Crystal structure of a copper–mefenamate complex solvated with diglyme and water

In the copper–mefenamate complex tetrakis[μ-2-(2,3-dimethylanilino)benzoato-κ2
 O:O′]bis[aquacopper(II)]–1-methoxy-2-(2-methoxyethoxy)ethane (1/2), [Cu2(C15H14NO2)4(H2O)2]·2C6H14O3, the asymmetric unit comprises a CuII cation coordinated to two mefenamate ligands solvated with a water molecule and a diglyme molecule. The complex adopts a paddlewheel motif and is compared to structural analogues crystallized with dimethylformamide and dimethyl sulfoxide.


Chemical context
Mefenamic acid is a non-steroidal anti-inflammatory drug (NSAID) that is synthesized through reaction of 2-chlorobenzoic acid and 2,3-dimethylaniline in the presence of a copper catalyst (Trinus et al., 1977). Subsequently, pharmacopoeia specifications for mefenamic acid specify a maximum limit of 10 ppm for the quantity of copper present in the final drug product (British Pharmacopoeia, 2017). In exploring strategies to ensure removal of copper from the crude reaction mixture, a new copper-mefenamate complex was isolated. The crystal structure of a copper-mefenamate complex solvated with water and diglyme is reported.

Structural commentary
The complex [Cu 2 (mefenamate) 4 (H 2 O) 2 ].2(diglyme) crystallizes in the space group P2 1 /n, with a {Cu 2 (RCO 2 ) 4 (H 2 O) 2 } paddlewheel motif that is typical for coordination of four carboxylate groups to two Cu II cations (Chong et al., 2022). Within the asymmetric unit (Fig. 1a), the planes of the 2,3dimethylphenyls from the two mefenamate molecules are 42.61 (1) apart. A water molecule occupies each of the apical positions of the paddlewheel motif, which is hydrogen bonded to a diglyme molecule (Fig. 1a). The diglyme molecule is oriented such that it fits between the 2,3-dimethyphenyl units of the two mefenamate molecules in the asymmetric unit and is hydrogen bonded to the coordinated water via the diglyme outer oxygen positions (Fig. 1a). A distorted square-pyramidal geometry is adopted by each Cu II cation in the paddlewheel motif ( Fig. 1b), with equatorial Cu-O distances of 1.968 (1), 1.961 (1), 1.954 (1), and 1.969 (1) Å between Cu II and the carboxylate moieties. The axial Cu-O distance, between the copper(II) cation and water molecule, is 2.108 (1) Å . The distance between the two Cu II cations is 2.6126 (4) Å . There is an intramolecular bond between the amine and carboxylate groups of the mefenamate, with OÁ Á ÁH distances of 1.86 (3) and 1.87 (2) Å for mefenamate units A and B, respectively (Table 1).

Supramolecular features
There are no obvious interactions, such asstacking, between neighbouring paddlewheel units within the packed structure. The paddlewheel units interact through edge-toface interactions of the phenyl groups of the mefanamate ligands (Fig. 1c). In the global packing of the structure, the paddlewheel units are arranged as 2D sheets along the crystallographic ab plane, with symmetry-equivalent sheets repeating throughout the crystallographic c axis at a distance corresponding to c. A second 2D arrangement is intercalated halfway between the symmetry-equivalent sheets.

Database survey
There are three other similar copper-mefenamate paddlewheel structures in the CSD (version 5.43, November 2021;Groom et al., 2016), with different solvents occupying the apical positions. Two entries, MPANCU10 (Yatsimirskii et al., 1979) and MPANCU20 (Mys'kiv et al., 1982), are with N,Ndimethylformamide (DMF) and one entry, SUTPIG (Facchin et al., 1998), has dimethyl sulfoxide (DMSO) occupying the apical position. The DMF analogue also crystallizes in a monoclinic space group ( Views of [Cu 2 (mefenamate) 4 (H 2 O) 2 ]Á2(diglyme) as an ORTEP representation with ellipsoids set to 50% probability: (a) asymmetric unit with hydrogen bonds highlighted (dashed blue lines), (b) a single paddlewheel unit of the complex, and (c) neighbouring units with edge-to-face interactions highlighted (dashed red lines). Table 1 Hydrogen-bond geometry (Å , ). in structures MPANCU20 and SUTPIG (Table 2). This may be attributed to the higher polarity of water (1.000) compared to DMF and DMSO (0.386 and 0.444, respectively; Reichardt & Welton, 2011). In the DMSO analogue, the 2,3-dimethylphenyls from the two mefenamate molecules within the asymmetric unit are almost coplanar, the planes are 9.06 apart, and the methyl groups of the DMSO point away from the 2,3-dimethylphenyls. For the DMF analogue, the two 2,3dimethylphenyls are oriented such that they can accommodate one of the methyl groups from the DMF, therefore the planes are 70.22 apart. Three polymorphic forms are known for mefenamic acid, with significant differences between the forms in the C9-N10-C11-C16 torsion angle 3 ( Fig. 1a; SeethaLekshmi & Guru Row, 2012). The larger torsion angle 3 observed with the copper complex (Table 2) is more consistent with those of the form I polymorph of À119.99 (XYANAC; McConnell & Company, 1976) and À120.1 (1) (XYANAC06; Mague & Ouzidan, 2017). The increased torsional angle can be explained by the location of the dimethylphenyl group with respect to the diglyme group. The phenyl group needs to rotate to ensure a more planar packing arrangement with the diglyme molecule. In comparison to other polymorphs, the metastable form II suffers from significant disorder around the dimethylphenyl ring system, however the torsion angle 3 is 68 (2) for XYANAC04 (SeethaLekshmi & Guru Row, 2012), 74.5 (3) for XYANAC05 (Yang et al., 2012) and À90 (2) for XYANAC07 (Abbas et al., 2017). The latter of these data collections is at high pressure and the disorder is not modelled, possibly because of the lack of data present due to the diamond anvil cell. The thermal parameters indicate that some disorder may still be present even at these higher pressures. For metastable form III, the reported torsion angle 3 is À80.8 (2) (XYANAC03; SeethaLekshmi & Guru Row, 2012).

Synthesis and crystallization
Chemicals were purchased from commercial suppliers and used as received without further purification. Deionized water was obtained from an in-house Milli-Q (Millipore) purification system. A solution was prepared comprising mefenamic acid (25.0 g), diglyme (281.6 g), water (74.7 g) and copper (II) acetate (7.3 g). An aliquot (4 mL) of this solution was removed and mefenamic acid (0.4 g) added to generate a slurry. The mixture was filtered and the filtrate stored in the dark at room temperature for two weeks, after which large green block-shaped crystals of the complex had formed.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 3. The diglyme moiety was found to be disordered over two positions. Initial isotropic refinement of the diglyme allowed the residual electron density to be observed. Using the functionality in OLEX2, the atoms were moved to ensure that they overlapped the electron density in a  Table 2 Comparison of selected geometries (Å , ).

Special details
Experimental. The X-ray intensities were collected on a Bruker D8 Venture diffractometer using a Photon 100 Detector. The data were reduced using APEX3 and absorption correction applied using SADABS (Bruker, 2016). The crystal structure was solved and refined using SHELXT and SHELXL via the Olex2 refinement package (Dolomanov et al., 2009). Non-hydrogen atom positions were refined anisotropically. Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes. Refinement. RIGU restarint applied. Diglyme disorder modelled using DFIX and SADI restraints. The ADPs for both diglyme parts were constrained using EADP constraint.