Synthesis and structure of 1-(2-bromophenyl)-2-chloro-3-(2-chloracetyl)-1H-indole

In this indole derivative, the dihedral angle between the mean plane of the indole ring system and the mean plane of the benzene ring of the 2-bromophenyl group is 77.6 (1)°. In the crystal, pairs of molecules are face-to-face embraced via two weak C—H⋯O hydrogen bonds, forming inversion dimers which are connected by head-to-head Cl⋯Cl intermolecular contacts to build a molecular sheet parallel to (101). Neighbouring sheets are stacked together by further short Cl⋯Cl intermolecular contacts to construct the three-dimensional structure.


Chemical context
Indole derivatives occur in many natural products and they have been widely used as intermediates in the pharmaceutical industry (Chaskar et al., 2010). Indolyl is the base skeleton of tryptophan, which is one of the essential amino acids of human beings. In addition, indole derivatives such as indole-3-acetic acid (Won et al., 2011), serotonin (Batsikadze et al., 2013) and melatonin (Diss et al., 2013) act as hormones existing in different kinds of plants and animals. Some indole derivatives show anticarcinogenic, hypotensive and antineoplastic activities . The indole skeleton can be found in many bioactive drugs, such as ajmalicine (Du et al., 2014), vinblastine (Ishikawa et al., 2008) and reserpine (Chen & Huang, 2005).

Structural commentary
As shown in Fig. 1, the molecule consists basically of two planes, the indole unit and the phenyl ring. Nine non-H atoms (N1/C1-C8) are essentially planar and their mean plane defines the indole plane. Five more non-H atoms are approximately co-planar with the indole core with deviations of À0.050 (2) Å for C15, 0.067 (1) Å for Cl1, 0.032 (1) Å for O1, À0.190 (2) Å for C16, and À0.355 (1) Å for Cl2. The C4-H4Á Á ÁO1 short intermolecular contact (see Table 1) plays an important role in keeping the four non-H atoms of chloracetyl co-planar with the indole plane. The mean plane of the 2-bromophenyl ring (defined as the mean plane of the six C atoms of the major component and six C atoms of the minor component of the disordered benzene ring of the 2-bromophenyl group) subtends a dihedral angle of 77.6 (1) to the indole plane.
The deviation of atom N1 from the C1,C8,C9 triangle is very small [0.005 (2) Å ], indicating sp 2 hybridization of this atom. The five-membered ring of the indole core shows similar bond-length characteristics to those of the reference structure 2-iodo-1-phenyl-1H-indole (Messaoud et al., 2015). The C1 C2 bond [1.374 (2) Å ] is slightly longer than a double bond and longer than that of the reference structure. This is because of certain C1 . . . C2 . . . C15 -conjugation of the three atoms, revealed by the shorter single bond C2-C15 [1.463 (2) Å ]. The C1-N1 bond shows strong double-bond character with a length of 1.365 (2) Å while C8-N1 [1.3939 (19) Å ] is shorter than a single C-N bond. Both the C1-N1 and the C8-N1 bond lengths are shorter than those of the reference structure.
The intermolecular interactions can be scaled by the electronic transfer integrals (t) between two neighbouring molecules and can be calculated according to Deng & Goddard, 2004) as t = (E HOMO À E HOMO-1 )/2 where E HOMO and E HOMO-1 are the energy levels of the HOMO (highest occupied molecular orbital) and the HOMO-1 orbital of a two-molecule pair, respectively. The calculation was carried out by DFT methods at the level of b31yp/6-311g(d) using the GAUSSIAN03 program (Frisch et al., 2003).   Symmetry code: (i) Àx þ 1; Ày þ 1; Àz þ 1.

Figure 2
A view along the a* direction, showing the C10-H10AÁ Á ÁO1 i hydrogen bond in a dimer and the Cl2Á Á ÁCl2 ii short contact forming chains along the b-axis direction. [Symmetry codes: (i) Àx + 1, Ày + 1, Àz + 1; (ii) Àx + 1, Ày + 2, Àz + 1.] the face-to-face molecular pair (the dimer), the Cl2Á Á ÁCl2 head-to-head pair, and the Cl1Á Á ÁCl1 side-by-side pair were calculated to be 0.051, 0.00053, 0.00076 eV, respectively. This indicates that the intermolecular interactions of the dimer are the strongest. Fig. 4 shows the calculated electronic transfer integrals (t) of an isolated face-to-face dimer versus the spacing between the two indole planes of the dimer. When varying the spacing, the molecular configuration is fixed to the X-ray molecular structure that resulted from a non-disorder refinement. The spacing (3.493 Å ) at the peak of the t-curve is slightly larger than the spacing [3.359 (3) Å ] in the X-ray structure, indicating a shrinking of the spacing of the dimer when the crystal packing is concerned.

Database survey
A search of the Cambridge Structural Database (WebCSD, last update 2016-10-26) for the substructure of the non-H 1Hindole skeleton gave 6467 hits. There are 151 structures which contain the 1-phenyl-1H-indole substructure. The only structure of the 2-halogen-1-phenyl-1H-indole type is 2-iodo-1phenyl-1H-indole (Messaoud et al., 2015) and no structure for the title compound. There are no records of this compound in the SciFinder Database.

Synthesis and crystallization
The title compound was synthesized in three steps (see Fig. 5). Firstly, compound 2 was synthesized by acylation of compound 1 with chloracetyl chloride in N, N-dimethylacetamide (DMF). Compound 1 (6.58 g, 26.5 mmol), chloracetyl chloride (3.2 mL, 40 mmol), and DMF solvent (2 mL) were added into a 250 mL flask and the mixture was stirred at 353 K for 2 h. Then 200 mL water was added into the mixture and it was kept stirring for 0.5 h. The colorless products (13.9 g) were compound 2 together with some unreacted chloracetyl chloride.
Secondly, a Friedel-Crafts reaction of compound 2, under the catalysis of anhydrous AlCl 3 , resulted in the ring-closure compound 3. To a 250 mL flask, compound 2 (8.22 g, The evolution of the calculated electronic transfer integrals (t) as a function of spacing between the two molecules of the face-to-face dimer. The optimized spacing at the peak t-curve and the spacing in the X-ray structure are indicated.

Figure 3
A view along the c-axis direction, showing the C-HÁ Á ÁO hydrogen bonds (see Table 1) and ClÁ Á ÁCl contacts as dashed lines. Only H atoms H4 and H10A have been included. The C atoms of the minor component of the disordered benzene ring have been omitted.  25.4 mmol) and anhydrous AlCl 3 (10.15 g, 76.1 mmol) were added and stirred mechanically for 15 minutes at 460 K. The mixture was poured into 200 mL water and extracted with CH 2 Cl 2 . The crude product was purified by silica gel column chromatography with ethyl acetate and petroleum ether (v/v = 1:10) as eluent. Compound 3 was obtained together with some residual chloracetyl chloride (3.50 g in all).
Finally, the title compound 4 was obtained as a by-product of trimerization of compound 3 in the presence of POCl 3 and chloracetyl chloride. As shown in Fig. 5, the Cl atom bonded to the indole core should come from POCl 3 , which is supported by our other experiment. Compound 3 (0.92 g, 3.2 mmol) and 6 mL POCl 3 were added into a 100 mL Schlenk tube and the mixture was stirred at 383 K in an argon atmosphere for 9 h. After cooling, the mixture was poured into 500 mL ice-water and stirred intensely until a black solid appeared. The solid was dissolved in CH 2 Cl 2 , washed with water and dried with MgSO 4 . The solvent was removed and the crude solid was initially separated by silica gel column chromatography with ethyl acetate and petroleum ether (v/v = 1:100) as eluent to obtain a mixture, which consists of the compound of trimerization (will be reported elsewhere) and the title compound 4. The colorless crystals of compound 4 (0.0093 g, m. p. 456-458 K), which were suitable for X-ray structure determination, were obtained by a silica gel column chromatography of the above mixture with n-hexane as eluent, following a quick evaporation of the n-hexane solution overnight. 1

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. H atoms of the disordered benzene ring were placed at calculated positions and refined using a riding-model approximation with C-H = 0.93 Å and U iso = 1.2U eq (C). All other H atoms were located in difference maps and freely refined, leading to C-H distances from 0.85 (2) to 1.08 (2) Å . The 2-bromophenyl group was refined as disordered over two sets of sites, which gave better results (R 1 = 0.032, Á max = 0.27). By comparison, the results of the nondisordered treatment were relatively poor (R 1 = 0.043, Á max = 0.93). However, the non-disordered molecular geometry was used for DFT calculation in this work. The 1 H NMR spectra of the title compound.  Data collection: APEX2 (Bruker, 2005); cell refinement: SAINT (Bruker, 2005); data reduction: SAINT (Bruker, 2005); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXTL (Sheldrick, 2008).

Special details
Experimental. Scan width 0.3° ω , Crystal to detector distance 5.964 cm, exposure time 10s, 10 hours for data collection, without scale. The 4 omiga-run take the following theta, initial-omiga, phi values and the following sweep-ranges, respectively -25, -28, 0, 186 (negatively run) -28, 146, 180, 186 (positively run) -33, -28, 90, 186 (negatively run) -33, 127, 270, 220 (positively run) 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. 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 > 2sigma(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 Occ. (