3,4-Di­fluoro-2-hy­dr­oxy­benzoic acid

In the title compound, C₇H₄F₂O₃, an intra­molecular O—H⋯O hydrogen bond is observed. In the crystal, inversion dimers linked by pairs of O—H⋯O hydrogen bonds generate R₂²(8) ring motifs. These dimers are linked by C—H⋯O and C—H⋯F hydrogen bonds, forming sheets lying parallel to (30-1). The sheets are linked by aromatic π–π stacking inter­actions [inter-centroid distance = 3.7817 (9) Å], forming a three-dimensional structure.

Related literature

For anti­body and gene-directed enzyme prodrug therapy, see: Springer et al. (1994); Davies et al. (2005). For the anti­microbial activity of fluorinated benzoic acid derivatives, see: Rajasekhar et al. (2013).

Experimental

Crystal data

• C₇H₄F₂O₃

• M_r = 174.10

• Monoclinic, P 2₁ /n

• a = 9.4252 (8) Å

• b = 6.8145 (5) Å

• c = 11.0391 (8) Å

• β = 106.257 (5)°

• V = 680.67 (9) ų

• Z = 4

• Mo Kα radiation

• μ = 0.17 mm⁻¹

• T = 296 K

• 0.20 × 0.16 × 0.12 mm

Data collection

• Bruker APEXII CCD area-detector diffractometer

• Absorption correction: multi-scan (SADABS; Sheldrick, 2007) T_min = 0.967, T_max = 0.980

• 6362 measured reflections

• 1344 independent reflections

• 1045 reflections with I > 2σ(I)

• R_int = 0.037

Refinement

• R[F² > 2σ(F²)] = 0.031

• wR(F²) = 0.094

• S = 1.09

• 1344 reflections

• 112 parameters

• H-atom parameters constrained

• Δρ_max = 0.19 e Å⁻³

• Δρ_min = −0.14 e Å⁻³

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O3—H3A⋯O1	0.82	1.92	2.6231 (14)	144
O2—H2⋯O1^i	0.82	1.85	2.6679 (14)	175
C3—H3⋯O3^ii	0.93	2.60	3.5269 (16)	177
C4—H4⋯F2^ii	0.93	2.53	3.2047 (16)	129
Symmetry codes: (i) -x+1, -y+1, -z; (ii) x, y-1, z.

Data collection: APEX2 (Bruker, 2009); cell refinement: APEX2 and SAINT-Plus (Bruker, 2009); data reduction: SAINT-Plus and XPREP (Bruker, 2009); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEP-3 for Windows (Farrugia, 2012) and Mercury (Macrae et al., 2008); software used to prepare material for publication: SHELXL97.

Supporting information

S1. Comment

Fluorinated benzoic acids have been used for the preparation of potential prodrugs intended for antibody and gene directed enzyme prodrugtherapy (Springer et al., 1994; Davies et al., 2005). Derivatives of fluorinated benzoic acid exhibit antimicrobial activity (Rajasekhar et al., 2013). In particular 3,4-difluoro-2-hydroxybenzoic acid has been used in the synthesis of benzisoxazole containing barbiturate derivatives, which shows prominent anticancer activity (our unpublished results). Hence, the crystal structure of the title compound, (I), C₇H₄F₂O_3, is determined.

In (I), the molecule is planar (r.m.s. deviation in the benzene ring = 0.006 (1)Å with a maximum deviation of 0.009 (1)Å for carbon) (Fig. 1). An intramolecular O3—H3A···O1 hydrogen bond in observed. In the crystal, inversion dimers linked by pairs of O2—H2···O1 hydrogen bonds are formed and generate R₂²(8) ring motifs (Fig. 2). Weak C3—H3···O3 and C4—H4···F2 intermolecular interactions and aromatic π-π stacking interactions [centroid-centroid separation = 3.7817 (9) Å] (Fig. 3) are also observed and contribute to packing stability.

Related literature

For antibody and gene-directed enzyme prodrug therapy, see: Springer et al. (1994); Davies et al. (2005). For the antimicrobial activity of fluorinated benzoic acid derivatives, see: Rajasekhar et al. (2013).

S2. Experimental

To an ice cooled and stirred solution of 2,3,4-trifluorobenzoic acid (0.028 mmol) in dimethylimidazolidinone (10 ml), solid sodium hydroxide (0.113 mmol) was added in portions, and the mixture was heated to 120°C for 2 h. The reaction was monitored by TLC. After the reaction was completed, the mixture was cooled to room temperature and neutralized (pH 5–6) with 2 N hydrochloric acid (7.5 ml). The title compound was separated out as white solid, filtered, washed with excess of water and dried. Colourless prisms of the title compound were grown in ethanol by slow the evaporation technique.

S3. Refinement

The hydroxy H-atoms were located in a difference Fourier map, and were refined isotropically with the O–H distance restrained to 0.82±0.01 Å. H atoms were positioned with idealized geometry using a riding model with C—H = 0.93 Å and were refined with isotropic displacement parameters (set to 1.2 times of the U_eq of the parent atom).

Computing details

Data collection: APEX2 (Bruker, 2009); cell refinement: APEX2 and SAINT-Plus (Bruker, 2009); data reduction: SAINT-Plus and XPREP (Bruker, 2009); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEP-3 for Windows (Farrugia, 2012) and Mercury (Macrae et al., 2008); software used to prepare material for publication: SHELXL97 (Sheldrick, 2008).

Figures

	Fig. 1. Molecular structure of the title compound, showing displacement ellipsoids drawn at the 50% probability level.
	Fig. 2. Molecular packing of the title compound viewed along the b axis. Dashed lines indicate O—H···O intramolecular and pairs of O—H···O intermolecular hydrogen bonds forming R2^2(8) ring motifs and weak C—H···O and C—H···F intermolecular interactions along [010].
	Fig. 3. Molecules displaying weak π-π interactions [centroid-centroid separation = 3.7817 (9) Å].

3,4-Difluoro-2-hydroxybenzoic acid

Crystal data

C7H4F2O3	Prism
Mr = 174.10	Dx = 1.699 Mg m^−3
Monoclinic, P21/n	Melting point: 448 K
Hall symbol: -P 2yn	Mo Kα radiation, λ = 0.71073 Å
a = 9.4252 (8) Å	Cell parameters from 1045 reflections
b = 6.8145 (5) Å	θ = 2.3–26.5°
c = 11.0391 (8) Å	µ = 0.17 mm^−1
β = 106.257 (5)°	T = 296 K
V = 680.67 (9) Å^3	Prism, colourless
Z = 4	0.20 × 0.16 × 0.12 mm
F(000) = 352

Data collection

Bruker APEXII CCD area-detector diffractometer	1344 independent reflections
Radiation source: fine-focus sealed tube	1045 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.037
Detector resolution: 1.6 pixels mm^-1	θmax = 26.0°, θmin = 2.5°
phi and ω scans	h = −11→11
Absorption correction: multi-scan (SADABS; Sheldrick, 2007)	k = −8→8
Tmin = 0.967, Tmax = 0.980	l = −13→13
6362 measured reflections

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)] = 0.031	H-atom parameters constrained
wR(F^2) = 0.094	w = 1/[σ^2(Fo^2) + (0.0514P)^2 + 0.0514P] where P = (Fo^2 + 2Fc^2)/3
S = 1.09	(Δ/σ)max < 0.001
1344 reflections	Δρmax = 0.19 e Å^−3
112 parameters	Δρmin = −0.14 e Å^−3
0 restraints	Extinction correction: SHELXL97 (Sheldrick, 2008), Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
0 constraints	Extinction coefficient: 0.018 (3)
Primary atom site location: structure-invariant direct methods

Special details

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds 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 > 2sigma(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
C1	0.55955 (13)	0.54118 (17)	0.18180 (14)	0.0376 (3)
C2	0.60924 (12)	0.57452 (17)	0.31759 (13)	0.0357 (3)
C3	0.64443 (13)	0.41737 (18)	0.40234 (13)	0.0400 (3)
H3	0.6343	0.2897	0.3713	0.046 (4)*
C4	0.69337 (14)	0.44745 (19)	0.52991 (15)	0.0458 (4)
H4	0.7180	0.3420	0.5854	0.065 (5)*
C5	0.70534 (14)	0.63748 (19)	0.57424 (14)	0.0443 (3)
C6	0.67106 (15)	0.79441 (18)	0.49292 (15)	0.0441 (4)
C7	0.62456 (13)	0.76688 (16)	0.36434 (14)	0.0380 (3)
O1	0.53519 (11)	0.67798 (13)	0.10424 (9)	0.0482 (3)
O2	0.54221 (10)	0.35741 (12)	0.14643 (10)	0.0503 (3)
H2	0.5139	0.3516	0.0692	0.075*
O3	0.59795 (11)	0.92951 (13)	0.29161 (10)	0.0543 (3)
H3A	0.5708	0.8976	0.2170	0.081*
F1	0.75075 (11)	0.67350 (13)	0.69839 (8)	0.0676 (3)
F2	0.68666 (12)	0.97767 (11)	0.54053 (10)	0.0686 (3)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.0438 (6)	0.0373 (7)	0.0310 (9)	−0.0007 (5)	0.0095 (6)	−0.0010 (5)
C2	0.0417 (6)	0.0361 (7)	0.0292 (9)	−0.0008 (4)	0.0096 (6)	−0.0007 (5)
C3	0.0536 (7)	0.0331 (6)	0.0325 (9)	0.0016 (5)	0.0107 (6)	0.0007 (5)
C4	0.0604 (8)	0.0391 (7)	0.0356 (10)	0.0030 (5)	0.0095 (7)	0.0064 (5)
C5	0.0544 (7)	0.0511 (8)	0.0248 (9)	−0.0034 (5)	0.0065 (6)	−0.0039 (6)
C6	0.0569 (7)	0.0347 (7)	0.0395 (10)	−0.0068 (5)	0.0113 (7)	−0.0071 (5)
C7	0.0470 (7)	0.0337 (6)	0.0323 (10)	−0.0032 (5)	0.0097 (6)	0.0017 (5)
O1	0.0712 (6)	0.0401 (5)	0.0296 (7)	−0.0009 (4)	0.0077 (5)	0.0017 (4)
O2	0.0771 (6)	0.0378 (5)	0.0319 (7)	−0.0016 (4)	0.0087 (5)	−0.0040 (4)
O3	0.0836 (7)	0.0340 (5)	0.0402 (7)	−0.0031 (4)	0.0091 (6)	0.0042 (4)
F1	0.0996 (7)	0.0677 (6)	0.0287 (6)	−0.0032 (5)	0.0065 (5)	−0.0070 (4)
F2	0.1113 (7)	0.0403 (5)	0.0474 (7)	−0.0096 (4)	0.0111 (6)	−0.0140 (4)

Geometric parameters (Å, º)

C1—O1	1.2429 (15)	C4—H4	0.9300
C1—O1	1.2429 (15)	C5—F1	1.3392 (16)
C1—O2	1.3083 (14)	C5—C6	1.375 (2)
C1—C2	1.458 (2)	C6—F2	1.3469 (14)
C2—C3	1.3994 (18)	C6—C7	1.376 (2)
C2—C7	1.4014 (17)	C7—O3	1.3502 (16)
C3—C4	1.369 (2)	O2—H2	0.8200
C3—H3	0.9300	O3—H3A	0.8200
C4—C5	1.3777 (19)
O1—C1—O2	121.92 (13)	C5—C4—H4	120.8
O1—C1—O2	121.92 (13)	F1—C5—C6	118.35 (12)
O1—C1—C2	122.39 (11)	F1—C5—C4	120.45 (12)
O1—C1—C2	122.39 (11)	C6—C5—C4	121.21 (14)
O2—C1—C2	115.69 (11)	F2—C6—C5	119.09 (14)
C3—C2—C7	119.27 (13)	F2—C6—C7	119.82 (12)
C3—C2—C1	121.06 (11)	C5—C6—C7	121.06 (12)
C7—C2—C1	119.66 (11)	O3—C7—C6	117.00 (12)
C4—C3—C2	121.45 (12)	O3—C7—C2	124.47 (14)
C4—C3—H3	119.3	C6—C7—C2	118.53 (12)
C2—C3—H3	119.3	C1—O2—H2	109.5
C3—C4—C5	118.46 (13)	C7—O3—H3A	109.5
C3—C4—H4	120.8
O1—C1—C2—C3	−176.05 (11)	F1—C5—C6—C7	179.65 (11)
O1—C1—C2—C3	−176.05 (11)	C4—C5—C6—C7	−0.5 (2)
O2—C1—C2—C3	3.89 (17)	F2—C6—C7—O3	0.61 (19)
O1—C1—C2—C7	2.86 (17)	C5—C6—C7—O3	−177.90 (11)
O1—C1—C2—C7	2.86 (17)	F2—C6—C7—C2	−179.95 (10)
O2—C1—C2—C7	−177.19 (10)	C5—C6—C7—C2	1.5 (2)
C7—C2—C3—C4	0.05 (18)	C3—C2—C7—O3	178.06 (11)
C1—C2—C3—C4	178.97 (10)	C1—C2—C7—O3	−0.87 (18)
C2—C3—C4—C5	1.03 (19)	C3—C2—C7—C6	−1.33 (18)
C3—C4—C5—F1	179.05 (11)	C1—C2—C7—C6	179.74 (10)
C3—C4—C5—C6	−0.8 (2)	O2—C1—O1—O1	0.00 (14)
F1—C5—C6—F2	1.1 (2)	C2—C1—O1—O1	0.00 (14)
C4—C5—C6—F2	−178.98 (12)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O3—H3A···O1	0.82	1.92	2.6231 (14)	144
O2—H2···O1^i	0.82	1.85	2.6679 (14)	175
C3—H3···O3^ii	0.93	2.60	3.5269 (16)	177
C4—H4···F2^ii	0.93	2.53	3.2047 (16)	129

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