Fluconazolium picrate

Grzegorz Dutkiewicz; C S Chidan Kumar; H S Yathirajan; B Narayana; Maciej Kubicki

doi:10.1107/S1600536810036329

. 2010 Sep 15;66(Pt 10):o2568. doi: 10.1107/S1600536810036329

Fluconazolium picrate

Grzegorz Dutkiewicz ^a, C S Chidan Kumar ^b, H S Yathirajan ^b, B Narayana ^c, Maciej Kubicki ^a,^*

PMCID: PMC2983200 PMID: 21587553

Abstract

The title compound, C₁₃H₁₃F₂N₆O⁺·C₆H₂N₃O₇ ⁻, is the first structurally characterized salt of the cation of fluconazole [systematic name 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol], a synthetic antifungal agent. In the crystal, the components are linked by O—H⋯O hydrogen bonding between the hydroxy group of the fluconazolium cation and the C=O(−) group of the picrate anion. This complex is additionally stabilized by secondary, but relatively short, C—H⋯O interactions. The dimers thus formed are connected by N—H⋯N cation–cation hydrogen bonds into helices running along [010]. Neighboring helices of opposite handedness are joined by weak anion–anion C—H⋯O(nitro) interactions. In the cation, the mean planes of the three rings are approximately, within ca 25°, parallel to the central C—O bond. In the picrate anion two nitro groups, in turn, are almost coplanar with the ring plane [forming dihedral angles of 6.5 (2) and 3.8 (2)°] while the third nitro group is significantly twisted [by 46.79 (13)°].

Related literature

For the antifungal properties of fluconazole, see: Brammer et al. (1990 ▶); Caira et al. (2003 ▶). For a description of the Cambridge Structural Database, see: Allen (2002 ▶).

Experimental

Crystal data

C₁₃H₁₃F₂N₆O⁺·C₆H₂N₃O₇ ⁻
M _r = 535.40
Monoclinic,
a = 5.647 (1) Å
b = 17.347 (2) Å
c = 22.571 (2) Å
β = 94.27 (1)°
V = 2204.9 (5) Å³
Z = 4
Mo Kα radiation
μ = 0.14 mm⁻¹
T = 100 K
0.2 × 0.2 × 0.15 mm

Data collection

Kuma KM-4-CCD four-circle diffractometer
18260 measured reflections
5165 independent reflections
3576 reflections with I > 2σ(I)
R _int = 0.023

Refinement

R[F ² > 2σ(F ²)] = 0.035
wR(F ²) = 0.082
S = 0.99
5165 reflections
403 parameters
All H-atom parameters refined
Δρ_max = 0.25 e Å⁻³
Δρ_min = −0.24 e Å⁻³

Data collection: CrysAlis PRO (Oxford Diffraction, 2009 ▶); cell refinement: CrysAlis PRO; data reduction: CrysAlis PRO; program(s) used to solve structure: SIR92 (Altomare et al., 1993 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: Stereochemical Workstation Operation Manual (Siemens, 1989 ▶); software used to prepare material for publication: SHELXL97.

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536810036329/dn2600sup1.cif

e-66-o2568-sup1.cif^{(23.8KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536810036329/dn2600Isup2.hkl

e-66-o2568-Isup2.hkl^{(247.8KB, hkl)}

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C1—H1A⋯O41	0.970 (14)	2.480 (13)	3.1698 (16)	127.9 (10)
O2—H2⋯O41	0.828 (17)	1.913 (17)	2.7365 (13)	173.0 (16)
C15—H15⋯O462	0.940 (15)	2.408 (13)	3.0231 (17)	122.8 (11)
C1—H1B⋯O2ⁱ	0.938 (13)	2.549 (12)	3.2306 (16)	129.8 (10)
N14—H14⋯N34ⁱⁱ	0.893 (19)	1.851 (19)	2.7301 (16)	167.8 (17)
C26—H26⋯N12ⁱⁱⁱ	0.938 (14)	2.456 (14)	3.3118 (18)	151.6 (11)
C43—H43⋯O442^iv	0.972 (18)	2.472 (16)	3.280 (2)	140.4 (13)

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Symmetry codes: (i) Inline graphic ; (ii) ; (iii) ; (iv) .

Acknowledgments

CSC thanks the University of Mysore for research facilities.

supplementary crystallographic information

Comment

Fluconazole is a synthetic antifungal agent that can be used for the treatment of a variety of Candida albicans and other fungal infections. It is currently the most widely used antifungal drug for maintenance therapy because it can be given orally, lacks major side effects, penetrates the central nervous system, and has broad efficiacy against most pathogenic yeasts, including Cryptococcus neoformans (Brammer et al., 1990). The preparation and crystal characterization of one of the polymorphs, a monohydrate, and an ethyl acetate solvate of the fluconazole is reported (Caira et al., 2003).

In the Cambridge Structural Database (Allen, 2002; version 5.31) there are 33 crystal structures of the metal complexes involving coordinated fluconazole molecule, three mentioned above structures of neutral fluconazole (including two solvates, a hydrate and an ethyl acetate), but the structure reported here is the first report on the protonated fluconazole, fluconazolium picrate (hereinafter referred to as 1, Scheme 1).

Figure 1 shows the perspective view of both charged components of 1. The fluconazolium cation is asymmetric (despite the possible symmetric conformation); both triazole rings are differently orientated with respect to the phenyl ring. The torsion angles C21—C2—N1—N11 and C21—C2—N3—N31 are -58.50 (13)° and 175.23 (10)°, respectively. The overall conformation of the cation might be described by mutual orientation of three planar fragments, a triazolinium ring (A), a 2,4-difluorophenyl ring (B) and the triazole ring (C). All these fragments are approximately planar, the largest deviations from the planarity are, maybe unexpectedly, obeserved within the phenyl ring (0.0120 (9) Å). The least squares planes make the dihedral angles of 52.51 (5)° (A/B), 24.53 (7)° (B/C) and 69.70 (6)° (A/C). As in the neutral fluconazole (Caira et al., 2003) all these planes are approximately (within ca 25°) parallel to the central C—O bond. In the picrate anion, the six-membered ring is within 0.0082 (10)Å planar, and two of three nitro groups are almost coplanar with the ring plane (dihedral angles of 6.5 (2)° for the NO₂ group para with respect to the C=O group, and 3.8 (2)° for one of the ortho groups), while the other ortho- group is significantly twisted, by an angle of 46.79 (13)°. The C—O bond of 1.2529 (15) Å, is longer than the typical C=O double bond, reflecting the anionic character of this, more appropriately described as C=O(-), bond.

The place of protonation is unequivocaly determined as N14. It is proved by (i) the location of the hydrogen atom in the difference Fourier map, and its subsequent succesful refinement, as well as by (ii) the geometrical characteristics of the nitrogen atoms.

The ionic components are joined by the O—H···O hydrogen bond and additionally by secondary - but relatively short C—H···O(nitro) contact (Figure 1). The geometrical details of hydrogen bonds are given in Table 1. In the crystal structure the cations are organized into the chains along the b-direction by means of N—H···N and C—H···O hydrogen bonds. The main structural motif is therefore a helix of cations with the anions attached subsequently to both sides of the helix (Fig. 2). It might be noted that the neighboring helical chains (which elements are related by 2₁ screw along y) of different screwness, are only loosely connected, by C—H···O hydrogen bonds between the picrate anions(Fig. 3).

Experimental

The title compound was synthesized by mixing equimolar amounts (1:1) of fluconazole (2 mmol) in 10 ml me thanol and picric acid (2 mmol) in 10 ml of methanol. The solution was stirred well and allowed to evaporate slowly at room temperature. Crystals suitable for single-crystal X-ray diffraction were grown from methanol solvent. The melting range was found to be 409 - 412 K.