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Acta Crystallogr Sect E Struct Rep Online. 2009 May 1; 65(Pt 5): o1170.
Published online 2009 April 30. doi:  10.1107/S1600536809015463
PMCID: PMC2977835

1-(4-Methoxy­phen­yl)-3-phenyl-1H-pyrazol-5-amine

Abstract

The synthesis of the title compound, C16H15N3O, is regiospecific and single-crystal X-ray diffraction provides the only means of unambiguous structural analysis, with the benzene ring bonded to the imine C atom. The phenyl ring and the essentially planar (r.m.s. deviation 0.0354 Å) methoxy­benzene group are rotated by 29.41 (5) and 37.01 (5)°, respectively, from the central pyrazole ring. An inter­molecular N—H(...)N hydrogen bond links symmetry-related mol­ecules into a C(5) chain, which runs parallel to the b axis.

Related literature

For background to this study, see: Gavrin et al. (2007 [triangle]); Joshi et al. (1979 [triangle]); Michaux & Charlier (2004 [triangle]); Ossipov et al. (2004 [triangle]); Raffa (2001 [triangle]).

An external file that holds a picture, illustration, etc.
Object name is e-65-o1170-scheme1.jpg

Experimental

Crystal data

  • C16H15N3O
  • M r = 265.31
  • Orthorhombic, An external file that holds a picture, illustration, etc.
Object name is e-65-o1170-efi1.jpg
  • a = 14.9638 (6) Å
  • b = 6.3639 (2) Å
  • c = 28.2466 (12) Å
  • V = 2689.87 (18) Å3
  • Z = 8
  • Mo Kα radiation
  • μ = 0.09 mm−1
  • T = 296 K
  • 0.35 × 0.35 × 0.05 mm

Data collection

  • Bruker Kappa APEXII diffractometer
  • Absorption correction: none
  • 11632 measured reflections
  • 3019 independent reflections
  • 2256 reflections with I > 2σ(I)
  • R int = 0.031

Refinement

  • R[F 2 > 2σ(F 2)] = 0.044
  • wR(F 2) = 0.111
  • S = 1.02
  • 3019 reflections
  • 190 parameters
  • H atoms treated by a mixture of independent and constrained refinement
  • Δρmax = 0.20 e Å−3
  • Δρmin = −0.15 e Å−3

Data collection: APEX2 (Bruker, 2007 [triangle]); cell refinement: SAINT (Bruker, 2007 [triangle]); data reduction: SAINT; program(s) used to solve structure: SHELXTL (Sheldrick, 2008 [triangle]); program(s) used to refine structure: SHELXTL; molecular graphics: ORTEP-3 for Windows (Farrugia, 1997 [triangle]) and Mercury (Macrae et al., 2008 [triangle]); software used to prepare material for publication: SHELXTL and local programs.

Table 1
Hydrogen-bond geometry (Å, °)

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536809015463/lh2810sup1.cif

Structure factors: contains datablocks I. DOI: 10.1107/S1600536809015463/lh2810Isup2.hkl

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

Acknowledgments

This work was supported by the United States Public Health Service, National Institute on Drug Abuse grants DA06284 and DA13449. We thank Professor Bob Downs, Department of Geosciences, University of Arizona, for the data collection.

supplementary crystallographic information

Comment

It has been pharmacologically shown that co-administration of opioids with cyclooxygenase (COX) inhibitors is synergistic and reduces development of drug tolerance (Raffa, 2001; Ossipov et al., 2004). The creation of bifunctional molecules having both COX2 inhibitory activity and Opioid mu agonist activity is a promising approach to retain better analgesic properties. We are investigating plausible COX2 pharmacophores that can be obtained for bifunctional design using known organic reactions. Based on the evidence so far (Joshi et al.,1979; Gavrin et al., 2007) we probed whether the reaction between hydrazine derivatives and benzoylacetonitrile will usefully yield pyrazoles as a product substituted with 1,5-vicinal diaryls, which is an important structural feature for COX2 inhibitory activity (Michaux & Charlier, 2004). We observed that the reaction between benzoylacetonitrile with 2-(4-methoxyphenyl)hydraziniumchloride is regiospecific which means it provides solely 1-(4-methoxyphenyl)-3-phenyl-1H-pyrazol-5-amine, (I), which is undesired for our purpose. Furthermore it cannot be correctly identified with one-dimensional nuclear Overhauser effect or two-dimensional heteronuclear multiple bond correlation spectroscopic methods, leaving single-crystal X-ray diffraction as the only possible means of unambiguous identification of the compound.

The molecular structure of (I) is shown in Figure 1. Two regioisomers were possible and here the structure is unambiguous with the phenyl ring (C11-C16) bonded to the imine carbon atom C1. Molecular dimensions are unexceptional. The methoxybenzyl group is essentially planar (r.m.s. deviation of a mean plane fitted through C4 to C10 and O is 0.0354 Å) and is rotated by 37.01 (5)° from the central pyrazole ring. The phenyl ring (C11-C16) is rotated by 29.41 (5)° from the central pyrazole ring. A lone N–H···N hydrogen bond links the molecules into a C(5) chain which runs parallel to the b axis(Figure 2).

Experimental

Benzoylacetonitrile (1.45 g, 10 mmol) in 50 ml of absolute ethanol was treated with 2-(4-methoxyphenyl) hydraziniumchloride (1.75 g, 10 mmol) under reflux for 1 day. The solvent was then removed by rotary evaporation and the residue was extracted with a 1:1 mix of dichloromethane and H2O. The organic layer was separated and dried with anhydrous MgSO4, filtered and then the solvent removed by rotary evaporation to leave a vrown residue. This was washed with hexane and recrystallized from dichloromethane. C16H15N3O, (I), yield = 90%. TOF MS EI m/z 264.9839. 1H NMR (CDCl3)δ 3.85 (s, 3H), 5.95 (s, 1H), 7.0 (d,2H), 7.25 (m,1H), 7.4 (t,2H) 7.5(d,2H), 7.8 (d,2H) 13CNMR (CDCl3) δ 55.50, 87.59, 114.61, 125. 522, 126.049, 127.626, 128.391, 131.463,133.551, 145.740, 151.043, 158.971

Refinement

Amine hydrogen atoms were freely refined. Aryl hydrogen atoms were refined with Uiso(H) = 1.2 Ueq(C) and a fixed C–H distance of 0.93 Å; methyl hydrogen atoms were refined with Uiso(H) = 1.5 Ueq(C) and a fixed C–H distance of 0.96 Å.

Figures

Fig. 1.
The molecular structure of (I) with displacement ellipsoids at the 50% probability level.
Fig. 2.
Part of the crystal structure of (I) showing a hydrogen bonded (dashed lines) chain.

Crystal data

C16H15N3OF(000) = 1120
Mr = 265.31Dx = 1.310 Mg m3
Orthorhombic, PbcaMo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ac 2abCell parameters from 2475 reflections
a = 14.9638 (6) Åθ = 2.7–28.6°
b = 6.3639 (2) ŵ = 0.09 mm1
c = 28.2466 (12) ÅT = 296 K
V = 2689.87 (18) Å3Plate, colourless
Z = 80.35 × 0.35 × 0.05 mm

Data collection

Bruker Kappa APEXII diffractometer2256 reflections with I > 2σ(I)
Radiation source: sealed tubeRint = 0.031
graphiteθmax = 28.3°, θmin = 2.0°
[var phi] and ω scansh = −19→16
11632 measured reflectionsk = −7→6
3019 independent reflectionsl = −36→37

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)] = 0.044Hydrogen site location: difference Fourier map
wR(F2) = 0.111H atoms treated by a mixture of independent and constrained refinement
S = 1.02w = 1/[σ2(Fo2) + (0.048P)2 + 0.671P] where P = (Fo2 + 2Fc2)/3
3019 reflections(Δ/σ)max = 0.001
190 parametersΔρmax = 0.20 e Å3
0 restraintsΔρmin = −0.15 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
O0.37170 (8)0.3584 (2)0.56552 (3)0.0537 (3)
N10.38199 (8)0.10523 (19)0.75399 (4)0.0327 (3)
N20.37654 (8)0.2595 (2)0.78830 (4)0.0357 (3)
N30.39632 (11)−0.2693 (2)0.74725 (6)0.0506 (4)
H3NA0.3945 (12)−0.386 (3)0.7646 (6)0.057 (6)*
H3NB0.3982 (15)−0.264 (4)0.7192 (8)0.083 (8)*
C10.38472 (9)0.1542 (2)0.82878 (5)0.0334 (3)
C20.39560 (10)−0.0607 (3)0.82140 (5)0.0401 (4)
H20.4031−0.16390.84440.048*
C30.39302 (9)−0.0890 (2)0.77325 (5)0.0359 (3)
C40.37681 (9)0.1656 (2)0.70563 (4)0.0317 (3)
C50.42957 (9)0.0699 (3)0.67137 (5)0.0391 (4)
H50.4681−0.03860.67970.047*
C60.42468 (10)0.1361 (3)0.62484 (5)0.0414 (4)
H60.45860.06880.60180.050*
C70.36981 (9)0.3015 (3)0.61242 (5)0.0379 (4)
C80.31728 (9)0.3982 (2)0.64632 (5)0.0374 (3)
H80.28030.50970.63810.045*
C90.32044 (9)0.3268 (2)0.69274 (4)0.0347 (3)
H90.28400.38870.71550.042*
C100.32253 (15)0.5386 (4)0.55199 (6)0.0687 (6)
H10A0.26040.51750.55910.103*
H10B0.32960.56200.51860.103*
H10C0.34420.65870.56910.103*
C110.38252 (9)0.2644 (3)0.87483 (5)0.0354 (3)
C120.33514 (10)0.4489 (3)0.88095 (5)0.0421 (4)
H120.30410.50730.85560.050*
C130.33371 (12)0.5473 (3)0.92489 (6)0.0534 (4)
H130.30180.67140.92890.064*
C140.37933 (12)0.4620 (3)0.96249 (6)0.0567 (5)
H140.37840.52850.99180.068*
C150.42634 (12)0.2785 (3)0.95670 (5)0.0550 (5)
H150.45710.22070.98220.066*
C160.42822 (11)0.1790 (3)0.91320 (5)0.0448 (4)
H160.46010.05460.90960.054*

Atomic displacement parameters (Å2)

U11U22U33U12U13U23
O0.0695 (8)0.0595 (9)0.0320 (5)0.0105 (6)0.0029 (5)0.0047 (5)
N10.0413 (6)0.0248 (8)0.0320 (5)−0.0005 (5)−0.0026 (4)−0.0017 (4)
N20.0451 (7)0.0306 (8)0.0315 (5)−0.0003 (5)−0.0004 (5)−0.0021 (5)
N30.0764 (10)0.0275 (9)0.0478 (8)−0.0004 (7)−0.0067 (7)−0.0014 (7)
C10.0349 (7)0.0311 (9)0.0342 (6)−0.0036 (6)0.0004 (5)0.0033 (6)
C20.0495 (8)0.0308 (10)0.0399 (7)−0.0004 (7)−0.0037 (6)0.0071 (6)
C30.0386 (7)0.0260 (9)0.0430 (7)−0.0005 (6)−0.0046 (5)0.0011 (6)
C40.0347 (7)0.0290 (9)0.0315 (6)−0.0037 (6)−0.0026 (5)0.0003 (5)
C50.0389 (7)0.0379 (10)0.0406 (7)0.0068 (6)−0.0009 (6)−0.0013 (6)
C60.0425 (8)0.0448 (11)0.0370 (7)0.0064 (7)0.0045 (6)−0.0061 (6)
C70.0418 (7)0.0405 (10)0.0315 (6)−0.0032 (6)−0.0007 (5)−0.0002 (6)
C80.0427 (8)0.0324 (9)0.0370 (7)0.0053 (6)−0.0031 (5)−0.0006 (6)
C90.0373 (7)0.0327 (9)0.0342 (6)0.0017 (6)0.0012 (5)−0.0048 (6)
C100.0913 (15)0.0668 (16)0.0481 (10)0.0174 (12)−0.0012 (9)0.0197 (9)
C110.0380 (7)0.0355 (10)0.0328 (6)−0.0062 (6)0.0033 (5)0.0032 (6)
C120.0463 (8)0.0394 (10)0.0406 (7)0.0001 (7)0.0015 (6)0.0012 (7)
C130.0587 (10)0.0483 (12)0.0532 (9)0.0046 (8)0.0083 (7)−0.0089 (8)
C140.0659 (11)0.0678 (15)0.0363 (8)−0.0051 (10)0.0071 (7)−0.0104 (8)
C150.0639 (11)0.0683 (15)0.0329 (7)−0.0030 (9)−0.0023 (7)0.0052 (8)
C160.0525 (9)0.0436 (11)0.0382 (7)0.0026 (8)0.0003 (6)0.0046 (7)

Geometric parameters (Å, °)

O—C71.3736 (16)C7—C81.3834 (19)
O—C101.415 (2)C8—H80.9300
N1—N21.3820 (16)C8—C91.3885 (18)
N1—C31.3607 (19)C9—H90.9300
N1—C41.4211 (16)C10—H10A0.9600
N2—C11.3307 (17)C10—H10B0.9600
N3—H3NA0.89 (2)C10—H10C0.9600
N3—H3NB0.79 (2)C11—C121.382 (2)
N3—C31.363 (2)C11—C161.392 (2)
C1—C21.393 (2)C12—H120.9300
C1—C111.4782 (19)C12—C131.391 (2)
C2—H20.9300C13—H130.9300
C2—C31.373 (2)C13—C141.374 (2)
C4—C51.3896 (19)C14—H140.9300
C4—C91.377 (2)C14—C151.373 (3)
C5—H50.9300C15—H150.9300
C5—C61.3823 (19)C15—C161.383 (2)
C6—H60.9300C16—H160.9300
C6—C71.380 (2)
C7—O—C10117.63 (13)C7—C8—C9119.26 (14)
N2—N1—C3111.85 (11)H8—C8—C9120.4
N2—N1—C4118.61 (12)C4—C9—C8120.95 (13)
C3—N1—C4129.54 (12)C4—C9—H9119.5
N1—N2—C1103.86 (12)C8—C9—H9119.5
H3NA—N3—H3NB126 (2)O—C10—H10A109.5
H3NA—N3—C3113.9 (12)O—C10—H10B109.5
H3NB—N3—C3120.3 (18)O—C10—H10C109.5
N2—C1—C2112.11 (12)H10A—C10—H10B109.5
N2—C1—C11121.01 (14)H10A—C10—H10C109.5
C2—C1—C11126.87 (13)H10B—C10—H10C109.5
C1—C2—H2127.1C1—C11—C12121.62 (13)
C1—C2—C3105.89 (13)C1—C11—C16119.26 (14)
H2—C2—C3127.1C12—C11—C16119.10 (14)
N1—C3—N3123.63 (13)C11—C12—H12119.9
N1—C3—C2106.28 (13)C11—C12—C13120.14 (15)
N3—C3—C2130.03 (15)H12—C12—C13119.9
N1—C4—C5121.32 (13)C12—C13—H13119.9
N1—C4—C9119.27 (12)C12—C13—C14120.28 (17)
C5—C4—C9119.38 (12)H13—C13—C14119.9
C4—C5—H5120.1C13—C14—H14120.1
C4—C5—C6119.90 (14)C13—C14—C15119.89 (15)
H5—C5—C6120.1H14—C14—C15120.1
C5—C6—H6119.8C14—C15—H15119.8
C5—C6—C7120.38 (13)C14—C15—C16120.38 (15)
H6—C6—C7119.8H15—C15—C16119.8
O—C7—C6115.73 (13)C11—C16—C15120.20 (16)
O—C7—C8124.18 (14)C11—C16—H16119.9
C6—C7—C8120.09 (13)C15—C16—H16119.9
C7—C8—H8120.4
C3—N1—N2—C10.13 (14)C10—O—C7—C85.6 (2)
C4—N1—N2—C1−179.13 (11)C5—C6—C7—O178.30 (14)
N1—N2—C1—C20.31 (15)C5—C6—C7—C8−1.9 (2)
N1—N2—C1—C11179.87 (11)O—C7—C8—C9179.71 (14)
N2—C1—C2—C3−0.62 (17)C6—C7—C8—C9−0.1 (2)
C11—C1—C2—C3179.85 (13)N1—C4—C9—C8176.33 (13)
N2—N1—C3—N3176.99 (14)C5—C4—C9—C8−1.6 (2)
N2—N1—C3—C2−0.51 (16)C7—C8—C9—C41.8 (2)
C4—N1—C3—N3−3.9 (2)N2—C1—C11—C1229.1 (2)
C4—N1—C3—C2178.65 (12)N2—C1—C11—C16−151.79 (14)
C1—C2—C3—N10.65 (16)C2—C1—C11—C12−151.35 (15)
C1—C2—C3—N3−176.62 (16)C2—C1—C11—C1627.7 (2)
N2—N1—C4—C5141.21 (14)C1—C11—C12—C13179.32 (14)
N2—N1—C4—C9−36.72 (18)C16—C11—C12—C130.3 (2)
C3—N1—C4—C5−37.9 (2)C11—C12—C13—C140.0 (3)
C3—N1—C4—C9144.17 (15)C12—C13—C14—C15−0.2 (3)
N1—C4—C5—C6−178.27 (13)C13—C14—C15—C160.1 (3)
C9—C4—C5—C6−0.3 (2)C14—C15—C16—C110.1 (3)
C4—C5—C6—C72.1 (2)C1—C11—C16—C15−179.39 (15)
C10—O—C7—C6−174.60 (16)C12—C11—C16—C15−0.3 (2)

Hydrogen-bond geometry (Å, °)

D—H···AD—HH···AD···AD—H···A
N3—H3NA···N2i0.89 (2)2.37 (2)3.228 (2)162.5 (16)

Symmetry codes: (i) x, y−1, z.

Footnotes

Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: LH2810).

References

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  • Joshi, K. C., Pathak, V. N. & Garg, U. (1979). J. Heterocycl. Chem.16, 1141–1145.
  • Macrae, C. F., Bruno, I. J., Chisholm, J. A., Edgington, P. R., McCabe, P., Pidcock, E., Rodriguez-Monge, L., Taylor, R., van de Streek, J. & Wood, P. A. (2008). J. Appl. Cryst.41, 466–470.
  • Michaux, C. & Charlier, C. (2004). Mini-Rev. Med. Chem 4, 603–615. [PubMed]
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