Crystallographic and spectroscopic characterization of racemic Mosher’s Acid

Mosher’s Acid (systematic name: 3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acid) is a carboxylic acid that when resolved can be employed as a chiral derivatizing agent. The two independent molecules in the asymmetric unit form a non-centrosymmetric homochiral dimer via intermolecularly hydrogen-bonded head-to-tail dimers with graph-set notation (8).


Chemical context
The title compound, -methoxy--trifluoromethylphenylacetic acid, or 3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acid, MTPA (I) is commonly known as Mosher's Acid. Mosher's Acid is an aromatic compound in which an asymmetric benzylic carbon atom is specifically substituted with a carboxylic acid group, a methoxy group and a trifluoromethyl substituent. When resolved and in its acid chloride form, it has been shown to be useful as a chiral derivatizing agent (CDA) with natural organic compounds (Cimmino et al., 2017). Originally, Mosher's Acid chloride was used to convert a mixture of enantiomers of amines or alcohols into diastereomeric amides or esters, respectively, in order to analyze the quantities of each enantiomer present within the sample by NMR (Dale et al., 1969), and also to elucidate the absolute stereochemistry of the starting material (Allen et al., 2008). Mosher's Acid has recently been used in NMR studies of the ring flip in the atrane cages of Group 14 metallatranes, where as an axial substituent it forces the Áand Ã-isomers to become diastereomeric (Glowacki et al., 2019). The synthesis of Mosher's Acid reported in early work converted phenyl trifluoromethyl ketone to -trifluoromethylphenylacetonitrile with sodium cyanide and methyl sulfate followed by treatment with concentrated sulfuric acid to obtain the acid (Dale et al., 1969). More recently, Mosher's Acid was obtained by treatment of phenyl trifluoromethyl ketone with trimethylsilyl trichloroacetate followed by hydrolysis (Goldberg & Alper, 1992). ISSN 2056-9890

Structural commentary
The molecular structure of the title compound ( Fig. 1) reveals that there are two independent molecules in the asymmetric unit. Each consists of a mono-substituted benzene ring including a methoxy group, a trifluoromethyl group, and a carboxylic acid on the asymmetric benzylic carbon atom. The molecules show slightly different conformations, specifically in regard to the disposition of the methoxy group. In the molecule with asymmetric carbon C11, the methoxy group is canted away from the phenyl ring, with a C15-C11-O3-C14 torsional angle of À175.55 (12) . In the other molecule, the methoxy group is bent in, with a C25-C21-O6-C24 torsional angle of À51.12 (15) .

Supramolecular features
Although the material is racemic, two independent molecules of the same chirality are observed to hydrogen bond together into pairwise dimers (Table 1, Fig. 2), with graph-set notation R 2 2 (8) and donor-acceptor hydrogen-bonding distances of 2.6616 (13) and 2.6801 (13) Å . The dimers further pack together via van der Waals interactions without any other notable intermolecular interactions such as -stacking or fluorinefluorine contacts less than the sum of the van der Waals radii. The hydrogen-bonded dimers stack along the crystallographic b-axis direction (Fig. 3).

Database survey
The Cambridge Structural Database (Version 5.40, update of March 2020; Groom et al., 2016) contains no structures of racemic or resolved Mosher's Acid itself. However, there are numerous structures of its carboxylate salts, and one example (UTUHUN) of the neutral acid co-crystallized with an imidazole (Tydlitá t et al., 2010). In this example, the bond lengths about the asymmetric carbon atom are similar to those observed in (I), with C-CO 2 H = 1.547 (5), C-CF 3 = 1.538 (6), C-C Ar 1.519 (5) and C-OCH 3 1.419 (5) Å , while the disposition of the methoxy group with a torsional angle of 170.02 is most similar to the unique molecule in (I) with asymmetric carbon atom C11.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. All non-hydrogen atoms were refined anisotropically. Hydrogen atoms on carbon were included in calculated positions and refined using a riding model with C-H = 0.95 and and 0.98 Å and U iso (H) = 1.2 and 1.5 Â U eq (C) of the aryl and methyl C atoms, respectively. The positions of the carboxylic acid hydrogen atoms were found in the difference map and the atom refined semi-freely using a distance restraint d(O-H) = 0.84 Å , and U iso (H) = 1.2 Â U eq (O).

3,3,3-Trifluoro-2-methoxy-2-phenylpropanoic acid
Crystal data Special details Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.