*3.3. Discussion*

In one of our works [18] we reviewed some particularities of crystal structures of several (but not all) proteinogenic amino acids to estimate their abilities to form heteromolecular discrete compounds consisting of molecules with different and the same chirality. It was stated that these amino acids were prone to form dimers with the molecules connected to each other by hydrogen bonds. Such dimeric molecules, in turn, are mutually interconnected via Van der Waals bonds. This arrangement is exemplified in Figure 11a, which depicts projections of the L-valine crystal structure onto the *ac* plane. It is distinctly seen that the dimer molecules form layers separated by Van der Waals contacts—i.e., the structure as a whole can be regarded as layered.

**Figure 11.** Projection of the L-valine crystal structure onto the *ac* plane of the monoclinic cell [18] (**a**) and projection of the L-alanine crystal structure onto the *bc* plane of the orthorhombic cell (**b**). Dotted lines are hydrogen bonds. The projections of the orthorhombic cell are plotted using the structural data from CSD (identifiers LVALIN01 and LALANINE54 [35]).

Both alanine and valine molecules (Figure 12a,b) contain a methyl (CH3) end group. However, alanine contains only one methyl on its end, while valine possesses two of them. At the first glance, this difference seems to be insignificant, but nevertheless it results in two amino acids with totally different crystal arrangements. While the crystal structure consisting of the dimeric molecule layers is quite viable for L-val (Figure 11a), this is not possible for L-ala.

**Figure 12.** Molecules of alanine (**a**), valine (**b**), and threonine (**c**).

Figure 11b shows the projection of the L-ala crystal structure onto the *bc* plane. It can be seen that there certainly are Van der Waals contacts in the direction of the *b* axis, but each of them is alternated with an N–H ... O hydrogen bond that results in a much more robust connection. At the same time, in the direction of the *c* axis there are two hydrogen bonds of the above type for every one of the Van der Waals bonds. Therefore, L-ala forms a "network" crystal structure (Figure 11b), similar to those of L-ser (Figure 10) and L-threonine (L-thr) [10], despite the fact that L-ser has a CH2OH end group (see Figure 2b) and L-thr possesses CH3 and OH end groups (Figure 12c). Furthermore, the acids L-ala, L-ser, and L-thr have another structural feature in common—that is, they all crystallize in the orthorhombic space group *P*212121.

The strong anisotropy of the crystal structure, which also resulted in a negative thermal expansion (contraction in the direction of the *a* axis), was observed as well in the related studies of L-threonine and L-*allo*-threonine [10]. A hinge mechanism can also be used to describe the thermal deformations of these diastereomers. Therefore, each one of L-ala, L-ser, L-thr and L-*allo*-thr has an orthorhombic crystal structure, while the L-valine, L-isoleucine, and L-leucine examined earlier [15–19] crystallize in monoclinic syngony.

Technically, the thermal deformations of the acids of both types ("layered" and "network") are similar to some extent. In both cases, the maximum and minimum (including "negative") thermal expansion is observed in the direction of the weakest and strongest intermolecular contacts, respectively. However, as deducible from changes of the monoclinic angle β at elevated temperatures, the leading role in structural deformations of monoclinic crystal structures belongs to shear deformations.

The observed response of the network orthorhombic structures to rising the temperature allowed to suspect a correlation between the resulting deformation and the range of intermolecular distance variation (chiefly Van der Waals contacts) as a result of deformation of the voids (channels) via a hinged mechanism in the corresponding structures (see, for example, Figures 9 and 10).

The thermal deformations of the crystal structures of L-ala and L-ser discussed in the present article are anisotropic. However, the anisotropy of the L-ala crystals is more evident in comparison with that observed in L-ser which can be caused by the greater concentration of the Van der Waals bonds in the structure of the former amino acid. The same phenomenon can account for significant differences in the changes of the parameters and volume of their orthorhombic cells and hence corresponding thermal expansion coefficients. Here, it is worth noting again that the α<sup>v</sup> value for L-ala is almost by a half greater than that of L-ser.

Obviously, the differences in the size and shape of L-ala and L-ser molecules play only a minor role in imposing considerable limitations on the isomorphic miscibility in the L-ala–L-ser system. A much greater part is played by the differences in the nature of the intermolecular contacts in the respective amino acids' structures—namely, by a significantly greater concentration of Van der Waals bonds in the crystal structure of L-ala compared to L-ser.
