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Acta Chim. Slov. 1999, 46(2), pp. 203-211
CRYSTAL STRUCTURE AND CHARACTERIZATION OF A NEW COPPER(II)-CIPROFLOXACIN (cf) COMPLEX [Cu(cf)(H2O)3]SO4.2H2O#
Iztok Turela*, Ljubo Goliča, Oscar Leonel Ruiz Ramirezb
University of Ljubljana, Faculty of Chemistry and Chemical Technology, Aškerčeva 5,
1000 Ljubljana, Slovenia Universidad Nacional Autonoma de Mexico, Instituto de Quimica, Mexico
(Received 18.3.1999)
Abstract
A   new   copper   complex   of  quinolone   ciprofloxacin   (cf)   with   the   formula
[Cu(cf)(H2O)3]SO4.2H2O was isolated and its crystal structure was determined by X-ray crystallography. There is a slightly distorted square pyramidal coordination around central copper ion in the structure. Quinolone molecule is bonded to the metal through carbonyl O(3) atom (Cu-O(3) =1.939(1) X) and carboxylic O(1) atom (Cu-O(1) =1.915(2) X). Two water molecules are coordinated to copper in the basal plane with distances Cu-O(8) =1.972 (2) X and Cu-O(9) =1.989(2) X. The apical water molecule is coordinated at a longer distance (Cu-O(10) =2.174(2)X). This structural pattern is considerably different from the bonding in copper-quinolone complexes reported in the literature so far.
Introduction
Quinolones are a group of synthetic antibacterial agents active against various microorganisms [1]. They have a complex forming ability with several metal cations and
Dedicated to the memory of Prof. Dr. Jože Šiftar
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they bond in most cases through carboxyl group at position 3 and ring carbonyl group at position 4. Ciprofloxacin (cf = 1-cyclopropyl-6-fluoro-4-oxo-7-(1-piperazinyl)-1,4-dihydroquinoline-3-carboxylic acid) is a typical member of this family (see Scheme).
O
O
HN
4'
OH
The crystal structures of the metal ion-quinolone complexes reported in the literature include several metal ions; copper [2-4], cobalt [5], silver [6], zinc [7] and cadmium [8, 9]. Simple copper complexes of various quinolones are the most frequent [2-4], but the number of copper complexes is higher if we also consider mixed ligand complexes containing additional ligands [10-13]. In all simple copper complexes reported, the copper(II) ion is bonded to two quinolone molecules bidentately through one of the carboxylic oxygens and ring carbonyl oxygen. In contrast it was found that metal ions are not bonded to the quinolone in the highly acidic medium. At such conditions ionic compounds containing protonated quinolones were isolated [14-17].
In our previous studies we have studied the copper(II)-ciprofloxacin system by different physico-chemical methods. The crystal structure of [Cu(cf)2]Cl2.6H2O was determined [2]. This system was also studied in the solution. The stability constants were calculated by potentiometric method [18] and the NMR relaxation rates were also determined [19]. From both later techniques the indications were obtained that appart from prevailing Cu:cf = 1:2 complex also some species with different bonding mode or even different stoichiometric ratio of metal-quinolone could be present in the solution.
The aim of this study was to isolate any new compounds from copper-cf system and to characterize the new products by different physico-chemical techniques.
5
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Experimental
Synthesis
Copper(II) sulphate pentahydrate (0.079 g) was dissolved in 20 mL of distilled water. The solution was stirred and ciprofloxacin (0.100 g) was added. The colour of the solution slightly changed from light blue to green. The green crystals were grown by evaporation on air. Found: C, 35.21; H, 4.70; N, 7.14. C17H28N3O12CuFS requires C, 35.14; H, 4.82; N, 7.24%.
Analyses and physical measurements
The analyses of carbon, hydrogen and nitrogen were carried out on a Perkin-Elmer 204C microanalyzer.
Infrared spectra were recorded in the solid state on Nujol mulls between CsI
windows on a Perkin-Elmer 1720X FT-IR spectrometer. Conditions: range 4000-220
--cm 1 , resolution 2 cm 1, number of scans 10.
Crystal data, data collection summary and refinement parameters of the title
compound are given in Table 1. An automated Enraf-Nonius CAD-4 diffractometer with
MoK" was used for the determination of the unit cell and data collection. The following
programs were used: for data collection CAD-4 Software [20], cell refinement: X-ray
PARAM (local program). Xtal 3.2 [21] was used for data reduction, solving and refining
the structure. ORTEP program was used to prepare molecular illustrations [22]. All
hydrogen atoms but two were found in the difference map and were not refined.
During the refinement of the structure a difference map showed some additional
maxima around sulfur with a reasonable S-O distance. These peaks correspond to
another position of sulfate group O4’, O5’, O6’ and O7’ with the same position of a
sulfur atom (Figure 1). The refinement was continued with constrained population
parameters of O4, O5, O6, O7 and O4’, O5’, O6’, O7’ to sum 1.0. The average angle
between these two orientations is 480.
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Figure 1: Disordered position of a sulfate ion.
Table 1. Crystal Data and Structure Refinement for [Cu(cf)(H2O)3]SO4.2H2O.
Empirical formula
Formula weight
Temperature
Wavelength
Crystal system
Space group
Unit cell dimensions
Volume
Z
Density (calculated)
Absorption coefficient
F(000)
Crystal size
Theta range for data collection
Index ranges
Reflections collected
Independentr eflections
Refinementm ethod
Data / restraints / parameters
Goodness-of-fit on F
Final R indices [I>2.5 (I) ]
R indices (all data)
Largest diff. peak and hole
C17H28CuFN3O12S
580.5
293(2) K
0.71069 C
Monoclinic
P21/c
a = 14.816(1) C
b = 14.965(2) C     $ = 93.02(1)°
c = 10.517(1) C
2328.6(4) C3
4
1.657 g/cm3
1.097 mm-1
1204
irregular form (0.30 x 0.38 x 0.38 mm)
1-28°
-19 # h #19, 0# k # 19, -13 # l #13
11667
5591[R(int) = 0.036]
Full-matrix least-squares on F
3654/ 7 / 353
0.936
R1 = 0.032 , wR2 = 0.031
R1 = 0.069, wR2 = 0.058
0.6 and -1.3 e.C-3
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Results and Discussion
Description of the Crystal Structure
There is a distorted square pyramidal coordination around copper ion in the crystal structure of [Cu(cf)(H2O)3]SO4.2H2O. A view of the complex with atomic labelling is given in Figure 2 and Figure 3 shows the stereoscopic view of the title compound unit cell. Final relevant atomic positions are given in Table 2.
Table 2. Fractional nonhydrogen atomic coordinates, equivalent isotropic displacement (A2) and population parameters.
= (1/3)SiSjUijai*aj*ai.aj
	x	y	z	Ueq	p
Cu	0.80393(2)	0.60057(2)	0.47467(2)	0.02677(7)	
S	1.02749(4)	0.68421(4)	0.23672(5)	0.0305(2)	
F	0.47828(9)	0.3958(1)	0.1047(1)	0.0462(5)	
O(1)	0.7510(1)	0.6554(1)	0.6174(1)	0.0350(5)	
O(2)	0.6469(1)	0.7365(1)	0.7048(2)	0.0450(6)	
O(3)	0.6904(1)	0.5480(1)	0.4124(2)	0.0329(5)	
O(4)	1.0263(2)	0.6242(2)	0.3448(3)	0.0511(9)	0.794(6)
O(5)	1.1158(2)	0.7288(3)	0.2332(4)	0.056(1)	0.794(6)
O(6)	1.0082(2)	0.6377(2)	0.1184(3)	0.066(1)	0.794(6)
O(7)	0.9599(3)	0.7562(2)	0.2522(4)	0.064(1)	0.794(6)
O(4')	1.0346(8)	0.712(1)	0.3668(9)	0.064(4)	0.206(6)
O(5')	1.1077(7)	0.7010(7)	0.168(1)	0.042(3)	0.206(6)
O(6')	1.0185(7)	0.5788(6)	0.248(1)	0.059(4)	0.206(6)
O(7')	0.9403(5)	0.7108(8)	0.180(1)	0.042(3)	0.206(6)
O(8)	0.9235(1)	0.6292(1)	0.5558(2)	0.0447(6)	
O(9)	0.8655(1)	0.5243(1)	0.3509(2)	0.0354(5)	
O(10)	0.7967(1)	0.7187(1)	0.3542(2)	0.0406(5)	
O(11)	0.8491(1)	0.3604(1)	0.4405(2)	0.0496(6)	
O(12)	0.1062(2)	0.6161(2)	-0.0883(2)	0.0668(8)	
N(1)	0.4407(1)	0.6558(1)	0.4671(2)	0.0267(5)	
N(81)	0.3060(1)	0.4698(1)	0.1291(2)	0.0287(5)	
N(84)	0.1500(1)	0.4410(1)	-0.0358(2)	0.0382(6)	
C(2)	0.5133(1)	0.6801(1)	0.5405(2)	0.0283(6)	
C(3)	0.5988(1)	0.6478(1)	0.5287(2)	0.0268(6)	
C(31)	0.6703(1)	0.6829(2)	0.6234(2)	0.0295(6)	
C(4)	0.6145(1)	0.5829(1)	0.4339(2)	0.0253(6)	
C(5)	0.5354(1)	0.5543(1)	0.3566(2)	0.0239(5)	
C(6)	0.5424(1)	0.4883(2)	0.2621(2)	0.0277(6)	
C(7)	0.4683(1)	0.4625(2)	0.1898(2)	0.0291(6)	
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C(8)	0.3809(1)	0.5001(1)	0.2022(2)	0.0251(5)
C(9)	0.3743(1)	0.5644(1)	0.2964(2)	0.0252(5)
C(10)	0.4498(1)	0.5913(1)	0.3731(2)	0.0237(5)
C(11)	0.3516(1)	0.6921(2)	0.4875(2)	0.0320(6)
C(12)	0.3148(2)	0.7624(2)	0.3980(3)	0.0489(9)
C(13)	0.3426(2)	0.7861(2)	0.5328(3)	0.0490(9)
C(82)	0.3124(2)	0.4663(2)	-0.0098(2)	0.0349(7)
C(83)	0.2393(2)	0.4074(2)	-0.0697(2)	0.0405(7)
C(85)	0.1426(2)	0.4441(2)	0.1047(2)	0.0347(7)
C(86)	0.2172(1)	0.5019(2)	0.1646(2)	0.0285(6)
Figure 2: View of the title compound. Note that the crystallographic numbering scheme is different as a conventional numbering scheme.
Table 3 lists selected values of bond distances and angles. The copper atom is coordinated in the plane by four oxygen atoms. Ciprofloxacin molecule is bonded to the metal through carbonyl O(3) atom (Cu-O(3) =1.939(1) C) and carboxylic O(1) atom
209
(Cu-O(1) =1.915(2) C). Two water molecules are coordinated to copper in the basal plane with distances (Cu-O(8) =1.972(2) C) and (Cu-O(9) =1.989(2) C). The apical water molecule is coordinated at a longer distance (Cu-O(10) =2.174(2)C). As far to our knowledge this is the first example of the metal-quinolone complex with such bonding where the molar ratio of metal:quinolone is 1:1 (normally 1:2 ratio was observed). The Cu-O(1) and Cu-O(3) lenghts are comparable to corresponding distances in the reported copper-quinolone complexes where two quinolones are bidentately bonded to the copper [2-4]. The charge of the [Cu(cf)(H2O)3]2+ cation is compensated by a sulphate anion. It is interesting that the terminal nitrogen atom of piperazine ring system of ciprofloxacin is protonated whereas the carboxylic group is deprotonated. The molecule of ciprofloxacin thus exists in the form of zwitter ion also in this compound.
Table 3: Selected Bond Distances (C)			and Angles (°).
Cu-O(1)	1.915(2)	O(1)-Cu-O(3)	93.15(7)
Cu-O(3)	1.939(1)	O(1)-Cu-O(8)	87.90(7)
Cu-O(8)	1.972(2)	O(1)-Cu-O(10)	95.65(7)
Cu-O(9)	1.989(2)	O(3)-Cu-O(8)	167.76(8)
Cu-O(10)	2.174(2)	O(3)-Cu-O(9)	88.03(7)
S-O(4')	1.43(1)	O(3)-Cu-O(10)	96.77(7)
S-O(6)	1.441(3)	O(8)-Cu-O(9)	88.58(7)
S-O(5')	1.44(1)	O(8)-Cu-O(10)	95.26(8)
S-O(4)	1.449(3)	O(9)-Cu-O(10)	95.49(7)
S-O(7')	1.451(8)	O(4')-S-O(5')	113.8(7)
S-O(5)	1.471(3)	O(4')-S-O(7')	109.5(7)
S-O(7)	1.485(4)	O(6)-S-O(4)	111.6(2)
S-O(6')	1.59(1)	O(6)-S-O(5)	109.5(2)
O(1)-C(31)	1.270(3)	O(6)-S-O(7)	109.9(2)
O(2)-C(31)	1.236(3)	O(5')-S-O(7')	119.1(7)
O(3)-C(4)	1.272(2)	O(5')-S-O(6')	106.5(6)
		O(4)-S-O(5)	110.4(2)
		O(4)-S-O(7)	109.1(2)
		O(7')-S-O(6')	103.0(6)
		O(5)-S-O(7)	106.2(2)
		O(4')-S-O(6')	103.1(8)
The quinolone  molecule  is  more or less planar with the exception of the cyclopropyl group that is sticking out of the plane, and the piperazine ring system that is
210
in the normal chair conformation. All the distances and angles between the atoms are comparable to those found in [Cu(cf)2]Cl2.6H2O [2].
There are additionally two water molecules in the structure that are involved in the complex hydrogen bonding network.
The infrared spectra of the title compound and [Cu(cf)2]Cl2.6H2O [2] are very similar due to the same atoms of quinolone involved in the bonding to the metal. The main difference represent the typical strong bands that could be assigned to free sulfate ion [23] vibrations and were found at 1142, 1085 and 632 cm-1 in the spectrum of the title compound.
Figure 3: Stereoscopic view of the title compound.
Supplementary Material: anisotropic thermal displacement parameters, hydrogen position parameters with isotropic displacement parameters, additional bond lenghts and angles, are available on request from the authors.
211
Acknowledgements
This work was supported by the grant No. Z1-8601-0103-98 of the Ministry of Sciences and Technology, Republic of Slovenia. We also thank to Prof. Dr. Manuel Salmon and Universidad Nacional Autonoma de Mexico, Instituto de Quimica, Mexico for the grant for O.L.R.R. (CONACYT 25267 A, DGAPA No. 1N500597).
References
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[19] I. Turel, J. Košmrlj, B. Andersen, E. Sletten, Metal Based Drugs, accepted for publication. [20] Enraf-Nonius, CAD-4 Software, Version 5.0, Enraf-Nonius, Delft, The Netherlands (1989). [21]  S.R. Hall, H. D. Flack, J. M. Stewart Editors, Xtal 3.2, Reference Manual, Universities of Western
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Povzetek
Sintetizirali smo nov bakrov kompleks kinolona ciprofloksacina s formulo [Cu(cf)(H2O)3]SO4.2H20 in določili njegovo kristalno strukturo. Koordinacijo okrog bakrovega iona v spojini lahko opišemo kot rahlo popačeno kvadratno piramido. Kinolon je vezan na kovino preko karbonilnega O(3) atoma (Cu-O(3) =1.939(1) X) in karboksilnega O(1) atoma (Cu-O(1) =1.915(2) X). Na baker sta v bazalni ravnini koordinirani še dve molekuli vode (Cu-O(8) =1.972(2) X) , (Cu-O(9) =1.989(2) X). Vrh piramide zaseda molekula vode na razdalji, ki je nekoliko daljša (Cu-O(10) =2.174(2)X). Način vezave je bistveno drugačen kot v bakrovih kompleksih kinolonov opisanih v literaturi.