4-Difluoro­methyl-1-(4-methyl­phen­yl)-1H-1,2,3-triazole

Costa, M.S.; Boechat, N.; Ferreira, V.F.; Wardell, S.M.S.V.; Skakle, J.M.S.

doi:10.1107/S1600536806013286

organic compounds

CRYSTALLOGRAPHIC
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ISSN: 2056-9890

Volume 62| Part 5| May 2006| Pages o1925-o1927

https://doi.org/10.1107/S1600536806013286

4-Difluoromethyl-1-(4-methylphenyl)-1H-1,2,3-triazole

Marilia S. Costa,^a Nubia Boechat,^a Vitor F. Ferreira,^b Solange M. S. V. Wardell ^a and Janet M. S. Skakle ^c ^*

^aFundação Oswaldo Cruz, Instituto de Tecnologia em Fármacos, Departamento de Síntese Orgânica, Manguinhos, CEP 21041-250 Rio de Janeiro, RJ, Brazil, ^bUniversidade Federal Fluminense, Departamento de Química Orgânica, Instituto de Química, Outeiro de São João Baptista, CEP 24020-150 Niterói, RJ, Brazil, and ^cDepartment of Chemistry, College of Physical Sciences, University of Aberdeen, Meston Walk, Aberdeen AB24 3UE, Scotland
^*Correspondence e-mail: j.skakle@abdn.ac.uk

(Received 11 April 2006; accepted 11 April 2006; online 21 April 2006)

In the crystal structure of the title compound, C₁₀H₉F₂N₃, weak hydrogen bonding involving the triazole and difluoromethyl groups leads to the formation of chains along [010]. The benzene and triazole rings are essentially coplanar, with an angle of 0.34 (17)° between the planes defined by the two rings.

Comment

Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains a leading cause of mortality worldwide. The World Health Organization estimates that about one-third of the world's population harbours latent infection of TB. Among such infected individuals, approximately eight million develop active TB, and almost two million of these die from the disease each year. 95% of new TB cases occur in developing countries. The current human immunodeficiency virus (AIDS) pandemic and resistance to the currently available drugs are proving major obstacles to the control of tuberculosis (Tewari et al., 2004 ; World Health Organization, 2005 ; Tripathi et al., 2005 ). Chemotherapy of TB started in the 1940s. Various drugs have been used against TB, including para-aminosalicylic acid, isoniazid, pyrazinamide, cycloserine, ethionamide, rifampicin and ethambutol. However, six decades have passed without any significant development of new chemical treatments of tuberculosis. TB really can be classed as a neglected disease.

In pursuit of new drugs for TB, we have synthesized a series of 1-aryl-4-difluoromethyl-1,2,3-triazole derivatives and evaluated their inhibitory activities against Mycobacterium tuberculosis. All derivatives exhibited tuberculosis inhibitory activity; a full description of biological tests will be reported elsewhere (Costa, Boechat, Rangel et al., 2006 ). The structure of 1-(4-methylphenyl)-4-difluoromethyl-1H-1,2,3-triazole, which exhibited 87% of inhibition at a concentration of 40.0 µg ml⁻¹, is reported here.

The geometry of the title molecular structure (Fig. 1) was analysed with the aid of PLATON (Spek, 2003 ). The methyl group is almost coplanar with the aryl ring, with a torsion angle C7—C8—C9—C91 = 178.2 (3)°. Excluding the difluoromethyl group, the molecule is planar, with an angle between the planes defined by the triazole and aryl rings of 0.34 (17) Å. This is in marked contrast to the orientations in1-(2,5-dimethoxyphenyl)-4-difluoromethyl-1H-1,2,3-triazole (Costa, Boechat, Ferreira, Wardell & Skakle, 2006 ), in which the substituent methoxy groups on the aryl ring cause a marked deviation from planarity.

With no scope for strong hydrogen bonding in the structure, weak hydrogen bonds exist (Table 1); an intramolecular hydrogen bond provides additional support between the triazole and aryl ring (C7—H7⋯N2). All other hydrogen bonds involve donors and acceptors within the triazole–difluoromethyl unit, and lead to the formation of chains along [010] (Fig. 2).

Figure 1
The molecular structure of the title compound, showing displacement ellipsoids at the 50% probability level. H atoms are shown as circles of arbitrary radii and the dashed line indicates a weak hydrogen bond.

Figure 2
Part of the structure of the title compound, showing the formation of hydrogen-bonded (dashed lines) chains along [010]. Ellipsoids and H atoms are shown as in Fig. 1

. [Symmetry code: (i) $[{3\over 2}]$ − x, − $[{1\over 2}]$ + y, $[{1\over 2}]$ − z].

Experimental

A solution of diazomalonaldehyde (5.0 mmol) in water (30 ml) was added dropwise to a stirred solution of 4-aminotoluene hydrochloride (4.5 mmol) in water (5 ml). The reaction mixture was stirred for 24 h at room temperature; the solid was collected, washed with cold water and crystallized from aqueous ethanol. The title compound was obtained in 93% yield as colourless solid, m.p. 351–352 K. Analysis calculated for C₁₀H₉F₂N₃: C 57.41, H 4.34, N 20.09%; found: C 57.45, H 4.37, N 19.97%. Full spectroscopic data are given in the CIF.

Crystal data

C₁₀H₉F₂N₃
M_r = 209.20
Monoclinic, P 2₁ /n
a = 4.6055 (6) Å
b = 9.4285 (9) Å
c = 21.459 (3) Å
β = 92.136 (5)°
V = 931.2 (2) Å³
Z = 4
D_x = 1.492 Mg m⁻³
Mo Kα radiation
μ = 0.12 mm⁻¹
T = 120 (2) K
Cut blade, colourless
0.22 × 0.11 × 0.03 mm

Data collection

Bruker–Nonius KappaCCD diffractometer
φ and ω scans
Absorption correction: multi-scan (SADABS; Sheldrick, 2003 ) T_min = 0.636, T_max = 1.000
8742 measured reflections
2112 independent reflections
1262 reflections with I > 2σ(I)
R_int = 0.071
θ_max = 27.7°

Refinement

Refinement on F²
R[F² > 2σ(F²)] = 0.062
wR(F²) = 0.160
S = 1.03
2112 reflections
139 parameters
H-atom parameters constrained
w = 1/[σ²(F_o²) + (0.0577P)² + 0.6473P] where P = (F_o² + 2F_c²)/3
(Δ/σ)_max < 0.001
Δρ_max = 0.24 e Å⁻³
Δρ_min = −0.32 e Å⁻³

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C7—H7⋯N2	0.95	2.45	2.780 (3)	100
C5—H5⋯F1ⁱ	0.93	2.52	3.421 (3)	164
C41—H41⋯N2ⁱ	1.00	2.46	3.458 (3)	173
C41—H41⋯N3ⁱ	1.00	2.47	3.403 (3)	155
Symmetry code: (i) $[-x+{\script{3\over 2}}, y-{\script{1\over 2}}, -z+{\script{1\over 2}}]$ .

All H atoms were located in difference maps and then treated as riding atoms, with C—H distances of 0.93 Å (triazole), 0.95 Å (aryl), 1.00 Å (tertiary –CHF₂) and 0.98 Å (methyl). U_iso values for the triazole and tertiary H were freely refined; otherwise U_iso(H) values were set at 1.2U_eq(aryl C) or 1.5U_eq(methyl C).

Data collection: COLLECT (Hooft, 1998 ); cell refinement: DENZO (Otwinowski & Minor, 1997 ) and COLLECT; data reduction: DENZO and COLLECT; program(s) used to solve structure: OSCAIL (McArdle, 2003 ) and SHELXS97 (Sheldrick, 1997 ); program(s) used to refine structure: OSCAIL and SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEP-3 for Windows (Farrugia, 1997 ); software used to prepare material for publication: CIFTAB (Sheldrick, 1997).

Supporting information

Crystal structure: contains datablocks global, I. DOI: https://doi.org/10.1107/S1600536806013286/lh2049sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S1600536806013286/lh2049Isup2.hkl

Computing details top

Data collection: COLLECT (Hooft, 1998); cell refinement: DENZO (Otwinowski & Minor, 1997) and COLLECT; data reduction: DENZO and COLLECT; program(s) used to solve structure: OSCAIL (McArdle, 2003) and SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: OSCAIL and SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEP-3 for Windows (Farrugia, 1997); software used to prepare material for publication: CIFTAB (Sheldrick, 1997).

4-Difluoromethyl-1-(4-methylphenyl)-1H-1,2,3-triazole top

Crystal data top

C₁₀H₉F₂N₃	F(000) = 432
M_r = 209.20	D_x = 1.492 Mg m⁻³
Monoclinic, P2₁/n	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2yn	Cell parameters from 1891 reflections
a = 4.6055 (6) Å	θ = 2.9–27.5°
b = 9.4285 (9) Å	µ = 0.12 mm⁻¹
c = 21.459 (3) Å	T = 120 K
β = 92.136 (5)°	Cut blade, colourless
V = 931.2 (2) Å³	0.22 × 0.11 × 0.03 mm
Z = 4

Data collection top

Bruker–Nonius KappaCCD diffractometer	2112 independent reflections
Radiation source: Bruker-Nonius FR591 rotating anode	1262 reflections with I > 2σ(I)
10 cm confocal mirrors monochromator	R_int = 0.071
Detector resolution: 9.091 pixels mm^-1	θ_max = 27.7°, θ_min = 3.6°
φ and ω scans	h = −5→6
Absorption correction: multi-scan (SADABS; Sheldrick, 2003)	k = −10→12
T_min = 0.636, T_max = 1.000	l = −27→18
8742 measured reflections

Refinement top

Refinement on F²	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F² > 2σ(F²)] = 0.062	Hydrogen site location: difference Fourier map
wR(F²) = 0.160	H-atom parameters constrained
S = 1.03	w = 1/[σ²(F_o²) + (0.0577P)² + 0.6473P] where P = (F_o² + 2F_c²)/3
2112 reflections	(Δ/σ)_max < 0.001
139 parameters	Δρ_max = 0.24 e Å⁻³
0 restraints	Δρ_min = −0.32 e Å⁻³

Special details top

Experimental. IR (KBr, ν_max, cm^-1): 3162, 1031, 3152, 1043. ¹H NMR (500 MHz, CDCl₃/Me₄Si): δ 2.43 (s, 1H, CH₃), 6.94 (t, 1H, CF₂H, J = 54.5 Hz), 7.31 (d, 2H, J = 8.8 Hz, arom.), 7.60 (d, 2H, J = 8.8 Hz, arom.), 8.18 (s, 1H, triazole); ¹³C NMR (125 MHz, CDCl₃/Me₄Si): δ 20.5 (CH₃), 109.5 (t, CF₂H, J = 233.4 Hz), 119.9, 139.1, 133.6, 129.8, 120.1, 142.7 (t, J = 28.5 Hz); ¹⁹F NMR (376.0 MHz, CDCl₃/CFCl₃): δ -112.3 (2 F, CHF₂); EIMS (m/z): 209 (M⁺, 42%), 180 (M⁺-29, 68%), 162 (M⁺-47, 40%), 130 (M⁺-79, 42%), 91 (M⁺-118, 100%).

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) top

	x	y	z	U_iso*/U_eq
N1	0.3195 (5)	0.8343 (2)	0.31724 (10)	0.0260 (5)
N2	0.3710 (5)	0.9715 (2)	0.30179 (11)	0.0310 (6)
N3	0.5439 (5)	0.9707 (2)	0.25457 (10)	0.0295 (6)
C4	0.6035 (5)	0.8331 (3)	0.24014 (12)	0.0250 (6)
C41	0.7803 (6)	0.7957 (3)	0.18634 (13)	0.0302 (7)
H41	0.8804	0.7028	0.1939	0.039 (8)*
F1	0.9784 (3)	0.89866 (16)	0.17542 (8)	0.0393 (5)
F2	0.6082 (3)	0.78929 (19)	0.13270 (8)	0.0431 (5)
C5	0.4641 (5)	0.7459 (3)	0.27948 (12)	0.0255 (6)
H5	0.4614	0.6481	0.2836	0.020 (7)*
C6	0.1326 (5)	0.8032 (3)	0.36744 (12)	0.0237 (6)
C7	0.0059 (6)	0.9134 (3)	0.39883 (13)	0.0308 (7)
H7	0.0411	1.0089	0.3872	0.037*
C8	−0.1735 (6)	0.8830 (3)	0.44753 (13)	0.0331 (7)
H8	−0.2600	0.9591	0.4692	0.040*
C9	−0.2305 (5)	0.7448 (3)	0.46568 (13)	0.0295 (7)
C91	−0.4185 (6)	0.7151 (3)	0.51982 (14)	0.0363 (7)
H91A	−0.3959	0.6157	0.5324	0.047*
H92B	−0.6221	0.7335	0.5076	0.047*
H93C	−0.3601	0.7768	0.5549	0.047*
C10	−0.1033 (6)	0.6371 (3)	0.43229 (13)	0.0308 (7)
H10	−0.1404	0.5414	0.4433	0.037*
C11	0.0768 (6)	0.6648 (3)	0.38327 (12)	0.0279 (6)
H11	0.1605	0.5890	0.3609	0.033*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
N1	0.0313 (12)	0.0172 (11)	0.0294 (13)	−0.0014 (9)	−0.0006 (10)	0.0012 (10)
N2	0.0445 (14)	0.0177 (12)	0.0309 (14)	−0.0011 (10)	0.0047 (12)	0.0025 (10)
N3	0.0411 (14)	0.0194 (12)	0.0283 (13)	−0.0006 (10)	0.0045 (11)	0.0014 (10)
C4	0.0294 (14)	0.0180 (13)	0.0274 (15)	−0.0021 (11)	−0.0009 (12)	0.0012 (11)
C41	0.0373 (16)	0.0207 (14)	0.0323 (17)	−0.0031 (12)	−0.0006 (13)	0.0034 (12)
F1	0.0369 (9)	0.0341 (10)	0.0475 (11)	−0.0100 (7)	0.0101 (8)	−0.0035 (8)
F2	0.0420 (10)	0.0563 (12)	0.0311 (10)	−0.0080 (8)	0.0021 (8)	−0.0078 (8)
C5	0.0270 (13)	0.0177 (14)	0.0314 (16)	0.0002 (11)	−0.0036 (12)	−0.0013 (11)
C6	0.0254 (13)	0.0229 (14)	0.0226 (14)	−0.0026 (11)	−0.0012 (11)	0.0017 (11)
C7	0.0342 (15)	0.0213 (14)	0.0370 (17)	0.0008 (12)	0.0008 (13)	−0.0006 (12)
C8	0.0315 (15)	0.0303 (15)	0.0375 (17)	0.0046 (12)	0.0021 (13)	−0.0037 (13)
C9	0.0223 (13)	0.0363 (17)	0.0297 (16)	−0.0014 (12)	−0.0035 (12)	0.0003 (13)
C91	0.0312 (15)	0.0401 (17)	0.0377 (18)	−0.0033 (13)	0.0037 (13)	−0.0010 (14)
C10	0.0387 (16)	0.0235 (14)	0.0302 (16)	−0.0047 (12)	0.0005 (13)	0.0022 (12)
C11	0.0335 (15)	0.0225 (14)	0.0276 (15)	0.0006 (11)	0.0000 (12)	−0.0023 (12)

Geometric parameters (Å, º) top

N1—C5	1.355 (3)	C7—C8	1.386 (4)
N1—N2	1.358 (3)	C7—H7	0.9500
N1—C6	1.434 (3)	C8—C9	1.388 (4)
N2—N3	1.312 (3)	C8—H8	0.9500
N3—C4	1.364 (3)	C9—C10	1.385 (4)
C4—C5	1.357 (4)	C9—C91	1.501 (4)
C4—C41	1.480 (4)	C91—H91A	0.9800
C41—F1	1.358 (3)	C91—H92B	0.9800
C41—F2	1.374 (3)	C91—H93C	0.9800
C41—H41	1.0000	C10—C11	1.388 (4)
C5—H5	0.9262	C10—H10	0.9500
C6—C11	1.375 (4)	C11—H11	0.9500
C6—C7	1.380 (4)

C5—N1—N2	110.2 (2)	C6—C7—H7	120.4
C5—N1—C6	130.2 (2)	C8—C7—H7	120.4
N2—N1—C6	119.6 (2)	C7—C8—C9	122.0 (2)
N3—N2—N1	107.44 (19)	C7—C8—H8	119.0
N2—N3—C4	108.3 (2)	C9—C8—H8	119.0
C5—C4—N3	109.3 (2)	C10—C9—C8	117.0 (2)
C5—C4—C41	128.9 (2)	C10—C9—C91	122.1 (2)
N3—C4—C41	121.7 (2)	C8—C9—C91	120.9 (2)
F1—C41—F2	104.9 (2)	C9—C91—H91A	109.5
F1—C41—C4	110.9 (2)	C9—C91—H92B	109.5
F2—C41—C4	110.3 (2)	H91A—C91—H92B	109.5
F1—C41—H41	110.2	C9—C91—H93C	109.5
F2—C41—H41	110.2	H91A—C91—H93C	109.5
C4—C41—H41	110.2	H92B—C91—H93C	109.5
N1—C5—C4	104.7 (2)	C9—C10—C11	122.0 (2)
N1—C5—H5	123.2	C9—C10—H10	119.0
C4—C5—H5	132.1	C11—C10—H10	119.0
C11—C6—C7	120.5 (2)	C6—C11—C10	119.2 (2)
C11—C6—N1	120.2 (2)	C6—C11—H11	120.4
C7—C6—N1	119.3 (2)	C10—C11—H11	120.4
C6—C7—C8	119.1 (2)

C5—N1—N2—N3	0.5 (3)	N2—N1—C6—C11	179.5 (2)
C6—N1—N2—N3	−179.3 (2)	C5—N1—C6—C7	−179.1 (3)
N1—N2—N3—C4	−0.3 (3)	N2—N1—C6—C7	0.6 (4)
N2—N3—C4—C5	−0.1 (3)	C11—C6—C7—C8	1.5 (4)
N2—N3—C4—C41	176.5 (2)	N1—C6—C7—C8	−179.7 (2)
C5—C4—C41—F1	−153.8 (3)	C6—C7—C8—C9	−0.2 (4)
N3—C4—C41—F1	30.4 (4)	C7—C8—C9—C10	−0.9 (4)
C5—C4—C41—F2	90.4 (3)	C7—C8—C9—C91	178.2 (3)
N3—C4—C41—F2	−85.4 (3)	C8—C9—C10—C11	0.8 (4)
N2—N1—C5—C4	−0.5 (3)	C91—C9—C10—C11	−178.2 (3)
C6—N1—C5—C4	179.3 (3)	C7—C6—C11—C10	−1.5 (4)
N3—C4—C5—N1	0.3 (3)	N1—C6—C11—C10	179.6 (2)
C41—C4—C5—N1	−175.8 (3)	C9—C10—C11—C6	0.4 (4)
C5—N1—C6—C11	−0.2 (4)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
C7—H7···N2	0.95	2.45	2.780 (3)	100
C5—H5···F1ⁱ	0.93	2.52	3.421 (3)	164
C41—H41···N2ⁱ	1.00	2.46	3.458 (3)	173
C41—H41···N3ⁱ	1.00	2.47	3.403 (3)	155

Symmetry code: (i) −x+3/2, y−1/2, −z+1/2.

Acknowledgements

We are indebted to the EPSRC for the use of both the Chemical Database Service at Daresbury, England, primarily for access to the Cambridge Structural Database (Fletcher et al., 1996 ), and the X-ray service at the University of Southampton, England, for data collection.

References

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