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Crystal structure, Hirshfeld analysis and mol­ecular docking with the vascular endothelial growth factor receptor-2 of (3Z)-5-fluoro-3-(hy­dr­oxy­imino)­indolin-2-one

aUniversidade Federal do Rio Grande (FURG), Escola de Química e Alimentos, Rio Grande, Brazil, bUniversidade Estadual Paulista (UNESP), Instituto de Química, Araraquara, Brazil, and cUniversidade Federal de Sergipe (UFS), Departamento de Química, São Cristóvão, Brazil
*Correspondence e-mail: vanessa.gervini@gmail.com

Edited by C. Rizzoli, Universita degli Studi di Parma, Italy (Received 27 May 2017; accepted 5 June 2017; online 7 June 2017)

The reaction between 5-fluoro­isatin and hydroxyl­amine hydro­chloride in acidic ethanol yields the title compound, C8H5FN2O2, whose mol­ecular structure matches the asymmetric unit and is nearly planar with an r.m.s. deviation for the mean plane through all non-H atoms of 0.0363 Å. In the crystal, the mol­ecules are linked by N—H⋯N, N—H⋯O and O—H⋯O hydrogen-bonding inter­actions into a two-dimensional network along the (100) plane, forming rings with R22(8) and R12(5) graph-set motifs. The crystal packing also features weak ππ inter­actions along the [100] direction [centroid-to-centroid distance 3.9860 (5) Å]. Additionally, the Hirshfeld surface analysis indicates that the major contributions for the crystal structure are the O⋯H (28.50%) and H⋯F (16.40%) inter­actions. An in silico evaluation of the title compound with the vascular endothelial growth factor receptor-2 (VEGFR-2) was carried out. The title compound and the selected biological target VEGFR-2 show the N—H⋯O(GLU94), (CYS96)N—H⋯O(isatine) and (PHE95)N—H⋯O(isatine) inter­molecular inter­actions, which suggests a solid theoretical structure–activity relationship.

1. Chemical context

The chemistry of isatin is already well documented due to its wide range of applications, especially in organic synthetic chemistry and medicinal chemistry. The first reports on the synthesis of isatin and isatin-based derivatives can be traced back to the first half of the 19th century (Erdmann, 1841a[Erdmann, O. L. (1841a). Ann. Chim. Phys. 3, 355-371.],b[Erdmann, O. L. (1841b). J. Prakt. Chem. 22, 257-299.]; Laurent, 1841[Laurent, A. (1841). Ann. Chim. Phys. 3, 371-383.]) and almost one hundred years after those publications, the review `The Chemistry of Isatin' showed the versatility of this mol­ecular fragment (Sumpter, 1944[Sumpter, W. C. (1944). Chem. Rev. 34, 393-434.]). Two recent examples of this are the synthesis of 1-[(2-methyl­benzimidazol-1-yl) meth­yl]-2-oxo-indolin-3-yl­idene]amino]­thio­urea, an in vitro and in silico Chikungunya virus inhibitor (Mishra et al., 2016[Mishra, P., Kumar, A., Mamidi, P., Kumar, S., Basantray, I., Saswat, T., Das, I., Nayak, T. K., Chattopadhyay, S., Subudhi, B. B. & Chattopadhyay, S. (2016). Sci. Rep. 6, 20122.]) and 5-chloro­isatin-4-methyl­thio­semi­carbazone, an inter­mediate in the HIV-1 (human immuno­deficiency virus type 1) RT (reverse transcriptase) inhibitor (Meleddu et al., 2017[Meleddu, R., Distinto, S., Corona, A., Tramontano, E., Bianco, G., Melis, C., Cottiglia, F. & Maccioni, E. (2017). J. Enzyme Inhib. Med. Chem. 32, 130-136.]). For these reasons, the crystal structure determination of isatin-based mol­ecules is an intensive research field and one of our major research aims. Herein, the structure, the Hirshfeld surface analysis and the mol­ecular docking with the vascular endothelial growth factor receptor-2 (VEGFR-2) of the 5-fluoro­isatin-3-oxime are reported.

[Scheme 1]

2. Structural commentary

The mol­ecular structure of the title compound (Fig. 1[link]) matches the asymmetric unit and it is nearly planar with an r.m.s. deviation from the mean plane of the non–H atoms of 0.0363 Å [from −0.0806 (9) Å for atom O2 to 0.0575 (11) Å for atom C2]. The C1—C2—N2—O2 and C3—C2—N2—O2 torsion angles are −174.24 (10) and −0.5 (2)°, respectively.

[Figure 1]
Figure 1
The mol­ecular structure of the title compound with displacement ellipsoids drawn at the 40% probability level.

3. Supra­molecular features and Hirshfeld surface analysis

In the crystal, the mol­ecules are connected by centrosymmetric pairs of N1—H4⋯O1i [symmetry code: (i) −x + 1, −y + 2, −z + 1] inter­molecular inter­actions into dimers with graph-set motif R22(8) (Table 1[link]). In addition, a remarkable feature consists in an asymmetric bifurcated hydrogen bond with graph-set motif R12(5) involving the H5 atom of the oxime group and the O1ii and N2ii atoms of a neighboring mol­ecule [symmetry code: (ii) −x + 1, y − [{1\over 2}], −z + [{3\over 2}]]. These two hydrogen bonds, which form rings with motifs R22(8) and R12(5), connect the mol­ecules into a two-dimensional, tape-like network parallel to the (100) plane. Finally, the mol­ecules are stacked along the [100] direction by weak ππ inter­actions (Fig. 2[link]) between the benzene and the indolic five-membered rings. The centroid-to-centroid distance is 3.9860 (5) Å).

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A D—H H⋯A DA D—H⋯A
N1—H4⋯O1i 0.91 (2) 1.96 (2) 2.8487 (16) 164.7 (18)
O2—H5⋯N2ii 0.99 (3) 2.69 (2) 3.2989 (16) 120.2 (18)
O2—H5⋯O1ii 0.99 (3) 1.77 (3) 2.7280 (15) 163 (2)
Symmetry codes: (i) -x+1, -y+2, -z+1; (ii) [-x+1, y-{\script{1\over 2}}, -z+{\script{3\over 2}}].
[Figure 2]
Figure 2
Crystal structure of the title compound viewed along the [010] direction. The H⋯O and H⋯N inter­actions in the crystal packing are shown as dashed lines and connect the mol­ecules into a two-dimensional H-bonded network along the (100) plane. The CgCg packing along the [100] direction is also shown as dashed lines.

The Hirshfeld surface analysis (Hirshfeld, 1977[Hirshfeld, H. L. (1977). Theor. Chim. Acta, 44, 129-138.]) of the crystal structure for the title compound was performed. The surface graphical representation, dnorm, with transparency and labelled atoms indicates, in magenta colour, the locations of the strongest inter­molecular contacts, e.g. H4, H5 and O1, which are important for the inter­molecular hydrogen bonding (Fig. 3[link]a). The Hirshfeld analysis suggests that the major contributions for the crystal packing amount to 25.40% for H⋯O, 16.40% for H⋯F and 16.10% for H⋯H inter­actions. Other important inter­molecular contacts for the cohesion of the structure are (values given in %): C⋯C = 11.30, H⋯N = 9.80 and H⋯C = 6.40 (Wolff et al., 2012[Wolff, S. K., Grimwood, D. J., McKinnon, J. J., Turner, M. J., Jayatilaka, D. & Spackman, M. A. (2012). CRYSTAL EXPLORER. University of Western Australia, Perth, Australia.]; Fig. 4[link]).

[Figure 3]
Figure 3
The Hirshfeld surface graphical representation (dnorm) for the asymmetric unit of (a) the title compound, 5-fluoro­isatin-3-oxime, and (b) the comparison compound, 5-chloro­isatin-3-oxime (Martins et al., 2016[Martins, B. B., Gervini, V. C., Pires, F. C., Bortoluzzi, A. J. & de Oliveira, A. B. (2016). IUCrData, 1, x161506.]). The surface regions with strongest inter­molecular inter­actions are drawn in magenta colour.
[Figure 4]
Figure 4
Hirshfeld surface two-dimensional fingerprint plots for the title compound showing the (a) H⋯O, (b) H⋯F, (c) H⋯H, (d) C⋯C, (e) H⋯N and (f) H⋯C contacts in detail (cyan dots). The contributions of the inter­actions to the crystal packing amount to 25.40%, 16.40%, 16.10%, 11.30%, 9.80% and 6.40%, respectively. The de (y axis) and di (x axis) values are the closest external and inter­nal distances (values in Å) from given points on the Hirshfeld surface contacts.

4. Comparison with a related structure

For a comparison with the title compound, 5-fluoro­isatin-3-oxime, the structure of the related compound 5-chloro­isatin-3-oxime (Martins et al., 2016[Martins, B. B., Gervini, V. C., Pires, F. C., Bortoluzzi, A. J. & de Oliveira, A. B. (2016). IUCrData, 1, x161506.]) was selected. Both structures are nearly planar, build a two-dimensional hydrogen-bonded network parallel to the (100) plane and show the mol­ecules stacked along the [100] direction. The Hirshfeld surface analysis (Hirshfeld, 1977[Hirshfeld, H. L. (1977). Theor. Chim. Acta, 44, 129-138.]) for 5-chloro­isatin-3-oxime was carried out and the Hirshfeld surface graphical representation, dnorm, with transparency and labelled atoms indicates, in magenta colour, the locations of the strongest inter­molecular contacts, e.g. H1, H5 and O1 (Fig. 3[link]b). Although the crystal packing (Figs. 2[link] and 5[link]) and the Hirshfeld surface graphical representations (Fig. 3[link]a,b) for the title compound and the 5-chloro­isatin-3-oxime are quite similar, the contributions of the inter­molecular inter­actions to the cohesion of the crystal structures have differences due to the halogen substituents. For example: for 5-chloro­isatin-3-oxime, the H⋯O inter­action amounts to 23.60% and the H⋯Cl inter­action amounts to 18.10%. The contributions to the crystal packing are shown as Hirshfeld surface two-dimensional fingerprint plots with cyan dots. The de (y axis) and di (x axis) values are the closest external and inter­nal distances (Å) from given points on the Hirshfeld surface contacts (Figs. 4[link] and 6[link]; Wolff et al., 2012[Wolff, S. K., Grimwood, D. J., McKinnon, J. J., Turner, M. J., Jayatilaka, D. & Spackman, M. A. (2012). CRYSTAL EXPLORER. University of Western Australia, Perth, Australia.]).

[Figure 5]
Figure 5
Crystal structure of the comparison compound 5-chloro­isatin-3-oxime (Martins et al., 2016[Martins, B. B., Gervini, V. C., Pires, F. C., Bortoluzzi, A. J. & de Oliveira, A. B. (2016). IUCrData, 1, x161506.]), viewed along the [010] direction.
[Figure 6]
Figure 6
Hirshfeld surface two-dimensional fingerprint plots for the comparison compound 5-chloro­isatin-3-oxime (Martins et al., 2016[Martins, B. B., Gervini, V. C., Pires, F. C., Bortoluzzi, A. J. & de Oliveira, A. B. (2016). IUCrData, 1, x161506.]) showing the (a) H⋯O and (b) H⋯Cl contacts in detail (cyan dots). The contributions of the inter­actions to the crystal packing amount to 23.60% and 18.10%. The de (y axis) and di (x axis) values are the closest external and inter­nal distances (values in Å) from given points on the Hirshfeld surface contacts.

5. Mol­ecular docking evaluation

For a lock-and-key supra­molecular analysis, a mol­ecular docking evaluation between the title compound and the vascular endothelial growth factor receptor-2 (VEGFR-2) was carried out. Initially, the semi-empirical equilibrium energy of the small mol­ecule was obtained using the PM6 Hamiltonian, but the experimental bond lengths were conserved. The calculated parameters were: heat of formation = −49.353 kJ mol−1, gradient normal = 0.90997, HOMO = −9.265 eV, LUMO = −1.337 eV and energy gap = 7.928 eV (Macrae et al., 2008[Macrae, C. F., Bruno, I. J., Chisholm, J. A., Edgington, P. R., McCabe, P., Pidcock, E., Rodriguez-Monge, L., Taylor, R., van de Streek, J. & Wood, P. A. (2008). J. Appl. Cryst. 41, 466-470.]; Stewart, 2013[Stewart, J. J. P. (2013). J. Mol. Model. 19, 1-32.], 2016[Stewart, J. J. P. (2016). MOPAC2016. Stewart Computational Chemistry, Colorado Springs, Colorado, United States of America.]). The biological target prediction for the title compound was calculated with the SwissTargetPrediction webserver based on the bioisosteric similarity to the isatin entity (Gfeller et al., 2013[Gfeller, D., Michielin, O. & Zoete, V. (2013). Bioinformatics, 29, 3073-3079.], 2014[Gfeller, D., Grosdidier, A., Wirth, M., Daina, A., Michielin, O. & Zoete, V. (2014). Nucleic Acids Res. 42, W32-W38.]). As result of this screening, the title compound showed a promising theoretical structure–activity relationship to kinase proteins sites: `Frequency Target Class' for kinases amounts to 33% [see the `SwissTargetPrediction report (5-fluoro­isatin-3-oxime)' in the Supporting information]. The protein kinases regulate several critical cellular processes (Wang & Cole, 2014[Wang, Z. & Cole, P. A. (2014). Methods Enzymol. 548, 1-21.]) and the vascular endothelial growth factor receptor-2 kinase inhibition is becoming an attractive subject for anti­cancer drug research (Gao et al., 2015[Gao, H., Su, P., Shi, Y., Shen, X., Zhang, Y., Dong, J. & Zhang, J. (2015). Eur. J. Med. Chem. 90, 232-240.]). The crystal structure of the vascular endothelial growth factor receptor-2 (VEGFR-2), PDB ID: 3WZD, was downloaded from Protein Data Bank (Okamoto et al., 2015[Okamoto, K., Ikemori-Kawada, M., Jestel, A., von König, K., Funahashi, Y., Matsushima, T., Tsuruoka, A., Inoue, A. & Matsui, J. (2015). ACS Med. Chem. Lett. 6, 89-94.]). Before the calculations, a stereochemical evaluation of the protein structure was carried out using the Ramachandran analysis (Lovell et al., 2003[Lovell, S. C., Davis, I. W., Arendall, W. B., de Bakker, P. I., Word, J. M., Prisant, M. G., Richardson, J. S. & Richardson, D. C. (2003). Proteins, 50, 437-450.]) and the number of residues in favoured regions for inter­molecular inter­actions was over 98% [see the `Number of residues in favoured region (VEGFR-2)' in the Supporting information]. The docking simulation was performed with the GOLD 5.5 software (Chen, 2015[Chen, Y.-C. (2015). Trends Pharmacol. Sci. 36, 78-95.]) and a grid of 25 Å was centered on the binding site of Levatinib in the VEGFR-2 kinase (Okamoto et al., 2015[Okamoto, K., Ikemori-Kawada, M., Jestel, A., von König, K., Funahashi, Y., Matsushima, T., Tsuruoka, A., Inoue, A. & Matsui, J. (2015). ACS Med. Chem. Lett. 6, 89-94.]). A redocking of the Levatinib compound, an oral multikinase inhibitor that selectively inhibits the vascular endothelial growth factor-2, was used as validation method for the mol­ecular docking protocol (see the `Re-docking of the Lenvatinib (kinase inhibitor and FDA approved drug)' in the Supporting information]. A calculated global free energy of −20.49 kJ mol−1 was found for the title compound and the selected biological target VEGFR-2 inter­action and the structure–activity relationship can be assumed by the following observed inter­molecular inter­actions, with the respective hydrogen-bond distances and angles: N—H⋯O(GLU94) [H⋯O = 2.03 Å, N—H⋯O = 174°], (CYS96)N—H⋯O(isatine) [H⋯O = 1.72 Å, N—H⋯O = 168°] and (PHE95)C—H⋯O(isatine) [H⋯O = 2.27 Å, C—H⋯O = 140°] (Fig. 7[link]). Another significant feature of the structure of the title compound is the oxygen atom of the isatin fragment. The O1 atom is a hydrogen-bond acceptor and bridges two D—H⋯O inter­actions (supra­molecular chemistry, Fig. 2[link]; Hirshfeld surface, Fig. 3[link]; mol­ecular docking with the biological target VEGFR-2 kinase, Fig. 7[link]).

[Figure 7]
Figure 7
Graphical representation of a lock-and-key model for the inter­molecular inter­actions between the title compound and selected residues of the VEGFR-2. The inter­actions are shown as dashed lines and the structure of the enzyme is simplified for clarity.

6. Synthesis and crystallization

All starting materials are commercially available and were used without further purification. The synthesis of the title compound was adapted from procedures reported previously (Martins et al., 2016[Martins, B. B., Gervini, V. C., Pires, F. C., Bortoluzzi, A. J. & de Oliveira, A. B. (2016). IUCrData, 1, x161506.]; O'Sullivan & Sadler, 1956[O'Sullivan, D. G. & Sadler, P. W. (1956). J. Chem. Soc. pp. 2202-2207.]; Sandmeyer, 1919[Sandmeyer, T. (1919). Helv. Chim. Acta, 2, 234-242.]; Sumpter, 1944[Sumpter, W. C. (1944). Chem. Rev. 34, 393-434.]). A glacial acetic acid catalyzed mixture of 5-fluoro­isatin (3 mmol) and hydroxyl­amine hydro­chloride (3 mmol) in ethanol (50 mL) was stirred and refluxed for 6 h. After cooling and filtering, single crystals suitable for X-ray diffraction were obtained from the ethano­lic solution by solvent evaporation.

7. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2[link]. The H4 and H5 atoms were located in a difference Fourier map and freely refined [N1—H4 = 0.91 (2) Å and O2—H5 = 0.99 (3) Å]. The H1, H2 and H3 atoms were positioned with idealized geometry (HFIX command) and refined using a riding model, with C—H = 0.95 Å and Uiso(H) = 1.2Ueq(C).

Table 2
Experimental details

Crystal data
Chemical formula C8H5FN2O2
Mr 180.14
Crystal system, space group Monoclinic, P21/c
Temperature (K) 200
a, b, c (Å) 7.3036 (10), 7.2045 (10), 14.009 (2)
β (°) 94.736 (4)
V3) 734.61 (18)
Z 4
Radiation type Mo Kα
μ (mm−1) 0.14
Crystal size (mm) 0.34 × 0.32 × 0.06
 
Data collection
Diffractometer Bruker APEXII CCD area detector
Absorption correction Multi-scan (SADABS; Krause et al., 2015[Krause, L., Herbst-Irmer, R., Sheldrick, G. M. & Stalke, D. (2015). J. Appl. Cryst. 48, 3-10.])
Tmin, Tmax 0.663, 0.746
No. of measured, independent and observed [I > 2σ(I)] reflections 8386, 2142, 1687
Rint 0.021
(sin θ/λ)max−1) 0.705
 
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.040, 0.108, 1.05
No. of reflections 2142
No. of parameters 126
H-atom treatment H atoms treated by a mixture of independent and constrained refinement
Δρmax, Δρmin (e Å−3) 0.30, −0.21
Computer programs: APEX2 and SAINT (Bruker, 2014[Bruker (2014). APEX2 and SAINT. Bruker AXS Inc., Madison, Wisconsin, USA.]), SHELXT2014/4 (Sheldrick, 2015a[Sheldrick, G. M. (2015a). Acta Cryst. A71, 3-8.]), SHELXL2016/6 (Sheldrick, 2015b[Sheldrick, G. M. (2015b). Acta Cryst. C71, 3-8.]), WinGX (Farrugia, 2012[Farrugia, L. J. (2012). J. Appl. Cryst. 45, 849-854.]), DIAMOND (Brandenburg, 2006[Brandenburg, K. (2006). DIAMOND. Crystal Impact GbR, Bonn, Germany.]), GOLD (Chen et al., 2015[Chen, Y.-C. (2015). Trends Pharmacol. Sci. 36, 78-95.]), MOPAC (Stewart, 2016[Stewart, J. J. P. (2016). MOPAC2016. Stewart Computational Chemistry, Colorado Springs, Colorado, United States of America.]), CRYSTAL EXPLORER (Wolff, et al., 2012[Wolff, S. K., Grimwood, D. J., McKinnon, J. J., Turner, M. J., Jayatilaka, D. & Spackman, M. A. (2012). CRYSTAL EXPLORER. University of Western Australia, Perth, Australia.]), publCIF (Westrip, 2010[Westrip, S. P. (2010). J. Appl. Cryst. 43, 920-925.]) and enCIFer (Allen et al., 2004[Allen, F. H., Johnson, O., Shields, G. P., Smith, B. R. & Towler, M. (2004). J. Appl. Cryst. 37, 335-338.]).

Supporting information


Computing details top

Data collection: APEX2 (Bruker, 2014); cell refinement: SAINT (Bruker, 2014); data reduction: SAINT (Bruker, 2014); program(s) used to solve structure: SHELXT2014/4 (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2016/6 (Sheldrick, 2015b), WinGX (Farrugia, 2012); molecular graphics: DIAMOND (Brandenburg, 2006), GOLD (Chen et al., 2015), MOPAC (Stewart, 2016), CRYSTAL EXPLORER (Wolff, et al., 2012); software used to prepare material for publication: publCIF (Westrip, 2010), enCIFer (Allen et al., 2004).

(3Z)-5-Fluoro-3-(hydroxyimino)indolin-2-one top
Crystal data top
C8H5FN2O2F(000) = 368
Mr = 180.14Dx = 1.629 Mg m3
Monoclinic, P21/cMo Kα radiation, λ = 0.71073 Å
a = 7.3036 (10) ÅCell parameters from 3387 reflections
b = 7.2045 (10) Åθ = 2.8–30.0°
c = 14.009 (2) ŵ = 0.14 mm1
β = 94.736 (4)°T = 200 K
V = 734.61 (18) Å3Plate, yellow
Z = 40.34 × 0.32 × 0.06 mm
Data collection top
Bruker APEXII CCD area detector
diffractometer
1687 reflections with I > 2σ(I)
Radiation source: fine-focus sealed X-ray tubeRint = 0.021
φ and ω scansθmax = 30.1°, θmin = 2.8°
Absorption correction: multi-scan
(SADABS; Krause et al., 2015)
h = 1010
Tmin = 0.663, Tmax = 0.746k = 107
8386 measured reflectionsl = 1919
2142 independent reflections
Refinement top
Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.040Hydrogen site location: mixed
wR(F2) = 0.108H atoms treated by a mixture of independent and constrained refinement
S = 1.05 w = 1/[σ2(Fo2) + (0.0428P)2 + 0.3741P]
where P = (Fo2 + 2Fc2)/3
2142 reflections(Δ/σ)max < 0.001
126 parametersΔρmax = 0.30 e Å3
0 restraintsΔρmin = 0.21 e Å3
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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
C10.40095 (17)0.78184 (19)0.56663 (9)0.0247 (3)
C20.34449 (16)0.59266 (19)0.59782 (9)0.0225 (3)
C30.25830 (15)0.49961 (19)0.51303 (8)0.0219 (3)
C40.18138 (17)0.3250 (2)0.49698 (10)0.0263 (3)
H10.1761750.2363600.5468690.032*
C50.11244 (18)0.2879 (2)0.40349 (10)0.0297 (3)
C60.11742 (18)0.4116 (2)0.32854 (10)0.0306 (3)
H20.0685960.3776530.2660220.037*
C70.19449 (18)0.5867 (2)0.34516 (9)0.0277 (3)
H30.1997490.6744480.2948470.033*
C80.26306 (16)0.62779 (19)0.43768 (9)0.0227 (3)
F10.03607 (14)0.11739 (14)0.38491 (7)0.0459 (3)
N10.34730 (16)0.79375 (17)0.47154 (8)0.0261 (3)
N20.39084 (15)0.54652 (17)0.68513 (8)0.0262 (3)
O10.48449 (15)0.90064 (15)0.61615 (7)0.0324 (3)
O20.34792 (15)0.36593 (15)0.70338 (7)0.0340 (3)
H40.384 (3)0.889 (3)0.4351 (15)0.046 (5)*
H50.409 (3)0.352 (3)0.7684 (18)0.073 (7)*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
C10.0267 (6)0.0261 (7)0.0210 (6)0.0027 (5)0.0005 (4)0.0002 (5)
C20.0219 (5)0.0254 (7)0.0201 (6)0.0032 (5)0.0008 (4)0.0008 (5)
C30.0190 (5)0.0268 (7)0.0197 (5)0.0034 (5)0.0007 (4)0.0020 (5)
C40.0241 (6)0.0297 (7)0.0249 (6)0.0013 (5)0.0013 (4)0.0016 (5)
C50.0261 (6)0.0307 (8)0.0318 (7)0.0015 (5)0.0006 (5)0.0086 (6)
C60.0262 (6)0.0418 (9)0.0230 (6)0.0020 (6)0.0030 (5)0.0077 (6)
C70.0248 (6)0.0375 (8)0.0202 (6)0.0031 (5)0.0013 (4)0.0005 (5)
C80.0197 (5)0.0280 (7)0.0203 (6)0.0037 (5)0.0006 (4)0.0008 (5)
F10.0545 (6)0.0398 (6)0.0416 (5)0.0143 (4)0.0063 (4)0.0097 (4)
N10.0310 (5)0.0262 (6)0.0204 (5)0.0006 (5)0.0023 (4)0.0032 (4)
N20.0293 (5)0.0279 (6)0.0214 (5)0.0006 (4)0.0010 (4)0.0018 (4)
O10.0454 (6)0.0279 (6)0.0230 (5)0.0052 (4)0.0025 (4)0.0014 (4)
O20.0434 (6)0.0314 (6)0.0263 (5)0.0062 (4)0.0029 (4)0.0069 (4)
Geometric parameters (Å, º) top
C1—O11.2313 (16)C5—C61.380 (2)
C1—N11.3599 (16)C6—C71.393 (2)
C1—C21.4994 (19)C6—H20.9500
C2—N21.2857 (16)C7—C81.3825 (18)
C2—C31.4605 (17)C7—H30.9500
C3—C41.3883 (19)C8—N11.4089 (18)
C3—C81.4051 (18)N1—H40.91 (2)
C4—C51.3898 (19)N2—O21.3674 (16)
C4—H10.9500O2—H50.99 (3)
C5—F11.3651 (17)
O1—C1—N1126.68 (13)C5—C6—C7119.57 (12)
O1—C1—C2127.09 (12)C5—C6—H2120.2
N1—C1—C2106.19 (11)C7—C6—H2120.2
N2—C2—C3135.81 (13)C8—C7—C6117.44 (13)
N2—C2—C1117.07 (12)C8—C7—H3121.3
C3—C2—C1106.90 (10)C6—C7—H3121.3
C4—C3—C8120.57 (12)C7—C8—C3122.27 (13)
C4—C3—C2133.56 (12)C7—C8—N1127.72 (13)
C8—C3—C2105.88 (12)C3—C8—N1110.00 (11)
C3—C4—C5115.94 (13)C1—N1—C8111.02 (11)
C3—C4—H1122.0C1—N1—H4121.6 (13)
C5—C4—H1122.0C8—N1—H4126.2 (13)
F1—C5—C6118.18 (12)C2—N2—O2112.17 (11)
F1—C5—C4117.62 (14)N2—O2—H5100.2 (15)
C6—C5—C4124.20 (14)
O1—C1—C2—N21.5 (2)C5—C6—C7—C80.05 (19)
N1—C1—C2—N2176.30 (12)C6—C7—C8—C30.59 (19)
O1—C1—C2—C3176.99 (13)C6—C7—C8—N1179.71 (12)
N1—C1—C2—C30.84 (13)C4—C3—C8—C70.73 (18)
N2—C2—C3—C45.3 (2)C2—C3—C8—C7179.29 (11)
C1—C2—C3—C4179.49 (13)C4—C3—C8—N1179.98 (11)
N2—C2—C3—C8174.73 (14)C2—C3—C8—N10.04 (14)
C1—C2—C3—C80.53 (13)O1—C1—N1—C8177.00 (13)
C8—C3—C4—C50.28 (18)C2—C1—N1—C80.83 (14)
C2—C3—C4—C5179.75 (13)C7—C8—N1—C1178.67 (12)
C3—C4—C5—F1179.86 (11)C3—C8—N1—C10.53 (15)
C3—C4—C5—C60.3 (2)C3—C2—N2—O20.5 (2)
F1—C5—C6—C7179.98 (12)C1—C2—N2—O2174.24 (10)
C4—C5—C6—C70.4 (2)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N1—H4···O1i0.91 (2)1.96 (2)2.8487 (16)164.7 (18)
O2—H5···N2ii0.99 (3)2.69 (2)3.2989 (16)120.2 (18)
O2—H5···O1ii0.99 (3)1.77 (3)2.7280 (15)163 (2)
Symmetry codes: (i) x+1, y+2, z+1; (ii) x+1, y1/2, z+3/2.
 

Acknowledgements

ABO is an associate researcher in the project `Di­nitrosyl complexes containing thiol and/or thio­semicarbazone: synthesis, characterization and treatment against cancer', founded by FAPESP, Proc. 2015/12098–0, and acknowledges Professor José C. M. Pereira (São Paulo State University, Brazil) for his support in this work. ABO also acknowledges the VCG for the invitation to be a visiting professor at the Federal University of Rio Grande, Brazil, where part of this work was developed. RLF thanks the CAPES foundation for the scholarship. The authors acknowledge Professor A. J. Bortoluzzi for the access to the experimental facilities and the data collection (Federal University of Santa Catarina, Brazil).

Funding information

Funding for this research was provided by: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior; Conselho Nacional de Desenvolvimento Científico e Tecnológico; Fundação de Amparo à Pesquisa do Estado de São Paulo; Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul.

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