organic compounds
4-(3-Methoxyphenoxy)butyric acid
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
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 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
|
Data collection
|
Refinement
|
Data collection: X-AREA (Stoe & Cie, 2001); cell 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
10.1107/S1600536809008186/ng2557sup1.cif
contains datablocks I, global. DOI:Structure factors: contains datablock I. DOI: 10.1107/S1600536809008186/ng2557Isup2.hkl
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 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).
(eluent 100% CH2Cl2), to obtain the pure product as a slightly yellow oil (1.486 g, 77%). 1H-NMR (CDCl3, 300 MHz):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 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).
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):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.
Data collection: X-AREA (Stoe & Cie, 2001); cell
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).C11H14O4 | F(000) = 448 |
Mr = 210.22 | Dx = 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 |
Stoe IPDS-II two-circle diffractometer | 2458 reflections with I > 2σ(I) |
Radiation source: fine-focus sealed tube | Rint = 0.057 |
Graphite monochromator | θmax = 29.6°, θmin = 3.7° |
ω scans | h = −13→13 |
15489 measured reflections | k = −7→7 |
2945 independent reflections | l = −28→25 |
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(Fo2) + (0.0677P)2 + 0.1161P] where P = (Fo2 + 2Fc2)/3 |
S = 1.07 | (Δ/σ)max = 0.001 |
2945 reflections | Δρmax = 0.31 e Å−3 |
142 parameters | Δρmin = −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) |
C11H14O4 | V = 1052.74 (12) Å3 |
Mr = 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)° |
Stoe IPDS-II two-circle diffractometer | 2458 reflections with I > 2σ(I) |
15489 measured reflections | Rint = 0.057 |
2945 independent reflections |
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 | Δρmax = 0.31 e Å−3 |
2945 reflections | Δρmin = −0.20 e Å−3 |
142 parameters |
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. |
x | y | z | Uiso*/Ueq | ||
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* |
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) |
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) |
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 |
Mr | 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 |
Rint | 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 |
Δρmax, Δρmin (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).
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
Lloyd, D. G., Hughes, R. B., Zisterer, D. M., Williams, D. C., Fattorusso, C., Catalanotti, B., Campiani, G. & Meegan, M. J. (2004). J. Med. Chem. 47, 5612–5615. Web of Science CrossRef PubMed CAS Google Scholar
Macrae, C. F., Edgington, P. R., McCabe, P., Pidcock, E., Shields, G. P., Taylor, R., Towler, M. & van de Streek, J. (2006). J. Appl. Cryst. 39, 453–457. Web of Science CrossRef CAS IUCr Journals Google Scholar
Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. Web of Science CrossRef CAS IUCr Journals Google Scholar
Smith, G., Shariff, S. M., O'Reilly, E. J. & Kennard, C. H. L. (1989). Polyhedron, 8, 39–43. CSD CrossRef CAS Web of Science Google Scholar
Spek, A. L. (2009). Acta Cryst. D65, 148–155. Web of Science CrossRef CAS IUCr Journals Google Scholar
Stoe & Cie (2001). X-AREA. Stoe & Cie, Darmstadt, Germany. Google Scholar
Tandon, V. K., Khanna, J. M., Arand, N. & Chandra, A. (1990). Tetrahedron, 46, 2871–2882. CrossRef CAS Web of Science Google Scholar
This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.
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.