Crystal structure of (R,S)-2-hydroxy-4-(methylsulfanyl)butanoic acid

Methionine hydroxy analogue, a common poultry feed supplement, has been obtained in crystalline form for the first time. The asymmetric unit contains two conformationally unequal molecules that are involved in a two-dimensional intermolecular hydrogen-bonding network.


Chemical context
-Hydroxy carboxylic acids are indispensable players in plant and animal metabolism, and many of these substances are commercially important chemicals, because of their wide use in chemical industries and as pharmaceuticals, skin-care agents, or nutritional supplements (Bhalla et al., 2013). 2-Hydroxy-4-(methylsulfanyl)butanoic acid (I) is a natural precursor in methionine biosynthesis, and, for decades, synthetic HMTBA has been used on an industrial scale as a supplement to animal feeds in order to boost methionine production, particularly in farmed poultry (Zhang et al., 2015). In spite of its large-scale manufacture and use, commercial HMTBA is supplied as a brown, syrupy, racemic mixture, and it has not been reported to crystallize, even when isolated in chromatographically and enantiomerically pure preparations (Busto et al., 2014). One possible reason is that HMTBA readily forms dimeric and trimeric condensation products (Koban & Koberstein, 1984) which, along with the deliquescent behavior, may impede its crystallization. Crystal structures of free aliphatic -hydroxy carboxylic acids are rare, as a result of their propensity to oligomerize. Metal salts provide a means for stabilization of the -hydroxy carboxylate monomers, and structures of two HMTBA metal salts, Cu[(R,S)-HMTBA] 2 (CCDC 1018852; Yang et al., 2015) and Zn[(R,S)-HMTBA] 2 (CCDC 671417; Predieri et al., 2009), have been solved by X-ray diffraction. In our attempts to separate monomeric and oligomeric forms of HMTBA, we have successfully isolated a high-purity crystalline sample of (I), shown in Fig. 1, and report here its characterization by X-ray diffraction. ISSN 2056-9890 2. Structural commentary (R,S)-HMTBA crystallizes in the monoclinic space group P2 1 / c; the asymmetric unit consists of two molecules in nonequivalent conformations, (IA) and (IB) ( Table 1). The ORTEP views of the molecules and numbering of the atoms are shown in Figs. 2 and 3. Bond lengths and valence angles in (I) are within ranges expected for the given structure. The C1-C5 backbone in (R)-(IA) is in the trans, trans, gauche+ (t, t, g+) conformation, with the chain of atoms C1A through S1A located in one plane [maximum deviation 0.144 (1) Å for C3A]. In the crystal of (R,S)-HMTBA copper salt (Yang et al., 2015), a similar (t, t, g+) backbone rotamer exists in the (S)-HMTBA molecule. Likewise, the respective (t, t, g+) conformation of the l-methionine side chain was found in theisoform of dl-Met crystal (CCDC 1028063;Gö rbitz et al., 2014). The backbone conformation in (R)-(IB) is the gauche+, trans, gauche+ rotamer. An identical (g+, t, g+) conformation was adopted by (R)-HMTBA, molecule C, which is coordinated to the zinc ion in the crystal of (R,S)-HMTBA zinc salt trihydrate (Predieri et al., 2009). The conformation around the C1-C2 bond in (R)-(IB) is close to eclipsed, in respect to the O1B and O3B atoms, with a O3B-C2B-C1B-O1B torsion angle of À10.81 (19) . A similar spatial arrangement of the O1 and O3 atoms was reported in the aforementioned copper and zinc salts of HMTBA (Table 1), where simultaneous coordination of the carboxylate and hydroxyl oxygen atoms to the metal ions provided for the formation of nearly flat fivemembered chelate rings (Yang et al., 2015;Predieri et al., 2009). In crystal structures of the simplest -hydroxy carboxylic acids, glycolic acid (CCDC 1169248;Pijper, 1971) and l(+)-lactic acid (CCDC 1303177; Schouten et al., 1994), the molecular fragments including non-hydrogen atoms of the hydroxyl and carboxyl groups are also nearly flat (Table 1) The atomic numbering and displacement ellipsoids at 50% probability level drawn for molecule (IA).

Figure 3
The atomic numbering and displacement ellipsoids at 50% probability level drawn for molecule (IB).

Supramolecular features
The crystal structure of (I) consists of alternating polar and non-polar sheets running along the bc plane ( Fig. 4) and containing short O-HÁ Á ÁO contacts within the polar layers ( Fig. 4 and Table 2). Such a double-layered arrangement is typical for crystal structures of aliphatic l--amino acids and many other polar molecules, and these are present in all reference structures of both HMTBA metal salts and methionine listed in Table 1. Within the polar sheets, the basic hydrogen-bonding pattern features infinite homodromic chains of hydrogen bonds spiraling along the b-axis direction (Fig. 5). The chains are linked through bifurcated hydrogen bonding that involves the hydroxyl O3B-H3B donor group and the carboxylate O1A acceptor. One can recognize three basic motifs in the hydrogen-bonding pattern (in accordance with the topological notation system by Bernstein et al., 1995): the C 4 4 (12) motif forms homodromic infinite chains, which link similarly oriented molecules; the small R 2 2 (4) ring and the large homodromic R 8 8 (24) ring, which are formed by the O3B-H3BÁ Á ÁO1A links and the homodromic infinite chains that run along the b axis in opposite directions and are located on the opposite 'half-sheets' of the polar layer. The resulting pattern of conjugated rings is shown in Fig. 5b: it represents one of two symmetrical, in respect to the twofold screw along the b axis, systems of hydrogen bonds that penetrate the polar layers.
In addition to the 'classical' O-HÁ Á ÁO hydrogen bonds, there is one intermolecular C2B-HAÁ Á ÁO2A contact ( Fig. 6 and Table 3) in the crystal structure of (I) that is shorter than the sum of the van der Waals radii. The Hirshfeld surface analysis (CrystalExplorer17.5; Spackman & Jayatilaka, 2009), however, reveals that the C-HÁ Á ÁO contacts do not contribute significantly to the crystal packing forces, but that a major 564 Mawhinney et al. Hydrogen bonding in crystal structure of (I). (a) A view of the unit-cell contents shown in projection down the a axis. Hydrogen bonds are shown as cyan dotted lines. (b) Hydrogen-bonding patterns in the crystal structure of (I), as viewed down the a axis. Table 1 Selected torsion angles ( ) in (I) and related structures.

Figure 4
The molecular packing in (I). Color code for crystallographic axes: red À a, green À b, blue À c. Highlighted are hydrophilic regions in the crystal.

Synthesis and crystallization
Purely monomeric HMTBA in its free acid form is not commercially available because of the known propensity ofhydroxy carboxylic acids to oligomerize when concentrated (Koban & Koberstein, 1984); thus, we have evaluated the composition of a commercially available (R,S)-2-hydroxy-4-

Figure 7
The two-dimensional fingerprint plots for ( (methylsulfanyl)butanoic acid (TCI America) as having 65-72% HMTBA monomer, 2.7-4.5% of its linear dimer, 0.14-0.35% of the linear trimer, and 28-35% water. A pure, anhydrous sample of racemic HMTBA monomer was prepared by employing a mild, short-path distillation technique that utilizes a sublimation apparatus (Fig. 1a), half submerged in an ethylene glycol bath that was maintained at 383 K. After 72 h, while under vacuum (10 torr) and the cold finger kept at 277 K, large colorless prisms of neat (I) were formed on the sublimator's condenser (Fig. 1b), which melted at 302.5 K.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 5. O-bound H atoms were located from the difference map and those bonded to C were placed in calculated positions. The coordinates of all H atoms were refined freely while the thermal parameters were constrained to ride on the carrier atoms, U iso (H) = 1.2-1.5U eq (C,O).

Funding information
Funding for this research was provided by: University of Missouri Agriculture Experiment Station Chemical Laboratories ; National Institute of Food and Agriculture (grant No. MO-HABC0002).  Data collection: APEX3 and SAINT (Bruker, 2017); cell refinement: APEX3 and SAINT (Bruker, 2017); data reduction: APEX3 and SAINT (Bruker, 2017); program(s) used to solve structure: SHELXT2014 (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2017 (Sheldrick, 2015b); molecular graphics: Mercury (Macrae et al., 2020); software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009) and publCIF (Westrip, 2010). 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.