Crystal and geometry-optimized structure, and Hirshfeld surface analysis of 1-(2-bromoethyl)indoline-2,3-dione

In the title compound, the isatin (1H-indole-2,3-dione) moiety is almost planar (r.m.s. deviation = 0.026 Å). In the crystal, molecules are linked by C—H⋯O hydrogen bonds, forming layers parallel to the ab plane, and enclosing (24) loops.


Chemical context
Isatin (1H-indole-2,3-dione) is an endogenous compound that has been identified in humans and possesses a wide range of biological activities, such as anxiogenic and sedative activities. It serves as a synthetically useful substrate which can be used to prepare a broad range of heterocyclic compounds, including molecules of pharmacological significance (Bekircan & Bektas, 2008). A variety of biological activities are associated with isatin, including central nervous system (CNS) activities (Raj, 2012). As part of our interest in the identification of bioactive compounds, we report herein on the synthesis, the crystal structure, and the geometry optimization and Hirshfeld surface analysis of the title isatin derivative, (I).

Structural commentary
The molecular structure of the title isatin derivative, (I), is illustrated in Fig. 1. It crystallized in the orthorhombic space group P2 1 2 1 2 1 with an absolute structure parameter of 0.015 (8). The bond lengths and angles of the isatin moiety are comparable with those reported for similar N-substituted isatin derivatives (Qachchachi et al., 2016a,b). ISSN 2056-9890 In compound (I), the isatin ring system is almost planar, with an r.m.s. deviation of the fitted atoms C1-C8/N1/O1/O2 of 0.026 Å . The sum of the bond angles around atom N1 is ca 360 , indicating little evidence for the presence of an sp 3 lone pair.

Database survey
A search of the Cambridge Structural Database (Version 5.37, update May 2016; Groom et al., 2016) for N-substituted isatin derivatives yielded 58 hits. These include five reports of the structure of isatin itself and four reports of the structure of Nmethylisatin. 13 of the structures involve an alkyl chain of two or more C atoms. The compound most similar to the title compound is 1-(3-bromopropyl)-1H-indole-2,3-dione (AKO-BIN), whose structure was published very recently (Qach-chachi et al., 2016a). A view of the structural overlap of this compound with that of compound (I) is shown in Fig. 3.

Geometry optimization
The geometry optimization of compound (I) was performed using the density functional theory (DFT) method with a 6-311++G** basis set. The crystal structure in the solid state was used as the starting structure for the calculations. The DFT calculations are performed with the GAUSSIAN09 program package (Frisch et al., 2013). The resulting geometrical parameters are compared with those obtained from an X-ray crystallography study. A superimposed analysis of (I) with its optimized structure gives an r.m.s. deviation of 0. The molecular structure of compound (I), showing the atom labelling. Displacement ellipsoids are drawn at the 30% probability level. Table 1 Hydrogen-bond geometry (Å , ). Symmetry codes: (i) Àx þ 1; y þ 1 2 ; Àz þ 1 2 ; (ii) Àx þ 2; y þ 1 2 ; Àz þ 1 2 .

Figure 2
A view along the c axis of the crystal packing of compound (I). The hydrogen bonds are shown as dashed lines (see Table 1) and, for clarity, only H atoms H2 and H10A have been included.
( Fig. 4). This indicates a twist leading to further separation between the isatin moiety and the benzene ring. Also, this suggests that the crystal packing could be influenced by the collective effect of the intermolecular interactions. To probe further, structure-based theoretical parameters, viz. HOMO and LUMO energy levels, total energy and dipole moment, were calculated and found to be À6.860 eV, À3.091 eV, À86134.81 eV and 7.2176 Debye, respectively. As a further structure-based test, semi-empirical molecular orbital calculations are carried out using the PM7 method in MOPAC2012 (Stewart, 2012;Maia et al., 2012). The PM7 method gave the HOMO and LUMO energy levels, total energy and dipole moment as À9.276 eV, À1.271 eV, À2334.96 eV and 5.8952 Debye, respectively. Also, the superimposed analysis of the X-ray structure with the isolated molecule in the gas phase by the PM7 method gave an r.m.s. deviation of 0.211 Å . Further, the N1-C8 and N1-C1 (X-ray: Views of the Hirshfeld surfaces mapped with d norm in two different orientations for compound (I). The represented interactions are labelled (see Table 1).

Figure 4
Superimposed fit of the molecule of compound (I) in the crystalline state (red) and after energy minimization (blue). (I) is shown in Fig. 5, and the respective points of intermolecular interactions are labelled. Two-dimensional fingerprint plots are used to quantify and visualize the intermolecular interactions present in the crystal structure and the same for the title compound is shown in Fig. 6. The result suggests that the share of intermolecular HÁ Á ÁH contacts in (I) is about 19.3%. The low percentage could be attributed to the presence of the Br atom in the bromoethylene group, which makes ca 18.7% contacts with H atoms (BrÁ Á ÁH). The next significant intermolecular contacts observed in the structure, i.e. OÁ Á ÁH, CÁ Á ÁH and CÁ Á ÁC, have relative contributions of 30.6, 18.8 and 3.1%, respectively.

Synthesis and crystallization
To a solution of 1-{2-[(2-bromoethyl)amino]phenyl}ethanone (1 equivalent) in DMSO were added I 2 (0.1 equivalents) and TBHP (1 equivalent, 70% in H 2 O) at ambient temperature, and the mixture was heated to 353 K. The progress of the reaction was monitored by thin-layer chromatography. Upon completion, the reaction mixture was allowed to cool to ambient temperature and was quenched with aqueous sodium thiosulfate and ethyl acetate. The organic phase was separated, dried over Na 2 SO 4 , filtered and concentrated. The crude product was purified by silica-gel column chromatography using hexane-ethyl acetate (9:1 v/v) as eluent. The title compound was obtained as a red solid (yield: 71%, 74.5 mg; m.p. 404-406 K). It was dissolved in a mixture of hexane-ethyl acetate (9:1 v/v) and left to slowly evaporate at room temperature, yielding brown block-like crystals after a period of 3 d.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. C-bound H atoms were included in calculated positions and treated as riding, with C-H = 0.93-0.97 Å and U iso (H) = 1.2U eq (C).

Special details
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.