Crystal structure, Hirshfeld surface analysis and inter­action energy and DFT studies of (S)-10-propargyl­pyrrolo­[2,1-c][1,4]benzodiazepine-5,11-dione

Jeroundi, D.; Mazzah, A.; Hökelek, T.; El Hadrami, E.M.; Renard, C.; Haoudi, A.; Essassi, E.M.

doi:10.1107/S2056989020002698

research communications

CRYSTALLOGRAPHIC
COMMUNICATIONS

ISSN: 2056-9890

Volume 76| Part 4| April 2020| Pages 467-472

https://doi.org/10.1107/S2056989020002698

Open

access

Crystal structure, Hirshfeld surface analysis and interaction energy and DFT studies of (S)-10-propargylpyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione

Dounia Jeroundi,^a ^* Ahmed Mazzah,^b Tuncer Hökelek,^c El Mestafa El Hadrami,^a Catherine Renard,^d Amal Haoudi ^a and El Mokhtar Essassi ^e

^aLaboratory of Applied Organic Chemistry, Sidi Mohamed Ben Abdellah University, Faculty of Sciences and Techniques, Road Immouzer, BP 2202 Fez, Morocco, ^bUSR 3290 Miniaturisation pour l'analyse, la synthèse et la protéomique, 59655, Villeneuve d'Ascq Cedex, Université Lille1, France, ^cDepartment of Physics, Hacettepe University, 06800 Beytepe, Ankara, Turkey, ^dUnité de Catalyse et de Chimie du Solide (UCCS), UMR 8181, Ecole Nationale Supérieure de Chimie de Lille, Université Lille 1, 59650 Villeneuve d'Ascq Cedex, France, and ^eLaboratoire de Chimie Organique Hétérocyclique URAC 21, Pôle de Compétence Pharmacochimie, Av. Ibn Battouta, BP 1014, Faculté des Sciences, Université Mohammed V, Rabat, Morocco
^*Correspondence e-mail: DouniaJeroundi2019@gmail.com

Edited by A. J. Lough, University of Toronto, Canada (Received 27 January 2020; accepted 26 February 2020; online 3 March 2020)

The title compound, C₁₅H₁₄N₂O₂, consists of pyrrole and benzodiazepine units linked to a propargyl moiety, where the pyrrole and diazepine rings adopt half-chair and boat conformations, respectively. The absolute configuration was assigned on the the basis of L-proline, which was used in the synthesis of benzodiazepine. In the crystal, weak C—H_Bnz⋯O_Diazp and C—H_Proprg⋯O_Diazp (Bnz = benzene, Diazp = diazepine and Proprg = propargyl) hydrogen bonds link the molecules into two-dimensional networks parallel to the bc plane, enclosing R₄⁴(28) ring motifs, with the networks forming oblique stacks along the a-axis direction. The Hirshfeld surface analysis of the crystal structure indicates that the most important contributions for the crystal packing are from H⋯H (49.8%), H⋯C/C⋯H (25.7%) and H⋯O/O⋯H (20.1%) interactions. Hydrogen bonding and van der Waals interactions are the dominant interactions in the crystal packing. Computational chemistry indicates that in the crystal, C—H⋯O hydrogen-bond energies are 38.8 (for C—H_Bnz⋯O_Diazp) and 27.1 (for C—H_Proprg⋯O_Diazp) kJ mol⁻¹. Density functional theory (DFT) optimized structures at the B3LYP/6–311 G(d,p) level are compared with the experimentally determined molecular structure in the solid state. The HOMO–LUMO behaviour was elucidated to determine the energy gap.

Keywords: crystal structure; benzodiazepine; pyrrole; Hirshfeld surface.

CCDC reference: 1986475

1. Chemical context

Over the past few decades, compounds bearing heterocyclic nuclei have received much attention of chemists and biologists because of their importance in the development of chemotherapeutic agents and a wide variety of drugs (Cargill et al., 1974 ; Micale et al., 2004 ; Hadac et al., 2006 ; Ourahou et al., 2011 ). 1,4-Benzodiazepines and their derivatives have attracted the attention of chemists since the early 1960s, mainly because of the broad spectrum of biological properties exhibited by this class of compounds, in particular their psychopharmacological properties (Thurston & Langley, 1986 ; Kamal et al., 2007 ; Antonow et al., 2007 ; Archer & Sternbach, 1968 ; Mohiuddin et al., 1986 , Bose et al., 1992 ; Gregson et al., 2004 ). The vast commercial success of these medicinal agents has resulted in their chemistry being a major focus of research in the field of medicinal chemistry and many such ring systems having been described (Benzeid et al., 2009a ,b ; Randles & Storr, 1984 ; Sugasawa et al., 1985 ; Cipolla et al., 2009 ). Pyrrolo[2,1-c][1,4]benzodiazepines are a group of potent chemicals produced by Streptomyces species. For their anticancer activity, see: Bose et al. (1992); Cargill et al. (1974); Gregson et al. (2004).

In a continuation of our research work on the advancement of benzodiazepine derivatives, we have developed a new synthethis for 10-propargylpyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione (Fig. 1) in good yield from pyrrolo[2,1-c][1,4]benzodiazepine with propargylbromide in the presence of tetra-n-butylammonium bromide (TBAB) as catalyst and potassium carbonate as base (Makosza & Jonczyk, 1976 ). The synthesized compound was characterized by single-crystal X-ray diffraction as well as Hirshfeld surface analysis. The results of the calculations by density functional theory (DFT), carried out at the B3LYP/6-311G (d,p) level, are compared with the experimentally determined molecular structure in the solid state.

Figure 1
The molecular structure of the title compound with the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probability level.

2. Structural commentary

The title compound, (I), consists of pyrrole and benzodiazepine units linked to a propargyl moiety (Fig. 1). The five-membered pyrrole ring (N1/C8/C10–C12) adopts a half-chair conformation [puckering parameters q₂ = 0.376 (3) Å and θ = 94.4 (4)°] while the seven-membered diazepine ring (N1/N2/C1/C6–C9) adopts a boat conformation [Q_T = 0.9262 (13), q₂ = 0.9070 (14), q₃ = 0.1875 (16) Å, φ₂ = 105.6 (4) and φ = 161.4 (5)°]. In the propargyl moiety, the N2—C13—C14 and C13—C14—C15 bond angles are 112.66 (17)° and 177.4 (3)°, respectively.

3. Supramolecular features

In the crystal, weak C—H_Bnz⋯O_Diazp and C—H_Proprg⋯O_Diazp (Bnz = benzene, Diazp = diazepine and Proprg = propargyl) hydrogen bonds (Table 1) link the molecules into two-dimensional networks parallel to the bc plane, enclosing $[R_{4}^{4}]$ (28) ring motifs (Fig. 2), with the networks forming oblique stacks along the a-axis direction.

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C2—H2⋯O2^vii	0.93	2.53	3.252 (2)	135
C13—H13A⋯O1^viii	0.97	2.54	3.395 (3)	147
Symmetry codes: (vii) x, y, z+1; (viii) $[-x+1, y-{\script{1\over 2}}, -z+1]$ .

Figure 2
A partial packing diagram viewed along the a-axis direction with weak intermolecular C—H_Bnz⋯O_Diazp and C—H_Proprg⋯O_Diazp (Bnz = benzene, Diazp = diazepine and Proprg = propargyl) hydrogen bonds (dashed lines). H atoms not included in hydrogen bonding have been omitted for clarity.

4. Hirshfeld surface analysis

In order to visualize the intermolecular interactions in the crystal of the title compound, a Hirshfeld surface (HS) analysis (Hirshfeld, 1977 ; Spackman & Jayatilaka, 2009 ) was carried out using Crystal Explorer 17.5 (Turner et al., 2017 ). In the HS plotted over d_norm (Fig. 3), the white surface indicates contacts with distances equal to the sum of van der Waals radii, and the red and blue colours indicate distances shorter (in close contact) or longer (distinct contact) than the van der Waals radii, respectively (Venkatesan et al., 2016 ). The bright-red spots appearing near O1, O2 and hydrogen atom H13A indicate their roles as the respective donors and acceptors; they also appear as blue and red regions corresponding to positive and negative potentials on the HS mapped over electrostatic potential (Spackman et al., 2008 ; Jayatilaka et al., 2005 ) shown in Fig. 4. Here the blue regions indicate positive electrostatic potential (hydrogen-bond donors), while the red regions indicate negative electrostatic potential (hydrogen-bond acceptors). The shape-index of the HS is a tool to visualize the π–π stacking by the presence of adjacent red and blue triangles; if there are no adjacent red and/or blue triangles, then there are no π–π interactions. Fig. 5 clearly suggests that there are no π–π interactions in (I).

Figure 3
View of the three-dimensional Hirshfeld surface of the title compound plotted over d_norm in the range −0.1285 to 1.4451 a.u.

Figure 4
View of the three-dimensional Hirshfeld surface of the title compound plotted over electrostatic potential energy in the range −0.0500 to 0.0500 a.u. using the STO-3 G basis set at the Hartree–Fock level of theory. Hydrogen-bond donors and acceptors are shown as blue and red regions around the atoms, corresponding to positive and negative potentials, respectively.

Figure 5
Hirshfeld surface of the title compound plotted over shape-index.

The overall two-dimensional fingerprint plot, Fig. 6a, and those delineated into H⋯H, H⋯C/C⋯H, H⋯O/O⋯H, C⋯C and H⋯N/N⋯H contacts (McKinnon et al., 2007 ) are illustrated in Fig. 6 b–f, respectively, together with their relative contributions to the Hirshfeld surface. The most important interaction is H⋯H contributing 49.8% to the overall crystal packing, which is reflected in Fig. 6b as widely scattered points of high density due to the large hydrogen content of the molecule with the tip at d_e = d_i = 1.13 Å. In the absence of C—H ⋯ π interactions, the pairs of characteristic wings in Fig. 6c arises from H⋯C/C⋯H contacts (25.7% contribution to the HS); the pair of spikes have tips at d_e + d_i = 2.80 Å. The thin and thick pairs of scattered points of wings in the fingerprint plot delineated into H⋯O/O⋯H contacts (Fig. 6d, 20.1%) have a symmetrical distribution of points with the edges at d_e + d_i = 2.42 and 2.44 Å, respectively. The C⋯C contacts (Fig. 6e, 1.8%) have a pliers-shaped distribution of points with the tips at d_e + d_i = 3.47 Å. Finally, the H ⋯ N/N⋯H interactions (1.8%) are reflected in Fig. 6f as thick wings with the tips at d_e + d_i = 3.04 Å. Selected contacts are listed in Table 2.

Table 2
Selected interatomic distances (Å)

O1⋯C15ⁱ	3.273 (4)	O2⋯H4ⁱⁱ	2.69
O1⋯C13ⁱⁱ	3.395 (3)	N1⋯N2	2.898 (2)
O2⋯C2ⁱⁱⁱ	3.252 (2)	C2⋯C10^v	3.558 (3)
O2⋯C11	3.303 (3)	C4⋯C12^vi	3.552 (4)
O2⋯C4ⁱⁱ	3.397 (3)	C5⋯C14	3.090 (4)
O1⋯H8^iv	2.82	C7⋯C15ⁱ	3.512 (4)
O1⋯H12A^iv	2.76	C1⋯H8	2.69
O1⋯H2	2.63	C3⋯H12A^vi	2.90
O1⋯H10A	2.73	C3⋯H11B^v	2.87
O1⋯H15ⁱ	2.81	C5⋯H13A	2.86
O1⋯H13Aⁱⁱ	2.54	C6⋯H8	2.69
O2⋯H2ⁱⁱⁱ	2.53	C7⋯H13Aⁱⁱ	2.93
O2⋯H12B	2.45	C13⋯H5	2.66
O2⋯H13B	2.32	C14⋯H5	2.92
O2⋯H11A	2.89	H5⋯H13A	2.32
Symmetry codes: (i) x-1, y, z; (ii) $[-x+1, y+{\script{1\over 2}}, -z+1]$ ; (iii) x, y, z-1; (iv) $[-x, y+{\script{1\over 2}}, -z+1]$ ; (v) $[-x, y-{\script{1\over 2}}, -z+1]$ ; (vi) x+1, y, z+1.

Figure 6
The full two-dimensional fingerprint plots for the title compound, showing (a) all interactions, and delineated into (b) H⋯H, (c) H⋯C/C⋯H, (d) H⋯O/O⋯H, (e) C⋯C and (f) H⋯N/N⋯H interactions. The d_i and d_e values are the closest internal and external distances (in Å) from given points on the Hirshfeld surface contacts.

The Hirshfeld surface representations with the function d_norm plotted onto the surface are shown for the H⋯H, H⋯C/C⋯H and H⋯O/O⋯H interactions in Fig. 7a–c, respectively.

Figure 7
Hirshfeld surface representations with the function d_norm plotted onto the surface for (a) H⋯H, (b) H⋯C/C⋯H and (c) H⋯O/O⋯H interactions.

The Hirshfeld surface analysis confirms the importance of H-atom contacts in establishing the packing. The large number of H⋯H, H⋯C/C⋯H and H⋯O/O⋯H interactions suggest that van der Waals interactions and hydrogen bonding play the major roles in the crystal packing (Hathwar et al., 2015 ).

5. Interaction energy calculations

The intermolecular interaction energies were calculated using the CE–B3LYP/6–31G(d,p) energy model in Crystal Explorer 17.5 (Turner et al., 2017), where a cluster of molecules is generated by applying crystallographic symmetry operations with respect to a selected central molecule within a default radius of 3.8 Å (Turner et al., 2014 ). The total intermolecular energy (E_tot) is the sum of electrostatic (E_ele), polarization (E_pol), dispersion (E_dis) and exchange-repulsion (E_rep) energies (Turner et al., 2015 ) with scale factors of 1.057, 0.740, 0.871 and 0.618, respectively (Mackenzie et al., 2017 ). Hydrogen-bonding interaction energies (in kJ mol⁻¹) were calculated as −13.2 (E_ele), −3.8 (E_pol), −45.1 (E_dis), 27.8 (E_rep) and −38.8 (E_tot) for C2—H2⋯O2 and −10.7 (E_ele), −4.0 (E_pol), −25.8 (E_dis), 15.7 (E_rep) and −27.1 (E_tot) for C13—H13A⋯O1.

6. DFT calculations

The optimized structure of the title compound in the gas phase was generated theoretically via density functional theory (DFT) using standard B3LYP functional and 6–311 G(d,p) basis-set calculations (Becke, 1993 ) as implemented in GAUSSIAN 09 (Frisch et al., 2009 ). The theoretical and experimental results were in good agreement (Table 3). The highest-occupied molecular orbital (HOMO), acting as an electron donor, and the lowest-unoccupied molecular orbital (LUMO), acting as an electron acceptor, are very important parameters for quantum chemistry. When the energy gap is small, the molecule is highly polarizable and has high chemical reactivity. The DFT calculations provide some important information on the reactivity and site selectivity of the molecular framework. E_HOMO and E_LUMO clarify the inevitable charge-exchange collaboration inside the studied material, and are given in Table 4 along with the electronegativity (χ), hardness (η), potential (μ), electrophilicity (ω) and softness (σ). The significance of η and σ is to evaluate both the reactivity and stability. The electron transition from the HOMO to the LUMO energy level is shown in Fig. 8. The HOMO and LUMO are localized in the plane extending from the whole 10-propargylpyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione ring. The energy band gap [ΔE = E_LUMO − E_HOMO] of the molecule is 3.4829 eV, and the frontier molecular orbital energies, E_HOMO and E_LUMO are −4.0030 and −0.5203 eV, respectively.

Table 3
Comparison of the selected (X-ray and DFT) geometric data (Å, °)

Bonds/angles	X-ray	B3LYP/6–311G(d,p)
O1—C7	1.231 (2)	1.30064
O2—C9	1.222 (2)	1.30459
N1—C7	1.337 (2)	1.44900
N1—C8	1.474 (2)	1.42892
N1—C10	1.476 (2)	1.41852
N2—C6	1.429 (2)	1.45461
N2—C9	1.362 (2)	1.45679
N2—C13	1.478 (2)	1.48990

C7—N1—C8	124.64 (14)	125.54242
C7—N1—C10	122.81 (16)	120.48706
C8—N1—C10	112.28 (14)	111.27162
C6—N2—C13	118.67 (14)	116.39016
C9—N2—C6	123.48 (14)	122.08303
C9—N2—C13	116.98 (15)	113.69042
C1—C6—N2	122.46 (14)	120.60573
C5—C6—N2	118.13 (15)	117.33963

Table 4
Calculated energies

Molecular Energy (a.u.) (eV)	Compound (I)
Total Energy, TE (eV)	−22499
E_HOMO (eV)	−4.0030
E_LUMO (eV)	−0.5203
Gap ΔE (eV)	3.4829
Dipole moment, μ (Debye)	2.2189
Ionization potential, I (eV)	4.0030
Electron affinity, A	0.5203
Electronegativity, χ	2.2617
Hardness, η	1.7414
Electrophilicity index, ω	1.4687
Softness, σ	0.5742
Fraction of electron transferred, ΔN	1.3605

Figure 8
The energy band gap of the title compound.

7. Database survey

A alkylated analogue has been reported, viz. 10-allyl-2,3-dihydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H,11aH)-dione (Benzeid et al., 2009a), as well as three similar structures, 2-hydroxy-10-propargylpyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione monohydrate (Ourahou et al. 2010 ), rac-9,10-dimethoxy-3-methyl-6-phenyl-7,7adihydrobenzo[b]benzo[4,5]isothiazolo[2,3-d][1,4]diazepine 12,12-dioxide (Bassin et al., 2011 ) and (S)-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-3,11-dione (Cheng et al. 2007 ).

8. Synthesis and crystallization

The synthesis of pyrrolobenzodiazepine is a simple condensation of isatoic anhydride on L-proline. Pyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione (2.15 mmol), propargyl bromide (2.15 mmol) and potassium carbonate (4.3 mmol) along with a catalytic amount of tetra-n-butyl ammonium bromide were stirred in N,N-dimethylformamide (20 ml) for 72 h. The solid material was removed by filtration and the solvent evaporated under vacuum. The residue was separated by chromatography on silica gel with an n-hexane–ethyl acetate (1:9) solvent system. The title compound was obtained as colourless crystals in 70% yield upon evaporation of the solvent.

9. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 5. The C-bound H atoms were positioned geometrically, with C—H = 0.93 Å (for aromatic and propagyl moiety's H atoms), 0.98 Å (for methine H atom) and 0.97 Å (for methylene H atoms), and constrained to ride on their parent atoms, with U_iso(H) = 1.U_eq(C).

Table 5
Experimental details

Crystal data
Chemical formula	C₁₅H₁₄N₂O₂
M_r	254.28
Crystal system, space group	Monoclinic, P2₁
Temperature (K)	299
a, b, c (Å)	8.4959 (2), 9.6479 (2), 8.7619 (2)
β (°)	116.921 (1)
V (Å³)	640.36 (3)
Z	2
Radiation type	Mo Kα
μ (mm⁻¹)	0.09
Crystal size (mm)	0.39 × 0.37 × 0.16

Data collection
Diffractometer	Bruker APEXII CCD
Absorption correction	Multi-scan (SADABS; Bruker, 2013 )
T_min, T_max	0.684, 0.746
No. of measured, independent and observed [I > 2σ(I)] reflections	12206, 3821, 3349
R_int	0.024
(sin θ/λ)_max (Å⁻¹)	0.714

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.039, 0.103, 1.06
No. of reflections	3821
No. of parameters	172
No. of restraints	1
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.20, −0.15
Absolute structure	Flack x determined using 1347 quotients [(I⁺)−(I⁻)]/[(I⁺)+(I⁻)] (Parsons et al., 2013 )
Absolute structure parameter	−0.4 (3)
Computer programs: APEX3 and SAINT (Bruker, 2013), SHELXT (Sheldrick, 2015a ), SHELXL (Sheldrick, 2015b ) and OLEX2 (Dolomanov et al., 2009 ).

Supporting information

CCDC reference: 1986475

Crystal structure: contains datablocks I, global. DOI: https://doi.org/10.1107/S2056989020002698/lh5947sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2056989020002698/lh5947Isup2.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2056989020002698/lh5947Isup3.cdx

Supporting information file. DOI: https://doi.org/10.1107/S2056989020002698/lh5947Isup4.cml

checkCIF report

Computing details top

Data collection: APEX3 (Bruker, 2013); cell refinement: SAINT (Bruker, 2013); data reduction: SAINT (Bruker, 2013); program(s) used to solve structure: SHELXT (Sheldrick, 2015a); program(s) used to refine structure: SHELXL (Sheldrick, 2015b); molecular graphics: OLEX2 (Dolomanov et al., 2009); software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009).

(S)-10-(Prop-2-yn-1-yl)pyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione top

Crystal data top

C₁₅H₁₄N₂O₂	F(000) = 268
M_r = 254.28	D_x = 1.319 Mg m⁻³
Monoclinic, P2₁	Mo Kα radiation, λ = 0.71073 Å
a = 8.4959 (2) Å	Cell parameters from 6478 reflections
b = 9.6479 (2) Å	θ = 2.6–28.5°
c = 8.7619 (2) Å	µ = 0.09 mm⁻¹
β = 116.921 (1)°	T = 299 K
V = 640.36 (3) Å³	Plate, clear light colourless
Z = 2	0.39 × 0.37 × 0.16 mm

Data collection top

Bruker APEXII CCD diffractometer	3349 reflections with I > 2σ(I)
φ and ω scans	R_int = 0.024
Absorption correction: multi-scan (SADABS; Bruker, 2013)	θ_max = 30.5°, θ_min = 2.6°
T_min = 0.684, T_max = 0.746	h = −12→12
12206 measured reflections	k = −13→13
3821 independent reflections	l = −12→12

Refinement top

Refinement on F²	Hydrogen site location: inferred from neighbouring sites
Least-squares matrix: full	H-atom parameters constrained
R[F² > 2σ(F²)] = 0.039	w = 1/[σ²(F_o²) + (0.0554P)² + 0.0351P] where P = (F_o² + 2F_c²)/3
wR(F²) = 0.103	(Δ/σ)_max < 0.001
S = 1.06	Δρ_max = 0.20 e Å⁻³
3821 reflections	Δρ_min = −0.15 e Å⁻³
172 parameters	Absolute structure: Flack x determined using 1347 quotients [(I⁺)-(I^-)]/[(I⁺)+(I^-)] (Parsons et al., 2013)
1 restraint	Absolute structure parameter: −0.4 (3)
Primary atom site location: dual

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

	x	y	z	U_iso*/U_eq
O1	0.1993 (2)	0.71379 (15)	0.67243 (19)	0.0515 (4)
O2	0.2576 (2)	0.4767 (2)	0.15885 (17)	0.0621 (4)
N1	0.10489 (19)	0.59648 (15)	0.42473 (19)	0.0384 (3)
N2	0.41816 (19)	0.46005 (16)	0.44625 (18)	0.0389 (3)
C1	0.3344 (2)	0.49614 (17)	0.68011 (19)	0.0342 (3)
C2	0.3604 (2)	0.4606 (2)	0.8441 (2)	0.0441 (4)
H2	0.297976	0.507584	0.892040	0.053*
C3	0.4764 (3)	0.3576 (2)	0.9365 (2)	0.0518 (5)
H3	0.491032	0.334562	1.045179	0.062*
C4	0.5709 (3)	0.2888 (2)	0.8670 (3)	0.0525 (5)
H4	0.650555	0.219823	0.929588	0.063*
C5	0.5477 (3)	0.3218 (2)	0.7046 (3)	0.0466 (4)
H5	0.611399	0.274396	0.658401	0.056*
C6	0.4297 (2)	0.42536 (17)	0.6096 (2)	0.0347 (3)
C7	0.2084 (2)	0.61152 (17)	0.5927 (2)	0.0360 (3)
C8	0.0974 (2)	0.47097 (19)	0.3258 (2)	0.0383 (3)
H8	0.088877	0.387499	0.385319	0.046*
C9	0.2629 (2)	0.4673 (2)	0.3002 (2)	0.0396 (4)
C10	−0.0288 (3)	0.7001 (2)	0.3214 (3)	0.0540 (5)
H10A	0.021993	0.792198	0.337758	0.065*
H10B	−0.126879	0.701151	0.349469	0.065*
C11	−0.0863 (3)	0.6494 (3)	0.1404 (3)	0.0668 (7)
H11A	−0.009804	0.685371	0.094619	0.080*
H11B	−0.206984	0.676803	0.065910	0.080*
C12	−0.0705 (3)	0.4919 (3)	0.1595 (3)	0.0561 (5)
H12A	−0.171813	0.452660	0.167103	0.067*
H12B	−0.060151	0.449916	0.063901	0.067*
C13	0.5822 (3)	0.4646 (3)	0.4271 (3)	0.0522 (5)
H13A	0.618467	0.370691	0.419118	0.063*
H13B	0.558798	0.512036	0.321305	0.063*
C14	0.7252 (3)	0.5347 (3)	0.5684 (3)	0.0559 (5)
C15	0.8456 (4)	0.5887 (4)	0.6817 (4)	0.0771 (8)
H15	0.940820	0.631390	0.771234	0.092*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O1	0.0594 (8)	0.0445 (7)	0.0560 (9)	−0.0014 (7)	0.0310 (7)	−0.0151 (6)
O2	0.0678 (9)	0.0904 (12)	0.0351 (7)	0.0028 (9)	0.0293 (6)	−0.0011 (8)
N1	0.0379 (7)	0.0392 (8)	0.0384 (8)	0.0031 (6)	0.0175 (6)	−0.0009 (6)
N2	0.0431 (7)	0.0439 (8)	0.0358 (7)	0.0055 (7)	0.0233 (6)	0.0027 (6)
C1	0.0366 (8)	0.0360 (8)	0.0303 (7)	−0.0079 (6)	0.0155 (6)	−0.0054 (6)
C2	0.0487 (9)	0.0538 (11)	0.0312 (8)	−0.0131 (9)	0.0191 (7)	−0.0088 (8)
C3	0.0566 (11)	0.0604 (12)	0.0291 (8)	−0.0183 (10)	0.0112 (8)	0.0028 (8)
C4	0.0526 (11)	0.0467 (11)	0.0432 (10)	−0.0022 (9)	0.0085 (9)	0.0108 (8)
C5	0.0476 (10)	0.0408 (10)	0.0479 (10)	0.0048 (8)	0.0186 (8)	0.0039 (8)
C6	0.0380 (8)	0.0349 (8)	0.0314 (8)	−0.0015 (6)	0.0160 (7)	0.0001 (6)
C7	0.0379 (8)	0.0362 (8)	0.0400 (9)	−0.0062 (6)	0.0230 (7)	−0.0055 (6)
C8	0.0425 (8)	0.0395 (8)	0.0326 (7)	−0.0066 (7)	0.0166 (6)	−0.0036 (7)
C9	0.0507 (9)	0.0383 (8)	0.0340 (8)	0.0012 (8)	0.0228 (7)	−0.0013 (7)
C10	0.0473 (10)	0.0560 (12)	0.0551 (12)	0.0131 (9)	0.0201 (9)	0.0082 (9)
C11	0.0597 (13)	0.0829 (17)	0.0490 (12)	0.0237 (13)	0.0169 (10)	0.0158 (12)
C12	0.0469 (10)	0.0737 (15)	0.0373 (9)	−0.0080 (10)	0.0099 (8)	−0.0042 (9)
C13	0.0510 (10)	0.0661 (13)	0.0520 (11)	0.0141 (10)	0.0343 (9)	0.0040 (10)
C14	0.0480 (11)	0.0657 (13)	0.0659 (14)	0.0053 (10)	0.0364 (11)	0.0103 (11)
C15	0.0588 (14)	0.093 (2)	0.0800 (19)	−0.0120 (14)	0.0319 (13)	0.0044 (15)

Geometric parameters (Å, º) top

O1—C7	1.231 (2)	C5—C6	1.393 (2)
O2—C9	1.222 (2)	C8—H8	0.9800
N1—C7	1.337 (2)	C8—C9	1.521 (3)
N1—C8	1.474 (2)	C8—C12	1.522 (3)
N1—C10	1.476 (2)	C10—H10A	0.9700
N2—C6	1.429 (2)	C10—H10B	0.9700
N2—C9	1.362 (2)	C10—C11	1.513 (3)
N2—C13	1.478 (2)	C11—H11A	0.9700
C1—C2	1.394 (2)	C11—H11B	0.9700
C1—C6	1.399 (2)	C11—C12	1.527 (4)
C1—C7	1.493 (2)	C12—H12A	0.9700
C2—H2	0.9300	C12—H12B	0.9700
C2—C3	1.376 (3)	C13—H13A	0.9700
C3—H3	0.9300	C13—H13B	0.9700
C3—C4	1.378 (3)	C13—C14	1.450 (3)
C4—H4	0.9300	C14—C15	1.176 (4)
C4—C5	1.382 (3)	C15—H15	0.9300
C5—H5	0.9300

O1···C15ⁱ	3.273 (4)	O2···H4ⁱⁱ	2.69
O1···C13ⁱⁱ	3.395 (3)	N1···N2	2.898 (2)
O2···C2ⁱⁱⁱ	3.252 (2)	C2···C10^v	3.558 (3)
O2···C11	3.303 (3)	C4···C12^vi	3.552 (4)
O2···C4ⁱⁱ	3.397 (3)	C5···C14	3.090 (4)
O1···H8^iv	2.82	C7···C15ⁱ	3.512 (4)
O1···H12A^iv	2.76	C1···H8	2.69
O1···H2	2.63	C3···H12A^vi	2.90
O1···H10A	2.73	C3···H11B^v	2.87
O1···H15ⁱ	2.81	C5···H13A	2.86
O1···H13Aⁱⁱ	2.54	C6···H8	2.69
O2···H2ⁱⁱⁱ	2.53	C7···H13Aⁱⁱ	2.93
O2···H12B	2.45	C13···H5	2.66
O2···H13B	2.32	C14···H5	2.92
O2···H11A	2.89	H5···H13A	2.32

C7—N1—C8	124.64 (14)	C9—C8—C12	112.98 (15)
C7—N1—C10	122.81 (16)	C12—C8—H8	110.8
C8—N1—C10	112.28 (14)	O2—C9—N2	122.16 (17)
C6—N2—C13	118.67 (14)	O2—C9—C8	122.34 (16)
C9—N2—C6	123.48 (14)	N2—C9—C8	115.42 (14)
C9—N2—C13	116.98 (15)	N1—C10—H10A	111.2
C2—C1—C6	118.81 (16)	N1—C10—H10B	111.2
C2—C1—C7	117.02 (15)	N1—C10—C11	102.59 (18)
C6—C1—C7	124.15 (14)	H10A—C10—H10B	109.2
C1—C2—H2	119.3	C11—C10—H10A	111.2
C3—C2—C1	121.41 (18)	C11—C10—H10B	111.2
C3—C2—H2	119.3	C10—C11—H11A	111.0
C2—C3—H3	120.2	C10—C11—H11B	111.0
C2—C3—C4	119.60 (18)	C10—C11—C12	103.65 (19)
C4—C3—H3	120.2	H11A—C11—H11B	109.0
C3—C4—H4	119.9	C12—C11—H11A	111.0
C3—C4—C5	120.23 (19)	C12—C11—H11B	111.0
C5—C4—H4	119.9	C8—C12—C11	103.60 (18)
C4—C5—H5	119.7	C8—C12—H12A	111.0
C4—C5—C6	120.63 (19)	C8—C12—H12B	111.0
C6—C5—H5	119.7	C11—C12—H12A	111.0
C1—C6—N2	122.46 (14)	C11—C12—H12B	111.0
C5—C6—N2	118.13 (15)	H12A—C12—H12B	109.0
C5—C6—C1	119.32 (15)	N2—C13—H13A	109.1
O1—C7—N1	122.16 (17)	N2—C13—H13B	109.1
O1—C7—C1	121.40 (16)	H13A—C13—H13B	107.8
N1—C7—C1	116.43 (14)	C14—C13—N2	112.66 (17)
N1—C8—H8	110.8	C14—C13—H13A	109.1
N1—C8—C9	108.01 (14)	C14—C13—H13B	109.1
N1—C8—C12	103.06 (16)	C15—C14—C13	177.4 (3)
C9—C8—H8	110.8	C14—C15—H15	180.0

Symmetry codes: (i) x−1, y, z; (ii) −x+1, y+1/2, −z+1; (iii) x, y, z−1; (iv) −x, y+1/2, −z+1; (v) −x, y−1/2, −z+1; (vi) x+1, y, z+1.

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
C2—H2···O2^vii	0.93	2.53	3.252 (2)	135
C13—H13A···O1^viii	0.97	2.54	3.395 (3)	147

Symmetry codes: (vii) x, y, z+1; (viii) −x+1, y−1/2, −z+1.

Comparison of the selected (X-ray and DFT) geometric data (Å, °) top

Bonds/angles	X-ray	B3LYP/6-311G(d,p)
O1—C7	1.231 (2)	1.30064
O2—C9	1.222 (2)	1.30459
N1—C7	1.337 (2)	1.44900
N1—C8	1.474 (2)	1.42892
N1—C10	1.476 (2)	1.41852
N2—C6	1.429 (2)	1.45461
N2—C9	1.362 (2)	1.45679
N2—C13	1.478 (2)	1.48990

C7—N1—C8	124.64 (14)	125.54242
C7—N1—C10	122.81 (16)	120.48706
C8—N1—C10	112.28 (14)	111.27162
C6—N2—C13	118.67 (14)	116.39016
C9—N2—C6	123.48 (14)	122.08303
C9—N2—C13	116.98 (15)	113.69042
C1—C6—N2	122.46 (14)	120.60573
C5—C6—N2	118.13 (15)	117.33963

Calculated energies top

Molecular Energy (a.u.) (eV)	Compound (I)
Total Energy, TE (eV)	-22498.546
E_HOMO (eV)	-4.0030
E_LUMO (eV)	-0.5203
Gap ΔE (eV)	3.4829
Dipole moment, µ (Debye)	2.2189
Ionisation potential, I (eV)	4.0030
Electron affinity, A	0.5203
Electronegativity, χ	2.2617
Hardness, η	1.7414
Electrophilicity index, ω	1.4687
Softness, σ	0.5742
Fraction of electron transferred, ΔN	1.3605

Funding information

TH is grateful to Hacettepe University Scientific Research Project Unit (grant No. 013 D04 602 004).

References

Antonow, D., Jenkins, T. C., Howard, P. W. & Thurston, D. E. (2007). Bioorg. Med. Chem. 15, 3041–3053. Web of Science CrossRef PubMed CAS Google Scholar
Archer, G. A. & Sternbach, L. H. (1968). Chem. Rev. 68, 747–784. CrossRef CAS Web of Science Google Scholar
Bassin, J. P., Shah, V. P., Martin, L. & Horton, P. N. (2011). Acta Cryst. E67, o684–o685. Web of Science CSD CrossRef IUCr Journals Google Scholar
Becke, A. D. (1993). J. Chem. Phys. 98, 5648–5652. CrossRef CAS Web of Science Google Scholar
Benzeid, H., Essassi, E. M., Saffon, N., Garrigues, B. & Ng, S. W. (2009a). Acta Cryst. E65, o2322. Web of Science CSD CrossRef IUCr Journals Google Scholar
Benzeid, H., Saffon, N., Garrigues, B., Essassi, E. M. & Ng, S. W. (2009b). Acta Cryst. E65, o2684. Web of Science CSD CrossRef IUCr Journals Google Scholar
Bose, D. S., Thompson, A. S., Ching, J. A., Hartley, J. A., Berardini, M. D., Jenkins, T. C., Neidle, S., Hurley, L. H. & Thurston, D. E. (1992). J. Am. Chem. Soc. 114, 4939–4941. CrossRef CAS Web of Science Google Scholar
Bruker (2013). APEX3, SAINT and SADABS. Bruker AXS, Inc., Madison, Wisconsin, USA. Google Scholar
Cargill, C., Bachmann, E. & Zbinden, G. (1974). J. Natl Cancer Inst. 53, 481–486. CrossRef CAS PubMed Web of Science Google Scholar
Cheng, M.-S., Ma, C., Liu, J.-H., Sha, Y. & Wang, Q.-H. (2007). Acta Cryst. E63, o4605. Web of Science CSD CrossRef IUCr Journals Google Scholar
Cipolla, L., Araújo, A. C., Airoldi, C. & Bini, D. (2009). Anticancer Agents Med. Chem. 9, 1–31. Web of Science CrossRef PubMed CAS Google Scholar
Dolomanov, O. V., Bourhis, L. J., Gildea, R. J., Howard, J. A. K. & Puschmann, H. (2009). J. Appl. Cryst. 42, 339–341. Web of Science CrossRef CAS IUCr Journals Google Scholar
Frisch, M. J., et al. (2009). GAUSSIAN09. Gaussian Inc., Wallingford, CT, USA. Google Scholar
Gregson, S. T., Howard, P. W., Gullick, D. R., Hamaguchi, A., Corcoran, K. E., Brooks, N. A., Hartley, J. A., Jenkins, T. C., Patel, S., Guille, M. J. & Thurston, D. E. (2004). J. Med. Chem. 47, 1161–1174. Web of Science CrossRef PubMed CAS Google Scholar
Hadac, E. M., Dawson, E. S., Darrow, J. W., Sugg, E. E., Lybrand, T. P. & Miller, L. J. (2006). J. Med. Chem. 49, 850–863. Web of Science CrossRef PubMed CAS Google Scholar
Hathwar, V. R., Sist, M., Jørgensen, M. R. V., Mamakhel, A. H., Wang, X., Hoffmann, C. M., Sugimoto, K., Overgaard, J. & Iversen, B. B. (2015). IUCrJ, 2, 563–574. Web of Science CSD CrossRef CAS PubMed IUCr Journals Google Scholar
Hirshfeld, H. L. (1977). Theor. Chim. Acta, 44, 129–138. CrossRef CAS Web of Science Google Scholar
Jayatilaka, D., Grimwood, D. J., Lee, A., Lemay, A., Russel, A. J., Taylor, C., Wolff, S. K., Cassam-Chenai, P. & Whitton, A. (2005). TONTO - A System for Computational Chemistry. Available at: https://hirshfeldsurface.net/ Google Scholar
Kamal, A., Reddy, K. L., Devaiah, V., Shankaraiah, N., Reddy, G. S. K. & Raghavan, S. (2007). J. Comb. Chem. 9, 29–42. Web of Science CrossRef PubMed CAS Google Scholar
Mackenzie, C. F., Spackman, P. R., Jayatilaka, D. & Spackman, M. A. (2017). IUCrJ, 4, 575–587. Web of Science CrossRef CAS PubMed IUCr Journals Google Scholar
Makosza, M. & Jonczyk, A. (1976). Org. Synth. 55, 91. Google Scholar
McKinnon, J. J., Jayatilaka, D. & Spackman, M. A. (2007). Chem. Commun. pp. 3814–3816. Web of Science CrossRef Google Scholar
Micale, N., Vairagoundar, R., Yakovlev, A. G. & Kozikowski, A. P. (2004). J. Med. Chem. 47, 6455–6458. Web of Science CrossRef PubMed CAS Google Scholar
Mohiuddin, C., Reddy, P. S., Ahmed, K. & Ratnam, C. V. (1986). Heterocycles, 24, 3489–3530. CAS Google Scholar
Ourahou, S., Chammache, M., Zouihri, H., Essassi, E. M. & Ng, S. W. (2010). Acta Cryst. E66, o731. Web of Science CSD CrossRef IUCr Journals Google Scholar
Ourahou, S., Zouihri, H., Massoui, M., Essassi, E. M. & Ng, S. W. (2011). Acta Cryst. E67, o1906. Web of Science CSD CrossRef IUCr Journals Google Scholar
Parsons, S., Flack, H. D. & Wagner, T. (2013). Acta Cryst. B69, 249–259. Web of Science CrossRef CAS IUCr Journals Google Scholar
Randles, K. R. & Storr, R. C. (1984). J. Chem. Soc. 22, 1485–1486. Google Scholar
Sheldrick, G. M. (2015a). Acta Cryst. A71, 3–8. Web of Science CrossRef IUCr Journals Google Scholar
Sheldrick, G. M. (2015b). Acta Cryst. C71, 3–8. Web of Science CrossRef IUCr Journals Google Scholar
Spackman, M. A. & Jayatilaka, D. (2009). CrystEngComm, 11, 19–32. Web of Science CrossRef CAS Google Scholar
Spackman, M. A., McKinnon, J. J. & Jayatilaka, D. (2008). CrystEngComm, 10, 377–388. CAS Google Scholar
Sugasawa, T., Adachi, M., Sasakura, K., Matsushita, A., Eigyo, M., Shiomi, T., Shintaku, H., Takahara, Y. & Murata, S. (1985). J. Med. Chem. 28, 699–707. CrossRef CAS PubMed Web of Science Google Scholar
Thurston, D. E. & Langley, D. R. (1986). J. Org. Chem. 51, 705–712. CrossRef CAS Web of Science Google Scholar
Turner, M. J., Grabowsky, S., Jayatilaka, D. & Spackman, M. A. (2014). J. Phys. Chem. Lett. 5, 4249–4255. Web of Science CrossRef CAS PubMed Google Scholar
Turner, M. J., McKinnon, J. J., Wolff, S. K., Grimwood, D. J., Spackman, P. R., Jayatilaka, D. & Spackman, M. A. (2017). CrystalExplorer17. The University of Western Australia. Google Scholar
Turner, M. J., Thomas, S. P., Shi, M. W., Jayatilaka, D. & Spackman, M. A. (2015). Chem. Commun. 51, 3735–3738. Web of Science CrossRef CAS Google Scholar
Venkatesan, P., Thamotharan, S., Ilangovan, A., Liang, H. & Sundius, T. (2016). Spectrochim. Acta Part A, 153, 625–636. Web of Science CSD CrossRef CAS Google Scholar

This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.