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Synthesis and structural studies on Z-2-benzylthio-4-hydroximinomethyl-1-p-methoxyphenyl imidazole metal complexes
Pdyhedrm Vol. 12, No. 5, pp. 507412, Printed in Great Britain
1993 0
0277-5387193 S6.00+.00 1993 Pergamon Press Ltd
SYNTHESIS AND STRUCTURAL STUDIES ON Z-2-BENZYLTHIO4HYDROXIMINOMETHY~l-pMETHOXYPHENYL IMIDAZOLE METAL COMPLEXES R. LOPEZ-GARZON, Departamento
M. N. MORENO-CARRETERO,* and J. M. SALAS-PEREGRIN
M. A. SALAS-PEREGRIN
de Quimica Inorganica, Facultad de Ciencias Experimentales, Universidad de Granada, 23071 Jdn, Spain
(Received 30 September 1992; accepted 22 October 1992) Abstract-Complexes of Z-2-benzyltbio-4-hydroximinomethyl-l-p-methoxyphenyl imidazole (Z-OXLME) with Co”, Ni”, Cui’, Zn”, Cd” and Hg” were prepared and characterized by IR, W-vis-NIR diffuse reflectance, ‘H and 13C NMR spectroscopies and magnetic and thermal measurements. In all the complexes the organic compound acts as a chelator through N(3)imidand Noximeatoms.
Organic compounds containing the oxime group are of great biological interest. In 1950, Wilson found that the hydroxylamine acts as a regenerator of the phosphorylated acetylcholinesterase. ’ Since then, many other oximic derivatives have been obtained with the aim of improving their toxicity ; among these derivatives several N-methyl derivatives of pyridinaldoximes, 2 the compound 1-dodecyl-2-hydroximinomethyl pyridinium3-5 and the quaternary salts derived from the 2-hydroximinomethyl imidazole may be highlighted. Other oximic derivatives, e.g. the a-cetoglutamic oxime acid and the dimethylglyoxime exhibit in vitro antitumor activity.“8 In some cases this activity is enhanced in the presence of certain metal ions ; so, Takamiya proved that the in vitro antitumor activity of the cr-cetoglutamic oxime acid is minor compared with that of their Fe” and Cu” metal chelates. Likewise, in the case of the dimethylglyoxime the in vitro antitumor activity is enhanced when the compound is supplied together with Cu” ions, but not with other metal ions like Ni”, Co”, Zn”, Fe”, Mn”, Hg’ or Hg11.6This suggests that the antitumoral activity of a metal chelate depends not only on its permeability through the cellular membrane, but of the structural characteristics of both metal ion and chelating agent. Thus, dimethyland glyoxime-copper bis-(acetylmonoxime)copper(I1) are both of them permeable to Erhlich carcinoma and 180 Cracker sarcoma cellules ; never* Author to whom correspondence should be addressed.
theless, only the former inhibited tumor development. Other oxime complexes, trans-bis[salicylaldoximate]copper(II) and trans-bis[resorcylaldoximato]copper(II), also show strong in vitro and in vivo anticancer activities against Leukaemia L 1210 and Erhlich ascites carcinome. 9 As a continuation of a previous work,” in which the coordination ability of the compound E-lp-ethoxyphenyl-4-hydroximinomethyl imidazole (EALDH) against several metal ions was studied, the present paper is focussed on the synthesis and characterization of metal complexes from the monoximic derivative Z-2-benzylthio-4-hydroximinomethyl-1-p-methoxyphenyl imidazole (ZOXLME) with Co”, Ni”, Ct.?, Zn”, Cd” and Hg”. The compound Z-OXLME differs structurally from the former in the presence of a benzylthio group substituted on C(2) of the imidazolic ring. These compounds are analogous to some others which are regenerators of the phosphorylated acetylcholinesterase. ’ ’ EXPERIMENTAL Preparation of the ligands and complexes The compound used as the ligand, Z-OXLME, was prepared according to a reported procedure. ’ ’ The complexes were obtained by adding with stirring the corresponding metallic chloride (1 mmol) to an ethanolic solution (75 cm3) of Z-
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OXLME (0.339 g, 1 mmol). The resulting solutions were evaporated in air until precipitation of the complexes occurred (about 3 days later), except in the case of the copper(I1) complex, which precipitated almost immediately. Apparatus and methods
Microanalyses of carbon, hydrogen and nitrogen were performed in the Technical Services of University of Granada (STUGRA). IR spectra were obtained on a Perkin-Elmer 983G spectrophotometer, from KBr pellets in the 400&250 cm-’ range and polyethylene pellets in the 600180 cm- ’ range. ‘H and ’ 3C NMR spectra were recorded on a Bruker AM-300 machine, using DMSO-d6 as a solvent and TMS as the internal standard. UV-vis-NIR reflectance spectra of the complexes in the 24&1400 nm range were obtained from pellets of the corresponding samples, using a Shimadzu MPC-3 100 spoctrophotometer and BaSO, as a reference. Magnetic susceptibilities of the ligand and complexes at room temperature were measured using Faraday-Bruker Magnet Mod. BEl 5 equipment. Dependence of susceptibility values on the temperature was measured on a Mannics DSM-8 susceptometer. The temperature range investigated was 8&280 K. The ESR spectrum of CuCl,(Z-OXLME) * 2Hz0 was obtained in the Xband using a Bruker E.S.P.-300 spectrometer. Finally, the thermal study of the: ligand and complexes was performed using a Mettler TA-3000 system, provided with a Mettler TGdO thermobalance and a DSC-20 differential scanhing calorimeter. TG curves were obtained on heating samples of the corresponding solids in a dynamic pure air atmosphere (100 cm3 n-tin-‘) in the 35-850°C temperature range, whereas DSC plots were recorded under a static air atmosphere in the temperature range between 35 and 450”C’In both cases a heating
rate of 10°C min- ’ and samples from 1 to 10 mg were utilized.
RESULTS
varying
in weight
AND DISCUSSION
The assignments of the bands of the IR spectra of Z-OXLME were performed in accordance with the literature.‘2-‘7 These assignments (Table 1) point out that the tautomeric form of Z-OXLME in the solid state is the hydroxioximic one instead of the nitronic one. The assignments of the broad band at 2844 cn- ’ at v(OH) of the oxime group and that of 1681 cm-’ at &OH) in plane deformation due to hydrogen bridged OH groups were proved by the shifting from 2720 to 2200 cm-’ of the former and the disappearance of the second upon deuteration of Z-OXLME. The low wave number value and widening of the v(OH) band (2844 cm- ‘), together with the appearance of the &OH) band in the IR spectrum of ZOXLME, prove the existence of an intramolecular hydrogen bridge I2between the OH group and probably the N(3) atom of the imidazole ring (as shown in Fig. l), which is favoured by the 2 conformation of the compound. NMR data are summarized in Table 2. It is noticeable that the value of the chemical shift of the hydroxylic hydrogen atoms in the ‘H NMR spectrum of Z-OXLME is high (11.60 ppm) compared to the one corresponding for EALDH (10.80 ppm), ’ O in which an intramolecular hydrogen bridge of the above type is prevented ; this fact is also in accordance with the structure depicted in Fig. 1. Moreover, the higher melting enthalpy of the compound EALDH (51 kJ mol- ‘) than ZOXLME (22 kJ mol- I), measured from their corresponding DSC plots, is also in accordance with the existence of stronger intramolecular interactions in the former compound than in the latter. The assignments of the signals corresponding to
Table 1. IR spectral data (cm- ‘) Compound
v(OH)
WH)
Z-OXLME CoCl,(Z-OXLME)* NiCl,(Z-OXLME), CuCl,(Z-OXLME) - 2H,O ZnCl,(Z-OXLME) CdCl,(Z-OXLME), CdCl,(Z-OXLME) * H *O HgCl,(Z-OXLME) - H20
2844 s,b 2844 m 3194 m 3442 m,b 3238 s 3294 m 3295 m 3311m
1681 m 1721 m 1722 m 1721 m -
V(C=N),,i,, 1609-1648m 1607-1639m 1607-1648m 1605-1639 m 1605-1647m 16061640 m 16061652 vs 1609-1631m
WC) 917s 1018s 1021s 997 s 1032s 1013 s 1012 m 1015s
v(M-Cl)
Iv(C==C), G==N)l,~.
1457 s, 1512 s 232 b,s 1444,lSlO s 327 s 1449, 1510 s 357 a,s 1441 m, 1508 s 303,346 s 1449, 1510 s 230 s 1443, 1510 s 253 a,s 1462 s, 1512, vs, 1579 vs 283 s 1443 s, 1510
a = double band ; b = broad ; s = strong ; m = medium ; w = weak ; vs = very strong.
Synthesis and structure of Z-OXLME
509
Table 2. NMR data (6, ppm)
Z-OXLME ZnCl,(Z-OXLME) CdCI,(Z-OXLME)
“C NMR
‘H NMR OHoximcC(5)_Hi,id. C&Hoxime
Compound
- H zO
11.60 10.95 10.90
7.47 7.63 7.61
7.95 8.05 8.00
cuoxime
C(4Xmid.
C(2hnicl.
C(5hnid.
140.30 141.50 137.16 126.69-132.64 142.21-142.35” 142.21-142.35” 137.26 131.42 _b 137.28 142.22” 142.22”
0 Doublet. bNot detected due to its low solubility.
DSC curves ; nevertheless, the accurate determination of dehydration energies has not been possible because the corresponding endothermic effects overlap with the exothermic effects, due to the pyrolysis of the organic ligand in the three hydrated complexes. The pyrolytic decomposition of Z-OXLME starts at 220°C via an intramolecular dehydration according to the following process : Fig. 1. Structure of the compound Z-OXLME.
+
R-HCk=N-OH
Hz0 + R-C=N.
The complexes show similar thermal behaviour. They start pyrolytic decomposition at the above temperature (except Hg” which starts the pyrolysis the carbon atoms of the imidazolic moiety together at 190°C by the sublimation of HgC12, as proved by with that of C, oxime, which are of special interest in order to supply information about the coordination the disappearance of the v(Cl-Hg) band in the IR spectrum of a sample heated up to the temperature pattern of Z-OXLME to the metal ions, are given in Table 2. The assignments were carried out on the 195°C). The above dehydration process gave rise to basis of those ones for analogous compounds, ’ ‘, ’ 2 the disappearance of the v(OH) and 6(OH) charactogether with the information provided by the teristic bands of the oxime group in the IR spectra of the ligand and their metal complexes. The DEPT technique. The colour, analytical data and proposed for- decompositions of the compounds proceed steadily mulae for the metal complexes are given in Table up to the formation of Co304, CuO, ZnO and Cd0 3. All of them contain the organic ligand in the residues. In the case of the mercury(I1) complex no neutral form and the metal/organic ligand stoi- residue was found at the end of the pyrolysis, due chiometries are either l/l (Cu”, Zn”, Cd” and Hg” to the whole sublimation of HgC12. complexes) or l/2 (Co”, Ni” and Cd” complexes). The complexes are fairly soluble in water, except Z-OXLME ligand binding mode copper(H), and ethanol. The hydrated character of M”Cl,(Z-OXLME). H20 complexes (MI’ = Cu, IR spectral data of the seven complexes in Table Hg and Cd) was determined from their TG and 1 show the shifting at higher wave number values Table 3. Colour, analytical
data (found, talc) and proposed formulae for the complexes
Compound
Colour
CoCl,(Z-OXLME), NiC12(Z-OXLME), CuCI,(Z-OXLME) * 2H,O ZnCI,(Z-OXLME) CdCl,(Z-OXLME), CdC12(Z-OXLME).H,O HgCI,(Z-OXLME) - H,O
Carmine Green Green White White White White
c (%) 53.4 54.8 42.8 46.2 50.2 40.4 34.5
(53.5) (53.5) (42.4) (45.4) (50.1) (40.0) (34.4)
H (%) 4.2 4.2 3.2 3.7 3.9 3.5 3.0
(4.2) (4.2) (4.1) (3.6) (3.9) (3.5) (3.0)
N (%) 10.1 (10.4) 10.3 (10.4) 7.9 (8.2) 8.7 (8.8) 9.4 (9.7) 7.3 (7.8) 6.5 (6.7)
510
R. LOPEZ-GARZON
of the v(N0) oxime characteristic band, which suggests, in accordance with the literature data, 12,18 that the coordination takes place through the Noxime atom instead of the Ooximeatom. This hypothesis is also supported by the increase in wave number of v(C=N),,, bands ; ’ * when the ligand acts as a chelator upon coordination, the possibility of retrodonating metal + ligand bonds gave rise to an increase in the rc-electronic delocalization, which is opposed to the above cited expected increase in V(C=Woxime * This fact would explain the variable increments in the frequency af the above cited band observed in the spectra of the complexes. From low-frequency IR ,data no evidence of v(M-N) bands were obtained, due to the high absorbance of the ligand. Nevertheless, in all cases a new and strong band was observed, which is assignable to the v(M-Cl) mode which suggests that the chloride ions are directly linked to the metal ions in all the complexes. The presence of only one band for this vibration mode indicates that chloride ligands are probably in transf positions. ’ 9 The IR spectra of those complexes having ligand: metal stoichiometries of 2: 1 5show in-plane deformation 6(OH) bands charaoteristic of O*-*H***O grouping, which suggests probable planar structures in which the interactions between the oxime groups of the two Z-OXLME molecules give rise to the above arrangement. The NMR spectra of the CdCl,(Z-OXLME) complex could not be obtained with enough resolution because of its poor solubility ; that of HgCl,(Z-OXLME) - H20, d&spite its good resolution, is equal to that of free SOXLME, due probably to its total dissociation in ‘solution. Thus, only the NMR spectra of ZnC12(Z-OXLME) and CdCl,(Z-OXLME) * H20 @es-e available. The assignment of the corresponding signals are summarized in Table 2, together with those of ZOXLME. The downfield shift of the C,H signal is due to the deshielding of a hydrogen atom on coordinating Noximeatoms to metal ions, whereas the strong shift to higher fi&l in NOH signals of both complexes can be explained on the basis of a change from the Z to the E isomer upon coordination to metal ions. This change becomes the breaking of the intramolecular hydrogen bridge interaction characteristic of the Z isomers, which produces a strong shielding-in the OH hydrogen atom.*’ Finally, the shifting to lower field values in the C(S)Himidsignal could be caused by a change in the electronic density of the imidazole moiety, this fact being consistent widh the coordination of the N(3)imidatom to the metal ions. ’3C NMR data also corroborate this hypothesis ; namely, the deshielding of C, and C(S)imidsignals is
et al.
in accordance with a chelation of the ligand in the E isomeric form, through the N(3) atom of the imidazolic ring and the N atom of the oxime group. ‘O It is interesting to point out that the deshielding in C(S)imidin Z-OXLME has also been observed upon the protonation of N(3)hia. ’ ’ Thus, the similarity in the IR spectra of all complexes, together with their formulae, suggests that the organic ligand Z-OXLME acts as a chelator, which is linked to the metal ions through the nitrogen atom of the oxime group and the N(3) atom of the imidazolic ring. Coordination environment of metal ions The magnetic moment value at room temperature for COC~~(Z-OXLME)~ complex, 4.80 B.M., is considerably higher than that corresponding to the expected spin-only value for a d’-system with three unpaired electrons.‘* The existence of an orbital contribution suggests an octahedral arrangement of the two halogen atoms and the two bidentate Z-OXLME molecules, in which the two chlorine atoms, according to far-IR data, are in trans positions. In accordance with this fact, the NIR-vis reflectance spectrum of this complex shows three bands assignable to the three expected transitions in octahedral complexes of cobalt(I1) ions;*’ thus, the band at 7.9 kK is assigned to the 4T,(F) c 4T,, transition and the two remaining at 13.8 and 18.6 kK (the first one being the weakest) are assigned to 4A2g(F)+ 4T,, and 4T,,(P) c 4T,, transitions, respectively. The above IR spectral data of the NiC12(ZOXLME)2 complex suggest that the two Cl- ions are coordinated to nickel(I1) in trans positions. On the other hand, the magnetic moment at room temperature for this complex is 2.90 B.M., which is in agreement with the expected one for the spin-only moment in a d*-system with two unpaired electrons. ’ * In accordance with this the two bidentate Z-OXLME molecules and the two Cl- ions could be in a distorted NiC12N4 octahedral arrangement. The three expected bands for octahedral complexes of nickel(II), corresponding to 3T,,(P) c 3A,, 3T,,(F) c 3A, and 3T2,(F) + 3A, transitions,*’ appear in the NIR-vis reflectance spectrum of the complex at 27.0, 15.6 and 10.0 kK, respectively. The most probable structure for these cobalt(I1) and nickel(I1) complexes is shown in Fig. 2. Spectral data for the CuCl,(Z-OXLME) * 2H20 complex suggest that the two water molecules are not coordinated to the metal ion, whereas the two Cl- ions are directly bound to copper ions.
511
Synthesis and structure of Z-OXLME
Curie-Weiss behaviour in the studied temperature range : UXM = V+
HO-N-
C= 0.242 cm3 K mol-‘; 8 = 23.29 K; p = 1.4OkO.03 B.M. (r value of l/xM vs T plot = 0.9932). In order to elucidate if this deviation from Curie’s law is due to the existence of temperature-independent paramagnetism (TIP), XMobserved values have been plotted versus T. The resulting curve has been adjusted, using the ENZFITTER nonlinear regression data analysis program (R. J. Leatherbarrow, Elsevier-Biosoft, 1987), to the general equation :
M -N-OH I .‘*. II
XM =XT+XTIP=
Fig.
2. Structure of COC~~(Z-OXLME)~, NiC12(ZOXLME)* and CdCII(Z-OXLME), complexes.
All these data suggest a four-coordinated CuC12N2 sphere for the metal ion in this complex. The magnetic moment at room temperature, 1.42 B.M., is considerably lower than that expected for the spin-only contribution in a d9-system ; 12~22 this fact suggests a probable antiferromagnetic interaction between copper(I1) ions and consequently a planar or distorted tetrahedral arrangement of the four donor atoms around each copper(I1) ion. In order to explain this fact magnetic susceptibility values of the complex were measured in the 8&280 K temperature range ; the results are presented in Fig. 3, which shows the variation of xrvrand l/xM versus T values. These data indicate that the complex follows
5-
-200
O%m Al/Xm 80.0 90.0 I 120.0 I lu).O I 180.0 I 210.0 I 240.0 I 2780 _
T-(K)
Fig. 3. Variation of xh( and l/xhl vs T for the CuCI,(ZOXLME) - 2H20 complex.
‘WC ;
c __
T-l-e
+XTIP,
in which both temperature-dependent and -independent contributions to the total value of paramagnetism have been taken into account. From this plot (Fig. 3) the following values have been obtained : XTlp = 1.237 x 1O-4 cm3 mol-‘, 0 = 9.9 K and C = 0.202 cm3 K mol- ‘. The agreement factor of this plot, defined as C(xobs- x~~,~)*/CX~~~~, was 1.5 x IO- 3.The 8 value indicates this compound displays a Curie behaviour in its temperaturedependent component. Knowing the XTipvalue, the magnetic moment of the Cu*+ ion in this complex has been calculated using the molar susceptibility of the compound corrected by both diamagnetic and TIP contributions. The value obtained for the magnetic moment is 1.26f0.03 B.M. This gives a ,&,p value of 0.14 B.M., which is in accordance with the values found in the literature for this magnitude.22 The ESR spectrum of CuCl,(Z-OXLME). 2H20 shows an isotropic signal at a g value of 2.11. This would suggest the presence of a copper(I1) ion in a complex containing grossly misaligned tetragonal axes ; this situation being, according to Hathaway and Billing, 23 the most common reason for the observation of an isotropic ESR spectrum. The reflectance spectrum of the complex presents an asymmetric band centred at 12.5 kK which may involve several d--f d transitions in square-planar or slightly distorted tetrahedral copper(I1) complexes. ” From exposed experimental data for the complexes ZnC12(Z-OXLME), CdCl,(Z-OXLME) and HgCl,(Z-OXLME) * H20, tetrahedral structures, as shown in Fig. 4, can be proposed. In the CdC12(Z-OXLME)2 complex, a CdN4C12 octahedral arrangement of the six donor atoms with the two Cl- ions in tram positions would be expected (see Fig. 2).
R. LOPEZ-GARZON
512 /
”KM.,dI HO’
O-CM3
-cH2
b cl
Fig. 4. Structure of ZnCldZ-OXLME), CdCl,(ZOXLME)*H,O and HgCl,(Z-OXLME)*H,O complexes.
REFERENCES 1. I. B. Wilson and F. Bergman, J. Biol. Chem. 1950, 185, 479. 2. I. B. Wilson and G. Ginsburg, Arch. Biochem. Biophys. 1955,54, 570. 3. I. B. Wilson, Biochem. Biophys. Actu 1958,27, 196. 4. E. J. Poziomek, B. E. Mackley and G. M. Steinberg, J. Org. Chem. 195823, 714. 5. Y. Ashani, H. E. Dery, J. Zahavy, W. Kunberg and S. Cohen, Isr. J. Chem. 1985, 3, 133. 6. K. Takamiya, Nature 1960; 185, 190. 7. K. Klkuchl and M. Matsuzawa, J. Antibiotics (Japan) 1955, Ser. B, 8, 170. 8. H. Kamata, J. Antibiotics (Japan) 1958, Ser. B, 11, 1.
et al.
9. P. 0. Lumme and H. 0. Elo, Znorg. Chim. Acta 1958, 107, L15 and refs therein. 10. R. Lopez-Garzon, M. A. Romero-Molina, A. Navarrete-Guijosa, J. M. Lopez-Gonzalez, G. Alvarez-Cienfuegos and M. Herrador-Pino, J. Znorg. Biochem. 1990,38, 139. 11. M. Herrador-Pino and J. Saenz de Buruaga, Anal. Quim. 1983,69C, 99. 12. K. Burger, Coordination Chemistry. Experimental Methods. Butterworth, London (1973). 13. R. E. Rundle and M. Parasol, J. Chem. Phys. 1952, 20, 1847. 14. B. Orel, M. Penko and D. Hadzi, Spectrochim. Actu 1980,36,859. 15. L. J. Bellamy, The Infrured Spectra of Complex Molecules, Vol. 11. Chapman and Hall, London (1980). 16. R. Blinc and D. Hadzi, Spectrochim. Actu 1960, 16, 853. 17. R. Blinc and D. Hadzi, J. Chem. Sot. 1958,4537. 18. M. E. Keeney and K. Osseo-Asare, Coord. Chem. Rev. 1984,59, 141. 19. R. Lopez-Garzon, D. Gutierrez-Valero, C. Valenzuela-Calahorro, N. Cruz-Perez and A. GarciaRodriguez, Monut. Chem. 1987, 118,553. 20. R. Lopez-Garzon, D. Gutierrez-Valero, M. Melguizo-Guijarro, M. Nogueras-Montiel and A. Sanchez-Rodrigo, Thermochim. Actu, in press. 21. A. B. P. Lever, Inorganic Electronic Spectroscopy, 2nd edn. Elsevier, New York (1986). 22. R. L. Carlin, Mugnetochemistry. Springer Verlag, New York (1986). 23. B. J. Hathaway and E. Billing, Coord. Chem. Rev. 1970,5, 143.
1993 0
0277-5387193 S6.00+.00 1993 Pergamon Press Ltd
SYNTHESIS AND STRUCTURAL STUDIES ON Z-2-BENZYLTHIO4HYDROXIMINOMETHY~l-pMETHOXYPHENYL IMIDAZOLE METAL COMPLEXES R. LOPEZ-GARZON, Departamento
M. N. MORENO-CARRETERO,* and J. M. SALAS-PEREGRIN
M. A. SALAS-PEREGRIN
de Quimica Inorganica, Facultad de Ciencias Experimentales, Universidad de Granada, 23071 Jdn, Spain
(Received 30 September 1992; accepted 22 October 1992) Abstract-Complexes of Z-2-benzyltbio-4-hydroximinomethyl-l-p-methoxyphenyl imidazole (Z-OXLME) with Co”, Ni”, Cui’, Zn”, Cd” and Hg” were prepared and characterized by IR, W-vis-NIR diffuse reflectance, ‘H and 13C NMR spectroscopies and magnetic and thermal measurements. In all the complexes the organic compound acts as a chelator through N(3)imidand Noximeatoms.
Organic compounds containing the oxime group are of great biological interest. In 1950, Wilson found that the hydroxylamine acts as a regenerator of the phosphorylated acetylcholinesterase. ’ Since then, many other oximic derivatives have been obtained with the aim of improving their toxicity ; among these derivatives several N-methyl derivatives of pyridinaldoximes, 2 the compound 1-dodecyl-2-hydroximinomethyl pyridinium3-5 and the quaternary salts derived from the 2-hydroximinomethyl imidazole may be highlighted. Other oximic derivatives, e.g. the a-cetoglutamic oxime acid and the dimethylglyoxime exhibit in vitro antitumor activity.“8 In some cases this activity is enhanced in the presence of certain metal ions ; so, Takamiya proved that the in vitro antitumor activity of the cr-cetoglutamic oxime acid is minor compared with that of their Fe” and Cu” metal chelates. Likewise, in the case of the dimethylglyoxime the in vitro antitumor activity is enhanced when the compound is supplied together with Cu” ions, but not with other metal ions like Ni”, Co”, Zn”, Fe”, Mn”, Hg’ or Hg11.6This suggests that the antitumoral activity of a metal chelate depends not only on its permeability through the cellular membrane, but of the structural characteristics of both metal ion and chelating agent. Thus, dimethyland glyoxime-copper bis-(acetylmonoxime)copper(I1) are both of them permeable to Erhlich carcinoma and 180 Cracker sarcoma cellules ; never* Author to whom correspondence should be addressed.
theless, only the former inhibited tumor development. Other oxime complexes, trans-bis[salicylaldoximate]copper(II) and trans-bis[resorcylaldoximato]copper(II), also show strong in vitro and in vivo anticancer activities against Leukaemia L 1210 and Erhlich ascites carcinome. 9 As a continuation of a previous work,” in which the coordination ability of the compound E-lp-ethoxyphenyl-4-hydroximinomethyl imidazole (EALDH) against several metal ions was studied, the present paper is focussed on the synthesis and characterization of metal complexes from the monoximic derivative Z-2-benzylthio-4-hydroximinomethyl-1-p-methoxyphenyl imidazole (ZOXLME) with Co”, Ni”, Ct.?, Zn”, Cd” and Hg”. The compound Z-OXLME differs structurally from the former in the presence of a benzylthio group substituted on C(2) of the imidazolic ring. These compounds are analogous to some others which are regenerators of the phosphorylated acetylcholinesterase. ’ ’ EXPERIMENTAL Preparation of the ligands and complexes The compound used as the ligand, Z-OXLME, was prepared according to a reported procedure. ’ ’ The complexes were obtained by adding with stirring the corresponding metallic chloride (1 mmol) to an ethanolic solution (75 cm3) of Z-
507
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R. LOPEZ-GARZON et al.
OXLME (0.339 g, 1 mmol). The resulting solutions were evaporated in air until precipitation of the complexes occurred (about 3 days later), except in the case of the copper(I1) complex, which precipitated almost immediately. Apparatus and methods
Microanalyses of carbon, hydrogen and nitrogen were performed in the Technical Services of University of Granada (STUGRA). IR spectra were obtained on a Perkin-Elmer 983G spectrophotometer, from KBr pellets in the 400&250 cm-’ range and polyethylene pellets in the 600180 cm- ’ range. ‘H and ’ 3C NMR spectra were recorded on a Bruker AM-300 machine, using DMSO-d6 as a solvent and TMS as the internal standard. UV-vis-NIR reflectance spectra of the complexes in the 24&1400 nm range were obtained from pellets of the corresponding samples, using a Shimadzu MPC-3 100 spoctrophotometer and BaSO, as a reference. Magnetic susceptibilities of the ligand and complexes at room temperature were measured using Faraday-Bruker Magnet Mod. BEl 5 equipment. Dependence of susceptibility values on the temperature was measured on a Mannics DSM-8 susceptometer. The temperature range investigated was 8&280 K. The ESR spectrum of CuCl,(Z-OXLME) * 2Hz0 was obtained in the Xband using a Bruker E.S.P.-300 spectrometer. Finally, the thermal study of the: ligand and complexes was performed using a Mettler TA-3000 system, provided with a Mettler TGdO thermobalance and a DSC-20 differential scanhing calorimeter. TG curves were obtained on heating samples of the corresponding solids in a dynamic pure air atmosphere (100 cm3 n-tin-‘) in the 35-850°C temperature range, whereas DSC plots were recorded under a static air atmosphere in the temperature range between 35 and 450”C’In both cases a heating
rate of 10°C min- ’ and samples from 1 to 10 mg were utilized.
RESULTS
varying
in weight
AND DISCUSSION
The assignments of the bands of the IR spectra of Z-OXLME were performed in accordance with the literature.‘2-‘7 These assignments (Table 1) point out that the tautomeric form of Z-OXLME in the solid state is the hydroxioximic one instead of the nitronic one. The assignments of the broad band at 2844 cn- ’ at v(OH) of the oxime group and that of 1681 cm-’ at &OH) in plane deformation due to hydrogen bridged OH groups were proved by the shifting from 2720 to 2200 cm-’ of the former and the disappearance of the second upon deuteration of Z-OXLME. The low wave number value and widening of the v(OH) band (2844 cm- ‘), together with the appearance of the &OH) band in the IR spectrum of ZOXLME, prove the existence of an intramolecular hydrogen bridge I2between the OH group and probably the N(3) atom of the imidazole ring (as shown in Fig. l), which is favoured by the 2 conformation of the compound. NMR data are summarized in Table 2. It is noticeable that the value of the chemical shift of the hydroxylic hydrogen atoms in the ‘H NMR spectrum of Z-OXLME is high (11.60 ppm) compared to the one corresponding for EALDH (10.80 ppm), ’ O in which an intramolecular hydrogen bridge of the above type is prevented ; this fact is also in accordance with the structure depicted in Fig. 1. Moreover, the higher melting enthalpy of the compound EALDH (51 kJ mol- ‘) than ZOXLME (22 kJ mol- I), measured from their corresponding DSC plots, is also in accordance with the existence of stronger intramolecular interactions in the former compound than in the latter. The assignments of the signals corresponding to
Table 1. IR spectral data (cm- ‘) Compound
v(OH)
WH)
Z-OXLME CoCl,(Z-OXLME)* NiCl,(Z-OXLME), CuCl,(Z-OXLME) - 2H,O ZnCl,(Z-OXLME) CdCl,(Z-OXLME), CdCl,(Z-OXLME) * H *O HgCl,(Z-OXLME) - H20
2844 s,b 2844 m 3194 m 3442 m,b 3238 s 3294 m 3295 m 3311m
1681 m 1721 m 1722 m 1721 m -
V(C=N),,i,, 1609-1648m 1607-1639m 1607-1648m 1605-1639 m 1605-1647m 16061640 m 16061652 vs 1609-1631m
WC) 917s 1018s 1021s 997 s 1032s 1013 s 1012 m 1015s
v(M-Cl)
Iv(C==C), G==N)l,~.
1457 s, 1512 s 232 b,s 1444,lSlO s 327 s 1449, 1510 s 357 a,s 1441 m, 1508 s 303,346 s 1449, 1510 s 230 s 1443, 1510 s 253 a,s 1462 s, 1512, vs, 1579 vs 283 s 1443 s, 1510
a = double band ; b = broad ; s = strong ; m = medium ; w = weak ; vs = very strong.
Synthesis and structure of Z-OXLME
509
Table 2. NMR data (6, ppm)
Z-OXLME ZnCl,(Z-OXLME) CdCI,(Z-OXLME)
“C NMR
‘H NMR OHoximcC(5)_Hi,id. C&Hoxime
Compound
- H zO
11.60 10.95 10.90
7.47 7.63 7.61
7.95 8.05 8.00
cuoxime
C(4Xmid.
C(2hnicl.
C(5hnid.
140.30 141.50 137.16 126.69-132.64 142.21-142.35” 142.21-142.35” 137.26 131.42 _b 137.28 142.22” 142.22”
0 Doublet. bNot detected due to its low solubility.
DSC curves ; nevertheless, the accurate determination of dehydration energies has not been possible because the corresponding endothermic effects overlap with the exothermic effects, due to the pyrolysis of the organic ligand in the three hydrated complexes. The pyrolytic decomposition of Z-OXLME starts at 220°C via an intramolecular dehydration according to the following process : Fig. 1. Structure of the compound Z-OXLME.
+
R-HCk=N-OH
Hz0 + R-C=N.
The complexes show similar thermal behaviour. They start pyrolytic decomposition at the above temperature (except Hg” which starts the pyrolysis the carbon atoms of the imidazolic moiety together at 190°C by the sublimation of HgC12, as proved by with that of C, oxime, which are of special interest in order to supply information about the coordination the disappearance of the v(Cl-Hg) band in the IR spectrum of a sample heated up to the temperature pattern of Z-OXLME to the metal ions, are given in Table 2. The assignments were carried out on the 195°C). The above dehydration process gave rise to basis of those ones for analogous compounds, ’ ‘, ’ 2 the disappearance of the v(OH) and 6(OH) charactogether with the information provided by the teristic bands of the oxime group in the IR spectra of the ligand and their metal complexes. The DEPT technique. The colour, analytical data and proposed for- decompositions of the compounds proceed steadily mulae for the metal complexes are given in Table up to the formation of Co304, CuO, ZnO and Cd0 3. All of them contain the organic ligand in the residues. In the case of the mercury(I1) complex no neutral form and the metal/organic ligand stoi- residue was found at the end of the pyrolysis, due chiometries are either l/l (Cu”, Zn”, Cd” and Hg” to the whole sublimation of HgC12. complexes) or l/2 (Co”, Ni” and Cd” complexes). The complexes are fairly soluble in water, except Z-OXLME ligand binding mode copper(H), and ethanol. The hydrated character of M”Cl,(Z-OXLME). H20 complexes (MI’ = Cu, IR spectral data of the seven complexes in Table Hg and Cd) was determined from their TG and 1 show the shifting at higher wave number values Table 3. Colour, analytical
data (found, talc) and proposed formulae for the complexes
Compound
Colour
CoCl,(Z-OXLME), NiC12(Z-OXLME), CuCI,(Z-OXLME) * 2H,O ZnCI,(Z-OXLME) CdCl,(Z-OXLME), CdC12(Z-OXLME).H,O HgCI,(Z-OXLME) - H,O
Carmine Green Green White White White White
c (%) 53.4 54.8 42.8 46.2 50.2 40.4 34.5
(53.5) (53.5) (42.4) (45.4) (50.1) (40.0) (34.4)
H (%) 4.2 4.2 3.2 3.7 3.9 3.5 3.0
(4.2) (4.2) (4.1) (3.6) (3.9) (3.5) (3.0)
N (%) 10.1 (10.4) 10.3 (10.4) 7.9 (8.2) 8.7 (8.8) 9.4 (9.7) 7.3 (7.8) 6.5 (6.7)
510
R. LOPEZ-GARZON
of the v(N0) oxime characteristic band, which suggests, in accordance with the literature data, 12,18 that the coordination takes place through the Noxime atom instead of the Ooximeatom. This hypothesis is also supported by the increase in wave number of v(C=N),,, bands ; ’ * when the ligand acts as a chelator upon coordination, the possibility of retrodonating metal + ligand bonds gave rise to an increase in the rc-electronic delocalization, which is opposed to the above cited expected increase in V(C=Woxime * This fact would explain the variable increments in the frequency af the above cited band observed in the spectra of the complexes. From low-frequency IR ,data no evidence of v(M-N) bands were obtained, due to the high absorbance of the ligand. Nevertheless, in all cases a new and strong band was observed, which is assignable to the v(M-Cl) mode which suggests that the chloride ions are directly linked to the metal ions in all the complexes. The presence of only one band for this vibration mode indicates that chloride ligands are probably in transf positions. ’ 9 The IR spectra of those complexes having ligand: metal stoichiometries of 2: 1 5show in-plane deformation 6(OH) bands charaoteristic of O*-*H***O grouping, which suggests probable planar structures in which the interactions between the oxime groups of the two Z-OXLME molecules give rise to the above arrangement. The NMR spectra of the CdCl,(Z-OXLME) complex could not be obtained with enough resolution because of its poor solubility ; that of HgCl,(Z-OXLME) - H20, d&spite its good resolution, is equal to that of free SOXLME, due probably to its total dissociation in ‘solution. Thus, only the NMR spectra of ZnC12(Z-OXLME) and CdCl,(Z-OXLME) * H20 @es-e available. The assignment of the corresponding signals are summarized in Table 2, together with those of ZOXLME. The downfield shift of the C,H signal is due to the deshielding of a hydrogen atom on coordinating Noximeatoms to metal ions, whereas the strong shift to higher fi&l in NOH signals of both complexes can be explained on the basis of a change from the Z to the E isomer upon coordination to metal ions. This change becomes the breaking of the intramolecular hydrogen bridge interaction characteristic of the Z isomers, which produces a strong shielding-in the OH hydrogen atom.*’ Finally, the shifting to lower field values in the C(S)Himidsignal could be caused by a change in the electronic density of the imidazole moiety, this fact being consistent widh the coordination of the N(3)imidatom to the metal ions. ’3C NMR data also corroborate this hypothesis ; namely, the deshielding of C, and C(S)imidsignals is
et al.
in accordance with a chelation of the ligand in the E isomeric form, through the N(3) atom of the imidazolic ring and the N atom of the oxime group. ‘O It is interesting to point out that the deshielding in C(S)imidin Z-OXLME has also been observed upon the protonation of N(3)hia. ’ ’ Thus, the similarity in the IR spectra of all complexes, together with their formulae, suggests that the organic ligand Z-OXLME acts as a chelator, which is linked to the metal ions through the nitrogen atom of the oxime group and the N(3) atom of the imidazolic ring. Coordination environment of metal ions The magnetic moment value at room temperature for COC~~(Z-OXLME)~ complex, 4.80 B.M., is considerably higher than that corresponding to the expected spin-only value for a d’-system with three unpaired electrons.‘* The existence of an orbital contribution suggests an octahedral arrangement of the two halogen atoms and the two bidentate Z-OXLME molecules, in which the two chlorine atoms, according to far-IR data, are in trans positions. In accordance with this fact, the NIR-vis reflectance spectrum of this complex shows three bands assignable to the three expected transitions in octahedral complexes of cobalt(I1) ions;*’ thus, the band at 7.9 kK is assigned to the 4T,(F) c 4T,, transition and the two remaining at 13.8 and 18.6 kK (the first one being the weakest) are assigned to 4A2g(F)+ 4T,, and 4T,,(P) c 4T,, transitions, respectively. The above IR spectral data of the NiC12(ZOXLME)2 complex suggest that the two Cl- ions are coordinated to nickel(I1) in trans positions. On the other hand, the magnetic moment at room temperature for this complex is 2.90 B.M., which is in agreement with the expected one for the spin-only moment in a d*-system with two unpaired electrons. ’ * In accordance with this the two bidentate Z-OXLME molecules and the two Cl- ions could be in a distorted NiC12N4 octahedral arrangement. The three expected bands for octahedral complexes of nickel(II), corresponding to 3T,,(P) c 3A,, 3T,,(F) c 3A, and 3T2,(F) + 3A, transitions,*’ appear in the NIR-vis reflectance spectrum of the complex at 27.0, 15.6 and 10.0 kK, respectively. The most probable structure for these cobalt(I1) and nickel(I1) complexes is shown in Fig. 2. Spectral data for the CuCl,(Z-OXLME) * 2H20 complex suggest that the two water molecules are not coordinated to the metal ion, whereas the two Cl- ions are directly bound to copper ions.
511
Synthesis and structure of Z-OXLME
Curie-Weiss behaviour in the studied temperature range : UXM = V+
HO-N-
C= 0.242 cm3 K mol-‘; 8 = 23.29 K; p = 1.4OkO.03 B.M. (r value of l/xM vs T plot = 0.9932). In order to elucidate if this deviation from Curie’s law is due to the existence of temperature-independent paramagnetism (TIP), XMobserved values have been plotted versus T. The resulting curve has been adjusted, using the ENZFITTER nonlinear regression data analysis program (R. J. Leatherbarrow, Elsevier-Biosoft, 1987), to the general equation :
M -N-OH I .‘*. II
XM =XT+XTIP=
Fig.
2. Structure of COC~~(Z-OXLME)~, NiC12(ZOXLME)* and CdCII(Z-OXLME), complexes.
All these data suggest a four-coordinated CuC12N2 sphere for the metal ion in this complex. The magnetic moment at room temperature, 1.42 B.M., is considerably lower than that expected for the spin-only contribution in a d9-system ; 12~22 this fact suggests a probable antiferromagnetic interaction between copper(I1) ions and consequently a planar or distorted tetrahedral arrangement of the four donor atoms around each copper(I1) ion. In order to explain this fact magnetic susceptibility values of the complex were measured in the 8&280 K temperature range ; the results are presented in Fig. 3, which shows the variation of xrvrand l/xM versus T values. These data indicate that the complex follows
5-
-200
O%m Al/Xm 80.0 90.0 I 120.0 I lu).O I 180.0 I 210.0 I 240.0 I 2780 _
T-(K)
Fig. 3. Variation of xh( and l/xhl vs T for the CuCI,(ZOXLME) - 2H20 complex.
‘WC ;
c __
T-l-e
+XTIP,
in which both temperature-dependent and -independent contributions to the total value of paramagnetism have been taken into account. From this plot (Fig. 3) the following values have been obtained : XTlp = 1.237 x 1O-4 cm3 mol-‘, 0 = 9.9 K and C = 0.202 cm3 K mol- ‘. The agreement factor of this plot, defined as C(xobs- x~~,~)*/CX~~~~, was 1.5 x IO- 3.The 8 value indicates this compound displays a Curie behaviour in its temperaturedependent component. Knowing the XTipvalue, the magnetic moment of the Cu*+ ion in this complex has been calculated using the molar susceptibility of the compound corrected by both diamagnetic and TIP contributions. The value obtained for the magnetic moment is 1.26f0.03 B.M. This gives a ,&,p value of 0.14 B.M., which is in accordance with the values found in the literature for this magnitude.22 The ESR spectrum of CuCl,(Z-OXLME). 2H20 shows an isotropic signal at a g value of 2.11. This would suggest the presence of a copper(I1) ion in a complex containing grossly misaligned tetragonal axes ; this situation being, according to Hathaway and Billing, 23 the most common reason for the observation of an isotropic ESR spectrum. The reflectance spectrum of the complex presents an asymmetric band centred at 12.5 kK which may involve several d--f d transitions in square-planar or slightly distorted tetrahedral copper(I1) complexes. ” From exposed experimental data for the complexes ZnC12(Z-OXLME), CdCl,(Z-OXLME) and HgCl,(Z-OXLME) * H20, tetrahedral structures, as shown in Fig. 4, can be proposed. In the CdC12(Z-OXLME)2 complex, a CdN4C12 octahedral arrangement of the six donor atoms with the two Cl- ions in tram positions would be expected (see Fig. 2).
R. LOPEZ-GARZON
512 /
”KM.,dI HO’
O-CM3
-cH2
b cl
Fig. 4. Structure of ZnCldZ-OXLME), CdCl,(ZOXLME)*H,O and HgCl,(Z-OXLME)*H,O complexes.
REFERENCES 1. I. B. Wilson and F. Bergman, J. Biol. Chem. 1950, 185, 479. 2. I. B. Wilson and G. Ginsburg, Arch. Biochem. Biophys. 1955,54, 570. 3. I. B. Wilson, Biochem. Biophys. Actu 1958,27, 196. 4. E. J. Poziomek, B. E. Mackley and G. M. Steinberg, J. Org. Chem. 195823, 714. 5. Y. Ashani, H. E. Dery, J. Zahavy, W. Kunberg and S. Cohen, Isr. J. Chem. 1985, 3, 133. 6. K. Takamiya, Nature 1960; 185, 190. 7. K. Klkuchl and M. Matsuzawa, J. Antibiotics (Japan) 1955, Ser. B, 8, 170. 8. H. Kamata, J. Antibiotics (Japan) 1958, Ser. B, 11, 1.
et al.
9. P. 0. Lumme and H. 0. Elo, Znorg. Chim. Acta 1958, 107, L15 and refs therein. 10. R. Lopez-Garzon, M. A. Romero-Molina, A. Navarrete-Guijosa, J. M. Lopez-Gonzalez, G. Alvarez-Cienfuegos and M. Herrador-Pino, J. Znorg. Biochem. 1990,38, 139. 11. M. Herrador-Pino and J. Saenz de Buruaga, Anal. Quim. 1983,69C, 99. 12. K. Burger, Coordination Chemistry. Experimental Methods. Butterworth, London (1973). 13. R. E. Rundle and M. Parasol, J. Chem. Phys. 1952, 20, 1847. 14. B. Orel, M. Penko and D. Hadzi, Spectrochim. Actu 1980,36,859. 15. L. J. Bellamy, The Infrured Spectra of Complex Molecules, Vol. 11. Chapman and Hall, London (1980). 16. R. Blinc and D. Hadzi, Spectrochim. Actu 1960, 16, 853. 17. R. Blinc and D. Hadzi, J. Chem. Sot. 1958,4537. 18. M. E. Keeney and K. Osseo-Asare, Coord. Chem. Rev. 1984,59, 141. 19. R. Lopez-Garzon, D. Gutierrez-Valero, C. Valenzuela-Calahorro, N. Cruz-Perez and A. GarciaRodriguez, Monut. Chem. 1987, 118,553. 20. R. Lopez-Garzon, D. Gutierrez-Valero, M. Melguizo-Guijarro, M. Nogueras-Montiel and A. Sanchez-Rodrigo, Thermochim. Actu, in press. 21. A. B. P. Lever, Inorganic Electronic Spectroscopy, 2nd edn. Elsevier, New York (1986). 22. R. L. Carlin, Mugnetochemistry. Springer Verlag, New York (1986). 23. B. J. Hathaway and E. Billing, Coord. Chem. Rev. 1970,5, 143.