Crystal structure of a new polymorph of (2S,3S)-2-amino-3-methylpentanoic acid

A new polymorph of (2S,3S)-2-amino-3-methylpentanoic acid, l-isoleucine C6H13NO2, crystallizes in the monoclinic space group P21 with four independent molecules in the asymmetric unit. In the crystal, N–H⋯O hydrogen bonds link two pairs of independent molecules and their symmetry-related counterparts to form two types of layers stacked in an anti-parallel manner parallel to (001). The hydrophobic aliphatic isopropyl groups protrude from these layers.


Chemical context
(2S,3S)-2-Amino-3-methylpentanoic acid, known as l-isoleucine (l-Ile), is one of the 20 amino acids common in animal proteins and required for normal functioning in humans. l-Ile is classified as a hydrophobic amino acid and is one of the two common amino acids that has a chiral side chain. l-Ile is essential for human muscle tissue recovery after exercise, along with Valine and Leucine.
The structure of l-Ile was first determined by Torii & Iitaka (1971). The crystal was found to belong to the monoclinic space group P2 1 , with four molecules in the unit cell, Z = 4. The asymmetric unit contains two independent molecules, with the side chain of the l-Ile molecules exhibiting two different conformations (Gö rbitz & Dalhus, 1996;Torii & Iitaka, 1971). Another polymorph in the orthorhombic space group P222 1 with the unit cell containing eight molecules was reported by Khawas (1970). The presence of an additional l-Ile polymorph is supported by X-ray powder diffraction measurements by Anuar et al. (2009), who suggested that l-Ile is prone to polymorphism as a result of the structural thermal motion of the aliphatic side chain.

Structural commentary 3. Supramolecular features
In the crystal, N-HÁ Á ÁO hydrogen bonds (Table 1) connect the molecules, forming layers parallel to (001). The polar side of l-Ile is embedded inside the layers while the side chains are oriented away, creating a hydrophobic surface. However, this hydrogen-bonding network has directionality along the polar b axis and specifically parallel to (001) (see Figs. 2 and 3). The adjacent layer is slightly rotated and grows in the opposite direction to the first one, an anti-parallel layer. The structure is composed of alternating layers with the hydrophilic side generating a hydrogen-bonding network growing in the opposite direction and the hydrophobic side chains are Symmetry codes: (i) x; y À 1; z; (ii) x; y þ 1; z; (iii) Àx þ 1; y þ 1 2 ; Àz þ 1; (iv) x À 1; y þ 1; z; (v) Àx þ 1; y À 1 2 ; Àz þ 1.

Figure 2
Part of the crystal structure viewed perpendicular to the ac plane showing adjacent anti-parallel layers formed by hydrogen-bonded pairs and symmetry-related molecules. The hydrophobic side chains protrude away and stack together. Displacement ellipsoids are shown at the 50% probability level (C atoms black, O red, N blue). H atoms are omitted for clarity. Blue dashed lines denote hydrogen bonds.

Figure 3
Part of the crystal structure viewed perpendicular to the bc plane showing adjacent anti-parallel layers formed by the hydrogen-bonded molecule pairs and symmetry-related molecules. The hydrophobic side chains protrude away and are stacked together. Displacement ellipsoids are shown at the 50% probability level (C atoms black, O red, N blue). H atoms are omitted for clarity. Blue dashed lines denote hydrogen bonds.

Figure 1
The asymmetric unit of the title compound with atomic numbering. Displacement ellipsoids are shown at the 50% probability level. directed outside. There is a slight offset between the layers to allow the hydrophobic side chains to fit the gaps in the adjacent layer surface.

Database survey
A comparison between the polymorph presented in this paper and the one reported by Gö rbitz & Dalhus (1996) is presented in Fig. 4. Both structures have the same monoclinic crystallographic P2 1 symmetry; however, one has four molecules in the unit cell and the other has only two. As described above, the layers show growth directionality and a pair of l-Ile molecules manage the layer organization. The new polymorph has alternating layers in opposite direction, anti-parallel, unlike the polymorph reported by Gö rbitz & Dalhus (1996), that has only parallel layers.

Synthesis and crystallization
Single crystals of l-Ile were grown from supersaturated aqueous solutions, via slow evaporation at 323 K in a cleanroom environment. The l-Ile powder (Holand-Moran 99%) was dissolved in water (Ultra-pure Millipore water, 18.2 M cm at 298 K, Millipore Synergy UV, Type 1 water) by heating to 353 K, with constant stirring until total dissolution. The hot solution was then filtered through cotton wool into glass crystallization dishes, which were covered with filter paper in order to allow slow evaporation, placed in a heating bath. Colorless crystal chunks, suitable for X-ray crystallographic Overlay of two structures with molecules presented as capped sticks along the b axis. The previous monoclinic P2 1 polymorph with two molecules in the asymmetric unit is the small unit cell with all molecules colored in gray and ordered in a parallel layer arrangement. The new monoclinic P2 1 polymorph has four molecules in the asymmetric unit (colored red, blue, yellow and green). The colors are according to symmetry equivalence. While the blue and red pairs form exactly the same network layer as the polymorph reported by Gö rbitz & Dalhus (1996), it is evident that the green and yellow pairs have a different orientation, with an anti-parallel layer arrangement. analysis were obtained. The absolute configuration of the title compound is already known.

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.