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

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.

The title compound, C 10 H 11 NO 5 , is of interest with respect to its antidyslipidemic activity. It was prepared by reaction of 4nitrophenol with ethyl 2-bromo-2-methylpropionate followed by ethyl ester hydrolysis. In the crystal, molecules are linked into centrosymmetric dimers by intermolecular O-HÁ Á ÁO hydrogen bonds and the dimers are connected into chains by weak C-HÁ Á ÁO interactions. The packing is further stabilized by offsetinteractions between adjacent benzene rings with a centroid-centroid distance of 3.8643 (17) Å .

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 R 2 2 (8) motifs (Bernstein et al., 1995) 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/H 2 O (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 CH 2 Cl 2 (3 x 10 ml), dried with Na 2 SO 4 , 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.
supplementary materials sup-2     Refinement. Refinement of F 2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expression of F 2 > σ(F 2 ) is used only for calculating Rfactors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger.