*3.1. Solubility Test and Preliminary Entrainment Experiment*

The tests showed that at room temperature *rac*-**1** has fairly good solubility in ethyl acetate, chloroform, acetonitrile and poor solubility in water and hexane. Diol *rac*-**1** is moderately soluble in CCl4, toluene and methyl *tert*-butyl ether (MTBE). Carbon tetrachloride turned out to be inconvenient for further experiments, since during the crystallization process, the formed crystals float to the surface of the solution and hardly form a distributed suspension. When cooling heated saturated solutions of diol **1** in toluene, an emulsion instead of suspension is initially obtained, which crystallizes only after a lapse of time. Of these three solvents, the reverse to the dissolution process, that is, effective spontaneous crystallization, runs smoothly only in MTBE. Therefore, a more detailed study of the dissolution and crystallization of both racemic and enantiopure **1** was carried out in this solvent.

Figure 1 shows the temperature dependence of the solubility of diol **1** stereoisomers in this solvent. The solid red circles identify the end of dissolution, and the red hollow circles—the starting points of crystallization for the racemic samples. Similarly, the behavior of enantiopure diol in the "dissolution–crystallization" cycle is characterized in blue. Concentration values for racemate are given per individual stereoisomer (i.e., the real values of racemate concentration are halved).

**Figure 1.** Temperature dependence of solubility (per single enantiomer, solid lines and circles) and for onset of crystallization (dashed lines, hollow circles) of *rac*-**1** (red) and (*S*)-**1** (blue) in methyl *tert*-butyl ether.

From the data obtained, it follows that the width of metastable zone for both *rac*-**1** and (*S*)-**1** varies slightly in the studied temperature range and amounts to 15 ± 2 ◦C. The chart analysis shows, that the experimental points, corresponding to the process of dissolution of enantiopure and racemic samples, do not lie on the common curve, and with increasing temperature the difference in solubility increases. This means that, for the system under study, Meyerhoffer's rule, according to which the racemate solubility twice as high the solubility of single enantiomer [42,43], is not performed. In turn, this means that the dissolution process for diol **1** is complicated by some, for the moment, unobvious effects. Meyerhoffer's coefficient high values are associated with a decrease of the metastable zone width and, consequently, with reduced spontaneous resolution efficiency [7]. Since in our case the width of the metastable zone is not very dependent on temperature, in the test experiment we carried out the crystallization stage during racemic diol **1** resolution by entrainment process at room temperature. The initial concentration of the individual stereoisomers was about 25 g·L−1, and the enantiomeric

composition of the mother liquor was monitored by HPLC. The results for four cycles (eight runs) of resolution are shown in Table 2.


**Table 2.** Resolution by entrainment of *rac*-3-(3.4-dimethylphenoxy)propane-1,2-diol, *rac*-**1** in methyl *tert*-butyl ether (20 mL, 5 mg of crystal seeds on every run; crystallization temperature 23.5 ± 0.5 ◦C).

<sup>1</sup> ee: enantiomeric excess (HPLC). <sup>2</sup> YE: Yield of enantiomer; YE(mg) <sup>=</sup> [Yield (mg) × ee (%)]/<sup>100</sup> − 5 (seed weight); YE(%) = [YE(mg) × 100]/Operation amount of (*R*)- or (*S*)-**1**(mg).

The results presented in the Table 2 allow us to state with certainty that spontaneous resolution during crystallization of *rac*-**1** does occur. At the same time, the realized procedure cannot be considered as a satisfactory one. The individual runs are, firstly, too long, and secondly, irreproducible. The latter applies to the enantiomeric composition of the crystalline crop as well. All this, together with the non-compliance of Meyerhoffer's rule, prompted us to study in more detail the phase behavior of diol **1**.
