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Acta Cryst. (2008). E64, o2261    [ doi:10.1107/S1600536808035411 ]

2-Methyl-2-(4-nitrophenoxy)propanoic acid

G. Navarrete-Vázquez, H. Torres-Gómez, S. Hidalgo-Figueroa and H. Tlahuext

Abstract top

The title compound, C10H11NO5, is of interest with respect to its antidyslipidemic activity. It was prepared by reaction of 4-nitrophenol with ethyl 2-bromo-2-methylpropionate followed by ethyl ester hydrolysis. In the crystal, molecules are linked into centrosymmetric dimers by intermolecular O-H...O hydrogen bonds and the dimers are connected into chains by weak C-H...O interactions. The packing is further stabilized by offset [pi]-[pi] interactions between adjacent benzene rings with a centroid-centroid distance of 3.8643 (17) Å.

Comment top

The fibrates belong to a class of lipid-modifying agents that decrease plasma triglycerides (Thorp, 1962; Miller & Spence, 1998; Forcheron et al., 2002). These compounds are used as therapeutic agents in the treatment of dyslipidemia, heart disease and diabetic complications in humans. The fibric acid pharmacophore has been of interest to medicinal chemists ever since the initial discovery that ethyl chlorophenoxyisobutyrate possessed hypolipidemic properties (Thorp & Waring, 1962).

In order to assist our knowledge about the electronic and steric requirements to shown antihyperlipidemic activity, we have determined the crystal structure of the title compound, (I), Fig 1, which is a bioisoster of clofibric acid, with a nitro group instead of chlorine atom. The crystal structure is stabilized by strong O5—H5A···O4 hydrogen-bonding interactions, forming R22(8) motifs (Bernstein et al., 1995) (Fig. 1; Table 2). In the crystal packing there are also weak C6—H6···O1 hydrogen bonding interactions that interconnect molecules into chains running along the b axis. The crystal structure is also stabilized by offset π–π interactions between two adjacent molecules, with a distance between centroids of the C1—C6 benzene rings [Cg1, Cg1" (Symmetry code: -x, y, -z + 1/2)] of 3.8643 (17) Å. (Fig. 2; Table 1).

Related literature top

For related literature on fibrate structures and hypolipidemic activity, see: Navarrete-Vázquez et al. (2008); Henry et al. (2003); Rath et al. (2005); Djinović et al. (1989); Thorp (1962); Thorp & Waring (1962); Miller & Spence (1998); Forcheron et al. (2002). For details of the graph-set analysis of hydrogen-bonding patterns, see: Bernstein et al. (1995)

Experimental top

A mixture of 4-nitrophenol (1.0 g, 4.44 mmol), potassium carbonate (1.22 g, 8.88 mmol) in acetonitrile, was added dropwise to 1.04 ml of ethyl 2-bromo-2-methylpropionate (1.29 g, 6.66 mmol). The mixture was stirred and heated under reflux for 8 h then poured onto cold water. The resulting oil was treated with a mixture of THF/MeOH/H2O (3:2:1), and LiOH (5 equiv) was added. The mixture stirred at room temperature for 3 h, 10% HCl solution added, and most of the organic solvents removed in vacuo. The partly solid residue was extracted with CH2Cl2 (3 x 10 ml), dried with Na2SO4, filtered, and concentrated in vacuo to give a yellow solid (m.p. 396 K). Single crystals of (I) were obtained from chloroform.

Refinement top

Aromatic and methyl H atoms were positioned geometrically, were constrained to the riding-model approximation [C-Haryl = 0.93 Å, Uiso(Haryl)= 1.2 U eq(Caryl); C-Hmethyl = 0.96 Å, Uiso(Hmethyl) = 1.5 Ueq(Cmethyl)]. Atom H5A, which is involved in hydrogen-bonding interaction, was located in a difference Fourier map and refined freely with istropic displacement parameters.

Computing details top

Data collection: SMART (Bruker, 2000); cell refinement: SAINT-Plus-NT (Bruker, 2001); data reduction: SAINT-Plus-NT (Bruker, 2001); program(s) used to solve structure: SHELXTL-NT (Sheldrick, 2008); program(s) used to refine structure: SHELXTL-NT (Sheldrick, 2008); molecular graphics: SHELXTL-NT (Sheldrick, 2008); software used to prepare material for publication: PLATON (Spek, 2003) and publCIF (Westrip, 2008).

Figures top
[Figure 1] Fig. 1. The molecular structure of I showing 50% probability displacement ellipsoids and the atomic numbering. H atoms are shown as small spheres of arbitrary radius.
[Figure 2] Fig. 2. Centrosymmetric dimers generated by O4—H4···O3 intermolecular hydrogen bonds (dotted lines) forming an R22(8) motif.
[Figure 3] Fig. 3. View of the offset π-π interaction and C—H···O hydrogen bonds between adjacent molecules. The dashed line indicates the vector between the centroids (Cg1, Cg1"). The hydrogen bond is represented by a dotted line and H atoms not involved in hydrogen bonding have been omitted for clarity.
2-Methyl-2-(4-nitrophenoxy)propanoic acid top
Crystal data top
C10H11NO5F(000) = 944
Mr = 225.20Dx = 1.378 Mg m−3
Monoclinic, C2/cMelting point: 396 K
Hall symbol: -C 2ycMo Kα radiation, λ = 0.71073 Å
a = 21.296 (3) ÅCell parameters from 5496 reflections
b = 7.0348 (9) Åθ = 2.5–2.9°
c = 14.518 (2) ŵ = 0.11 mm−1
β = 93.794 (2)°T = 294 K
V = 2170.2 (5) Å3Prism, colourless
Z = 80.32 × 0.25 × 0.20 mm
Data collection top
Bruker SMART APEX CCD area-detector
diffractometer		1920 independent reflections
Radiation source: fine-focus sealed tube1745 reflections with I > 2σ(I)
graphiteRint = 0.035
φ and ω scansθmax = 25.0°, θmin = 1.9°
Absorption correction: multi-scan
(SADABS; Sheldrick, 1996)		h = −25→25
Tmin = 0.763, Tmax = 0.978k = −8→8
10072 measured reflectionsl = −17→17
Refinement top
Refinement on F2Secondary atom site location: difference Fourier map
Least-squares matrix: fullHydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.065H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.163 w = 1/[σ2(Fo2) + (0.0689P)2 + 2.0562P]
where P = (Fo2 + 2Fc2)/3
S = 1.12(Δ/σ)max < 0.001
1920 reflectionsΔρmax = 0.23 e Å−3
152 parametersΔρmin = −0.22 e Å−3
0 restraintsExtinction correction: SHELXTL-NT (Sheldrick, 2008), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4
Primary atom site location: structure-invariant direct methodsExtinction coefficient: 0.020 (2)
Crystal data top
C10H11NO5V = 2170.2 (5) Å3
Mr = 225.20Z = 8
Monoclinic, C2/cMo Kα radiation
a = 21.296 (3) ŵ = 0.11 mm−1
b = 7.0348 (9) ÅT = 294 K
c = 14.518 (2) Å0.32 × 0.25 × 0.20 mm
β = 93.794 (2)°
Data collection top
Bruker SMART APEX CCD area-detector
diffractometer		1920 independent reflections
Absorption correction: multi-scan
(SADABS; Sheldrick, 1996)		1745 reflections with I > 2σ(I)
Tmin = 0.763, Tmax = 0.978Rint = 0.035
10072 measured reflectionsθmax = 25.0°
Refinement top
R[F2 > 2σ(F2)] = 0.065H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.163Δρmax = 0.23 e Å−3
S = 1.12Δρmin = −0.22 e Å−3
1920 reflectionsAbsolute structure: ?
152 parametersFlack parameter: ?
0 restraintsRogers parameter: ?
Special details top

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
xyzUiso*/Ueq
C10.43849 (11)0.9257 (3)0.38604 (15)0.0513 (6)
C20.42396 (12)0.7351 (4)0.3768 (2)0.0696 (8)
H20.38220.69540.37470.084*
C30.47162 (13)0.6040 (4)0.3706 (2)0.0783 (9)
H30.46230.47540.36410.094*
C40.53299 (12)0.6654 (4)0.3741 (2)0.0667 (7)
C50.54791 (12)0.8533 (4)0.38383 (19)0.0661 (7)
H50.58970.89260.38660.079*
C60.50077 (11)0.9819 (4)0.38940 (18)0.0613 (7)
H60.51061.11030.39560.074*
C70.33120 (11)1.0562 (4)0.36820 (17)0.0584 (7)
C80.29840 (10)0.9120 (3)0.42697 (16)0.0532 (6)
C90.30573 (14)1.2523 (4)0.3905 (2)0.0801 (9)
H9A0.31831.28440.45330.120*
H9B0.26061.25120.38230.120*
H9C0.32221.34480.34990.120*
C100.32173 (14)1.0132 (5)0.26611 (19)0.0772 (8)
H10A0.34491.10330.23200.116*
H10B0.27781.02210.24710.116*
H10C0.33650.88710.25440.116*
H5A0.2918 (16)0.838 (5)0.547 (3)0.101 (11)*
N10.58387 (13)0.5287 (4)0.3648 (2)0.0966 (9)
O10.57049 (14)0.3662 (4)0.3469 (3)0.1713 (19)
O20.63689 (12)0.5842 (4)0.3687 (3)0.1449 (13)
O30.39722 (7)1.0706 (2)0.39675 (12)0.0594 (5)
O40.25911 (8)0.8033 (3)0.39279 (12)0.0711 (6)
O50.31446 (10)0.9212 (3)0.51375 (13)0.0770 (7)
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
C10.0472 (12)0.0552 (14)0.0519 (13)−0.0041 (10)0.0076 (9)0.0040 (10)
C20.0477 (13)0.0595 (16)0.103 (2)−0.0087 (12)0.0140 (13)0.0028 (14)
C30.0658 (17)0.0506 (15)0.121 (2)−0.0042 (13)0.0250 (16)0.0062 (15)
C40.0515 (14)0.0686 (17)0.0816 (18)0.0059 (13)0.0163 (12)0.0123 (14)
C50.0453 (13)0.0758 (18)0.0784 (17)−0.0102 (13)0.0142 (12)−0.0012 (14)
C60.0536 (14)0.0583 (14)0.0736 (16)−0.0112 (12)0.0151 (11)−0.0034 (12)
C70.0481 (13)0.0609 (15)0.0659 (15)0.0001 (11)0.0021 (10)0.0060 (12)
C80.0418 (11)0.0595 (14)0.0583 (14)0.0012 (10)0.0025 (10)−0.0016 (11)
C90.0691 (17)0.0653 (17)0.106 (2)0.0078 (14)0.0085 (15)0.0093 (16)
C100.0730 (18)0.092 (2)0.0657 (17)−0.0098 (16)0.0012 (13)0.0144 (15)
N10.0659 (17)0.0787 (19)0.148 (3)0.0083 (14)0.0311 (16)0.0179 (18)
O10.105 (2)0.0664 (17)0.353 (6)0.0126 (15)0.091 (3)0.017 (2)
O20.0574 (15)0.127 (2)0.252 (4)0.0171 (15)0.0225 (18)−0.013 (2)
O30.0483 (9)0.0532 (10)0.0770 (12)−0.0036 (7)0.0049 (8)−0.0015 (8)
O40.0619 (11)0.0864 (14)0.0648 (11)−0.0253 (10)0.0017 (8)−0.0029 (9)
O50.0797 (13)0.0928 (15)0.0581 (11)−0.0337 (11)0.0008 (9)0.0035 (10)
Geometric parameters (Å, °) top
C1—O31.361 (3)C7—C81.524 (3)
C1—C21.380 (4)C7—C91.525 (4)
C1—C61.382 (3)C8—O41.215 (3)
C2—C31.379 (4)C8—O51.285 (3)
C2—H20.9300C9—H9A0.9600
C3—C41.374 (4)C9—H9B0.9600
C3—H30.9300C9—H9C0.9600
C4—C51.365 (4)C10—H10A0.9600
C4—N11.462 (4)C10—H10B0.9600
C5—C61.358 (4)C10—H10C0.9600
C5—H50.9300N1—O21.193 (4)
C6—H60.9300N1—O11.202 (4)
C7—O31.443 (3)O5—H5A0.92 (4)
C7—C101.513 (4)
O3—C1—C2126.6 (2)C10—C7—C9111.2 (2)
O3—C1—C6114.0 (2)C8—C7—C9107.5 (2)
C2—C1—C6119.3 (2)O4—C8—O5124.3 (2)
C3—C2—C1119.6 (2)O4—C8—C7121.3 (2)
C3—C2—H2120.2O5—C8—C7114.4 (2)
C1—C2—H2120.2C7—C9—H9A109.5
C4—C3—C2119.3 (3)C7—C9—H9B109.5
C4—C3—H3120.3H9A—C9—H9B109.5
C2—C3—H3120.3C7—C9—H9C109.5
C5—C4—C3121.5 (2)H9A—C9—H9C109.5
C5—C4—N1118.6 (2)H9B—C9—H9C109.5
C3—C4—N1119.9 (3)C7—C10—H10A109.5
C6—C5—C4118.9 (2)C7—C10—H10B109.5
C6—C5—H5120.5H10A—C10—H10B109.5
C4—C5—H5120.5C7—C10—H10C109.5
C5—C6—C1121.2 (2)H10A—C10—H10C109.5
C5—C6—H6119.4H10B—C10—H10C109.5
C1—C6—H6119.4O2—N1—O1122.1 (3)
O3—C7—C10111.1 (2)O2—N1—C4119.0 (3)
O3—C7—C8111.08 (19)O1—N1—C4118.6 (3)
C10—C7—C8112.3 (2)C1—O3—C7122.60 (18)
O3—C7—C9103.2 (2)C8—O5—H5A111 (2)
O3—C1—C2—C3−177.1 (3)O3—C7—C8—O542.7 (3)
C6—C1—C2—C3−0.3 (4)C10—C7—C8—O5167.7 (2)
C1—C2—C3—C40.2 (5)C9—C7—C8—O5−69.6 (3)
C2—C3—C4—C50.2 (5)C5—C4—N1—O22.2 (5)
C2—C3—C4—N1−178.2 (3)C3—C4—N1—O2−179.4 (4)
C3—C4—C5—C6−0.6 (4)C5—C4—N1—O1−172.6 (4)
N1—C4—C5—C6177.8 (3)C3—C4—N1—O15.9 (5)
C4—C5—C6—C10.5 (4)C2—C1—O3—C7−22.5 (4)
O3—C1—C6—C5177.1 (2)C6—C1—O3—C7160.6 (2)
C2—C1—C6—C5−0.1 (4)C10—C7—O3—C1−58.6 (3)
O3—C7—C8—O4−139.5 (2)C8—C7—O3—C167.2 (3)
C10—C7—C8—O4−14.5 (3)C9—C7—O3—C1−177.9 (2)
C9—C7—C8—O4108.2 (3)
Hydrogen-bond geometry (Å, °) top
D—H···AD—HH···AD···AD—H···A
O5—H5A···O4i0.92 (4)1.75 (4)2.659 (3)173 (3)
C6—H6···O1ii0.932.343.165 (4)147
Symmetry codes: (i) −x+1/2, −y+3/2, −z+1; (ii) x, y+1, z.
Table 1
Hydrogen-bond geometry (Å, °) top
D—H···AD—HH···AD···AD—H···A
O5—H5A···O4i0.92 (4)1.75 (4)2.659 (3)173 (3)
C6—H6···O1ii0.932.343.165 (4)147
Symmetry codes: (i) −x+1/2, −y+3/2, −z+1; (ii) x, y+1, z.
Acknowledgements top

This work was supported by the Consejo Nacional de Ciencia y Tecnología (CONACyT) under grants Nos. 55591 and 3562P-E.

references
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