*3.5. X-ray Di*ff*raction Investigations*

As shown in the previous sections, only the β-*rac*-**1** form differs markedly in energy (Section 3.3) and in internal organization (Section 3.4) from the rest studied. This conclusion fully coincides with the data in Figure 6, where the experimental powder diffraction patterns of the crystalline forms α-*rac*-**1**, β-*rac*-**1**, (*R*+*S*)-**1** and (*R*)-**1** are compared. The only curve that differs markedly from the others is the β-*rac*-**1** phase diffractogram.

**Figure 6.** Comparison of experimental powder X-ray diffraction (PXRD) patterns of (*R*)-**1**, (*R*+*S*)-**1**, α-*rac*-**1**, and β-*rac*-**1** forms and simulated PXRD patterns of (*R*)-**1** forms.

X-ray powder diffraction also clearly reveals the metastable nature of this phase. While other diffractograms retain all the main features for a long time, the β-*rac*-**1** phase begins to change already during the experiment. Figure 7 shows the diffraction patterns of this phase which was freshly prepared or stored for two months. While on the diffractogram of the fresh sample there are only traces of the impurity signals (for example, in the region of scattering angles 2θ 6◦–7◦ and 11◦–12◦), on the diffractogram of the aged sample the peaks belonging to the α-*rac*-**1** phase are clearly visible (if they do not prevail).

As we now know, enantiopure diol **1** exists in a single stable crystalline modification, which allows one to obtain good quality single crystals suitable for X-ray diffraction. The results of an X-ray experiment for (*R*)-**1** crystals are shown in Table 1. Figure 8a shows the only symmetry independent molecule present in the unit cell of these crystals.

In general, the conformation of the glycerol fragment in the molecules of glycerol aromatic ethers can be characterized by torsion angles H1O1C1C2, O1C1C2C3, C1C2C3O3, C2C3O3C4, C3O3C4C5, H2O2C2C3, O2C2C3O3. In the order of listing, for (*R*)-**1** they are 146.4◦; 50.9◦; 53.2◦; 175.4◦; −177.6◦; 155.8◦; and 175.9◦, which corresponds respectively to *ac*, *sc*, *sc*, *ap*, *ap*, *ac*, and *ap* conformation. According to our previous experience, such a conformation is inherent in compounds that form a homochiral guaifenesin-like supramolecular motif in their crystals [47]. The main supramolecular synthon in such crystals is the sequence of intermolecular hydrogen bonds {O1−H1···O2 , O2 −H2 ···O1 , O1 −H1 ···O2}, that is, the **C2 2(4)** chain formed around a screw axis 21 parallel to the *b* axis. Donor (O2−H2 and O1 −H1 ) and acceptor (O2 and O1 ) fragments that are not involved in the construction

of this chain form another chain **C2 2(4)** around the adjacent axis 21. Together, the guaifenesin-like motif represents a bilayer parallel to *0ba* plane. It is this motif that is realized in (*R*)-**1** crystals.

**Figure 7.** Comparison of experimental and simulated PXRD patterns forα-*rac*-**1** andβ-*rac*-**1** polymorphs.

**Figure 8.** (**a**) Geometry of the molecules in (*R*)-**1** crystals. (**b**) Conditional superposition of *R*-enantiomers in (*R*)-**1** (blue) and α-*rac*-**1** crystals (red).

The investigated crystal of the racemic sample α-*rac*-**1** was of lower quality and with noticeable twinning, which is not surprising for the metastable phase. The structure was solved in monoclinic syngony with cell parameters close to the parameters of the enantiopure orthorhombic crystal (Table 1), except that the angle β = 93.559◦ differs significantly from 90◦. The structure of α-*rac*-**1** was refined in the space group *P*21/n with the only symmetry independent molecule. The experimental powder diffraction patterns of the α-*rac*-**1** form are generally consistent with the calculated one (Figure 7). Some differences in peak intensities are associated with twinning of crystals and the presence of insignificant texturing of the sample.

The geometry of the symmetrically-independent *R*-enantiomer molecule in α-*rac*-**1** crystals turned out to be almost identical to that just described for the independent molecule in (*R*)-**1** crystals. A visual evidence of such an identity is a conditional superposition of the *R*-enantiomers present in crystals of both forms (Figure 8b). For systems with close molecular geometry and close cell parameters, it is natural to expect a similar supramolecular organization. Indeed, the same guaifenesin-like motif is realized in α-*rac*-**1** crystals as in (*R*)-**1** crystals. The only, but important, difference between the internal organization of this pair is that in (*R*)-**1** crystals all homochiral bilayers are formed by the same enantiomers, and in crystals of α-*rac*-**1** each individual bilayer is homochiral, but adjacent bilayers are formed by opposite enantiomers (Figure 9). A similar situation was described by us in detail on the example of 3-(4-*n*-buthylphenoxy)propane-1,2-diol [47].

**Figure 9.** Stacking of H-bonded homochiral bilayers in (*R*)-**1** (**a**) and α-*rac*-**1** (**b**) crystals.

The process of the formation of crystals of homochiral and racemic samples can be represented as layer-by-layer stacking of homochiral 2D bilayer structures along the direction *0c* (Figure 9). In the first case, the bilayers are connected by screw axes 21, and in the second, by inversion centers. Although the calculated packing coefficients in crystals of enantiopure and racemic forms (69.9% and 70.0%, respectively) practically coincide, the second packing method, apparently, required a certain shift of the 2D bilayers relative to each other, which has resulted in a deviation of the monoclinic angle from 90◦. Perhaps the same effect also explains the fact of a noticeable twinning of the crystals of the racemic sample in comparison with the enantiopure ones.

From the entire preceding text, it is obvious that the structure of the crystalline β-*rac*-**1** polymorph should be noticeably different from the structure of other identified modifications. Its metastable nature does not allow to obtain stable crystals of the required quality for the study of their internal structure by SC-XRD method. However, despite weak scattering (Figure 7), we tried to index diffractogram and solve the structure of β-*rac*-**1** form from powder diffraction data. It should be added that this form is difficult to obtain as a pure one-component system and it always contains other phases in impurity quantities. Over time, the content of these phases grows, as can be seen from a comparison of the diffraction patterns of β-*rac*-**1** samples freshly prepared and stored for some time (Figure 7). However, knowledge of the position of the peaks for known phases allows us to ignore these reflections at the stage of indexing and the structure solving.

Indexing of the powder diffraction pattern of the β-*rac*-**1** form by several independent software packages made it possible to index it in a triclinic cell whose parameters (a = 19.27(1)Å, b = 12.38(7)Å, c = 5.54(7)Å, α = 93.22(4), β = 94.14(7), γ = 72.87(3)◦, V = 1258(1) Å3) differ markedly from those for the enantiopure and α-*rac*-**1** forms. According to preliminary results obtained using the EXPO 2014 software package [41], the β-*rac*-**1** structure was solved in the space group *P*-1 with two independent molecules in an asymmetric unit. A good coincidence of the experimental powder diffraction pattern of β-*rac*-**1** polycrystalline sample and the diffraction pattern calculated from the atom coordinates of the molecules in this cell testify to the correct choice of the cell and the determined geometry of molecular fragments (Figure 7). According to preliminary data, two independent A and B molecules of diol **1**, noticeably different in their geometry, are present in β-*rac*-**1** crystal (Figure 10).

**Figure 10.** Probable geometry of two symmetrically-independent *R*-molecules in β-*rac*-**1** crystals.

The principal supramolecular motif in β-*rac*-**1** crystals is illustrated in Figure 11. As can be seen from the Figure, each independent molecule due to the classical hydrogen bonds O−H···O is bonded with its enantiomer into a separate centrosymmetric dimer, and already A-A and B-B dimers act as subunits in the formation of the 1D construct oriented along the crystallographic direction *b*.

**Figure 11.** The principal supramolecular motif in β-*rac*-**1** crystals.

As recommended by Bernstein et al. [48], such a hydrogen bonding pattern may be called a "chain of rings". Extending somewhat the system of symbols proposed in the review [48], such a motif with two different rings can be designated as **C2 2(11)[R2 2(4)R2 2(10)]**. Such a sophisticated packing based on a one-dimensional motif can hardly be dense. Indeed, preliminary calculations point that the Kitaygorodsky packing index is below 60% (KPI = 56.1%).

#### *3.6. Direct Resolution of Rac-1 by Entrainment Procedure*

In general, our study of the phase behavior of 3-(3,4-dimethylphenoxy)propane-1,2-diol **1** showed that the conglomerate (*R*+*S*)*-***1** is the most stable crystalline modification of the racemate, which does not contain signs of a solid solution and is not prone to phase transformations. Other detected racemic forms are metastable and more soluble than conglomerate. Therefore, an increase in the crystallization temperature of the solution should help to increase the efficiency of the process of direct resolution of racemic **1** by reducing the supersaturation for undesirable forms and approximating the crystallization conditions to equilibrium ones. Further, the results of a pilot experiment (Section 3.1) showed that crystallization of pure racemic **1** is accompanied by a significant and irreproducible induction period duration. We believed that some supersaturation of the initial solution with the target component should contribute to a decrease in the influence of this factor on the crystallization stage of a specific enantiomer. Finally, an increase in the relative amount of introduced crystal seeds should be an important factor that favorably affects the kinetics of the process. With all that in mind, we planned and implemented an experiment the details of which are shown in Table 4.


**Table 4.** Resolution by entrainment of *rac*-3-(3.4-dimethylphenoxy)propane-1,2-diol, *rac*-**1** in methyl *tert*-butyl ether (60 mL, 75 mg of crystal seeds on every run; crystallization temperature 27 ◦C).

<sup>1</sup> Sample slightly enriched with (*S*)-enantiomer (5.4% *ee*). <sup>2</sup> *YE*: Yield of enantiomer; *YE*(g) <sup>=</sup> [Yield × *ee*]/100 – 0.075; *YE*(%) = [*YE*(g) ×100]/Operation amount of (*R*)- or (*S*)-**1**.

In Figure 12, the same process of separation of racemic *rac*-**1** is clearly illustrated by changes in the enantiomeric excess values of its mother liquor. Solid circles indicate *ee* values, upon reaching which the process was interrupted and the precipitate formed was filtered off. Then, compensating amounts of *rac*-**1** and solvent were added to the heated mother liquor, after which the process was repeated.

**Figure 12.** Mother liquor enantiomeric excess vs time of preferential crystallization of slightly enantiomerically enriched diol **1**. Closed circles represent the values of *ee*, on reaching which the process was interrupted.

A comparison of the data of Tables 2 and 4 shows that the yield of the pure enantiomer increases from 11% to 17%–18%, the process proceeds more reproducibly, in a constant temperature range and with a smaller scatter in the *ee* values (72%–78%) of its filtered precipitates. In principle, the proposed resolution procedure can be scaled and repeated as many times as necessary. A high degree of enantiomeric purity of collected (*R*)- and (*S*)-diols can be achieved by crop recrystallization from mixture of EtOAc:hexane (1:2).
