Supra­molecular hydrogen-bonding patterns in 1:1 cocrystals of 5-fluoro­uracil with 4-methyl­benzoic acid and 3-nitro­benzoic acid

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.

Computing details

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)

Crystal data

C8H8O2·C4H3FN2O2	F(000) = 552
Mr = 266.23	Dx = 1.536 Mg m^−3
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71073 Å
a = 13.6345 (15) Å	Cell parameters from 2342 reflections
b = 6.9015 (7) Å	θ = 3.1–26.4°
c = 12.6905 (14) Å	µ = 0.13 mm^−1
β = 105.429 (4)°	T = 100 K
V = 1151.1 (2) Å^3	Prism, colorless
Z = 4	0.44 × 0.04 × 0.04 mm

Data collection

Rigaku AFC-8S diffractometer	1678 reflections with I > 2σ(I)
Radiation source: fine focus sealed tube	Rint = 0.079
ω scans	θmax = 26.4°, θmin = 3.1°
Absorption correction: multi-scan multi-scan	h = −17→16
Tmin = 0.946, Tmax = 0.995	k = −7→8
9799 measured reflections	l = −15→15
2342 independent reflections

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: mixed
R[F^2 > 2σ(F^2)] = 0.048	H atoms treated by a mixture of independent and constrained refinement
wR(F^2) = 0.120	w = 1/[σ^2(Fo^2) + (0.0601P)^2 + 0.1554P] where P = (Fo^2 + 2Fc^2)/3
S = 1.05	(Δ/σ)max < 0.001
2342 reflections	Δρmax = 0.35 e Å^−3
183 parameters	Δρmin = −0.30 e Å^−3
0 restraints	Extinction correction: SHELXL2016 (Sheldrick 2015), Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.013 (3)

Special details

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 (Ų)

	x	y	z	Uiso*/Ueq
F5	0.10468 (8)	0.05054 (17)	0.15449 (9)	0.0211 (3)
N3	0.36334 (12)	0.2174 (2)	0.22730 (13)	0.0146 (4)
O1	0.51204 (10)	0.0516 (2)	0.25019 (12)	0.0180 (4)
N1	0.36319 (12)	−0.1161 (2)	0.21398 (13)	0.0132 (4)
O4	0.62655 (10)	−0.0178 (2)	0.03616 (11)	0.0212 (4)
O2	0.21597 (11)	0.3903 (2)	0.20567 (11)	0.0199 (4)
O3	0.52852 (10)	0.2460 (2)	0.00029 (13)	0.0244 (4)
H3A	0.482273	0.162287	−0.009283	0.037*
C4	0.25757 (15)	0.2345 (3)	0.20563 (15)	0.0150 (5)
C12	0.69405 (15)	0.4884 (3)	0.02979 (15)	0.0156 (5)
H12	0.627936	0.542261	0.003245	0.019*
C6	0.25836 (15)	−0.1185 (3)	0.18795 (15)	0.0143 (5)
H6	0.222590	−0.237967	0.174487	0.017*
C14	0.61661 (15)	0.1611 (3)	0.02805 (15)	0.0163 (5)
C11	0.77881 (15)	0.6068 (3)	0.04931 (15)	0.0165 (5)
H11	0.770087	0.742067	0.036260	0.020*
C5	0.20752 (15)	0.0481 (3)	0.18179 (15)	0.0143 (5)
C10	0.87688 (15)	0.5318 (3)	0.08776 (16)	0.0166 (5)
C2	0.41836 (15)	0.0506 (3)	0.23211 (15)	0.0135 (5)
C7	0.70591 (15)	0.2900 (3)	0.04916 (15)	0.0143 (5)
C9	0.88797 (15)	0.3329 (3)	0.10711 (15)	0.0170 (5)
H9	0.954088	0.278901	0.133197	0.020*
C13	0.96810 (15)	0.6628 (3)	0.10798 (17)	0.0235 (5)
H13A	1.030147	0.586473	0.136170	0.035*
H13B	0.963260	0.762054	0.161614	0.035*
H13C	0.970342	0.725394	0.039336	0.035*
C8	0.80330 (15)	0.2134 (3)	0.08858 (16)	0.0165 (5)
H8	0.811801	0.078425	0.102873	0.020*
H3	0.4000 (17)	0.327 (4)	0.2393 (17)	0.027 (6)*
H1	0.4017 (16)	−0.228 (3)	0.2232 (18)	0.027 (6)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
F5	0.0124 (7)	0.0201 (7)	0.0294 (7)	0.0016 (5)	0.0031 (5)	0.0016 (5)
N3	0.0147 (9)	0.0075 (9)	0.0216 (9)	0.0000 (7)	0.0046 (7)	−0.0001 (7)
O1	0.0125 (8)	0.0124 (8)	0.0294 (8)	−0.0003 (6)	0.0059 (6)	−0.0006 (6)
N1	0.0138 (9)	0.0076 (9)	0.0189 (9)	0.0020 (7)	0.0054 (7)	0.0006 (7)
O4	0.0179 (8)	0.0127 (8)	0.0321 (9)	0.0003 (6)	0.0052 (7)	−0.0001 (7)
O2	0.0223 (8)	0.0122 (8)	0.0254 (8)	0.0059 (6)	0.0068 (6)	0.0008 (6)
O3	0.0122 (8)	0.0176 (8)	0.0416 (9)	−0.0012 (6)	0.0043 (7)	0.0004 (7)
C4	0.0201 (12)	0.0136 (11)	0.0124 (10)	0.0021 (8)	0.0061 (9)	0.0022 (8)
C12	0.0170 (11)	0.0150 (10)	0.0149 (10)	0.0030 (8)	0.0046 (8)	0.0002 (8)
C6	0.0165 (11)	0.0133 (11)	0.0141 (10)	−0.0050 (8)	0.0058 (8)	−0.0015 (8)
C14	0.0161 (12)	0.0164 (12)	0.0162 (10)	0.0018 (8)	0.0042 (8)	−0.0005 (8)
C11	0.0198 (12)	0.0140 (11)	0.0164 (10)	0.0005 (8)	0.0061 (8)	0.0004 (8)
C5	0.0122 (11)	0.0157 (11)	0.0158 (10)	0.0013 (8)	0.0049 (8)	0.0008 (8)
C10	0.0185 (11)	0.0196 (12)	0.0130 (9)	−0.0033 (9)	0.0065 (8)	−0.0027 (9)
C2	0.0168 (12)	0.0099 (11)	0.0143 (10)	0.0000 (8)	0.0052 (8)	0.0011 (8)
C7	0.0168 (11)	0.0146 (10)	0.0127 (9)	−0.0002 (8)	0.0062 (8)	−0.0015 (8)
C9	0.0159 (11)	0.0189 (11)	0.0163 (10)	0.0019 (9)	0.0043 (8)	−0.0020 (9)
C13	0.0211 (12)	0.0224 (13)	0.0271 (12)	−0.0040 (9)	0.0065 (10)	−0.0011 (10)
C8	0.0205 (12)	0.0128 (10)	0.0168 (10)	0.0023 (9)	0.0060 (9)	−0.0006 (8)

Geometric parameters (Å, º)

F5—C5	1.352 (2)	C12—H12	0.9500
N3—C2	1.367 (3)	C6—C5	1.334 (3)
N3—C4	1.399 (3)	C6—H6	0.9500
N3—H3	0.90 (3)	C14—C7	1.474 (3)
O1—C2	1.236 (2)	C11—C10	1.395 (3)
N1—C2	1.360 (2)	C11—H11	0.9500
N1—C6	1.379 (3)	C10—C9	1.395 (3)
N1—H1	0.92 (2)	C10—C13	1.504 (3)
O4—C14	1.243 (3)	C7—C8	1.393 (3)
O2—C4	1.216 (2)	C9—C8	1.387 (3)
O3—C14	1.298 (2)	C9—H9	0.9500
O3—H3A	0.8400	C13—H13A	0.9800
C4—C5	1.450 (3)	C13—H13B	0.9800
C12—C11	1.383 (3)	C13—H13C	0.9800
C12—C7	1.393 (3)	C8—H8	0.9500
C2—N3—C4	127.20 (17)	C6—C5—C4	122.96 (19)
C2—N3—H3	115.4 (15)	F5—C5—C4	116.14 (17)
C4—N3—H3	117.4 (15)	C11—C10—C9	118.39 (18)
C2—N1—C6	122.83 (17)	C11—C10—C13	120.57 (19)
C2—N1—H1	114.5 (14)	C9—C10—C13	121.04 (19)
C6—N1—H1	122.7 (14)	O1—C2—N1	122.25 (18)
C14—O3—H3A	109.5	O1—C2—N3	122.11 (18)
O2—C4—N3	122.08 (18)	N1—C2—N3	115.64 (18)
O2—C4—C5	126.24 (19)	C8—C7—C12	119.43 (18)
N3—C4—C5	111.67 (17)	C8—C7—C14	119.92 (19)
C11—C12—C7	119.80 (18)	C12—C7—C14	120.65 (18)
C11—C12—H12	120.1	C8—C9—C10	120.59 (19)
C7—C12—H12	120.1	C8—C9—H9	119.7
C5—C6—N1	119.55 (18)	C10—C9—H9	119.7
C5—C6—H6	120.2	C10—C13—H13A	109.5
N1—C6—H6	120.2	C10—C13—H13B	109.5
O4—C14—O3	122.92 (18)	H13A—C13—H13B	109.5
O4—C14—C7	121.18 (17)	C10—C13—H13C	109.5
O3—C14—C7	115.90 (18)	H13A—C13—H13C	109.5
C12—C11—C10	121.39 (19)	H13B—C13—H13C	109.5
C12—C11—H11	119.3	C9—C8—C7	120.4 (2)
C10—C11—H11	119.3	C9—C8—H8	119.8
C6—C5—F5	120.89 (18)	C7—C8—H8	119.8

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···O1^i	0.92	1.90	2.819 (2)	176
N3—H3···O1^ii	0.90	1.94	2.834 (2)	172
O3—H3A···O4^iii	0.84	1.74	2.578 (2)	171
C9—H9···F5^iv	0.95	2.55	3.456 (2)	161
C11—H11···O4^v	0.95	2.56	3.296 (3)	134
C12—H12···O3^vi	0.95	2.58	3.478 (3)	159

Symmetry codes: (i) −x+1, y−1/2, −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)

Crystal data

C7H5NO4·C4H3FN2O2	Z = 2
Mr = 297.20	F(000) = 304
Triclinic, P1	Dx = 1.594 Mg m^−3
a = 5.9011 (12) Å	Mo Kα radiation, λ = 0.71073 Å
b = 9.795 (2) Å	Cell parameters from 2561 reflections
c = 11.674 (2) Å	θ = 3.4–26.7°
α = 110.76 (3)°	µ = 0.14 mm^−1
β = 91.84 (3)°	T = 293 K
γ = 99.59 (3)°	Prism, colorless
V = 619.1 (2) Å^3	0.62 × 0.11 × 0.11 mm

Data collection

Rigaku AFC-8S diffractometer	2105 reflections with I > 2σ(I)
Radiation source: fine focus sealed tube	Rint = 0.016
ω scans	θmax = 26.7°, θmin = 3.4°
Absorption correction: multi-scan multi-scan	h = −7→7
Tmin = 0.918, Tmax = 0.985	k = −12→12
5924 measured reflections	l = −13→14
2561 independent reflections

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)] = 0.066	Hydrogen site location: mixed
wR(F^2) = 0.205	H atoms treated by a mixture of independent and constrained refinement
S = 1.04	w = 1/[σ^2(Fo^2) + (0.139P)^2 + 0.1069P] where P = (Fo^2 + 2Fc^2)/3
2561 reflections	(Δ/σ)max < 0.001
202 parameters	Δρmax = 0.49 e Å^−3
0 restraints	Δρmin = −0.29 e Å^−3

Special details

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 (Ų)

	x	y	z	Uiso*/Ueq
O4	0.7981 (3)	1.20390 (19)	0.71123 (19)	0.0755 (5)
O5	0.5941 (3)	0.68971 (16)	0.42494 (14)	0.0612 (4)
O6	0.2576 (3)	0.55509 (17)	0.43764 (17)	0.0732 (5)
N4	0.6148 (3)	1.19743 (19)	0.75797 (17)	0.0592 (5)
C7	0.4468 (3)	1.0562 (2)	0.71008 (17)	0.0490 (5)
C8	0.5065 (3)	0.9385 (2)	0.61646 (17)	0.0464 (4)
H8A	0.6484	0.9482	0.5848	0.056*
C9	0.3480 (3)	0.80524 (19)	0.57124 (16)	0.0458 (4)
C10	0.1374 (3)	0.7928 (2)	0.62048 (19)	0.0534 (5)
H10A	0.0318	0.7034	0.5900	0.064*
C11	0.0838 (4)	0.9126 (3)	0.7145 (2)	0.0598 (5)
H11	−0.0576	0.9033	0.7466	0.072*
C12	0.2403 (4)	1.0471 (2)	0.7612 (2)	0.0563 (5)
H12A	0.2065	1.1281	0.8248	0.068*
C13	0.4139 (3)	0.6788 (2)	0.47154 (18)	0.0505 (5)
F5	1.1001 (2)	0.32118 (16)	0.00619 (14)	0.0804 (5)
O1	0.3609 (3)	0.33000 (16)	0.25901 (15)	0.0620 (4)
O2	0.7579 (3)	0.07189 (15)	−0.04578 (14)	0.0600 (4)
N1	0.7020 (3)	0.45115 (18)	0.22568 (17)	0.0546 (5)
N3	0.5619 (3)	0.20428 (17)	0.10662 (15)	0.0481 (4)
C2	0.5314 (3)	0.3299 (2)	0.20078 (19)	0.0493 (4)
C4	0.7460 (3)	0.1895 (2)	0.03648 (17)	0.0481 (4)
C5	0.9166 (3)	0.3250 (2)	0.0697 (2)	0.0550 (5)
C6	0.8921 (4)	0.4504 (2)	0.1614 (2)	0.0553 (5)
H6A	1.0040	0.5363	0.1810	0.066*
O3	0.5638 (4)	1.3022 (2)	0.84047 (18)	0.0830 (6)
H1	0.662 (5)	0.531 (4)	0.286 (3)	0.078 (8)*
H3	0.457 (5)	0.132 (4)	0.086 (3)	0.072 (8)*
H6	0.327 (6)	0.476 (5)	0.384 (4)	0.109 (12)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O4	0.0695 (10)	0.0523 (9)	0.0873 (12)	−0.0055 (7)	0.0026 (9)	0.0127 (9)
O5	0.0591 (8)	0.0438 (7)	0.0644 (9)	0.0044 (6)	0.0208 (7)	0.0014 (6)
O6	0.0726 (10)	0.0399 (8)	0.0835 (12)	−0.0038 (7)	0.0305 (8)	−0.0014 (7)
N4	0.0742 (11)	0.0383 (8)	0.0542 (9)	0.0064 (7)	−0.0030 (8)	0.0063 (7)
C7	0.0568 (10)	0.0379 (9)	0.0452 (9)	0.0066 (7)	0.0015 (8)	0.0079 (7)
C8	0.0496 (9)	0.0399 (9)	0.0455 (9)	0.0071 (7)	0.0058 (7)	0.0110 (7)
C9	0.0506 (9)	0.0379 (9)	0.0429 (9)	0.0067 (7)	0.0073 (7)	0.0082 (7)
C10	0.0501 (10)	0.0457 (10)	0.0557 (11)	0.0040 (7)	0.0082 (8)	0.0099 (8)
C11	0.0508 (10)	0.0600 (12)	0.0630 (12)	0.0138 (8)	0.0165 (9)	0.0134 (10)
C12	0.0630 (11)	0.0476 (10)	0.0510 (10)	0.0181 (8)	0.0095 (8)	0.0056 (8)
C13	0.0553 (10)	0.0381 (9)	0.0507 (10)	0.0067 (7)	0.0104 (8)	0.0077 (8)
F5	0.0730 (9)	0.0635 (9)	0.0768 (9)	−0.0036 (7)	0.0348 (7)	−0.0029 (7)
O1	0.0598 (8)	0.0408 (7)	0.0690 (9)	0.0033 (6)	0.0231 (7)	0.0019 (6)
O2	0.0668 (9)	0.0395 (7)	0.0568 (8)	0.0049 (6)	0.0165 (7)	−0.0013 (6)
N1	0.0565 (9)	0.0340 (8)	0.0584 (10)	0.0028 (6)	0.0152 (7)	0.0009 (7)
N3	0.0517 (9)	0.0324 (7)	0.0491 (8)	0.0025 (6)	0.0086 (7)	0.0036 (6)
C2	0.0516 (9)	0.0360 (8)	0.0525 (10)	0.0072 (7)	0.0090 (8)	0.0070 (7)
C4	0.0546 (10)	0.0367 (9)	0.0432 (9)	0.0076 (7)	0.0072 (7)	0.0031 (7)
C5	0.0521 (10)	0.0453 (10)	0.0563 (11)	0.0031 (8)	0.0140 (8)	0.0069 (8)
C6	0.0562 (11)	0.0405 (9)	0.0540 (10)	−0.0028 (7)	0.0087 (8)	0.0040 (8)
O3	0.1112 (14)	0.0448 (8)	0.0696 (11)	0.0085 (8)	0.0050 (10)	−0.0042 (8)

Geometric parameters (Å, º)

O4—N4	1.229 (3)	C11—H11	0.9300
O5—C13	1.216 (2)	C12—H12A	0.9300
O6—C13	1.319 (2)	F5—C5	1.330 (2)
O6—H6	0.97 (5)	O1—C2	1.232 (2)
N4—O3	1.222 (3)	O2—C4	1.225 (2)
N4—C7	1.473 (3)	N1—C2	1.359 (3)
C7—C12	1.377 (3)	N1—C6	1.369 (3)
C7—C8	1.384 (3)	N1—H1	0.92 (4)
C8—C9	1.389 (3)	N3—C2	1.372 (3)
C8—H8A	0.9300	N3—C4	1.377 (3)
C9—C10	1.391 (3)	N3—H3	0.82 (3)
C9—C13	1.485 (3)	C4—C5	1.446 (3)
C10—C11	1.383 (3)	C5—C6	1.346 (3)
C10—H10A	0.9300	C6—H6A	0.9300
C11—C12	1.392 (3)
C13—O6—H6	107 (2)	O5—C13—O6	123.48 (18)
O3—N4—O4	123.5 (2)	O5—C13—C9	122.82 (17)
O3—N4—C7	118.5 (2)	O6—C13—C9	113.70 (17)
O4—N4—C7	117.94 (18)	C2—N1—C6	122.97 (17)
C12—C7—C8	123.37 (18)	C2—N1—H1	109.4 (19)
C12—C7—N4	118.71 (18)	C6—N1—H1	127.4 (19)
C8—C7—N4	117.92 (18)	C2—N3—C4	126.74 (16)
C7—C8—C9	117.92 (18)	C2—N3—H3	117 (2)
C7—C8—H8A	121.0	C4—N3—H3	116 (2)
C9—C8—H8A	121.0	O1—C2—N1	123.08 (18)
C8—C9—C10	120.07 (18)	O1—C2—N3	121.32 (17)
C8—C9—C13	117.70 (17)	N1—C2—N3	115.59 (17)
C10—C9—C13	122.22 (17)	O2—C4—N3	121.89 (17)
C11—C10—C9	120.45 (18)	O2—C4—C5	124.85 (19)
C11—C10—H10A	119.8	N3—C4—C5	113.26 (16)
C9—C10—H10A	119.8	F5—C5—C6	121.00 (18)
C10—C11—C12	120.41 (19)	F5—C5—C4	117.38 (18)
C10—C11—H11	119.8	C6—C5—C4	121.63 (19)
C12—C11—H11	119.8	C5—C6—N1	119.80 (18)
C7—C12—C11	117.78 (19)	C5—C6—H6A	120.1
C7—C12—H12A	121.1	N1—C6—H6A	120.1
C11—C12—H12A	121.1

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···O5	0.92 (4)	1.92 (3)	2.831 (3)	174 (3)
N3—H3···O2^i	0.82 (4)	2.07 (4)	2.870 (2)	168 (3)
O6—H6···O1	0.97 (4)	1.69 (6)	2.618 (3)	160 (4)
C6—H6A···O4^ii	0.93	2.46	3.349 (3)	159
C12—H12A···F5^iii	0.93	2.47	3.394 (3)	173

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