4-(3-Methoxy­phen­oxy)butyric acid

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

doi:10.1107/S1600536809008186

organic compounds

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ISSN: 2056-9890

Volume 65| Part 4| April 2009| Page o778

doi:10.1107/S1600536809008186

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4-(3-Methoxyphenoxy)butyric acid

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

^aÉcole Nationale Supérieure de Chimie de Paris, Laboratoire Charles Friedel, UMR CNRS 7223, 11 rue Pierre et Marie Curie, 75231 Paris Cedex 05, France, and ^bInstitut für Anorganische Chemie, J. W. Goethe-Universität Frankfurt, Max-von-Laue-Strasse 7, 60438 Frankfurt/Main, Germany
^*Correspondence e-mail: bolte@chemie.uni-frankfurt.de

(Received 5 March 2009; accepted 5 March 2009; online 19 March 2009)

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, P 2₁ /n
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[F² > 2σ(F²)] = 0.043
wR(F²) = 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

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

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 ).

Supporting information

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

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

checkCIF report

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).

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

	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.
	Fig. 2. Packing diagram of the title compound with view onto the ac plane. Hydrogen bonds shown as dashed lines.
	Fig. 3. The numbering of the ethyl ester of the title compound.
	Fig. 4. The numbering of the title compound.

4-(3-Methoxyphenoxy)butyric acid top

Crystal data top

C₁₁H₁₄O₄	F(000) = 448
M_r = 210.22	D_x = 1.326 Mg m⁻³
Monoclinic, P2₁/n	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2yn	Cell parameters from 15224 reflections
a = 9.6509 (6) Å	θ = 3.7–29.5°
b = 5.3998 (4) Å	µ = 0.10 mm⁻¹
c = 20.2033 (13) Å	T = 173 K
β = 90.822 (5)°	Block, colourless
V = 1052.74 (12) Å³	0.32 × 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 tube	R_int = 0.057
Graphite monochromator	θ_max = 29.6°, θ_min = 3.7°
ω scans	h = −13→13
15489 measured reflections	k = −7→7
2945 independent reflections	l = −28→25

Refinement top

Refinement on F²	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F² > 2σ(F²)] = 0.043	H atoms treated by a mixture of independent and constrained refinement
wR(F²) = 0.120	w = 1/[σ²(F_o²) + (0.0677P)² + 0.1161P] where P = (F_o² + 2F_c²)/3
S = 1.07	(Δ/σ)_max = 0.001
2945 reflections	Δρ_max = 0.31 e Å⁻³
142 parameters	Δρ_min = −0.20 e Å⁻³
0 restraints	Extinction correction: SHELXL97 (Sheldrick, 2008), Fc^*=kFc[1+0.001xFc²λ³/sin(2θ)]^-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.048 (5)

Crystal data top

C₁₁H₁₄O₄	V = 1052.74 (12) Å³
M_r = 210.22	Z = 4
Monoclinic, P2₁/n	Mo Kα radiation
a = 9.6509 (6) Å	µ = 0.10 mm⁻¹
b = 5.3998 (4) Å	T = 173 K
c = 20.2033 (13) Å	0.32 × 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 reflections	R_int = 0.057
2945 independent reflections

Refinement top

R[F² > 2σ(F²)] = 0.043	0 restraints
wR(F²) = 0.120	H atoms treated by a mixture of independent and constrained refinement
S = 1.07	Δρ_max = 0.31 e Å⁻³
2945 reflections	Δρ_min = −0.20 e Å⁻³
142 parameters

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

	x	y	z	U_iso*/U_eq
O1	0.32321 (7)	0.55314 (15)	0.64594 (4)	0.03035 (19)
C1	0.36009 (11)	0.72446 (18)	0.59488 (5)	0.0263 (2)
H1A	0.3840	0.6344	0.5539	0.032*
H1B	0.4411	0.8248	0.6091	0.032*
C2	0.23475 (10)	0.89015 (19)	0.58265 (5)	0.0265 (2)
H2A	0.2151	0.9860	0.6232	0.032*
H2B	0.1527	0.7866	0.5721	0.032*
C3	0.26116 (11)	1.0679 (2)	0.52546 (5)	0.0286 (2)
H3A	0.3491	1.1572	0.5343	0.034*
H3B	0.2727	0.9704	0.4844	0.034*
C4	0.14701 (11)	1.25525 (19)	0.51430 (5)	0.0269 (2)
O41	0.17803 (9)	1.41971 (15)	0.46803 (4)	0.0342 (2)
H41	0.1036 (18)	1.526 (3)	0.4617 (8)	0.056 (5)*
O42	0.03810 (8)	1.25686 (16)	0.54438 (5)	0.0382 (2)
C11	0.42179 (10)	0.38789 (18)	0.66811 (5)	0.0245 (2)
C12	0.55358 (10)	0.36401 (18)	0.64103 (5)	0.0253 (2)
H12	0.5814	0.4682	0.6058	0.030*
C13	0.64437 (10)	0.18317 (18)	0.66685 (5)	0.0243 (2)
C14	0.60524 (11)	0.02991 (19)	0.71884 (5)	0.0263 (2)
H14	0.6668	−0.0927	0.7358	0.032*
C15	0.47284 (10)	0.06066 (19)	0.74563 (5)	0.0278 (2)
H15	0.4454	−0.0420	0.7813	0.033*
C16	0.38130 (11)	0.23721 (19)	0.72120 (5)	0.0270 (2)
H16	0.2923	0.2562	0.7401	0.032*
O13	0.77149 (8)	0.17389 (15)	0.63728 (4)	0.0316 (2)
C17	0.86678 (11)	−0.0111 (2)	0.66159 (5)	0.0334 (3)
H17A	0.8863	0.0179	0.7087	0.050*
H17B	0.9532	−0.0014	0.6369	0.050*
H17C	0.8257	−0.1758	0.6558	0.050*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O1	0.0250 (4)	0.0310 (4)	0.0350 (4)	0.0067 (3)	0.0021 (3)	0.0095 (3)
C1	0.0255 (5)	0.0255 (5)	0.0277 (5)	0.0032 (4)	−0.0012 (4)	0.0029 (4)
C2	0.0262 (5)	0.0251 (5)	0.0281 (5)	0.0052 (4)	−0.0032 (4)	0.0004 (4)
C3	0.0290 (5)	0.0275 (5)	0.0294 (5)	0.0056 (4)	−0.0011 (4)	0.0014 (4)
C4	0.0291 (5)	0.0247 (5)	0.0268 (5)	0.0022 (4)	−0.0036 (4)	0.0007 (4)
O41	0.0362 (4)	0.0313 (4)	0.0351 (4)	0.0080 (3)	0.0025 (3)	0.0096 (3)
O42	0.0318 (4)	0.0371 (5)	0.0458 (5)	0.0105 (3)	0.0055 (4)	0.0148 (4)
C11	0.0238 (4)	0.0231 (4)	0.0266 (5)	0.0024 (3)	−0.0027 (4)	0.0014 (4)
C12	0.0263 (5)	0.0255 (5)	0.0240 (4)	0.0018 (3)	−0.0002 (3)	0.0035 (3)
C13	0.0237 (4)	0.0257 (4)	0.0235 (4)	0.0021 (3)	−0.0008 (3)	−0.0002 (4)
C14	0.0273 (5)	0.0250 (5)	0.0265 (5)	0.0018 (4)	−0.0033 (4)	0.0035 (4)
C15	0.0280 (5)	0.0282 (5)	0.0273 (5)	−0.0025 (4)	−0.0011 (4)	0.0050 (4)
C16	0.0245 (5)	0.0286 (5)	0.0280 (5)	−0.0010 (4)	0.0002 (4)	0.0020 (4)
O13	0.0266 (4)	0.0380 (4)	0.0303 (4)	0.0100 (3)	0.0048 (3)	0.0095 (3)
C17	0.0301 (5)	0.0382 (6)	0.0319 (5)	0.0128 (4)	0.0026 (4)	0.0059 (4)

Geometric parameters (Å, º) top

O1—C11	1.3747 (11)	C11—C16	1.4061 (14)
O1—C1	1.4343 (12)	C12—C13	1.4072 (13)
C1—C2	1.5219 (13)	C12—H12	0.9500
C1—H1A	0.9900	C13—O13	1.3732 (12)
C1—H1B	0.9900	C13—C14	1.3935 (14)
C2—C3	1.5263 (14)	C14—C15	1.4047 (14)
C2—H2A	0.9900	C14—H14	0.9500
C2—H2B	0.9900	C15—C16	1.3858 (14)
C3—C4	1.5103 (14)	C15—H15	0.9500
C3—H3A	0.9900	C16—H16	0.9500
C3—H3B	0.9900	O13—C17	1.4394 (12)
C4—O42	1.2217 (13)	C17—H17A	0.9800
C4—O41	1.3268 (13)	C17—H17B	0.9800
O41—H41	0.927 (18)	C17—H17C	0.9800
C11—C12	1.3977 (13)

C11—O1—C1	118.38 (8)	O1—C11—C16	115.18 (9)
O1—C1—C2	106.92 (8)	C12—C11—C16	120.64 (9)
O1—C1—H1A	110.3	C11—C12—C13	118.96 (9)
C2—C1—H1A	110.3	C11—C12—H12	120.5
O1—C1—H1B	110.3	C13—C12—H12	120.5
C2—C1—H1B	110.3	O13—C13—C14	124.03 (9)
H1A—C1—H1B	108.6	O13—C13—C12	114.80 (8)
C1—C2—C3	110.58 (8)	C14—C13—C12	121.16 (9)
C1—C2—H2A	109.5	C13—C14—C15	118.56 (9)
C3—C2—H2A	109.5	C13—C14—H14	120.7
C1—C2—H2B	109.5	C15—C14—H14	120.7
C3—C2—H2B	109.5	C16—C15—C14	121.53 (9)
H2A—C2—H2B	108.1	C16—C15—H15	119.2
C4—C3—C2	113.88 (9)	C14—C15—H15	119.2
C4—C3—H3A	108.8	C15—C16—C11	119.14 (9)
C2—C3—H3A	108.8	C15—C16—H16	120.4
C4—C3—H3B	108.8	C11—C16—H16	120.4
C2—C3—H3B	108.8	C13—O13—C17	116.57 (8)
H3A—C3—H3B	107.7	O13—C17—H17A	109.5
O42—C4—O41	123.38 (9)	O13—C17—H17B	109.5
O42—C4—C3	124.16 (9)	H17A—C17—H17B	109.5
O41—C4—C3	112.46 (9)	O13—C17—H17C	109.5
C4—O41—H41	109.2 (11)	H17A—C17—H17C	109.5
O1—C11—C12	124.18 (9)	H17B—C17—H17C	109.5

C11—O1—C1—C2	−177.45 (8)	C11—C12—C13—C14	−0.36 (15)
O1—C1—C2—C3	−176.12 (8)	O13—C13—C14—C15	178.91 (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—C16	0.51 (16)
C2—C3—C4—O41	174.73 (9)	C14—C15—C16—C11	0.38 (16)
C1—O1—C11—C12	−4.53 (15)	O1—C11—C16—C15	178.32 (9)
C1—O1—C11—C16	175.88 (9)	C12—C11—C16—C15	−1.28 (15)
O1—C11—C12—C13	−178.30 (9)	C14—C13—O13—C17	1.43 (15)
C16—C11—C12—C13	1.27 (15)	C12—C13—O13—C17	−179.11 (9)
C11—C12—C13—O13	−179.83 (9)

Hydrogen-bond geometry (Å, º) top

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

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

Experimental details

Crystal data
Chemical formula	C₁₁H₁₄O₄
M_r	210.22
Crystal system, space group	Monoclinic, P2₁/n
Temperature (K)	173
a, b, c (Å)	9.6509 (6), 5.3998 (4), 20.2033 (13)
β (°)	90.822 (5)
V (Å³)	1052.74 (12)
Z	4
Radiation type	Mo Kα
µ (mm⁻¹)	0.10
Crystal size (mm)	0.32 × 0.27 × 0.25

Data collection
Diffractometer	Stoe IPDS-II two-circle diffractometer
Absorption correction	–
No. of measured, independent and observed [I > 2σ(I)] reflections	15489, 2945, 2458
R_int	0.057
(sin θ/λ)_max (Å⁻¹)	0.694

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.043, 0.120, 1.07
No. of reflections	2945
No. of parameters	142
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δρ_max, Δρ_min (e Å⁻³)	0.31, −0.20

Computer programs: X-AREA (Stoe & Cie, 2001), SHELXS97 (Sheldrick, 2008), XP in SHELXTL-Plus (Sheldrick, 2008) and Mercury (Bruno et al., 2002), SHELXL97 (Sheldrick, 2008) and PLATON (Spek, 2009).

Hydrogen-bond geometry (Å, º) top

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

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

Acknowledgements

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

References

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