7-Nitro­indazole

The title compound, C₇H₅N₃O₂, is an inhibitor of nitric oxide synthase and mono­amine oxidase. The N1H tautomer crystallized as a dimer and adopts a planar conformation assisted by intramolecular hydrogen bonding.

S1. Comment

7-Nitroindazole, (I), is an inhibitor of nitric oxide synthase (NOS), the enzyme responsible for the generation of the ubiquitous neurotransmitter nitric oxide (Moore et al., 1993). In the early 1990 s, it was discovered that (I) exhibited selectivity for neuronal NOS (nNOS) (Babbedge et al., 1993; MacKenzie et al., 1994) and it soon became the standard investigative tool for the study of effects related to nNOS (Rivier, 1998). Shortly after these findings, it became clear that (I) may have utility as a neuroprotecting agent when it was found that it protected against MPTP-induced neurotoxicity in the mouse (Schulz et al., 1995; Przedborski et al., 1996) and baboon (Hantraye et al., 1996). Although initial arguments suggested that nNOS may mediate, in part, MPTP-induced neurotoxicity (Przedborski et al., 1996), more recent studies in the mouse (Castagnoli et al., 1997) and rat (Desvignes et al., 1999) provided evidence that (I) also is an inhibitor of monoamine oxidase B (MAO-B), which may contribute to the protective effect of this compound against MPTP neurotoxicity (Di Monte et al., 1997). It has now been suggested and that this action on MAO-B, rather than NOS inhibition, is the mechanism by which (I) prevents MPTP-induced ATP depletion (Royland et al., 1999).

The conformation of (I) is of interest because of its unique ability to inhibit both MAO-B and nNOS, two biologically important enzyme systems. Furthermore, its general use as an investigative drug to study the inhibition of nNOS makes a structural study of this molecule important. Several reversible inhibitors of MAO have planar structures, including the endogenous indole derivative isatin, (Medvedev et al., 1995) an MAO-B selective inhibitor, and the commercially available (in Europe) phenyloxazolidinone toloxatone, an MAO-A selective inhibitor (Moureau et al., 1992, 1995).

Von Auwers, in 1891, was the first to report that indazoles exist in a tautomeric equilibrium. Evidence obtained from molecular refractivity measurements in Von Auwers' laboratory later suggested the predominance of the tautomer possessing the benzenoid structure (Von Auwers et al., 1937). It was also shown by UV spectroscopy (Rousseau & Linwall, 1950) as well as by proton (Elguero et al., 1966) and ¹⁴N NMR (Witanowski et al., 1972) that the data from indazole more closely resemble those obtained from 1-methylindazole than those from 2-methylindazole, further supporting evidence for the predominance of the benzenoid structure. The crystal structure of indazoles (Escande et al., 1974; Escande & Lapasset, 1974) also supported these conclusions. Ab initio studies by the group of Elguero (Catalan & Elguero, 1994; Catalan et al., 1996) suggested that indazole occurs in the N1H tautomeric form in the gas phase and in solution both in the ground and excited states and that the N1H tautomer is more stable than its N2H congener by 4 kcal mol⁻¹.

Compound (I) adopts, in the solid state, a planar conformation assisted by intramolecular hydrogen bonding between the 7-nitro group and a H atom on N1 of the indazole structure. An H atom was unambigously detected from the Fourier difference map on N1 but not on N2. This H atom is further engaged in an intermolecular hydrogen bond leading to the formation of stable dimers in the crystal packing (Table 1). A planar conformation would have been less likely if the N2H tautomer had formed.

S2. Experimental

The title compound was purchased from Research Biochemicals International (lot ZXY-296 C) as a crystalline sample.

S3. Refinement

The H atom on N1 was located by difference synthesis (N—H = 0.86 Å). All H atoms were treated as riding atoms (C—H = 0.93 Å).

Computing details

Data collection: CAD-4 EXPRESS (Enraf-Nonius, 1989); cell refinement: CAD-4 EXPRESS; data reduction: HELENA (Spek, 1997); program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: PLATON (Spek, 1990).

(I)

Crystal data

C7H5N3O2	Z = 4
Mr = 163.14	F(000) = 336
Monoclinic-, P21/n	Dx = 1.560 Mg m^−3
a = 5.020 (1) Å	Cu Kα radiation, λ = 1.5418 Å
b = 9.636 (1) Å	Cell parameters from 25 reflections
c = 14.506 (1) Å	θ = 40–45°
α = 90°	µ = 1.01 mm^−1
β = 98.232 (4)°	T = 293 K
γ = 90°	Needle, orange–yellow
V = 694.46 (16) Å^3	0.70 × 0.25 × 0.18 mm

Data collection

Enraf-Nonius diffractometer	1223 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.010
Graphite monochromator	θmax = 71.9°, θmin = 5.5°
θ/2θ scans	h = 0→6
Absorption correction: analytical (Spek, 1997)	k = −8→11
Tmin = 0.537, Tmax = 0.839	l = −17→17
1877 measured reflections	3 standard reflections every 60 min
1355 independent reflections	intensity decay: 2%

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.037	H-atom parameters constrained
wR(F^2) = 0.109	Calculated w = 1/[σ^2(Fo^2) + (0.0544P)^2 + 0.1541P] where P = (Fo^2 + 2Fc^2)/3
S = 1.10	(Δ/σ)max = 0.001
1355 reflections	Δρmax = 0.20 e Å^−3
110 parameters	Δρmin = −0.15 e Å^−3
0 restraints	Extinction correction: SHELXL97, Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.0079 (12)

Special details

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 (Ų)

	x	y	z	Uiso*/Ueq
C7	0.4179 (3)	0.28020 (14)	0.04060 (9)	0.0407 (3)
C6	0.2458 (3)	0.33636 (16)	0.09695 (11)	0.0474 (4)
H6	0.1338	0.4098	0.0753	0.057*
C5	0.2390 (3)	0.28378 (17)	0.18587 (11)	0.0503 (4)
H5	0.1229	0.3232	0.2230	0.060*
C4	0.4001 (3)	0.17484 (16)	0.22000 (10)	0.0470 (4)
H4	0.3930	0.1403	0.2795	0.056*
C3A	0.5750 (3)	0.11678 (15)	0.16378 (10)	0.0418 (3)
C3	0.7637 (3)	0.00659 (17)	0.17263 (11)	0.0499 (4)
H3	0.8028	−0.0486	0.2254	0.060*
N2	0.8762 (2)	−0.00789 (13)	0.09720 (9)	0.0511 (4)
N1	0.7668 (2)	0.09196 (12)	0.03689 (8)	0.0447 (3)
H1	0.8091	0.1041	−0.0179	0.054*
C1A	0.5843 (3)	0.16938 (14)	0.07349 (9)	0.0384 (3)
N8	0.4260 (3)	0.33609 (13)	−0.05120 (9)	0.0500 (3)
O9	0.5911 (3)	0.28690 (14)	−0.09639 (8)	0.0706 (4)
O10	0.2714 (3)	0.43003 (14)	−0.08015 (9)	0.0680 (4)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C7	0.0403 (7)	0.0418 (7)	0.0409 (7)	−0.0041 (5)	0.0088 (5)	−0.0035 (5)
C6	0.0426 (7)	0.0463 (8)	0.0543 (8)	0.0037 (6)	0.0109 (6)	−0.0070 (6)
C5	0.0459 (8)	0.0571 (9)	0.0519 (8)	0.0004 (7)	0.0205 (6)	−0.0123 (7)
C4	0.0475 (8)	0.0561 (9)	0.0402 (7)	−0.0043 (6)	0.0157 (6)	−0.0047 (6)
C3A	0.0384 (7)	0.0456 (7)	0.0426 (7)	−0.0033 (6)	0.0100 (5)	−0.0038 (6)
C3	0.0453 (8)	0.0523 (8)	0.0532 (8)	0.0037 (6)	0.0101 (6)	0.0029 (7)
N2	0.0438 (7)	0.0503 (7)	0.0608 (8)	0.0064 (5)	0.0128 (5)	−0.0042 (6)
N1	0.0421 (6)	0.0480 (7)	0.0470 (6)	0.0008 (5)	0.0169 (5)	−0.0066 (5)
C1A	0.0340 (6)	0.0417 (7)	0.0415 (7)	−0.0054 (5)	0.0120 (5)	−0.0085 (5)
N8	0.0553 (7)	0.0507 (7)	0.0449 (7)	−0.0056 (6)	0.0102 (5)	−0.0012 (5)
O9	0.0865 (9)	0.0781 (9)	0.0549 (7)	0.0056 (7)	0.0357 (6)	0.0059 (6)
O10	0.0755 (8)	0.0666 (8)	0.0594 (7)	0.0098 (6)	0.0011 (6)	0.0119 (6)

Geometric parameters (Å, º)

C7—C6	1.3818 (19)	C3A—C1A	1.4115 (19)
C7—C1A	1.3970 (19)	C3A—C3	1.417 (2)
C7—N8	1.4425 (18)	C3—N2	1.309 (2)
C6—C5	1.391 (2)	C3—H3	0.9300
C6—H6	0.9300	N2—N1	1.3620 (18)
C5—C4	1.374 (2)	N1—C1A	1.3480 (17)
C5—H5	0.9300	N1—H1	0.8600
C4—C3A	1.3975 (19)	N8—O9	1.2234 (17)
C4—H4	0.9300	N8—O10	1.2265 (18)
C6—C7—C1A	119.42 (13)	C1A—C3A—C3	104.04 (12)
C6—C7—N8	120.17 (13)	N2—C3—C3A	111.54 (14)
C1A—C7—N8	120.41 (12)	N2—C3—H3	124.2
C7—C6—C5	120.42 (14)	C3A—C3—H3	124.2
C7—C6—H6	119.8	C3—N2—N1	106.21 (12)
C5—C6—H6	119.8	C1A—N1—N2	111.85 (11)
C4—C5—C6	121.42 (13)	C1A—N1—H1	124.1
C4—C5—H5	119.3	N2—N1—H1	124.1
C6—C5—H5	119.3	N1—C1A—C7	134.06 (13)
C5—C4—C3A	118.83 (13)	N1—C1A—C3A	106.35 (12)
C5—C4—H4	120.6	C7—C1A—C3A	119.58 (12)
C3A—C4—H4	120.6	O9—N8—O10	123.12 (14)
C4—C3A—C1A	120.32 (13)	O9—N8—C7	117.43 (13)
C4—C3A—C3	135.63 (14)	O10—N8—C7	119.45 (13)
C1A—C7—C6—C5	0.4 (2)	C6—C7—C1A—N1	178.93 (14)
N8—C7—C6—C5	−179.38 (13)	N8—C7—C1A—N1	−1.3 (2)
C7—C6—C5—C4	−0.4 (2)	C6—C7—C1A—C3A	−0.2 (2)
C6—C5—C4—C3A	0.3 (2)	N8—C7—C1A—C3A	179.54 (12)
C5—C4—C3A—C1A	−0.2 (2)	C4—C3A—C1A—N1	−179.25 (12)
C5—C4—C3A—C3	−179.04 (16)	C3—C3A—C1A—N1	−0.06 (15)
C4—C3A—C3—N2	178.86 (16)	C4—C3A—C1A—C7	0.1 (2)
C1A—C3A—C3—N2	−0.13 (17)	C3—C3A—C1A—C7	179.31 (12)
C3A—C3—N2—N1	0.27 (17)	C6—C7—N8—O9	176.57 (14)
C3—N2—N1—C1A	−0.31 (16)	C1A—C7—N8—O9	−3.2 (2)
N2—N1—C1A—C7	−179.01 (14)	C6—C7—N8—O10	−2.9 (2)
N2—N1—C1A—C3A	0.23 (15)	C1A—C7—N8—O10	177.36 (12)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···N2^i	0.86	2.28	2.941 (2)	134
N1—H1···O9	0.86	2.29	2.749 (2)	114

Symmetry code: (i) −x+2, −y, −z.