Supporting information
Crystallographic Information File (CIF) https://doi.org/10.1107/S2053229614003684/cu3047sup1.cif | |
Structure factor file (CIF format) https://doi.org/10.1107/S2053229614003684/cu30471sup2.hkl | |
Structure factor file (CIF format) https://doi.org/10.1107/S2053229614003684/cu30472sup3.hkl | |
Chemical Markup Language (CML) file https://doi.org/10.1107/S2053229614003684/cu30471sup4.cml | |
Chemical Markup Language (CML) file https://doi.org/10.1107/S2053229614003684/cu30472sup5.cml |
CCDC references: 987640; 987641
Isoniazid (pyridine-4-carbohydrazide) is a pharmaceutically active compound widely used in the treatment of tuberculosis (LoBue & Moser, 2003). It is known to have synergistic activity with cinnamic acid (Rastogi et al., 1998; Chen et al., 2011).
Recently, we have reported two polymorphs of the cinnamic acid–isoniazid cocrystal (Sarcevica et al., 2013). Polymorph I crystallizes in the triclinic P1 space group and polymorph II crystallizes in the monoclinic P21/c space group. In this study, a third polymorph, denoted polymorph III, has been isolated and its structure determined.
Isoniazid shows a propensity to form O—H···Npy hydrogen bonds (py is pyridine) in cocrystals with carboxylic acids. Homomeric hydrazide–hydrazide interactions are also characteristic of such cocrystals (Lemmerer et al., 2010; Lemmerer & Bernstein, 2011). It is possible to change the hydrogen-bonding preferences in a crystal structure by modifying the functional groups. The ability to influence the hydrogen-bonding preferences by modifying the hydrazide group of isoniazid has been investigated (Lemmerer et al., 2010, 2011; Lemmerer, 2012).
In this study, the in situ modification of isoniazid with acetone and cocrystallization with cinnamic acid have been performed. The differences between the hydrogen-bonding motifs in cinnamic acid cocrystals with isoniazid [cinnamic acid–pyridine-4-carbohydrazide (1/1), (1)] and its reaction product with acetone [cinnamic acid–N'-(propan-2-ylidene)isonicotinohydrazide (1/1), (2)] are identified.
All chemicals were purchased from commercial suppliers and were used without further purification. For the preparation of the cinnamic acid–isoniazid cocrystal polymorph III, (1), isoniazid (68.6 mg, 0.500 mmol) and cinnamic acid (74.1 mg, 0.500 mmol) were dissolved in a hot (343 K) ethyl acetate–acetonitrile solution (5 ml, 1:1 v/v). Slow evaporation of the solvent under ambient conditions produced single crystals of (1) (m.p. 399 K).
The cinnamic acid–N'-(propan-2-ylidene)isonicotinohydrazide (1/1)cocrystal, (2), was prepared by adapting the crystallization method described in the literature (Lemmerer et al., 2010, 2011; Lemmerer, 2012). The product was obtained by cocrystallization of isoniazid (68.6 mg, 0.500 mmol) and cinnamic acid (74.1 mg, 0.500 mmol) from acetone (5.0 ml) at room temperature. Slow evaporation of the solvent under ambient conditions produced single crystals of (2) (yield 60%; m.p. 377 K). Elemental analysis, calculated: C 66.45, H 5.89, N 12.91, O 14.75%; found: C 65.88, H 5.65, N 12.98, O 15.49%. Spectroscopic analysis: 1H NMR (300 MHz, CDCl3, δ, p.p.m.): 9.59 (1H, m, N9—H9), 8.75–8.78 (2H, m, C2—H2, C6—H6), 7.76 (1H, d, J = 16.1 Hz, C18—H18), 7.68–7.70 (2H, m, C3—H3, C5—H5), 7.54–7.56 (2H, m, C20—H20, C24—H24), 7.38–7.40 (3H, m, C21—H21, C22—H22, C23—H23), 6.46 (1H, d, J = 16.1 Hz, C17—H17), 2.15–2.19 (6H, m, C12—H12A, C12—H12B, C12—H12C, C13—H13A, C13—H13B, C13—H13C); IR (KBr, λmax, cm-1): 1636 (C═O), 1671 (C═O), 2990–3040 (COOH group bands), 3236 (N—H).
Crystal data, data collection and structure refinement details are summarized in Table 1. The O- and N-bound H atoms of (1) and (2) were located in Fourier difference maps. Subsequently, the O-bound H atoms were positioned geometrically with O—H = 0.82 Å, while the positions of the N-bound H atoms were freely refined. The displacement parameters of O- and N-bound H atoms were refined isotropically. C-bound H atoms were refined in riding positions, with C—H = 0.93–0.96 Å, and Uiso(H) = 1.5Ueq(C) for methyl H atoms and 1.2Ueq(C) otherwise. The 001 reflection was omitted from the refinement of (1). The floating-origin restraint was generated for (2).
Cocrystal (1) crystallizes in the triclinic P1 space group with one isoniazid and one cinnamic acid molecule in the asymmetric unit. The molecular structure and atom-numbering scheme of (1) are presented in Fig. 1.
The carboxylic acid group of cinnamic acid is connected to the pyridine N atom by an O—H···N hydrogen bond (Table 2). An additional weak C—H···O interaction prompts the formation of a cyclic hydrogen-bonded R22(7) graph-set motif (Bernstein et al., 1995) between the pyridine ring and the carboxylic acid group. The carbonyl O atom of the cinnamic acid molecule is also connected to the hydrazide group of isoniazid to form an N—H···O hydrogen bond. These motifs combine to form a hydrogen-bonded acid–base–acid–base cyclic synthon with the R44(16) graph set (Fig. 2). Such synthons are also observed in the crystal structures of cinnamic acid–isoniazid cocrystal polymorphs I and II. Four-molecule synthons in (1) are connected by weak N—H···O interactions (N···O = 3.09 Å) between the hydrazide groups of isoniazid. Such interactions are not present in cinnamic acid–isoniazid cocrystal polymorphs I and II. The packing of the synthons in polymorphs I, II and III is shown in Fig. 2.
The torsion angles C5—C4—C7—N9, C4—C7—N9—N10 and C21—C16—C15—C14 of the three polymorphs express the conformational differences between the isoniazid and cinnamic acid molecules. The dihedral angles between the planes of the carboxylic acid group and the pyridine ring characterize the planarity of the four-molecule assembly. The values of the torsion and dihedral angles of each polymorph are listed in Table 3.
In the crystal structures of all three cinnamic acid–isoniazid cocrystal polymorphs, hydrogen-bonded acid–base–acid–base rings tend to order with antiparallel cinnamic acid molecules next to each other (Fig. 2). A coplanar arrangement of the cinnamic acid–isoniazid hydrogen-bonded rings in polymorphs I and III results in planar sheets. These sheets in the crystal structure of polymorph III are then arranged in layers to allow an offset face-to-face π–π stacking between the aromatic rings of cinnamic acid and the pyridine rings of isoniazid [symmetry operation (x + 1, y + 1, z); angle between ring planes = 6.92°, distance between centroids = 3.90 Å and shift = 1.69 Å] and between symmetry-related cinnamic acid molecules [symmetry code (-x + 3, -y + 2, -z + 1); angle between ring planes = 0.00°, distance between centroids = 3.78 Å and shift = 1.43 Å]. For comparison, in the crystal structure of polymorph I the aromatic ring of the cinnamic acid forms π–π interactions with the pyridine ring of isoniazid. The centroid-to-centroid distances between the aromatic rings of cinnamic acid and isoniazid [symmetry codes (x - 1, y - 1, z) and (x, y - 1, z)] are 3.66 and 3.80 Å, respectively. The correspondig shifts in polymorph I are 1.32 and 1.62 Å. The angle between the plane of the cinnamic acid aromatic ring and that of isoniazid [symmetry codes (x - 1, y - 1, z) and (x, y - 1, z) [what do these symmetry codes relate to?]] pyridine ring is 0.85°. In the crystal structure of polymorph II, the isoniazid and cinnamic acid molecules are located above each other. Offset π–π interactions are observed between the cinnamic acid molecules and between the isoniazid molecules (distance between centroids of aromatic rings = 3.75 Å, shift = 1.26 Å and angle between ring planes = 0.00°).
The cinnamic acid–N'-(propan-2-ylidene)isonicotinohydrazide (1/1) cocrystal, (2), crystallizes in the orthorhombic Pb21a space group. The asymmetric unit contains one isonicotinohydrazide and one cinnamic acid molecule (Fig. 3).
The characteristic carboxylic acid–pyridine heterosynthon forms between the cinnamic acid and N'-(propan-2-ylidene)isonicotinohydrazide molecules in (2) (Table 4 and Fig. 3). The angle between the plane of the carboxylic acid group of cinnamic acid and the plane of the pyridine ring of isoniazid is 76.2° and, in the absence of weak C—H···O hydrogen bonding, a simple D graph set forms. The carboxylic acid–pyridine synthon forms in all known N'-(propan-2-ylidene)isonicotinohydrazide–carboxylic acid cocrystal structures (Lemmerer et al., 2010, 2011; Lemmerer, 2012).
The propan-2-ylidene substituent hinders the formation of an N—H···O hydrogen bond between the hydrazide and carboxylic acid groups. However, an N—H···O hydrogen bond to a symmetry-related [Symmetry code?] N'-(propan-2-ylidene)isonicotinohydrazide molecule is formed and the isonicotinohydrazide molecules in (2) are linked into linear chains that extend along the crystallographic b axis (Fig. 4). Such chains have been observed in N'-(propan-2-ylidene)isonicotinohydrazide cocrystals with other carboxylic acids, for example succinic acid, salicylic acid and 3-hydroxybenzoic acid (Lemmerer et al., 2010, 2011; Lemmerer, 2012). Alternating layers of N'-(propan-2-ylidene)isonicotinohydrazide and cinnamic acid are stacked to form a sandwich-type packing (Fig. 5).
In conclusion, isoniazid tends to form a hydrogen-bonded R44(16) synthon with cinnamic acid. These synthon-based assemblies have different spatial arrangements, giving rise to polymorphism of the cinnamic acid–isoniazid cocrystal. Modification of the isoniazid hydrazide group by replacing the –NH2 functional group can be utilized to hinder the formation of the cyclic cinnamic acid–isoniazid hydrogen-bonded R44(16) synthon.
For both compounds, data collection: COLLECT (Nonius, 1998); cell refinement: SCALEPACK (Otwinowski & Minor, 1997); data reduction: DENZO and SCALEPACK (Otwinowski & Minor, 1997); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEP-3 for Windows (Farrugia, 2012). Software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009) for (1); SHELXL97 (Sheldrick, 2008) for (2).
C6H7N3O·C9H8O2 | Z = 2 |
Mr = 285.30 | F(000) = 300 |
Triclinic, P1 | Dx = 1.373 Mg m−3 |
Hall symbol: -P 1 | Melting point: 399 K |
a = 6.4872 (2) Å | Mo Kα radiation, λ = 0.71073 Å |
b = 8.1478 (4) Å | Cell parameters from 8000 reflections |
c = 13.56030 (11) Å | θ = 1.0–27.5° |
α = 95.1691 (11)° | µ = 0.10 mm−1 |
β = 101.1111 (11)° | T = 173 K |
γ = 98.6376 (17)° | Plate, colourless |
V = 690.08 (4) Å3 | 0.5 × 0.4 × 0.4 mm |
Bruker Nonius KappaCCD area-detector diffractometer | 2430 reflections with I > 2σ(I) |
Radiation source: fine-focus sealed tube | Rint = 0.023 |
Horizonally mounted graphite crystal monochromator | θmax = 27.5°, θmin = 3.1° |
Detector resolution: 9 pixels mm-1 | h = −8→8 |
ϕ and ω scans | k = −10→9 |
4637 measured reflections | l = −17→17 |
3145 independent reflections |
Refinement on F2 | Primary atom site location: structure-invariant direct methods |
Least-squares matrix: full | Secondary atom site location: difference Fourier map |
R[F2 > 2σ(F2)] = 0.045 | Hydrogen site location: inferred from neighbouring sites |
wR(F2) = 0.123 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.05 | w = 1/[σ2(Fo2) + (0.0537P)2 + 0.1682P] where P = (Fo2 + 2Fc2)/3 |
3145 reflections | (Δ/σ)max < 0.001 |
204 parameters | Δρmax = 0.35 e Å−3 |
0 restraints | Δρmin = −0.20 e Å−3 |
C6H7N3O·C9H8O2 | γ = 98.6376 (17)° |
Mr = 285.30 | V = 690.08 (4) Å3 |
Triclinic, P1 | Z = 2 |
a = 6.4872 (2) Å | Mo Kα radiation |
b = 8.1478 (4) Å | µ = 0.10 mm−1 |
c = 13.56030 (11) Å | T = 173 K |
α = 95.1691 (11)° | 0.5 × 0.4 × 0.4 mm |
β = 101.1111 (11)° |
Bruker Nonius KappaCCD area-detector diffractometer | 2430 reflections with I > 2σ(I) |
4637 measured reflections | Rint = 0.023 |
3145 independent reflections |
R[F2 > 2σ(F2)] = 0.045 | 0 restraints |
wR(F2) = 0.123 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.05 | Δρmax = 0.35 e Å−3 |
3145 reflections | Δρmin = −0.20 e Å−3 |
204 parameters |
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. |
x | y | z | Uiso*/Ueq | ||
N1 | 0.69034 (18) | 0.56375 (15) | 0.79286 (9) | 0.0270 (3) | |
C2 | 0.4774 (2) | 0.53573 (19) | 0.76533 (11) | 0.0284 (3) | |
H2 | 0.4135 | 0.5896 | 0.7130 | 0.034* | |
C3 | 0.3481 (2) | 0.43007 (18) | 0.81138 (10) | 0.0267 (3) | |
H3 | 0.2006 | 0.4147 | 0.7904 | 0.032* | |
C4 | 0.4394 (2) | 0.34763 (16) | 0.88859 (10) | 0.0220 (3) | |
C5 | 0.6608 (2) | 0.37391 (17) | 0.91641 (11) | 0.0260 (3) | |
H5 | 0.7288 | 0.3193 | 0.9672 | 0.031* | |
C6 | 0.7780 (2) | 0.48296 (18) | 0.86703 (11) | 0.0277 (3) | |
H6 | 0.9258 | 0.5009 | 0.8866 | 0.033* | |
C7 | 0.2918 (2) | 0.23682 (16) | 0.93853 (10) | 0.0223 (3) | |
O8 | 0.09778 (15) | 0.21558 (13) | 0.90755 (8) | 0.0326 (3) | |
N9 | 0.38371 (18) | 0.16741 (15) | 1.01730 (9) | 0.0243 (3) | |
H9 | 0.519 (3) | 0.185 (2) | 1.0433 (13) | 0.033 (4)* | |
N10 | 0.26216 (19) | 0.06591 (17) | 1.07273 (10) | 0.0291 (3) | |
H10A | 0.163 (3) | 0.125 (3) | 1.0915 (14) | 0.049 (5)* | |
H10B | 0.186 (3) | −0.026 (2) | 1.0273 (14) | 0.041 (5)* | |
O11 | 0.95518 (17) | 0.77111 (15) | 0.71545 (8) | 0.0388 (3) | |
H11 | 0.8749 | 0.7073 | 0.7403 | 0.080 (8)* | |
O12 | 1.16107 (15) | 0.79207 (13) | 0.86998 (8) | 0.0309 (3) | |
C13 | 1.1330 (2) | 0.82833 (18) | 0.78323 (11) | 0.0272 (3) | |
C14 | 1.2994 (2) | 0.93732 (18) | 0.74799 (11) | 0.0292 (3) | |
H14 | 1.4340 | 0.9658 | 0.7901 | 0.035* | |
C15 | 1.2681 (2) | 0.99692 (18) | 0.65973 (11) | 0.0288 (3) | |
H15 | 1.1330 | 0.9667 | 0.6183 | 0.035* | |
C16 | 1.4284 (2) | 1.10700 (18) | 0.62148 (11) | 0.0290 (3) | |
C17 | 1.3616 (3) | 1.1835 (2) | 0.53647 (12) | 0.0357 (4) | |
H17 | 1.2176 | 1.1653 | 0.5058 | 0.043* | |
C18 | 1.5056 (3) | 1.2866 (2) | 0.49655 (13) | 0.0443 (4) | |
H18 | 1.4579 | 1.3376 | 0.4398 | 0.053* | |
C19 | 1.7189 (3) | 1.3136 (2) | 0.54044 (14) | 0.0481 (5) | |
H19 | 1.8156 | 1.3831 | 0.5136 | 0.058* | |
C20 | 1.7898 (3) | 1.2373 (2) | 0.62477 (13) | 0.0428 (4) | |
H20 | 1.9344 | 1.2547 | 0.6541 | 0.051* | |
C21 | 1.6455 (3) | 1.1347 (2) | 0.66566 (12) | 0.0348 (4) | |
H21 | 1.6937 | 1.0843 | 0.7226 | 0.042* |
U11 | U22 | U33 | U12 | U13 | U23 | |
N1 | 0.0284 (6) | 0.0258 (6) | 0.0276 (6) | 0.0016 (5) | 0.0095 (5) | 0.0043 (5) |
C2 | 0.0284 (7) | 0.0317 (8) | 0.0255 (7) | 0.0035 (6) | 0.0056 (5) | 0.0084 (6) |
C3 | 0.0219 (6) | 0.0315 (8) | 0.0254 (7) | 0.0022 (5) | 0.0034 (5) | 0.0034 (6) |
C4 | 0.0219 (6) | 0.0190 (7) | 0.0249 (7) | 0.0011 (5) | 0.0075 (5) | 0.0004 (5) |
C5 | 0.0230 (7) | 0.0244 (7) | 0.0317 (8) | 0.0042 (5) | 0.0060 (5) | 0.0084 (6) |
C6 | 0.0212 (7) | 0.0277 (7) | 0.0355 (8) | 0.0021 (5) | 0.0093 (5) | 0.0067 (6) |
C7 | 0.0197 (6) | 0.0196 (6) | 0.0275 (7) | 0.0018 (5) | 0.0062 (5) | 0.0024 (5) |
O8 | 0.0188 (5) | 0.0377 (6) | 0.0415 (6) | 0.0008 (4) | 0.0046 (4) | 0.0153 (5) |
N9 | 0.0176 (6) | 0.0271 (6) | 0.0279 (6) | −0.0008 (5) | 0.0055 (5) | 0.0085 (5) |
N10 | 0.0219 (6) | 0.0319 (7) | 0.0341 (7) | −0.0016 (5) | 0.0081 (5) | 0.0124 (6) |
O11 | 0.0305 (6) | 0.0502 (7) | 0.0313 (6) | −0.0095 (5) | 0.0038 (4) | 0.0157 (5) |
O12 | 0.0280 (5) | 0.0347 (6) | 0.0297 (6) | 0.0012 (4) | 0.0056 (4) | 0.0100 (4) |
C13 | 0.0245 (7) | 0.0260 (7) | 0.0321 (8) | 0.0032 (5) | 0.0091 (6) | 0.0045 (6) |
C14 | 0.0260 (7) | 0.0294 (8) | 0.0314 (8) | −0.0004 (6) | 0.0071 (6) | 0.0050 (6) |
C15 | 0.0270 (7) | 0.0302 (8) | 0.0287 (8) | 0.0031 (6) | 0.0056 (6) | 0.0043 (6) |
C16 | 0.0357 (8) | 0.0245 (7) | 0.0279 (8) | 0.0015 (6) | 0.0126 (6) | 0.0021 (6) |
C17 | 0.0397 (8) | 0.0354 (9) | 0.0309 (8) | −0.0003 (7) | 0.0097 (6) | 0.0048 (7) |
C18 | 0.0613 (12) | 0.0387 (10) | 0.0337 (9) | −0.0017 (8) | 0.0167 (8) | 0.0104 (7) |
C19 | 0.0594 (12) | 0.0367 (10) | 0.0479 (11) | −0.0139 (8) | 0.0290 (9) | 0.0022 (8) |
C20 | 0.0355 (9) | 0.0413 (10) | 0.0463 (10) | −0.0077 (7) | 0.0123 (7) | −0.0067 (8) |
C21 | 0.0370 (8) | 0.0338 (8) | 0.0326 (8) | 0.0020 (6) | 0.0093 (6) | 0.0022 (6) |
N1—C6 | 1.3340 (19) | O11—H11 | 0.8200 |
N1—C2 | 1.3382 (18) | O12—C13 | 1.2250 (17) |
C2—C3 | 1.3843 (19) | C13—C14 | 1.4729 (19) |
C2—H2 | 0.9300 | C14—C15 | 1.323 (2) |
C3—C4 | 1.380 (2) | C14—H14 | 0.9300 |
C3—H3 | 0.9300 | C15—C16 | 1.472 (2) |
C4—C5 | 1.3910 (18) | C15—H15 | 0.9300 |
C4—C7 | 1.5137 (18) | C16—C17 | 1.387 (2) |
C5—C6 | 1.3842 (19) | C16—C21 | 1.396 (2) |
C5—H5 | 0.9300 | C17—C18 | 1.383 (2) |
C6—H6 | 0.9300 | C17—H17 | 0.9300 |
C7—O8 | 1.2279 (16) | C18—C19 | 1.373 (3) |
C7—N9 | 1.3346 (18) | C18—H18 | 0.9300 |
N9—N10 | 1.4196 (16) | C19—C20 | 1.385 (3) |
N9—H9 | 0.866 (18) | C19—H19 | 0.9300 |
N10—H10A | 0.92 (2) | C20—C21 | 1.390 (2) |
N10—H10B | 0.94 (2) | C20—H20 | 0.9300 |
O11—C13 | 1.3213 (18) | C21—H21 | 0.9300 |
C6—N1—C2 | 117.35 (12) | O12—C13—C14 | 121.37 (13) |
N1—C2—C3 | 122.83 (13) | O11—C13—C14 | 115.98 (13) |
N1—C2—H2 | 118.6 | C15—C14—C13 | 123.62 (14) |
C3—C2—H2 | 118.6 | C15—C14—H14 | 118.2 |
C4—C3—C2 | 119.62 (13) | C13—C14—H14 | 118.2 |
C4—C3—H3 | 120.2 | C14—C15—C16 | 125.66 (14) |
C2—C3—H3 | 120.2 | C14—C15—H15 | 117.2 |
C3—C4—C5 | 117.86 (12) | C16—C15—H15 | 117.2 |
C3—C4—C7 | 117.79 (12) | C17—C16—C21 | 118.56 (14) |
C5—C4—C7 | 124.34 (13) | C17—C16—C15 | 118.59 (14) |
C6—C5—C4 | 118.75 (13) | C21—C16—C15 | 122.84 (14) |
C6—C5—H5 | 120.6 | C18—C17—C16 | 121.05 (16) |
C4—C5—H5 | 120.6 | C18—C17—H17 | 119.5 |
N1—C6—C5 | 123.57 (13) | C16—C17—H17 | 119.5 |
N1—C6—H6 | 118.2 | C19—C18—C17 | 120.15 (17) |
C5—C6—H6 | 118.2 | C19—C18—H18 | 119.9 |
O8—C7—N9 | 122.90 (12) | C17—C18—H18 | 119.9 |
O8—C7—C4 | 120.54 (12) | C18—C19—C20 | 119.86 (15) |
N9—C7—C4 | 116.55 (11) | C18—C19—H19 | 120.1 |
C7—N9—N10 | 121.90 (11) | C20—C19—H19 | 120.1 |
C7—N9—H9 | 125.2 (11) | C19—C20—C21 | 120.21 (16) |
N10—N9—H9 | 112.7 (11) | C19—C20—H20 | 119.9 |
N9—N10—H10A | 107.6 (12) | C21—C20—H20 | 119.9 |
N9—N10—H10B | 106.6 (11) | C20—C21—C16 | 120.16 (16) |
H10A—N10—H10B | 106.5 (17) | C20—C21—H21 | 119.9 |
C13—O11—H11 | 109.5 | C16—C21—H21 | 119.9 |
O12—C13—O11 | 122.64 (12) |
D—H···A | D—H | H···A | D···A | D—H···A |
N9—H9···O12i | 0.866 (18) | 2.151 (19) | 3.0071 (15) | 169.9 (15) |
O11—H11···N1 | 0.82 | 1.84 | 2.6554 (15) | 179 |
N10—H10A···O12ii | 0.92 (2) | 2.44 (2) | 3.3309 (17) | 164.5 (16) |
N10—H10B···O12iii | 0.94 (2) | 2.449 (19) | 3.2753 (18) | 147.3 (15) |
N10—H10B···O8iv | 0.94 (2) | 2.563 (18) | 3.0865 (15) | 115.7 (13) |
C6—H6···O12 | 0.93 | 2.67 | 3.2535 (16) | 121 |
Symmetry codes: (i) −x+2, −y+1, −z+2; (ii) −x+1, −y+1, −z+2; (iii) x−1, y−1, z; (iv) −x, −y, −z+2. |
C9H11N3O·C9H8O2 | Dx = 1.274 Mg m−3 |
Mr = 325.36 | Melting point: 377 K |
Orthorhombic, Pca21 | Mo Kα radiation, λ = 0.71073 Å |
Hall symbol: P -2a -2ab | Cell parameters from 18975 reflections |
a = 8.8818 (1) Å | θ = 1.0–27.5° |
b = 21.0445 (4) Å | µ = 0.09 mm−1 |
c = 9.0764 (1) Å | T = 173 K |
V = 1696.50 (4) Å3 | Prism, colourless |
Z = 4 | 0.4 × 0.3 × 0.2 mm |
F(000) = 688.0 |
Nonius KappaCCD area-detector diffractometer | 1791 reflections with I > 2σ(I) |
Radiation source: fine-focus sealed tube | Rint = 0.023 |
Horizonally mounted graphite crystal monochromator | θmax = 27.5°, θmin = 2.5° |
Detector resolution: 9 pixels mm-1 | h = −11→11 |
ϕ and ω scans | k = −27→27 |
3694 measured reflections | l = −11→11 |
2058 independent reflections |
Refinement on F2 | Primary atom site location: structure-invariant direct methods |
Least-squares matrix: full | Secondary atom site location: difference Fourier map |
R[F2 > 2σ(F2)] = 0.037 | Hydrogen site location: inferred from neighbouring sites |
wR(F2) = 0.088 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.05 | w = 1/[σ2(Fo2) + (0.0412P)2 + 0.2535P] where P = (Fo2 + 2Fc2)/3 |
2058 reflections | (Δ/σ)max < 0.001 |
225 parameters | Δρmax = 0.25 e Å−3 |
1 restraint | Δρmin = −0.14 e Å−3 |
C9H11N3O·C9H8O2 | V = 1696.50 (4) Å3 |
Mr = 325.36 | Z = 4 |
Orthorhombic, Pca21 | Mo Kα radiation |
a = 8.8818 (1) Å | µ = 0.09 mm−1 |
b = 21.0445 (4) Å | T = 173 K |
c = 9.0764 (1) Å | 0.4 × 0.3 × 0.2 mm |
Nonius KappaCCD area-detector diffractometer | 1791 reflections with I > 2σ(I) |
3694 measured reflections | Rint = 0.023 |
2058 independent reflections |
R[F2 > 2σ(F2)] = 0.037 | 1 restraint |
wR(F2) = 0.088 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.05 | Δρmax = 0.25 e Å−3 |
2058 reflections | Δρmin = −0.14 e Å−3 |
225 parameters |
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. |
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 > 2sigma(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. |
x | y | z | Uiso*/Ueq | ||
N1 | 0.9050 (2) | 0.16280 (8) | 0.3969 (2) | 0.0365 (4) | |
C2 | 0.9888 (3) | 0.11412 (10) | 0.3498 (2) | 0.0327 (5) | |
H2 | 1.0693 | 0.1226 | 0.2873 | 0.039* | |
C3 | 0.9615 (2) | 0.05154 (9) | 0.3896 (2) | 0.0289 (4) | |
H3 | 1.0220 | 0.0189 | 0.3542 | 0.035* | |
C4 | 0.8415 (2) | 0.03878 (9) | 0.4836 (2) | 0.0267 (4) | |
C5 | 0.7550 (3) | 0.08914 (9) | 0.5332 (2) | 0.0340 (5) | |
H5 | 0.6745 | 0.0821 | 0.5967 | 0.041* | |
C6 | 0.7896 (3) | 0.14979 (10) | 0.4874 (3) | 0.0394 (5) | |
H6 | 0.7303 | 0.1833 | 0.5206 | 0.047* | |
C7 | 0.8091 (2) | −0.02658 (9) | 0.5420 (2) | 0.0274 (4) | |
O8 | 0.7528 (2) | −0.03385 (6) | 0.66400 (17) | 0.0380 (4) | |
N9 | 0.8529 (2) | −0.07475 (8) | 0.45257 (18) | 0.0287 (4) | |
H9 | 0.859 (2) | −0.0660 (10) | 0.357 (3) | 0.028 (6)* | |
N10 | 0.8372 (2) | −0.13715 (8) | 0.50252 (19) | 0.0321 (4) | |
C11 | 0.8835 (2) | −0.18048 (10) | 0.4137 (2) | 0.0325 (5) | |
C12 | 0.9508 (3) | −0.17017 (11) | 0.2650 (3) | 0.0412 (5) | |
H12A | 0.8725 | −0.1607 | 0.1955 | 0.062* | |
H12B | 1.0031 | −0.2079 | 0.2346 | 0.062* | |
H12C | 1.0203 | −0.1353 | 0.2691 | 0.062* | |
C13 | 0.8648 (3) | −0.24761 (11) | 0.4648 (3) | 0.0487 (6) | |
H13A | 0.8263 | −0.2478 | 0.5636 | 0.073* | |
H13B | 0.9606 | −0.2688 | 0.4626 | 0.073* | |
H13C | 0.7957 | −0.2693 | 0.4010 | 0.073* | |
O14 | 0.9817 (2) | 0.28333 (8) | 0.3413 (2) | 0.0521 (5) | |
H14 | 0.9562 | 0.2459 | 0.3452 | 0.087 (12)* | |
O15 | 0.7904 (2) | 0.28889 (8) | 0.1846 (3) | 0.0713 (6) | |
C16 | 0.8914 (3) | 0.31398 (11) | 0.2545 (3) | 0.0453 (6) | |
C17 | 0.9244 (3) | 0.38341 (11) | 0.2513 (3) | 0.0466 (6) | |
H17 | 0.9992 | 0.3994 | 0.3128 | 0.056* | |
C18 | 0.8519 (3) | 0.42263 (11) | 0.1651 (3) | 0.0424 (5) | |
H18 | 0.7819 | 0.4048 | 0.1011 | 0.051* | |
C19 | 0.8696 (3) | 0.49226 (10) | 0.1588 (3) | 0.0378 (5) | |
C20 | 0.9695 (3) | 0.52573 (11) | 0.2481 (3) | 0.0419 (5) | |
H20 | 1.0298 | 0.5039 | 0.3149 | 0.050* | |
C21 | 0.9798 (3) | 0.59133 (11) | 0.2383 (3) | 0.0473 (6) | |
H21 | 1.0465 | 0.6134 | 0.2985 | 0.057* | |
C22 | 0.8905 (3) | 0.62406 (11) | 0.1388 (3) | 0.0490 (6) | |
H22 | 0.8983 | 0.6680 | 0.1313 | 0.059* | |
C23 | 0.7906 (3) | 0.59175 (11) | 0.0514 (3) | 0.0501 (6) | |
H23 | 0.7299 | 0.6138 | −0.0146 | 0.060* | |
C24 | 0.7801 (3) | 0.52611 (11) | 0.0615 (3) | 0.0448 (6) | |
H24 | 0.7118 | 0.5045 | 0.0021 | 0.054* |
U11 | U22 | U33 | U12 | U13 | U23 | |
N1 | 0.0398 (10) | 0.0313 (9) | 0.0383 (10) | −0.0013 (8) | −0.0076 (9) | 0.0003 (8) |
C2 | 0.0352 (11) | 0.0345 (11) | 0.0285 (10) | −0.0069 (9) | −0.0026 (9) | 0.0008 (9) |
C3 | 0.0319 (10) | 0.0285 (10) | 0.0263 (9) | 0.0004 (8) | −0.0019 (9) | −0.0017 (8) |
C4 | 0.0285 (9) | 0.0312 (10) | 0.0205 (9) | 0.0003 (8) | −0.0042 (8) | 0.0008 (8) |
C5 | 0.0312 (9) | 0.0374 (11) | 0.0333 (11) | 0.0048 (10) | 0.0009 (9) | −0.0009 (9) |
C6 | 0.0404 (12) | 0.0330 (11) | 0.0447 (13) | 0.0053 (9) | −0.0042 (11) | −0.0028 (10) |
C7 | 0.0286 (9) | 0.0311 (10) | 0.0225 (10) | 0.0006 (8) | −0.0048 (8) | 0.0011 (8) |
O8 | 0.0510 (8) | 0.0390 (8) | 0.0240 (7) | 0.0019 (8) | 0.0067 (7) | 0.0030 (7) |
N9 | 0.0360 (9) | 0.0281 (9) | 0.0222 (8) | −0.0010 (7) | 0.0009 (7) | 0.0047 (7) |
N10 | 0.0407 (10) | 0.0280 (9) | 0.0276 (8) | −0.0016 (7) | −0.0029 (8) | 0.0051 (7) |
C11 | 0.0350 (11) | 0.0313 (11) | 0.0312 (10) | −0.0005 (9) | −0.0047 (10) | 0.0041 (9) |
C12 | 0.0535 (14) | 0.0357 (12) | 0.0345 (11) | 0.0073 (10) | 0.0030 (11) | −0.0002 (10) |
C13 | 0.0694 (17) | 0.0306 (12) | 0.0460 (14) | −0.0012 (11) | −0.0023 (12) | 0.0034 (10) |
O14 | 0.0616 (11) | 0.0300 (8) | 0.0648 (12) | −0.0080 (8) | −0.0123 (10) | 0.0065 (9) |
O15 | 0.0756 (15) | 0.0452 (10) | 0.0932 (15) | 0.0001 (10) | −0.0329 (13) | 0.0041 (11) |
C16 | 0.0482 (14) | 0.0336 (12) | 0.0541 (14) | −0.0007 (11) | 0.0020 (12) | −0.0035 (12) |
C17 | 0.0463 (13) | 0.0419 (13) | 0.0517 (14) | −0.0021 (11) | −0.0065 (13) | 0.0034 (12) |
C18 | 0.0407 (12) | 0.0425 (13) | 0.0439 (13) | 0.0017 (10) | 0.0044 (11) | 0.0004 (11) |
C19 | 0.0395 (11) | 0.0337 (11) | 0.0404 (11) | 0.0038 (10) | 0.0128 (10) | 0.0023 (10) |
C20 | 0.0387 (12) | 0.0390 (12) | 0.0482 (13) | 0.0062 (10) | 0.0038 (11) | 0.0087 (11) |
C21 | 0.0458 (13) | 0.0403 (14) | 0.0559 (16) | −0.0017 (11) | 0.0061 (12) | −0.0012 (11) |
C22 | 0.0617 (16) | 0.0309 (12) | 0.0544 (16) | 0.0051 (11) | 0.0139 (13) | 0.0072 (11) |
C23 | 0.0605 (16) | 0.0434 (14) | 0.0464 (14) | 0.0103 (12) | 0.0043 (14) | 0.0123 (12) |
C24 | 0.0483 (14) | 0.0471 (13) | 0.0391 (13) | 0.0012 (11) | 0.0032 (12) | 0.0046 (11) |
N1—C2 | 1.337 (3) | C13—H13B | 0.9600 |
N1—C6 | 1.341 (3) | C13—H13C | 0.9600 |
C2—C3 | 1.387 (3) | O14—C16 | 1.296 (3) |
C2—H2 | 0.9300 | O14—H14 | 0.8200 |
C3—C4 | 1.392 (3) | O15—C16 | 1.219 (3) |
C3—H3 | 0.9300 | C16—C17 | 1.491 (3) |
C4—C5 | 1.384 (3) | C17—C18 | 1.307 (3) |
C4—C7 | 1.502 (3) | C17—H17 | 0.9300 |
C5—C6 | 1.377 (3) | C18—C19 | 1.475 (3) |
C5—H5 | 0.9300 | C18—H18 | 0.9300 |
C6—H6 | 0.9300 | C19—C24 | 1.385 (3) |
C7—O8 | 1.225 (3) | C19—C20 | 1.393 (3) |
C7—N9 | 1.356 (3) | C20—C21 | 1.387 (3) |
N9—N10 | 1.396 (2) | C20—H20 | 0.9300 |
N9—H9 | 0.89 (2) | C21—C22 | 1.385 (4) |
N10—C11 | 1.284 (3) | C21—H21 | 0.9300 |
C11—C12 | 1.493 (3) | C22—C23 | 1.371 (4) |
C11—C13 | 1.496 (3) | C22—H22 | 0.9300 |
C12—H12A | 0.9600 | C23—C24 | 1.387 (3) |
C12—H12B | 0.9600 | C23—H23 | 0.9300 |
C12—H12C | 0.9600 | C24—H24 | 0.9300 |
C13—H13A | 0.9600 | ||
C2—N1—C6 | 117.71 (18) | C11—C13—H13B | 109.5 |
N1—C2—C3 | 123.2 (2) | H13A—C13—H13B | 109.5 |
N1—C2—H2 | 118.4 | C11—C13—H13C | 109.5 |
C3—C2—H2 | 118.4 | H13A—C13—H13C | 109.5 |
C2—C3—C4 | 118.49 (19) | H13B—C13—H13C | 109.5 |
C2—C3—H3 | 120.8 | C16—O14—H14 | 109.5 |
C4—C3—H3 | 120.8 | O15—C16—O14 | 123.8 (2) |
C5—C4—C3 | 118.47 (18) | O15—C16—C17 | 124.0 (2) |
C5—C4—C7 | 118.72 (18) | O14—C16—C17 | 112.2 (2) |
C3—C4—C7 | 122.66 (17) | C18—C17—C16 | 122.2 (2) |
C6—C5—C4 | 119.2 (2) | C18—C17—H17 | 118.9 |
C6—C5—H5 | 120.4 | C16—C17—H17 | 118.9 |
C4—C5—H5 | 120.4 | C17—C18—C19 | 126.7 (2) |
N1—C6—C5 | 123.0 (2) | C17—C18—H18 | 116.6 |
N1—C6—H6 | 118.5 | C19—C18—H18 | 116.6 |
C5—C6—H6 | 118.5 | C24—C19—C20 | 118.5 (2) |
O8—C7—N9 | 124.41 (19) | C24—C19—C18 | 118.3 (2) |
O8—C7—C4 | 120.77 (18) | C20—C19—C18 | 123.2 (2) |
N9—C7—C4 | 114.77 (17) | C21—C20—C19 | 120.5 (2) |
C7—N9—N10 | 118.72 (17) | C21—C20—H20 | 119.7 |
C7—N9—H9 | 116.6 (14) | C19—C20—H20 | 119.7 |
N10—N9—H9 | 121.2 (14) | C22—C21—C20 | 120.0 (2) |
C11—N10—N9 | 115.61 (17) | C22—C21—H21 | 120.0 |
N10—C11—C12 | 126.34 (19) | C20—C21—H21 | 120.0 |
N10—C11—C13 | 116.1 (2) | C23—C22—C21 | 120.1 (2) |
C12—C11—C13 | 117.5 (2) | C23—C22—H22 | 120.0 |
C11—C12—H12A | 109.5 | C21—C22—H22 | 120.0 |
C11—C12—H12B | 109.5 | C22—C23—C24 | 119.9 (2) |
H12A—C12—H12B | 109.5 | C22—C23—H23 | 120.0 |
C11—C12—H12C | 109.5 | C24—C23—H23 | 120.0 |
H12A—C12—H12C | 109.5 | C19—C24—C23 | 121.0 (2) |
H12B—C12—H12C | 109.5 | C19—C24—H24 | 119.5 |
C11—C13—H13A | 109.5 | C23—C24—H24 | 119.5 |
D—H···A | D—H | H···A | D···A | D—H···A |
N9—H9···O8i | 0.89 (2) | 2.12 (2) | 2.912 (2) | 147 (2) |
O14—H14···N1 | 0.82 (1) | 1.87 (1) | 2.675 (2) | 168 (1) |
Symmetry code: (i) −x+3/2, y+1/2, z−1. |
Experimental details
(1) | (2) | |
Crystal data | ||
Chemical formula | C6H7N3O·C9H8O2 | C9H11N3O·C9H8O2 |
Mr | 285.30 | 325.36 |
Crystal system, space group | Triclinic, P1 | Orthorhombic, Pca21 |
Temperature (K) | 173 | 173 |
a, b, c (Å) | 6.4872 (2), 8.1478 (4), 13.56030 (11) | 8.8818 (1), 21.0445 (4), 9.0764 (1) |
α, β, γ (°) | 95.1691 (11), 101.1111 (11), 98.6376 (17) | 90, 90, 90 |
V (Å3) | 690.08 (4) | 1696.50 (4) |
Z | 2 | 4 |
Radiation type | Mo Kα | Mo Kα |
µ (mm−1) | 0.10 | 0.09 |
Crystal size (mm) | 0.5 × 0.4 × 0.4 | 0.4 × 0.3 × 0.2 |
Data collection | ||
Diffractometer | Bruker Nonius KappaCCD area-detector diffractometer | Nonius KappaCCD area-detector diffractometer |
Absorption correction | – | – |
No. of measured, independent and observed [I > 2σ(I)] reflections | 4637, 3145, 2430 | 3694, 2058, 1791 |
Rint | 0.023 | 0.023 |
(sin θ/λ)max (Å−1) | 0.649 | 0.649 |
Refinement | ||
R[F2 > 2σ(F2)], wR(F2), S | 0.045, 0.123, 1.05 | 0.037, 0.088, 1.05 |
No. of reflections | 3145 | 2058 |
No. of parameters | 204 | 225 |
No. of restraints | 0 | 1 |
H-atom treatment | H atoms treated by a mixture of independent and constrained refinement | H atoms treated by a mixture of independent and constrained refinement |
Δρmax, Δρmin (e Å−3) | 0.35, −0.20 | 0.25, −0.14 |
Computer programs: COLLECT (Nonius, 1998), DENZO and SCALEPACK (Otwinowski & Minor, 1997), SHELXS97 (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008), ORTEP-3 for Windows (Farrugia, 2012), OLEX2 (Dolomanov et al., 2009).
D—H···A | D—H | H···A | D···A | D—H···A |
N9—H9···O12i | 0.866 (18) | 2.151 (19) | 3.0071 (15) | 169.9 (15) |
O11—H11···N1 | 0.82 | 1.84 | 2.6554 (15) | 178.6 |
N10—H10A···O12ii | 0.92 (2) | 2.44 (2) | 3.3309 (17) | 164.5 (16) |
N10—H10B···O12iii | 0.94 (2) | 2.449 (19) | 3.2753 (18) | 147.3 (15) |
N10—H10B···O8iv | 0.94 (2) | 2.563 (18) | 3.0865 (15) | 115.7 (13) |
C6—H6···O12 | 0.93 | 2.67 | 3.2535 (16) | 121.1 |
Symmetry codes: (i) −x+2, −y+1, −z+2; (ii) −x+1, −y+1, −z+2; (iii) x−1, y−1, z; (iv) −x, −y, −z+2. |
The dihedral angle is between the planes of the carboxylic acid group and the pyridine ring. |
Polymorph | I | II | III |
Dihedral angle* | 17.65 | 8.91 | 28.76 |
C5—C4—C7—N9 | 0.3 (2) | 12.9 (6) | 3.3 (2) |
C4—C7–N9—N10 | -179.9 (1) | 174.2 (3) | 177.7 (1) |
C21(17)—C16—C15—C14 | -6.6 (2) | 7.0 (7) | 13.2 (2) |
D—H···A | D—H | H···A | D···A | D—H···A |
N9—H9···O8i | 0.89 (2) | 2.12 (2) | 2.912 (2) | 147 (2) |
O14—H14···N1 | 0.820 (2) | 1.867 (2) | 2.675 (2) | 167.75 (14) |
Symmetry code: (i) −x+3/2, y+1/2, z−1. |