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Acta Crystallogr Sect E Struct Rep Online. 2009 September 1; 65(Pt 9): o2292–o2293.
Published online 2009 August 29. doi:  10.1107/S160053680903390X
PMCID: PMC2969931

4-Hydr­oxy-3-meth­oxy-5-nitro­aceto­phenone (5-nitro­apocynin)

Abstract

The title mol­ecule, C9H9NO5, is close to planar (r.m.s. deviation from the mean plane of the non-H atoms = 0.058 Å). The OH group forms a bifurcated O—H(...)(O,O) hydrogen bond, with the intra­molecular component to a nitro O atom and the inter­molecular component to a keto O atom, the latter resulting in chains along [20An external file that holds a picture, illustration, etc.
Object name is e-65-o2292-efi3.jpg]. A C—H(...)O inter­action reinforces the packing.

Related literature

For medicinal background, see: Gernapudi et al. (2009 [triangle]); Geronikaki & Gavalas (2006 [triangle]); Hayashi et al. (2005 [triangle]); Heumuller et al. (2008 [triangle]); Matés et al. (2009 [triangle]); Muijsers et al. (2001 [triangle]); Sawa et al. (2000 [triangle]); Schopfer et al. (2003 [triangle]); Stefanska & Pawliczak (2008 [triangle]); Stolk et al. (1994 [triangle]); Tajik et al. (2009 [triangle]); Thomas et al. (2002 [triangle]); Touyz (2008 [triangle]); Ximenes et al. (2007 [triangle]).

An external file that holds a picture, illustration, etc.
Object name is e-65-o2292-scheme1.jpg

Experimental

Crystal data

  • C9H9NO5
  • M r = 211.17
  • Monoclinic, An external file that holds a picture, illustration, etc.
Object name is e-65-o2292-efi4.jpg
  • a = 6.6598 (10) Å
  • b = 16.815 (2) Å
  • c = 8.0491 (11) Å
  • β = 96.485 (7)°
  • V = 895.6 (2) Å3
  • Z = 4
  • Mo Kα radiation
  • μ = 0.13 mm−1
  • T = 90 K
  • 0.40 × 0.30 × 0.15 mm

Data collection

  • Nonius KappaCCD diffractometer with Oxford Cryostream
  • Absorption correction: none
  • 22479 measured reflections
  • 4255 independent reflections
  • 3226 reflections with I > 2σ(I)
  • R int = 0.025

Refinement

  • R[F 2 > 2σ(F 2)] = 0.042
  • wR(F 2) = 0.120
  • S = 1.04
  • 4255 reflections
  • 147 parameters
  • H atoms treated by a mixture of independent and constrained refinement
  • Δρmax = 0.62 e Å−3
  • Δρmin = −0.32 e Å−3

Data collection: COLLECT (Nonius, 2000 [triangle]); cell refinement: SCALEPACK (Otwinowski & Minor, 1997 [triangle]); data reduction: DENZO (Otwinowski & Minor, 1997 [triangle]) and SCALEPACK; program(s) used to solve structure: SIR97 (Altomare et al., 1999 [triangle]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 [triangle]); molecular graphics: ORTEP-3 for Windows (Farrugia, 1997 [triangle]); software used to prepare material for publication: SHELXL97.

Table 1
Hydrogen-bond geometry (Å, °)

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S160053680903390X/hb5058sup1.cif

Structure factors: contains datablocks I. DOI: 10.1107/S160053680903390X/hb5058Isup2.hkl

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Acknowledgments

We thank Dr Michelle Claville for helpful discussions, Ms Bianca King for help with the melting-point determination and Mr Joseph Allison for help with the GC–MS–EI analysis. This publication was made possible by National Science Foundation (NSF) grant HRD 0450375 (from the HBCU-RISE program) and US Department of Education grant PO31B040030 (Title III, Part B - Strengthening Historically Black Graduate Institutions). The LBRN summer fellowship [provided as part of National Institutes of Health (NIH) grant P20 RR16456] to Sainath Babu is gratefully acknowledged. The contents of this publication are solely the responsibility of authors and do not necessarily represent the official views of the NSF, NIH or the US Department of Education. The purchase of the diffractometer was made possible by grant No. LEQSF (1999–2000)-ENH-TR-13, administered by the Louisiana Board of Regents.

supplementary crystallographic information

Comment

The growing concern of multiple side effects associated with the use of steroidal anti-inflammatory drugs has led investigators to explore alternative and more natural remedies to counter oxidative stress in cancer and other degenerative diseases (Geronikaki & Gavalas, 2006; Matés et al., 2009). Apocynin (4-hydroxy-3-methoxy-acetophenone), also called acetovanillone, isolated from plants belonging to the apocyanaceae family (e.g., Apocynum cannabinum) seems to be a promising drug (or prodrug) that can be effective in various inflammatory conditions (Hayashi et al., 2005; Muijsers et al., 2001; Stefanska & Pawliczak, 2008). For a long time, apocynin has been thought to inhibit plasma membrane NADPH oxidase activity by interfering with the assembly of its cytosolic components, p40, p47, and p67 (Stolk et al., 1994). This view of a direct action of apocynin on the NADPH oxidase system has been challenged in recent years (Heumuller et al., 2008). Suggestions have been made that apocynin requires metabolic activation to diapocynin (DiApo), presumably involving intracellular peroxidase(s) (Touyz, 2008; Ximenes et al., 2007). In a recent study, we showed that apocynin readily reacts with free radicals of carbonate (CO3.-) and nitrogen dioxide (.NO2) formed in reactions of peroxynitrite (PN) with CO2, resulting in the formation of 5-nitroapocynin and DiApo as major products (Gernapudi et al., 2009). Based on these observations, it has been suggested that a detailed study of the oxidative transformation of apocynin and its derivates by PN/CO2 and possibly other oxidative, nitrative and/or nitrosative systems (Sawa et al., 2000; Schopfer et al., 2003; Thomas et al., 2002) would be necessary to provide a template for screening of antioxidant activity and a module that could help in the design of effective inhibitors of the NADPH oxidase system. Towards this end, we have synthesized 5-nitroapocynin using sodium nitrate in combination with an acidic ionic liquid, 1-butyl-3-methylimidazolium hydrogen sulfate ([bmim] [HSO4]), in CH3CN solvent at room temperature (Fig. 3).

The molecule is shown in Fig. 1. The phenyl ring is essentially planar, with RMS deviation 0.0046 Å and maximum deviation 0.0069 (6) Å for C5. The substituents are twisted only slightly out of the phenyl plane, as described in the Abstract. Figure 2 shows the hydrogen bonding pattern, in which the OH group forms both an intramolecular interaction and a much less linear intermolecular interaction. These are described in Table 2, and form a chain in the [201] direction. The intermolecular component is accompanied by a near-linear C2–H2···O4 (at x - 1, 1/2 - y, 1/2 + z) interaction, having C···O distance 3.3831 (12) Å, H···O distance 2.439 (12) Å, and angle 171.4 (11)° about H. The N1–O4 bond, 1.2438 (10) Å, to the O atom involved in the intramolecular hydrogen bond, is slightly longer than the other, N1–O5, 1.2255 (10) Å.

Experimental

Chemicals and solvents used in the synthesis and recrystallization were obtained as follows: apocynin, [bmim] [HSO4], and sodium nitrate from Sigma (St. Louis, MO) and acetonitrile and hexane from Mallinckrodt (Phillipsburg, NJ). Water used was ultrapure with resistance ≥18.2 MΩ/cm.

Nitration of apocynin (Fig. 3) was performed according to the method of Tajik and colleagues (Tajik et al., 2009) with some modifications. Briefly, to 3.32 g (20 mmol) of apocynin in 80 ml of CH3CN was added 5.72 g (20 mmol) of [bmim] [HSO4] and 1.7 g (20 mmol) of NaNO3, and the mixture was stirred at room temperature. Aliquots (0. 1 ml each) of the reaction mixture, drawn at various time points, were diluted 100–500-fold with 0.1 N NaOH and measured photometrically at 410 nm. When the absorbance at 410 nm reached a maximum (i.e., typically after 24 h), the reaction mixture was filtered and the filtrate evaporated under low pressure (200 mm H g) with mild heating (50°C or slightly higher). The thick brown liquid-like residue was extracted with hot hexane and recrystallized twice. The compound resolved as a single peak (retention time = 11.507 min) on Varian VF-5MS capillary column (30-m length, 0.25-mm internal diameter, 0.25-µm film thickness) with helium as the carrier gas at a flow of 1 ml. min-1 (injection port, 250°C; oven, 60°C for 5 min (isothermal); 20°C min-1 up to 230°C (ramp), and held at 230 °C for 18.5 min (isothermal); split, 25:1). The ion chromatogram of the peak eluting at 11.507 min showed a molecular ion [M]+ at m/z 211 (31%; relative to the base peak) and other fragments at m/z values of 196 (100%; base peak; [M—CH3]+), 150 (23%; [M—CH3NO2]+.), 122 (11%; [M—C2H3NO3]+.) and 79 (6%; [M—C4H6NO4]+.) (Fig. 4). Single crystals of (I) in the form of golden-yellow needles were grown from methanol.

Refinement

H atoms on C were located from difference maps, and their coordinates were refined, except for those on methyl groups, which were idealized with C—H distance 0.98 Å. A torsional parameter was refined for each methyl group. Uiso for H were assigned as 1.2 times Ueq of the attached atoms (1.5 for methyl). The top ten difference map peaks lie on bonds, the largest at the midpoint of C3—C4, 0.71 Å from C4.

Figures

Fig. 1.
The molecular structure of (I): ellipsoids at the 50% level, with H atoms having arbitrary radius.
Fig. 2.
A portion of the hydrogen-bonded chain, showing the bifurcated hydrogen bond and accompanying C–H···O interaction; (ii) x - 1, 1/2 - y, 1/2 + z.
Fig. 3.
Nitration of apocynin
Fig. 4.
A proposed route of mass spectrometry-electron ionization (70 eV) fragmentation of 4-hydroxy-3-methoxy-5-nitroacetophenone.

Crystal data

C9H9NO5F(000) = 440
Mr = 211.17Dx = 1.566 Mg m3
Monoclinic, P21/cMo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ybcCell parameters from 4183 reflections
a = 6.6598 (10) Åθ = 2.5–36.3°
b = 16.815 (2) ŵ = 0.13 mm1
c = 8.0491 (11) ÅT = 90 K
β = 96.485 (7)°Needle fragment, golden yellow
V = 895.6 (2) Å30.40 × 0.30 × 0.15 mm
Z = 4

Data collection

Nonius KappaCCD diffractometer with Oxford Cryostream3226 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tubeRint = 0.025
graphiteθmax = 36.3°, θmin = 2.8°
ω and [var phi] scansh = −10→10
22479 measured reflectionsk = −28→26
4255 independent reflectionsl = −13→13

Refinement

Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.042Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.120H atoms treated by a mixture of independent and constrained refinement
S = 1.04w = 1/[σ2(Fo2) + (0.0585P)2 + 0.2019P] where P = (Fo2 + 2Fc2)/3
4255 reflections(Δ/σ)max < 0.001
147 parametersΔρmax = 0.62 e Å3
0 restraintsΔρmin = −0.32 e Å3

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 (Å2)

xyzUiso*/Ueq
O10.70859 (9)0.17341 (4)0.57565 (8)0.01682 (13)
H1O0.805 (2)0.1965 (9)0.5277 (18)0.025*
O20.40131 (9)0.12263 (4)0.70993 (9)0.01727 (13)
O30.03482 (9)0.36827 (4)0.88871 (9)0.01850 (14)
O40.90549 (10)0.29612 (4)0.48481 (9)0.02148 (15)
O50.81333 (10)0.41618 (4)0.53665 (9)0.02082 (14)
N10.79036 (11)0.34401 (4)0.54412 (9)0.01483 (13)
C10.32973 (11)0.33924 (5)0.76315 (10)0.01274 (14)
C20.29375 (12)0.25663 (5)0.77082 (10)0.01340 (14)
H20.1831 (18)0.2368 (8)0.8237 (15)0.016*
C30.42194 (12)0.20294 (5)0.70775 (10)0.01312 (14)
C40.59325 (12)0.22979 (5)0.63245 (10)0.01309 (14)
C50.62316 (11)0.31230 (5)0.62424 (10)0.01315 (14)
C60.49407 (12)0.36689 (5)0.68977 (10)0.01365 (14)
H60.5227 (18)0.4219 (8)0.6815 (15)0.016*
C70.22582 (13)0.09248 (5)0.77728 (12)0.01791 (16)
H7A0.23250.10660.89590.027*
H7B0.22110.03450.76540.027*
H7C0.10410.11580.71650.027*
C80.18762 (12)0.39440 (5)0.83692 (10)0.01404 (14)
C90.23465 (14)0.48181 (5)0.84358 (12)0.01944 (17)
H9A0.21050.50430.73080.029*
H9B0.37660.48970.88760.029*
H9C0.14760.50840.91670.029*

Atomic displacement parameters (Å2)

U11U22U33U12U13U23
O10.0147 (3)0.0152 (3)0.0220 (3)0.0018 (2)0.0084 (2)−0.0013 (2)
O20.0163 (3)0.0115 (3)0.0255 (3)−0.0003 (2)0.0087 (2)0.0008 (2)
O30.0156 (3)0.0183 (3)0.0233 (3)−0.0003 (2)0.0094 (2)−0.0002 (2)
O40.0179 (3)0.0203 (3)0.0287 (3)−0.0003 (2)0.0136 (3)−0.0035 (3)
O50.0232 (3)0.0155 (3)0.0257 (3)−0.0043 (2)0.0110 (3)0.0008 (2)
N10.0137 (3)0.0163 (3)0.0152 (3)−0.0018 (2)0.0047 (2)−0.0004 (2)
C10.0120 (3)0.0131 (3)0.0137 (3)0.0005 (2)0.0036 (2)0.0006 (2)
C20.0123 (3)0.0135 (3)0.0150 (3)−0.0002 (2)0.0042 (2)0.0007 (3)
C30.0124 (3)0.0126 (3)0.0148 (3)−0.0004 (2)0.0033 (2)0.0009 (3)
C40.0118 (3)0.0144 (3)0.0135 (3)0.0008 (2)0.0033 (2)−0.0004 (3)
C50.0111 (3)0.0152 (3)0.0139 (3)−0.0015 (2)0.0044 (2)0.0002 (3)
C60.0133 (3)0.0135 (3)0.0147 (3)−0.0003 (2)0.0038 (2)0.0005 (3)
C70.0172 (3)0.0152 (3)0.0223 (4)−0.0020 (3)0.0065 (3)0.0023 (3)
C80.0136 (3)0.0146 (3)0.0145 (3)0.0013 (2)0.0039 (3)0.0012 (3)
C90.0201 (4)0.0134 (3)0.0264 (4)0.0013 (3)0.0095 (3)0.0010 (3)

Geometric parameters (Å, °)

O1—C41.3330 (10)C2—H20.952 (12)
O1—H1O0.878 (14)C3—C41.4245 (11)
O2—C31.3576 (10)C4—C51.4043 (12)
O2—C71.4352 (11)C5—C61.4008 (11)
O3—C81.2240 (10)C6—H60.948 (13)
O4—N11.2438 (10)C7—H7A0.9800
O5—N11.2255 (10)C7—H7B0.9800
N1—C51.4499 (10)C7—H7C0.9800
C1—C61.3817 (11)C8—C91.5026 (12)
C1—C21.4120 (12)C9—H9A0.9800
C1—C81.4952 (11)C9—H9B0.9800
C2—C31.3783 (11)C9—H9C0.9800
C4—O1—H1O108.5 (10)C4—C5—N1120.29 (7)
C3—O2—C7116.37 (7)C1—C6—C5119.34 (8)
O5—N1—O4122.44 (7)C1—C6—H6122.2 (7)
O5—N1—C5119.50 (7)C5—C6—H6118.4 (7)
O4—N1—C5118.06 (7)O2—C7—H7A109.5
C6—C1—C2119.75 (7)O2—C7—H7B109.5
C6—C1—C8121.91 (7)H7A—C7—H7B109.5
C2—C1—C8118.34 (7)O2—C7—H7C109.5
C3—C2—C1120.87 (7)H7A—C7—H7C109.5
C3—C2—H2118.5 (8)H7B—C7—H7C109.5
C1—C2—H2120.6 (8)O3—C8—C1120.03 (8)
O2—C3—C2125.38 (7)O3—C8—C9121.13 (8)
O2—C3—C4114.07 (7)C1—C8—C9118.83 (7)
C2—C3—C4120.55 (7)C8—C9—H9A109.5
O1—C4—C5126.60 (7)C8—C9—H9B109.5
O1—C4—C3116.15 (7)H9A—C9—H9B109.5
C5—C4—C3117.24 (7)C8—C9—H9C109.5
C6—C5—C4122.23 (7)H9A—C9—H9C109.5
C6—C5—N1117.47 (7)H9B—C9—H9C109.5
C6—C1—C2—C30.78 (12)C3—C4—C5—N1−177.86 (7)
C8—C1—C2—C3−178.74 (7)O5—N1—C5—C60.14 (12)
C7—O2—C3—C22.89 (12)O4—N1—C5—C6−179.69 (7)
C7—O2—C3—C4−177.15 (7)O5—N1—C5—C4179.34 (8)
C1—C2—C3—O2179.60 (8)O4—N1—C5—C4−0.48 (12)
C1—C2—C3—C4−0.36 (12)C2—C1—C6—C5−0.15 (12)
O2—C3—C4—O1−0.18 (10)C8—C1—C6—C5179.35 (7)
C2—C3—C4—O1179.78 (7)C4—C5—C6—C1−0.92 (12)
O2—C3—C4—C5179.38 (7)N1—C5—C6—C1178.27 (7)
C2—C3—C4—C5−0.66 (12)C6—C1—C8—O3174.11 (8)
O1—C4—C5—C6−179.19 (8)C2—C1—C8—O3−6.38 (12)
C3—C4—C5—C61.31 (12)C6—C1—C8—C9−5.00 (12)
O1—C4—C5—N11.65 (13)C2—C1—C8—C9174.51 (8)

Hydrogen-bond geometry (Å, °)

D—H···AD—HH···AD···AD—H···A
O1—H1O···O40.878 (14)1.850 (15)2.5939 (10)141.3 (13)
O1—H1O···O3i0.878 (14)2.271 (14)2.8660 (9)124.9 (12)
C2—H2···O4ii0.952 (12)2.439 (12)3.3831 (12)171.4 (11)

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

Footnotes

Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: HB5058).

References

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