylidenemalonate and cyclopropylamine from Aldrich. Diethyl- 1,3-dithiolan-2-ylidenemalonate,15 diethyl cyclohexylidenemalonate,‘6 and 3-aminohexahydroazepine’7 were prepared according to the respec tive known procedures. Substituted ylidenemalonates were used after hydrolysis by the standard method. ci.s-Diaminediiodoplatinum(I1) was pre*Authors to whom correspondence should be addressed. pared by the literature method.‘* 1397
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S. S. LEE et al.
Synthesis of cis-3-aminohexahydroazepine(cyclohexylidenemalonato)platinum(ZZ) (1)
cis-3-aminohexaTo a suspension of hydroazepinediiodoplatinum(I1) (1 .OO g, 1.78 mmol) in 50 cm3 of water was added silver sulphate (0.53 g, 1.70 rnmol) in 100 cm3 of water. The reaction solution was stirred for 2h and then silver iodide formed was filtered off. To the filtrate was added dropwise barium cyclohexylidenemalonate * HZ0 (0.57 g, 1.70 mmol) in 50 cm3 of water and the reaction mixture was stirred further for 2h. After barium sulphate was filtered off the filtrate was condensed to 5 cm’. Excess acetone was added to the filtrate to obtain the yellow product (yield 67%). Recrystallization of the product in water gave crystals [m.p. 180°C (dec.)] suitable for X-ray crystallography. Found (Calc. for C,5H24N204Pt *2H20) : C, 33.9(34.2); H, 5.2(5.4); N, 5.1(5.3%). IR (KBr, cm-‘): vasym(COO), 1636, 1617; v,,,(COO), 1379. ‘H NMR(D,O, ppm): 3.15 _- 2.42(br, 2.40 - 2.08(br, 5H) ; 4H) ; 1.85 - 1.40(br, 12H). 13CNMR(D20, ppm) : 178.7, 152.5, 130.5, 58.3, 53.7, 34.1, 33.9, 33.1, 29.3, 29.1, 26.9,22.8,22.6, 22.5. Synthesis of cis-3-aminohexahydroazepine(isopropylidenemalonato)platinum(ZZ) (2) cis - 3 - Aminohexahydroazepinediiodoplatinum (II) (1.00 g, 1.78 mmol) was reacted with barium isopropylidenemalonate * 2H20 (0.54 g, 1.70 mmol) in the same manner as for 1. The resultant white solid was obtained in 71% yield. The crude product was recrystallized in water to obtain colourless crystals [m.p. 180°C (dec.)]. Found (Calc. for CIZH2,,NZ04Pt): C, 31.7(31.9); H, 4.5(4.5); N, 6.1(6.2%). IR(KBr, cm-‘): v,,,,(COO), 1637, 1618; v,,,(COO), 1342. ‘H NMR(D20, ppm): 3.04 N 2.50(br, 5H); 2.2O(m, 2H); 1.89(s, 6H); 1.90 - 1.65(br, 4H). ’ 3C NMR(D20, ppm) : 177.2, 145.9, 133.4, 58.7, 58.2, 53.8, 33.7, 27.8, 22.8, 22.7, 22.5. Synthesis of cis-3-aminohexahydroazepine( elan-2-ylidenemalonato)platinum(ZZ) (3)
1,Zdithi-
cis - 3 - Aminohexahydroazepinediiodoplatinum (II) (1.00 g, 1.78 mmol) was treated with barium 1,3-dithiolan-2-ylidenemalonate *2H20 (0.64 g, 1.70 mmol) in the same procedure as for 1. The resultant solid was recrystallized from water. The yellow crystals [m.p. 165°C (dec.)] were obtained in 65% yield. Found (Calc. for C12H,8N204S2Pt. 3H,O): C, 25.3(25.4); H, 4.3(4.3); N, 5.0(4.9%). IR(KBr, cm- ‘) : vasym(COO), 1591, 1566 ; vsym,
1358. ‘H NMR(D*O, ppm): 3.38(s, 4H); 3.30 2.52(br, 5H) ; 2.20(m, 2H) ; 1.90 - 1.62(br, 4H). Synthesis of cis-bis(cyclopropylamine)(l,3-dithiolan2-ylidenemalonato)platinum(ZZ) (4)
Reaction of cis-bis(cyclopropylamine)diiodoplatinum(I1) (1.00 g, 1.78 mmol) with barium 1,3dithiolan-2-ylidenemalonate - 2H20 (0.64 g, 1.70 mmol) was carried out according to the same procedure as for 1. Recrystallization of the crude product from dimethylformamide resulted in yellow crystals [m.p. 170°C (dec.)] in 69% yield. Found (Calc. for C,2H,8N204SZPt - C3H,NO) : C, 31.3(31.6); H, 4.2(4.4); N, 7.5(7.4%). IR(KBr, cm-‘) : v,&COO), 1574, 1532 ; v,,,(COO), 1359. ‘H NMR(D*O, ppm): 7.86 (s, 1H); 3.21(s, 4H); 2.86(s, 3H); 2.70(s, 3H); 2.58(br, 2H); 0.85(br, 4H) ; 0.71(br, 4H). X-ray crystallography
All the crystallographic data were obtained on an Enraf-Nonius CAD 4 automatic diffractometer with graphiie-monochromated molybdenum radiation (I(Kcl,) = 0.70930 A, il(KaJ = 0.71359 A) at ambient temperature of 23 f 2°C. Preliminary diffractometric investigation indicated orthorhombic and monoclinic system for 1. 2H20 and 4 - C3H7N0, respectively. Accurate cell dimensions were obtained from the setting angles of 25 wellcentred reflections by using a least-square procedure. During the data collection, three standard reflections monitored after every 1 h did not reveal any systematic variation in intensity. The space group of each crystal was determined uniquely from the systematic absences. The structures were solved by the conventional heavy atom method, followed by successive difference Fourier synthesis. The nonhydrogen atoms were refined anisotropically by using SHELX-76.” Hydrogen atoms were placed in calculated positions and refined only for the isotropic thermal factors. Crystal parameters and procedural information corresponding to data collection and structure refinement are given in Table 1. RESULTS AND DISCUSSION Synthesis andproperties
The reaction of diaminediiodoplatinum(I1) with an appropriate barium ylidene malonate in water smoothly afforded the title complexes according to general method as shown in eqs (1) and (2).*’ All
S. S. LEE et al.
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180°C. The complexes are moderately soluble and fairly stable in water. Crystal structures of 1. 2H20 and 4 - C3H7N0
The molecular structure and labelling scheme for 1 - 2H20 are shown in Fig. 1. Bond distances and
bond angles are listed in Table 2. The complex is a discrete molecule with no close intermolecular contacts. The local geometry around the platinum atom is a slightly distorted square planar: distances of Pt-N( l), Pt-N(2), Pt-O( l), and Pt-O(2) are 2.012(11), 2.030(12), 2.032(11) and 2.022(10) A, respectively, and the bond angles of N(2) -Pt-N( l), N( l)-Pt-O(2), N(2)--Pt-O( l), and O(2)---Pt-O(1) are 84.2(5), 93.9(5), 93.8(5), and 88.2(4)“, respectively. The amine ligand is bonded to the platinum atom in a bidentate fashion resulting in cis position to provide a suitable bite angle. The angles of N(l)-Pt-O(2) i93.9(5)“]
and N(2)-Pt-O( 1) [93.8(5)“] are splayed out with the concomitant closing of the bite angle of the bidentate amine ligand. The bite angle [84.2(5)“] of 3-aminohexahydroazepine is in part responsible for the slight distortion from square planar. The bond lengths of C(21)-0(4) [1.239(16) A] and C(22)-0(3) [1.215( 15) A] are shorter than C(21)--0(2) [1.307(15) A] and C(22)-0(1) [1.294(16) A], being consistent with typical monodentate carboxylates in other platinum(I1) complexes.*l Interestingly, the cyclohexyl ring of the anionic ligand roughly parallels with the 7-membered ring of the amine ligand. In particular, the conformation of the cyclohexylidenemalonate ligand in 1 - 2H,O is fairly bent in contrast to that in 4 * C3H7N0 as will be explained later. The other interesting feature is that the length [ 1.298( 18) A] of double bond C( lo)-C(20) in 1. 2H20 is much shorter than the corresponding bond length (1.34 A) of the general ethylene group,** supporting the
Table 2. Bond distances (A) and bond angles (“) for 1. 2Hz0 Pt-o( 1) Pt--o(2) Pt-N( 1) Pt-N(2) O(l)--c(22) 0(2)--c(21) o(3)-~(22) o(4)-~(21) C(2O)-c(21) C(2O)-cJ(22) C(2O)-c(lO) C(1lF(l2) C(1l)-c(lO) O(2)_-pt---W) N(l)-P&O(l) N(l)-Pt-O(2) N(2)-Pt-O(1) N(2)-Pt-O(2) N(2)-Pt-N( 1) C(22W(ltiPt C(21)-0(2tPt w2~t2owt21) wQ-w3)--c(21)
ww-vokw2) 0(4)--c(2 1)-o(2) C(2OW(21 )-o(2) c(2O)--c(2 1W(4) 0(3)--c(22~0(1) C(20)--c(22)--0( 1) ~(20~(22)--0(3) C(lO)--c(l l)-c(l2) ~(13>--~(12~(11)
2.032(11) 2.022(10) 2.012(11) 2.030(12) 1.294(16) 1.307(15) 1.215(15) 1.239(16) 1.473(17) 1.551(17) 1.298(18) 1.556(22) 1.542(19) 88.2(4) 177.7(4) 93.9(5) 93.8(5) 177.4(4) 84.2(5) 118.0(9) 117.1(8) 111.6(l) 126.4(2) 122.0(2) 116.9(1) 119.5(2) 123.6(2) 120.1(2) 117.8(l) 122.1(2) 110.1(2) 111.2(6)
C(l2+c(l3) C(l3)--c(l4) C(l4+c(l5) C(l5)-c(lO) C(l)_-c(2) C(l)_N(2) C(2)-C(3) C(2)_N(l) C(3)--c(4) C(4)--c(5) C(5)--c(6) C(6)_N(2)
W4FtW-W9 C(15)-C(14+c(13) C(lO)-W5)-W4) C(1l)--c(lO)--c(2O) C(l5)-c(lO~(20) c(l5)--c(1o~c(ll) Nt2W(l)--C(2) ~(3)--~(2tc(l) N(l+C(Z)--C(l) N(l)+2)--C(3) C(4)-C(3W(2) C(5)-C(4)--c(3) C(6)_-c(5W(4) N(2_(6)-C(5) C(2)-N( I)--Pt C( l)-N(2)-Pt C(6)-N(2FPt C(6)-N(2)----c(l)
1.493(29) 1.466(25) 1.475(21) 1.526(18) 1.493(19) 1.505(18) 1.485(18) 1.516(18) 1.553(24) l&2(25) 1.492(24) 1.508(19)
113.9(5) 111.5(4) 110.1(3) 120.7(1) 126.3(3) 112.3(l) 108.0(l) 118.3(4) 105.9(l) 110.7(1) 118.8(2) 113.4(5) 119.3(4) 115.4(3) 109.0(8) 108.6(9) 113.7(9) 116.1(2)
Ylidenemalonatoplatinum(I1) complexes
Fig. 2. ORTEP drawing of 4 - C3H,N0 along with the atomic labelling scheme. Solvated molecule was omitted for clarity.
Table 3. Bond distances (A) and bond angles (“) for 4 *C ,H ,NO Pko( 1) Pt-O(2) Pt-N( 1) Pt-N(2) S(l)_C(4) S(l)--c(5) S(2)--c(4) S(2)-C(6) 0(1)--c(l) 0(2)-C(2) 0(3)--C(l) 0(4)--c(2) 0(2)--Pt-o( 1) N(l)-P&-O(l) N( l)--Pt-O(2) N(2)-Pt-O( 1) N(2)--Pt-O(2) N(2)--Pt-N( 1) C(5)-S(l)--c(4) C(6)_S(2)_C(4) C(l)--O(lFPt C(2)-O(2)--Pt C(7)-N( l)-Pt C(lO)-N(2FPt O(3)-C(lW(l) C(3)-W)--o(l) C(3WW)--o(3) 0(4)-C(2)-~2) C(3)-C(2)--0(2) C(3)---C(2)--0(4)
1.985(5) 1.993(5) 2.044(6) 2.026(6) 1.741(6) 1.742(10) 1.760(6) 1.778(9) 1.312(8) 1.291(8) 1.223(8) 1.226(8) 92.8(2) 86.3(2) 178.9(2) 177.1(2) 88.1(2) 92.7(2) 98.9(4) 96.6(4) 126.7(4) 126.8(4) 114.9(6) 117.8(j) 118.0(6) 121.3(6) 120.7(6) 119.2(6) 121.7(6) 119.0(6)
N(l)-C(7) N(2WJlO) C(lWX3) C(2)--c(3) C(3)--C(4) C(5)-C(6) C(7)_C(8) C(7)--c(9) C(SyC(9) C(lO)-C(ll) C(lO)--C(l2) C(1 l)--c(l2) C(2)--~(3)-~(1) C(4)-C(3)_C(l) C(4)--c(3)---C(2) S(2)-~(4)--s( 1J C(3)--c(4)-S(l) C(3)--c(4k-S(2) C(6)_C(5)_St 1) C(5)_C(6>-S(2) C(8)--c(7k--N(l) C(9)--c(7)_N(l) C(9)-C(7)-C(8) C(9)_C(8)--c(7) C(8)--c(9)--c(7) C(l l)-C(lO)-N(2) C( 12~C( 10)-N(2) C(l2)--c(lOWXll) C(l2)--c(l l>--c(lO) C(11)--c(12)--c(10)
1.450(16) 1.463( 10) 1.478(9) 1.488(9) 1.374(9) 1.451(8) 1.448(9) l&8(9) 1.477(9) 1.452(11) 1.473(12) 1.458(15) 125.8(6) 116.1(6) 118.1(6) 113.7(3) 123.9(5) 122.4(5) 113.5(8) 115.7(7) 119.6(7) 118.5(2) 60.8(5) 60.3(5) 58.9(5) 121.1(8) 119.8(8) 59.8(7) 60.8(6) 59.4(6)
S. S. LEE et al.
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absence of resonance structures through the anionic carboxylate ligand even though the ligand is a, /?unsaturated system. Furthermore, the mean length (1.51 A) of C(2O)-C(21) and C(2O)-C(22) approaches that of a typical single bond.23 The molecular geometry of 4 - C3H,N0 is depicted in Fig. 2, where the atomic numbering scheme is defined. The bond distances and angles appear in Table 3. The local geometry around the platinum atom approximates to square planar with each nitrogen atom in cis position: distances of Pt-N(l), Pt-N(2), Pt-O(l), and Pt-O(2) are 2.044(6), 2.026(6), 1.985(5), and 1.993(5) A, respectively, and bond angles of N(2)-P&-N(l), N( l)-Pt-0( I), N(2)-Pt-O(2), and O(2)-PtO(1) are 92.7(2), 86.3(2), 88.1(2), and 92.8(2)“, respectively. The bond lengths of Pt-0 [1.985(5) A; 1.993(5) A] are slightly short relative to the counterpart [2.032(11) 8, ; 2.022(10) A] of 1. 2H20, probably due to exchange of amine ligand. The bond fashion of carboxylates is similar to that in 1. 2H20. The most interesting observation is that the length of C(3)--C(4) double bond [1.374(g) A] is significantly longer than that [1.298( 18) A] of 1. 2Hz0, reflecting the presence of the following resonance structures in 4. C3H7N0 containing sulphur atom in the anionic ligand in contrast to 1. 2H20, in which no resonance structure is allowed. The C-S bond lengths [1.741(6), 1.742(10), 1.760(6), and 1.778(9) A] in 4*C3H,N0 are also shorter than that (1.82 fk) of a typically isolated C-S single bond,24 presumably owing to the presence of the resonance structures. In addition to the bond lengths, dihedral angles in Table 4 well explain the resonance phenomena. The large dihedral angle between planes for the anionic ligand in 1 - 2Hz0 does not accommodate the resonance structures B and C whereas the small dihedral angle for 4 - C3H7N0 allows the contribution of the resonance structures. On the other hand, the distances of O(3). . .S(1)(2.53 A) and O(4). . .S(2)(2.55 A) are much shorter than that of van der Waals radii (3.30
-
etc
Ylidenemalonatoplatinum(I1) complexes
h25 which does not rule out the possibility of the heteroaromatic26 5-membered rings consisting of C(2), O(4), S(2), C(4) and C(3) or C(3), C(4), S(l), O(3) and C(1). Spectroscopic
andphysicochemicalproperties
It is generally known that the asymmetric and the symmetric carboxylate stretching frequencies of the metal complexes depend on the bonding mode of the carboxylate ligand. The Av(v,,~~-v,& values larger than 200cm-’ for the title complexes indicate that the carboxylates act as monodentate ligands. For 3 * 3H20 and 4 - C3H,N0 ‘H resonances for SCH2- appear at 3.38 ppm and 3.21 ppm as a singlet, respectively, indicating that both carboxylates coordinated to the platinum atom are unchanged in aqueous solution. Appearance of single 13Cchemical shift for the carboxylate ligands at 178.7 and 177.2 ppm for 1 -2H20 and 2, respectively, in water also suggests that the bonding mode of the carboxylates is retained in solution without the dissociation of the carboxylate ligands. Conductivity measurements in aqueous solution also indicate that the title complexes are essentially non-electrolytes at least for 1 day at room temperature. The molar conductivity values for all the complexes are in the range of 27-38 cm2 Sz-’ mall’, which is much lower than that (about 120 cm2 R-’ mall’) for 1: 1 electrolyte.27 In conclusion, the physicochemical data in solution are consistent with the structure in the solid state. The study of the title complexes indicates that a prominent structural feature strongly depends on the presence or absence of the sulphur atom in the anionic ylidenemalonate ligand. Acknowledgment-This cially by the Ministry Korea.
research was supported finanof Science and Technology
in
REFERENCES 1. S. D. William and L. H. Einhorn, in Cisplutin : Current Status and New Developments, p. 323. Academic
Press, New York (1980).
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2. P. J. Leohrer and L. H. Einhom, Ann. Intern. Med. 1984,100,704. 3. B. Rosenberg, Cancer Treat. Rep. 1979,63, 1433. 4. D. D. Von Hoff, R. Schilsky and C. M. Reichart, Cancer Treat. Rep. 1979,63, 1439. 5. I. H. Krakoff, Cancer Treat. Rep. 1979,63, 1523. 6. A. Kedar, M. E. Cohen and A. I. Freeman, Cancer Treat. Rep. 1978,62, 819. 7. J. H. Burchenal, K. Kalaher, T. O’Toole and J. Chisholm, Cancer Res. 1977, 37,2455. 8. A. Eastman and E. Bresnick, Biochem. Pharmac. 1981,30,2721. 9. A. Pasini, Znorg. Chim. Acta 1987, 137, 57. 10. C. F. J. Barnard, M. J. Cleare and P. C. Hydes, Chem. Brit. 1986, 1001. 11. S. E. Sherman and S. J. Lippard, Chem. Rev. 1987, 87, 1153. 12. C. G. Van Kralingen, J. Reedijk and A. L. Spek, Znorg. Chem. 1980,19, 1481. 13. Y. S. Sohn, K. M. Kim, J. H. Jeong, D. Y. Noh, C. 0. Lee and S. U. Choi, J. Znorg. Biochem. in press. 14. Y. S. Sohn and K. M. Kim, U.S. Pat. 5,142,075 (1992). 15. N. Katagiri, S. Ise, N. Watanabe and C. Kaneko, Chem. Pharm. Bull. 1990,38,3242. 16. C. Holmberg, Liebigs Ann. Chem. 1981,748. 17. M. Saburi, K. Miyamura, M. Morita, Y. Mizoguchi, S. Yoshikawa, S. Tsuboyama, T. Sakurai and K. Tsuboyama, Bull. Chem. Sot. Jpn 1987,60,141. 18. G. L. Johnson, Znorg. Syn. 1966,8,242. 19. G. M. Sheldrick, SHELX-76: Program for Crystal Structure Determination, University of Cambridge, Cambridge, U.K. (1976). 20. R. C. Harrison and C. A. Mcauliffe, Znorg. Chim. Acta 1980,46, L15. 21. P. Bitha, G. 0. Morton, T. S. Dunne, E. F. Delos Santos, Y. Lin, S. R. Boone, R. C. Haltiwanger and C. G. Pierpont, Znorg. Chem. 1990, 29, 645. 22. R. T. Morrison and R. N. Boyd, Organic Chemistry, 3rd ed., p. 145. Allyn and Bacon Inc., Boston (1973). 23. See ref. 22, p. 74. 24. V. Huang, R. J. Drake and D. W. Stephan, Znorg. Chem. 1993,32,3022. 25. J. E. Huheey, Inorganic Chemistry : Principle of Structure and Reactivity, 3rd ed., p. 256. Harger & Row, New York (1983). 26. F. Wudl, G. Srdanov, B. Rosenau, D. Wellman, K. Williams and S. D. Cox, J. Am. Chem. Sot. 1988, 110, 1316. 27. M. Sneed and J. Maynard, General Inorganic Chemistry, p. 813. Van Nostrand, New York (1942).
Pergamon 0277%5387(93)EOO5H
SYNTHESIS AND STRUCTURAL PROPERTIES OF YLIDENEMALONATOPLATINUM@) COMPLEXES SUNG SIL LEE and MOO JIN JUN Department of Chemistry, Yonsei University, Seoul 120-749, Korea and KWAN MOOK KIM, OK-SANG JUNG* and YOUN SO0 SOHN*
Inorganic Chemistry Laboratory, Korea Institute of Science and Technology, Seoul 130-650, Korea (Received 28 September
1993 ; accepted 16 November 1993)
Abstract-New
platinum(I1) complexes A2Pt(OOC)2C=CR2 (1, A2 = 3-aminohexahydroazepine, R2 = -(CHJ5- ; 2, A2 = 3-aminohexahydroazepine, R = CH3 ; 3, A2 = 3-aminohexahydroazepine, R2 = -SCH2CH2S- ; 4, A = cyclopropylamine, R2 = -SCH2CH2 S-) have been prepared and characterized. The molecular structures of the representative complexes 1 *2H20 and 4. C3H7N0 were determined by X-ray analysis. The platinum atoms for 1. 2H20 and 4 * C3H7N0 achieve a typical square planar arrangement with each nitrogen atom in cis position. For 1 *2H20 an unusually short c=C bond [1.298(18) A] has been observed in contrast to the corresponding bond [1.374(g)& in 4 - C3H7N0. The spectroscopic and physicochemical data disclose that these platinum complexes are stable and their molecular structures are retained in aqueous solution.
cis-Diaminedichloroplatinum(I1) is one of the most effective oncolytic agents against cancers of the testes, ovaries, bladder and neck.‘” However, its usefulness is limited due to severe toxicities such as nephrotoxicity, nausea/vomiting, and myelosuppression along with development of resistance in the tumor cell.“’ Accordingly, a great number of analogues have been synthesized and screened for better anticancer agents.g-12 In order to overcome the drawbacks a new series of ylidenemalonatoplatinum(I1) complexes that contain nitrogen donor coligands has been synthesized and screened in our laboratory. I3914In a continuing effort to extend the chemistry of the platinum complexes, the structural features for an interesting family of ylidenemalonatoplatinum(II) are discussed based on the crystal structures together with physicochemical properties.
EXPERIMENTAL
Elemental analyses were performed by the Advanced Analysis Centre at KIST. The infrared spectra in the 4000 - 4OOcrn region were measured as KBr pellets on a MIDAC model 101025 FT-IR spectrophotometer. ‘H- and 13C-NMR spectra were recorded on a Varian Gemini-300 NMR spectrometer relative to SiMe, as an external standard or dioxane as an internal standard. Conductivities in aqueous solution were determined on a Fisher YSI Model 32 Conductance Meter. Potassium tetrachloroplatinate(II) was purchased from Kojima, and diethyl isopropylidenemalonate and cyclopropylamine from Aldrich. Diethyl- 1,3-dithiolan-2-ylidenemalonate,15 diethyl cyclohexylidenemalonate,‘6 and 3-aminohexahydroazepine’7 were prepared according to the respec tive known procedures. Substituted ylidenemalonates were used after hydrolysis by the standard method. ci.s-Diaminediiodoplatinum(I1) was pre*Authors to whom correspondence should be addressed. pared by the literature method.‘* 1397
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S. S. LEE et al.
Synthesis of cis-3-aminohexahydroazepine(cyclohexylidenemalonato)platinum(ZZ) (1)
cis-3-aminohexaTo a suspension of hydroazepinediiodoplatinum(I1) (1 .OO g, 1.78 mmol) in 50 cm3 of water was added silver sulphate (0.53 g, 1.70 rnmol) in 100 cm3 of water. The reaction solution was stirred for 2h and then silver iodide formed was filtered off. To the filtrate was added dropwise barium cyclohexylidenemalonate * HZ0 (0.57 g, 1.70 mmol) in 50 cm3 of water and the reaction mixture was stirred further for 2h. After barium sulphate was filtered off the filtrate was condensed to 5 cm’. Excess acetone was added to the filtrate to obtain the yellow product (yield 67%). Recrystallization of the product in water gave crystals [m.p. 180°C (dec.)] suitable for X-ray crystallography. Found (Calc. for C,5H24N204Pt *2H20) : C, 33.9(34.2); H, 5.2(5.4); N, 5.1(5.3%). IR (KBr, cm-‘): vasym(COO), 1636, 1617; v,,,(COO), 1379. ‘H NMR(D,O, ppm): 3.15 _- 2.42(br, 2.40 - 2.08(br, 5H) ; 4H) ; 1.85 - 1.40(br, 12H). 13CNMR(D20, ppm) : 178.7, 152.5, 130.5, 58.3, 53.7, 34.1, 33.9, 33.1, 29.3, 29.1, 26.9,22.8,22.6, 22.5. Synthesis of cis-3-aminohexahydroazepine(isopropylidenemalonato)platinum(ZZ) (2) cis - 3 - Aminohexahydroazepinediiodoplatinum (II) (1.00 g, 1.78 mmol) was reacted with barium isopropylidenemalonate * 2H20 (0.54 g, 1.70 mmol) in the same manner as for 1. The resultant white solid was obtained in 71% yield. The crude product was recrystallized in water to obtain colourless crystals [m.p. 180°C (dec.)]. Found (Calc. for CIZH2,,NZ04Pt): C, 31.7(31.9); H, 4.5(4.5); N, 6.1(6.2%). IR(KBr, cm-‘): v,,,,(COO), 1637, 1618; v,,,(COO), 1342. ‘H NMR(D20, ppm): 3.04 N 2.50(br, 5H); 2.2O(m, 2H); 1.89(s, 6H); 1.90 - 1.65(br, 4H). ’ 3C NMR(D20, ppm) : 177.2, 145.9, 133.4, 58.7, 58.2, 53.8, 33.7, 27.8, 22.8, 22.7, 22.5. Synthesis of cis-3-aminohexahydroazepine( elan-2-ylidenemalonato)platinum(ZZ) (3)
1,Zdithi-
cis - 3 - Aminohexahydroazepinediiodoplatinum (II) (1.00 g, 1.78 mmol) was treated with barium 1,3-dithiolan-2-ylidenemalonate *2H20 (0.64 g, 1.70 mmol) in the same procedure as for 1. The resultant solid was recrystallized from water. The yellow crystals [m.p. 165°C (dec.)] were obtained in 65% yield. Found (Calc. for C12H,8N204S2Pt. 3H,O): C, 25.3(25.4); H, 4.3(4.3); N, 5.0(4.9%). IR(KBr, cm- ‘) : vasym(COO), 1591, 1566 ; vsym,
1358. ‘H NMR(D*O, ppm): 3.38(s, 4H); 3.30 2.52(br, 5H) ; 2.20(m, 2H) ; 1.90 - 1.62(br, 4H). Synthesis of cis-bis(cyclopropylamine)(l,3-dithiolan2-ylidenemalonato)platinum(ZZ) (4)
Reaction of cis-bis(cyclopropylamine)diiodoplatinum(I1) (1.00 g, 1.78 mmol) with barium 1,3dithiolan-2-ylidenemalonate - 2H20 (0.64 g, 1.70 mmol) was carried out according to the same procedure as for 1. Recrystallization of the crude product from dimethylformamide resulted in yellow crystals [m.p. 170°C (dec.)] in 69% yield. Found (Calc. for C,2H,8N204SZPt - C3H,NO) : C, 31.3(31.6); H, 4.2(4.4); N, 7.5(7.4%). IR(KBr, cm-‘) : v,&COO), 1574, 1532 ; v,,,(COO), 1359. ‘H NMR(D*O, ppm): 7.86 (s, 1H); 3.21(s, 4H); 2.86(s, 3H); 2.70(s, 3H); 2.58(br, 2H); 0.85(br, 4H) ; 0.71(br, 4H). X-ray crystallography
All the crystallographic data were obtained on an Enraf-Nonius CAD 4 automatic diffractometer with graphiie-monochromated molybdenum radiation (I(Kcl,) = 0.70930 A, il(KaJ = 0.71359 A) at ambient temperature of 23 f 2°C. Preliminary diffractometric investigation indicated orthorhombic and monoclinic system for 1. 2H20 and 4 - C3H7N0, respectively. Accurate cell dimensions were obtained from the setting angles of 25 wellcentred reflections by using a least-square procedure. During the data collection, three standard reflections monitored after every 1 h did not reveal any systematic variation in intensity. The space group of each crystal was determined uniquely from the systematic absences. The structures were solved by the conventional heavy atom method, followed by successive difference Fourier synthesis. The nonhydrogen atoms were refined anisotropically by using SHELX-76.” Hydrogen atoms were placed in calculated positions and refined only for the isotropic thermal factors. Crystal parameters and procedural information corresponding to data collection and structure refinement are given in Table 1. RESULTS AND DISCUSSION Synthesis andproperties
The reaction of diaminediiodoplatinum(I1) with an appropriate barium ylidene malonate in water smoothly afforded the title complexes according to general method as shown in eqs (1) and (2).*’ All
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180°C. The complexes are moderately soluble and fairly stable in water. Crystal structures of 1. 2H20 and 4 - C3H7N0
The molecular structure and labelling scheme for 1 - 2H20 are shown in Fig. 1. Bond distances and
bond angles are listed in Table 2. The complex is a discrete molecule with no close intermolecular contacts. The local geometry around the platinum atom is a slightly distorted square planar: distances of Pt-N( l), Pt-N(2), Pt-O( l), and Pt-O(2) are 2.012(11), 2.030(12), 2.032(11) and 2.022(10) A, respectively, and the bond angles of N(2) -Pt-N( l), N( l)-Pt-O(2), N(2)--Pt-O( l), and O(2)---Pt-O(1) are 84.2(5), 93.9(5), 93.8(5), and 88.2(4)“, respectively. The amine ligand is bonded to the platinum atom in a bidentate fashion resulting in cis position to provide a suitable bite angle. The angles of N(l)-Pt-O(2) i93.9(5)“]
and N(2)-Pt-O( 1) [93.8(5)“] are splayed out with the concomitant closing of the bite angle of the bidentate amine ligand. The bite angle [84.2(5)“] of 3-aminohexahydroazepine is in part responsible for the slight distortion from square planar. The bond lengths of C(21)-0(4) [1.239(16) A] and C(22)-0(3) [1.215( 15) A] are shorter than C(21)--0(2) [1.307(15) A] and C(22)-0(1) [1.294(16) A], being consistent with typical monodentate carboxylates in other platinum(I1) complexes.*l Interestingly, the cyclohexyl ring of the anionic ligand roughly parallels with the 7-membered ring of the amine ligand. In particular, the conformation of the cyclohexylidenemalonate ligand in 1 - 2H,O is fairly bent in contrast to that in 4 * C3H7N0 as will be explained later. The other interesting feature is that the length [ 1.298( 18) A] of double bond C( lo)-C(20) in 1. 2H20 is much shorter than the corresponding bond length (1.34 A) of the general ethylene group,** supporting the
Table 2. Bond distances (A) and bond angles (“) for 1. 2Hz0 Pt-o( 1) Pt--o(2) Pt-N( 1) Pt-N(2) O(l)--c(22) 0(2)--c(21) o(3)-~(22) o(4)-~(21) C(2O)-c(21) C(2O)-cJ(22) C(2O)-c(lO) C(1lF(l2) C(1l)-c(lO) O(2)_-pt---W) N(l)-P&O(l) N(l)-Pt-O(2) N(2)-Pt-O(1) N(2)-Pt-O(2) N(2)-Pt-N( 1) C(22W(ltiPt C(21)-0(2tPt w2~t2owt21) wQ-w3)--c(21)
ww-vokw2) 0(4)--c(2 1)-o(2) C(2OW(21 )-o(2) c(2O)--c(2 1W(4) 0(3)--c(22~0(1) C(20)--c(22)--0( 1) ~(20~(22)--0(3) C(lO)--c(l l)-c(l2) ~(13>--~(12~(11)
2.032(11) 2.022(10) 2.012(11) 2.030(12) 1.294(16) 1.307(15) 1.215(15) 1.239(16) 1.473(17) 1.551(17) 1.298(18) 1.556(22) 1.542(19) 88.2(4) 177.7(4) 93.9(5) 93.8(5) 177.4(4) 84.2(5) 118.0(9) 117.1(8) 111.6(l) 126.4(2) 122.0(2) 116.9(1) 119.5(2) 123.6(2) 120.1(2) 117.8(l) 122.1(2) 110.1(2) 111.2(6)
C(l2+c(l3) C(l3)--c(l4) C(l4+c(l5) C(l5)-c(lO) C(l)_-c(2) C(l)_N(2) C(2)-C(3) C(2)_N(l) C(3)--c(4) C(4)--c(5) C(5)--c(6) C(6)_N(2)
W4FtW-W9 C(15)-C(14+c(13) C(lO)-W5)-W4) C(1l)--c(lO)--c(2O) C(l5)-c(lO~(20) c(l5)--c(1o~c(ll) Nt2W(l)--C(2) ~(3)--~(2tc(l) N(l+C(Z)--C(l) N(l)+2)--C(3) C(4)-C(3W(2) C(5)-C(4)--c(3) C(6)_-c(5W(4) N(2_(6)-C(5) C(2)-N( I)--Pt C( l)-N(2)-Pt C(6)-N(2FPt C(6)-N(2)----c(l)
1.493(29) 1.466(25) 1.475(21) 1.526(18) 1.493(19) 1.505(18) 1.485(18) 1.516(18) 1.553(24) l&2(25) 1.492(24) 1.508(19)
113.9(5) 111.5(4) 110.1(3) 120.7(1) 126.3(3) 112.3(l) 108.0(l) 118.3(4) 105.9(l) 110.7(1) 118.8(2) 113.4(5) 119.3(4) 115.4(3) 109.0(8) 108.6(9) 113.7(9) 116.1(2)
Ylidenemalonatoplatinum(I1) complexes
Fig. 2. ORTEP drawing of 4 - C3H,N0 along with the atomic labelling scheme. Solvated molecule was omitted for clarity.
Table 3. Bond distances (A) and bond angles (“) for 4 *C ,H ,NO Pko( 1) Pt-O(2) Pt-N( 1) Pt-N(2) S(l)_C(4) S(l)--c(5) S(2)--c(4) S(2)-C(6) 0(1)--c(l) 0(2)-C(2) 0(3)--C(l) 0(4)--c(2) 0(2)--Pt-o( 1) N(l)-P&-O(l) N( l)--Pt-O(2) N(2)-Pt-O( 1) N(2)--Pt-O(2) N(2)--Pt-N( 1) C(5)-S(l)--c(4) C(6)_S(2)_C(4) C(l)--O(lFPt C(2)-O(2)--Pt C(7)-N( l)-Pt C(lO)-N(2FPt O(3)-C(lW(l) C(3)-W)--o(l) C(3WW)--o(3) 0(4)-C(2)-~2) C(3)-C(2)--0(2) C(3)---C(2)--0(4)
1.985(5) 1.993(5) 2.044(6) 2.026(6) 1.741(6) 1.742(10) 1.760(6) 1.778(9) 1.312(8) 1.291(8) 1.223(8) 1.226(8) 92.8(2) 86.3(2) 178.9(2) 177.1(2) 88.1(2) 92.7(2) 98.9(4) 96.6(4) 126.7(4) 126.8(4) 114.9(6) 117.8(j) 118.0(6) 121.3(6) 120.7(6) 119.2(6) 121.7(6) 119.0(6)
N(l)-C(7) N(2WJlO) C(lWX3) C(2)--c(3) C(3)--C(4) C(5)-C(6) C(7)_C(8) C(7)--c(9) C(SyC(9) C(lO)-C(ll) C(lO)--C(l2) C(1 l)--c(l2) C(2)--~(3)-~(1) C(4)-C(3)_C(l) C(4)--c(3)---C(2) S(2)-~(4)--s( 1J C(3)--c(4)-S(l) C(3)--c(4k-S(2) C(6)_C(5)_St 1) C(5)_C(6>-S(2) C(8)--c(7k--N(l) C(9)--c(7)_N(l) C(9)-C(7)-C(8) C(9)_C(8)--c(7) C(8)--c(9)--c(7) C(l l)-C(lO)-N(2) C( 12~C( 10)-N(2) C(l2)--c(lOWXll) C(l2)--c(l l>--c(lO) C(11)--c(12)--c(10)
1.450(16) 1.463( 10) 1.478(9) 1.488(9) 1.374(9) 1.451(8) 1.448(9) l&8(9) 1.477(9) 1.452(11) 1.473(12) 1.458(15) 125.8(6) 116.1(6) 118.1(6) 113.7(3) 123.9(5) 122.4(5) 113.5(8) 115.7(7) 119.6(7) 118.5(2) 60.8(5) 60.3(5) 58.9(5) 121.1(8) 119.8(8) 59.8(7) 60.8(6) 59.4(6)
S. S. LEE et al.
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absence of resonance structures through the anionic carboxylate ligand even though the ligand is a, /?unsaturated system. Furthermore, the mean length (1.51 A) of C(2O)-C(21) and C(2O)-C(22) approaches that of a typical single bond.23 The molecular geometry of 4 - C3H,N0 is depicted in Fig. 2, where the atomic numbering scheme is defined. The bond distances and angles appear in Table 3. The local geometry around the platinum atom approximates to square planar with each nitrogen atom in cis position: distances of Pt-N(l), Pt-N(2), Pt-O(l), and Pt-O(2) are 2.044(6), 2.026(6), 1.985(5), and 1.993(5) A, respectively, and bond angles of N(2)-P&-N(l), N( l)-Pt-0( I), N(2)-Pt-O(2), and O(2)-PtO(1) are 92.7(2), 86.3(2), 88.1(2), and 92.8(2)“, respectively. The bond lengths of Pt-0 [1.985(5) A; 1.993(5) A] are slightly short relative to the counterpart [2.032(11) 8, ; 2.022(10) A] of 1. 2H20, probably due to exchange of amine ligand. The bond fashion of carboxylates is similar to that in 1. 2H20. The most interesting observation is that the length of C(3)--C(4) double bond [1.374(g) A] is significantly longer than that [1.298( 18) A] of 1. 2Hz0, reflecting the presence of the following resonance structures in 4. C3H7N0 containing sulphur atom in the anionic ligand in contrast to 1. 2H20, in which no resonance structure is allowed. The C-S bond lengths [1.741(6), 1.742(10), 1.760(6), and 1.778(9) A] in 4*C3H,N0 are also shorter than that (1.82 fk) of a typically isolated C-S single bond,24 presumably owing to the presence of the resonance structures. In addition to the bond lengths, dihedral angles in Table 4 well explain the resonance phenomena. The large dihedral angle between planes for the anionic ligand in 1 - 2Hz0 does not accommodate the resonance structures B and C whereas the small dihedral angle for 4 - C3H7N0 allows the contribution of the resonance structures. On the other hand, the distances of O(3). . .S(1)(2.53 A) and O(4). . .S(2)(2.55 A) are much shorter than that of van der Waals radii (3.30
-
etc
Ylidenemalonatoplatinum(I1) complexes
h25 which does not rule out the possibility of the heteroaromatic26 5-membered rings consisting of C(2), O(4), S(2), C(4) and C(3) or C(3), C(4), S(l), O(3) and C(1). Spectroscopic
andphysicochemicalproperties
It is generally known that the asymmetric and the symmetric carboxylate stretching frequencies of the metal complexes depend on the bonding mode of the carboxylate ligand. The Av(v,,~~-v,& values larger than 200cm-’ for the title complexes indicate that the carboxylates act as monodentate ligands. For 3 * 3H20 and 4 - C3H,N0 ‘H resonances for SCH2- appear at 3.38 ppm and 3.21 ppm as a singlet, respectively, indicating that both carboxylates coordinated to the platinum atom are unchanged in aqueous solution. Appearance of single 13Cchemical shift for the carboxylate ligands at 178.7 and 177.2 ppm for 1 -2H20 and 2, respectively, in water also suggests that the bonding mode of the carboxylates is retained in solution without the dissociation of the carboxylate ligands. Conductivity measurements in aqueous solution also indicate that the title complexes are essentially non-electrolytes at least for 1 day at room temperature. The molar conductivity values for all the complexes are in the range of 27-38 cm2 Sz-’ mall’, which is much lower than that (about 120 cm2 R-’ mall’) for 1: 1 electrolyte.27 In conclusion, the physicochemical data in solution are consistent with the structure in the solid state. The study of the title complexes indicates that a prominent structural feature strongly depends on the presence or absence of the sulphur atom in the anionic ylidenemalonate ligand. Acknowledgment-This cially by the Ministry Korea.
research was supported finanof Science and Technology
in
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2. P. J. Leohrer and L. H. Einhom, Ann. Intern. Med. 1984,100,704. 3. B. Rosenberg, Cancer Treat. Rep. 1979,63, 1433. 4. D. D. Von Hoff, R. Schilsky and C. M. Reichart, Cancer Treat. Rep. 1979,63, 1439. 5. I. H. Krakoff, Cancer Treat. Rep. 1979,63, 1523. 6. A. Kedar, M. E. Cohen and A. I. Freeman, Cancer Treat. Rep. 1978,62, 819. 7. J. H. Burchenal, K. Kalaher, T. O’Toole and J. Chisholm, Cancer Res. 1977, 37,2455. 8. A. Eastman and E. Bresnick, Biochem. Pharmac. 1981,30,2721. 9. A. Pasini, Znorg. Chim. Acta 1987, 137, 57. 10. C. F. J. Barnard, M. J. Cleare and P. C. Hydes, Chem. Brit. 1986, 1001. 11. S. E. Sherman and S. J. Lippard, Chem. Rev. 1987, 87, 1153. 12. C. G. Van Kralingen, J. Reedijk and A. L. Spek, Znorg. Chem. 1980,19, 1481. 13. Y. S. Sohn, K. M. Kim, J. H. Jeong, D. Y. Noh, C. 0. Lee and S. U. Choi, J. Znorg. Biochem. in press. 14. Y. S. Sohn and K. M. Kim, U.S. Pat. 5,142,075 (1992). 15. N. Katagiri, S. Ise, N. Watanabe and C. Kaneko, Chem. Pharm. Bull. 1990,38,3242. 16. C. Holmberg, Liebigs Ann. Chem. 1981,748. 17. M. Saburi, K. Miyamura, M. Morita, Y. Mizoguchi, S. Yoshikawa, S. Tsuboyama, T. Sakurai and K. Tsuboyama, Bull. Chem. Sot. Jpn 1987,60,141. 18. G. L. Johnson, Znorg. Syn. 1966,8,242. 19. G. M. Sheldrick, SHELX-76: Program for Crystal Structure Determination, University of Cambridge, Cambridge, U.K. (1976). 20. R. C. Harrison and C. A. Mcauliffe, Znorg. Chim. Acta 1980,46, L15. 21. P. Bitha, G. 0. Morton, T. S. Dunne, E. F. Delos Santos, Y. Lin, S. R. Boone, R. C. Haltiwanger and C. G. Pierpont, Znorg. Chem. 1990, 29, 645. 22. R. T. Morrison and R. N. Boyd, Organic Chemistry, 3rd ed., p. 145. Allyn and Bacon Inc., Boston (1973). 23. See ref. 22, p. 74. 24. V. Huang, R. J. Drake and D. W. Stephan, Znorg. Chem. 1993,32,3022. 25. J. E. Huheey, Inorganic Chemistry : Principle of Structure and Reactivity, 3rd ed., p. 256. Harger & Row, New York (1983). 26. F. Wudl, G. Srdanov, B. Rosenau, D. Wellman, K. Williams and S. D. Cox, J. Am. Chem. Sot. 1988, 110, 1316. 27. M. Sneed and J. Maynard, General Inorganic Chemistry, p. 813. Van Nostrand, New York (1942).