New polymorphs of an old drug: conformational and synthon polymorphism of 5-nitrofurazone

Two new polymorphic forms of 5-nitrofurazone (5-nitro-2-furaldehyde semicarbazone) have been synthesized and structurally characterized by single-crystal and powder X-ray diffraction methods, vibrational spectroscopy (FT–IR and temperature Raman), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and Hirshfeld surface analysis. The compound crystallizes in three different polymorphic forms P2₁/a (polymorph α), P2₁ (polymorph β) and P2₁/c (polymorph γ), the crystal structures of two of which (polymorphs β and γ) represent new structure determinations. The solid-state molecular organization in the three crystal forms is analyzed and discussed in terms of molecular conformation, crystal packing and hydrogen-bonded networks. All three crystals are formed from trans geometrical isomers, but the molecular conformation of the α-polymorph is syn–anti–anti–anti, while that of β- and γ-polymorphs is syn–anti–syn–syn. As a consequence of this the hydrogen-bond donor and acceptor sites of the molecules are oriented differently, which in turn results in different hydrogen-bond connectivity and packing patterns.

Computing details

For both compounds, data collection: Oxford Diffraction (2010). CrysAlis CCD, Version 1.171.33.42; cell refinement: Oxford Diffraction (2010). CrysAlis RED, Version 1.171.33.42; data reduction: Oxford Diffraction (2010). CrysAlis RED, Version 1.171.33.42; program(s) used to solve structure: SHELXS97 (Sheldrick, 1990); program(s) used to refine structure: SHELXL2014/7 (Sheldrick, 2015); molecular graphics: Brandenburg & Putz (2006). Diamond 3.0. Crystal and Molecular Structure Visualisation, University of Bonn, Germany; software used to prepare material for publication: SHELXL2014/7 (Sheldrick, 2015).

(1066p)

Crystal data

C6H6N4O4	F(000) = 204
Mr = 198.15	Dx = 1.547 Mg m^−3 Dm = 1.54 Mg m^−3 Dm measured by floatation
Monoclinic, P21	Mo Kα radiation, λ = 0.71073 Å
a = 4.1964 (3) Å	Cell parameters from 1345 reflections
b = 7.0129 (5) Å	θ = 3.0–29.4°
c = 14.4528 (10) Å	µ = 0.13 mm^−1
β = 90.924 (7)°	T = 295 K
V = 425.28 (5) Å^3	Parallelepiped, yellow
Z = 2	0.24 × 0.22 × 0.16 mm

Data collection

KUMA KM-4 CCD diffractometer	1893 independent reflections
Radiation source: fine-focus sealed tube	1386 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.020
Detector resolution: 1024x1024 with blocks 2x2 pixels mm^-1	θmax = 29.4°, θmin = 2.8°
ω–scan	h = −5→5
Absorption correction: numerical Oxford Diffraction (2010). CrysAlis Red, Version 1.171.33.42	k = −7→9
Tmin = 0.974, Tmax = 0.984	l = −19→19
5895 measured reflections

Refinement

Refinement on F^2	Hydrogen site location: mixed
Least-squares matrix: full	H atoms treated by a mixture of independent and constrained refinement
R[F^2 > 2σ(F^2)] = 0.032	w = 1/[σ^2(Fo^2) + (0.027P)^2] where P = (Fo^2 + 2Fc^2)/3
wR(F^2) = 0.059	(Δ/σ)max < 0.001
S = 1.00	Δρmax = 0.10 e Å^−3
1893 reflections	Δρmin = −0.10 e Å^−3
136 parameters	Absolute structure: Flack x determined using 449 quotients [(I+)-(I-)]/[(I+)+(I-)] (Parsons, Flack and Wagner, Acta Cryst. B69 (2013) 249-259).
1 restraint	Absolute structure parameter: −0.1 (1)

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.

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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
O1	0.4383 (3)	0.3386 (2)	0.22542 (8)	0.0459 (3)
C1	0.6066 (5)	0.3173 (4)	0.14708 (13)	0.0459 (5)
C2	0.5733 (5)	0.1441 (4)	0.10957 (14)	0.0566 (6)
H2	0.6671	0.0992	0.0559	0.068*
C3	0.3674 (5)	0.0438 (4)	0.16786 (14)	0.0542 (6)
H3	0.2976	−0.0812	0.1605	0.065*
C4	0.2904 (4)	0.1661 (3)	0.23720 (12)	0.0412 (5)
N1	0.7921 (5)	0.4765 (3)	0.12053 (13)	0.0609 (5)
O2	0.9453 (4)	0.4585 (3)	0.04943 (11)	0.0849 (6)
O3	0.7958 (5)	0.6193 (3)	0.16871 (13)	0.0914 (6)
C5	0.0920 (4)	0.1536 (3)	0.31757 (12)	0.0411 (5)
H5	0.0562	0.2599	0.3544	0.049*
N2	−0.0334 (3)	−0.0075 (2)	0.33688 (10)	0.0415 (4)
N3	−0.2195 (4)	−0.0118 (2)	0.41303 (11)	0.0432 (4)
H1	−0.276 (5)	0.095 (3)	0.4419 (14)	0.052*
C6	−0.3527 (5)	−0.1777 (3)	0.44125 (12)	0.0433 (5)
O4	−0.5107 (4)	−0.17866 (19)	0.51261 (9)	0.0526 (4)
N4	−0.3018 (6)	−0.3317 (3)	0.39040 (16)	0.0697 (6)
H41	−0.207 (6)	−0.327 (4)	0.3380 (17)	0.084*
H42	−0.387 (6)	−0.439 (4)	0.4090 (17)	0.084*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.0465 (7)	0.0500 (9)	0.0415 (7)	0.0037 (7)	0.0135 (6)	0.0046 (7)
C1	0.0392 (10)	0.0605 (13)	0.0384 (10)	0.0064 (12)	0.0114 (9)	0.0094 (12)
C2	0.0458 (11)	0.0825 (18)	0.0419 (11)	0.0076 (13)	0.0105 (10)	−0.0077 (14)
C3	0.0510 (12)	0.0594 (14)	0.0525 (12)	0.0008 (11)	0.0090 (11)	−0.0110 (11)
C4	0.0364 (9)	0.0448 (12)	0.0423 (11)	0.0035 (10)	0.0014 (9)	0.0011 (11)
N1	0.0581 (11)	0.0729 (14)	0.0521 (11)	0.0063 (11)	0.0154 (10)	0.0172 (11)
O2	0.0801 (11)	0.1127 (16)	0.0629 (10)	0.0028 (11)	0.0343 (9)	0.0236 (10)
O3	0.1134 (14)	0.0678 (13)	0.0942 (13)	−0.0168 (11)	0.0420 (12)	0.0029 (12)
C5	0.0405 (9)	0.0437 (13)	0.0394 (10)	0.0038 (11)	0.0062 (9)	0.0016 (11)
N2	0.0402 (9)	0.0436 (11)	0.0408 (9)	0.0056 (8)	0.0088 (8)	0.0027 (8)
N3	0.0507 (9)	0.0359 (11)	0.0435 (9)	0.0037 (9)	0.0149 (8)	−0.0014 (8)
C6	0.0542 (11)	0.0338 (10)	0.0422 (11)	0.0051 (11)	0.0080 (9)	0.0031 (11)
O4	0.0757 (9)	0.0357 (8)	0.0471 (7)	−0.0004 (9)	0.0224 (7)	0.0025 (7)
N4	0.1099 (17)	0.0356 (11)	0.0650 (12)	−0.0034 (11)	0.0421 (12)	−0.0020 (10)

Geometric parameters (Å, º)

O1—C1	1.352 (2)	N1—O2	1.228 (2)
O1—C4	1.372 (3)	C5—N2	1.278 (3)
C1—C2	1.336 (3)	C5—H5	0.9300
C1—N1	1.418 (3)	N2—N3	1.360 (2)
C2—C3	1.405 (3)	N3—C6	1.357 (3)
C2—H2	0.9300	N3—H1	0.89 (2)
C3—C4	1.362 (3)	C6—O4	1.235 (2)
C3—H3	0.9300	C6—N4	1.326 (3)
C4—C5	1.443 (2)	N4—H41	0.86 (2)
N1—O3	1.220 (3)	N4—H42	0.88 (3)
C1—O1—C4	104.45 (18)	O2—N1—C1	116.3 (2)
C2—C1—O1	112.82 (19)	N2—C5—C4	118.33 (18)
C2—C1—N1	131.31 (19)	N2—C5—H5	120.8
O1—C1—N1	115.8 (2)	C4—C5—H5	120.8
C1—C2—C3	105.82 (19)	C5—N2—N3	116.11 (16)
C1—C2—H2	127.1	C6—N3—N2	120.47 (17)
C3—C2—H2	127.1	C6—N3—H1	117.7 (14)
C4—C3—C2	106.4 (2)	N2—N3—H1	121.5 (14)
C4—C3—H3	126.8	O4—C6—N4	123.5 (2)
C2—C3—H3	126.8	O4—C6—N3	119.02 (19)
C3—C4—O1	110.54 (17)	N4—C6—N3	117.47 (16)
C3—C4—C5	134.5 (2)	C6—N4—H41	123 (2)
O1—C4—C5	114.95 (16)	C6—N4—H42	117.5 (17)
O3—N1—O2	124.1 (2)	H41—N4—H42	120 (3)
O3—N1—C1	119.61 (18)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N3—H1···O4^i	0.89 (2)	1.94 (2)	2.817 (2)	166.6 (19)
N4—H41···O3^ii	0.86 (2)	2.48 (2)	3.255 (3)	151 (2)
N4—H42···O4^iii	0.88 (3)	2.07 (3)	2.922 (2)	162 (2)

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

(1061)

Crystal data

C6H6N4O4	F(000) = 408
Mr = 198.15	Dx = 1.592 Mg m^−3 Dm = 1.59 Mg m^−3 Dm measured by floatation
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71073 Å
a = 13.5703 (6) Å	Cell parameters from 1345 reflections
b = 7.8254 (3) Å	θ = 3.0–29.4°
c = 7.9677 (4) Å	µ = 0.14 mm^−1
β = 102.260 (4)°	T = 295 K
V = 826.82 (6) Å^3	Parallelepiped, orange
Z = 4	0.31 × 0.27 × 0.22 mm

Data collection

KUMA KM-4 with CCD detector diffractometer	2127 independent reflections
Radiation source: fine-focus sealed tube	1614 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.015
Detector resolution: 1024x1024 with blocks 2x2 pixels mm^-1	θmax = 29.4°, θmin = 3.0°
ω–scan	h = −18→17
Absorption correction: numerical Oxford Diffraction (2010). CrysAlis Red, Version 1.171.33.42	k = −10→10
Tmin = 0.961, Tmax = 0.976	l = −10→10
11142 measured reflections

Refinement

Refinement on F^2	0 restraints
Least-squares matrix: full	Hydrogen site location: mixed
R[F^2 > 2σ(F^2)] = 0.029	H atoms treated by a mixture of independent and constrained refinement
wR(F^2) = 0.081	w = 1/[σ^2(Fo^2) + (0.0523P)^2 + 0.0108P] where P = (Fo^2 + 2Fc^2)/3
S = 1.00	(Δ/σ)max = 0.001
2127 reflections	Δρmax = 0.13 e Å^−3
136 parameters	Δρmin = −0.17 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.

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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
O1	0.23439 (4)	0.16292 (7)	0.51987 (7)	0.03382 (16)
C1	0.15329 (6)	0.13258 (11)	0.58773 (11)	0.0340 (2)
C2	0.10884 (7)	0.27700 (12)	0.62574 (12)	0.0413 (2)
H2	0.0519	0.2863	0.6727	0.050*
C3	0.16699 (7)	0.41115 (12)	0.57904 (12)	0.0405 (2)
H3	0.1561	0.5276	0.5899	0.049*
C4	0.24227 (6)	0.33758 (11)	0.51490 (10)	0.03248 (19)
N1	0.12908 (6)	−0.04135 (10)	0.60652 (10)	0.0428 (2)
O2	0.05919 (6)	−0.07059 (11)	0.67792 (10)	0.0605 (2)
O3	0.17783 (7)	−0.15180 (9)	0.55223 (12)	0.0687 (3)
C5	0.32308 (6)	0.39903 (10)	0.44028 (11)	0.0338 (2)
H5	0.3657	0.3223	0.4018	0.041*
N2	0.33598 (5)	0.56055 (9)	0.42712 (9)	0.03357 (18)
N3	0.41281 (6)	0.60742 (9)	0.35253 (9)	0.03636 (19)
H3N	0.4528 (8)	0.5333 (14)	0.3129 (13)	0.044*
C6	0.43657 (7)	0.77623 (11)	0.34068 (11)	0.0361 (2)
O4	0.51014 (6)	0.81353 (9)	0.28090 (10)	0.0538 (2)
N4	0.37769 (7)	0.88891 (11)	0.39663 (13)	0.0512 (2)
H41	0.3235 (10)	0.8565 (15)	0.4398 (15)	0.061*
H42	0.3926 (9)	0.9933 (17)	0.3896 (15)	0.061*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.0349 (3)	0.0241 (3)	0.0465 (3)	−0.0035 (2)	0.0178 (3)	0.0008 (2)
C1	0.0336 (4)	0.0312 (4)	0.0402 (4)	−0.0067 (3)	0.0145 (4)	0.0015 (3)
C2	0.0396 (5)	0.0407 (5)	0.0493 (5)	−0.0024 (4)	0.0224 (4)	−0.0020 (4)
C3	0.0452 (5)	0.0290 (4)	0.0518 (5)	−0.0019 (4)	0.0206 (4)	−0.0026 (4)
C4	0.0365 (4)	0.0244 (4)	0.0379 (4)	−0.0041 (3)	0.0110 (3)	0.0006 (3)
N1	0.0426 (4)	0.0357 (4)	0.0527 (5)	−0.0115 (3)	0.0160 (4)	0.0039 (3)
O2	0.0564 (5)	0.0596 (5)	0.0735 (5)	−0.0212 (4)	0.0314 (4)	0.0094 (4)
O3	0.0774 (6)	0.0284 (4)	0.1119 (7)	−0.0068 (3)	0.0466 (5)	−0.0026 (4)
C5	0.0361 (4)	0.0262 (4)	0.0429 (5)	−0.0022 (3)	0.0165 (4)	0.0003 (3)
N2	0.0354 (4)	0.0277 (3)	0.0418 (4)	−0.0034 (3)	0.0176 (3)	0.0006 (3)
N3	0.0420 (4)	0.0228 (3)	0.0524 (4)	−0.0014 (3)	0.0284 (4)	−0.0009 (3)
C6	0.0378 (5)	0.0258 (4)	0.0470 (5)	−0.0018 (3)	0.0145 (4)	0.0058 (3)
O4	0.0472 (4)	0.0351 (4)	0.0885 (5)	−0.0040 (3)	0.0356 (4)	0.0141 (3)
N4	0.0582 (6)	0.0235 (4)	0.0803 (6)	0.0016 (4)	0.0335 (5)	−0.0002 (4)

Geometric parameters (Å, º)

O1—C1	1.3464 (10)	N1—O2	1.2266 (11)
O1—C4	1.3722 (10)	C5—N2	1.2834 (11)
C1—C2	1.3455 (13)	C5—H5	0.9300
C1—N1	1.4155 (11)	N2—N3	1.3557 (10)
C2—C3	1.4099 (13)	N3—C6	1.3678 (11)
C2—H2	0.9300	N3—H3N	0.896 (12)
C3—C4	1.3631 (13)	C6—O4	1.2291 (11)
C3—H3	0.9300	C6—N4	1.3289 (12)
C4—C5	1.4367 (12)	N4—H41	0.911 (13)
N1—O3	1.2221 (11)	N4—H42	0.846 (13)
C1—O1—C4	105.22 (6)	O2—N1—C1	116.62 (9)
C2—C1—O1	112.71 (7)	N2—C5—C4	119.52 (8)
C2—C1—N1	131.20 (8)	N2—C5—H5	120.2
O1—C1—N1	116.10 (8)	C4—C5—H5	120.2
C1—C2—C3	105.26 (8)	C5—N2—N3	115.67 (7)
C1—C2—H2	127.4	N2—N3—C6	120.41 (7)
C3—C2—H2	127.4	N2—N3—H3N	124.0 (7)
C4—C3—C2	106.89 (8)	C6—N3—H3N	115.6 (7)
C4—C3—H3	126.6	O4—C6—N4	124.62 (8)
C2—C3—H3	126.6	O4—C6—N3	118.62 (8)
C3—C4—O1	109.92 (7)	N4—C6—N3	116.76 (8)
C3—C4—C5	135.44 (9)	C6—N4—H41	122.2 (8)
O1—C4—C5	114.60 (7)	C6—N4—H42	116.7 (9)
O3—N1—O2	124.21 (8)	H41—N4—H42	121.2 (12)
O3—N1—C1	119.17 (8)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N3—H3N···O4^i	0.896 (12)	1.982 (12)	2.8258 (10)	156.3 (10)
N4—H41···O3^ii	0.911 (13)	2.338 (13)	3.2283 (13)	165.4 (11)

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