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

Abstract

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 π–π inter­actions between adjacent benzene rings with a centroid–centroid distance of 3.8643 (17) Å.

Related literature

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

Crystal data

• C₁₀H₁₁NO₅

• M _r = 225.20

• Monoclinic,

• a = 21.296 (3) Å

• b = 7.0348 (9) Å

• c = 14.518 (2) Å

• β = 93.794 (2)°

• V = 2170.2 (5) ų

• Z = 8

• Mo Kα radiation

• μ = 0.11 mm⁻¹

• T = 294 (2) K

• 0.32 × 0.25 × 0.20 mm

Data collection

• Bruker SMART APEX CCD area-detector diffractometer

• Absorption correction: multi-scan (SADABS; Sheldrick, 1996 ▶) T _min = 0.763, T _max = 0.978

• 10072 measured reflections

• 1920 independent reflections

• 1745 reflections with I > 2σ(I)

• R _int = 0.035

Refinement

• R[F ² > 2σ(F ²)] = 0.065

• wR(F ²) = 0.163

• S = 1.12

• 1920 reflections

• 152 parameters

• H atoms treated by a mixture of independent and constrained refinement

• Δρ_max = 0.23 e Å⁻³

• Δρ_min = −0.22 e Å⁻³

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

Supplementary Material

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

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O5—H5A⋯O4i	0.92 (4)	1.75 (4)	2.659 (3)	173 (3)
C6—H6⋯O1ii	0.93	2.34	3.165 (4)	147

Symmetry codes: (i) ; (ii) .

supplementary crystallographic information

Comment

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).

Experimental

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

Aromatic and methyl H atoms were positioned geometrically, were constrained to the riding-model approximation [C-H_aryl = 0.93 Å, U_iso(H_aryl)= 1.2 U _eq(C_aryl); C-H_methyl = 0.96 Å, U_iso(H_methyl) = 1.5 U_eq(C_methyl)]. Atom H5A, which is involved in hydrogen-bonding interaction, was located in a difference Fourier map and refined freely with istropic displacement parameters.

Figures

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.

Fig. 2.

Centrosymmetric dimers generated by O4—H4···O3 intermolecular hydrogen bonds (dotted lines) forming an R22(8) motif.

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.

Crystal data

C10H11NO5	F000 = 944
Mr = 225.20	Dx = 1.378 Mg m−3
Monoclinic, C2/c	Melting point: 396 K
Hall symbol: -C 2yc	Mo Kα radiation λ = 0.71073 Å
a = 21.296 (3) Å	Cell parameters from 5496 reflections
b = 7.0348 (9) Å	θ = 2.5–2.9º
c = 14.518 (2) Å	µ = 0.11 mm−1
β = 93.794 (2)º	T = 294 (2) K
V = 2170.2 (5) Å3	Prism, colourless
Z = 8	0.32 × 0.25 × 0.20 mm

Data collection

Bruker SMART APEX CCD area-detector diffractometer	1920 independent reflections
Radiation source: fine-focus sealed tube	1745 reflections with I > 2σ(I)
Monochromator: graphite	Rint = 0.035
T = 294(2) K	θmax = 25.0º
φ and ω scans	θmin = 1.9º
Absorption correction: multi-scan(SADABS; Sheldrick, 1996)	h = −25→25
Tmin = 0.763, Tmax = 0.978	k = −8→8
10072 measured reflections	l = −17→17

Refinement

Refinement on F2	Hydrogen site location: inferred from neighbouring sites
Least-squares matrix: full	H atoms treated by a mixture of independent and constrained refinement
R[F2 > 2σ(F2)] = 0.065	w = 1/[σ2(Fo2) + (0.0689P)2 + 2.0562P] where P = (Fo2 + 2Fc2)/3
wR(F2) = 0.163	(Δ/σ)max < 0.001
S = 1.12	Δρmax = 0.23 e Å−3
1920 reflections	Δρmin = −0.22 e Å−3
152 parameters	Extinction correction: SHELXTL-NT (Sheldrick, 2008), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.020 (2)
Secondary atom site location: difference Fourier map

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 (Ų)

	x	y	z	Uiso*/Ueq
C1	0.43849 (11)	0.9257 (3)	0.38604 (15)	0.0513 (6)
C2	0.42396 (12)	0.7351 (4)	0.3768 (2)	0.0696 (8)
H2	0.3822	0.6954	0.3747	0.084*
C3	0.47162 (13)	0.6040 (4)	0.3706 (2)	0.0783 (9)
H3	0.4623	0.4754	0.3641	0.094*
C4	0.53299 (12)	0.6654 (4)	0.3741 (2)	0.0667 (7)
C5	0.54791 (12)	0.8533 (4)	0.38383 (19)	0.0661 (7)
H5	0.5897	0.8926	0.3866	0.079*
C6	0.50077 (11)	0.9819 (4)	0.38940 (18)	0.0613 (7)
H6	0.5106	1.1103	0.3956	0.074*
C7	0.33120 (11)	1.0562 (4)	0.36820 (17)	0.0584 (7)
C8	0.29840 (10)	0.9120 (3)	0.42697 (16)	0.0532 (6)
C9	0.30573 (14)	1.2523 (4)	0.3905 (2)	0.0801 (9)
H9A	0.3183	1.2844	0.4533	0.120*
H9B	0.2606	1.2512	0.3823	0.120*
H9C	0.3222	1.3448	0.3499	0.120*
C10	0.32173 (14)	1.0132 (5)	0.26611 (19)	0.0772 (8)
H10A	0.3449	1.1033	0.2320	0.116*
H10B	0.2778	1.0221	0.2471	0.116*
H10C	0.3365	0.8871	0.2544	0.116*
H5A	0.2918 (16)	0.838 (5)	0.547 (3)	0.101 (11)*
N1	0.58387 (13)	0.5287 (4)	0.3648 (2)	0.0966 (9)
O1	0.57049 (14)	0.3662 (4)	0.3469 (3)	0.1713 (19)
O2	0.63689 (12)	0.5842 (4)	0.3687 (3)	0.1449 (13)
O3	0.39722 (7)	1.0706 (2)	0.39675 (12)	0.0594 (5)
O4	0.25911 (8)	0.8033 (3)	0.39279 (12)	0.0711 (6)
O5	0.31446 (10)	0.9212 (3)	0.51375 (13)	0.0770 (7)

Atomic displacement parameters (Ų)

	U11	U22	U33	U12	U13	U23
C1	0.0472 (12)	0.0552 (14)	0.0519 (13)	−0.0041 (10)	0.0076 (9)	0.0040 (10)
C2	0.0477 (13)	0.0595 (16)	0.103 (2)	−0.0087 (12)	0.0140 (13)	0.0028 (14)
C3	0.0658 (17)	0.0506 (15)	0.121 (2)	−0.0042 (13)	0.0250 (16)	0.0062 (15)
C4	0.0515 (14)	0.0686 (17)	0.0816 (18)	0.0059 (13)	0.0163 (12)	0.0123 (14)
C5	0.0453 (13)	0.0758 (18)	0.0784 (17)	−0.0102 (13)	0.0142 (12)	−0.0012 (14)
C6	0.0536 (14)	0.0583 (14)	0.0736 (16)	−0.0112 (12)	0.0151 (11)	−0.0034 (12)
C7	0.0481 (13)	0.0609 (15)	0.0659 (15)	0.0001 (11)	0.0021 (10)	0.0060 (12)
C8	0.0418 (11)	0.0595 (14)	0.0583 (14)	0.0012 (10)	0.0025 (10)	−0.0016 (11)
C9	0.0691 (17)	0.0653 (17)	0.106 (2)	0.0078 (14)	0.0085 (15)	0.0093 (16)
C10	0.0730 (18)	0.092 (2)	0.0657 (17)	−0.0098 (16)	0.0012 (13)	0.0144 (15)
N1	0.0659 (17)	0.0787 (19)	0.148 (3)	0.0083 (14)	0.0311 (16)	0.0179 (18)
O1	0.105 (2)	0.0664 (17)	0.353 (6)	0.0126 (15)	0.091 (3)	0.017 (2)
O2	0.0574 (15)	0.127 (2)	0.252 (4)	0.0171 (15)	0.0225 (18)	−0.013 (2)
O3	0.0483 (9)	0.0532 (10)	0.0770 (12)	−0.0036 (7)	0.0049 (8)	−0.0015 (8)
O4	0.0619 (11)	0.0864 (14)	0.0648 (11)	−0.0253 (10)	0.0017 (8)	−0.0029 (9)
O5	0.0797 (13)	0.0928 (15)	0.0581 (11)	−0.0337 (11)	0.0008 (9)	0.0035 (10)

Geometric parameters (Å, °)

C1—O3	1.361 (3)	C7—C8	1.524 (3)
C1—C2	1.380 (4)	C7—C9	1.525 (4)
C1—C6	1.382 (3)	C8—O4	1.215 (3)
C2—C3	1.379 (4)	C8—O5	1.285 (3)
C2—H2	0.9300	C9—H9A	0.9600
C3—C4	1.374 (4)	C9—H9B	0.9600
C3—H3	0.9300	C9—H9C	0.9600
C4—C5	1.365 (4)	C10—H10A	0.9600
C4—N1	1.462 (4)	C10—H10B	0.9600
C5—C6	1.358 (4)	C10—H10C	0.9600
C5—H5	0.9300	N1—O2	1.193 (4)
C6—H6	0.9300	N1—O1	1.202 (4)
C7—O3	1.443 (3)	O5—H5A	0.92 (4)
C7—C10	1.513 (4)
O3—C1—C2	126.6 (2)	C10—C7—C9	111.2 (2)
O3—C1—C6	114.0 (2)	C8—C7—C9	107.5 (2)
C2—C1—C6	119.3 (2)	O4—C8—O5	124.3 (2)
C3—C2—C1	119.6 (2)	O4—C8—C7	121.3 (2)
C3—C2—H2	120.2	O5—C8—C7	114.4 (2)
C1—C2—H2	120.2	C7—C9—H9A	109.5
C4—C3—C2	119.3 (3)	C7—C9—H9B	109.5
C4—C3—H3	120.3	H9A—C9—H9B	109.5
C2—C3—H3	120.3	C7—C9—H9C	109.5
C5—C4—C3	121.5 (2)	H9A—C9—H9C	109.5
C5—C4—N1	118.6 (2)	H9B—C9—H9C	109.5
C3—C4—N1	119.9 (3)	C7—C10—H10A	109.5
C6—C5—C4	118.9 (2)	C7—C10—H10B	109.5
C6—C5—H5	120.5	H10A—C10—H10B	109.5
C4—C5—H5	120.5	C7—C10—H10C	109.5
C5—C6—C1	121.2 (2)	H10A—C10—H10C	109.5
C5—C6—H6	119.4	H10B—C10—H10C	109.5
C1—C6—H6	119.4	O2—N1—O1	122.1 (3)
O3—C7—C10	111.1 (2)	O2—N1—C4	119.0 (3)
O3—C7—C8	111.08 (19)	O1—N1—C4	118.6 (3)
C10—C7—C8	112.3 (2)	C1—O3—C7	122.60 (18)
O3—C7—C9	103.2 (2)	C8—O5—H5A	111 (2)
O3—C1—C2—C3	−177.1 (3)	O3—C7—C8—O5	42.7 (3)
C6—C1—C2—C3	−0.3 (4)	C10—C7—C8—O5	167.7 (2)
C1—C2—C3—C4	0.2 (5)	C9—C7—C8—O5	−69.6 (3)
C2—C3—C4—C5	0.2 (5)	C5—C4—N1—O2	2.2 (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—C6	177.8 (3)	C3—C4—N1—O1	5.9 (5)
C4—C5—C6—C1	0.5 (4)	C2—C1—O3—C7	−22.5 (4)
O3—C1—C6—C5	177.1 (2)	C6—C1—O3—C7	160.6 (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—C1	67.2 (3)
C10—C7—C8—O4	−14.5 (3)	C9—C7—O3—C1	−177.9 (2)
C9—C7—C8—O4	108.2 (3)

Hydrogen-bond geometry (Å, °)

D—H···A	D—H	H···A	D···A	D—H···A
O5—H5A···O4i	0.92 (4)	1.75 (4)	2.659 (3)	173 (3)
C6—H6···O1ii	0.93	2.34	3.165 (4)	147

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