Nicotinohydrazide

organic compounds Acta Crystallographica Section E Experimental Structure Reports Online Crystal data V = 650.10 (13) Å3 Z=4 Mo K radiation  = 0.10 mm1 T = 293 (2) K 0.46  0.30  0.20 mm C6H7N3O Mr = 137.15 Orthorhombic, P21 21 21 a = 3.8855 (7) Å b = 10.5191 (5) Å c = 15.9058 (9) Å ISSN 1600-5368 Nicotinohydrazide Jacks P. Priebe, Renata S. Mello, Faruk Nome and Adailton J. Bortoluzzi* Data collection Depto. de Quı́mica, Universidade Federal de Santa Catarina, 88040-900 Florianópolis, Santa Catarina, Brazil Correspondence e-mail: adajb@qmc.ufsc.br Enraf–Nonius CAD-4 diffractometer Absorption correction: none 1534 measured reflections 1051 independent reflections Received 25 October 2007; accepted 11 December 2007 Refinement Key indicators: single-crystal X-ray study; T = 293 K; mean (C–C) = 0.002 Å; R factor = 0.031; wR factor = 0.087; data-to-parameter ratio = 11.4. R[F 2 > 2(F 2)] = 0.031 wR(F 2) = 0.087 S = 1.09 1051 reflections The title molecule (alternative name: pyridine-3-carbohydrazide; C6H7N3O) was obtained from the reaction of ethyl nicotinate with hydrazine hydrate in methanol. In the amide group, the C—N bond is relatively short, suggesting some degree of electronic delocalization in the molecule. The stabilized conformation may be compared with those of isomeric compounds picolinohydrazide (pyridine-2-carbohydrazide) and isonicotinohydrazide (pyridine-4-carbohydrazide). In the title isomer, the pyridine ring forms an angle of 33.79 (9)
with the plane of the non-H atoms of the hydrazide group. This lack of coplanarity between the hydrazide functionality and the pyridine ring is considerably greater than that observed in isonicotinohydrazide (dihedral angle = 17.14
), while picolinohydrazide is almost fully planar. The title isomer forms intermolecular N—H  O and N—H  N hydrogen bonds, which stabilize the crystal structure. 866 reflections with I > 2(I) Rint = 0.015 3 standard reflections every 200 reflections intensity decay: <1% 92 parameters H-atom parameters constrained
max = 0.18 e Å3
min = 0.15 e Å3 Table 1 Hydrogen-bond geometry (Å,
). D—H H  A D  A D—H  A N2—H2N  N1 N3—H3NA  O1ii N3—H3NB  O1iii 0.88 0.87 0.85 2.11 2.22 2.55 2.975 (2) 3.045 (2) 3.155 (2) 166 157 130 Symmetry codes: (i) x  12; y þ 32; z þ 1. x þ 1; y  12; z þ 12; D—H  A i (ii) x þ 12; y þ 32; z þ 1; (iii) Table 2 Selected bond lengths (Å) of nicotinohydrazide (I), picolinic acid hydrazide (II) and isonicotinohydrazide (III). (I) (II) (III) 1.418 (2) 1.335 (2) 1.231 (2) 1.503 (2) 1.422 1.334 1.235 1.507 1.429 1.346 1.235 1.513 Related literature N2—N3 C6—N2 C6—O1 C6—C2 The structure of the same compound has been determined independently and is reported in the following paper (Portalone & Colapietro, 2008). The structures of picolinohydrazide (Zareef et al., 2006) and isonicotinohydrazide (Jensen, 1954; Bhat et al., 1974) have been published. For related literature on the biological activity of these molecules, see: Ouelleta et al. (2004); Zhao et al. (2007). For related literature, see: Bhat et al. (1974); Zareef et al. (2006). Data collection: CAD-4 EXPRESS (Enraf–Nonius, 1994); cell refinement: CAD-4 EXPRESS; data reduction: HELENA (Spek, 1996); program(s) used to solve structure: SIR97 (Altomare et al., 1999); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: PLATON (Spek, 2003) and Mercury (Macrae et al., 2006); software used to prepare material for publication: SHELXL97. The authors thank the Conselho Nacional de Desenvolvimento Cientı́fico e Tecnológico (CNPq), Fundação de Apoio à Pesquisa Cientı́fica e Tecnológica do Estado de Santa Catarina (FAPESC), Financiadora de Estudos e Projetos (FINEP) and Coordenação de Aperfeiçoamento de Pessoal de Nı́vel Superior (CAPES). Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: BH2145). o302 # 2008 International Union of Crystallography doi:10.1107/S160053680706655X Acta Cryst. (2008). E64, o302–o303 organic compounds 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. Bhat, T. N., Singh, T. P. & Vijayan, M. (1974). Acta Cryst. B30, 2921–2922. Enraf–Nonius (1994). CAD-4 EXPRESS. Version 5.1/1.2. Enraf–Nonius, Delft, The Netherlands. Jensen, L. H. (1954). J. Am. Chem. Soc. 76, 4663–4667. 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. Acta Cryst. (2008). E64, o302–o303 Ouelleta, M., Aitkenb, S. M., Englishc, A. M. & Percivala, M. D. (2004). Arch. Biochem. Biophys. 431, 107–118. Portalone, G. & Colapietro, M. (2008). Acta Cryst. E64, o304. Sheldrick, G. M. (1997). SHELXL97. University of Göttingen, Germany. Spek, A. L. (1996). HELENA. University of Utrecht, The Netherlands. Spek, A. L. (2003). J. Appl. Cryst. 36, 7–13. Zareef, M., Iqbla, R., Zaidi, J. H., Qadeer, G., Wong, W. Y. & Akhtar, H. (2006). Z. Kristallogr. New Cryst. Struct. 221, 307–308. Zhao, X., Yu, S. & Magliozzo, R. S. (2007). Biochemistry, 46, 3161–3170. Priebe et al.  C6H7N3O o303 supplementary materials supplementary materials Acta Cryst. (2008). E64, o302-o303 [ doi:10.1107/S160053680706655X ] Nicotinohydrazide J. P. Priebe, R. S. Mello, F. Nome and A. J. Bortoluzzi Comment The importance of aromatic hydrazides is closely related to their biological activity and to the fact that they can be used for the syntheses of several other biologically active compounds. Nicotinohydrazide, (I), for example, is an efficient peroxidase-activated inhibitor of the POX activity of PGHS-2 (Ouelleta et al., 2004). On the other hand, the isomer isonicotinohydrazide, (III, scheme 2), is not a potent inhibitor, with an IC50 of 129 mM against 15 mM for (I). Structure also plays a major role in the activity of the anti-tuberculosis drug isonicotinohydrazide, which requires Mycobacterium tuberculosis catalase-peroxidase (KatG) activation to produce an acyl-NAD adduct (Zhao et al., 2007). This adduct is of extreme importance since it is an inhibitor of the enoyl reductase (Mtb InhA), essential for the biosynthesis of acids present in mycobacterial cell walls. Picolinohydrazide, (II), and isonicotinohydrazide, (III), generate the hydrazideNAD adduct in this system, while nicotinohydrazide, (I), does not. However, the yield of the (II)-NAD adduct is around 35% of that of the (III)-NAD adduct. As a result, (III) is a potent antituberculosis drug, while (I) and (II) are not. In this context, studies of structural analogues of these biologically active compounds become fundamental and will be useful in elucidating the mechanism of action, which strongly depends on substrate selection and binding stoichiometry to the (III) binding site in KatG, which still has not been completely elucidated. The crystal structures of picolinohydrazide, (II) (Zareef et al., 2006), and isonicotinohydrazide, (III) (Jensen, 1954; Bhat et al., 1974), have been previously reported and the structure of nicotinohydrazide (I) is here described. The three isomeric hydrazides are distinguished by just the position of the N atom in the pyridine ring with respect to hydrazide group (scheme 2). A selection of their structural parameters is shown in Table 2. When the structural parameters of isomeric hydrazides are compared, some interesting aspects can be observed, which depend on the structural relation between the N atom in the ring and the hydrazide group. Indeed, while (II) crystallizes in the monoclinic system, isomers (I) and (III) crystallize in the orthorhombic system. The C6═O1 bond length in (I) and also in (II) and (III) are smaller than those usually observed in carboxylic acids (1.365 Å, Zareef et al., 2006). Similarly, the C6—N2 bond distance observed in (I) is consistent with those reported for (II) and (III) hydrazides, suggesting a significant partial double-bond character; the bond lengths are consistent with resonance hybrids between a polar and a neutral form (Bhat et al., 1974). Similar to the results reported (Bhat et al., 1974) for isonicotinohydrazide, the N2—N3 and C2—C6 bonds of (II) have distances similar to their corresponding single bonds. In (I), the pyridine ring bond lengths are very similar to those obtained in related compounds and the ring lies in a plane which forms an angle of 33.79 (9)° with that of the non-H atoms in the hydrazide group. This lack of coplanarity between the hydrazide functionality and the pyridine ring is considerably greater than that observed in isonicotinohydrazide (−17.14°), while picolinohydrazide is almost fully planar, probably because in (II) N2 is in the same side and therefore closer to N1, favoring intramolecular N2—H···N1 hydrogen bond. Conversely, in the crystal structure of (I) N2 and N1 are on opposite sides of the molecule, and in this case only intermolecular hydrogen bonding takes place. The intermolecular hydrogen bonds N3—H···O1 and N2—H···N1 (Table 1), which form a three-dimensional polymeric structure (Fig. 2) are fundamental for the stability of the crystal structure of (I). sup-1 supplementary materials Experimental Nicotinic acid hydrazine was synthesized by the reaction of ethyl nicotinate (43.9 mmol) and hydrazine hydrate 99% (27.5 mmol) in methanol. The reaction mixture was refluxed for 24 h., yielding a yellow solution. Upon cooling to 298 K, the product precipitated and it was washed with methanol and filtered. Colorless needle shaped crystals of (I) suitable for X-ray analysis were grown by recrystallization from a chloroform-methanol (9:1) solution by slow evaporation at room temperature. Refinement All non-H atoms were refined with anisotropic displacement parameters. H atoms attached to C atoms were added at their calculated positions, with C—H = 0.93 Å and Uiso(H) = 1.2Ueq(carrier C). H atoms of the hydrazide group were found in a difference map and treated with a riding model and with Uiso(H) = 1.2Ueq(carrier N). In the absence of significant anomalous scattering effects, no Friedel pairs were collected. Figures Fig. 1. The molecular structure of (I) with labeling scheme. Displacement ellipsoids are shown at the 40% probability level. Fig. 2. Packing of (I) showing the molecules connected through hydrogen bonds and stacked along [100]. Fig. 3. The structures of (I)–(III). Pyridine-3-carbohydrazide Crystal data C6H7N3O F000 = 288 Mr = 137.15 Dx = 1.401 Mg m−3 Orthorhombic, P212121 Hall symbol: P 2ac 2ab a = 3.8855 (7) Å b = 10.5191 (5) Å c = 15.9058 (9) Å sup-2 Mo Kα radiation λ = 0.71073 Å Cell parameters from 25 reflections θ = 5.5–18.7º µ = 0.10 mm−1 T = 293 (2) K supplementary materials V = 650.10 (13) Å3 Z=4 Prismatic, colourless 0.46 × 0.30 × 0.20 mm Data collection Enraf–Nonius CAD-4 diffractometer Rint = 0.015 Radiation source: fine-focus sealed tube θmax = 29.0º Monochromator: graphite θmin = 2.3º T = 293(2) K ω–2θ scans Absorption correction: none 1534 measured reflections 1051 independent reflections 866 reflections with I > 2σ(I) h = −5→2 k = −14→0 l = −21→0 3 standard reflections every 200 reflections intensity decay: <1% Refinement Refinement on F2 H-atom parameters constrained w = 1/[σ2(Fo2) + (0.0344P)2 + 0.1144P] Least-squares matrix: full where P = (Fo2 + 2Fc2)/3 R[F2 > 2σ(F2)] = 0.031 (Δ/σ)max < 0.001 wR(F2) = 0.087 Δρmax = 0.18 e Å−3 S = 1.09 Δρmin = −0.15 e Å−3 1051 reflections 92 parameters Primary atom site location: structure-invariant direct methods Secondary atom site location: difference Fourier map Hydrogen site location: inferred from neighbouring sites Extinction correction: SHELXL97 (Sheldrick, 1997), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4 Extinction coefficient: 0.040 (6) Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) C1 H1 C2 C3 H3 C4 H4 C5 H5 C6 N1 N2 x y z Uiso*/Ueq 0.3825 (5) 0.4007 0.2298 (5) 0.2025 (5) 0.1029 0.3262 (6) 0.3114 0.4720 (7) 0.5524 0.0965 (5) 0.5043 (5) 0.1167 (5) 0.84759 (16) 0.9092 0.73203 (14) 0.64013 (16) 0.5617 0.66735 (19) 0.6076 0.78517 (19) 0.8032 0.71648 (17) 0.87491 (14) 0.59906 (15) 0.25136 (11) 0.2930 0.27215 (10) 0.20969 (10) 0.2212 0.12995 (11) 0.0870 0.11576 (11) 0.0620 0.36028 (10) 0.17489 (10) 0.39179 (9) 0.0373 (4) 0.045* 0.0319 (4) 0.0382 (4) 0.046* 0.0455 (5) 0.055* 0.0472 (5) 0.057* 0.0344 (4) 0.0440 (4) 0.0405 (4) sup-3 supplementary materials H2N N3 H3NA H3NB O1 0.2155 −0.0001 (5) 0.0877 −0.2101 −0.0227 (5) 0.5365 0.56759 (16) 0.6189 0.5876 0.80795 (12) 0.3637 0.47365 (9) 0.5112 0.4784 0.39876 (8) 0.049* 0.0472 (4) 0.057* 0.057* 0.0487 (4) Atomic displacement parameters (Å2) C1 C2 C3 C4 C5 C6 N1 N2 N3 O1 U11 0.0405 (9) 0.0312 (8) 0.0445 (11) 0.0594 (14) 0.0550 (13) 0.0324 (9) 0.0481 (10) 0.0505 (10) 0.0557 (11) 0.0604 (10) U22 0.0307 (7) 0.0314 (7) 0.0316 (8) 0.0442 (9) 0.0522 (10) 0.0367 (8) 0.0388 (7) 0.0373 (7) 0.0519 (9) 0.0447 (7) U33 0.0405 (9) 0.0330 (7) 0.0384 (8) 0.0328 (8) 0.0345 (8) 0.0339 (7) 0.0451 (8) 0.0337 (7) 0.0338 (7) 0.0409 (6) U12 0.0021 (8) 0.0041 (8) 0.0007 (8) 0.0060 (11) 0.0062 (11) 0.0012 (8) 0.0002 (8) 0.0027 (7) −0.0021 (10) 0.0120 (7) U13 −0.0023 (8) −0.0025 (7) −0.0049 (8) −0.0039 (9) 0.0050 (9) −0.0035 (7) 0.0019 (8) 0.0057 (7) 0.0028 (8) 0.0060 (7) U23 −0.0007 (6) −0.0001 (6) −0.0009 (7) −0.0057 (7) 0.0069 (8) −0.0040 (7) 0.0078 (6) 0.0007 (6) 0.0045 (6) −0.0060 (5) Geometric parameters (Å, °) C1—N1 C1—C2 C1—H1 C2—C3 C2—C6 C3—C4 C3—H3 C4—C5 C4—H4 1.336 (2) 1.392 (2) 0.9300 1.390 (2) 1.503 (2) 1.386 (2) 0.9300 1.381 (3) 0.9300 C5—N1 C5—H5 C6—O1 C6—N2 N2—N3 N2—H2N N3—H3NA N3—H3NB 1.338 (2) 0.9300 1.231 (2) 1.335 (2) 1.418 (2) 0.8830 0.8746 0.8461 N1—C1—C2 N1—C1—H1 C2—C1—H1 C3—C2—C1 C3—C2—C6 C1—C2—C6 C4—C3—C2 C4—C3—H3 C2—C3—H3 C5—C4—C3 C5—C4—H4 C3—C4—H4 N1—C5—C4 123.70 (16) 118.2 118.2 118.02 (16) 124.35 (16) 117.60 (15) 118.93 (17) 120.5 120.5 118.49 (17) 120.8 120.8 123.81 (17) N1—C5—H5 C4—C5—H5 O1—C6—N2 O1—C6—C2 N2—C6—C2 C1—N1—C5 C6—N2—N3 C6—N2—H2N N3—N2—H2N N2—N3—H3NA N2—N3—H3NB H3NA—N3—H3NB 118.1 118.1 123.96 (16) 120.55 (16) 115.49 (15) 117.04 (16) 122.80 (15) 121.7 115.4 111.0 109.4 99.3 Hydrogen-bond geometry (Å, °) D—H···A sup-4 D—H H···A D···A D—H···A supplementary materials N2—H2N···N1i 0.88 2.11 2.975 (2) 166 0.87 2.22 3.045 (2) 157 0.85 2.55 3.155 (2) N3—H3NB···O1 Symmetry codes: (i) −x+1, y−1/2, −z+1/2; (ii) x+1/2, −y+3/2, −z+1; (iii) x−1/2, −y+3/2, −z+1. 130 ii N3—H3NA···O1 iii Bond lengths and angles (Å, °) of nicotinohydrazide (I), picolinic acid hydrazide (II) and isonicotinohydrazide (III) N2—N3 C6—N2 C6—O1 C6—C2 (I) 1.418 (2) 1.335 (2) 1.231 (2) 1.503 (2) (II) 1.422 1.334 1.235 1.507 (III) 1.429 1.346 1.235 1.513 N3—N2—C6 N2—C6—O1 N2—C6—C2 O1—C6—C2 122.80 (15) 123.96 (16) 115.49 (15) 120.55 (16) 121.45 123.04 116.08 120.87 121.06 122.07 115.90 122.00 N3—N2—C6—O1 C2—N2—C6—N3 N2—C6—C2—C3 0.17 (32) 179.56 (19) 34.62 (27) 177.39 177.72 177.06 175.13 173.03 162.86 sup-5 supplementary materials Fig. 1 sup-6 supplementary materials Fig. 2 sup-7 supplementary materials Fig. 3 sup-8