5-Methoxy­methyl-4-phen­oxy-1H-pyrazol-3-ol

In the title compound, C₁₁H₁₂N₂O₃, the pyrazole ring system is essentially planar [maximum deviation = 0.002 (2) Å] and forms a dihedral angle of 66.93 (9)° with the benzene ring. In the crystal packing, pairs of inter­molecular N—H...O and O—H...N hydrogen bonds connect neighbouring mol­ecules into dimers, generating R₂²(10) and R₂²(8) ring motifs, respectively. The crystal structure is further stabilized by C—H...π inter­actions.

Key indicators

• Single-crystal X-ray study
• T = 100 K
• Mean [sigma](C-C) = 0.002 Å
• R factor = 0.058
• wR factor = 0.138
• Data-to-parameter ratio = 17.8

checkCIF/PLATON results

No syntax errors found



Alert level C
SHFSU01_ALERT_2_C  Test not performed. _refine_ls_shift/su_max and
            _refine_ls_shift/esd_max not present.
            Absolute value of the parameter shift to su ratio given   0.001
PLAT912_ALERT_4_C Missing # of FCF Reflections Above STh/L=  0.600          4
PLAT927_ALERT_1_C Reported and Calculated  wR2 * 100.0 Differ by .      -0.13

Alert level G
PLAT960_ALERT_3_G Number of Intensities with I .LT. - 2*sig(I) ..           2
PLAT063_ALERT_4_G Crystal Size Likely too Large for Beam Size ....       0.69 mm
PLAT720_ALERT_4_G Number of Unusual/Non-Standard Labels ..........          2

   0 ALERT level A = In general: serious problem
   0 ALERT level B = Potentially serious problem
   3 ALERT level C = Check and explain
   3 ALERT level G = General alerts; check

   1 ALERT type 1 CIF construction/syntax error, inconsistent or missing data
   1 ALERT type 2 Indicator that the structure model may be wrong or deficient
   1 ALERT type 3 Indicator that the structure quality may be low
   3 ALERT type 4 Improvement, methodology, query or suggestion
   0 ALERT type 5 Informative message, check

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S1. Comment

Pyrazoles are an important class of heterocyclic compounds and many pyrazole derivatives have a broad spectrum of biological activities such as anti-inflammatory (Singh et al., 1978; Tewari & Mishra, 2001), anti-viral (Genin et al., 2000; Storer et al., 1999), anti-tumor (Hsu et al., 1956; Skipper et al., 1955), and herbicidal (Jung et al., 2002; Kudo et al., 1999) activities. Recently urea derivatives of pyrazole been reported as potent inhibitors of P³⁸ kinase (Duma, 2000), On the other hand, pyrazole derivatives are anti-angiogenic agent (Qiao et al., 2003), A3 adenosine receptor antagonist (Baraldi et al., 2003), neuropeptide YY5 receptor antagonists (Stamford & Wu, 2004) and kinase inhibitor for the treatment of type 2 diabetes, hyperlipidemia and obesity (Brown et al., 2004) as well as thrombopiotinmimetics (Heerding, 2003). Since the high electronegativity of halogens (particularly chlorine and fluorine) in the aromatic part of the drug molecules play an important role in enhancing their biological activity, we are interested to have 4-fluoro and 4-chloro substituted phenyl rings in the aromatic part of a 1,5-diaryl pyrazole. As part of our on going research programme aiming at the synthesis of new anti-microbial compounds, herein we report the crystal structure of a novel pyrazole derivative.

In the crystal structure (Fig. 1), the pyrazole ring system (C7/C8/N2/N1/C11) is approximately planar, with a maximum deviation of 0.002 (2) Å for atom C11. The dihedral angle formed between the mean plane of pyrazole ring and the benzene ring (C1–C6) is 66.93 (9)°. The bond lengths (Allen et al., 1987) and angles are within normal ranges and comparable to a closely related structure (Goh et al., 2009).

In the crystal packing (Fig. 2), pairs of intermolecular N2—H1N2···O2ⁱ and O3—H1O3···N1ⁱⁱ hydrogen bonds (Table 1) connect neighbouring molecules, into dimers, generating R₂²(10) and R₂²(8) ring motifs (Bernstein et al., 1995), respectively. The crystal structure is further stabilized by C—H···π interactions (Table 1), involving the C1–C6 (centroid Cg1) benzene ring.

Related literature

For the biological activity of pyrazoles, see: Genin et al. (2000); Hsu et al. (1956); Jung et al. (2002); Kudo et al. (1999); Singh et al. (1978); Skipper et al. (1955); Storer et al. (1999); Tewari & Mishra (2001). For pyrazole derivatives, see: Baraldi et al. (2003); Brown et al. (2004); Duma et al. (2000); Heerding (2003); Qiao et al. (2003); Stamford & Wu (2004). For a related structure, see: Goh et al. (2009). For hydrogen-bond motifs, see: Bernstein et al. (1995). For bond-length data, see: Allen et al. (1987). For the stability of the temperature controller used for the data collection, see: Cosier & Glazer (1986). Cg1 is the centroid of the C1–C6 benzene ring.

S2. Experimental

LiHMDS (19.4 ml, 1.0 min THF, 19.4 mmol) was added quickly to the solution of oxyacetic acid ethyl ester (1.0 g, 5.5 mmol) in toluene (15.0 ml) using syringe at 195 K with agitation and the anion formed was allowed to stand for approximately 1 min, and then 2-methoxyacetyl chloride (1.0 ml, 13.8 mmol) was added into the lot with stirring. Reaction mixture was removed from acetone-dry ice bath and stirred for 10 min then acetic acid (2.0 ml) was added with stirring. Ethanol (15.0 ml) and hydrazine hydrate (1.5 ml, 44.0 mmol) was added and refluxed for 10 min. Reaction mixture was concentrated to dryness under reduced pressure and redissolved in ethyl acetate. The organic layer was washed with saturated brine solution, dried over Na₂SO₄ and evaporated under reduced pressure. Crude product was purified by column chromatography using a mixture of 1:99 methanol and ethylacetate. Pale yellow solid was obtained. Mp. 418.8–419.8 K. Yield: 57%.

S3. Refinement

All hydrogen atoms were located in a difference map and were refined freely. [Range of C—H = 0.94 (2)–1.03 (2) Å].

Computing details

Data collection: APEX2 (Bruker, 2005); cell refinement: SAINT (Bruker, 2005); data reduction: SAINT (Bruker, 2005); program(s) used to solve structure: SHELXTL (Sheldrick, 2008); program(s) used to refine structure: SHELXTL (Sheldrick, 2008); molecular graphics: SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXTL (Sheldrick, 2008) and PLATON (Spek, 2009).

Figures

	Fig. 1. The molecular structure of the title compound, showing 50% probability displacement ellipsoids and the atom numbering scheme.
	Fig. 2. The crystal packing of the title compound, viewed along a axis. Intermolecular hydrogen bonds are shown by dashed lines.

5-Methoxymethyl-4-phenoxy-1H-pyrazol-3-ol

Crystal data

C11H12N2O3	F(000) = 464
Mr = 220.23	Dx = 1.355 Mg m^−3
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ybc	Cell parameters from 6087 reflections
a = 8.8876 (5) Å	θ = 2.3–32.2°
b = 10.3031 (5) Å	µ = 0.10 mm^−1
c = 12.0083 (6) Å	T = 100 K
β = 100.917 (3)°	Plate, yellow
V = 1079.7 (1) Å^3	0.69 × 0.57 × 0.18 mm
Z = 4

Data collection

Bruker SMART APEXII CCD area-detector diffractometer	3433 independent reflections
Radiation source: fine-focus sealed tube	2373 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.032
ϕ and ω scans	θmax = 31.0°, θmin = 2.3°
Absorption correction: multi-scan (SADABS; Bruker, 2005)	h = −12→11
Tmin = 0.934, Tmax = 0.983	k = −14→14
14470 measured reflections	l = −17→17

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.058	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.138	All H-atom parameters refined
S = 1.10	w = 1/[σ^2(Fo^2) + (0.0465P)^2 + 0.7446P] where P = (Fo^2 + 2Fc^2)/3
3433 reflections	(Δ/σ)max < 0.001
193 parameters	Δρmax = 0.45 e Å^−3
0 restraints	Δρmin = −0.33 e Å^−3

Special details

Experimental. The crystal was placed in the cold stream of an Oxford Cyrosystems Cobra open-flow nitrogen cryostat (Cosier & Glazer, 1986) operating at 100.0 (1) K.

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
O1	0.79382 (13)	0.20467 (12)	0.25817 (9)	0.0209 (3)
O2	0.84461 (13)	0.54359 (11)	0.06550 (11)	0.0243 (3)
O3	0.86330 (14)	−0.01790 (11)	0.10686 (10)	0.0210 (3)
N1	0.97188 (15)	0.15166 (12)	0.01762 (11)	0.0187 (3)
N2	0.98156 (16)	0.28291 (13)	0.03420 (12)	0.0197 (3)
C1	0.5751 (2)	0.2793 (2)	0.32287 (16)	0.0313 (4)
C2	0.4180 (2)	0.2854 (2)	0.31444 (19)	0.0373 (5)
C3	0.3212 (2)	0.2243 (2)	0.22663 (17)	0.0315 (4)
C4	0.3817 (2)	0.1569 (2)	0.14638 (17)	0.0339 (4)
C5	0.5396 (2)	0.1508 (2)	0.15308 (16)	0.0293 (4)
C6	0.63487 (18)	0.21173 (15)	0.24200 (13)	0.0182 (3)
C7	0.85883 (17)	0.21114 (15)	0.16285 (13)	0.0178 (3)
C8	0.91537 (18)	0.32155 (15)	0.12032 (13)	0.0188 (3)
C9	0.9123 (2)	0.46065 (16)	0.15618 (14)	0.0222 (3)
C10	0.6866 (2)	0.51602 (19)	0.02363 (19)	0.0310 (4)
C11	0.89717 (17)	0.10779 (15)	0.09653 (13)	0.0177 (3)
H1A	0.644 (3)	0.324 (2)	0.3821 (19)	0.042 (6)*
H2A	0.375 (3)	0.334 (3)	0.368 (2)	0.056 (8)*
H3A	0.214 (3)	0.227 (2)	0.2222 (19)	0.039 (6)*
H4A	0.315 (3)	0.112 (3)	0.087 (2)	0.050 (7)*
H5A	0.583 (2)	0.106 (2)	0.0976 (18)	0.033 (6)*
H9A	1.017 (2)	0.4927 (19)	0.1791 (16)	0.021 (5)*
H9B	0.853 (2)	0.466 (2)	0.2184 (17)	0.028 (5)*
H10A	0.678 (2)	0.428 (2)	−0.0107 (19)	0.038 (6)*
H10B	0.652 (3)	0.582 (3)	−0.032 (2)	0.047 (7)*
H10C	0.625 (3)	0.518 (2)	0.088 (2)	0.041 (6)*
H1N2	1.038 (2)	0.329 (2)	−0.0073 (17)	0.024 (5)*
H1O3	0.924 (3)	−0.065 (2)	0.067 (2)	0.047 (7)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.0193 (5)	0.0261 (6)	0.0184 (5)	0.0006 (5)	0.0062 (4)	−0.0018 (4)
O2	0.0232 (6)	0.0139 (6)	0.0362 (7)	−0.0005 (4)	0.0070 (5)	0.0036 (5)
O3	0.0265 (6)	0.0133 (5)	0.0264 (6)	−0.0028 (5)	0.0134 (5)	−0.0010 (4)
N1	0.0228 (7)	0.0116 (6)	0.0232 (6)	0.0002 (5)	0.0081 (5)	0.0000 (5)
N2	0.0233 (7)	0.0131 (6)	0.0246 (7)	−0.0006 (5)	0.0091 (5)	0.0009 (5)
C1	0.0302 (9)	0.0340 (11)	0.0320 (9)	−0.0006 (8)	0.0114 (7)	−0.0121 (8)
C2	0.0321 (10)	0.0416 (12)	0.0431 (11)	0.0074 (9)	0.0194 (9)	−0.0070 (9)
C3	0.0215 (8)	0.0372 (11)	0.0378 (10)	0.0046 (8)	0.0110 (7)	0.0117 (8)
C4	0.0228 (9)	0.0446 (12)	0.0332 (10)	−0.0023 (8)	0.0027 (7)	−0.0019 (9)
C5	0.0236 (9)	0.0364 (11)	0.0286 (9)	0.0012 (7)	0.0065 (7)	−0.0094 (8)
C6	0.0198 (7)	0.0143 (7)	0.0220 (7)	0.0012 (6)	0.0080 (6)	0.0024 (6)
C7	0.0187 (7)	0.0175 (7)	0.0178 (7)	0.0007 (6)	0.0051 (5)	−0.0002 (6)
C8	0.0191 (7)	0.0154 (7)	0.0218 (7)	0.0013 (6)	0.0038 (6)	−0.0012 (6)
C9	0.0254 (8)	0.0153 (8)	0.0263 (8)	0.0004 (6)	0.0056 (6)	−0.0022 (6)
C10	0.0238 (9)	0.0213 (9)	0.0462 (11)	0.0011 (7)	0.0020 (8)	0.0031 (8)
C11	0.0181 (7)	0.0159 (7)	0.0198 (7)	−0.0007 (6)	0.0054 (5)	0.0001 (6)

Geometric parameters (Å, º)

O1—C7	1.3781 (18)	C3—C4	1.377 (3)
O1—C6	1.3910 (19)	C3—H3A	0.94 (2)
O2—C9	1.425 (2)	C4—C5	1.392 (3)
O2—C10	1.427 (2)	C4—H4A	0.96 (3)
O3—C11	1.3406 (19)	C5—C6	1.382 (2)
O3—H1O3	0.92 (3)	C5—H5A	0.95 (2)
N1—C11	1.335 (2)	C7—C8	1.380 (2)
N1—N2	1.3672 (19)	C7—C11	1.410 (2)
N2—C8	1.343 (2)	C8—C9	1.498 (2)
N2—H1N2	0.91 (2)	C9—H9A	0.98 (2)
C1—C6	1.380 (2)	C9—H9B	0.99 (2)
C1—C2	1.383 (3)	C10—H10A	0.99 (2)
C1—H1A	0.96 (2)	C10—H10B	0.96 (3)
C2—C3	1.380 (3)	C10—H10C	1.03 (2)
C2—H2A	0.95 (3)
C7—O1—C6	117.13 (12)	C1—C6—O1	116.36 (15)
C9—O2—C10	113.24 (13)	C5—C6—O1	122.80 (14)
C11—O3—H1O3	107.0 (15)	O1—C7—C8	125.92 (14)
C11—N1—N2	104.93 (13)	O1—C7—C11	128.09 (14)
C8—N2—N1	112.37 (13)	C8—C7—C11	105.64 (14)
C8—N2—H1N2	129.8 (13)	N2—C8—C7	106.50 (14)
N1—N2—H1N2	117.5 (13)	N2—C8—C9	122.63 (14)
C6—C1—C2	119.29 (18)	C7—C8—C9	130.87 (15)
C6—C1—H1A	119.0 (14)	O2—C9—C8	112.47 (13)
C2—C1—H1A	121.7 (14)	O2—C9—H9A	104.7 (11)
C3—C2—C1	120.65 (18)	C8—C9—H9A	109.7 (11)
C3—C2—H2A	119.0 (16)	O2—C9—H9B	109.6 (12)
C1—C2—H2A	120.3 (16)	C8—C9—H9B	107.9 (12)
C4—C3—C2	119.72 (17)	H9A—C9—H9B	112.5 (16)
C4—C3—H3A	119.8 (14)	O2—C10—H10A	108.6 (13)
C2—C3—H3A	120.5 (14)	O2—C10—H10B	105.4 (14)
C3—C4—C5	120.34 (18)	H10A—C10—H10B	111.7 (19)
C3—C4—H4A	119.9 (15)	O2—C10—H10C	111.1 (13)
C5—C4—H4A	119.7 (15)	H10A—C10—H10C	108.8 (18)
C6—C5—C4	119.20 (17)	H10B—C10—H10C	111.3 (19)
C6—C5—H5A	119.6 (13)	N1—C11—O3	122.92 (14)
C4—C5—H5A	121.2 (13)	N1—C11—C7	110.57 (14)
C1—C6—C5	120.79 (16)	O3—C11—C7	126.51 (14)
C11—N1—N2—C8	−0.09 (17)	N1—N2—C8—C9	179.33 (14)
C6—C1—C2—C3	0.3 (3)	O1—C7—C8—N2	173.96 (14)
C1—C2—C3—C4	−0.2 (3)	C11—C7—C8—N2	0.26 (17)
C2—C3—C4—C5	−0.4 (3)	O1—C7—C8—C9	−5.4 (3)
C3—C4—C5—C6	0.9 (3)	C11—C7—C8—C9	−179.12 (16)
C2—C1—C6—C5	0.2 (3)	C10—O2—C9—C8	64.02 (19)
C2—C1—C6—O1	−177.32 (17)	N2—C8—C9—O2	56.1 (2)
C4—C5—C6—C1	−0.7 (3)	C7—C8—C9—O2	−124.58 (18)
C4—C5—C6—O1	176.57 (17)	N2—N1—C11—O3	179.16 (14)
C7—O1—C6—C1	−142.80 (16)	N2—N1—C11—C7	0.26 (17)
C7—O1—C6—C5	39.8 (2)	O1—C7—C11—N1	−173.85 (14)
C6—O1—C7—C8	95.50 (18)	C8—C7—C11—N1	−0.33 (18)
C6—O1—C7—C11	−92.22 (19)	O1—C7—C11—O3	7.3 (3)
N1—N2—C8—C7	−0.12 (18)	C8—C7—C11—O3	−179.19 (15)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N2—H1N2···O2^i	0.91 (2)	1.89 (2)	2.7778 (18)	165.7 (19)
O3—H1O3···N1^ii	0.92 (2)	1.74 (2)	2.6663 (18)	176 (2)
C3—H3A···Cg1^iii	0.94 (2)	2.77 (3)	2.73	147.6 (18)

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