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Acta Crystallogr Sect E Struct Rep Online. 2008 March 1; 64(Pt 3): o634.
Published online 2008 February 27. doi:  10.1107/S1600536808005023
PMCID: PMC2960770

Benznidazole

Abstract

The conformation of the title compound [systematic name: N-benzyl-2-(2-nitro­imidazol-1-yl)acetamide], C12H12N4O3, can be described in terms of the relative orientation of three planar fragments, the imidazol group (A), benzyl group (B), and the acetamide fragment (C), with corresponding dihedral angles: A/C = 88.17 (4), B/C = 67.12 (5) and A/B = 21.11 (4)°. The crystal packing is enhanced by a network of strong inter­molecular N—H(...)O hydrogen bonds.

Related literature

For related literature, see: Coura & Castro (2002 [triangle]); Lamas et al. (2006 [triangle]); Morilla et al. (2004 [triangle]); Silva et al. (2007 [triangle]).

An external file that holds a picture, illustration, etc.
Object name is e-64-0o634-scheme1.jpg

Experimental

Crystal data

  • C12H12N4O3
  • M r = 260.26
  • Monoclinic, An external file that holds a picture, illustration, etc.
Object name is e-64-0o634-efi1.jpg
  • a = 4.65560 (10) Å
  • b = 10.9113 (2) Å
  • c = 11.7681 (3) Å
  • β = 90.6680 (10)°
  • V = 597.76 (2) Å3
  • Z = 2
  • Mo Kα radiation
  • μ = 0.11 mm−1
  • T = 100 (2) K
  • 0.34 × 0.16 × 0.12 mm

Data collection

  • Bruker APEXII CCD diffractometer
  • Absorption correction: multi-scan (SADABS; Bruker, 2001 [triangle]) T min = 0.861, T max = 0.987
  • 11597 measured reflections
  • 1287 independent reflections
  • 1216 reflections with I > 2σ(I)
  • R int = 0.012

Refinement

  • R[F 2 > 2σ(F 2)] = 0.025
  • wR(F 2) = 0.066
  • S = 1.08
  • 1287 reflections
  • 176 parameters
  • 1 restraint
  • H atoms treated by a mixture of independent and constrained refinement
  • Δρmax = 0.14 e Å−3
  • Δρmin = −0.22 e Å−3

Data collection: APEX2 (Bruker, 2007 [triangle]); cell refinement: APEX2; data reduction: APEX2; program(s) used to solve structure: SIR97 (Altomare et al., 1999 [triangle]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 [triangle]); molecular graphics: Mercury (Macrae et al., 2006 [triangle]) and ORTEP-3 for Windows (Farrugia, 1997 [triangle]); software used to prepare material for publication: WinGX (Farrugia, 1999 [triangle]) and PLATON (Spek, 2003 [triangle]).

Table 1
Hydrogen-bond geometry (Å, °)

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536808005023/om2213sup1.cif

Structure factors: contains datablocks I. DOI: 10.1107/S1600536808005023/om2213Isup2.hkl

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

Acknowledgments

The authors thank LAFEPE/Brazil, CNPq/Brazil and Xunta de Galicia (project No. PGIDT01BIO20302PR) for supporting this work.

supplementary crystallographic information

Comment

The title compound, Benznidazole, is the drug of choice in the treatment of Chagas disease, a protozoan infection caused by the parasite Trypanosoma cruzi. This illness constitutes a major public health problem for developing nations, affecting sundries Latin America countries, being considered a neglected disease according to World Health Organization (Coura & Castro, 2002; Lamas et al., 2006). In spite of the epidemiological importance of this disease, currently the only available therapeutic agent is Benznidazole, especially effective in the acute phase of infection (Morilla et al., 2004).

The conformation of the title compound (Fig. 1) can be described by the mutual orientation of three approximately planar fragments, A, B and C: one imidazole group (fragment A: N12, C13, N14, C15, C16, N17, O18 and O19 atoms) for which the maximum deviation from the least-squares plane is -0.067 (1) Å, the benzene group (fragment B: C1, C2, C3, C4, C5, C6 and C7 atoms) whose maximum deviation from the mentioned planarity is -0.013 (2), and the central acetamide (fragment C: N8, C9, O10 and C11 atoms), with a deviation of 0.024 (1) Å. The corresponding dihedral angles are: A/C = 88.17 (4)°, B/C = 67.12 (5)° and A/B = 21.11 (4)°.

The strategy of self-assembly through weak interactions is of central importance for efficient and specific biological reactions. In our case we can find one strong intermolecular O···HN hydrogen bond between N(8)–H(8) and O(10) that almost lies along the "a" axis (Fig. 2).

Experimental

Benznidazole was supplied by Laboratório Farmacêutico do Estado de Pernambuco/LAFEPE batch 13871(Recife, Brazil). Purity was estimated by differential scanning calorimetry (DSC-50 Shimadzu) and high-performance liquid chromatography (HPLC Shimadzu) and found to be 99.9% (Silva et al., 2007). Yellow crystals suitable for X-ray analysis were grown from a solution of methanol and acetonitrile (1:1 v/v) at 298 K over a period of a few days in air.

Data collection: APEX2 (Bruker, 2007); cell refinement: APEX2 (Bruker, 2007); data reduction: APEX2 (Bruker, 2007); Absorption correction: SADABS (Bruker, 2001); program used to solve structure: SIR97 (Altomare et al., 1999); program used to refinement structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEP-3 (Farrugia, 1997) and Mercury (Macrae et al., 2006); software used to prepare material for publication: WinGX (Farrugia, 1999); geometric calculations: PLATON (Spek, 2003).

Refinement

The H8 atom was located in a difference map and refined. The rest of the H atoms were positioned geometrically and refined with use of a riding model with C—H = 0.95 - 0.99Å and Uiso = 1.2 times Ueq of the bonded C. Friedel pairs were merged for the final refinement.

Figures

Fig. 1.
The molecule of Benznidazole showing the atom-labeling scheme. Displacement ellipsoids are drawn at the 50% probability level.
Fig. 2.
Hydrogen bond network along the a direction.
Fig. 3.
An interactive view of Benznidazole.

Crystal data

C12H12N4O3F000 = 272
Mr = 260.26Dx = 1.446 Mg m3
Monoclinic, P21Mo Kα radiation λ = 0.7107 Å
Hall symbol: P 2ybCell parameters from 1992 reflections
a = 4.65560 (10) Åθ = 3.0–28.3º
b = 10.9113 (2) ŵ = 0.11 mm1
c = 11.7681 (3) ÅT = 100 (2) K
β = 90.6680 (10)ºPrism, colourless
V = 597.76 (2) Å30.34 × 0.16 × 0.12 mm
Z = 2

Data collection

Bruker APEXII CCD diffractometer1287 independent reflections
Radiation source: fine-focus sealed tube1216 reflections with I > 2σ(I)
Monochromator: graphiteRint = 0.012
T = 100(2) Kθmax = 26.4º
ω and [var phi] scansθmin = 1.7º
Absorption correction: multi-scan(SADABS; Bruker, 2001)h = −5→5
Tmin = 0.861, Tmax = 0.987k = −13→13
11597 measured reflectionsl = −14→14

Refinement

Refinement on F2Secondary atom site location: difference Fourier map
Least-squares matrix: fullHydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.025H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.066  w = 1/[σ2(Fo2) + (0.0385P)2 + 0.0782P] where P = (Fo2 + 2Fc2)/3
S = 1.08(Δ/σ)max = 0.001
1287 reflectionsΔρmax = 0.14 e Å3
176 parametersΔρmin = −0.22 e Å3
1 restraintExtinction correction: none
Primary atom site location: structure-invariant direct methods

Special details

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s 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 > σ(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)

xyzUiso*/Ueq
C10.4003 (3)0.40584 (12)0.08674 (11)0.0161 (3)
C20.2787 (3)0.42354 (13)−0.02020 (12)0.0185 (3)
H20.33680.4915−0.06490.022*
C30.0725 (3)0.34290 (15)−0.06277 (12)0.0228 (3)
H3−0.00960.3558−0.13610.027*
C4−0.0126 (3)0.24393 (15)0.00205 (14)0.0249 (3)
H4−0.15590.1896−0.02630.03*
C50.1101 (3)0.22366 (13)0.10809 (13)0.0245 (3)
H50.05360.15480.15180.029*
C60.3162 (3)0.30441 (13)0.15048 (12)0.0199 (3)
H60.40030.29040.22330.024*
C70.6208 (3)0.49433 (14)0.13271 (12)0.0183 (3)
H7A0.79960.44940.15210.022*
H7B0.66640.55580.07370.022*
N80.5145 (3)0.55688 (11)0.23428 (10)0.0162 (3)
H80.338 (4)0.5619 (16)0.2452 (14)0.019 (4)*
C90.6898 (3)0.62199 (12)0.30060 (11)0.0136 (3)
O100.94844 (19)0.63427 (9)0.28473 (8)0.0174 (2)
C110.5490 (3)0.67480 (13)0.40651 (12)0.0169 (3)
H11A0.35790.70850.38590.02*
H11B0.52110.60870.46290.02*
N120.7269 (2)0.77163 (10)0.45668 (9)0.0155 (2)
C130.7665 (3)0.89028 (13)0.42442 (11)0.0173 (3)
N140.9577 (3)0.94933 (12)0.48657 (10)0.0212 (3)
C151.0495 (3)0.86385 (13)0.56313 (12)0.0202 (3)
H151.19010.87810.62080.024*
C160.9113 (3)0.75456 (13)0.54557 (11)0.0178 (3)
H160.9390.6810.58750.021*
N170.6082 (3)0.94740 (12)0.33348 (10)0.0239 (3)
O180.4426 (2)0.88404 (11)0.27695 (9)0.0306 (3)
O190.6452 (3)1.05789 (11)0.31808 (11)0.0419 (3)

Atomic displacement parameters (Å2)

U11U22U33U12U13U23
C10.0137 (6)0.0156 (7)0.0191 (6)0.0026 (6)0.0028 (5)−0.0051 (5)
C20.0202 (7)0.0166 (7)0.0187 (7)0.0025 (6)0.0021 (5)−0.0016 (5)
C30.0208 (7)0.0276 (8)0.0199 (7)0.0040 (7)−0.0040 (6)−0.0089 (6)
C40.0191 (7)0.0216 (8)0.0340 (8)−0.0045 (6)0.0008 (6)−0.0137 (6)
C50.0251 (8)0.0152 (8)0.0333 (8)−0.0025 (6)0.0055 (6)−0.0029 (6)
C60.0212 (7)0.0192 (8)0.0193 (7)−0.0006 (6)0.0004 (5)−0.0023 (6)
C70.0161 (7)0.0196 (7)0.0193 (7)−0.0006 (6)0.0030 (5)−0.0047 (6)
N80.0106 (6)0.0182 (6)0.0198 (6)−0.0003 (5)0.0016 (4)−0.0057 (5)
C90.0153 (7)0.0096 (6)0.0159 (6)0.0013 (5)0.0000 (5)0.0008 (5)
O100.0134 (5)0.0189 (5)0.0198 (4)−0.0008 (4)0.0010 (4)−0.0031 (4)
C110.0160 (6)0.0155 (7)0.0194 (7)−0.0036 (6)0.0012 (5)−0.0059 (5)
N120.0168 (6)0.0139 (6)0.0159 (5)−0.0011 (5)0.0020 (4)−0.0024 (5)
C130.0221 (7)0.0133 (7)0.0164 (6)0.0005 (6)−0.0001 (5)−0.0013 (5)
N140.0281 (7)0.0169 (6)0.0187 (6)−0.0036 (6)−0.0021 (5)−0.0029 (5)
C150.0236 (8)0.0176 (7)0.0194 (7)0.0005 (6)−0.0037 (6)−0.0044 (5)
C160.0210 (7)0.0153 (7)0.0171 (6)0.0029 (6)−0.0014 (5)−0.0014 (5)
N170.0325 (8)0.0211 (7)0.0179 (6)0.0008 (6)−0.0037 (5)0.0002 (5)
O180.0347 (6)0.0323 (7)0.0244 (5)−0.0023 (5)−0.0114 (5)−0.0012 (5)
O190.0699 (10)0.0196 (6)0.0358 (6)−0.0031 (6)−0.0180 (6)0.0077 (5)

Geometric parameters (Å, °)

O10—C91.2281 (16)C15—C161.370 (2)
N17—O181.2260 (17)C15—H150.95
N17—O191.2316 (18)C4—C31.383 (2)
N17—C131.4348 (18)C4—C51.384 (2)
N12—C161.3581 (18)C4—H40.95
N12—C131.3622 (19)C5—C61.391 (2)
N12—C111.4628 (17)C5—H50.95
N8—C91.3286 (17)C3—H30.95
N8—C71.4675 (17)C7—C11.505 (2)
N8—H80.836 (18)C7—H7A0.99
C9—C111.5278 (18)C7—H7B0.99
C2—C11.3875 (19)C1—C61.396 (2)
C2—C31.391 (2)C11—H11A0.99
C2—H20.95C11—H11B0.99
N14—C131.3144 (19)C16—H160.95
N14—C151.3620 (19)C6—H60.95
O18—N17—O19124.07 (13)C4—C3—H3120.1
O18—N17—C13118.30 (12)C2—C3—H3120.1
O19—N17—C13117.62 (13)N8—C7—C1110.86 (11)
C16—N12—C13104.99 (12)N8—C7—H7A109.5
C16—N12—C11124.17 (12)C1—C7—H7A109.5
C13—N12—C11130.67 (12)N8—C7—H7B109.5
C9—N8—C7121.09 (12)C1—C7—H7B109.5
C9—N8—H8118.2 (12)H7A—C7—H7B108.1
C7—N8—H8119.9 (11)C2—C1—C6118.93 (13)
O10—C9—N8124.46 (12)C2—C1—C7120.41 (13)
O10—C9—C11120.91 (12)C6—C1—C7120.65 (12)
N8—C9—C11114.48 (11)N12—C11—C9110.81 (11)
C1—C2—C3120.75 (13)N12—C11—H11A109.5
C1—C2—H2119.6C9—C11—H11A109.5
C3—C2—H2119.6N12—C11—H11B109.5
C13—N14—C15103.74 (12)C9—C11—H11B109.5
N14—C15—C16110.69 (12)H11A—C11—H11B108.1
N14—C15—H15124.7N12—C16—C15106.76 (13)
C16—C15—H15124.7N12—C16—H16126.6
C3—C4—C5120.29 (14)C15—C16—H16126.6
C3—C4—H4119.9C5—C6—C1120.41 (13)
C5—C4—H4119.9C5—C6—H6119.8
C4—C5—C6119.86 (14)C1—C6—H6119.8
C4—C5—H5120.1N14—C13—N12113.81 (12)
C6—C5—H5120.1N14—C13—N17122.74 (13)
C4—C3—C2119.74 (13)N12—C13—N17123.42 (12)
C7—N8—C9—O10−1.0 (2)C11—N12—C16—C15176.45 (12)
C7—N8—C9—C11−176.53 (13)N14—C15—C16—N12−0.46 (16)
C13—N14—C15—C160.00 (16)C4—C5—C6—C10.0 (2)
C3—C4—C5—C61.1 (2)C2—C1—C6—C5−1.1 (2)
C5—C4—C3—C2−1.1 (2)C7—C1—C6—C5179.30 (13)
C1—C2—C3—C40.0 (2)C15—N14—C13—N120.48 (16)
C9—N8—C7—C1167.75 (12)C15—N14—C13—N17178.56 (13)
C3—C2—C1—C61.1 (2)C16—N12—C13—N14−0.77 (16)
C3—C2—C1—C7−179.29 (13)C11—N12—C13—N14−176.13 (13)
N8—C7—C1—C2116.20 (14)C16—N12—C13—N17−178.83 (13)
N8—C7—C1—C6−64.20 (17)C11—N12—C13—N175.8 (2)
C16—N12—C11—C9−97.72 (15)O18—N17—C13—N14177.06 (14)
C13—N12—C11—C976.86 (17)O19—N17—C13—N14−3.8 (2)
O10—C9—C11—N1220.40 (18)O18—N17—C13—N12−5.0 (2)
N8—C9—C11—N12−163.87 (11)O19—N17—C13—N12174.08 (14)
C13—N12—C16—C150.70 (14)

Hydrogen-bond geometry (Å, °)

D—H···AD—HH···AD···AD—H···A
N8—H8···O10i0.835 (19)2.037 (18)2.837 (2)160.2 (17)

Symmetry codes: (i) x−1, y, z.

Footnotes

Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: OM2213).

References

  • Altomare, A., Burla, M. C., Camalli, M., Cascarano, G. L., Giacovazzo, C., Guagliardi, A., Moliterni, A. G. G., Polidori, G. & Spagna, R. (1999). J. Appl. Cryst.32, 115–119.
  • Bruker (2001). SADABS Bruker AXS Inc., Madison, Wisconsin, USA.
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  • Farrugia, L. J. (1997). J. Appl. Cryst.30, 565.
  • Farrugia, L. J. (1999). J. Appl. Cryst.32, 837–838.
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  • Macrae, C. F., Edgington, P. R., McCabe, P., Pidcock, E., Shields, G. P., Taylor, R., Towler, M. & van de Streek, J. (2006). J. Appl. Cryst.39, 453–457.
  • Morilla, M. J., Montanari, J. A., Prieto, M. J., Lopez, M. O., Petray, P. B. & Romero, E. L. (2004). Int. J. Pharm.278, 311–318. [PubMed]
  • Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. [PubMed]
  • Silva, A. L. M., Soares-Sobrinho, J. L., Rolim-Neto, P. J., Silva, R. M. F., Medeiros, F. P. M. & Lima, L. G. (2007). Quím. Nova, 30, 1163–1166.
  • Spek, A. L. (2003). J. Appl. Cryst.36, 7–13.

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