Crystal structures of the pyrazinamide–p-amino­benzoic acid (1/1) cocrystal and the transamidation reaction product 4-(pyrazine-2-carboxamido)­benzoic acid in the molten state

The synthesis of pharmaceutical cocrystals is a strategy to enhance the performance of active pharmaceutical ingredients (APIs) without affecting their therapeutic efficiency. The 1:1 pharmaceutical cocrystal of the anti­tuberculosis drug pyrazinamide (PZA) and the cocrystal former p-amino­benzoic acid (p-ABA), C₇H₇NO₂·C₅H₅N₃O, (1), was synthesized successfully and characterized by relevant solid-state characterization methods. The cocrystal crystallizes in the monoclinic space group P2₁/n containing one mol­ecule of each component. Both mol­ecules associate via inter­molecular O—H...O and N—H...O hydrogen bonds [O...O = 2.6102 (15) Å and O—H...O = 168.3 (19)°; N...O = 2.9259 (18) Å and N—H...O = 167.7 (16)°] to generate a dimeric acid–amide synthon. Neighbouring dimers are linked centrosymmetrically through N—H...O inter­actions [N...O = 3.1201 (18) Å and N—H...O = 136.9 (14)°] to form a tetra­meric assembly supplemented by C—H...N inter­actions [C...N = 3.5277 (19) Å and C—H...N = 147°]. Linking of these tetra­meric assemblies through N—H...O [N...O = 3.3026 (19) Å and N—H...O = 143.1 (17)°], N—H...N [N...N = 3.221 (2) Å and N—H...N = 177.9 (17)°] and C—H...O [C...O = 3.5354 (18) Å and C—H...O = 152°] inter­actions creates the two-dimensional packing. Recrystallization of the cocrystals from the molten state revealed the formation of 4-(pyrazine-2-carboxamido)­benzoic acid, C₁₂H₉N₃O₃, (2), through a trans­amidation reaction between PZA and p-ABA. Carboxamide (2) crystallizes in the triclinic space group P with one mol­ecule in the asymmetric unit. Mol­ecules of (2) form a centrosymmetric dimeric homosynthon through an acid–acid O—H...O hydrogen bond [O...O = 2.666 (3) Å and O—H...O = 178 (4)°]. Neighbouring assemblies are connected centrosymmetrically via a C—H...N inter­action [C...N = 3.365 (3) Å and C—H...N = 142°] engaging the pyrazine groups to generate a linear chain. Adjacent chains are connected loosely via C—H...O inter­actions [C...O = 3.212 (3) Å and C—H...O = 149°] to generate a two-dimensional sheet structure. Closely associated two-dimensional sheets in both compounds are stacked via aromatic π-stacking inter­actions engaging the pyrazine and benzene rings to create a three-dimensional multi-stack structure.

S1. Introduction

The synthesis of cocrystals and the study of their physicochemical properties has developed into a contemporary area of research comprising pharmaceutical solids (Aakeröy & Salmon, 2005; Schultheiss & Newman, 2009; Vishweshwar et al., 2006), agrochemicals (Nauha & Nissinen, 2011), high-energy materials (Bolton et al., 2012; Millar et al., 2012) etc. There has been constant and consistent endeavour in recent years to develop active pharmaceutical ingredient (API) cocrystals with a suitable cocrystal former because of the exploitation of this approach in the tuning of the physicochemical properties of an API that could be economically beneficial and academically inspiring (Babu & Nangia, 2011; Porter et al., 2008; Atipamula et al., 2012). Therefore, the synthesis of pharmaceutical cocrystals is a pioneering strategy to enhance the performance of APIs without affecting their therapeutic efficiency.

Pyrazinamide (pyrazine-2-carboxamide, PZA) is one of the most important frontline medicines used for the treatment of tuberculosis (TB) (Zhang & Mitchison, 2003). A total of four polymorphs of PZA are reported in the literature (Cherukuvada et al., 2010). Several cocrystals of PZA have also been reported with cocrystal formers that include 4-nitro­benzamide (Aakeroy et al., 2004), 2,5-di­hydroxy­benzoic acid (McMahon et al., 2005), 4-amino­salicylic acid (Grobelny et al., 2011), 2-amino­benzoic acid (Abourahma et al., 2011), succinic and fumaric acids (Cherukuvada & Nangia, 2012), vanillic, gallic, 1-hy­droxy-2-naphthoic and indole-2-carb­oxy­lic acids (Adalder et al., 2012), malonic and glutaric acids (Luo & Sun, 2013), 3,4-di­hydroxy­benzoic and m-hy­droxy­benzoic acids (Lou et al., 2013), and hydro­chloro­thia­zide (Wang et al., 2014). All these cocrystals were thoroughly characterized using appropriate solid-state characterization methods. Abourahma et al. (2011) reported the single-crystal structures of cocrystals of PZA with the ortho and meta isomers of amino­benzoic acid (ABA), as well as the meta and para isomers of hy­droxy­benzoic acid. However, they failed to study the single-crystal structure of PZA–p-ABA cocrystals because of its polycrystalline nature.

We report here the successful preparation of single crystals of the PZA–p-ABA cocrystal, (1). The current study also reveals an inter­esting transamidation reaction (Rao et al., 2013; Picq et al., 1999) between PZA and p-ABA in the molten state during a hot-stage microscopy study, yielding the corresponding carboxamide, (2), in crystalline form. Both compounds were thoroughly characterized using single-crystal and powder X-ray diffraction, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and ¹H NMR and IR spectroscopies. A detailed crystal structure analysis of both compounds has been carried out, revealing the dominance of classical O—H···O, N—H···O and N—H···N hydrogen-bonding inter­actions in the molecular packing of these crystals.

S2. Experimental

S2.1. Synthesis and crystallization

Cocrystallization was carried out from equimolar amounts of commercial samples of PZA and p-ABA by grinding (dry grinding as well as solvent-assisted grinding) and slow evaporation from the solution under ambient conditions. The grinding experiment was carried out manually using a mortar and pestle for about 15 min. A 1:1 stoichiometric molar ratio of PZA and p-ABA was ground using dry (neat) and liquid-assisted (or kneading) grinding methods. In the liquid-assisted grinding, a small amount of an ethanol–water mixture (1:1 v/v) was added during grinding. The ground sample was characterized using powder X-ray diffraction to verify the formation of the cocrystal by comparing it with the simulated powder pattern from the single-crystal XRD of the molecular cocrystal. The same ground material was used for solution crystallization. The ground sample was dissolved in an ethanol–water mixture (1:1 v/v) and heated at 318–323 K for about 10–15 min to dissolve the sample. The hot solution was then filtered into a conical flask to remove traces of undissolved compound or any foreign material, and the solution was evaporated at room temperature to yield block-shaped crystals of (1) (Fig. 1). The cocrystallization was also attempted from various organic solvents, such as acetone, ethyl acetate, aceto­nitrile, methanol, nitro­methane, chloro­form and an acetone–methanol mixture [Solvent ratio?], which [ALL?] gave block-shaped cocrystals, while crystallization from 1,4-dioxane, water, tetra­hydro­furan and di­chloro­methane resulted in the separate crystallization of both components. Crystals of carboxamide (2) were obtained by heating cocrystal (1) on a hot plate until it melted and subsequently cooling the melt. Carboxamide (2) was also synthesized by heating the physical mixture of PZA and p-ABA on a hot stage until it melted and then cooling the melt-produced crystals of carboxamide (2) (Fig. 1). Both cocrystal (1) and carboxamide (2) were characterized by single-crystal X-ray diffraction analysis (SC-XRD), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), NMR and IR spectroscopies, and hot-stage microscopy (HSM).

Analysis for cocrystal (1): m.p. 452–453 K; IR (Nujol, ν, cm^-1): 1595, 1670, 3321, 3342, 3414; ¹H NMR (200 MHz, DMSO-d₆, δ, p.p.m.): 5.88 (br s, 2H), 6.54 (d, J = 8.6 Hz, 2H), 7.61 (d, J = 8.6 Hz, 2H), 7.88 (br s, 1H), 8.28 (br s, 1H), 8.73 (m, 1H), 8.86 (d, J = 2.40 Hz, 1H), 9.19 (d, J = 1.4 Hz, 1H).

Analysis for compound (2): m.p. 597–598 K; IR (Nujol, ν, cm^-1): 3340, 1680; ¹H NMR (200 MHz, DMSO-d₆, δ, p.p.m.): 7.91–8.01 (m, 2H), 8.02–8.13 (m, 2 H), 8.86 (m, 1H), 8.97 (d, J = 2.5 Hz, 1H), 9.34 (d, J = 1.5 Hz, 1H), 11.05 (s, 1H, D₂O exchangeable), 12.84 (br s, 1H, D₂O exchangeable) (see Supporting information for the NMR and IR spectra; Figs. S1–S4).

S2.2. DSC analysis

The thermal behaviour of cocrystal (1) and carboxamide (2) was investigated by measuring the enthalpy change on a TA Q-100 Differential Scanning Calorimeter instrument. Crystals obtained from crystallization were first air-dried before they were used for DSC analysis. Crystals (3–5 mg) were placed in a sealed aluminum pan (40 µl) with a crimped pan closure and were analysed from room temperature to 573 K using the empty pan as the reference. The heating rate was 2 K min^-1 and nitro­gen gas was used for purging. DSC analysis of cocrystal (1) showed two endothermic peaks, the first being sharp and the second a small hump. The first endotherm, centred at 452.8 K, indicates melting followed by the formation of carboxamide (2) (as suggested by HSM and single-crystal diffraction studies; see below) and the second endotherm is attributed to the melting of carboxamide (2). However, DSC analysis of freshly prepared carboxamide (2) revealed a sharp melting endotherm at 599.8 K (see Supporting information for the DSC plots; Figs. S5–S6).

S2.3. PXRD analysis

The experimental powder X-ray diffraction patterns were recorded on a Rigaku Micromax-007HF instrument (high-intensity microfocus rotating-anode X-ray generator) with an R-axis detector IV++ at a continuous scanning rate of 2° 2θ min^-1 using Cu Kα radiation (40 kV, 30 mA) with the intensity of the diffracted X-rays being collected at inter­vals of 0.1° 2θ. A nickel filter was used to remove Cu Kβ radiation. The PXRD patterns of cocrystal (1) obtained from solution crystallization and liquid-assisted grinding are different from the diffractograms of PZA and p-ABA and match well with the diffraction pattern of cocrystal (1) simulated from its single-crystal diffraction data (see the Supporting information for the PXRD patterns; Figs. S7 and S8). However, the powder diffractogram of cocrystal (1) obtained from the dry-grinding experiment also reveals the presence of individual diffraction peaks for PZA and p-ABA (see the Supporting information for the PXRD patterns; Fig. S6 [Should this be S9?]). Further, the diffraction pattern of the crystals produced from the melt crystallization of cocrystal (1) is different from that of cocrystal (1), PZA and p-ABA (see the Supporting information for the PXRD patterns; Fig. S9).

S2.4. TGA study

Thermogravimetric analysis was performed using a TA SDT Q600 TGA instrument. Samples were prepared by placing a small amount of material (7–8 mg) in a standard aluminum pan (180 µl). The pan was then heated from ambient temperature (303 K) to 773 K with a heating rate of 10 K min^-1. Nitro­gen gas was used for purging, with a flow rate of 100 ml min^-1. TGA analysis of cocrystal (1) revealed a weight loss after melting which was attributed to the release of ammonia from the melt reaction. The TGA analysis of carboxamide (2) did not reveal any weight loss on heating (see the Supporting information for the TGA plots; Figs. S10 and S11).

S2.5. IR spectroscopy

The solid-state IR spectra of cocrystal (1) and amide (2) were acquired using a Bruker ALPHA FT–IR spectrophotometer at room temperature in Nujol in the 500–4000 cm^-1 range (see the Supporting information for the IR spectra; Fig. S4).

S2.6. HSM analysis

The cocrystals were heated on a P350 heating stage and images were recorded using a CCD camera attached to a Leica MZ75 polarizing microscope. Leica IM 50 software was used for image capture and analysis. The HSM study of the cocrystal showed the appearance of thin needles on the surface of large crystals at around 443 K. The unit-cell determination of these needles revealed them to be cocrystals. Further, upon heating, the cocrystals began to melt at 453 K and form thin plate-shaped crystals, which melted completely at 492.2 K (see the Supporting information for the crystal photomicrographs; Fig. S12). Determination of the crystal structure of the thin plate confirmed the formation of carboxamide (2). This indicates that the transamidation reaction between PZA and p-ABA has occurred in the molten state, yielding the corresponding carboxamide (2) with the release of ammonia (Fig. 2). To confirm the formation of carboxamide (2), HSM studies were carried out a few more times and in all the experiments carboxamide (2) was obtained. HSM studies were also carried out on a physical mixture of PZA and p-ABA at around 473–483 K that also revealed the formation of carboxamide (2).

S2.7. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 1. For both compounds, H atoms bound to N atoms (NH₂ and NH) and the hy­droxy group of the carb­oxy­lic acid groups were located in difference Fourier maps and refined isotropically. Other phenyl H atoms were placed in geometrically idealized positions, with C—H = 0.93 Å, and constrained to ride on their parent atoms, with U_iso(H) = 1.2U_eq(C).

S3. Results and discussion

Crystallization of pyrazinamide (PZA) and p-amino­benzoic acid (p-ABA) from various common organic solvents (except 1,4-dioxane, water, tetra­hydro­furan and di­chloro­methane) yielded block-shaped cocrystals suitable for single-crystal X-ray analysis. Both neat grinding and liquid-assisted grinding also led to cocrystal (1) formation, as indicated by powder X-ray diffraction studies.

Cocrystal (1) consists of equimolar amounts of PZA and p-ABA, as revealed by ¹H NMR spectroscopy and single-crystal X-ray diffraction analysis. The DSC profile of cocrystal (1) showed that it is stable up to the melting point and there was no structural phase-change transition prior to its melting. TGA did not reveal any weight loss before melting, although some weight loss was observed after melting of the crystals, corresponding to the release of ammonia after the transamidation reaction between PZA and p-ABA. HSM and single-crystal and powder X-ray diffraction studies revealed the formation of carboxamide (2) after the transamidation reaction in the molten state. The structure of carboxamide (2) was also confirmed by ¹H NMR spectroscopy and single-crystal X-ray diffraction analysis. DSC and TGA studies of carboxamide (2) did not reveal a phase change before or a weight loss after melting.

Cocrystal (1) crystallizes in the monoclinic P2₁/n space group containing one molecule each of PZA and p-ABA in the asymmetric unit (Fig. 3). Both molecules are associated via an acid–amide heterodimer synthon (Desiraju, 1995) through conventional O2—H2···O1 and N3—H3A···O3 hydrogen bonds (Fig. 3 and Table 2). In O—H···O hydrogen-bond formation, the hy­droxy group of p-ABA donates its H atom to the carbonyl O atom of PZA and, in turn, the amine group of PZA donates one of its H atoms to the carbonyl O atom of the carb­oxy­lic acid group of p-ABA to generate the N—H···O hydrogen bond. Neighbouring dimers are linked via N3—H3B···O3ⁱ hydrogen bonds (full details and symmetry code in Table 2) involving the other H atom of the amine group and the carbonyl O atom of the carb­oxy­lic acid group to generate a tetra­meric assembly, also supplemented by a C8—H8···N2 inter­action (Fig. 4 and Table 2). Adjacent tetra­mers along the crystallographic 2₁-screw axis (b axis) are joined through N4—H4A···O2ⁱⁱ and C11—H11···O1ⁱⁱ inter­actions (Table 2) to form a two-dimensional helical sheet structure (Fig. 5). This association also brings the unit-cell-translated tetra­mers along the b axis into proximity to make an N4—H4B···N1ⁱⁱⁱ hydrogen bond (Table 2). Neighbouring sheets are stacked in a centrosymmetric fashion through aromatic π–π inter­actions between pyrazine and benzene rings [Cg1···Cg2 = 3.6019 (9) Å and dihedral angle = 6.30 (7)°; symmetry code: (v) -x + 1, -y + 1, -z + 1; Cg1 is the centroid of the C7–C12 benzene ring and Cg2 is the centroid of the N1–C2 pyrazine ring] to create an undulating pattern in the bc plane supported by a weak C4—H4···O1^iv contact (Fig. 6 and Table 2).

The crystal structure of carboxamide (2) belongs to the triclinic P1 space group containing one molecule in the asymmetric unit (Fig. 7). The conformation of the molecule as observed in the crystal structure reveals a planar geometry wherein both the pyrazine and benzoic acid groups are in the same plane. Closely associated molecules form an acid–acid homodimer synthon (Desiraju, 1995) through O2—H2···O1ⁱ hydrogen bonds (Fig. 8 and Table 3). Neighbouring dimers are further connected by C11—H11···N3ⁱⁱ inter­actions (Table 3), engaging pyrazine groups across the inversion centre to generate an extended molecular string (Fig. 9). Neighbouring strings are joined through C4—H4···O3ⁱⁱⁱ inter­actions (Table 3) involving a C—H group of the benzoic acid and the carbonyl O atom of the carboxamide group to create a two-dimensional molecular sheet (Fig. 9). Adjacent sheets are stacked centrosymmetrically via aromatic π–π inter­actions between pyrazine and benzene rings [Cg1···Cg2 = 3.7399 (15) Å and dihedral angle = 8.18 (12)°; symmetry code: (iv) -x + 1, -y + 2, -z + 2; Cg1 is the centroid of the N2–C10 pyrazine ring and Cg2 is the centroid of the C2–C7 benzene ring] to create a multiple-stack structure (Fig. 10).

In conclusion, the single-crystal structure of cocrystal (1) of pyrazinamide and p-amino­benzoic acid has been prepared and its molten-state transamidation product, carboxamide (2), has been isolated. Both compounds have been thoroughly characterized by relevant solid-state characterization methods. As expected, the molecules of cocrystal (1) are associated via an acid–amide heterodimer synthon and these are further linked to each other through an N—H···O hydrogen bond to yield the tetra­mer. The arrangement of the tetra­mer through weak inter­actions leads to a two-dimensional undulating sheet structure. Conversely, the closely linked molecules of carboxamide (2) form an acid–acid homodimer synthon (as the obvious choice) and its subsequent association via weak contacts reveals the generation of a two-dimensional planar sheet structure. The occurrence of an effective transamidation reaction between pyrazinamide and p-amino­benzoic acid in the molten state with better selectivity and complete reproducibility is intriguing. In general, molecular cocrystals provide a good platform for investigating heteromolecular reactions, either in the crystalline state or in the molten state, with high selectivity and an excellent conversion rate not feasible in solution or in a single-component crystal or its melt (MacGillivray et al., 2008; Tamboli et al., 2013). Similar reactions between other carboxamides and amines in the molten state are currently being explored.

Computing details

For both compounds, data collection: APEX2 (Bruker, 2006); cell refinement: SAINT (Bruker, 2006); data reduction: SAINT (Bruker, 2006); 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) and Mercury (Macrae et al., 2008); software used to prepare material for publication: SHELXS97 (Sheldrick, 2008), PLATON (Spek, 2009) and publCIF (Westrip, 2010).

Figures

	Fig. 1. The crystals of (1) and (2). [Please provide descriptive caption]
	Fig. 2. The transamidation reaction between pyrazinamide (PZA) and p-aminobenzoic acid (p-ABA) in the molten state.
	Fig. 3. A view of the components of (1), showing the atom-numbering scheme and the dimeric association of pyrazinamide (PZA) and p-aminobenzoic acid (p-ABA) molecules through acid–amide, O2—H2···O1 and N3—H3A···O3 hydrogen bonds (dashed lines). Displacement ellipsoids are drawn at the 50% probability level.
	Fig. 4. The linking of adjacent dimers of (1) through centrosymmetric N3—H3B···O3^i and C8—H8···N2^i hydrogen bonds (dotted lines) to generate the tetrameric synthon. [Symmetry code: (i) -x + 2, -y + 1, -z + 1.]
	Fig. 5. The joining of neighbouring tetramers of (1) through N4—H4A···O2^ii, N4—H4B···N1^iii and C11—H11···O1^ii interactions (dotted lines) to create the two-dimensional helical sheet structure. [Symmetry codes: (ii) -x + 1/2, y + 1/2, -z + 1/2; (iii) x, y + 1, z.]
	Fig. 6. (a) The joining of adjacent sheets of (1) through C4—H4···O1^iv interactions (dashed lines) and aromatic π–π^v stacking interactions (dotted lines) to generate the undulating three-dimensional pattern shown in part (b). [Symmetry codes: (iv) x + 1/2, -y + 1/2, z + 1/2; (v) -x + 1, -y + 1, -z + 1.]
	Fig. 7. A view of the components of (2), showing the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probability level.
	Fig. 8. The formation of the dimeric acid–acid synthon in (2) through O2—H2···O1^i hydrogen bonding (dotted lines). [Symmetry code: (i) -x + 1, -y + 1, -z + 1.]
	Fig. 9. The joining of adjacent dimeric synthons of (2) through C4—H4···O3^ii and C11—H11···N3^iii contacts (dotted lines) to generate the two-dimensional sheet pattern in the ac plane. [Symmetry codes: (ii) x - 1, y, z; (iii) -x + 1, -y + 2, -z + 3.]
	Fig. 10. (a) The weaving of adjacent parallel two-dimensional sheets of (2) through aromatic π–π^iv stacking interactions (dashed lines) to generate the multiple-stack structure shown in part (b). [Symmetry code: (iv) -x + 1, -y + 2, -z + 2.]

(1) Pyrazine-2-carboxamide–4-aminobenzoic acid (1/1)

Crystal data

C7H7NO2·C5H5N3O	F(000) = 544
Mr = 260.26	Dx = 1.432 Mg m^−3
Monoclinic, P21/n	Mo Kα radiation, λ = 0.71073 Å
a = 7.9293 (8) Å	Cell parameters from 5708 reflections
b = 15.1231 (16) Å	θ = 2.4–31.9°
c = 10.2490 (12) Å	µ = 0.11 mm^−1
β = 100.862 (6)°	T = 296 K
V = 1207.0 (2) Å^3	Block, colourless
Z = 4	0.42 × 0.36 × 0.30 mm

Data collection

Bruker APEXII CCD area-detector diffractometer	2132 independent reflections
Radiation source: fine-focus sealed tube	1756 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.019
φ and ω scans	θmax = 25.0°, θmin = 2.4°
Absorption correction: multi-scan (SADABS; Bruker, 2006)	h = −9→9
Tmin = 0.957, Tmax = 0.969	k = −16→17
9627 measured reflections	l = −10→12

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.037	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.095	H atoms treated by a mixture of independent and constrained refinement
S = 1.05	w = 1/[σ^2(Fo^2) + (0.0468P)^2 + 0.2371P] where P = (Fo^2 + 2Fc^2)/3
2132 reflections	(Δ/σ)max < 0.001
184 parameters	Δρmax = 0.14 e Å^−3
0 restraints	Δρmin = −0.18 e Å^−3

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 (Ų)

	x	y	z	Uiso*/Ueq
O1	0.58680 (13)	0.37637 (7)	0.36785 (11)	0.0517 (3)
O2	0.49599 (14)	0.53990 (8)	0.31130 (12)	0.0584 (3)
O3	0.75052 (13)	0.58388 (7)	0.42341 (11)	0.0547 (3)
N1	0.65534 (17)	0.10432 (8)	0.39661 (14)	0.0547 (4)
N2	0.89391 (15)	0.22476 (8)	0.53250 (12)	0.0451 (3)
N3	0.85200 (18)	0.40066 (10)	0.48778 (14)	0.0488 (4)
N4	0.3948 (2)	0.95519 (10)	0.25288 (17)	0.0605 (4)
C1	0.7944 (2)	0.07923 (11)	0.48214 (17)	0.0551 (4)
H1	0.8129	0.0191	0.4978	0.066*
C2	0.6363 (2)	0.19190 (10)	0.38044 (16)	0.0475 (4)
H2A	0.5414	0.2134	0.3215	0.057*
C3	0.75314 (16)	0.25135 (9)	0.44858 (13)	0.0373 (3)
C4	0.9121 (2)	0.13802 (10)	0.54852 (16)	0.0529 (4)
H4	1.0076	0.1163	0.6066	0.063*
C5	0.72558 (17)	0.34889 (9)	0.43164 (13)	0.0380 (3)
C6	0.60904 (18)	0.60223 (9)	0.35883 (14)	0.0406 (4)
C7	0.54941 (17)	0.69295 (9)	0.32778 (13)	0.0372 (3)
C8	0.65468 (18)	0.76301 (10)	0.37902 (15)	0.0451 (4)
H8	0.7618	0.7514	0.4309	0.054*
C9	0.60351 (19)	0.84909 (10)	0.35450 (15)	0.0484 (4)
H9	0.6759	0.8948	0.3909	0.058*
C10	0.44456 (18)	0.86920 (10)	0.27581 (14)	0.0422 (4)
C11	0.33981 (19)	0.79880 (10)	0.22312 (15)	0.0460 (4)
H11	0.2337	0.8103	0.1696	0.055*
C12	0.39059 (18)	0.71314 (10)	0.24887 (14)	0.0426 (4)
H12	0.3179	0.6674	0.2131	0.051*
H4A	0.298 (3)	0.9642 (13)	0.202 (2)	0.081 (7)*
H4B	0.473 (3)	1.0005 (15)	0.2937 (19)	0.082 (6)*
H2	0.542 (3)	0.4823 (14)	0.3382 (19)	0.083 (6)*
H3B	0.950 (2)	0.3760 (11)	0.5277 (17)	0.060 (5)*
H3A	0.837 (2)	0.4591 (13)	0.4714 (17)	0.064 (5)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.0417 (6)	0.0360 (6)	0.0704 (7)	−0.0004 (5)	−0.0064 (5)	0.0005 (5)
O2	0.0449 (6)	0.0371 (7)	0.0844 (9)	−0.0027 (5)	−0.0109 (6)	0.0000 (6)
O3	0.0421 (6)	0.0372 (6)	0.0755 (8)	0.0038 (5)	−0.0117 (6)	0.0005 (5)
N1	0.0577 (9)	0.0353 (8)	0.0681 (9)	−0.0031 (6)	0.0054 (7)	−0.0065 (6)
N2	0.0433 (7)	0.0393 (7)	0.0500 (8)	0.0030 (6)	0.0029 (6)	−0.0009 (6)
N3	0.0412 (7)	0.0333 (7)	0.0669 (9)	−0.0011 (6)	−0.0042 (6)	−0.0042 (6)
N4	0.0533 (9)	0.0428 (9)	0.0800 (11)	0.0099 (7)	−0.0015 (8)	0.0122 (8)
C1	0.0617 (11)	0.0332 (9)	0.0699 (11)	0.0065 (8)	0.0116 (9)	−0.0003 (8)
C2	0.0448 (9)	0.0380 (9)	0.0567 (10)	0.0015 (7)	0.0018 (7)	−0.0016 (7)
C3	0.0362 (7)	0.0363 (8)	0.0396 (8)	0.0005 (6)	0.0083 (6)	−0.0020 (6)
C4	0.0522 (9)	0.0419 (9)	0.0605 (10)	0.0102 (8)	0.0004 (8)	0.0027 (8)
C5	0.0368 (8)	0.0352 (8)	0.0410 (8)	−0.0006 (6)	0.0055 (6)	−0.0023 (6)
C6	0.0364 (8)	0.0376 (8)	0.0462 (9)	−0.0009 (6)	0.0039 (7)	−0.0024 (7)
C7	0.0340 (7)	0.0372 (8)	0.0396 (8)	0.0012 (6)	0.0050 (6)	0.0014 (6)
C8	0.0355 (8)	0.0402 (9)	0.0544 (9)	0.0042 (6)	−0.0040 (7)	0.0013 (7)
C9	0.0416 (8)	0.0362 (8)	0.0623 (10)	−0.0006 (7)	−0.0022 (7)	−0.0003 (7)
C10	0.0406 (8)	0.0392 (8)	0.0470 (9)	0.0062 (7)	0.0092 (7)	0.0073 (7)
C11	0.0343 (8)	0.0499 (10)	0.0500 (9)	0.0045 (7)	−0.0014 (7)	0.0092 (7)
C12	0.0354 (8)	0.0422 (9)	0.0472 (9)	−0.0028 (6)	0.0006 (6)	0.0026 (7)

Geometric parameters (Å, º)

O1—C5	1.2405 (16)	C2—C3	1.383 (2)
O2—C6	1.3287 (17)	C2—H2A	0.9300
O2—H2	0.97 (2)	C3—C5	1.496 (2)
O3—C6	1.2218 (17)	C4—H4	0.9300
N1—C1	1.328 (2)	C6—C7	1.467 (2)
N1—C2	1.340 (2)	C7—C8	1.390 (2)
N2—C4	1.327 (2)	C7—C12	1.396 (2)
N2—C3	1.3360 (17)	C8—C9	1.372 (2)
N3—C5	1.3133 (18)	C8—H8	0.9300
N3—H3A	0.90 (2)	C9—C10	1.396 (2)
N3—H3B	0.887 (18)	C9—H9	0.9300
N4—C10	1.366 (2)	C10—C11	1.395 (2)
N4—H4A	0.85 (2)	C11—C12	1.368 (2)
N4—H4B	0.96 (2)	C11—H11	0.9300
C1—C4	1.373 (2)	C12—H12	0.9300
C1—H1	0.9300
C6—O2—H2	109.4 (12)	N3—C5—C3	116.92 (12)
C1—N1—C2	115.13 (14)	O3—C6—O2	121.66 (13)
C4—N2—C3	115.82 (13)	O3—C6—C7	123.75 (13)
C5—N3—H3A	116.1 (11)	O2—C6—C7	114.59 (12)
C5—N3—H3B	118.6 (11)	C8—C7—C12	117.68 (13)
H3A—N3—H3B	124.6 (16)	C8—C7—C6	119.02 (12)
C10—N4—H4A	117.6 (14)	C12—C7—C6	123.31 (13)
C10—N4—H4B	117.2 (13)	C9—C8—C7	121.20 (13)
H4A—N4—H4B	125.2 (19)	C9—C8—H8	119.4
N1—C1—C4	122.97 (15)	C7—C8—H8	119.4
N1—C1—H1	118.5	C8—C9—C10	121.07 (14)
C4—C1—H1	118.5	C8—C9—H9	119.5
N1—C2—C3	122.09 (15)	C10—C9—H9	119.5
N1—C2—H2A	119.0	N4—C10—C11	121.86 (14)
C3—C2—H2A	119.0	N4—C10—C9	120.46 (15)
N2—C3—C2	121.90 (14)	C11—C10—C9	117.69 (14)
N2—C3—C5	117.24 (12)	C12—C11—C10	121.06 (14)
C2—C3—C5	120.86 (13)	C12—C11—H11	119.5
N2—C4—C1	122.08 (15)	C10—C11—H11	119.5
N2—C4—H4	119.0	C11—C12—C7	121.30 (14)
C1—C4—H4	119.0	C11—C12—H12	119.4
O1—C5—N3	123.92 (13)	C7—C12—H12	119.4
O1—C5—C3	119.15 (12)
C2—N1—C1—C4	−0.7 (2)	O2—C6—C7—C8	176.59 (13)
C1—N1—C2—C3	−0.3 (2)	O3—C6—C7—C12	176.98 (14)
C4—N2—C3—C2	−1.6 (2)	O2—C6—C7—C12	−3.2 (2)
C4—N2—C3—C5	177.99 (13)	C12—C7—C8—C9	0.8 (2)
N1—C2—C3—N2	1.5 (2)	C6—C7—C8—C9	−178.96 (14)
N1—C2—C3—C5	−178.06 (14)	C7—C8—C9—C10	−0.8 (2)
C3—N2—C4—C1	0.6 (2)	C8—C9—C10—N4	179.57 (15)
N1—C1—C4—N2	0.6 (3)	C8—C9—C10—C11	0.0 (2)
N2—C3—C5—O1	−171.12 (12)	N4—C10—C11—C12	−178.90 (15)
C2—C3—C5—O1	8.5 (2)	C9—C10—C11—C12	0.6 (2)
N2—C3—C5—N3	8.25 (19)	C10—C11—C12—C7	−0.6 (2)
C2—C3—C5—N3	−172.18 (13)	C8—C7—C12—C11	−0.2 (2)
O3—C6—C7—C8	−3.2 (2)	C6—C7—C12—C11	179.60 (14)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O2—H2···O1	0.97 (2)	1.65 (2)	2.6102 (15)	168.3 (19)
N3—H3A···O3	0.90 (2)	2.04 (2)	2.9259 (18)	167.7 (16)
N3—H3B···O3^i	0.887 (18)	2.413 (17)	3.1201 (18)	136.9 (14)
C8—H8···N2^i	0.93	2.71	3.5277 (19)	147
N4—H4A···O2^ii	0.86 (2)	2.58 (2)	3.3026 (19)	143.1 (17)
C11—H11···O1^ii	0.93	2.69	3.5354 (18)	152
N4—H4B···N1^iii	0.96 (2)	2.26 (2)	3.221 (2)	177.9 (17)
C4—H4···O1^iv	0.93	2.64	3.312 (2)	130

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

(2) 4-(Pyrazine-2-carboxamido)benzoic acid

Crystal data

C12H9N3O3	Z = 2
Mr = 243.22	F(000) = 252
Triclinic, P1	Dx = 1.497 Mg m^−3
a = 6.0535 (5) Å	Mo Kα radiation, λ = 0.71073 Å
b = 7.4159 (6) Å	Cell parameters from 1404 reflections
c = 13.2548 (10) Å	θ = 3.1–30.2°
α = 85.612 (5)°	µ = 0.11 mm^−1
β = 81.900 (5)°	T = 296 K
γ = 66.398 (5)°	Plate, colourless
V = 539.69 (7) Å^3	0.36 × 0.28 × 0.21 mm

Data collection

Bruker APEXII CCD area-detector diffractometer	1908 independent reflections
Radiation source: fine-focus sealed tube	1383 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.041
φ and ω scans	θmax = 25.0°, θmin = 3.0°
Absorption correction: multi-scan (SADABS; Bruker, 2006)	h = −7→7
Tmin = 0.961, Tmax = 0.977	k = −8→8
5721 measured reflections	l = −15→15

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.054	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.134	H atoms treated by a mixture of independent and constrained refinement
S = 1.06	w = 1/[σ^2(Fo^2) + (0.056P)^2 + 0.1999P] where P = (Fo^2 + 2Fc^2)/3
1908 reflections	(Δ/σ)max < 0.001
164 parameters	Δρmax = 0.20 e Å^−3
0 restraints	Δρmin = −0.31 e Å^−3

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 (Ų)

	x	y	z	Uiso*/Ueq
O1	0.3068 (4)	0.5923 (3)	0.60290 (14)	0.0585 (6)
O2	0.7036 (4)	0.5203 (3)	0.58201 (14)	0.0580 (6)
O3	0.8121 (3)	0.7531 (3)	1.06954 (13)	0.0507 (5)
N1	0.4345 (4)	0.7768 (3)	1.04650 (15)	0.0356 (5)
N2	0.2723 (4)	0.8881 (3)	1.24129 (15)	0.0394 (5)
N3	0.5818 (4)	0.9261 (3)	1.36829 (16)	0.0488 (6)
C1	0.4945 (5)	0.5782 (4)	0.63617 (18)	0.0393 (6)
C2	0.4886 (4)	0.6281 (3)	0.74272 (17)	0.0336 (6)
C3	0.2664 (4)	0.7013 (4)	0.80398 (18)	0.0384 (6)
H3	0.1254	0.7169	0.7775	0.046*
C4	0.2531 (4)	0.7505 (4)	0.90277 (17)	0.0373 (6)
H4	0.1030	0.8014	0.9423	0.045*
C5	0.4617 (4)	0.7252 (3)	0.94433 (17)	0.0322 (6)
C6	0.6860 (4)	0.6489 (4)	0.88418 (17)	0.0359 (6)
H6	0.8276	0.6300	0.9111	0.043*
C7	0.6960 (4)	0.6017 (4)	0.78455 (17)	0.0369 (6)
H7	0.8457	0.5510	0.7447	0.044*
C8	0.6007 (4)	0.7877 (3)	1.10190 (17)	0.0338 (6)
C9	0.5042 (4)	0.8502 (3)	1.20937 (17)	0.0318 (6)
C10	0.1968 (5)	0.9456 (4)	1.33738 (19)	0.0464 (7)
H10	0.0360	0.9730	1.3633	0.056*
C11	0.3490 (5)	0.9657 (4)	1.39924 (19)	0.0503 (7)
H11	0.2867	1.0087	1.4654	0.060*
C12	0.6572 (5)	0.8673 (4)	1.27259 (18)	0.0411 (6)
H12	0.8191	0.8367	1.2473	0.049*
H1	0.296 (5)	0.801 (4)	1.082 (2)	0.043 (8)*
H2	0.702 (6)	0.482 (5)	0.5229 (17)	0.092 (12)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.0531 (12)	0.0902 (16)	0.0368 (10)	−0.0302 (11)	−0.0046 (9)	−0.0215 (10)
O2	0.0511 (12)	0.0898 (15)	0.0308 (10)	−0.0246 (11)	0.0045 (9)	−0.0216 (10)
O3	0.0382 (11)	0.0790 (14)	0.0387 (10)	−0.0269 (10)	0.0037 (8)	−0.0181 (9)
N1	0.0320 (11)	0.0504 (13)	0.0241 (10)	−0.0163 (10)	0.0011 (8)	−0.0074 (9)
N2	0.0382 (12)	0.0539 (14)	0.0282 (11)	−0.0204 (10)	0.0001 (9)	−0.0085 (9)
N3	0.0513 (15)	0.0691 (16)	0.0323 (12)	−0.0294 (13)	−0.0030 (10)	−0.0110 (11)
C1	0.0458 (16)	0.0442 (16)	0.0304 (13)	−0.0202 (13)	−0.0019 (12)	−0.0062 (11)
C2	0.0383 (14)	0.0365 (14)	0.0293 (12)	−0.0178 (11)	−0.0033 (10)	−0.0038 (10)
C3	0.0339 (14)	0.0518 (16)	0.0334 (13)	−0.0203 (13)	−0.0053 (11)	−0.0026 (11)
C4	0.0316 (13)	0.0508 (16)	0.0305 (12)	−0.0185 (12)	0.0038 (10)	−0.0077 (11)
C5	0.0381 (14)	0.0348 (14)	0.0262 (12)	−0.0182 (11)	0.0013 (10)	−0.0037 (10)
C6	0.0310 (13)	0.0449 (15)	0.0319 (13)	−0.0141 (12)	−0.0028 (10)	−0.0091 (11)
C7	0.0324 (13)	0.0459 (15)	0.0303 (13)	−0.0139 (12)	0.0045 (10)	−0.0120 (11)
C8	0.0355 (14)	0.0328 (14)	0.0313 (13)	−0.0126 (11)	0.0011 (11)	−0.0035 (10)
C9	0.0357 (13)	0.0333 (13)	0.0268 (12)	−0.0146 (11)	−0.0009 (10)	−0.0034 (10)
C10	0.0421 (15)	0.0667 (19)	0.0307 (13)	−0.0228 (14)	0.0059 (11)	−0.0128 (12)
C11	0.0590 (18)	0.072 (2)	0.0274 (13)	−0.0330 (16)	0.0018 (12)	−0.0142 (13)
C12	0.0407 (15)	0.0518 (17)	0.0342 (13)	−0.0210 (13)	−0.0041 (11)	−0.0075 (12)

Geometric parameters (Å, º)

O1—C1	1.240 (3)	C3—C4	1.369 (3)
O2—C1	1.289 (3)	C3—H3	0.9300
O2—H2	0.855 (19)	C4—C5	1.386 (3)
O3—C8	1.220 (3)	C4—H4	0.9300
N1—C8	1.355 (3)	C5—C6	1.396 (3)
N1—C5	1.406 (3)	C6—C7	1.379 (3)
N1—H1	0.86 (3)	C6—H6	0.9300
N2—C9	1.327 (3)	C7—H7	0.9300
N2—C10	1.333 (3)	C8—C9	1.495 (3)
N3—C11	1.329 (3)	C9—C12	1.381 (3)
N3—C12	1.330 (3)	C10—C11	1.373 (4)
C1—C2	1.479 (3)	C10—H10	0.9300
C2—C7	1.380 (3)	C11—H11	0.9300
C2—C3	1.392 (3)	C12—H12	0.9300
C1—O2—H2	113 (2)	C7—C6—C5	119.5 (2)
C8—N1—C5	129.6 (2)	C7—C6—H6	120.2
C8—N1—H1	112.3 (17)	C5—C6—H6	120.2
C5—N1—H1	118.1 (18)	C6—C7—C2	121.4 (2)
C9—N2—C10	115.9 (2)	C6—C7—H7	119.3
C11—N3—C12	115.3 (2)	C2—C7—H7	119.3
O1—C1—O2	123.2 (2)	O3—C8—N1	124.8 (2)
O1—C1—C2	120.8 (2)	O3—C8—C9	120.7 (2)
O2—C1—C2	115.9 (2)	N1—C8—C9	114.5 (2)
C7—C2—C3	118.5 (2)	N2—C9—C12	121.8 (2)
C7—C2—C1	122.5 (2)	N2—C9—C8	118.8 (2)
C3—C2—C1	119.0 (2)	C12—C9—C8	119.4 (2)
C4—C3—C2	120.8 (2)	N2—C10—C11	122.0 (2)
C4—C3—H3	119.6	N2—C10—H10	119.0
C2—C3—H3	119.6	C11—C10—H10	119.0
C3—C4—C5	120.6 (2)	N3—C11—C10	122.5 (2)
C3—C4—H4	119.7	N3—C11—H11	118.7
C5—C4—H4	119.7	C10—C11—H11	118.7
C4—C5—C6	119.2 (2)	N3—C12—C9	122.5 (2)
C4—C5—N1	117.5 (2)	N3—C12—H12	118.8
C6—C5—N1	123.3 (2)	C9—C12—H12	118.8
O1—C1—C2—C7	175.5 (2)	C1—C2—C7—C6	−179.8 (2)
O2—C1—C2—C7	−4.4 (4)	C5—N1—C8—O3	0.3 (4)
O1—C1—C2—C3	−3.3 (4)	C5—N1—C8—C9	179.4 (2)
O2—C1—C2—C3	176.8 (2)	C10—N2—C9—C12	0.7 (4)
C7—C2—C3—C4	1.6 (4)	C10—N2—C9—C8	−179.1 (2)
C1—C2—C3—C4	−179.5 (2)	O3—C8—C9—N2	179.4 (2)
C2—C3—C4—C5	−1.1 (4)	N1—C8—C9—N2	0.2 (3)
C3—C4—C5—C6	0.1 (4)	O3—C8—C9—C12	−0.5 (4)
C3—C4—C5—N1	−179.3 (2)	N1—C8—C9—C12	−179.7 (2)
C8—N1—C5—C4	−171.8 (2)	C9—N2—C10—C11	0.4 (4)
C8—N1—C5—C6	8.9 (4)	C12—N3—C11—C10	0.7 (4)
C4—C5—C6—C7	0.5 (4)	N2—C10—C11—N3	−1.2 (5)
N1—C5—C6—C7	179.8 (2)	C11—N3—C12—C9	0.5 (4)
C5—C6—C7—C2	−0.1 (4)	N2—C9—C12—N3	−1.3 (4)
C3—C2—C7—C6	−1.0 (4)	C8—C9—C12—N3	178.6 (2)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O2—H2···O1^i	0.86 (2)	1.81 (2)	2.666 (3)	178 (4)
C11—H11···N3^ii	0.93	2.59	3.365 (3)	142
C4—H4···O3^iii	0.93	2.38	3.212 (3)	149

Symmetry codes: (i) −x+1, −y+1, −z+1; (ii) −x+1, −y+2, −z+3; (iii) x−1, y, z.