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Acta Cryst. (2009). E65, o778    [ doi:10.1107/S1600536809008186 ]

4-(3-Methoxyphenoxy)butyric acid

J. Heilmann-Brohl, G. Jaouen and M. Bolte

Abstract top

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.

Comment top

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.

Related literature top

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 top

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).

Refinement top

H atoms bonded to C were refined with fixed individual displacement parameters [U(H) = 1.2 Ueq(C) or U(H) = 1.5 Ueq(Cmethyl)] using a riding model with Caromatic—H = 0.95 Å, Cmethyl—H = 0.98 Å, and Cmethylene—H = 0.99 Å. The methyl group was allowed to rotate but not to tip. the hydroxy H atom was freely refined.

Computing details top

Data collection: X-AREA (Stoe & Cie, 2001); cell refinement: X-AREA (Stoe & Cie, 2001); data reduction: X-AREA (Stoe & Cie, 2001); 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 (Bruno et al., 2002); software used to prepare material for publication: SHELXL97 (Sheldrick, 2008) and PLATON (Spek, 2009).

Figures top
[Figure 1] Fig. 1. Perspective view of the title compound with the atom numbering scheme; displacement ellipsoids are at the 50% probability level; H atoms are drawn as small spheres of arbitrary radii.
[Figure 2] Fig. 2. Packing diagram of the title compound with view onto the ac plane. Hydrogen bonds shown as dashed lines.
[Figure 3] Fig. 3. The numbering of the ethyl ester of the title compound.
[Figure 4] Fig. 4. The numbering of the title compound.
4-(3-Methoxyphenoxy)butyric acid top
Crystal data top
C11H14O4F(000) = 448
Mr = 210.22Dx = 1.326 Mg m−3
Monoclinic, P21/nMo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ynCell parameters from 15224 reflections
a = 9.6509 (6) Åθ = 3.7–29.5°
b = 5.3998 (4) ŵ = 0.10 mm−1
c = 20.2033 (13) ÅT = 173 K
β = 90.822 (5)°Block, colourless
V = 1052.74 (12) Å30.32 × 0.27 × 0.25 mm
Z = 4
Data collection top
Stoe IPDS-II two-circle
diffractometer		2458 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tubeRint = 0.057
graphiteθmax = 29.6°, θmin = 3.7°
ω scansh = −13→13
15489 measured reflectionsk = −7→7
2945 independent reflectionsl = −28→25
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)] = 0.043H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.120 w = 1/[σ2(Fo2) + (0.0677P)2 + 0.1161P]
where P = (Fo2 + 2Fc2)/3
S = 1.07(Δ/σ)max = 0.001
2945 reflectionsΔρmax = 0.31 e Å−3
142 parametersΔρmin = −0.20 e Å−3
0 restraintsExtinction correction: SHELXL97 (Sheldrick, 2008), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4
Primary atom site location: structure-invariant direct methodsExtinction coefficient: 0.048 (5)
Crystal data top
C11H14O4V = 1052.74 (12) Å3
Mr = 210.22Z = 4
Monoclinic, P21/nMo Kα radiation
a = 9.6509 (6) ŵ = 0.10 mm−1
b = 5.3998 (4) ÅT = 173 K
c = 20.2033 (13) Å0.32 × 0.27 × 0.25 mm
β = 90.822 (5)°
Data collection top
Stoe IPDS-II two-circle
diffractometer		2458 reflections with I > 2σ(I)
15489 measured reflectionsRint = 0.057
2945 independent reflectionsθmax = 29.6°
Refinement top
R[F2 > 2σ(F2)] = 0.043H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.120Δρmax = 0.31 e Å−3
S = 1.07Δρmin = −0.20 e Å−3
2945 reflectionsAbsolute structure: ?
142 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
O10.32321 (7)0.55314 (15)0.64594 (4)0.03035 (19)
C10.36009 (11)0.72446 (18)0.59488 (5)0.0263 (2)
H1A0.38400.63440.55390.032*
H1B0.44110.82480.60910.032*
C20.23475 (10)0.89015 (19)0.58265 (5)0.0265 (2)
H2A0.21510.98600.62320.032*
H2B0.15270.78660.57210.032*
C30.26116 (11)1.0679 (2)0.52546 (5)0.0286 (2)
H3A0.34911.15720.53430.034*
H3B0.27270.97040.48440.034*
C40.14701 (11)1.25525 (19)0.51430 (5)0.0269 (2)
O410.17803 (9)1.41971 (15)0.46803 (4)0.0342 (2)
H410.1036 (18)1.526 (3)0.4617 (8)0.056 (5)*
O420.03810 (8)1.25686 (16)0.54438 (5)0.0382 (2)
C110.42179 (10)0.38789 (18)0.66811 (5)0.0245 (2)
C120.55358 (10)0.36401 (18)0.64103 (5)0.0253 (2)
H120.58140.46820.60580.030*
C130.64437 (10)0.18317 (18)0.66685 (5)0.0243 (2)
C140.60524 (11)0.02991 (19)0.71884 (5)0.0263 (2)
H140.6668−0.09270.73580.032*
C150.47284 (10)0.06066 (19)0.74563 (5)0.0278 (2)
H150.4454−0.04200.78130.033*
C160.38130 (11)0.23721 (19)0.72120 (5)0.0270 (2)
H160.29230.25620.74010.032*
O130.77149 (8)0.17389 (15)0.63728 (4)0.0316 (2)
C170.86678 (11)−0.0111 (2)0.66159 (5)0.0334 (3)
H17A0.88630.01790.70870.050*
H17B0.9532−0.00140.63690.050*
H17C0.8257−0.17580.65580.050*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
O10.0250 (4)0.0310 (4)0.0350 (4)0.0067 (3)0.0021 (3)0.0095 (3)
C10.0255 (5)0.0255 (5)0.0277 (5)0.0032 (4)−0.0012 (4)0.0029 (4)
C20.0262 (5)0.0251 (5)0.0281 (5)0.0052 (4)−0.0032 (4)0.0004 (4)
C30.0290 (5)0.0275 (5)0.0294 (5)0.0056 (4)−0.0011 (4)0.0014 (4)
C40.0291 (5)0.0247 (5)0.0268 (5)0.0022 (4)−0.0036 (4)0.0007 (4)
O410.0362 (4)0.0313 (4)0.0351 (4)0.0080 (3)0.0025 (3)0.0096 (3)
O420.0318 (4)0.0371 (5)0.0458 (5)0.0105 (3)0.0055 (4)0.0148 (4)
C110.0238 (4)0.0231 (4)0.0266 (5)0.0024 (3)−0.0027 (4)0.0014 (4)
C120.0263 (5)0.0255 (5)0.0240 (4)0.0018 (3)−0.0002 (3)0.0035 (3)
C130.0237 (4)0.0257 (4)0.0235 (4)0.0021 (3)−0.0008 (3)−0.0002 (4)
C140.0273 (5)0.0250 (5)0.0265 (5)0.0018 (4)−0.0033 (4)0.0035 (4)
C150.0280 (5)0.0282 (5)0.0273 (5)−0.0025 (4)−0.0011 (4)0.0050 (4)
C160.0245 (5)0.0286 (5)0.0280 (5)−0.0010 (4)0.0002 (4)0.0020 (4)
O130.0266 (4)0.0380 (4)0.0303 (4)0.0100 (3)0.0048 (3)0.0095 (3)
C170.0301 (5)0.0382 (6)0.0319 (5)0.0128 (4)0.0026 (4)0.0059 (4)
Geometric parameters (Å, °) top
O1—C111.3747 (11)C11—C161.4061 (14)
O1—C11.4343 (12)C12—C131.4072 (13)
C1—C21.5219 (13)C12—H120.9500
C1—H1A0.9900C13—O131.3732 (12)
C1—H1B0.9900C13—C141.3935 (14)
C2—C31.5263 (14)C14—C151.4047 (14)
C2—H2A0.9900C14—H140.9500
C2—H2B0.9900C15—C161.3858 (14)
C3—C41.5103 (14)C15—H150.9500
C3—H3A0.9900C16—H160.9500
C3—H3B0.9900O13—C171.4394 (12)
C4—O421.2217 (13)C17—H17A0.9800
C4—O411.3268 (13)C17—H17B0.9800
O41—H410.927 (18)C17—H17C0.9800
C11—C121.3977 (13)
C11—O1—C1118.38 (8)O1—C11—C16115.18 (9)
O1—C1—C2106.92 (8)C12—C11—C16120.64 (9)
O1—C1—H1A110.3C11—C12—C13118.96 (9)
C2—C1—H1A110.3C11—C12—H12120.5
O1—C1—H1B110.3C13—C12—H12120.5
C2—C1—H1B110.3O13—C13—C14124.03 (9)
H1A—C1—H1B108.6O13—C13—C12114.80 (8)
C1—C2—C3110.58 (8)C14—C13—C12121.16 (9)
C1—C2—H2A109.5C13—C14—C15118.56 (9)
C3—C2—H2A109.5C13—C14—H14120.7
C1—C2—H2B109.5C15—C14—H14120.7
C3—C2—H2B109.5C16—C15—C14121.53 (9)
H2A—C2—H2B108.1C16—C15—H15119.2
C4—C3—C2113.88 (9)C14—C15—H15119.2
C4—C3—H3A108.8C15—C16—C11119.14 (9)
C2—C3—H3A108.8C15—C16—H16120.4
C4—C3—H3B108.8C11—C16—H16120.4
C2—C3—H3B108.8C13—O13—C17116.57 (8)
H3A—C3—H3B107.7O13—C17—H17A109.5
O42—C4—O41123.38 (9)O13—C17—H17B109.5
O42—C4—C3124.16 (9)H17A—C17—H17B109.5
O41—C4—C3112.46 (9)O13—C17—H17C109.5
C4—O41—H41109.2 (11)H17A—C17—H17C109.5
O1—C11—C12124.18 (9)H17B—C17—H17C109.5
C11—O1—C1—C2−177.45 (8)C11—C12—C13—C14−0.36 (15)
O1—C1—C2—C3−176.12 (8)O13—C13—C14—C15178.91 (9)
C1—C2—C3—C4−174.52 (9)C12—C13—C14—C15−0.52 (15)
C2—C3—C4—O42−5.13 (16)C13—C14—C15—C160.51 (16)
C2—C3—C4—O41174.73 (9)C14—C15—C16—C110.38 (16)
C1—O1—C11—C12−4.53 (15)O1—C11—C16—C15178.32 (9)
C1—O1—C11—C16175.88 (9)C12—C11—C16—C15−1.28 (15)
O1—C11—C12—C13−178.30 (9)C14—C13—O13—C171.43 (15)
C16—C11—C12—C131.27 (15)C12—C13—O13—C17−179.11 (9)
C11—C12—C13—O13−179.83 (9)
Hydrogen-bond geometry (Å, °) top
D—H···AD—HH···AD···AD—H···A
O41—H41···O42i0.927 (18)1.804 (19)2.7292 (11)175.5 (16)
C17—H17B···O42ii0.982.483.2477 (14)135
Symmetry codes: (i) −x, −y+3, −z+1; (ii) x+1, y−1, z.
Table 1
Hydrogen-bond geometry (Å, °) top
D—H···AD—HH···AD···AD—H···A
O41—H41···O42i0.927 (18)1.804 (19)2.7292 (11)175.5 (16)
C17—H17B···O42ii0.982.483.2477 (14)135
Symmetry codes: (i) −x, −y+3, −z+1; (ii) x+1, y−1, z.
Acknowledgements top

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

references
References top

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