(3E)-5-Chloro-3-(2-phenyl­hydrazinyl­idene)-1H-indol-2(3H)-one

Bittencourt, V.C.D.; Almeida, R.M.F.C.; Bortoluzzi, A.J.; Gervini, V.C.; Oliveira, A.B. de

doi:10.1107/S2414314616002583

organic compounds

IUCrDATA

ISSN: 2414-3146

Volume 1| Part 2| February 2016| x160258

https://doi.org/10.1107/S2414314616002583

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(3E)-5-Chloro-3-(2-phenylhydrazinylidene)-1H-indol-2(3H)-one

Viviane C. D. Bittencourt,^a Roberta M. F. C. Almeida,^a Adailton J. Bortoluzzi,^b Vanessa C. Gervini ^a ^* and Adriano Bof de Oliveira ^c

^aEscola de Química e Alimentos, Universidade Federal do Rio Grande, Av. Itália km 08, Campus Carreiros, 96203-900 Rio Grande-RS, Brazil, ^bDepartamento de Química, Universidade Federal de Santa Catarina, Campus Universitário Trindade, 88040-900 Florianópolis-SC, Brazil, and ^cDepartamento de Química, Universidade Federal de Sergipe, Av. Marechal Rondon s/n, Campus, 49100-000 São Cristóvão-SE, Brazil
^*Correspondence e-mail: vanessa.gervini@gmail.com

Edited by H. Ishida, Okayama University, Japan (Received 5 February 2016; accepted 12 February 2016; online 20 February 2016)

The reaction between 5-cholroisatin and phenylhydrazine yields the title compound, C₁₄H₁₀ClN₃O. The molecular structure deviates slightly from the ideal planarity, with an r.m.s. deviation of 0.1372 (12) Å for the non-H atoms. An N—H⋯O intramolecular interaction is observed, which supports an E conformation with respect to the C=N bond. In the crystal, molecules are linked by a pair of N—H⋯O interactions into an inversion dimer. The dimers are linked by weak C—H⋯Cl interactions, formng a tape structure along [101]. The tapes are also linked through a weak π–π interaction [centroid–centroid distance = 3.5773 (8) Å] into a layer parallel to (-111). An in silico evaluation of the title compound with a topoisomerase enzyme was performed and the global free energy of −26.59 kJ mol⁻¹ was found.

Keywords: crystal structure; chloroisatin derivative; phenylhydrazone derivative; two-dimensional hydrogen-bonded network; in silico evaluation.

CCDC reference: 1453122

Structure description

The chemistry of isatin derivatives covers a wide range of scientific disciplines with special attention to medicinal chemistry (Vine et al., 2013 ). As part of our ongoing research into isatin derivatives, we report herein the crystal structure of the title compound (common name: 5-chloroisatine-3-phenylhydrazone).

The title molecule is nearly planar, with the r.m.s. deviation for the non-H atoms being 0.1372 (12) Å for atom C11 (Fig. 1). In the crystal, molecules are linked by N—H⋯O and weak C—H⋯Cl interactions (Table 1) into a hydrogen-bonded tape structure along [101] (Fig. 2). In addition, a weak π–π interaction between the pyrrole and phenyl rings [centroid–centroid distance = 3.5773 (8) Å] connects the tapes, forming a layer parallel to ( $[\overline{1}]$ 11). C⋯C contacts of C2ⁱⁱⁱ⋯C9 = 3.2866 (15) Å, C7ⁱⁱⁱ⋯C7 = 3.3309 (14) Å and C13⋯C6^iv = 3.3888 (14) Å are also observed between adjacent tapes [Fig. 3; symmetry codes: (iii) −x + 1, −y + 2, −z + 1; (iv) −x + 1, −y + 1, −z + 1].

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N3—H1N3⋯O1	0.95	2.00	2.7581 (12)	136
N1—H1N1⋯O1ⁱ	0.89	1.97	2.8431 (12)	167
C14—H8⋯Cl1ⁱⁱ	0.95	2.90	3.5476 (12)	127
Symmetry codes: (i) -x+2, -y+2, -z+1; (ii) x+1, y, z+1.

Figure 1
The molecular structure of the title compound, showing the atom labelling and displacement ellipsoids drawn at the 50% probability level.

Figure 2
A packing diagram of the title compound, viewed along the c axis. Intermolecular N—H⋯O and C—H⋯Cl hydrogen bonds are shown as dashed lines. The planar hydrogen-bonded tapes are stacked along the b axis. Intramolecular N—H⋯O interactions are not shown for clarity.

Figure 3
A packing diagram of the title compound, viewed along the a axis. The weak C⋯C contacts are shown as dashed lines. [Symmetry codes: (iii) −x + 1, −y + 2, −z + 1; (iv) −x + 1, −y + 1, −z + 1.]

An in silico evaluation of the title compound with the DNA topoisomerase IIα was performed using PatchDock (Duhovny et al., 2002 ; Schneidman-Duhovny et al., 2005 ) and FireDock (Andrusier et al., 2007 ; Mashiach et al., 2008 ). The crystal data of the enzyme was obtained from Protein Data Bank (PDB ID: 1ZXM; Wei et al., 2005 ). Intermolecular interactions between the isatin–hydrazone derivative and the DNA topoisomerase IIα were found with the lowest binding energy score after 50 RBO cycles (Rigid-Body Optimization). The selected nonbonding interactions are H1N1⋯O (SER320) = 2.4849 Å, OE1 (GLN309)⋯Cl1 = 2.5168 Å, O (GLN310)⋯Cg1 = 2.18535 Å and CG2 (ILE311)⋯Cg2 = 3.58398 Å, where Cg1 and Cg2 are the centroids of the pyrrole aromatic ring and the terminal phenyl ring, respectively (Fig. 4). The global free energy of −26.59 kJ mol⁻¹ was found for the 5-chloroisatine-3-phenylhydrazone/DNA topoisomerase IIα interaction. After the refinement, the top-ranked conformation was analysed using the Discovery Studio Modeling Environment software (Accelrys Software, 2013 ). The results of the evaluation agree with literature data for molecular docking and cytotoxic activity of hydrazone derivatives against breast cancer cells (Dandawate et al., 2012 ).

Figure 4
Intermolecular interactions between the title compound and the DNA topoisomerase IIα enzyme. The interactions are shown as yellow dashed lines and the figure is simplified for clarity.

Synthesis and crystallization

All starting materials are commercially available and were used without further purification. The synthesis was adapted from a procedure reported previously (Hajare et al., 2009 ; Fonseca et al., 2011 ). The glacial acetic acid catalyzed reaction of 5-chloroisatin (3 mmol) and phenylhydrazine (3 mmol) in methanol (40 ml) was refluxed for 4 h. After cooling and filtering, single crystals suitable for X-ray diffraction were obtained.

Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2.

Table 2
Experimental details

Crystal data
Chemical formula	C₁₄H₁₀ClN₃O
M_r	271.70
Crystal system, space group	Triclinic, P $[\overline{1}]$
Temperature (K)	200
a, b, c (Å)	6.8759 (4), 8.2563 (5), 12.0403 (7)
α, β, γ (°)	109.156 (2), 103.979 (2), 91.485 (2)
V (Å³)	622.41 (6)
Z	2
Radiation type	Mo Kα
μ (mm⁻¹)	0.30
Crystal size (mm)	0.40 × 0.18 × 0.02

Data collection
Diffractometer	Bruker APEXII CCD
Absorption correction	Multi-scan (SADABS; Bruker, 2013 )
T_min, T_max	0.706, 0.746
No. of measured, independent and observed [I > 2σ(I)] reflections	14457, 3638, 2877
R_int	0.021
(sin θ/λ)_max (Å⁻¹)	0.705

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.035, 0.104, 1.09
No. of reflections	3638
No. of parameters	172
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.39, −0.21
Computer programs: APEX2 (Bruker, 2013), SAINT (Bruker, 2013), SHELXS97 (Sheldrick, 2008 ), SHELXL97 (Sheldrick, 2008), DIAMOND (Brandenburg, 2006 ), publCIF (Westrip, 2010 ), enCIFer (Allen et al., 2004 ).

Structural data

CCDC reference: 1453122

Crystal structure: contains datablocks I, Global. DOI: https://doi.org/10.1107/S2414314616002583/is5445sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2414314616002583/is5445Isup2.hkl

Figure: Surface view of the DNA topoisomerase II alpha enzyme. The docked title compound is shown in a red stick model. DOI: https://doi.org/10.1107/S2414314616002583/is5445sup3.tif

Supporting information file. DOI: https://doi.org/10.1107/S2414314616002583/is5445Isup4.cml

checkCIF report

Computing details top

Data collection: APEX2 (Bruker, 2013); cell refinement: SAINT (Bruker, 2013); data reduction: SAINT (Bruker, 2013); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: DIAMOND (Brandenburg, 2006); software used to prepare material for publication: publCIF (Westrip, 2010) and enCIFer (Allen et al., 2004).

(3E)-5-Chloro-3-(2-phenylhydrazinylidene)-1H-indol-2(3H)-one top

Crystal data top

C₁₄H₁₀ClN₃O	Z = 2
M_r = 271.70	F(000) = 280
Triclinic, P1	D_x = 1.450 Mg m⁻³
a = 6.8759 (4) Å	Mo Kα radiation, λ = 0.71073 Å
b = 8.2563 (5) Å	Cell parameters from 6679 reflections
c = 12.0403 (7) Å	θ = 2.6–30.0°
α = 109.156 (2)°	µ = 0.30 mm⁻¹
β = 103.979 (2)°	T = 200 K
γ = 91.485 (2)°	Plate, yellow
V = 622.41 (6) Å³	0.40 × 0.18 × 0.02 mm

Data collection top

Bruker APEXII CCD diffractometer	3638 independent reflections
Radiation source: fine-focus sealed tube, Bruker APEXII	2877 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.021
φ and ω scans	θ_max = 30.1°, θ_min = 1.9°
Absorption correction: multi-scan (SADABS; Bruker, 2013)	h = −9→9
T_min = 0.706, T_max = 0.746	k = −11→11
14457 measured reflections	l = −16→16

Refinement top

Refinement on F²	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F² > 2σ(F²)] = 0.035	Hydrogen site location: inferred from neighbouring sites
wR(F²) = 0.104	H-atom parameters constrained
S = 1.09	w = 1/[σ²(F_o²) + (0.0597P)² + 0.0323P] where P = (F_o² + 2F_c²)/3
3638 reflections	(Δ/σ)_max < 0.001
172 parameters	Δρ_max = 0.39 e Å⁻³
0 restraints	Δρ_min = −0.21 e Å⁻³

Special details top

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 F² against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The threshold expression of F² > 2sigma(F²) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F² 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 (Å²) top

	x	y	z	U_iso*/U_eq
C1	0.58736 (15)	0.89630 (14)	0.28628 (10)	0.0247 (2)
C2	0.55505 (17)	0.93700 (15)	0.18143 (11)	0.0296 (2)
H1	0.6619	0.9890	0.1627	0.036*
C3	0.36025 (18)	0.89929 (16)	0.10383 (11)	0.0322 (3)
H2	0.3329	0.9255	0.0308	0.039*
C4	0.20611 (17)	0.82329 (16)	0.13323 (11)	0.0305 (2)
C5	0.23752 (16)	0.78126 (15)	0.23827 (10)	0.0277 (2)
H3	0.1304	0.7292	0.2567	0.033*
C6	0.43115 (15)	0.81814 (13)	0.31527 (10)	0.0239 (2)
C7	0.51991 (15)	0.79309 (13)	0.42956 (10)	0.0238 (2)
C8	0.73649 (15)	0.86214 (14)	0.46652 (10)	0.0254 (2)
C9	0.43396 (16)	0.65136 (14)	0.66321 (10)	0.0250 (2)
C10	0.22536 (17)	0.61127 (16)	0.63139 (11)	0.0319 (3)
H4	0.1434	0.6236	0.5595	0.038*
C11	0.1392 (2)	0.55320 (18)	0.70614 (13)	0.0402 (3)
H5	−0.0029	0.5250	0.6847	0.048*
C12	0.2568 (2)	0.53545 (18)	0.81179 (12)	0.0392 (3)
H6	0.1959	0.4954	0.8623	0.047*
C13	0.4635 (2)	0.57654 (17)	0.84283 (11)	0.0366 (3)
H7	0.5447	0.5653	0.9153	0.044*
C14	0.55336 (18)	0.63397 (15)	0.76915 (11)	0.0305 (2)
H8	0.6956	0.6613	0.7907	0.037*
Cl1	−0.03571 (5)	0.77931 (5)	0.03465 (3)	0.04731 (12)
N3	0.53041 (13)	0.71228 (12)	0.59226 (8)	0.0268 (2)
H1N3	0.6698	0.7526	0.6194	0.040*
N1	0.76714 (13)	0.92054 (13)	0.37801 (9)	0.0279 (2)
H1N1	0.8812	0.9812	0.3846	0.042*
N2	0.42461 (13)	0.72598 (11)	0.48848 (8)	0.0249 (2)
O1	0.86352 (11)	0.86715 (11)	0.56087 (8)	0.0320 (2)

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
C1	0.0212 (5)	0.0253 (5)	0.0263 (5)	0.0014 (4)	0.0054 (4)	0.0079 (4)
C2	0.0292 (5)	0.0334 (6)	0.0288 (5)	0.0011 (4)	0.0098 (4)	0.0126 (5)
C3	0.0340 (6)	0.0381 (6)	0.0260 (5)	0.0045 (5)	0.0065 (5)	0.0140 (5)
C4	0.0249 (5)	0.0373 (6)	0.0271 (5)	0.0040 (4)	0.0024 (4)	0.0115 (5)
C5	0.0221 (5)	0.0320 (6)	0.0278 (5)	0.0002 (4)	0.0037 (4)	0.0108 (4)
C6	0.0218 (5)	0.0242 (5)	0.0252 (5)	0.0015 (4)	0.0055 (4)	0.0087 (4)
C7	0.0200 (4)	0.0245 (5)	0.0254 (5)	0.0006 (4)	0.0035 (4)	0.0085 (4)
C8	0.0207 (5)	0.0256 (5)	0.0286 (5)	0.0006 (4)	0.0042 (4)	0.0096 (4)
C9	0.0264 (5)	0.0221 (5)	0.0250 (5)	0.0004 (4)	0.0051 (4)	0.0074 (4)
C10	0.0269 (5)	0.0373 (6)	0.0318 (6)	−0.0005 (5)	0.0035 (4)	0.0157 (5)
C11	0.0317 (6)	0.0489 (8)	0.0420 (7)	−0.0041 (5)	0.0112 (5)	0.0179 (6)
C12	0.0457 (7)	0.0412 (7)	0.0348 (6)	−0.0031 (6)	0.0150 (6)	0.0159 (5)
C13	0.0455 (7)	0.0378 (7)	0.0264 (6)	0.0021 (5)	0.0054 (5)	0.0142 (5)
C14	0.0290 (5)	0.0330 (6)	0.0275 (5)	0.0010 (4)	0.0026 (4)	0.0114 (5)
Cl1	0.02844 (16)	0.0736 (3)	0.03773 (19)	0.00142 (15)	−0.00409 (12)	0.02592 (17)
N3	0.0215 (4)	0.0317 (5)	0.0263 (5)	−0.0017 (3)	0.0014 (3)	0.0128 (4)
N1	0.0200 (4)	0.0341 (5)	0.0293 (5)	−0.0020 (4)	0.0042 (3)	0.0126 (4)
N2	0.0233 (4)	0.0258 (5)	0.0244 (4)	0.0004 (3)	0.0032 (3)	0.0096 (4)
O1	0.0216 (4)	0.0400 (5)	0.0331 (4)	−0.0018 (3)	−0.0001 (3)	0.0165 (4)

Geometric parameters (Å, º) top

C1—C2	1.3794 (16)	C9—C10	1.3929 (15)
C1—N1	1.4038 (13)	C9—C14	1.3935 (15)
C1—C6	1.4089 (14)	C9—N3	1.4004 (14)
C2—C3	1.3953 (16)	C10—C11	1.3844 (17)
C2—H1	0.9500	C10—H4	0.9500
C3—C4	1.3910 (17)	C11—C12	1.3874 (18)
C3—H2	0.9500	C11—H5	0.9500
C4—C5	1.3880 (16)	C12—C13	1.3819 (19)
C4—Cl1	1.7429 (11)	C12—H6	0.9500
C5—C6	1.3864 (14)	C13—C14	1.3853 (17)
C5—H3	0.9500	C13—H7	0.9500
C6—C7	1.4479 (15)	C14—H8	0.9500
C7—N2	1.3051 (13)	N3—N2	1.3271 (12)
C7—C8	1.4866 (14)	N3—H1N3	0.9470
C8—O1	1.2422 (13)	N1—H1N1	0.8924
C8—N1	1.3613 (14)

C2—C1—N1	128.82 (10)	C10—C9—N3	121.88 (10)
C2—C1—C6	121.93 (10)	C14—C9—N3	117.84 (10)
N1—C1—C6	109.24 (9)	C11—C10—C9	119.00 (11)
C1—C2—C3	117.80 (10)	C11—C10—H4	120.5
C1—C2—H1	121.1	C9—C10—H4	120.5
C3—C2—H1	121.1	C10—C11—C12	121.15 (12)
C4—C3—C2	120.09 (10)	C10—C11—H5	119.4
C4—C3—H2	120.0	C12—C11—H5	119.4
C2—C3—H2	120.0	C13—C12—C11	119.36 (12)
C5—C4—C3	122.47 (10)	C13—C12—H6	120.3
C5—C4—Cl1	118.70 (9)	C11—C12—H6	120.3
C3—C4—Cl1	118.83 (9)	C12—C13—C14	120.57 (11)
C6—C5—C4	117.51 (10)	C12—C13—H7	119.7
C6—C5—H3	121.2	C14—C13—H7	119.7
C4—C5—H3	121.2	C13—C14—C9	119.65 (11)
C5—C6—C1	120.19 (10)	C13—C14—H8	120.2
C5—C6—C7	133.19 (10)	C9—C14—H8	120.2
C1—C6—C7	106.62 (9)	N2—N3—C9	120.29 (9)
N2—C7—C6	125.89 (9)	N2—N3—H1N3	118.1
N2—C7—C8	127.52 (10)	C9—N3—H1N3	121.4
C6—C7—C8	106.58 (9)	C8—N1—C1	110.82 (9)
O1—C8—N1	126.93 (10)	C8—N1—H1N1	123.5
O1—C8—C7	126.34 (10)	C1—N1—H1N1	124.9
N1—C8—C7	106.73 (9)	C7—N2—N3	117.79 (9)
C10—C9—C14	120.27 (10)

N1—C1—C2—C3	179.90 (11)	N2—C7—C8—N1	−179.18 (11)
C6—C1—C2—C3	0.42 (17)	C6—C7—C8—N1	−0.52 (12)
C1—C2—C3—C4	0.07 (18)	C14—C9—C10—C11	−0.35 (18)
C2—C3—C4—C5	−0.35 (19)	N3—C9—C10—C11	−179.38 (11)
C2—C3—C4—Cl1	179.58 (9)	C9—C10—C11—C12	0.4 (2)
C3—C4—C5—C6	0.14 (17)	C10—C11—C12—C13	0.0 (2)
Cl1—C4—C5—C6	−179.80 (9)	C11—C12—C13—C14	−0.4 (2)
C4—C5—C6—C1	0.34 (16)	C12—C13—C14—C9	0.38 (19)
C4—C5—C6—C7	−179.66 (11)	C10—C9—C14—C13	−0.01 (18)
C2—C1—C6—C5	−0.64 (17)	N3—C9—C14—C13	179.05 (11)
N1—C1—C6—C5	179.79 (10)	C10—C9—N3—N2	−3.13 (16)
C2—C1—C6—C7	179.36 (10)	C14—C9—N3—N2	177.82 (10)
N1—C1—C6—C7	−0.21 (12)	O1—C8—N1—C1	−178.77 (11)
C5—C6—C7—N2	−0.9 (2)	C7—C8—N1—C1	0.40 (12)
C1—C6—C7—N2	179.13 (10)	C2—C1—N1—C8	−179.66 (11)
C5—C6—C7—C8	−179.56 (11)	C6—C1—N1—C8	−0.13 (13)
C1—C6—C7—C8	0.44 (12)	C6—C7—N2—N3	179.80 (10)
N2—C7—C8—O1	0.00 (19)	C8—C7—N2—N3	−1.79 (17)
C6—C7—C8—O1	178.66 (11)	C9—N3—N2—C7	175.99 (10)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N3—H1N3···O1	0.95	2.00	2.7581 (12)	136
N1—H1N1···O1ⁱ	0.89	1.97	2.8431 (12)	167
C14—H8···Cl1ⁱⁱ	0.95	2.90	3.5476 (12)	127

Symmetry codes: (i) −x+2, −y+2, −z+1; (ii) x+1, y, z+1.

Acknowledgements

The authors acknowledge the Laboratory of Crystallography at the Federal University of Santa Catarina and the financial support from FINEP (Brazil). A. BO acknowledges Professor José C. M. Pereira (UNESP, Brazil) and FAPESP (Brazil) for the support through the Proc. 2015/12098-0. M. Sc. Renan Lira de Farias (Federal University of Sergipe, Brazil) is gratefully acknowledged for his help with the molecular docking calculations.

References

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