Crystal structure of (RS)-4-(3-carb­oxy-1-ethyl-6,8-di­fluoro-4-oxo-1,4-di­hydro­quinolin-7-yl)-2-methyl­piperazin-1-ium 3-carb­oxy-5-fluoro­benzoate

Feng, S.; Zhu, G.-L.; Sun, J.-J.; Chen, C.; Zhang, Z.-H.

doi:10.1107/S2056989018016961

research communications

CRYSTALLOGRAPHIC
COMMUNICATIONS

ISSN: 2056-9890

Volume 75| Part 1| January 2019| Pages 68-70

https://doi.org/10.1107/S2056989018016961

Open

access

Crystal structure of (RS)-4-(3-carboxy-1-ethyl-6,8-difluoro-4-oxo-1,4-dihydroquinolin-7-yl)-2-methylpiperazin-1-ium 3-carboxy-5-fluorobenzoate

Sheng Feng,^a Gui-Liang Zhu,^a Jia-Jia Sun,^a Chen Chen ^b and Zhi-Hui Zhang ^b ^*

^aSchool of Environmental and Safety Engineering, Changzhou University, Changzhou, 213164, People's Republic of China, and ^bJiangsu Key Laboratory of Advanced Catalytic Materials and Technology, Changzhou, University, Changzhou 213164, People's Republic of China
^*Correspondence e-mail: zhangzh@cczu.edu.cn

Edited by M. Weil, Vienna University of Technology, Austria (Received 29 October 2018; accepted 29 November 2018; online 1 January 2019)

In the title organic salt, C₁₇H₂₀F₂N₃O₃⁺·C₈H₄FO₄⁻, proton transfer leads to one protonated lomefloxacin molecule (HLf⁺) and one 3-carboxy-5-fluorobenzoate (5-F-Hip⁻) anion in the asymmetric unit. The HLf⁺ cation is bent, with a dihedral angle of 38.3 (1)° between the quinoline ring and the piperazinium moiety. In the crystal, two kinds of N—H⋯O and O—H⋯O hydrogen-bonded chains cross-link each other to produce a three-dimensional network structure that is additionally stabilized by weak C—H⋯O and C—H⋯F hydrogen bonds, as well as π–π interactions. The methyl group attached to the piperazinium ring is disordered over two sets of sites [refined ratio: 0.645 (5):0.335 (5)], indicating the presence of both enantiomers of the cation in the structure.

Keywords: crystal structure; proton transfer; lomefloxacin; hydrogen-bonded network.

CCDC reference: 1025160

1. Chemical context

Lomefloxacin [Lf; systematic name: (RS)-4-(3-carboxy-1-ethyl-6,8-difluoro-4-oxo-1,4-dihydroquinolin-7-yl)-2-methylpiperazine] belongs to the fluoroquinolones that represent an important family of highly effective broad-spectrum antibacterial agents (Ross & Riley, 1990 ; Reddy et al., 2011 ; Huang et al., 2013 ). Lomefloxacin is very useful for the treatment of a variety of infections, although its therapeutic action as a drug is limited due to poor aqueous solubility (1.03 mg ml⁻¹, Ross & Riley, 1990). Using salts of lomefloxacin may overcome this problem. Several binary and ternary salts of lomefloxacin have been reported with supramolecular arrangements of the cationic and anionic moieties, such as the terephthalate (Zhou et al., 2006 ), isophthalate (Zhang et al., 2015 ), picrate (Jasinski et al., 2011 ) or hydrochloride (Holstein et al., 2012 ). However, the number of compounds related to solubility improvement is rather limited (Zhang et al., 2015).

In this context, we have used 3-carboxy-5-fluorobenzoic acid (5-F-H₂ip) for a proton-transfer reaction, and report here synthesis and crystal structure of the produced salt (HLf)⁺·(5-F-Hip⁻), (I).

2. Structural commentary

The structures of the molecular entities of (I) are displayed in Fig. 1. Unlike other lomefloxacin salts (Zhang et al., 2015), the title compound reveals no guest solvents residing in the crystal structure. In the asymmetric unit, there is one HLf⁺ cation and one 5-F-Hip⁻ anion, i.e. only one proton has been transferred from the free acid. Within the HLf⁺ moiety, a non-planar conformation of the molecule is formed with a dihedral angle of 38.3 (1)° between the aromatic ring plane and the piperazinium ring (the latter exhibits a chair conformation). An intramolecular S(6) hydrogen-bonding pattern (Etter et al., 1990 ) is found between the carboxylic group and the carbonyl O atom (O2—H2⋯O1; Table 1). The 5-F-Hip⁻ anion is nearly planar (r.m.s. deviation = 0.132 Å), with the highest deviation of 0.2645 (13) Å for the carboxylate O6 atom.

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O5—H5⋯O7ⁱ	0.82	1.75	2.557 (2)	167
O2—H2⋯O1	0.82	1.78	2.535 (3)	153
N1—H1B⋯O7ⁱⁱ	0.89	2.48	3.046 (2)	122
N1—H1B⋯O6ⁱⁱ	0.89	1.91	2.790 (2)	170
N1—H1A⋯O3ⁱⁱⁱ	0.89	1.94	2.811 (2)	165
C21—H21⋯O4^iv	0.93	2.61	3.534 (3)	173
C17—H17C⋯F1	0.96	2.45	2.985 (3)	115
C17—H17B⋯F3^v	0.96	2.53	3.380 (3)	148
C16—H16B⋯F1^v	0.97	2.48	3.394 (3)	157
C16—H16B⋯F1	0.97	2.16	2.682 (2)	112
C16—H16A⋯O6^vi	0.97	2.35	3.287 (3)	162
C14—H14⋯O6^vi	0.93	2.59	3.448 (3)	154
C4—H4A⋯O4^v	0.97	2.60	3.274 (3)	127
C2—H2B⋯F2	0.97	2.30	2.883 (2)	118
C2—H2A⋯F3	0.97	2.57	3.078 (2)	113
Symmetry codes: (i) $[x-{\script{1\over 2}}, -y+{\script{1\over 2}}, z-{\script{1\over 2}}]$ ; (ii) $[x-{\script{1\over 2}}, -y+{\script{1\over 2}}, z+{\script{1\over 2}}]$ ; (iii) x, y, z+1; (iv) $[x+{\script{1\over 2}}, -y+{\script{1\over 2}}, z+{\script{1\over 2}}]$ ; (v) -x, -y, -z+1; (vi) $[-x+{\script{1\over 2}}, y-{\script{1\over 2}}, -z+{\script{1\over 2}}]$ .

Figure 1
Molecular structures of the cation and anion in the title salt. Displacement ellipsoids are drawn at the 30% probability level.

3. Supramolecular features

In the crystal structure, N1—H1A⋯O3ⁱⁱⁱ interactions between the amino function of the piperazinium moiety and the non-protonated O atom of the carboxylic group of a neighboring HLf⁺ cation result in a head-to-tail chain motif with descriptor C(13). Adjacent 5-F-Hip⁻ moieties also form a head-to-tail chain, based on a C(8) pattern, involving O5—H5⋯O7ⁱ bonds between the carboxylic acid function and the carboxylate function. The two kinds of chains interlink with each other through N1—H1B⋯O6ⁱⁱ interactions between the second H atom of the amino group of the cation and one of the carboxylate O atoms of the anion to form a three-dimensional network structure. Within this array (Fig. 2), additional weak C—H⋯O and C—H⋯F interactions are present (Table 1) as additional stabilization forces, along with π–π interactions between fluoroquinolone benzene rings of the cations and and phenyl rings of the anions with a centroid-to-centroid separation of 3.7895 (12) Å.

Figure 2
A perspective view of (I)

showing the N—H⋯O and O—H⋯O hydrogen-bonding interactions (dotted lines) between the two kinds of chains. `Acidic' chains, i.e. chains involving only the anion, are shown in red for clarity.

4. Database survey

Two crystal structures (Zhang et al., 2015) based on lomefloxacin and isophthalic acid have been reported in the CSD (Verson 5.39; Groom et al., 2016 ) viz. CURKAD [4-(3-carboxy-1-ethyl-6,8-difluoro-4-oxo-1,4-dihydroquinolin-7-yl)-2-methylpiperazin-1-ium 3-carboxybenzoate hydrate] and CURKIL [4-(3-carboxy-1-ethyl-6,8-difluoro-4-oxo-1,4-dihydroquinolin-7-yl)-2-methylpiperazin-1-ium 2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-olate isophthalic acid methanol solvate monohydrate]. Both CURKAD and the title compound are proton-transfer compounds from isophthalic acids to the piperazine NH groups. In the structure of CURKIL, the isophthalic acid moiety remains protonated, and co-crystallized barbituric acid is the proton donor in this case. With respect to the supramolecular networks in these structures, the contribution of the extra fluorine atom in (I) leads to additional hydrogen bonds of the type C—H⋯F.

5. Synthesis and crystallization

A methanol solution (6 ml) of 5-fluoroisophthalic acid (5-F-H₂ip; 20 mg, 0.1 mmol) was mixed with a slurry of lomefloxacin (Lf) (35 mg, 0.1 mmol) in 5 ml water under stirring. The mixture was exposed to ultrasound for ca 20 min, and was then filtered and left to slowly evaporate. Colourless block-like single crystals suitable for X-ray analysis were obtained after several weeks. Yield: 65% (35 mg, based on Lf). Analysis calculated for C₂₅H₂₄F₃N₃O₇: C, 56.08; H, 4.52; N, 7.85%. Found: C, 56.06; H, 4.50; N, 7.82%. FT–IR (KBr pellet, cm⁻¹): 3431b, 3070 (w), 2475 (w), 1718 (s), 1620 (vs, 1539 (m), 1456 (s), 1371 (m), 1275 (s), 1090 (m), 959 (m), 901 (w), 766 (m), 689 (m), 521 (w).

6. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2. H atoms bonded to C were placed geometrically and refined in a riding model: C—H = 0.96–0.98 Å; U_iso(H) = 1.2U_eq(C) or 1.5U_eq(C-methyl). All O-bound and N-bound H atoms were initially found in difference electron-density maps, and then refined using a riding model [O—H = 0.82 Å and N—H = 0.89 Å; U_iso(H) = 1.2U_eq(N) and 1.5U_eq(O)]. The methyl group bound to the piperazinium ring is disordered over two positions with occupancies of 0.645 (5) and 0.355 (5).

Table 2
Experimental details

Crystal data
Chemical formula	C₁₇H₂₀F₂N₃O₃⁺·C₈H₄FO₄⁻
M_r	535.47
Crystal system, space group	Monoclinic, P2₁/n
Temperature (K)	296
a, b, c (Å)	10.4324 (12), 16.5656 (19), 14.0448 (17)
β (°)	100.707 (3)
V (Å³)	2384.9 (5)
Z	4
Radiation type	Mo Kα
μ (mm⁻¹)	0.13
Crystal size (mm)	0.22 × 0.20 × 0.16

Data collection
Diffractometer	Bruker APEXII CCD
Absorption correction	Multi-scan (SADABS; Bruker, 2010 )
T_min, T_max	0.970, 0.980
No. of measured, independent and observed [I > 2σ(I)] reflections	16570, 6292, 4335
R_int	0.035
(sin θ/λ)_max (Å⁻¹)	0.711

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.054, 0.161, 0.98
No. of reflections	6292
No. of parameters	358
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.29, −0.28
Computer programs: APEX2 and SAINT (Bruker, 2010), SHELXS97 and SHELXTL (Sheldrick, 2008 ), SHELXL2014 (Sheldrick, 2015 ) and publCIF (Westrip, 2010 ).

Supporting information

CCDC reference: 1025160

Crystal structure: contains datablock I. DOI: https://doi.org/10.1107/S2056989018016961/wm5472sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2056989018016961/wm5472Isup2.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2056989018016961/wm5472Isup3.cml

checkCIF report

Computing details top

Data collection: APEX2 (Bruker, 2010); cell refinement: SAINT (Bruker, 2010); data reduction: SAINT (Bruker, 2010); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL2014 (Sheldrick, 2015); molecular graphics: SHELXTL (Sheldrick, 2008); software used to prepare material for publication: publCIF (Westrip, 2010).

(RS)-4-(3-Carboxy-1-ethyl-6,8-difluoro-4-oxo-1,4-dihydroquinolin-7-yl)-2-methylpiperazin-1-ium 3-carboxy-5-fluorobenzoate top

Crystal data top

C₁₇H₂₀F₂N₃O₃⁺·C₈H₄FO₄⁻	F(000) = 1112
M_r = 535.47	D_x = 1.491 Mg m⁻³
Monoclinic, P2₁/n	Mo Kα radiation, λ = 0.71073 Å
a = 10.4324 (12) Å	Cell parameters from 5522 reflections
b = 16.5656 (19) Å	θ = 2.2–29.9°
c = 14.0448 (17) Å	µ = 0.13 mm⁻¹
β = 100.707 (3)°	T = 296 K
V = 2384.9 (5) Å³	Block, colorless
Z = 4	0.22 × 0.20 × 0.16 mm

Data collection top

Bruker APEXII CCD diffractometer	4335 reflections with I > 2σ(I)
φ and ω scans	R_int = 0.035
Absorption correction: multi-scan (SADABS; Bruker, 2010)	θ_max = 30.4°, θ_min = 1.9°
T_min = 0.970, T_max = 0.980	h = −14→14
16570 measured reflections	k = −23→21
6292 independent reflections	l = −19→13

Refinement top

Refinement on F²	0 restraints
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F² > 2σ(F²)] = 0.054	H-atom parameters constrained
wR(F²) = 0.161	w = 1/[σ²(F_o²) + (0.085P)² + 0.686P] where P = (F_o² + 2F_c²)/3
S = 0.98	(Δ/σ)_max < 0.001
6292 reflections	Δρ_max = 0.29 e Å⁻³
358 parameters	Δρ_min = −0.28 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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq	Occ. (<1)
C2	0.2703 (2)	0.12846 (10)	0.77391 (12)	0.0390 (4)
H2A	0.1793	0.1429	0.7531	0.047*
H2B	0.3232	0.1710	0.7536	0.047*
C3	0.21645 (19)	−0.01366 (11)	0.75432 (12)	0.0385 (4)
H3A	0.2383	−0.0636	0.7249	0.046*
H3B	0.1251	−0.0021	0.7299	0.046*
C4	0.23908 (19)	−0.02326 (11)	0.86352 (12)	0.0391 (4)
H4A	0.1800	−0.0637	0.8804	0.047*
H4B	0.3277	−0.0416	0.8868	0.047*
C1	0.30073 (19)	0.12083 (11)	0.88315 (12)	0.0398 (4)	0.645 (5)
H1	0.3925	0.1055	0.9030	0.048*	0.645 (5)
C5	0.2784 (4)	0.1988 (2)	0.9320 (2)	0.0587 (11)	0.645 (5)
H5A	0.2890	0.1903	1.0006	0.088*	0.645 (5)
H5B	0.1915	0.2177	0.9074	0.088*	0.645 (5)
H5C	0.3403	0.2383	0.9191	0.088*	0.645 (5)
C1'	0.30073 (19)	0.12083 (11)	0.88315 (12)	0.0398 (4)	0.355 (5)
H1'	0.2728	0.1712	0.9098	0.048*	0.355 (5)
C5'	0.4401 (7)	0.1112 (5)	0.9223 (4)	0.064 (2)	0.355 (5)
H5'1	0.4858	0.1593	0.9101	0.096*	0.355 (5)
H5'2	0.4734	0.0660	0.8917	0.096*	0.355 (5)
H5'3	0.4525	0.1020	0.9909	0.096*	0.355 (5)
C6	0.32692 (16)	0.05742 (10)	0.63571 (11)	0.0314 (3)
C7	0.25702 (16)	0.02250 (11)	0.55222 (12)	0.0348 (4)
C8	0.29167 (16)	0.02851 (11)	0.46031 (11)	0.0360 (4)
C9	0.39760 (17)	0.07840 (11)	0.45220 (12)	0.0375 (4)
C10	0.46920 (18)	0.11506 (11)	0.53468 (13)	0.0378 (4)
H10	0.5396	0.1481	0.5295	0.045*
C11	0.43600 (17)	0.10242 (11)	0.62229 (12)	0.0354 (4)
C12	0.4354 (2)	0.09342 (13)	0.35878 (13)	0.0468 (5)
C13	0.3573 (2)	0.05467 (14)	0.27828 (13)	0.0511 (5)
C14	0.2580 (2)	0.00583 (15)	0.29119 (13)	0.0533 (6)
H14	0.2103	−0.0191	0.2366	0.064*
C15	0.3820 (3)	0.06630 (18)	0.17808 (15)	0.0690 (8)
C16	0.12118 (19)	−0.07161 (18)	0.37829 (15)	0.0621 (7)
H16A	0.0763	−0.0816	0.3124	0.075*
H16B	0.0576	−0.0514	0.4148	0.075*
C17	0.1759 (2)	−0.14920 (18)	0.4221 (2)	0.0711 (8)
H17A	0.2399	−0.1692	0.3869	0.107*
H17B	0.1070	−0.1880	0.4192	0.107*
H17C	0.2161	−0.1403	0.4885	0.107*
C18	0.15025 (16)	0.22254 (10)	0.33449 (12)	0.0331 (4)
C19	0.25938 (16)	0.27147 (10)	0.33760 (12)	0.0331 (4)
H19	0.2883	0.2841	0.2806	0.040*
C20	0.32544 (16)	0.30154 (10)	0.42577 (11)	0.0325 (3)
C21	0.28309 (17)	0.28192 (11)	0.51078 (12)	0.0352 (4)
H21	0.3271	0.3008	0.5703	0.042*
C22	0.17472 (17)	0.23394 (12)	0.50507 (12)	0.0389 (4)
C23	0.10696 (17)	0.20350 (11)	0.41930 (12)	0.0374 (4)
H23	0.0340	0.1710	0.4182	0.045*
C24	0.07378 (18)	0.18979 (11)	0.24192 (13)	0.0398 (4)
C25	0.44349 (18)	0.35535 (11)	0.43029 (12)	0.0390 (4)
F1	0.14586 (10)	−0.01682 (8)	0.56051 (8)	0.0542 (3)
F2	0.51182 (11)	0.13417 (7)	0.70199 (8)	0.0502 (3)
F3	0.13353 (12)	0.21463 (9)	0.58853 (8)	0.0600 (4)
N1	0.21749 (14)	0.05481 (9)	0.91112 (10)	0.0366 (3)
H1A	0.2354	0.0485	0.9751	0.044*
H1B	0.1339	0.0688	0.8945	0.044*
N2	0.29693 (15)	0.05198 (8)	0.72827 (10)	0.0349 (3)
N3	0.22256 (15)	−0.00954 (12)	0.37700 (10)	0.0466 (4)
O1	0.52996 (17)	0.13801 (11)	0.35126 (11)	0.0634 (4)
O2	0.4753 (2)	0.11777 (15)	0.16934 (12)	0.0864 (6)
H2	0.5061	0.1367	0.2226	0.130*
O3	0.3194 (2)	0.03032 (14)	0.10876 (11)	0.0906 (7)
O4	−0.03217 (17)	0.16034 (13)	0.23770 (11)	0.0770 (6)
O5	0.13137 (13)	0.19749 (9)	0.16727 (9)	0.0483 (3)
H5	0.0852	0.1778	0.1192	0.073*
O6	0.46630 (13)	0.38375 (9)	0.35255 (9)	0.0500 (4)
O7	0.51218 (16)	0.36907 (10)	0.51142 (10)	0.0619 (4)

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
C2	0.0599 (11)	0.0327 (9)	0.0257 (8)	0.0003 (8)	0.0111 (8)	−0.0032 (7)
C3	0.0511 (10)	0.0366 (9)	0.0280 (8)	−0.0052 (8)	0.0074 (7)	−0.0045 (7)
C4	0.0526 (10)	0.0355 (9)	0.0297 (8)	0.0002 (8)	0.0089 (7)	0.0023 (7)
C1	0.0533 (10)	0.0421 (10)	0.0244 (8)	−0.0045 (8)	0.0079 (7)	−0.0076 (7)
C5	0.087 (3)	0.052 (2)	0.0429 (18)	−0.0161 (17)	0.0286 (17)	−0.0244 (15)
C1'	0.0533 (10)	0.0421 (10)	0.0244 (8)	−0.0045 (8)	0.0079 (7)	−0.0076 (7)
C5'	0.066 (4)	0.091 (5)	0.033 (3)	−0.029 (4)	0.006 (3)	0.000 (3)
C6	0.0390 (8)	0.0346 (8)	0.0204 (7)	0.0060 (7)	0.0047 (6)	−0.0019 (6)
C7	0.0321 (8)	0.0470 (10)	0.0252 (8)	0.0041 (7)	0.0050 (6)	−0.0063 (7)
C8	0.0358 (8)	0.0502 (10)	0.0201 (7)	0.0152 (7)	0.0005 (6)	−0.0052 (7)
C9	0.0411 (9)	0.0482 (10)	0.0240 (8)	0.0183 (8)	0.0084 (7)	0.0030 (7)
C10	0.0411 (9)	0.0401 (9)	0.0337 (9)	0.0066 (7)	0.0111 (7)	0.0017 (7)
C11	0.0418 (9)	0.0362 (9)	0.0262 (8)	0.0040 (7)	0.0011 (7)	−0.0031 (7)
C12	0.0539 (11)	0.0578 (12)	0.0312 (9)	0.0269 (10)	0.0143 (8)	0.0094 (8)
C13	0.0613 (12)	0.0703 (14)	0.0233 (8)	0.0313 (11)	0.0119 (8)	0.0059 (8)
C14	0.0551 (12)	0.0824 (15)	0.0194 (8)	0.0299 (11)	−0.0009 (8)	−0.0088 (9)
C15	0.0890 (18)	0.0935 (19)	0.0263 (10)	0.0476 (16)	0.0155 (11)	0.0118 (11)
C16	0.0340 (10)	0.113 (2)	0.0366 (10)	0.0000 (11)	0.0000 (8)	−0.0361 (12)
C17	0.0545 (13)	0.0898 (19)	0.0727 (16)	−0.0240 (13)	0.0213 (12)	−0.0368 (15)
C18	0.0350 (8)	0.0344 (8)	0.0284 (8)	0.0011 (7)	0.0014 (7)	0.0012 (6)
C19	0.0377 (8)	0.0372 (9)	0.0236 (7)	0.0006 (7)	0.0036 (6)	0.0052 (6)
C20	0.0367 (8)	0.0331 (8)	0.0262 (8)	0.0031 (7)	0.0016 (6)	0.0046 (6)
C21	0.0406 (9)	0.0405 (9)	0.0225 (7)	0.0050 (7)	0.0010 (6)	0.0017 (6)
C22	0.0399 (9)	0.0517 (11)	0.0261 (8)	0.0057 (8)	0.0091 (7)	0.0082 (7)
C23	0.0345 (8)	0.0428 (10)	0.0344 (9)	0.0006 (7)	0.0054 (7)	0.0068 (7)
C24	0.0452 (10)	0.0417 (10)	0.0307 (8)	−0.0073 (8)	0.0023 (7)	0.0016 (7)
C25	0.0415 (9)	0.0446 (10)	0.0271 (8)	−0.0048 (8)	−0.0038 (7)	0.0082 (7)
F1	0.0424 (6)	0.0885 (9)	0.0324 (6)	−0.0148 (6)	0.0091 (5)	−0.0211 (6)
F2	0.0567 (7)	0.0588 (7)	0.0332 (6)	−0.0169 (5)	0.0034 (5)	−0.0103 (5)
F3	0.0566 (7)	0.0962 (10)	0.0305 (6)	−0.0063 (7)	0.0170 (5)	0.0108 (6)
N1	0.0432 (8)	0.0460 (8)	0.0210 (6)	0.0023 (6)	0.0072 (6)	−0.0016 (6)
N2	0.0506 (8)	0.0330 (7)	0.0219 (6)	−0.0036 (6)	0.0087 (6)	−0.0057 (5)
N3	0.0396 (8)	0.0754 (12)	0.0227 (7)	0.0143 (8)	0.0002 (6)	−0.0126 (7)
O1	0.0681 (10)	0.0823 (11)	0.0460 (8)	0.0089 (9)	0.0270 (8)	0.0126 (8)
O2	0.1021 (15)	0.1232 (18)	0.0419 (9)	0.0267 (13)	0.0340 (10)	0.0196 (10)
O3	0.1254 (16)	0.1244 (17)	0.0205 (7)	0.0381 (14)	0.0098 (9)	0.0027 (9)
O4	0.0699 (10)	0.1159 (15)	0.0427 (8)	−0.0525 (11)	0.0038 (8)	−0.0062 (9)
O5	0.0497 (8)	0.0640 (9)	0.0298 (6)	−0.0099 (6)	0.0036 (6)	−0.0103 (6)
O6	0.0497 (8)	0.0677 (9)	0.0292 (6)	−0.0176 (7)	−0.0014 (6)	0.0136 (6)
O7	0.0681 (9)	0.0778 (11)	0.0312 (7)	−0.0309 (8)	−0.0134 (7)	0.0147 (7)

Geometric parameters (Å, º) top

C2—N2	1.469 (2)	C12—O1	1.252 (3)
C2—C1	1.513 (2)	C12—C13	1.419 (3)
C2—C1'	1.513 (2)	C13—C14	1.353 (3)
C2—H2A	0.9700	C13—C15	1.490 (3)
C2—H2B	0.9700	C14—N3	1.349 (2)
C3—N2	1.461 (2)	C14—H14	0.9300
C3—C4	1.516 (2)	C15—O3	1.222 (4)
C3—H3A	0.9700	C15—O2	1.317 (4)
C3—H3B	0.9700	C16—N3	1.478 (3)
C4—N1	1.492 (2)	C16—C17	1.492 (4)
C4—H4A	0.9700	C16—H16A	0.9700
C4—H4B	0.9700	C16—H16B	0.9700
C1—N1	1.494 (2)	C17—H17A	0.9600
C1—C5	1.501 (3)	C17—H17B	0.9600
C1—H1	0.9800	C17—H17C	0.9600
C5—H5A	0.9600	C18—C23	1.386 (2)
C5—H5B	0.9600	C18—C19	1.392 (2)
C5—H5C	0.9600	C18—C24	1.495 (2)
C1'—C5'	1.465 (7)	C19—C20	1.393 (2)
C1'—N1	1.494 (2)	C19—H19	0.9300
C1'—H1'	0.9800	C20—C21	1.386 (2)
C5'—H5'1	0.9600	C20—C25	1.512 (2)
C5'—H5'2	0.9600	C21—C22	1.372 (3)
C5'—H5'3	0.9600	C21—H21	0.9300
C6—C7	1.387 (2)	C22—F3	1.3594 (19)
C6—N2	1.395 (2)	C22—C23	1.374 (3)
C6—C11	1.402 (2)	C23—H23	0.9300
C7—F1	1.354 (2)	C24—O4	1.200 (2)
C7—C8	1.407 (2)	C24—O5	1.308 (2)
C8—C9	1.402 (3)	C25—O7	1.249 (2)
C8—N3	1.405 (2)	C25—O6	1.252 (2)
C9—C10	1.395 (3)	N1—H1A	0.8900
C9—C12	1.460 (2)	N1—H1B	0.8900
C10—C11	1.355 (2)	O2—H2	0.8200
C10—H10	0.9300	O5—H5	0.8200
C11—F2	1.351 (2)

N2—C2—C1	110.44 (14)	O1—C12—C9	121.66 (19)
N2—C2—C1'	110.44 (14)	C13—C12—C9	115.34 (19)
N2—C2—H2A	109.6	C14—C13—C12	120.31 (17)
C1—C2—H2A	109.6	C14—C13—C15	118.4 (2)
N2—C2—H2B	109.6	C12—C13—C15	121.3 (2)
C1—C2—H2B	109.6	N3—C14—C13	125.18 (19)
H2A—C2—H2B	108.1	N3—C14—H14	117.4
N2—C3—C4	110.04 (14)	C13—C14—H14	117.4
N2—C3—H3A	109.7	O3—C15—O2	122.4 (2)
C4—C3—H3A	109.7	O3—C15—C13	122.0 (3)
N2—C3—H3B	109.7	O2—C15—C13	115.6 (2)
C4—C3—H3B	109.7	N3—C16—C17	112.61 (17)
H3A—C3—H3B	108.2	N3—C16—H16A	109.1
N1—C4—C3	110.75 (14)	C17—C16—H16A	109.1
N1—C4—H4A	109.5	N3—C16—H16B	109.1
C3—C4—H4A	109.5	C17—C16—H16B	109.1
N1—C4—H4B	109.5	H16A—C16—H16B	107.8
C3—C4—H4B	109.5	C16—C17—H17A	109.5
H4A—C4—H4B	108.1	C16—C17—H17B	109.5
N1—C1—C5	111.26 (18)	H17A—C17—H17B	109.5
N1—C1—C2	107.76 (14)	C16—C17—H17C	109.5
C5—C1—C2	111.7 (2)	H17A—C17—H17C	109.5
N1—C1—H1	108.7	H17B—C17—H17C	109.5
C5—C1—H1	108.7	C23—C18—C19	120.05 (15)
C2—C1—H1	108.7	C23—C18—C24	117.27 (15)
C1—C5—H5A	109.5	C19—C18—C24	122.67 (15)
C1—C5—H5B	109.5	C18—C19—C20	120.20 (15)
H5A—C5—H5B	109.5	C18—C19—H19	119.9
C1—C5—H5C	109.5	C20—C19—H19	119.9
H5A—C5—H5C	109.5	C21—C20—C19	119.84 (16)
H5B—C5—H5C	109.5	C21—C20—C25	119.31 (15)
C5'—C1'—N1	114.0 (3)	C19—C20—C25	120.85 (14)
C5'—C1'—C2	113.4 (3)	C22—C21—C20	118.46 (16)
N1—C1'—C2	107.76 (14)	C22—C21—H21	120.8
C5'—C1'—H1'	107.1	C20—C21—H21	120.8
N1—C1'—H1'	107.1	F3—C22—C21	118.36 (16)
C2—C1'—H1'	107.1	F3—C22—C23	118.42 (16)
C1'—C5'—H5'1	109.5	C21—C22—C23	123.22 (15)
C1'—C5'—H5'2	109.5	C22—C23—C18	118.23 (16)
H5'1—C5'—H5'2	109.5	C22—C23—H23	120.9
C1'—C5'—H5'3	109.5	C18—C23—H23	120.9
H5'1—C5'—H5'3	109.5	O4—C24—O5	123.81 (17)
H5'2—C5'—H5'3	109.5	O4—C24—C18	121.90 (17)
C7—C6—N2	125.94 (15)	O5—C24—C18	114.29 (15)
C7—C6—C11	114.87 (14)	O7—C25—O6	123.89 (17)
N2—C6—C11	119.18 (14)	O7—C25—C20	118.06 (15)
F1—C7—C6	116.89 (14)	O6—C25—C20	118.06 (15)
F1—C7—C8	118.88 (15)	C4—N1—C1'	111.92 (13)
C6—C7—C8	124.17 (16)	C4—N1—C1	111.92 (13)
C9—C8—N3	119.17 (15)	C4—N1—H1A	109.2
C9—C8—C7	117.20 (15)	C1—N1—H1A	109.2
N3—C8—C7	123.56 (17)	C4—N1—H1B	109.2
C10—C9—C8	119.86 (15)	C1—N1—H1B	109.2
C10—C9—C12	118.66 (18)	H1A—N1—H1B	107.9
C8—C9—C12	121.49 (17)	C6—N2—C3	121.34 (13)
C11—C10—C9	119.92 (17)	C6—N2—C2	116.36 (13)
C11—C10—H10	120.0	C3—N2—C2	111.61 (13)
C9—C10—H10	120.0	C14—N3—C8	118.45 (18)
F2—C11—C10	118.87 (16)	C14—N3—C16	117.24 (17)
F2—C11—C6	117.42 (14)	C8—N3—C16	124.05 (16)
C10—C11—C6	123.71 (16)	C15—O2—H2	109.5
O1—C12—C13	123.00 (18)	C24—O5—H5	109.5

N2—C3—C4—N1	54.3 (2)	C18—C19—C20—C25	−179.48 (16)
N2—C2—C1—N1	−59.2 (2)	C19—C20—C21—C22	−1.1 (3)
N2—C2—C1—C5	178.3 (2)	C25—C20—C21—C22	179.11 (16)
N2—C2—C1'—C5'	67.9 (4)	C20—C21—C22—F3	179.86 (15)
N2—C2—C1'—N1	−59.2 (2)	C20—C21—C22—C23	0.8 (3)
N2—C6—C7—F1	3.7 (3)	F3—C22—C23—C18	−179.23 (16)
C11—C6—C7—F1	−175.55 (15)	C21—C22—C23—C18	−0.2 (3)
N2—C6—C7—C8	−179.07 (16)	C19—C18—C23—C22	−0.2 (3)
C11—C6—C7—C8	1.7 (3)	C24—C18—C23—C22	−179.07 (16)
F1—C7—C8—C9	171.85 (15)	C23—C18—C24—O4	12.6 (3)
C6—C7—C8—C9	−5.3 (3)	C19—C18—C24—O4	−166.2 (2)
F1—C7—C8—N3	−5.2 (3)	C23—C18—C24—O5	−168.50 (16)
C6—C7—C8—N3	177.68 (16)	C19—C18—C24—O5	12.6 (3)
N3—C8—C9—C10	−178.45 (15)	C21—C20—C25—O7	12.1 (3)
C7—C8—C9—C10	4.4 (2)	C19—C20—C25—O7	−167.74 (18)
N3—C8—C9—C12	1.7 (2)	C21—C20—C25—O6	−167.64 (17)
C7—C8—C9—C12	−175.47 (15)	C19—C20—C25—O6	12.5 (3)
C8—C9—C10—C11	−0.1 (3)	C3—C4—N1—C1'	−55.9 (2)
C12—C9—C10—C11	179.77 (16)	C3—C4—N1—C1	−55.9 (2)
C9—C10—C11—F2	175.67 (15)	C5'—C1'—N1—C4	−69.3 (3)
C9—C10—C11—C6	−3.9 (3)	C2—C1'—N1—C4	57.47 (19)
C7—C6—C11—F2	−176.49 (15)	C5—C1—N1—C4	−179.7 (2)
N2—C6—C11—F2	4.2 (2)	C2—C1—N1—C4	57.47 (19)
C7—C6—C11—C10	3.1 (3)	C7—C6—N2—C3	22.2 (3)
N2—C6—C11—C10	−176.24 (16)	C11—C6—N2—C3	−158.57 (16)
C10—C9—C12—O1	0.1 (3)	C7—C6—N2—C2	−119.34 (19)
C8—C9—C12—O1	179.95 (17)	C11—C6—N2—C2	59.9 (2)
C10—C9—C12—C13	−179.44 (16)	C4—C3—N2—C6	159.44 (15)
C8—C9—C12—C13	0.4 (2)	C4—C3—N2—C2	−57.40 (19)
O1—C12—C13—C14	178.65 (19)	C1—C2—N2—C6	−153.88 (15)
C9—C12—C13—C14	−1.8 (3)	C1'—C2—N2—C6	−153.88 (15)
O1—C12—C13—C15	−1.3 (3)	C1—C2—N2—C3	61.0 (2)
C9—C12—C13—C15	178.26 (17)	C1'—C2—N2—C3	61.0 (2)
C12—C13—C14—N3	1.2 (3)	C13—C14—N3—C8	1.0 (3)
C15—C13—C14—N3	−178.91 (19)	C13—C14—N3—C16	−173.3 (2)
C14—C13—C15—O3	−3.4 (3)	C9—C8—N3—C14	−2.4 (2)
C12—C13—C15—O3	176.5 (2)	C7—C8—N3—C14	174.54 (17)
C14—C13—C15—O2	176.5 (2)	C9—C8—N3—C16	171.48 (18)
C12—C13—C15—O2	−3.6 (3)	C7—C8—N3—C16	−11.6 (3)
C23—C18—C19—C20	−0.1 (3)	C17—C16—N3—C14	104.7 (2)
C24—C18—C19—C20	178.77 (16)	C17—C16—N3—C8	−69.3 (2)
C18—C19—C20—C21	0.7 (3)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O5—H5···O7ⁱ	0.82	1.75	2.557 (2)	167
O2—H2···O1	0.82	1.78	2.535 (3)	153
N1—H1B···O7ⁱⁱ	0.89	2.48	3.046 (2)	122
N1—H1B···O6ⁱⁱ	0.89	1.91	2.790 (2)	170
N1—H1A···O3ⁱⁱⁱ	0.89	1.94	2.811 (2)	165
C21—H21···O4^iv	0.93	2.61	3.534 (3)	173
C17—H17C···F1	0.96	2.45	2.985 (3)	115
C17—H17B···F3^v	0.96	2.53	3.380 (3)	148
C16—H16B···F1^v	0.97	2.48	3.394 (3)	157
C16—H16B···F1	0.97	2.16	2.682 (2)	112
C16—H16A···O6^vi	0.97	2.35	3.287 (3)	162
C14—H14···O6^vi	0.93	2.59	3.448 (3)	154
C4—H4A···O4^v	0.97	2.60	3.274 (3)	127
C2—H2B···F2	0.97	2.30	2.883 (2)	118
C2—H2A···F3	0.97	2.57	3.078 (2)	113

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

Funding information

We acknowledge financial support from Jiangsu Key Laboratory of Advanced Catalytic Materials and Technology (grant No. BM2012110).

References

Bruker (2010). APEX2, SAINT and SADABS. Bruker AXS Inc., Madison, Wisconsin, USA. Google Scholar
Etter, M. C., MacDonald, J. C. & Bernstein, J. (1990). Acta Cryst. B46, 256–262. CrossRef CAS Web of Science IUCr Journals Google Scholar
Groom, C. R., Bruno, I. J., Lightfoot, M. P. & Ward, S. C. (2016). Acta Cryst. B72, 171–179. Web of Science CrossRef IUCr Journals Google Scholar
Holstein, J. J., Hübschle, C. B. & Dittrich, B. (2012). CrystEngComm, 14, 2520–2531. Web of Science CrossRef CAS Google Scholar
Huang, X. F., Zhang, Z. H., Zhang, Q. Q., Wang, L. Z., He, M. Y., Chen, Q., Song, G. Q., Wei, L., Wang, F. & Du, M. (2013). CrystEngComm, 15, 6090–6100. Web of Science CrossRef CAS Google Scholar
Jasinski, J. P., Butcher, R. J., Siddegowda, M. S., Yathirajan, H. S. & Hakim Al-arique, Q. N. M. (2011). Acta Cryst. E67, o483–o484. Web of Science CrossRef CAS IUCr Journals Google Scholar
Reddy, J. S., Ganesh, S. V., Nagalapalli, R., Dandela, R., Solomon, K. A., Kumar, K. A., Goud, N. R. & Nangia, A. (2011). J. Pharm. Sci. 100, 3160–3176. Web of Science CrossRef CAS PubMed Google Scholar
Ross, D. L. & Riley, C. M. (1990). Int. J. Pharm. 63, 237–250. CrossRef CAS Web of Science Google Scholar
Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. Web of Science CrossRef CAS IUCr Journals Google Scholar
Sheldrick, G. M. (2015). Acta Cryst. C71, 3–8. Web of Science CrossRef IUCr Journals Google Scholar
Westrip, S. P. (2010). J. Appl. Cryst. 43, 920–925. Web of Science CrossRef CAS IUCr Journals Google Scholar
Zhang, Z.-H., Zhang, Q., Zhang, Q.-Q., Chen, C., He, M.-Y., Chen, Q., Song, G.-Q., Xuan, X.-P. & Huang, X.-F. (2015). Acta Cryst. B71, 437–446. CrossRef IUCr Journals Google Scholar
Zhou, T., Zhao, L. & Guo, J. X. (2006). Z. Kristallogr. New Cryst. Struct. 221, 495–496. 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.