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The design of a pharmaceutical cocrystal is based on the identification of specific hydrogen-bond donor and acceptor groups in active pharmaceutical ingredients (APIs) in order to choose a `complementary inter­acting' mol­ecule that can act as an efficient coformer. 5-Fluoro­uracil (5FU) is a pyrimidine derivative with two N—H donors and C=O acceptors and shows a diversity of hydrogen-bonding motifs. Two 1:1 cocrystals of 5-fluoro­uracil (5FU), namely 5-fluoro­uracil–4-methyl­benzoic acid (5FU–MBA), C4H3FN2O2·C8H8O2, (I), and 5-fluoro­uracil–3-nitro­benzoic acid (5FU–NBA), C4H3FN2O2·C7H5NO4, (II), have been prepared and characterized by single-crystal X-ray diffraction. In (I), the MBA mol­ecules form carb­oxy­lic acid dimers [R22(8) homosynthon]. Similarly, the 5FU mol­ecules form two types of base pair via a pair of N—H...O hydrogen bonds [R22(8) homosynthon]. In (II), 5FU inter­acts with the carb­oxy­lic acid group of NBA via N—H...O and O—H...O hydrogen bonds, generating an R22(8) ring motif (heterosynthon). Furthermore, the 5FU mol­ecules form base pairs [R22(8) homosynthon] via N—H...O hydrogen bonds. Both of the crystal structures are stabilized by C—H...F interactions.

Supporting information

cif

Crystallographic Information File (CIF) https://doi.org/10.1107/S2053229617001486/ov3081sup1.cif
Contains datablocks I, II

hkl

Structure factor file (CIF format) https://doi.org/10.1107/S2053229617001486/ov3081Isup2.hkl
Contains datablock I

hkl

Structure factor file (CIF format) https://doi.org/10.1107/S2053229617001486/ov3081IIsup3.hkl
Contains datablock II

CCDC references: 1530032; 1530031

Computing details top

For both compounds, data collection: CrystalClear (Rigaku/MSC, 2008); cell refinement: CrystalClear (Rigaku/MSC, 2008); data reduction: CrystalClear (Rigaku/MSC, 2008). Program(s) used to solve structure: SHELXS97 (Sheldrick, 2008) for (I); SHELXL97 (Sheldrick, 2008) for (II). Program(s) used to refine structure: SHELXL2016 (Sheldrick, 2015) for (I); SHELXL2014 (Sheldrick, 2015) for (II). For both compounds, molecular graphics: PLATON (Spek, 2009), Mercury (Macrae et al., 2008) and POVRay (Cason, 2004); software used to prepare material for publication: PLATON (Spek, 2009) and publCIF (Westrip, 2010).

(I) 5-Fluorouracil–4-methylbenzoic acid (1/1) top
Crystal data top
C8H8O2·C4H3FN2O2F(000) = 552
Mr = 266.23Dx = 1.536 Mg m3
Monoclinic, P21/cMo Kα radiation, λ = 0.71073 Å
a = 13.6345 (15) ÅCell parameters from 2342 reflections
b = 6.9015 (7) Åθ = 3.1–26.4°
c = 12.6905 (14) ŵ = 0.13 mm1
β = 105.429 (4)°T = 100 K
V = 1151.1 (2) Å3Prism, colorless
Z = 40.44 × 0.04 × 0.04 mm
Data collection top
Rigaku AFC-8S
diffractometer
1678 reflections with I > 2σ(I)
Radiation source: fine focus sealed tubeRint = 0.079
ω scansθmax = 26.4°, θmin = 3.1°
Absorption correction: multi-scan
multi-scan
h = 1716
Tmin = 0.946, Tmax = 0.995k = 78
9799 measured reflectionsl = 1515
2342 independent reflections
Refinement top
Refinement on F2Secondary atom site location: difference Fourier map
Least-squares matrix: fullHydrogen site location: mixed
R[F2 > 2σ(F2)] = 0.048H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.120 w = 1/[σ2(Fo2) + (0.0601P)2 + 0.1554P]
where P = (Fo2 + 2Fc2)/3
S = 1.05(Δ/σ)max < 0.001
2342 reflectionsΔρmax = 0.35 e Å3
183 parametersΔρmin = 0.30 e Å3
0 restraintsExtinction correction: SHELXL2016 (Sheldrick 2015), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4
Primary atom site location: structure-invariant direct methodsExtinction coefficient: 0.013 (3)
Special details top

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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
F50.10468 (8)0.05054 (17)0.15449 (9)0.0211 (3)
N30.36334 (12)0.2174 (2)0.22730 (13)0.0146 (4)
O10.51204 (10)0.0516 (2)0.25019 (12)0.0180 (4)
N10.36319 (12)0.1161 (2)0.21398 (13)0.0132 (4)
O40.62655 (10)0.0178 (2)0.03616 (11)0.0212 (4)
O20.21597 (11)0.3903 (2)0.20567 (11)0.0199 (4)
O30.52852 (10)0.2460 (2)0.00029 (13)0.0244 (4)
H3A0.4822730.1622870.0092830.037*
C40.25757 (15)0.2345 (3)0.20563 (15)0.0150 (5)
C120.69405 (15)0.4884 (3)0.02979 (15)0.0156 (5)
H120.6279360.5422610.0032450.019*
C60.25836 (15)0.1185 (3)0.18795 (15)0.0143 (5)
H60.2225900.2379670.1744870.017*
C140.61661 (15)0.1611 (3)0.02805 (15)0.0163 (5)
C110.77881 (15)0.6068 (3)0.04931 (15)0.0165 (5)
H110.7700870.7420670.0362600.020*
C50.20752 (15)0.0481 (3)0.18179 (15)0.0143 (5)
C100.87688 (15)0.5318 (3)0.08776 (16)0.0166 (5)
C20.41836 (15)0.0506 (3)0.23211 (15)0.0135 (5)
C70.70591 (15)0.2900 (3)0.04916 (15)0.0143 (5)
C90.88797 (15)0.3329 (3)0.10711 (15)0.0170 (5)
H90.9540880.2789010.1331970.020*
C130.96810 (15)0.6628 (3)0.10798 (17)0.0235 (5)
H13A1.0301470.5864730.1361700.035*
H13B0.9632600.7620540.1616140.035*
H13C0.9703420.7253940.0393360.035*
C80.80330 (15)0.2134 (3)0.08858 (16)0.0165 (5)
H80.8118010.0784250.1028730.020*
H30.4000 (17)0.327 (4)0.2393 (17)0.027 (6)*
H10.4017 (16)0.228 (3)0.2232 (18)0.027 (6)*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
F50.0124 (7)0.0201 (7)0.0294 (7)0.0016 (5)0.0031 (5)0.0016 (5)
N30.0147 (9)0.0075 (9)0.0216 (9)0.0000 (7)0.0046 (7)0.0001 (7)
O10.0125 (8)0.0124 (8)0.0294 (8)0.0003 (6)0.0059 (6)0.0006 (6)
N10.0138 (9)0.0076 (9)0.0189 (9)0.0020 (7)0.0054 (7)0.0006 (7)
O40.0179 (8)0.0127 (8)0.0321 (9)0.0003 (6)0.0052 (7)0.0001 (7)
O20.0223 (8)0.0122 (8)0.0254 (8)0.0059 (6)0.0068 (6)0.0008 (6)
O30.0122 (8)0.0176 (8)0.0416 (9)0.0012 (6)0.0043 (7)0.0004 (7)
C40.0201 (12)0.0136 (11)0.0124 (10)0.0021 (8)0.0061 (9)0.0022 (8)
C120.0170 (11)0.0150 (10)0.0149 (10)0.0030 (8)0.0046 (8)0.0002 (8)
C60.0165 (11)0.0133 (11)0.0141 (10)0.0050 (8)0.0058 (8)0.0015 (8)
C140.0161 (12)0.0164 (12)0.0162 (10)0.0018 (8)0.0042 (8)0.0005 (8)
C110.0198 (12)0.0140 (11)0.0164 (10)0.0005 (8)0.0061 (8)0.0004 (8)
C50.0122 (11)0.0157 (11)0.0158 (10)0.0013 (8)0.0049 (8)0.0008 (8)
C100.0185 (11)0.0196 (12)0.0130 (9)0.0033 (9)0.0065 (8)0.0027 (9)
C20.0168 (12)0.0099 (11)0.0143 (10)0.0000 (8)0.0052 (8)0.0011 (8)
C70.0168 (11)0.0146 (10)0.0127 (9)0.0002 (8)0.0062 (8)0.0015 (8)
C90.0159 (11)0.0189 (11)0.0163 (10)0.0019 (9)0.0043 (8)0.0020 (9)
C130.0211 (12)0.0224 (13)0.0271 (12)0.0040 (9)0.0065 (10)0.0011 (10)
C80.0205 (12)0.0128 (10)0.0168 (10)0.0023 (9)0.0060 (9)0.0006 (8)
Geometric parameters (Å, º) top
F5—C51.352 (2)C12—H120.9500
N3—C21.367 (3)C6—C51.334 (3)
N3—C41.399 (3)C6—H60.9500
N3—H30.90 (3)C14—C71.474 (3)
O1—C21.236 (2)C11—C101.395 (3)
N1—C21.360 (2)C11—H110.9500
N1—C61.379 (3)C10—C91.395 (3)
N1—H10.92 (2)C10—C131.504 (3)
O4—C141.243 (3)C7—C81.393 (3)
O2—C41.216 (2)C9—C81.387 (3)
O3—C141.298 (2)C9—H90.9500
O3—H3A0.8400C13—H13A0.9800
C4—C51.450 (3)C13—H13B0.9800
C12—C111.383 (3)C13—H13C0.9800
C12—C71.393 (3)C8—H80.9500
C2—N3—C4127.20 (17)C6—C5—C4122.96 (19)
C2—N3—H3115.4 (15)F5—C5—C4116.14 (17)
C4—N3—H3117.4 (15)C11—C10—C9118.39 (18)
C2—N1—C6122.83 (17)C11—C10—C13120.57 (19)
C2—N1—H1114.5 (14)C9—C10—C13121.04 (19)
C6—N1—H1122.7 (14)O1—C2—N1122.25 (18)
C14—O3—H3A109.5O1—C2—N3122.11 (18)
O2—C4—N3122.08 (18)N1—C2—N3115.64 (18)
O2—C4—C5126.24 (19)C8—C7—C12119.43 (18)
N3—C4—C5111.67 (17)C8—C7—C14119.92 (19)
C11—C12—C7119.80 (18)C12—C7—C14120.65 (18)
C11—C12—H12120.1C8—C9—C10120.59 (19)
C7—C12—H12120.1C8—C9—H9119.7
C5—C6—N1119.55 (18)C10—C9—H9119.7
C5—C6—H6120.2C10—C13—H13A109.5
N1—C6—H6120.2C10—C13—H13B109.5
O4—C14—O3122.92 (18)H13A—C13—H13B109.5
O4—C14—C7121.18 (17)C10—C13—H13C109.5
O3—C14—C7115.90 (18)H13A—C13—H13C109.5
C12—C11—C10121.39 (19)H13B—C13—H13C109.5
C12—C11—H11119.3C9—C8—C7120.4 (2)
C10—C11—H11119.3C9—C8—H8119.8
C6—C5—F5120.89 (18)C7—C8—H8119.8
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N1—H1···O1i0.921.902.819 (2)176
N3—H3···O1ii0.901.942.834 (2)172
O3—H3A···O4iii0.841.742.578 (2)171
C9—H9···F5iv0.952.553.456 (2)161
C11—H11···O4v0.952.563.296 (3)134
C12—H12···O3vi0.952.583.478 (3)159
Symmetry codes: (i) x+1, y1/2, z+1/2; (ii) x+1, y+1/2, z+1/2; (iii) x+1, y, z; (iv) x+1, y, z; (v) x, y+1, z; (vi) x+1, y+1, z.
(II) 5-Fluorouracil–3-nitrobenzoic acid (1/1) top
Crystal data top
C7H5NO4·C4H3FN2O2Z = 2
Mr = 297.20F(000) = 304
Triclinic, P1Dx = 1.594 Mg m3
a = 5.9011 (12) ÅMo Kα radiation, λ = 0.71073 Å
b = 9.795 (2) ÅCell parameters from 2561 reflections
c = 11.674 (2) Åθ = 3.4–26.7°
α = 110.76 (3)°µ = 0.14 mm1
β = 91.84 (3)°T = 293 K
γ = 99.59 (3)°Prism, colorless
V = 619.1 (2) Å30.62 × 0.11 × 0.11 mm
Data collection top
Rigaku AFC-8S
diffractometer
2105 reflections with I > 2σ(I)
Radiation source: fine focus sealed tubeRint = 0.016
ω scansθmax = 26.7°, θmin = 3.4°
Absorption correction: multi-scan
multi-scan
h = 77
Tmin = 0.918, Tmax = 0.985k = 1212
5924 measured reflectionsl = 1314
2561 independent reflections
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)] = 0.066Hydrogen site location: mixed
wR(F2) = 0.205H atoms treated by a mixture of independent and constrained refinement
S = 1.04 w = 1/[σ2(Fo2) + (0.139P)2 + 0.1069P]
where P = (Fo2 + 2Fc2)/3
2561 reflections(Δ/σ)max < 0.001
202 parametersΔρmax = 0.49 e Å3
0 restraintsΔρmin = 0.29 e Å3
Special details top

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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
O40.7981 (3)1.20390 (19)0.71123 (19)0.0755 (5)
O50.5941 (3)0.68971 (16)0.42494 (14)0.0612 (4)
O60.2576 (3)0.55509 (17)0.43764 (17)0.0732 (5)
N40.6148 (3)1.19743 (19)0.75797 (17)0.0592 (5)
C70.4468 (3)1.0562 (2)0.71008 (17)0.0490 (5)
C80.5065 (3)0.9385 (2)0.61646 (17)0.0464 (4)
H8A0.64840.94820.58480.056*
C90.3480 (3)0.80524 (19)0.57124 (16)0.0458 (4)
C100.1374 (3)0.7928 (2)0.62048 (19)0.0534 (5)
H10A0.03180.70340.59000.064*
C110.0838 (4)0.9126 (3)0.7145 (2)0.0598 (5)
H110.05760.90330.74660.072*
C120.2403 (4)1.0471 (2)0.7612 (2)0.0563 (5)
H12A0.20651.12810.82480.068*
C130.4139 (3)0.6788 (2)0.47154 (18)0.0505 (5)
F51.1001 (2)0.32118 (16)0.00619 (14)0.0804 (5)
O10.3609 (3)0.33000 (16)0.25901 (15)0.0620 (4)
O20.7579 (3)0.07189 (15)0.04578 (14)0.0600 (4)
N10.7020 (3)0.45115 (18)0.22568 (17)0.0546 (5)
N30.5619 (3)0.20428 (17)0.10662 (15)0.0481 (4)
C20.5314 (3)0.3299 (2)0.20078 (19)0.0493 (4)
C40.7460 (3)0.1895 (2)0.03648 (17)0.0481 (4)
C50.9166 (3)0.3250 (2)0.0697 (2)0.0550 (5)
C60.8921 (4)0.4504 (2)0.1614 (2)0.0553 (5)
H6A1.00400.53630.18100.066*
O30.5638 (4)1.3022 (2)0.84047 (18)0.0830 (6)
H10.662 (5)0.531 (4)0.286 (3)0.078 (8)*
H30.457 (5)0.132 (4)0.086 (3)0.072 (8)*
H60.327 (6)0.476 (5)0.384 (4)0.109 (12)*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
O40.0695 (10)0.0523 (9)0.0873 (12)0.0055 (7)0.0026 (9)0.0127 (9)
O50.0591 (8)0.0438 (7)0.0644 (9)0.0044 (6)0.0208 (7)0.0014 (6)
O60.0726 (10)0.0399 (8)0.0835 (12)0.0038 (7)0.0305 (8)0.0014 (7)
N40.0742 (11)0.0383 (8)0.0542 (9)0.0064 (7)0.0030 (8)0.0063 (7)
C70.0568 (10)0.0379 (9)0.0452 (9)0.0066 (7)0.0015 (8)0.0079 (7)
C80.0496 (9)0.0399 (9)0.0455 (9)0.0071 (7)0.0058 (7)0.0110 (7)
C90.0506 (9)0.0379 (9)0.0429 (9)0.0067 (7)0.0073 (7)0.0082 (7)
C100.0501 (10)0.0457 (10)0.0557 (11)0.0040 (7)0.0082 (8)0.0099 (8)
C110.0508 (10)0.0600 (12)0.0630 (12)0.0138 (8)0.0165 (9)0.0134 (10)
C120.0630 (11)0.0476 (10)0.0510 (10)0.0181 (8)0.0095 (8)0.0056 (8)
C130.0553 (10)0.0381 (9)0.0507 (10)0.0067 (7)0.0104 (8)0.0077 (8)
F50.0730 (9)0.0635 (9)0.0768 (9)0.0036 (7)0.0348 (7)0.0029 (7)
O10.0598 (8)0.0408 (7)0.0690 (9)0.0033 (6)0.0231 (7)0.0019 (6)
O20.0668 (9)0.0395 (7)0.0568 (8)0.0049 (6)0.0165 (7)0.0013 (6)
N10.0565 (9)0.0340 (8)0.0584 (10)0.0028 (6)0.0152 (7)0.0009 (7)
N30.0517 (9)0.0324 (7)0.0491 (8)0.0025 (6)0.0086 (7)0.0036 (6)
C20.0516 (9)0.0360 (8)0.0525 (10)0.0072 (7)0.0090 (8)0.0070 (7)
C40.0546 (10)0.0367 (9)0.0432 (9)0.0076 (7)0.0072 (7)0.0031 (7)
C50.0521 (10)0.0453 (10)0.0563 (11)0.0031 (8)0.0140 (8)0.0069 (8)
C60.0562 (11)0.0405 (9)0.0540 (10)0.0028 (7)0.0087 (8)0.0040 (8)
O30.1112 (14)0.0448 (8)0.0696 (11)0.0085 (8)0.0050 (10)0.0042 (8)
Geometric parameters (Å, º) top
O4—N41.229 (3)C11—H110.9300
O5—C131.216 (2)C12—H12A0.9300
O6—C131.319 (2)F5—C51.330 (2)
O6—H60.97 (5)O1—C21.232 (2)
N4—O31.222 (3)O2—C41.225 (2)
N4—C71.473 (3)N1—C21.359 (3)
C7—C121.377 (3)N1—C61.369 (3)
C7—C81.384 (3)N1—H10.92 (4)
C8—C91.389 (3)N3—C21.372 (3)
C8—H8A0.9300N3—C41.377 (3)
C9—C101.391 (3)N3—H30.82 (3)
C9—C131.485 (3)C4—C51.446 (3)
C10—C111.383 (3)C5—C61.346 (3)
C10—H10A0.9300C6—H6A0.9300
C11—C121.392 (3)
C13—O6—H6107 (2)O5—C13—O6123.48 (18)
O3—N4—O4123.5 (2)O5—C13—C9122.82 (17)
O3—N4—C7118.5 (2)O6—C13—C9113.70 (17)
O4—N4—C7117.94 (18)C2—N1—C6122.97 (17)
C12—C7—C8123.37 (18)C2—N1—H1109.4 (19)
C12—C7—N4118.71 (18)C6—N1—H1127.4 (19)
C8—C7—N4117.92 (18)C2—N3—C4126.74 (16)
C7—C8—C9117.92 (18)C2—N3—H3117 (2)
C7—C8—H8A121.0C4—N3—H3116 (2)
C9—C8—H8A121.0O1—C2—N1123.08 (18)
C8—C9—C10120.07 (18)O1—C2—N3121.32 (17)
C8—C9—C13117.70 (17)N1—C2—N3115.59 (17)
C10—C9—C13122.22 (17)O2—C4—N3121.89 (17)
C11—C10—C9120.45 (18)O2—C4—C5124.85 (19)
C11—C10—H10A119.8N3—C4—C5113.26 (16)
C9—C10—H10A119.8F5—C5—C6121.00 (18)
C10—C11—C12120.41 (19)F5—C5—C4117.38 (18)
C10—C11—H11119.8C6—C5—C4121.63 (19)
C12—C11—H11119.8C5—C6—N1119.80 (18)
C7—C12—C11117.78 (19)C5—C6—H6A120.1
C7—C12—H12A121.1N1—C6—H6A120.1
C11—C12—H12A121.1
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N1—H1···O50.92 (4)1.92 (3)2.831 (3)174 (3)
N3—H3···O2i0.82 (4)2.07 (4)2.870 (2)168 (3)
O6—H6···O10.97 (4)1.69 (6)2.618 (3)160 (4)
C6—H6A···O4ii0.932.463.349 (3)159
C12—H12A···F5iii0.932.473.394 (3)173
Symmetry codes: (i) x+1, y, z; (ii) x+2, y+2, z+1; (iii) x1, y+1, z+1.
 

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