Powder diffraction study of the hydrogen bonds in nitroxoline and its hydrochloride

The crystal structures of 8-hydroxy-5-nitro­quinoline, C₉H₆N₂O₃, (I), and 8-hydroxy-5-nitro­quinolinium chloride, C₉H₇N₂O₃⁺·Cl^-, (II), have been determined from X-ray powder data. In (I), the mol­ecules are linked via moderately strong hydrogen bonds to form dimers. Such a packing motif is likely to be responsible for the low solubility of (I) in water. In (II), the inversion-related cations form stacks, and anions fill the interstack channels.

S1. Comment

Nitroxoline, or 8-hydroxy-5-nitroquinoline, (I), also known as 5NOK, shows antibacterial and fungicidal activity. In particular, it is used for the treatment of infections of the genito-urinary system. Compound (I) has low solubility in water, but its solubility increases considerably in alkalis and acids.

To date, it has not been clear whether the molecule of (I) in the crystal exists as the neutral form, or as a zwitterion resulting from proton transfer from the hydroxy group to the quinoline N atom. DFT (density functional theory) calculations for isolated molecules predict that the zwitterionic form is 31 kJ mol^-1 less stable than the neutral one. This difference, while significant, is not large enough to exclude the zwitterion from consideration, since it can be overshadowed by the effects of the medium. Query. However, visible spectroscopy, together with semi-empirical calculations on the INDO-CISD level (Dick & Nickel, 1983), gives strong evidence for the presence of the neutral molecule. Recently, the INDO-CISD technique was proven to be suitable for reproducing the spectra of nitronaphthalenoles (Yatsenko et al., 2001). For (I), INDO-CISD calculations predict that the neutral form should have its π–π absorption maximum in the near-UV region, at 307 nm. The protonation of the quinoline N atom shifts this band bathochromically by 40 nm, whereas in the case of the zwitterion, this maximum is shifted to 391 nm and a new absorption band appears at 635 nm. Thus, the zwitterion should absorb light essentially in the whole of the visible region. In practice, crystals of (I) are light yellow, with no absorption maximum in the visible region, and the hydrochloride salt, (II), is deeper in colour than (I), in full agreement with the results of the calculations for the neutral form and cation, and with the spectroscopic data for solutions (Ermakov et al., 1985). \sch

The molecule of (I) is nearly planar, the dihedral angle formed by the least squares planes through the naphthalene and nitro moieties being only 6.3 (4)°. The dihedral angle formed by the planes through the naphthalene moieties of adjacent molecules is 44.8 (5)°. Details of the hydrogen bonds are given in Table 1. Molecules related by the 2 axis form dimers, as shown in Fig. 1. We have carried out the DFT optimization of one such dimer, starting from the crystallographic geometry. The resulting geometry does not significantly differ from the experimental one. After the optimization, the angle subtended by two naphthalene moieties increased to 64° and the hydroxy group is twisted by 15° with respect to the naphthalene plane, thus facilitating the hydrogen bonding: the O8—H8···N1 angle increased to 155°, the C9—N1···H8 angle became 129° (versus 135° in the crystal) and the O···N distance was 0.07 Å shorter than in the crystal. The DFT-calculated energy of the dimer is 19.8 kJ mol^-1 lower than the energy of two isolated molecules of (I). This is an exaggerated estimation for the hydrogen-bonding energy in this dimer, owing to the basis-set superposition error.

The dimers in (I) form stacks along [001], with an interplanar distance of 3.446 (8) Å between two neighbouring naphthalene fragments. It is likely that, under the effect of stacking interactions, the dimers flatten in the crystal, at the cost of distortion of the hydrogen-bonding geometry.

In (II), the cations form stacks along [100] (Fig. 2), with interplanar distances of 3.341 (10) and 3.447 (10) Å. The nitro group is twisted by 12.4 (5)° with respect to the naphthalene moiety. The anions make short contacts to NH, OH and CH groups, which can be considered as hydrogen bonds (Table 2).

Table 1. Hydrogen bonds and short C—H···O contacts (Å, °) for (I)

Table 2. Hydrogen bonds and short C—H···Cl(O) contacts (Å, °) for (II)

S2. Experimental

Compound (I) was prepared by oxidation of 8-hydroxy-5-nitrosoquinoline by HNO₃, followed by recrystallization from ethanol, giving very thin needles. The sample obtained from aqueous solution gave an identical diffraction pattern, although of lower quality. Compound (II) was prepared by recrystallization of (I) from 5% HCl.

S3. Refinement

The DFT and INDO-CISD calculations were performed using programs provided by Dr D. N. Laikov (Laikov, 1997) and Professor B. Dick (Dick & Nickel, 1983), respectively. The DFT calculations were carried out using the BLYP (Becke-Lee-Yang-Parr) exchange-correlation function (Becke, 1988; Lee, Yang & Parr, 1988) with a triple zeta basis set, including polarization and diffuse functions for all atoms. The orthorhombic and monoclinic cell dimensions of (I) and (II) were determined with ITO (Visser, 1969) and TREOR90 (Werner et al., 1985), respectively, and refined to M₂₀ = 18 for (I) and 22 for (II), and F = 43 for (I) and 39 for (II), using the first 26 and 32 peak positions, respectively. The initial molecular models were built with MOPAC7 (Stewart, 1993) on the PM3 level (Stewart, 1989). In (I), the position and orientation of the molecule were determined using the grid-search procedure (Chernyshev & Schenk, 1998). In (II), the position and orientation of the cation and the position of the anion were determined using the simulated annealing procedure (Zhukov et al., 2001). The X-ray diffraction profiles and the differences between the measured and calculated profiles after the Rietveld refinement are shown in Figs. 3 and 4. The final R_B values were 0.067 for (I) and 0.076 for (II). The Cl atom was refined anisotropically; the C, N and O atoms were refined isotropically and were gathered together into groups with a common U_iso parameter for each group. The H atoms were placed in geometrically calculated positions and their isotropic displacement parameters were fixed. The planarity of the naphthalene fragments and the nitro groups was restrained. The anisotropy of the diffraction-line broadening was approximated by a quartic form in hkl (Popa, 1998). The standard uncertainties obtained from the Rietveld refinement were corrected for serial correlation effects (Bérar & Lelann, 1991).

Computing details

For both compounds, data collection: local program; cell refinement: LSPAID (Visser, 1986); program(s) used to solve structure: MRIA (Zlokazov & Chernyshev, 1992); program(s) used to refine structure: MRIA; molecular graphics: PLATON (Spek, 2001); software used to prepare material for publication: PARST (Nardelli, 1983).

Figures

	Fig. 1. The hydrogen-bonded dimers in (I) showing the atom-labelling scheme.
	Fig. 2. The Cl···H contacts in (II); the atom-labelling scheme is the same as for (I) in Fig. 1.
	Fig. 3. The Rietveld plot for (I) showing the observed and difference profiles. The reflection positions are shown above the difference profile. The high-angle area is magnified by a factor of 10.
	Fig. 4. The Rietveld plot for (II) showing the observed and difference profiles. The reflection positions are shown above the difference profile. The high-angle area is magnified by a factor of 10.

(I) 8-hydroxy-5-nitroquinoline

Crystal data

C9H6N2O3	F(000) = 1568
Mr = 190.16	Dx = 1.549 Mg m^−3
Orthorhombic, Fdd2	Cu Kα radiation, λ = 1.5418 Å
a = 28.049 (7) Å	T = 295 K
b = 31.198 (8) Å	Particle morphology: needle
c = 3.727 (1) Å	light yellow
V = 3261.4 (15) Å^3	flat sheet, 25 × 25 mm
Z = 16

Data collection

DRON-3M diffractometer (Burevestnik, Russia)	Data collection mode: reflection
Radiation source: X-ray sealed tube	Scan method: step
Ni filtered monochromator	2θmin = 7.90°, 2θmax = 70.0°, 2θstep = 0.02°
Specimen mounting: pressed as a thin layer in the specimen holder

Refinement

Refinement on Inet	92 parameters
Least-squares matrix: full with fixed elements per cycle	11 restraints
Rp = 0.035	0 constraints
Rwp = 0.048	H-atom parameters constrained
Rexp = 0.023	Weighting scheme based on measured s.u.'s
χ^2 = 4.427	(Δ/σ)max = 0.045
3151 data points	Background function: Chebyshev polynomial up to the 5th order
Excluded region(s): 7.00 - 7.88	Preferred orientation correction: Spherical harmonics (Ahtee et al., 1989)
Profile function: split-type pseudo-Voigt

Special details

Experimental. specimen was rotated in its plane

Refinement. H atoms were placed in calculated positions. The planarity of the naphthalene and nitro groups was restrained.

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

	x	y	z	Uiso*/Ueq
N1	0.04038 (10)	0.45902 (13)	−0.1163	0.0660 (13)*
C2	0.03319 (11)	0.41938 (14)	−0.2495 (14)	0.0660 (13)*
C3	0.07072 (12)	0.38965 (10)	−0.2867 (15)	0.0660 (13)*
C4	0.11631 (12)	0.39958 (12)	−0.1868 (13)	0.0660 (13)*
C5	0.16940 (11)	0.45789 (13)	0.0708 (18)	0.0660 (13)*
C6	0.17411 (10)	0.49972 (14)	0.2017 (18)	0.0660 (13)*
C7	0.13449 (11)	0.52722 (10)	0.2295 (13)	0.0660 (13)*
C8	0.09105 (12)	0.51330 (14)	0.1169 (16)	0.0660 (13)*
C9	0.08603 (12)	0.46949 (13)	−0.016 (2)	0.0660 (13)*
C10	0.12520 (12)	0.44153 (12)	−0.0431 (13)	0.0660 (13)*
N5	0.21257 (11)	0.43142 (12)	0.0490 (19)	0.0929 (12)*
O1	0.21057 (12)	0.39570 (12)	−0.086 (2)	0.0929 (12)*
O2	0.24904 (11)	0.44491 (12)	0.188 (2)	0.0929 (12)*
O8	0.05370 (8)	0.53875 (12)	0.143 (2)	0.0929 (12)*
H2	0.0001	0.4114	−0.3223	0.101*
H3	0.0637	0.3605	−0.3851	0.101*
H4	0.1423	0.3779	−0.2133	0.101*
H6	0.2063	0.5096	0.2831	0.101*
H7	0.1404	0.5565	0.3291	0.101*
H8	0.0268	0.5261	0.0648	0.101*

Geometric parameters (Å, º)

O1—N5	1.224 (6)	C6—C7	1.408 (5)
O2—N5	1.221 (6)	C7—C8	1.360 (5)
O8—C8	1.318 (5)	C8—C9	1.461 (6)
N1—C2	1.348 (6)	C9—C10	1.406 (5)
N1—C9	1.373 (5)	O8—H8	0.900
N5—C5	1.468 (5)	C2—H2	1.000
C2—C3	1.410 (5)	C3—H3	1.000
C3—C4	1.367 (5)	C4—H4	1.000
C4—C10	1.436 (6)	C6—H6	1.000
C5—C6	1.399 (6)	C7—H7	1.001
C5—C10	1.406 (5)
C2—N1—C9	117.3 (3)	N1—C9—C10	124.1 (4)
O1—N5—O2	121.8 (4)	C8—C9—C10	122.0 (3)
O1—N5—C5	119.8 (4)	C4—C10—C5	126.6 (3)
O2—N5—C5	118.3 (4)	C4—C10—C9	117.2 (3)
N1—C2—C3	121.9 (3)	C5—C10—C9	116.2 (4)
C2—C3—C4	121.5 (3)	C8—O8—H8	112
C3—C4—C10	118.1 (3)	N1—C2—H2	118
N5—C5—C6	117.8 (3)	C3—C2—H2	120
N5—C5—C10	120.4 (4)	C2—C3—H3	119
C6—C5—C10	121.8 (3)	C4—C3—H3	119
C5—C6—C7	121.3 (3)	C3—C4—H4	120
C6—C7—C8	119.3 (4)	C10—C4—H4	122
O8—C8—C7	119.8 (4)	C5—C6—H6	119
O8—C8—C9	120.8 (3)	C7—C6—H6	120
C7—C8—C9	119.3 (3)	C6—C7—H7	117
N1—C9—C8	113.9 (3)	C8—C7—H7	124

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O8—H8···N1^i	0.90	2.05	2.811 (5)	141
C6—H6···O2^ii	1.00	2.42	3.304 (7)	147
C3—H3···O2^iii	1.00	2.59	3.472 (6)	147

Symmetry codes: (i) −x, −y+1, z; (ii) −x+1/2, −y+1, z+1/2; (iii) x−1/4, −y+3/4, z−3/4.

(II) 8-hydroxy-5-nitroquinolinium chloride

Crystal data

C9H7N2O3^+·Cl^−	Z = 4
Mr = 226.62	F(000) = 464
Monoclinic, P21/c	Dx = 1.633 Mg m^−3
a = 7.566 (4) Å	Cu Kα radiation, λ = 1.5418 Å
b = 7.467 (4) Å	T = 295 K
c = 16.334 (7) Å	Particle morphology: plate
β = 92.49 (3)°	yellow
V = 921.9 (8) Å^3	flat sheet, 25 × 25 mm

Data collection

DRON-3M diffractometer (Burevestnik, Russia)	Data collection mode: reflection
Radiation source: X-ray sealed tube	Scan method: step
Ni filtered monochromator	2θmin = 9.40°, 2θmax = 70.0°, 2θstep = 0.02°
Specimen mounting: pressed as a thin layer in the specimen holder

Refinement

Refinement on Inet	112 parameters
Least-squares matrix: full with fixed elements per cycle	11 restraints
Rp = 0.040	0 constraints
Rwp = 0.056	H-atom parameters constrained
Rexp = 0.030	Weighting scheme based on measured s.u.'s
χ^2 = 3.423	(Δ/σ)max = 0.048
3251 data points	Background function: Chebyshev polynomial up to the 5th order
Excluded region(s): 5.00 - 9.38	Preferred orientation correction: Spherical harmonics (Ahtee et al., 1989)
Profile function: split-type pseudo-Voigt

Special details

Experimental. specimen was rotated in its plane

Refinement. H atoms were placed in calculated positions. The planarity of the naphthalene and nitro groups was restrained.

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

	x	y	z	Uiso*/Ueq
N1	0.1586 (9)	0.6092 (7)	0.5789 (3)	0.0479 (8)*
C2	0.1701 (17)	0.4818 (9)	0.6368 (3)	0.0479 (8)*
C3	0.2416 (13)	0.3103 (7)	0.6208 (3)	0.0479 (8)*
C4	0.3032 (10)	0.2718 (7)	0.5439 (3)	0.0479 (8)*
C5	0.3476 (10)	0.3879 (7)	0.3982 (3)	0.0479 (8)*
C6	0.3301 (9)	0.5309 (7)	0.3430 (3)	0.0479 (8)*
C7	0.2551 (16)	0.6951 (8)	0.3652 (3)	0.0479 (8)*
C8	0.1991 (17)	0.7180 (8)	0.4453 (3)	0.0479 (8)*
C9	0.2180 (15)	0.5725 (8)	0.5031 (3)	0.0479 (8)*
C10	0.2941 (8)	0.4056 (7)	0.4812 (3)	0.0479 (8)*
N5	0.4301 (13)	0.2229 (8)	0.3675 (3)	0.0884 (11)*
O1	0.4767 (14)	0.1042 (8)	0.4171 (3)	0.0884 (11)*
O2	0.4452 (17)	0.2071 (8)	0.2944 (3)	0.0884 (11)*
O8	0.1263 (12)	0.8706 (7)	0.4704 (2)	0.0884 (11)*
Cl1	−0.0019 (7)	0.9048 (4)	0.6691 (2)	0.0603 (6)
H1	0.1128	0.7170	0.5907	0.0761*
H2	0.1274	0.5086	0.6925	0.0761*
H3	0.2494	0.2186	0.6655	0.0761*
H4	0.3544	0.1517	0.5313	0.0761*
H6	0.3715	0.5144	0.2863	0.0761*
H7	0.2434	0.7956	0.3249	0.0761*
H8	0.1189	0.9557	0.4365	0.0761*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
Cl1	0.059 (6)	0.062 (3)	0.060 (2)	−0.012 (5)	−0.031 (3)	0.017 (3)

Geometric parameters (Å, º)

O1—N5	1.242 (8)	C6—C7	1.405 (9)
O2—N5	1.210 (7)	C7—C8	1.403 (9)
O8—C8	1.338 (10)	C8—C9	1.442 (8)
N1—C2	1.342 (8)	C9—C10	1.425 (9)
N1—C9	1.363 (8)	O8—H8	0.843
N5—C5	1.479 (9)	N1—H1	0.900
C2—C3	1.419 (10)	C2—H2	0.999
C3—C4	1.389 (8)	C3—H3	1.001
C4—C10	1.430 (7)	C4—H4	1.002
C5—C6	1.400 (7)	C6—H6	0.998
C5—C10	1.438 (7)	C7—H7	0.999
C2—N1—C9	118.9 (6)	C8—C9—C10	121.6 (6)
O1—N5—O2	122.5 (7)	C4—C10—C5	127.2 (5)
O1—N5—C5	119.1 (5)	C4—C10—C9	116.0 (5)
O2—N5—C5	118.4 (6)	C5—C10—C9	116.8 (5)
N1—C2—C3	121.6 (6)	C8—O8—H8	117
C2—C3—C4	119.9 (5)	C2—N1—H1	120
C3—C4—C10	119.7 (5)	C9—N1—H1	121
N5—C5—C6	116.5 (5)	N1—C2—H2	119
N5—C5—C10	122.5 (5)	C3—C2—H2	119
C6—C5—C10	121.0 (5)	C2—C3—H3	120
C5—C6—C7	121.8 (5)	C4—C3—H3	120
C6—C7—C8	119.3 (5)	C3—C4—H4	121
O8—C8—C7	122.3 (5)	C10—C4—H4	119
O8—C8—C9	118.1 (6)	C5—C6—H6	119
C7—C8—C9	119.6 (6)	C7—C6—H6	120
N1—C9—C8	114.6 (6)	C6—C7—H7	121
N1—C9—C10	123.8 (5)	C8—C7—H7	120

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···Cl1	0.90	2.11	2.945 (7)	154
O8—H8···Cl1^i	0.84	2.17	2.950 (6)	154
C2—H2···Cl1^ii	1.00	2.61	3.515 (8)	151
C4—H4···O1^iii	1.00	2.43	3.312 (10)	147
C6—H6···O2^iv	1.00	2.43	3.161 (10)	130
C3—H3···O2^v	1.00	2.58	3.170 (10)	118

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