J Chem Crystallogr (2007) 37:707712 DOI 10.

1007/s10870-007-9236-3

ORIGINAL PAPER

Synthesis, Characterization and Crystal Structure of a Polymeric Zinc(II) Complex Containing the Antimalarial Quinine as Ligand
Joshua Ayoola Obaleye Mino R. Caira Adedibu C. Tella

Received: 1 February 2007 / Accepted: 27 July 2007 / Published online: 23 August 2007 Springer Science+Business Media, LLC 2007

Abstract A novel polymeric zinc(II) complex of quinine, [chlorosulphato (2-ethenyl)-4-azabicyclo[2.2.2]oct-5-ylium(6-methoxyquinolin-4-yl) methanol zinc(II)] has been synthesized and characterized. Single-crystal X-ray diffraction analysis of the complex (C20H25ClN2O6SZn) revealed that quinine forms a zigzag coordination polymeric complex with Zn(II) of extended chains ZnCl OSO2OZnOSO2OZnCl. The crystals are monoclinic, space group C2 with a = 20.5035(5), b = 9.7943(2), , b = 96.578(2), Z = 4, V = 2350.3(1) A 3. c = 11.7814(4) A The complex exhibits a tetrahedral geometry. Each Zn(II) centre is thus coordinated to an O atom from each of two sulphate bridges, a Cl atom and quinoline atom N(4) of the quinine moiety. The second quinuclidine nitrogen in the quinine is protonated. In the crystal, there is linkage of two polymeric chains related by a twofold rotation axis, resulting in a bilayer. The linking is achieved by hydrogen bonding from the quinine cation which provides two donors (OH, N+H), to oxygen atoms of sulphate groups which act as acceptors. Keywords Crystal structure Polymeric zinc complex Quinine FTIR

Introduction In the search for novel drugs against Chloroquine-resistant malaria parasites, the modication of existing anti-malarial drugs by co-ordination to a metal centre has attracted considerable attention in recent years. The synthetic strategy involves modication of the activity of the antimalarial drugs through the incorporation of a transition metal into the molecular structure. This, of course, enhanced anti-malarial activities of such complexes. The electronic changes that are anticipated when drugs are coordinated to metal ions and the subtle changes that occur as the metals are varied might be able to deceive/ confuse the parasites and hence enhance the efcacy of the drugs. Despite the fact that various metal complexes of anti-malarial drugs (Amodiaquine, Primaquine, Chloroquine) [13] and ferrocenic complexes (of chloroquine, [4] meoquine, [5] quinine [5] and artemisinin [6]) have been reported, their mode of coordination and geometry still remain a matter of discussion. Very few reports on the preparation and coordination chemistry of quinine have appeared in literature. To the best of our knowledge, this is the rst account of a Zn(II) complex of quinine with an extended polymeric structure. Quinine has four potential donor sites which are the OH group, quinuclidinic nitrogen, quinolinic nitrogen and the olenic C=C (Fig. 1). The drug may act as a ligand by forming a stable vemembered ring with some metals through the quinuclidinic nitrogen and the hydroxyl oxygen (bidentate) or by binding through the quinolinic aromatic nitrogen (monodentate site). Tsangaris and co-workers [7] synthesized Cu(II), Ni(II), Co(II) and Cr(II) complexes of quinine and proposed the participation of both quinolinic and quinuclidinic nitrogens in the coordination, without evidencing,

J. A. Obaleye (&) A. C. Tella Department of Chemistry, University of Ilorin, Ilorin, Nigeria e-mail: jobaleye@yahoo.com M. R. Caira Department of Chemistry, University of Cape Town, Rondebosch, South Africa

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Fig. 1 Molecular structure of quinine

in methanol (10 mL) was added. The mixture was stirred and heated (ca 60 C) for 1 h, and cooled to room temperature (Scheme 1). The resulting turbid solution was ltered to remove starting materials. By slow evaporation of the ltrate at room temperature, off- white single crystals suitable for X-ray analysis were obtained after 3 weeks. The complex was identied as [Zn(II) (Quin)Cl(SO4)]?, M.wt = 522.34, Yield: 75% m.pt. [ 285 C with decomposition, IR (KBr pellet): 3,360.76, 2,975.34, 2,662.91, 1,621.86, 1,594.38, 1,517.67, 1,474.76, 1,434.86, 1,367.82, 1,321.85, 1,252.40, 1,186.36, 1,115.42, 1,014.91, 976.83, 920.30, 877.36, 861.01, 835.67, 803.79, 718.44, 669.41, 648.17, 618.73, 602.97, 558.32, 469.97, 435.14 cm1. Anal. Calcd for C20H25N2O6SZnCl: C, 45.90; H, 5.05; N, 5.15; S, 5.60; Zn, 12.34 Found: C, 46.00; H, 4.80; N, 5.40; S, 6.10; Zn, 12.48.

however, the involvement or not of the hydroxyl oxygen. Both coordination modes were also observed by Hubel et al [8] in some quinine organometallic complexes with Pt(II) and Pd(II). Coordination of transition metals using the four potential donor sites of Quinine was also reported by Hubel et al. [9]. The pharmacological action of quinine seems to be associated with its ability to form metal complexes. As Zn(II) is an important metal ion present in living organisms, and also in continuation with our studies on metaldrug complexes [1014]. We now report on the synthesis of a polymeric quinine complex. Furthermore, the properties of the complex are described in detail with regard to its crystal structure. Experimental Section General Procedures and Materials Quinine hemisulfate was pharmaceutical grade (Sigma Pharmaceutical). All other commercial solvents and reagents were of high purity (Aldrich & Sigma) and were used without further purication. ZnCl2 (Aldrich) was used as metal ion source. Physical Measurements Infrared spectra in the range 4,000400 cm1 were obtained from samples in the form of KBr pellets using a Unicam FTIR spectrometer. The content of zinc was determined by atomic absorption spectroscopy with a Pelkin Elmer spectrometer, model 3110. Synthesis of the Complex To a solution of quinine hemisulfate (0.782 g, 2 mmol) in methanol (10 mL), a solution of ZnCl2 (0.272 g, 2 mmol)

Crystallographic Data Collection and Renement of the Structure of [ZnCl (C20H25N2O2 SO4)]? Intensity data were collected using a Nonius Kappa CCD diffractometer and graphite- monochromated MoKa radiation, with the crystal specimen mounted on a bre with Paratone N oil (Exxon Chemical Co., TX, USA.) and cooled in a stream of nitrogen vapour. Suitable combinations of / and x-scans based on the strategy indicated by program COLLECT [15] were employed. Unit cell renement and data reduction were performed with DENZO-SMN [16] and empirical absorption corrections were

Scheme 1

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709 ) for the title compound Table 2 Selected bond distances (A C20H25ClN2O6SZn Zn(25)Cl(26) Zn(25)O(27) Zn(25)N(4) Zn(25)O(30) 2.205(2) 1.982(4) 2.053(4) 1.950(4) S(28)O(27) S(28)O(29) S(28)O(30) S(28)O(31)

applied to the data using program SADABS [17]. The position of the Zn atom was determined by the heavy-atom method using SHELXS-86 [18] and the remaining atoms, including hydrogens, were located from successive difference Fourier maps. Program SHELXL-97 [19] was used for full-matrix least-squares renement on F2, with nonhydrogen atoms treated anisotropically and H atoms isotropically in a riding model with Uiso values 1.21.5 times those of their parent atoms. The program X-seed [20] was employed as a graphical interface. Crystal data and renement details are listed in Table 1. Tables 2, 3 and 4 list selected molecular parameters and hydrogen bond data respectively.

Table 3 Selected bond angles () and torsion angles () for the title compound C20H25ClN2O6SZn Cl(26)Zn(25)O(27) Cl(26)Zn(25)N(4) Cl(26)Zn(25)O(30) O(27)Zn(25)N(4) O(27)Zn(25)O(30)a 119.2(1) 111.4(1) 107.3(1) 95.2(2) 106.1(2) 117.8 (2) 109.3(2) 103.5(2) 109.7(2) 111.3(3) 112.2(2) 110.5(2) 128.4(2) 131.6(2) 124.3(3) 71.7(3) 169.6(3) 51.7(3)
b

Results and Discussion The complex is obtained as an off-white crystalline solid in 75% yield. Elemental analysis of the product for C, H, N, and S was consistent with the formula. The infrared spectrum of the complex in the far IR region 4,000400 cm1 was compared with that of the ligand as given in Fig. 2. The latter presents a broad band (3,3643,211 cm1) due to the OH stretching vibration from sets of overlapping absorptions [7, 8]. This is probably due to the hygroscopic nature of the ligand. This band is intensied and strong in the complex at 3,361 cm1, which is also
Table 1 Crystallographic data for C20H25ClN2O6SZn CCDC deposition number Empirical formula Formula weight (g mol1) Crystal system Space group Temperature (K) Radiation ) Wavelength (A Crystal size (mm) ) a(A ) b(A ) C(A b () 3) V (A Z Dc (g/cm3) F(000) Data/parameters/restraints R1, wR2 for 3669 data with I [ 2r(I) R1, wR2 (all data) Flack parameter Shift/esd: max, min 629265 C20H25ClN2O6SZn 522.34 Monoclinic C2 113 2 MoKa 0.71073 0.03 0.07 0.08 20.5035(5) 9.7943(2) 11.7814(4) 96.578(1) 2350.3(1) 4 1.476 1,080 4,181/282/1 0.0453, 0.1190 0.0558, 0.1257 0.00(2) 0.001, \0.001

N(4)Zn(25)O(30)a O(27)S(28)O(29) O(27)S(28)O(30) O(27)S(28)O(31) O(29)S(28)O(30) O(29)S(28)O(31) O(30)S(28)O(31) Zn(25)O(27)S(28) S(28)O(30)Zn(25)b S(28)O(27)Zn(25)O(30)a Zn(25)O(27)S(28)O(29) Zn(25)O(27)S(28)O(30) Zn(25)O(27)S(28)O(31)
a

Symmetry operations: x, + y, 1z; x, + y, 1z

Table 4 Hydrogen bond parameters DHA O(14)H(14)O(27) N(20)H(20)O(29)

a b

) HA/(A 1.95 2.40 1.96

a b

) DA/(A 2.785(5) 3.166(6) 2.823(6)

DHA/() 173.1 139.9 152.8

N(20)H(20)O(31)b

Symmetry operations: 1x, y, 1z; 1/2 + x, + y, z

conrmed by the absorption band due to the OH bending mode located at 1,620 cm1 [21]. The absorption band of 2,575 cm1 due to NH+ stretching is observed in the free ligand, and is also present in the complex, but shifted to 2,662 cm1, indicating that the protonated state of the quinuclidinic nitrogen remains upon complexation [2224]. The absorption band at 2,975 cm1 is quite intense, with a shoulder at $2,900 cm1 due mainly to the CH stretching vibration of the methylene group present in the quinuclidine molecule [7, 25]. The band at 1,509 cm1 corresponding to m(C=N) is shifted to higher frequency (1,518 cm1) upon complexation [26]. This shift of $10 cm1 is probably due to the involvement of the C=N group

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in complex formation. Shifts of this frequency to the higher and lower wave number side, as well as no change, have also been reported in the literature [27]. The band at 619 cm1 in the free ligand is shifted to 603 cm1 and another band at 644 cm1 is shifted to 619 cm1 on complex formation [27]. This indicates that the nitrogen atom of the quinoline group is involved in coordination. Disappearance of the band at 1,345 cm1 and the observation of the bands of the SO2 4 group due to SO stretching at 1,186, 1,115, 1,015 and 977 cm1 in the complex indicate the coordination of SO2 4 to the metal. These frequencies agree with values obtained for C2m bridging sulfato group complexes [28]. The Zn(II) atom is tetrahedrally coordinated to two oxy, gen atoms with average ZnO bond length of 1.966(6) A comparing favourably with the range 1.9422.164 A usually observed for zinc complexes [29, 30]. The ZnN distance of is very similar to related zinc-nitrogen bond 2.053(4) A lengths observed in the zwitterionic structure of the product between ZnCl2 and cinchonine [9]. The OZnO bond angle of 106.1(2) is in agreement with angles that are usually obtained for tetrahedral complexes [30]. The SO bond lengths are comparable to the values found in four-coordinate zinc with related ligands containing the SO2group [31, 32]. The bond lengths S(28) O(29) and S(28)O(31) are signicantly shorter than S(28)O(27) and S(28)O(30) (Table 2). This is no doubt due to the presence of double bond character in the former pair and coordination of the latter two oxygen atoms to the metal atom [32]. The same trend is observed for the O=S=O bond angle which is smaller than the OSO bond angle in ... ZnOSOZn.... The geometrical parameters are in good agreement with those reported in the literature for compounds containing SO2 groups [32, 33]. The framework of the structure ZnClSO4 would give a net framework charge of 1. The excess negative charge 1 is then balanced by protonation of quinine, as given in the formula. The nature of the polymeric chain generated by the 21-axis parallel to the crystal b-axis is evident from Fig. 3. The polar space group requires all of the quinine molecules present to have the same absolute conguration, which is that with the R-conguration at C13 and C18, and the S-conguration at C15 and C17, in accord with previous studies [9, 23, 24]. The structure of this complex is interesting because it has extended zigzag chains. The coordination environment of the Zn(II) ion is tetrahedral and the metal center is bonded to a chloride ion Cl(26), oxygen atoms O(27) and O(30)i from bridging sulphate ions, and the quinoline nitrogen atom N(4) of the quinine moiety. There is linking of two polymeric chains related by the crystallographic twofold rotation axis to form a bilayer.

Fig. 2 The infra red spectra of polymeric zinc(II) quinine complex (A) and quinine hemisulfate (B)

Fig. 3 Portion of the polymeric chain showing atomic numbering of the asymmetric unit. For clarity, carbon atoms are labeled with a numeral only and H atoms are omitted. Atom O30i is the 21-screwrelated equivalent of O30. Thermal ellipsoids are drawn at the 40% probability level

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extensive network of hydrogen bonds contributes to the stabilization of the crystal structure. It has also been demonstrated here that hydrogen bonds play important roles in the self-assembly of the polymeric zinc(II) complex of quinine. Hydrogen bonding turns out to be one of the dominant stabilizing contributions in the crystal packing.

Conclusion To the best of our knowledge this work represents the rst study of a polymeric complex of zinc(II) containing quinine. Surprisingly, an oxygen atom from the sulfate counter-ion in quinine hemisulfate is coordinated to the Zn(II) centre.
Fig. 4 Hydrogen bonding of type OHO and N+HO (bifurcated) responsible for bilayer formation

Supporting Information Available The linking is achieved by hydrogen bonding (Table 4, Fig. 4) and assisted by some measure of p-stacking of ). quinoline rings (ring centroid-centroid distances $3.9 A There is a network of hydrogen bonds of the type OHO and N+HO, as shown in Fig. 4 and listed in Table 4. The quinine cation provides donors (OH and N+H) and the sulfate oxygen atoms act as acceptors. Thus, multipoint hydrogen bond interactions with a range of ) are present donoracceptor (DA) distances (2.783.17 A in the complex. The crystal packing is depicted in Fig. 5. The packing of the (C20H25ClN2O6SZn) units in the crystal structure consists of chains parallel to the b-axis, mutually interacting through the hydrogen bonding described above. An CCDC 629265 contains the supplementary Crystallographic data for this paper. These data can be obtained free of charge at http://www.ccdc.cam.ac.uk/conts/retrieving. html or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +4 1223336 033; e-mail: deposit@ccdc.cam.ac.uk).
Acknowledgment We are grateful for nancial support from Unilorin Senate Research Grant Committee. We thank the University of Cape Town and the NRF (Pretoria) for research support.

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Fig. 5 Packing diagram of the crystal structure of the title complex viewed down [010]

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