Tetrakis{2-[2-(2,6-dichloroanilino)phenyl]ethanoato-κ2 O:O′}bis[(dimethyl sulfoxide-κO)copper(II)](Cu—Cu): a binuclear CuII complex with the non-steroidal anti-inflammatory drug diclofenac

The title compound, [Cu2(C14H10Cl2NO2)4(C2H6OS)2], comprises a CuII 2 core that is quadruply bridged by four carboxylate ligands with the dimethyl sulfoxide ligands binding along the Cu⋯Cu axis. The four carboxylate ligands bind in a bidentate syn–syn bridging mode. Molecules reside on crystallographic inversion centres bisecting the mid-point of the Cu⋯Cu axis. There are no intermolecular interactions of note.

The title compound, [Cu 2 (C 14 H 10 Cl 2 NO 2 ) 4 (C 2 H 6 OS) 2 ], comprises a Cu II 2 core that is quadruply bridged by four carboxylate ligands with the dimethyl sulfoxide ligands binding along the CuÁ Á ÁCu axis. The four carboxylate ligands bind in a bidentate syn-syn bridging mode. Molecules reside on crystallographic inversion centres bisecting the mid-point of the CuÁ Á ÁCu axis. There are no intermolecular interactions of note.

Related literature
Cu II complexes of non-steroidal anti-inflammatory drugs (NSAIDs) show enhanced anti-inflammatory activity and reduced gastrointestinal toxicity compared with their uncomplexed parent drug, see: Weder et al. (2002). The structure of the Cu-NSAID is likely to be an important factor for its biological activity. For example, the anti-tumor activity of the monomeric Cu II complex of aspirin ([Cu(Asp) 2 (py) 2 ]) is reportedly more effective than the dimeric [Cu 2 (Asp) 4 ] complex, see: Oberley & Buettner (1979). It has been shown that dinuclear Cu-NSAID complexes exhibit similar biological activity to mononuclear complexes, but with higher stability (Dimiza et al., 2011), making them relevant compounds in the treatment of tumor cell lines (Theodorou et al., 1999). For mono-and binuclear Cu II complexes of diclofenac, see: Sayen et al. (2012) Table 1 Selected geometric parameters (Å , ).  gastrointestinal toxicity compared with their uncomplexed parent drug (Weder et al., 2002). Furthermore, little is known of their pharmacokinetic and biodistribution profile in both humans and animals, stabilty in biological media, or of the relative potency/efficacy of the Cu II monomeric versus Cu II dimeric complexes. The structure of the Cu-NSAID is likely to be an important factor for its biological activity. For example, the anti-tumor activity of the monomeric Cu II complex of aspirin ([Cu(Asp) 2 (py) 2 ]) is reportedly more effective than the dimeric [Cu 2 (Asp) 4 ] complex (Oberley & Buettner, 1979). Thus, it appears to be essential to obtain structural information on Cu (II) complexes of NSAIDs in order to fully understand their biological activity. Being able to act as a ligand through its carboxylate function of the aromatic ring, different diclofenac complexes (Cu-NSAID complex) were described in the literature. It gives rise to a mononuclear [Cu(diclofenac) 2 (H 2 O) 2 ].2H 2 O complex (Sayen et al., 2012) and a binuclear [Cu 2 (diclofenac) 4 (DMF) 2 ] complex without a metal-metal bond (Kovala-Demertzi et al., 1997). The former resulted in a distorted octahedral geometry, whereas the latter resulted in a binuclear copper complex where each metal centre is described as a perfect square bipyramid with a DMF oxygen occupying apical position. In order to favour the metal···metal bond, which stabilizes the complex and thus impact the biological activity, we have tried various coordinating solvents during the recrystallization.
The structure of the binuclear [bis(2-[2-(2,6-dichlorophenyl)aminophenyl]ethanoate)bis(DMSO)copper(II)] complex (I) has been obtained. It consists of a quadruply bridged neutral molecule lying on a crystallographic centre of inversion ( Fig. 1). Indeed, the four carboxylato moieties act as bridging ligands exhibiting a centre of symmetry midway between the two Cu atoms. The solvent used in the synthesis binds in the position trans to the Cu-Cu axis. The dimeric structure has a Cu-Cu distance of 2.6619 (12) Å, with an octahedral stereochemistry tetragonally elongated along the Cu-Cu-O solvent axis due to the Jahn-Teller effect (Table 1).
In the binuclear unit, the carboxylic acids are fully deprotonated to balance the charge from the Cu II ions. The stability of the structure is ensured via a network of /p···/p interactions involving the phenyl acetate rings of the diclofenac molecules. On the other hand, no intermolecular H-bonding is observed (Fig. 2).
The use of DMSO solvent allowed the formation of a binuclear complex with a Cu 2 metal core, which stabilizes the complex in biological media. It was shown that binuclear Cu-NSAID complexes exhibit similar biological activity as the mononuclear complex, but with a higher stability (Dimiza et al., 2011), making them relevant compounds in the treatment of tumor cell lines (Theodorou et al., 1999).
The [bis(2-[2-(2,6-dichlorophenyl)aminophenyl]ethanoate)bis(DMSO)copper(II)] was prepared from a mixture of copper sulfate and diclofenac sodium salt in the molar ratio 1:2 in deionized water. After stirring for 2 hrs at room temperature, the reaction mixture was filtered and the green precipitate was washed with water and dried in air. Crystals suitable for Xray diffraction measurements were obtained by slow evaporation of a DMSO solution of the complex.

Figure 1
A representation of the title compound (I) with displacement ellipsoids at the 30% probability level.  The π···π stacking interactions in the [Cu 2 (diclofenac) 4 (DMSO) 2 ] complex (H atoms are omitted for clarity).

Tetrakis{2-[2-(2,6-dichloroanilino)phenyl]ethanoato-κ 2 O:O′}bis[(dimethyl sulfoxide-κO)copper(II)](Cu-Cu)
Crystal data Refinement. Refinement of F 2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expression of F 2 > σ(F 2 ) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 )
x y z U iso */U eq