2-(3-Bromo-4-meth­oxy­phen­yl)acetic acid

Ilia A Guzei; Alan R Gunderson; Nicholas J Hill

doi:10.1107/S1600536810020143

. 2010 Jun 5;66(Pt 7):o1555–o1556. doi: 10.1107/S1600536810020143

2-(3-Bromo-4-methoxyphenyl)acetic acid

Ilia A Guzei ^a,^*, Alan R Gunderson ^a, Nicholas J Hill ^a

PMCID: PMC3007027 PMID: 21587800

Abstract

The title compound C₉H₉BrO₃, was synthesized by the regioselective bromination of 4-methoxyphenylacetic acid using bromine in acetic acid in a 84% yield. In the molecular structure, the methoxy group is almost coplanar with the phenyl ring within 0.06 Å; the acetic acid substituent is tilted by 78.15 (7)° relative to the ring. The C—C—C angles at the OMe, acetyl and Br substituents are 118.2 (2), 118.4 (2) and 121.5 (2)°, respectively, indicating that the Br atom is electron-withdrawing, whereas the other substituents possess electron-donating properties. In the crystal, the molecules form centrosymmetric strongly O—H⋯O hydrogen-bonded dimers of the type R ₂ ²(8).

Related literature

For the use of the title compound in the synthesis of natural products such as Combretastatin A-4, see: Zou et al. (2008 ▶); for Verongamine, see: Wasserman & Wang (1998 ▶) and for model Vancomycin-type systems, see: Ghosh et al. (2009 ▶). The iodo-analogue featured in the synthesis of (+)-Phleichrome and (+)-Calphostin D, see: Morgan et al. (2010 ▶). For the synthesis of the title compound, see: Coutts et al., (1970 ▶); Morgan et al., (2007 ▶); Zou et al. (2008 ▶); Ghosh et al. (2009 ▶). For background for our program to introduce natural product synthesis, crystal growing techniques and single crystal X-ray diffraction data analysis into the undergraduate curriculum, see: Findlater et al., (2010 ▶); Guzei et al., (2010a ▶). For a discussion of hydrogen-bonding motif assignment, see: Guzei et al. (2010b ▶). Outlier reflections were omitted based on the statistics test described by Prince & Nicholson (1983 ▶) and Rollett (1988 ▶), and implemented in FCF_filter (Guzei, 2007 ▶).

Experimental

Crystal data

C₉H₉BrO₃
M _r = 245.06
Monoclinic,
a = 12.5022 (4) Å
b = 8.2690 (2) Å
c = 9.0199 (3) Å
β = 93.573 (1)°
V = 930.67 (5) Å³
Z = 4
Cu Kα radiation
μ = 5.81 mm⁻¹
T = 120 K
0.46 × 0.37 × 0.19 mm

Data collection

Bruker SMART APEXII area-detector diffractometer
Absorption correction: analytical (SADABS; Bruker, 2007 ▶) T _min = 0.177, T _max = 0.398
12598 measured reflections
1725 independent reflections
1708 reflections with I > 2σ(I)
R _int = 0.030

Refinement

R[F ² > 2σ(F ²)] = 0.026
wR(F ²) = 0.073
S = 1.08
1725 reflections
120 parameters
H-atom parameters constrained
Δρ_max = 0.86 e Å⁻³
Δρ_min = −0.47 e Å⁻³

Data collection: APEX2 (Bruker, 2007 ▶); cell refinement: SAINT-Plus (Bruker, 2007 ▶); data reduction: SAINT-Plus; program(s) used to solve structure: SHELXTL (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXTL; molecular graphics: SHELXTL; software used to prepare material for publication: publCIF (Westrip, 2010 ▶) and modiCIFer (Guzei, 2007 ▶).

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536810020143/rk2206sup1.cif

e-66-o1555-sup1.cif^{(14.8KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536810020143/rk2206Isup2.hkl

e-66-o1555-Isup2.hkl^{(85KB, hkl)}

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Enhanced figure: interactive version of Fig. 1

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O3—H3⋯O2ⁱ	0.84	1.82	2.661 (2)	179

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Symmetry code: (i) Inline graphic .

supplementary crystallographic information

Comment

Recently, we have been pursuing simple organic and organometallic compounds as candidates for the introduction of (a) natural product synthesis into the undergraduate teaching laboratory and (b) crystal growing techniques and single crystal X-ray diffraction data analysis into the undergraduate curriculum (Findlater et al., 2010; Guzei at al., 2010a). The 3-bromo-4-methoxyphenylacetic acid I has been employed in the synthesis of natural products such as Combretastatin A-4, (Zou et al., 2008), Verongamine (Wasserman & Wang, 1998) and model Vancomycin-type systems (Ghosh et al., 2009). The iodo-analogue features in the synthesis of the perylenequinones (+)-Phleichrome and (+)-Calphostin D, (Morgan et al., 2010). Our interest in I stems from its role in the synthesis of the antimitotic compound Combretastatin A-4 via a simple Perkin condensation/decarboxylation sequence (Zou et al., 2008). This concise route, employing commercially available starting materials, followed by the facile purification of I to furnish high quality crystals makes it ideal in both regards. Compound I is readily synthesized by the regioselective bromination of 4-methoxyphenylacetic acid using bromine in acetic acid (Coutts et al., 1970; Morgan et al., 2007; Zou et al., 2008; Ghosh et al., 2009). Compound I was isolated and characterized by NMR, mp, and single-crystal X-ray analysis. There are three main structural aspects students should identify. First, the positions of the alkyl substituents on the phenyl ring. The methoxy-group is almost coplanar with the ring, torsion angle C7—O1—C1—C6 is 1.2 (3)°, whereas the acetic acid terminus is nearly perpendicular to the ring with the dihedral angle between the planes defined by atoms C1—C6 and atoms C4,C8,C9,O2,O3 spanning 78.15 (7)°. Secondly, the distortions of the C—C—C angles from 120° at the substituents of the phenyl ring reflect their electronic properties. The stronger the electron-withdrawing power of a substituent, the larger the C—C—C angle. The angles at OMe, Ac and Br are 118.2 (2), 118.4 (2), and 121.5 (2)°, respectively, indicating that the Br atom is electron-withdrawing, whereas the other substituents possess electron-donating properties. Of course, the magnitude of the values is affected by the neighbouring substituents. Thirdly, the molecules of I form centrosymmetric strongly hydrogen-bonded dimers in the lattice. The hydrogen bonding motif is R₂²(8). A topical discussion of hydrogen bonding motif assignment was published by Guzei et al., 2010b.

Experimental

To a stirred solution of 4-methoxyphenylacetic acid (10 g, 60.2 mmol) in acetic acid (60 ml) was added a solution of bromine (9.62 g, 3.1 ml, 60.2 mmol) in acetic acid (30 ml) slowly dropwise over 30 min. The mixture was stirred at room temperature (60 min) and then poured into 500 ml ice–water. The resultant pale yellow, turbid mixture was stirred (10 min), filtered, rinsed with ice–water (3×10 ml), air-dried (20 min) and recrystallized from hot xylene to give a white crystalline powder. Yield 12.41 g, 84 %. M.p. 386.3–387.2 K.

¹H NMR (CDCl₃): δ 3.56 (2H, s, CH₂); 3.89 (3H, s, OCH₃), 6.86 (1H, d), 7.19 (1H, dd), 7.48 (1H, d). ¹³C(¹H) NMR (CDCl₃): δ 39.9; 56.5; 111.9; 112.2; 127.0; 129.6; 134.6; 155.5; 178.0.