Crystal structures of three halide salts of l-asparagine: an isostructural series

The monohydrated chloride, bromide and iodide salt forms of the amino acid l-asparagine form an isostructural series.


Chemical context
Changing the salt form of an organic material is a well known way of altering the material's physical properties whilst retaining many of the chemical properties inherent to the organic fragment. Selection of the salt form with the most suitable properties is thus an important consideration in the development of pharmaceutical materials and indeed of other fine chemicals (Stahl & Wermuth, 2008;Bastin et al., 2000;Kennedy et al., 2012). Often, the main property of interest is solubility, but salt selection may also be used to alter properties such as crystal morphology, hygroscopicity or stability, as well as mechanical properties such as hardness and strength (Stahl & Wermuth, 2008;Sun & Grant, 2001;Hao & Iqbal, 1997;de Moraes et al., 2017). In short, any bulk property that depends in some way on the packing or on the intermolecular forces within the crystalline array structure may be altered by changing the salt-forming counter-ion. Despite the common usage of salt selection strategies, our understanding of what effect on properties any particular change of counter-ion will have is extremely limited. This means, for example, that it is not currently possible to predict which salt form of an active pharmaceutical ingredient (API) will be the most soluble or have the best compaction properties. In this area, isostructural series of structures are especially interesting as they allow changes in properties to be related to changes in intermolecular interaction strength or type without the complication of changes to the overall gross structure (Galcera & Molins, 2009;Allan et al., 2018). Here we present the structures of three isostructural halide salts of l-asparagine, namely

Supramolecular features
Isostructurality is also indicated by examination of the hydrogen bonding, Tables 1-3 and Fig. 4. The three compounds all make the same number and type of hydrogen bonds, with the main difference being the increasing DÁ Á ÁA distances caused by the different anion sizes. Where A = X there is a 7.4 to 11.5% increase in DÁ Á ÁA distance from Cl to I, whereas where A = O there is a smaller 0.6 to 4.0% increase. The only exception is the sole intramolecular interaction.  View of the contents of the asymmetric unit of (II). Non-H atoms are drawn as 50% probability ellipsoids and H atoms as spheres of arbitrary size.

Figure 3
View of the contents of the asymmetric unit of (III). Non-H atoms are drawn as 50% probability ellipsoids and H atoms as spheres of arbitrary size.

Figure 1
View of the contents of the asymmetric unit of (I). Non-H atoms are drawn as 50% probability ellipsoids and H atoms as spheres of arbitrary size.

Figure 4
View of all the unique hydrogen-bonding contacts made by the contents of the asymmetric unit of (I).

Figure 6
Packing diagram of (III) as viewed down the a-axis direction.
organic hydrates (Gillon et al., 2003;Briggs et al., 2012). These interactions combine to give the structure shown in Fig. 6 with alternating layers of organic cations and halide anions lying parallel to the ab plane.

Database survey
The only other known structure of a simple salt of S-asparagine is that of the nitrate (Aarthy et al., 2005). Here both the cations in a Z 0 = 2 structure adopt different conformations from that found for the halides: compare N-C-C-O(acid C O) of À176.9 (6) and 173.2 (5) and N-C-C-O(amide) of À123.2 (7) and 77.0 (4) with the equivalent values given above. The structures of two simple salts of racemic asparagine have also been reported. These are the nitrate and the perchlorate forms (Moussa Slimane et al., 2009;Guenifa et al., 2009). All these literature forms are anhydrous, but despite this difference and further differences in anion type and cation geometry, all form the same R(8) 2 2 -based, one-dimensional hydrogen-bonded chain motif seen in the halide salts (I), (II) and (III).

Synthesis and crystallization
Salt forms of l-asparagine were prepared by dissolving 29 mmol of the amino acid in 90 ml of distilled water. The solution was stirred and heated slightly until complete dissolution had occurred. The solution was then equally divided between three vials. To each vial was added 1 ml of concentrated acid, either hydrochloric acid, hydrobromic acid or hydroiodic acid. The first crystals appeared after 24 h of sitting at room temperature. Crystals suitable for analyses [colourless prisms for (I), colourless tablets for (II) and colourless rods for (III)] were obtained directly from the mother liquors and were removed from these solutions just prior to data collection.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 4. Structure solution for (III) was by substitution from the Br equivalent. All H atoms bound to C were placed in calculated positions and refined in riding modes. C-H distances were 0.99 and 1.00 Å for CH 2 and CH   Refined as an inversion twin Absolute structure parameter À0.02 (2) À0.022 (11) À0.07 (4) groups respectively, with U(H) iso = 1.2U eq (C). With the exception noted below, all other H atoms were observed and positioned as found. For (I) these were refined isotropically, but for (II) restraints were required for the NH 3 and OH 2 atoms. For (III) all H atoms required restraints to be applied. N-H distances were restrained to 0.90 (1) Å and O-H distances to 0.88 (1) Å . U(H) iso = 1.2U eq of the parent atom.
The exception was the NH 3 group of (III). The best model involved treating this as a rigid tetrahedral group and allowing only rotation around the C-N bond. For this group, U iso (H) = 1.5U eq (N). Compound (III) was refined as an inversion twin.

L-Asparaginium chloride monohydrate (I)
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.

L-Asparaginium bromide monohydrate (II)
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.

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. Refinement. Refined as a two-component inversion twin.