Crystal structure of bis[4-(1H-pyrrol-1-yl)phenyl] ferrocene-1,1′-dicarboxylate: a potential chemotherapeutic drug

The solid-state structure of a disubstituted ferrocene with electrochemically active pendant groups has been determined. This is a potential chemotherapeutic drug.

The title iron(II) complex, [Fe(C 16 H 12 NO 2 ) 2 ], crystallizes in the orthorhombic space group Pbca with the Fe 2+ cation positioned on an inversion center. The cyclopentadienyl (Cp) rings adopt an anti conformation in contrast with other substituted ferrocenes in which the Cp rings appear in a nearly eclipsed conformation. The Cp and the aromatic rings are positioned out of the plane, with a twist angle of 70.20 (12) , and the C(Cp)-C(CO) bond length is shorter than a typical C-C single bond, which suggests a partial double-bond character and delocalization with the Cp system. The structure of the complex is compared to other functionalized ferrocenes synthesized in our laboratory.

Chemical context
The gold standard of treatment for breast cancer has traditionally been cisplatin, a metal-based agent. Its administration, alone or in combination with other drugs, is also highly effective against various other types of cancers, including ovarian, head and neck, bladder, testicular and lung cancers (Galanski et al., 2005;Sandler et al., 2011). However, its clinical use suffers from major drawbacks, such as severe toxic side effects including neurotoxicity, hepatotoxicity, and nephrotoxicity (Pabla & Dong, 2008), as well as a drug-resistance phenomenon which leads to unsuccessful treatment (Dempke et al., 2000). Consequently, other metal-based drugs have been investigated, among them ferrocenes (Kö pf-Maier et al., 1984). Ferrocene has the versatility of easy functionalization providing a fertile field for structural modification and to study structure-activity relationship (SAR).

Structural commentary
The asymmetric unit contains one half-molecule since Fe 2+ lies on an inversion center, Fig. 1. This symmetry is implied by the NMR data where only one set of signals were found for H2/H5 and H3/H4 of the Cp rings, as well as the H2/H6 and H3/H5 of the phenyl and H2/H5 and H3/H4 of the pyrrole groups. Consequently, the Cp rings adopt a perfect anti conformation. The average Fe-C(Cp) bond length is 2.044 (10) Å , which is very similar to that reported for ferrocene (Dunitz et al., 1956) and other structures previously reported by our lab (Vera et al., 2014;Gao et al., 2009). The Fe-C bond length of the substituted carbon [Fe-C1 2.032 (2) Å ] is shorter that the remaining Fe-C bond lengths due to the inductive effect of the carboxylate on the Cp ring. The twist angles between the Cp ring and the carboxylate and the Cp ring and the aromatic ring are 14.4 (3) (above the Cp plane) and 70.20 (12) , respectively.
To put it in perspective, we compare (I) with previously synthesized ferrocenes in our group containing only one Cp functionalized and a phenyl group attached to the carboxylate, but with Br and Cl instead of pyrrole in the 4-position, (II) and (III) (CCDC 949002 and 949003, Vera et al., 2014). First, in the 4-bromophenyl and 4-chlorophenyl derivatives, the Cp rings are positioned in a nearly eclipsed conformation and parallel with stagger angles < 3 and Cp tilt angles of 0.48-1.25 . In contrast, (I) has a perfect anti conformation. The carbonyl carbon of (I) has a distorted trigonal-planar geometry, analogous to the 4-chlorophenyl and 4-bromophenyl ferrocenecarboxylates. The twist angles between the Cp ring and the carboxylate for 4-bromo and 4-chlorophenyl ferrocenecarboxylates (6.75-10.15 ) are smaller than that of the subject complex, 14.4 (3) . Additionally, as mentioned previously, the carbonyl oxygen of (I) lies above the Cp plane whereas for the bromo and chloro derivatives, the carbonyl oxygens lie below the Cp plane. The twist angle between the Cp and the aromatic ring is 70.20 (12) in (I), while in (II) and (III) the two rings are positioned at higher angles, approaching a perpendicular position.
The average Fe-C(Cp*) bond lengths of the substituted Cp rings in the 4-bromo and 4-chlorophenyl derivatives are identical, within experimental error, as in (I) [2.044 (13) Å ]. As mentioned before, the Fe-C bond length where the pendant group is attached is substantially shorter than the remaining Fe-C(Cp) distances. The same bonding pattern is also observed for the 4-bromo and 4-chlorophenyl ferrocenecarboxylates. The C(Cp)-C(CO) bond length in (I), C1-C6, is shorter than a typical C-C single bond, [1.473 (3) versus 1.54 Å (single bond); Pauling, 1960]. This suggests partial double-bond character and delocalization with the Cp system in analogous manner to that for the 4-bromo and 4chloro derivatives.
In the structure of the disubstituted ferrocene Fe(C 5 H 4-CO 2 CH 3 ) 2 , (IV) (Gao et al., 2009), the average Fe-C(Cp) bond lengths are 2.048 (11)/2.049 (14) Å , similar to the title complex but the Cp rings adopt almost an eclipsed conformation with a stagger angle of 2.37 (Fig. 2). In addition, the functional groups are not positioned perfectly anti to each other. The Fe-C(Cp)-C(CO) bond in (IV) [1.477 (4) Å ] is notably shorter than a typical C-C single bond (1.54 Å ), in a The molecular structure of (I), with displacement ellipsoids drawn at the 30% probability level. Unlabelled atoms are related to labelled ones by the symmetry operation Àx, Ày, Àz. similar manner to the title complex, suggesting delocalization with the Cp system.

Synthesis and crystallization
The synthesis of (I) was accomplished by treating 1,1 0ferrocenedicarboxylic acid with oxalyl chloride according to Crystallization of (I) was performed inside an NMR tube containing CD 2 Cl 2 for a period of two weeks, obtaining blockshaped orange crystals suitable for X-ray diffraction.

Special details
Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 )