4-(3-Methoxy­phen­oxy)butyric acid

Julia Heilmann-Brohl; Gérard Jaouen; Michael Bolte

doi:10.1107/S1600536809008186

. 2009 Mar 19;65(Pt 4):o778. doi: 10.1107/S1600536809008186

4-(3-Methoxyphenoxy)butyric acid

Julia Heilmann-Brohl ^a, Gérard Jaouen ^a, Michael Bolte ^b,^*

PMCID: PMC2968774 PMID: 21582503

Abstract

In the title compound, C₁₁H₁₄O₄, an intermediate for the synthesis of a new kind of estrogen receptor modulator, all non-H atoms lie on a common plane (r.m.s. deviation = 0.0472 Å). All C—C bonds in the side chain are in a trans conformation, and the hydroxyl group is also trans to the methylene chain. In the crystal structure, molecules form centrosymmetric dimers showing a head-to-head arrangement which is stabilized by O—H⋯O hydrogen bonds. A weak C—H⋯O contact is also present.

Related literature

For the synthesis of 4-(3-methoxy-phenoxy)-butyric acid, see Tandon et al. (1990 ▶). For estrogen receptor modulators, see Lloyd et al. (2004 ▶). For a similar carboxylic acid, see: Smith et al. (1989 ▶).

Experimental

Crystal data

C₁₁H₁₄O₄
M _r = 210.22
Monoclinic,
a = 9.6509 (6) Å
b = 5.3998 (4) Å
c = 20.2033 (13) Å
β = 90.822 (5)°
V = 1052.74 (12) Å³
Z = 4
Mo Kα radiation
μ = 0.10 mm⁻¹
T = 173 K
0.32 × 0.27 × 0.25 mm

Data collection

Stoe IPDS-II two-circle diffractometer
Absorption correction: none
15489 measured reflections
2945 independent reflections
2458 reflections with I > 2σ(I)
R _int = 0.057

Refinement

R[F ² > 2σ(F ²)] = 0.043
wR(F ²) = 0.120
S = 1.07
2945 reflections
142 parameters
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.31 e Å⁻³
Δρ_min = −0.20 e Å⁻³

Data collection: X-AREA (Stoe & Cie, 2001 ▶); cell refinement: X-AREA; data reduction: X-AREA; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: XP in SHELXTL-Plus (Sheldrick, 2008 ▶) and Mercury (Macrae et al., 2006 ▶); software used to prepare material for publication: SHELXL97 and PLATON (Spek, 2009 ▶).

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536809008186/ng2557sup1.cif

e-65-0o778-sup1.cif^{(16.4KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536809008186/ng2557Isup2.hkl

e-65-0o778-Isup2.hkl^{(144.6KB, hkl)}

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
O41—H41⋯O42ⁱ	0.927 (18)	1.804 (19)	2.7292 (11)	175.5 (16)
C17—H17B⋯O42ⁱⁱ	0.98	2.48	3.2477 (14)	135

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Symmetry codes: (i) Inline graphic ; (ii) .

Acknowledgments

JHB acknowledges a fellowship from the Postdoc Programme of the German Academic Exchange Service (DAAD).

supplementary crystallographic information

Comment

4-(3-Methoxyphenoxy)butyric acid is an intermediate for the synthesis of a new kind of estrogen receptor modulators (Lloyd et al., 2004). All non-H atoms of the title compound (Fig. 1) lie in a common plane (r.m.s. deviation 0.0472 Å). All C—C bonds in the side chain are in a trans conformation, and the hydroxyl group is also trans to the methylene chain. In the crystal, the molecules form centrosymmetric dimers showing a head-to-head arrangement which is stabilized by O—H···O hydrogen bonds (Fig. 2). In addition to this classical hydrogen bond, there is weak C—H···O contact (Table 1).

Two comparable structures, 4-(4-chlorophenoxy)butanoic acid and 4-(2,4-dichlorophenoxy)butanoic acid, (Smith et al., 1989) adopt a very similar conformation as the title compound. However, the carboxyl group in these structures is slightly twisted out of the molecular plane. The HO—C(O)—CH₂—CH₂ torsion angle is 161.6° and 170.1° in 4-(4-chlorophenoxy)butanoic acid and 4-(2,4-dichlorophenoxy)butanoic acid, respectively, whereas this torsion angle amounts to 174.73 (9)° in the title compound.

Experimental

Synthesis of 4-(3-methoxy-phenoxy)-butyric acid ethyl ester (scheme 2):

Cs₃CO₃ (9.666 mmol, 3.149 g) was added to a solution of 3-methoxyphenol (8.055 mmol, 1.000 g) in acetone (20 ml) and the mixture was stirred for 5 min at r.t.. Ethyl-4-bromobutyrate (8.055 mmol, 1.571 g) was added and the reaction mixture was heated under reflux for 28 h. After cooling to r.t. the slurry was poured onto H₂O/ice/HCl and the aqeous phase was extracted with CH₂Cl₂ (4 x 25 ml). The combined organic layers were washed with H₂O (3 x 25 ml), dried over MgSO₄ and the solvent was removed under reduced pressure to yield the crude product as a slightly yellow oil. The crude product was subjected to a column chromatography (eluent 100% CH₂Cl₂), to obtain the pure product as a slightly yellow oil (1.486 g, 77%). ¹H-NMR (CDCl₃, 300 MHz): δ = 7.165 (tr, J = 8.1 Hz, 1H, C₆H₄), 6.519 – 6.447 (m, 3H, C₆H₄), 4.146 (q, J = 7.2 Hz, 2H, H12), 3.987 (tr, J = 6.2 Hz, 2H, H⁸), 3.780 (s, 3H, O—CH₃), 2.509 (tr, J = 7.2 Hz, 2H H¹⁰), 2.145 - 2.055 (m, 2H H⁹), 1.259 (tr, J = 7.2 Hz, 3H, H¹³).

Synthesis of 4-(3-methoxy-phenoxy)-butyric acid (scheme 3):

4-(3-methoxy-phenoxy)-butyric acid ethyl ester (2.938 mmol, 0.700 g) is dissolved in acetone (10 ml) and H₂O (5 ml) and 1 M NaOH (20 ml) is added. The reaction mixture is stirred at r.t. for 1 h and is then poured into H₂O/HCl (50 ml). The aqeous phase is extracted with CH₂Cl₂ (4 x 25 ml), and the combined organic layers are washed with H₂O (2 x 30 ml), dried over MgSO₄ and the solvent is evaporated. The crude product is obtained as light yellow oil from which colourless crystals – suitable for X-Ray analysis - start to grow within 30 min. Purification of the crude product is conducted by column chromatography. The by-products are removed by elution with CH₂Cl₂. The desired product is then eluted with MeOH. After evaporation of MeOH, the pure product is obtained as an off-white crystalline solid (0.352 g, 58%). ¹H-NMR (CDCl₃, 300 MHz): δ = 7.171 (tr, J = 8.3 Hz, 1H, C₆H₄), 6.526 - 6.447 (m, 3H, C₆H₄), 4.010 (tr, J = 6.0 Hz, 2H, H⁸), 3.787 (s, 3H, O—CH₃), 2.592 (tr, J = 7.4 Hz, 2H, H¹⁰), 2.174 - 2.073 (m, 2H, H⁹), n.o. (COOH).