supplementary materials


gw2133 scheme

Acta Cryst. (2013). E69, o940    [ doi:10.1107/S1600536813013445 ]

Pyridine-4-carbaldehyde-fumaric acid (2/1)

B. Sandhu, S. Draguta, M. S. Fonari, M. Antipin and T. V. Timofeeva

Abstract top

In the title co-crystal, 2C6H5NO·C4H4O4, two crystallographically different hydrogen-bonded trimers are formed, one in which the components occupy general positions, and one generated by an inversion centre. This results in the uncommon situation of Z = 3 for a triclinic crystal. In the formula units, molecules are linked by O-H...N hydrogen bonds.

Comment top

The co-crystallization process is widely used to obtain new solid forms of active pharmaceutical ingredients (API) with enhanced physiochemical properties such as stability, dissolution rate, and solubility without altering their pharmacological behavior (Aakeroy et al. 2006; Desiraju, 2003). The pyridine-4-carboxaldehyde and fumaric acid are widely used in the biological and medicinal fields. Pyridine-4-carboxaldehyde is used as a starting material for the preparation of cytokine suppressive drugs to treat arthritis (Boehm et al. 1996). Fumaric acid is of interest since it is known to form supramolecular assemblies with N-aromatic bases (Batchelor et al.2000) and is generally regarded as safe (GRAS) in the list of pharmaceutically acceptable cocrystal formers. The asymmetric unit of the title compound contains three planar molecules of pyridine-4-carboxaldehyde, and one and a half molecules of fumaric acid. They comprise two crystallographically different H-bonded trimers (C6H5NO)2.(C4H4O4), one of which occupies general position, while another resides on an inversion center in the triclinic unit cell as shown in Fig. 1. In the fumaric acid molecules, the C22—O6, C19—O4, and C23—O8 bond distances of 1.220 (3) Å, 1.219 (2) Å, 1.215 (3) Å are much shorter than the C22—O7, C19—O5, and C23—O9 bond distances of 1.312 (3) Å, 1.318 (2) Å, and 1.317 (2) Å respectively, indicating the neutral carboxyl groups in the crystal structure (Liu et al. 2003). However, the carboxylic O—H-atoms are on their way to the pyridine nitrogen atoms as it follows from the increased O—H distances in comparison with the standard values (0.86 Å).

The dihedral angles between the planar pyridine rings and the mean planes of fumaric acid molecules are 19.2° and 22.2° in the first, and of 25.7° in the second formula units in the crystal structure.

In the trimer, the neutral entities are held together via two (COOH) H···N (pyridine) hydrogen-bonds forming a complementary ADA array. The slightly corrugated aggregates are packed in stacks as shown in Fig. 2. The crystal packing is further stabilized by the weak C—H···O intermolecular interactions with participation of carbonyl oxygen atoms.

Related literature top

For background to the synthetic procedure, see: Aakeroy et al. (2006); Desiraju (2003). For the use of pyridine-4-carboxaldehyde in cytokine suppressive drugs, see: Boehm et al. (1996). For molecular complexes of neutral pyridine derivatives and neutral fumaric acid, see: Bowes et al. (2003); Aakeroy et al. (2002, 2006, 2007); Batchelor et al. (2000). For a related structure, see: Liu et al. (2003).

Experimental top

Pyridine-4-carboxaldehyde (19.3 µL, 0.20 mmol) was dissolved in 5 ml of ethanol. To this solution was added fumaric acid (0.012 g, 0.10 mmol) in 5 mL of ethanol. The resulting solution was heated until the both compounds were dissolved completely and allowed to stand for slow evaporation. White prisms were obtained after 3 days. mp 215–220°C.

Refinement top

The hydrogen atoms of carboxylic groups of O5, O7 and O9 were localized in the difference-Fourier map and refined freely in isotropic approximation. The other hydrogen atoms were placed in calculated positions with C—H = 0.93 Å and refined in the riding model with fixed isotropic displacement parameters [Uiso(H) = 1.2Ueq(C)].

Computing details top

Data collection: APEX2 (Bruker, 2005); cell refinement: SAINT (Bruker, 2001); data reduction: SAINT (Bruker, 2001); program(s) used to solve structure: SHELXTL (Sheldrick, 2008); program(s) used to refine structure: SHELXTL (Sheldrick, 2008); molecular graphics: SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXTL (Sheldrick, 2008).

Figures top
[Figure 1] Fig. 1. The molecular structure of (C6H5NO)2.(C4H4O4) showing (50%) probablity displacement ellipsoids and the atoms numbering scheme.
[Figure 2] Fig. 2. Crystal packing showing intermolecular hydrogen bonding interactions, view along c axis.
Pyridine-4-carbaldehyde–fumaric acid (2/1) top
Crystal data top
2C6H5NO·C4H4O4Z = 3
Mr = 330.29F(000) = 516
Triclinic, P1Dx = 1.424 Mg m3
Hall symbol: -P 1Mo Kα radiation, λ = 0.71073 Å
a = 6.9388 (12) ÅCell parameters from 15620 reflections
b = 10.1962 (18) Åθ = 2.5–30.8°
c = 17.002 (3) ŵ = 0.11 mm1
α = 82.450 (3)°T = 100 K
β = 78.615 (3)°Prism, white
γ = 80.064 (3)°0.04 × 0.03 × 0.02 mm
V = 1155.6 (4) Å3
Data collection top
Bruker APEXII CCD
diffractometer
5022 independent reflections
Radiation source: fine-focus sealed tube4351 reflections with I > 2σ(I)
Graphite monochromatorRint = 0.018
φ and ω scansθmax = 27.0°, θmin = 2.0°
Absorption correction: multi-scan
(SADABS; Sheldrick, 2003)
h = 88
Tmin = 0.996, Tmax = 0.998k = 1313
11918 measured reflectionsl = 2121
Refinement top
Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.033Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.094H atoms treated by a mixture of independent and constrained refinement
S = 1.06 w = 1/[σ2(Fo2) + (0.0502P)2 + 0.2407P]
where P = (Fo2 + 2Fc2)/3
5022 reflections(Δ/σ)max = 0.001
337 parametersΔρmax = 0.30 e Å3
0 restraintsΔρmin = 0.24 e Å3
Crystal data top
2C6H5NO·C4H4O4γ = 80.064 (3)°
Mr = 330.29V = 1155.6 (4) Å3
Triclinic, P1Z = 3
a = 6.9388 (12) ÅMo Kα radiation
b = 10.1962 (18) ŵ = 0.11 mm1
c = 17.002 (3) ÅT = 100 K
α = 82.450 (3)°0.04 × 0.03 × 0.02 mm
β = 78.615 (3)°
Data collection top
Bruker APEXII CCD
diffractometer
5022 independent reflections
Absorption correction: multi-scan
(SADABS; Sheldrick, 2003)
4351 reflections with I > 2σ(I)
Tmin = 0.996, Tmax = 0.998Rint = 0.018
11918 measured reflectionsθmax = 27.0°
Refinement top
R[F2 > 2σ(F2)] = 0.033H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.094Δρmax = 0.30 e Å3
S = 1.06Δρmin = 0.24 e Å3
5022 reflectionsAbsolute structure: ?
337 parametersFlack parameter: ?
0 restraintsRogers parameter: ?
Special details top

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) top
xyzUiso*/Ueq
O10.03877 (12)0.13984 (9)0.93015 (5)0.02957 (19)
O30.32546 (12)0.76849 (8)0.60910 (4)0.02667 (18)
O20.31931 (13)0.49716 (8)0.26052 (5)0.02852 (19)
O80.41401 (12)0.85465 (8)0.13133 (4)0.02579 (18)
O90.53088 (12)1.02613 (8)0.16686 (4)0.02420 (18)
H9A0.497 (3)0.9765 (19)0.2235 (11)0.069 (6)*
O60.09363 (12)0.27889 (8)0.18081 (4)0.02574 (18)
O70.22987 (12)0.45738 (8)0.19320 (4)0.02386 (18)
O50.10344 (12)0.24097 (8)0.47468 (4)0.02441 (18)
H50.104 (3)0.222 (2)0.5358 (12)0.076 (6)*
O40.24013 (12)0.41873 (8)0.48845 (4)0.02556 (18)
N10.08206 (13)0.17896 (9)0.62885 (5)0.02060 (19)
N30.44019 (13)0.91008 (9)0.31230 (5)0.02018 (19)
N20.24664 (13)0.50591 (9)0.03924 (5)0.02043 (19)
C40.07788 (15)0.27059 (11)0.67926 (7)0.0227 (2)
H40.09190.35980.65730.027*
C30.05391 (15)0.24005 (11)0.76207 (6)0.0217 (2)
H30.05000.30720.79640.026*
C20.03570 (15)0.10889 (10)0.79403 (6)0.0192 (2)
C60.03953 (15)0.01376 (10)0.74200 (6)0.0204 (2)
H60.02650.07630.76220.024*
C50.06278 (15)0.05330 (11)0.65996 (6)0.0208 (2)
H5A0.06520.01150.62430.025*
C10.01669 (15)0.06833 (11)0.88228 (6)0.0231 (2)
H10.01450.01850.90200.028*
C160.40393 (15)0.97924 (10)0.37691 (6)0.0214 (2)
H160.40641.07300.36890.026*
C150.36315 (15)0.91885 (10)0.45471 (6)0.0207 (2)
H150.33470.97060.49930.025*
C140.36431 (14)0.78107 (10)0.46684 (6)0.0184 (2)
C180.40079 (15)0.70913 (10)0.40001 (6)0.0206 (2)
H180.40110.61510.40640.025*
C170.43668 (15)0.77782 (11)0.32371 (6)0.0216 (2)
H170.45960.72930.27790.026*
C130.33112 (15)0.71201 (11)0.55014 (6)0.0211 (2)
H130.31380.62050.55720.025*
C110.23959 (15)0.40809 (11)0.00530 (6)0.0219 (2)
H110.21560.32300.02130.026*
C120.26613 (15)0.42703 (10)0.08878 (6)0.0206 (2)
H120.26290.35580.11910.025*
C80.29763 (14)0.55274 (10)0.12722 (6)0.0188 (2)
C90.30255 (15)0.65446 (10)0.08099 (6)0.0203 (2)
H90.32240.74130.10590.024*
C100.27795 (15)0.62679 (10)0.00226 (6)0.0205 (2)
H100.28350.69570.03400.025*
C70.32694 (15)0.57964 (11)0.21668 (6)0.0214 (2)
H7A0.35290.66590.24050.026*
C230.48373 (15)0.95840 (10)0.11436 (6)0.0198 (2)
C240.52458 (16)1.02301 (11)0.03024 (6)0.0228 (2)
H240.58851.10030.02010.027*
C220.15105 (15)0.34887 (10)0.22167 (6)0.0192 (2)
C210.13369 (15)0.31551 (10)0.31054 (6)0.0202 (2)
H210.07090.24070.33470.024*
C200.20063 (15)0.38402 (10)0.35802 (6)0.0200 (2)
H200.26330.45900.33400.024*
C190.18294 (15)0.35002 (10)0.44683 (6)0.0193 (2)
H70.231 (3)0.471 (2)0.1308 (12)0.077 (6)*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
O10.0306 (4)0.0372 (5)0.0216 (4)0.0025 (3)0.0053 (3)0.0080 (3)
O30.0327 (4)0.0302 (4)0.0173 (4)0.0076 (3)0.0034 (3)0.0010 (3)
O20.0369 (5)0.0287 (4)0.0214 (4)0.0058 (3)0.0054 (3)0.0065 (3)
O80.0331 (4)0.0260 (4)0.0196 (4)0.0131 (3)0.0037 (3)0.0027 (3)
O90.0328 (4)0.0262 (4)0.0154 (4)0.0109 (3)0.0047 (3)0.0004 (3)
O60.0345 (4)0.0251 (4)0.0205 (4)0.0114 (3)0.0067 (3)0.0005 (3)
O70.0316 (4)0.0245 (4)0.0168 (4)0.0131 (3)0.0033 (3)0.0033 (3)
O50.0333 (4)0.0244 (4)0.0171 (4)0.0126 (3)0.0042 (3)0.0029 (3)
O40.0322 (4)0.0261 (4)0.0211 (4)0.0108 (3)0.0063 (3)0.0016 (3)
N10.0189 (4)0.0237 (5)0.0186 (4)0.0052 (3)0.0027 (3)0.0017 (3)
N30.0197 (4)0.0228 (4)0.0178 (4)0.0044 (3)0.0031 (3)0.0001 (3)
N20.0187 (4)0.0232 (5)0.0188 (4)0.0047 (3)0.0024 (3)0.0009 (3)
C40.0221 (5)0.0190 (5)0.0273 (5)0.0056 (4)0.0058 (4)0.0024 (4)
C30.0231 (5)0.0199 (5)0.0237 (5)0.0049 (4)0.0055 (4)0.0036 (4)
C20.0161 (5)0.0222 (5)0.0191 (5)0.0041 (4)0.0022 (4)0.0017 (4)
C60.0209 (5)0.0185 (5)0.0214 (5)0.0056 (4)0.0022 (4)0.0002 (4)
C50.0216 (5)0.0220 (5)0.0191 (5)0.0052 (4)0.0019 (4)0.0035 (4)
C10.0215 (5)0.0268 (5)0.0196 (5)0.0030 (4)0.0021 (4)0.0006 (4)
C160.0233 (5)0.0190 (5)0.0222 (5)0.0054 (4)0.0039 (4)0.0011 (4)
C150.0217 (5)0.0215 (5)0.0198 (5)0.0052 (4)0.0031 (4)0.0041 (4)
C140.0161 (5)0.0222 (5)0.0175 (5)0.0056 (4)0.0029 (4)0.0006 (4)
C180.0218 (5)0.0194 (5)0.0214 (5)0.0047 (4)0.0040 (4)0.0030 (4)
C170.0219 (5)0.0241 (5)0.0197 (5)0.0041 (4)0.0033 (4)0.0050 (4)
C130.0205 (5)0.0226 (5)0.0202 (5)0.0060 (4)0.0033 (4)0.0005 (4)
C110.0210 (5)0.0201 (5)0.0252 (5)0.0062 (4)0.0054 (4)0.0023 (4)
C120.0214 (5)0.0194 (5)0.0227 (5)0.0052 (4)0.0058 (4)0.0022 (4)
C80.0161 (5)0.0221 (5)0.0182 (5)0.0032 (4)0.0032 (4)0.0017 (4)
C90.0216 (5)0.0184 (5)0.0208 (5)0.0048 (4)0.0035 (4)0.0002 (4)
C100.0213 (5)0.0209 (5)0.0192 (5)0.0038 (4)0.0027 (4)0.0028 (4)
C70.0226 (5)0.0226 (5)0.0188 (5)0.0040 (4)0.0038 (4)0.0008 (4)
C230.0186 (5)0.0229 (5)0.0174 (5)0.0036 (4)0.0029 (4)0.0002 (4)
C240.0281 (5)0.0230 (5)0.0185 (5)0.0109 (4)0.0035 (4)0.0022 (4)
C220.0185 (5)0.0200 (5)0.0179 (5)0.0036 (4)0.0019 (4)0.0008 (4)
C210.0211 (5)0.0207 (5)0.0180 (5)0.0060 (4)0.0019 (4)0.0024 (4)
C200.0210 (5)0.0194 (5)0.0188 (5)0.0058 (4)0.0018 (4)0.0022 (4)
C190.0183 (5)0.0200 (5)0.0188 (5)0.0039 (4)0.0022 (4)0.0006 (4)
Geometric parameters (Å, º) top
O1—C11.2089 (14)C16—C151.3810 (14)
O3—C131.2109 (13)C16—H160.9500
O2—C71.2089 (13)C15—C141.3917 (15)
O8—C231.2155 (13)C15—H150.9500
O9—C231.3175 (13)C14—C181.3909 (14)
O9—H9A1.030 (19)C14—C131.4898 (14)
O6—C221.2199 (13)C18—C171.3890 (14)
O7—C221.3119 (12)C18—H180.9500
O7—H71.050 (19)C17—H170.9500
O5—C191.3171 (12)C13—H130.9500
O5—H51.03 (2)C11—C121.3866 (15)
O4—C191.2191 (13)C11—H110.9500
N1—C51.3388 (14)C12—C81.3921 (14)
N1—C41.3415 (14)C12—H120.9500
N3—C171.3408 (14)C8—C91.3897 (14)
N3—C161.3418 (13)C8—C71.4892 (14)
N2—C101.3403 (14)C9—C101.3888 (14)
N2—C111.3419 (14)C9—H90.9500
C4—C31.3846 (15)C10—H100.9500
C4—H40.9500C7—H7A0.9500
C3—C21.3928 (14)C23—C241.4888 (14)
C3—H30.9500C24—C24i1.309 (2)
C2—C61.3896 (14)C24—H240.9500
C2—C11.4890 (14)C22—C211.4900 (14)
C6—C51.3856 (14)C21—C201.3280 (15)
C6—H60.9500C21—H210.9500
C5—H5A0.9500C20—C191.4897 (14)
C1—H10.9500C20—H200.9500
C23—O9—H9A108.3 (10)O3—C13—C14122.26 (10)
C22—O7—H7107.3 (11)O3—C13—H13118.9
C19—O5—H5109.4 (11)C14—C13—H13118.9
C5—N1—C4118.60 (9)N2—C11—C12122.25 (9)
C17—N3—C16118.84 (9)N2—C11—H11118.9
C10—N2—C11119.23 (9)C12—C11—H11118.9
N1—C4—C3122.46 (10)C11—C12—C8118.55 (9)
N1—C4—H4118.8C11—C12—H12120.7
C3—C4—H4118.8C8—C12—H12120.7
C4—C3—C2118.67 (10)C9—C8—C12119.17 (9)
C4—C3—H3120.7C9—C8—C7119.64 (9)
C2—C3—H3120.7C12—C8—C7121.19 (9)
C6—C2—C3119.03 (9)C10—C9—C8118.76 (9)
C6—C2—C1119.58 (9)C10—C9—H9120.6
C3—C2—C1121.37 (9)C8—C9—H9120.6
C5—C6—C2118.45 (9)N2—C10—C9122.02 (9)
C5—C6—H6120.8N2—C10—H10119.0
C2—C6—H6120.8C9—C10—H10119.0
N1—C5—C6122.79 (9)O2—C7—C8123.27 (10)
N1—C5—H5A118.6O2—C7—H7A118.4
C6—C5—H5A118.6C8—C7—H7A118.4
O1—C1—C2123.58 (10)O8—C23—O9124.76 (9)
O1—C1—H1118.2O8—C23—C24122.67 (9)
C2—C1—H1118.2O9—C23—C24112.57 (9)
N3—C16—C15122.25 (10)C24i—C24—C23122.28 (12)
N3—C16—H16118.9C24i—C24—H24118.9
C15—C16—H16118.9C23—C24—H24118.9
C16—C15—C14119.04 (9)O6—C22—O7124.52 (9)
C16—C15—H15120.5O6—C22—C21120.91 (9)
C14—C15—H15120.5O7—C22—C21114.57 (9)
C15—C14—C18118.86 (9)C20—C21—C22123.99 (9)
C15—C14—C13120.32 (9)C20—C21—H21118.0
C18—C14—C13120.81 (9)C22—C21—H21118.0
C17—C18—C14118.51 (10)C21—C20—C19123.71 (9)
C17—C18—H18120.7C21—C20—H20118.1
C14—C18—H18120.7C19—C20—H20118.1
N3—C17—C18122.46 (9)O4—C19—O5124.32 (9)
N3—C17—H17118.8O4—C19—C20121.40 (9)
C18—C17—H17118.8O5—C19—C20114.27 (9)
Symmetry code: (i) x+1, y+2, z.
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O9—H9A···N31.030 (19)1.576 (19)2.6047 (12)176.1 (17)
O5—H5···N11.03 (2)1.57 (2)2.5952 (12)172.0 (18)
O7—H7···N21.050 (19)1.54 (2)2.5826 (12)172.9 (18)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O9—H9A···N31.030 (19)1.576 (19)2.6047 (12)176.1 (17)
O5—H5···N11.03 (2)1.57 (2)2.5952 (12)172.0 (18)
O7—H7···N21.050 (19)1.54 (2)2.5826 (12)172.9 (18)
Acknowledgements top

The authors are grateful for NSF support via DMR grant 0934212 (PREM) and CHE 0832622.)

references
References top

Aakeroy, C. B., Beatty, A. M. & Helfrich, B. A. (2002). J. Am. Chem. Soc. 124, 14425–14432.

Aakeroy, C. B., Hussain, I. & Desper, J. (2006). Cryst. Growth Des. 6, 474–480.

Aakeroy, C. B., Hussain, I., Forbes, S. & Desper, J. (2007). CrystEngComm, 9, 46–54.

Batchelor, E., Klinowski, J. & Jones, W. (2000). J. Mater. Chem. 10, 839–848.

Boehm, J. C., Smietana, J. M., Sorenson, M. E., Garigipati, R. S., Gallagher, T. F., Sheldrake, P. L., Bradbeer, J., Badger, A. M., Laydon, J. T., Lee, J. C., Hillegass, L. M., Griswold, D. E., Breton, J. J., Chabot-Fletcher, M. C. & Adams, J. L. (1996). J. Med. Chem. 39, 3929–3937.

Bowes, K. F., Ferguson, G., Lough, A. J. & Glidewell, C. (2003). Acta Cryst. B59, 100–117.

Bruker (2001). SAINT. Bruker AXS Inc., Madison, Wisconsin, USA.

Bruker (2005). APEX2. Bruker AXS Inc., Madison, Wisconsin, USA.

Desiraju, G. R. (2003). CrystEngComm, 5, 466–467.

Liu, Y., Xu, D.-J. & Hung, C.-H. (2003). Acta Cryst. E59, m297–m299.

Sheldrick, G. M. (2003). SADABS. Bruker AXS Inc., Madison, Wisconsin, USA.

Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122.