Crystallization features and spontaneous resolution of 3-(2,6-dimethoxyphenoxy)propane-1,2-diol: The case of stable conglomerate and metastable solid solution

Article abstract of DOI:10.1016/j.molstruc.2017.05.091

Phase behavior of 3-(2,6-dimethoxyphenoxy)propane-1,2-diol 1 was investigated by IR spectroscopy, X-ray diffraction, and DSC methods. Racemic diol 1 prone to spontaneous resolution and has been resolved into (S)- and (R)-enantiomers by a preferential crystallization procedure. Separation takes place, but it gives crystalline precipitates with moderate (60–70%) enantiomeric excess values. The plausible reason is the formation of metastable phase of solid solution during the crystallization.

Full text of DOI:10.1016/j.molstruc.2017.05.091

Accepted Manuscript
Crystallization features and spontaneous resolution of 3-(2,6-dimethoxyphenoxy)
propane-1,2-diol: the case of stable conglomerate and metastable solid solution
Alexander A. Bredikhin, Zemfira A. Bredikhina, Olga A. Antonovich, Dmitry V.
Zakharychev, Dmitry B. Krivolapov
PII:
S0022-2860(17)30702-0
10.1016/j.molstruc.2017.05.091
MOLSTR 23832
DOI:
Reference:
To appear in:
Journal of Molecular Structure
Received Date:
Revised Date:
Accepted Date:
17 February 2017
12 May 2017
18 May 2017
Please cite this article as: Alexander A. Bredikhin, Zemfira A. Bredikhina, Olga A. Antonovich,
Dmitry V. Zakharychev, Dmitry B. Krivolapov, Crystallization features and spontaneous resolution
of 3-(2,6-dimethoxyphenoxy)propane-1,2-diol: the case of stable conglomerate and metastable
solid solution, Journal of Molecular Structure (2017), doi: 10.1016/j.molstruc.2017.05.091
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ACCEPTED MANUSCRIPT
HIGHLIGHTS

Crystalline 3-(2,6-dimethoxyphenoxy)propane-1,2-diol was investigated by X-ray, IR, and
DSC techniques.



The crystal, selected from racemate, belongs to orthorhombic Sohncke space groups P2 2 2 .
1
1 1
Racemic 3-(2,6-dimethoxyphenoxy)propane-1,2-diol was resolved by entrainment procedure.
Along with stable conglomerate, metastable solid solution is formed during a kinetically
controlled crystallization.

ACCEPTED MANUSCRIPT
Crystallization features and spontaneous resolution
of 3-(2,6-dimethoxyphenoxy)propane-1,2-diol: the case of stable
conglomerate and metastable solid solution

Alexander A. Bredikhin, Zemfira A. Bredikhina, Olga A. Antonovich, Dmitry V. Zakharychev,
Dmitry B. Krivolapov
A.E. Arbuzov Institute of Organic and Physical Chemistry of Kazan Scientific Center of Russian Academy of
Sciences, Arbuzov St., 8, Kazan 420088, Russian Federation
ABSTRACT: Phase behavior of 3-(2,6-dimethoxyphenoxy)propane-1,2-diol 1 was investigated
by IR spectroscopy, X-ray diffraction, and DSC methods. Racemic diol 1 prone to spontaneous
resolution and has been resolved into (S)- and (R)-enantiomers by a preferential crystallization
procedure. Separation takes place, but it gives crystalline precipitates with moderate (60-70%)
enantiomeric excess values. The plausible reason is the formation of metastable phase of solid
solution during the crystallization.
Keywords: Aryl glycerol ethers; Single crystal X-ray analysis; Crystal packing; Racemic
conglomerate; Preferential crystallization; Metastable solid solution
1
. Introduction
For a wide practical application of direct methods of racemate resolution, that do not require for
its implementation any enantiopure auxiliary substances and materials [1], it is necessary to
expand the range of chiral compounds, for which the ability to spontaneous resolution is reliably
proven [2]. The object of this work is the terminal phenyl glycerol ether carrying two methoxy
groups in the ortho positions of the phenyl ring, 3-(2,6-dimethoxyphenoxy)propane-1,2-diol 1
(Chart 1). This diol is in obvious structural relationship with the mono-ortho-methoxy diol 2, the
well-known drug guaifenesin. Our recent structural studies have shown that the introduction of
such substituents as methoxy or methyl group or a chlorine atom at the ortho position of the
benzene ring in glycerol ethers 2-6 combines them into a common group according the type of
their crystallization: all of them exhibit spontaneous resolution property during crystallization of
the racemic material [3-6].

Corresponding author. Tel.: +7 843 2727393; fax: +7 843 2731872.
E-mail address: baa@iopc.ru (A.A. Bredikhin)

ACCEPTED MANUSCRIPT
OMe
OMe
O
OH
O
OH
OH
OMe
CH3
OH
OH
OH
1
3
2
4
CH3
O
O
CH3
Cl
OH
OH
Cl
O
O
OH
OH
Cl
OH
OH
5
6
Chart 1. Mono- and di-ortho-substituted phenyl glycerol ethers 1-6.
Diol 1 acts as a precursor in the synthesis of compound 7, a close analog of the 1-
adrenoceptor antagonist WB4101 [7], belonging to the class of 1,4-benzodioxanes (Chart 2). It is
known that its S enantiomer possess remarkably higher affinity toward  -adrenoceptors than the
1
R enantiomer [8]. In this connection, the efficient production of single enantiomeric diols 1 is
gaining, along with academic, in practical importance.
OMe
Cl-
Cl-
O
O
MeO
O
O
O
MeO
O
H
N
+
H
N
+
*
*
OMe
OMe
WB4101
7
Chart 2. 1,4-Benzodioxanes, exhibiting a pronounced affinity toward  -adrenoceptors.
1
According to the literature, the difference in melting temperatures between enantiopure (73-
7
4°C) [7] and racemic (52-53.5°C) [9] diols 1 is ~ 20 °C. This suggests that the diol 1, like
other members of the family of 1-6, crystallizes in the form of a normal conglomerate, which
creates prerequisites for its production in enantiopure forms by direct methods.

ACCEPTED MANUSCRIPT
2
. Experimental
2
.1. Instrumentation
1
The NMR spectra were recorded on a Bruker Avance-400 spectrometer (399.9 МHz for H
1
3
and 100.5 МHz for C) in CDCl with the signals of the solvent as the internal standard. The IR
3
spectra of the polycrystalline samples of rac- and (R)-diols 1 under investigations in KBr pellets
were recorded on a Bruker Tensor 27 spectrometer. Optical rotations were measured on a
Perkin–Elmer model 341 polarimeter. Melting points for general purposes were determined
using a Boëtius apparatus and are uncorrected. The melting curves were measured on a
NETZSCH 204 F1 Phoenix DSC differential scanning calorimeter in sealing aluminum pans
-1
with the rate of heating of 5 °C∙min . The mass of the samples amounted to approximately ~1
mg and was controlled with Sartorius CPA2P balance. Temperature scale and heat flux were
calibrated according standard procedure and verified by naphthalene sample. HPLC analyses
were performed on a Shimadzu LC-20AD system controller, UV monitor 275 nm was used as
detector. The columns used, from Daicel Inc., were Chiralcel OJ or OD (0.46 x 25 cm); eluent
-1
hexane: isopropanol = 4:1 v/v; flow rate: 1 ml∙min .
2
.2. Materials
Racemic 3-chloropropane-1,2-diol (99+%), and 2,6-dimethoxyphenol (99%) were purchased
from Acros Organics; (R)-3-chloropropane-1,2-diol (97%, 98% ee), and (S)-3-chloropropane-
1
,2-diol (98%, 98% ee) were purchased from Alfa Aesar.
2
.2.1. rac-3-(2,6-Dimethoxyphenoxy)propane-1,2-diol, rac-1
Racemic diol rac-1 was prepared by analogy with published procedure [10]. A solution of
,6-dimethoxyphenol (25 g, 0.16 mol) in 45 ml of absolute ethanol was added to a solution of
2
metal sodium (3.7 g, 0.16 mol) in 80 ml of absolute ethanol. The suspension was stirred for 30
min warming to 70 °C, then 3-chloropropane-1,2-diol (23.2 g, 0.21 mol) was added under argon
atmosphere. The reaction mixture was refluxed for 4-5 h and filtered. The filtrate was distilled,
and the fraction boiling at 175-195 °C (0.8 mm) (19 g, 52%) was crystallized from Et O/n-
2

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o
pentane to afford 9.9 g (27%) of rac-1: white solid, mp 50–53 °C (50.7 C, DSC); {lit. [9]: mp
o
1
5
3
2-53.5 C}. H NMR, : 3.04 (br. s, 2H, OH), 3.70 (approx. dd, J = 11.4, 3.9 Hz; 1H, CH OH),
2
.78 (approx. dd, 1H, J = 11.4, 2.4 Hz; 1H, CH OH), 3.88 (s, 6H, OCH ), 3.93-4.00 (m, 2H,
2
3
OCH ), 4.22-4.27 (m, 1H, CH, CHOH), 6.61 (d, J = 8.4 Hz, 2H, C ,4ArH), 7.03 (t, J = 8.4 Hz,
2
2
5
13
1
1
2
H, C H). С NMR δ: 56.1 (2 CH O), 63.5 (CH ), 70.4 (CH), 75.9 (OCH ), 105.2 (C3,5Ar),
Ar 3 2 2
24.1 (C ), 136.9 (C -ipso), 153.2 (C2,6Ar-ipso).
4
1
Ar
Ar
.2.2. (R)-3-(2,6-Dimethoxyphenoxy)propane-1,2-diol (R)-1
Compound (R)-1 used hereinafter as seed crystals was obtained from (R)-3-chloropropane-
,2-diol (R)-9 (0.93 g, 8.4 mmol) and 2,6-dimethoxyphenol (1 g, 6.5 mmol) as described for
1
racemic diol. The reaction mixture was refluxed for 4 h and then filtered. The volume of the
resulting filtrate was reduced to about one third followed by the water addition (20 ml) and
extraction with EtOAc (3 × 50 ml). The combined organic layers were dried over MgSO and the
4
solvent was removed. The resulting oil 1.42 g (89%) was purified by column chromatography
(silica gel, eluent: light petroleum/EtOAc = 4:1) to afford diol (R)-1 as a colorless oil (0.29 g,
1
9
9.6 %.) Diol was crystallized from Et O/n-pentane to afford analytically pure (R)-1 (0.15 g,
2
%); white solid, mp 72-73 °C (71.9 C, DSC), [α] = –13.2 (c 1; EtOH); [α]D20 = -19.6 (c 1;
o
20
D
МТBE), [α]36520 = -62.4 (c 1; МТBE); {lit.[7]: mp 73-74 C, [α] = –13.3 (c 1, EtOH)}; > 99%
o
25
D
ee {for reliable ee determination the crude diol was transformed into a diastereromeric mixture
o
of cyclic sulfites via reaction between (R)-1 (1 equiv) and SOCl (1.1 equiv) in CH Cl at 0 C.
2
2
2
The procedure of analysis is described in detail and illustrated by the example of nitro substituted
phenyl glycerol ethers in our previous work [11]. Chiral HPLC analysis of the reaction mixture:
о
Daicel Chiralcel OD column; column temperature 25 С; t = 12.3 min (major), t = 13.0 min
R
R
(
minor); t = 13.7 min (major), t = 15.2 min (minor]}. NMR spectra for (R)-1 were identical to
R R
those cited above for rac-1.
.2.3. (S)-3-(2,6-Dimethoxyphenoxy)propane-1,2-diol (S)-1
2

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Diol (S)-1 used as seed was obtained from (S)-3-chloropropane-1,2-diol (S)-3 (1.97 g, 18
mmol) and 2,6-dimethoxyphenol (2 g, 13 mmol) as described for diol (R)-1. The resulting thick
oil (0.74 g, 25%) was crystallized from ether/pentane to afford analytically pure (S)-1 (0.35 g,
o
20
20
1
1
9
2%); white solid, mp 72-73 °C (71.8 C, DSC), [α] = +13.1 (c 1; EtOH ), [α] = +19.5 (c
D аbs. D
; MTBE), [α]36520 = +62.2 (c 1; MTBE); {lit. [7]: mp 73-74 C, [α] = +11.9 (c 1, EtOH)};
o
25
D
о
9% ee [chiral HPLC analysis, Chiralcel OJ column, column temperature 10 С; t = 23.5 min
R
(
minor), t = 24.8 min (major)]. NMR spectra were identical to those cited above for rac-1.
R
2
.3.
X-ray analysis
The crystals of rac-1 for single crystal X-ray diffraction analysis were prepared by slow
evaporation of the saturated solution of the corresponding sample in mixture of diethyl
ether/pentane. A single crystal, selected at random from the racemic polycrystalline sample,
which was kept in long contact with the mother liquor, was used for X-ray analysis; hereinafter
this crystal is designated as R-1.
The X-ray diffraction data for this crystal were collected on a Bruker Smart Apex II AXS
Apex II CCD diffractometer in the ω-scan and φ-scan modes using graphite monochromated Mo
Kα (λ 0.71073 Å) radiation at 296(2) K. The crystal data, data collection, and the refinement
parameters are given in Table 1.
Data were corrected for the absorption effect using SADABS program [12]. The structures
were solved by direct method and refined by the full matrix least-squares using SHELX [13] and
WinGX [14] programs. All non-hydrogen atoms were refined anisotropically. All hydrogen
atoms were inserted at calculated positions and refined as riding atoms except the hydrogen
atoms of OH groups which were located from difference maps and refined isotropically. All
figures were made using Mercury program [15]. Molecular structures and conformations were
analyzed by PLATON [16].
Crystallographic data for the structure of (R)-1 reported in this paper were deposited with the
Cambridge Crystallographic Data Centre as supplementary publication number CCDC 1529709.

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Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK, (fax: +44-(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).
Table 1
Crystallographic data for diol R-1.
Compound
Formula
R-1
C H O
5
1
1
16
M (g/mol)
228.24
296(2)
Temperature, K
Crystal class
Space group
Crystal size
Z, Z´
Orthorhombic
P2 2 2
1 1
1
0.30x0.30x0.05 mm3
4, 1
Cell parameters
a = 4.984(3) Ǻ,
b = 12.826(7) Ǻ,
c = 18.071(9) Å
V, Ǻ3
1155.1(10)
488
F(000)
calc g/cm3
1.312


, cm-1
1.04
range, deg
1.947 – 25.981
11448
Reflections measured
Independent reflections / 2249/
R(int)
0
.0451
Number of parameters / 151/
restraints
0
Reflections [I2(I)]
R / wR [I2(I)]
1627
0.0567 / 0.1267
1
2
R / wR (all reflections) 0.0829/ 0.1397
1
2
Goodness-of-fit on F2
1.001
-3
max/min (eǺ )
0.290 / -0.200
2
.4. Resolution of racemic 3-(2,6-dimethoxyphenoxy)propane-1,2-diol rac-1 by preferential
crystallization (resolution by entrainment)

ACCEPTED MANUSCRIPT
Experiments on the stereoselective crystallization of rac-1 were performed in a two-necked
flask equipped with a magnetic stirrer, water condenser and thermometer placed in a water bath
at a controlled temperature. During the resolution small portions of the mother liquor were taken
through a syringe equipped with Teflon filter and were analyzed by polarimetry (cell path length
1
00 mm; wavelength 365 nm; 20 °C).
Example of the resolution by entrainment of rac-3-(2,6-dimethoxyphenoxy)propane-1,2-diol
in MTBE without the initial enantiomeric enrichment of a starting mixture: 2.52 g of rac-1 was
1
dissolved in 50 ml of MTBE at 34-35 °C and was cooled with stirring to 14 °C. Then a portion
of finely ground crystalline seeds of (R)-1 (10 mg, 0.4% by weight) was added. The solution was
stirred and incubated at a temperature of 14 ± 0.5 ° C for 90 min. The precipitate was filtered,
collected and dried to obtain 130 mg of (R)-1 (62% ее). To the filtrate, which remained after
separation of the precipitate, 120 mg of rac-1 was added, and the system was heated to 34-35 °C
until full homogenization after which it was cooled to 14 °C, and seeded with finely ground
crystals of (S)-1 (10 mg). The solution was stirred at a temperature of 14 ± 0.5 °C, and filtered
after 150 min; 204 mg of (S)-1 (59 % ее) were obtained. Likewise, the cycle was repeated
several times, each time adding the lacking amount of racemic diol. Details of subsequent runs
No. 3-6 are shown in Table 2. A high degree of enantiomeric purity of collected diols can be
achieved by recrystallization from Et O/hexane. For example: a portion of (R)-1 (0.57 g, 67 %
2
ee) was crystallized from 20 ml of ether/hexane ~6/1 and then from 7 ml of ether; 0.19 g (33%)
of (R)-1 {[α]D20 = -13.1 (с 1; EtOH), 99% ee} was obtained as result. Similarly, after
recrystallization of combined portions of (S)-enantiomer (0.59 g, 63 % ee), pure (S)-1 {0.18 g;
[
α]D20 = +12.2 (с 1; EtOH), 94% ee} was obtained.
3
. Results and discussion
3
.1.
Synthesis
Reaction of sodium 2,6-dimethoxyphenolate 8 with chloropropane diol 9 was used in the
literature [9,10] for synthesis of racemic diol 1. Note that the authors of [9] point out that the

ACCEPTED MANUSCRIPT
desired product is difficult to purify by distillation. In the cited paper, to prepare the analytically
pure diol 1, the oily crude product was converted into dioxolan 10, from which, after distillation
and acid hydrolysis, rac-1 was recovered as a solid (mp 52-53.5 °C) in an overall yield of about
3
5 %.
OH
OMe
OH
OMe
ONa
OMe
OMe
O
Cl
OH
Na
9
Me2CO
rac-1
1%
O
EtOH
8
OMe
8
OMe
O
10
We were able to crystallize rac-1 from a mixture of diethyl ether and pentane immediately
after distillation of crude reaction mixture without conversion of the product to acetonide 10.
After further recrystallization the yield of analytically pure rac-1 was 27%.
In the paper [7] enantiopure 3-tosyloxy-1,2-propanediol acetonide was used as a source of
chirality for enantiopure diol 1 production. The total yield of the diol starting from tosylate was
about 28%. In this paper, to obtain small amounts of enantiopure diol for research purposes, and
to use as enantiopure crystal seeds in the future, we have used commercially available
enantiopure (R)- and (S)-3-chloropropane-1,2-diols (see Experimental Part).
OMe
OH + Cl
OMe
O
Na
OH
OH
EtOH
HO
H
H
OH
OMe
OMe
(
R)-9
(
R)-1
OMe
OMe
O
Na
OH
OH + Cl
OMe
OH
OH
EtOH
H
OH
OMe
H
(
S)-9
(
S)-1
3
.2. Single-crystal X-ray diffraction data for diol 1
With prolonged (more than a week) maintaining of crystalline precipitate of racemic diol 1 in
contact with the mother liquor the well-shaped needle-like crystals arise. The single crystal
selected at random from this racemic polycrystalline sample was investigated by X-ray

ACCEPTED MANUSCRIPT
diffraction analysis (Table 1). It turned out that its unit cell belongs to Sohncke space group P
21
2 2 and contains a single symmetrically independent molecule having, in this particular case,
1 1
(R)-configuration of a chiral center. This means that during equilibrium crystallization of
racemic 1 a spontaneous resolution of the racemate into its enantiomers is realized, and in this
respect the ortho,ortho-dimethoxy substituted phenyl glycerol ether does not fall out of the total
series of compounds 1-6 (Chart 1). However, a more detailed study of its molecular and crystal
structure revealed substantial differences inherent to this compound.
Fig. 1. Molecular structure of diol R-1 and the numbering of the atoms, adopted in this paper.
Figure 1 shows the structure of molecules 1 in R-1 crystals. From the figure, it is immediately
evident that the atoms adjacent to the aromatic ring of the molecule, O3-O5, C4-C11 and H6-H8
lie in a common plane (maximum deviation from which is 0.107 Å for the O3 atom). But, unlike
the prototype molecules 3 and 5, the alkoxy moiety in compound 1 is not orthogonal to the plane
and is in anticlinal conformation (dihedral angle С9С4О3С3 is about -120°). The cause (or
effect) of this is the formation of a stable intramolecular hydrogen bond О2-Н2···О5 ( ОНО =
1
72°, d (O···O) = 2.967 Å). In turn, the formation of a strong intramolecular H-bond deprives of
the secondary hydroxyl group of the molecule the possibility to participate in the formation of
intermolecular hydrogen bonds (IMHB) and thus the opportunity to form a primary
supramolecular crystal-formative motif.

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In every currently investigated enantiopure terminal aromatic ethers of glycerol the
indispensable element of such supramolecular motif was a single or double helix, formation of
which requires the participation of both of the vicinal hydroxyl groups. The primary motif,
which is realized in scalemic 1 crystals, is a one-dimensional ribbon, organized around the screw
axis 2 , parallel to the direction 0a (Fig. 2).
1
Fig. 2. Primary crystal-formative supramolecular motif in R-1 crystals; blue dotted line marks
intramolecular, and red dotted line - intermolecular hydrogen bonds O-H···O'.
Molecules that form the 1D arrays (in this case - enantiomers R-1) bonded to each other by
zigzag sequence of strong IMHBs O1-H1···O1' ( ОНО = 165°, d (O···O) = 2.876 Å).
Integration of the primary 1D elements into 3D crystal packing is shown in Fig. 3.
Fig. 3. Detail of crystal packing; view along 0a axis.

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Formed in such a way homochiral packing is sufficiently dense (PI = 68.2%) and in equilibrium
conditions of crystal growth is more stable than an ordered packing of heterochiral racemic
compound. At the same time the R-1 packing has a visible porous structure. Perhaps this "not
ideality" of the lattice, tolerated to a certain freedom during its formation, in other crystallization
conditions allows to realize different type of crystalline organization. This topic will be
discussed further.
3
.3. Other data on the nature of diol 1 stable solid phase
Differential scanning calorimetry method was used to determine temperature and enthalpy of
melting for enantiopure (ee = 0.994) and equilibrium racemic samples of diol 1. The values of
A
o
A
R
o
R
these variables are, respectively, T = 71.5 C, ΔH = 29.6 kJ/mole, and T = 50.7 C, ΔH =
f
f
f
f
2
7.1 kJ/mole. Substitution of the data for enantiopure sample in Schroeder - van Laar equation
퐴
푓
푇
푅
푓
퐴
푓
[
17] (푇 =‒ ∆퐻
) enables to evaluate the melting point for eutectic of pure
퐴
푓
퐴
푓
ln
(
0.5
)
푅푇 ‒ ∆퐻
enantiomers of 51.1 °C. This value is in good agreement with the experimental value of the
o
racemate melting point (50.7 C), which again indicates a high probability of crystallization of
diol 1 stereoisomers in the form of normal racemic conglomerate.
This fact is also confirmed by the high degree of similarity (Fig. 4) of the IR spectra of
crystalline samples of racemic and enantiopure 1. Details of the quantitative comparison of the
spectra are described in our previous papers [18].
Fig. 4. IR spectra of racemic (red curves) and enantiopure (blue curves) samples of diol 1 (a) and
a graphical representation of the correlation between them (b).

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In conjunction with the above X-ray diffraction results, these data suggest that at room
temperature stable crystalline form of racemic diol 1 is normal conglomerate.
3
.4. Direct resolution of rac-1 by entrainment
Crystallization of the racemic 2,6-dimethoxyphenoxypropane-1,2-diol as a normal
conglomerate is a favorable factor to resolve it into individual enantiomers by entrainment
approach. Preliminary tests showed that at room temperature rac-1 solubility is practically
unlimited in ethyl acetate, methylene chloride, chloroform, fairly soluble in lower alcohols,
water, and benzene. Quantitatively, the solubility of rac-1 at 22 °C was 29.2, 23.4 and 18.0
-1
mg·ml in toluene, methyl tert-butyl ether (MTBE), and CCl , respectively. Of these three
4
solvents the reverse to dissolution process, that is, effective spontaneous crystallization, was
observed only in MTBE. Therefore, a more detailed study of the solubility and crystallization of
both racemic and enantiopure 1 was carried out in MTBE.
Fig. 5. Temperature dependence of solubility (per single enantiomer, solid lines) and for onset of
crystallization (dotted lines) of rac-1 (red) and (S)-1 (blue) in MTBE.
Figure 5 shows the temperature dependence of the solubility of diol 1 stereoisomers in
MTBE. 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). From the data obtained it follows that the width of metastable zone for rac-1 is about 22
°
C, while for (S)-1 this value is about 11 °C. From the charts analysis, it can also be concluded

ACCEPTED MANUSCRIPT
that, with increasing temperature, the experimental points, corresponding to the process of
dissolution of enantiopure and racemic samples, no longer lie on a single curve. That is, when
the temperature is above 30 ± 5 °C, Meyerhoffer’s rule, stating that the solubility of the racemate
is twice as high as that of the pure enantiomer [19], is no longer verified. In turn, this means that
the dissolution process for diol 1 is complicated by concentration and solvation effects.
Meyerhoffer’s coefficient high values are associated with a decrease of the metastable zone
width and, consequently, with reduced spontaneous resolution efficiency [1]. This means that the
process of direct resolution should be preferably conducted at concentrations of the individual
-1
stereoisomer lower than 30 g·l and, accordingly, at temperature below 25 °C.
Table 2
Resolution by entrainment (3 circles, 6 runs) of rac-1 in MTBE (50 ml, 10 mg of crystal seeds
on every run, crystallization temperature 14 ± 0.5 °C).
Operation
amount of
enantiomers,
(
R)-1 and (S)-1 obtained
Added
amount
of rac-
Resolution
time, min
Run
YEa,
Yield,
mg
(mg)
ee, %
1
, (mg)
(
R)-1
(S)-1
1260
1295
1240
1298
1240
1293
mg
%
1
2
3
4
5
6
2520
120
194
170
194
156
1260
1225
1280
1222
1280
1227
90
(R) 130
(S) 204
(R) 180
(S) 203
(R) 166
(S) 152
62
59
70
62
70
63
71
110
116
116
106
86
5.6
8.5
9.1
8.9
8.3
6.6
150
120
120
150
150
a)
YE: Yield enantiomer; YE(mg) = [Yield(mg) × ee (%)]/100 – 10; YE(%) = [YE(mg) ×100] /
Operation amount of (R)- or (S)-1(mg)
Table 2 presents the stereoselective crystallization of racemic diol 1 without preliminary
enantiomeric enrichment in MTBE at the above conditions. Technical details of the process are
given in the experimental part. In Fig. 6 the same process of rac-1 resolution is illustrated
through changes in mother liquor optical rotation values (red lines and circles). The solid circles
indicate the values of optical rotation at which the process was interrupted and the precipitate

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was filtered off. Then the compensating amounts of rac-1 and the solvent were added to
preheated mother liquor, and the process was repeated (see Experimental section).
From Table 2 it is clear, that the separation process is carried out with moderate values of
the enantiomeric purity of the crystalline solid (60-70%). Nevertheless, initially moderate yield
of pure enantiomer (5.6% in the first stage) is increasing to 9.8%. At the same time, despite the
moderate efficiency characteristics of the process, each separation step creates the required
enantiomeric enrichment of the mother liquor with the opposite enantiomer.
Fig. 6. Mother liquor optical rotation (T = 20 °C; cell length 100 mm; λ = 365 nm) vs time of
preferential crystallization of racemic (red) and slightly enantiomerically enriched diol 1 (navy
blue). Closed circles represent the values of optical rotation, on reaching which the process was
interrupted.
We have tried to increase the separation efficiency through the creation of a small
enantiomeric enrichment (~ 3% ee) in the first separation stage. The experimental results are
shown in Table 3 and Fig. 6. The diagram (Fig. 6, blue lines and circles) depicts the entire
separation process. In this experiment, the precipitate is filtered off at a time when the value of
specific rotation of the mother liquor reaches the maximum value with the opposite sign and then
stops growing (blue solid circles). In each run, the temperature was gradually decreased during
crystallization (the table lists the temperature interval between the onset of crystallization and its
end). The table shows that the yield of pure enantiomer always increases compared with the

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previous one and reaches the value of 15% (Table. 3), but the enantiomeric excess of the filtered
crystals in the two versions (cf. Table 2) are in the general range of 58-70%. In carrying out the
resolution with even greater initial enrichment of the starting solution (~ 11% ee), the yield of
single enantiomers increases to 25%, but an enantiomeric purity of the precipitate (64% ee) is
retained substantially the same. This constancy made us suspect that under kinetically controlled
crystallization, another metastable phase(s) could be formed with an enantiomeric composition
which differs from that of a normal conglomerate. It is obvious that such a phenomenon can
complicate the process of spontaneous resolution and reduce its effectiveness.
Table 3
Resolution by entrainment of slightly enriched 1 in MTBE (50 ml, 10 mg of crystal seeds on
every run, crystallization temperature 12 ± 2 °C).
Operation amount
Added
amount
of rac-
(R)-1 and (S)-1 obtained
YEb,
of enantiomers,
mg)
Resolution
time, min
Run
T, °C
(
Yield,
ee, %
mg
1
, (mg)
(R)-1
1070
1018
1069
993
(S)-1
1008
1060
1009
1086
1003
1069
mg
104
103
154
163
131
112
%
1
2
3
4
5
2000a
168
184
232
237
194
15-12
13-12
13-11
12-11
13-11
12-10.5
210
120
120
330
420
130
(R) 178
(S) 194
(R) 241
(S) 247
(R) 204
(S) 203
64
58
68
70
69
60
9.7
9.7
14.4
15.0
12.3
10.5
1074
1009
6
а)
Additional amount of (R)-1 78 mg (80 % ее).
b)
YE: Yield enantiomer; YE(mg) = [Yield(mg) × ee (%)]/100 – 10; YE(%) = [YE(mg) ×100] /
Operation amount of (R)- or (S)-1(mg)
3
.5. Re-investigation of the nature of diol 1 crystallization
For the analysis of the phase behavior of the system in the metastable region DSC
thermograms were obtained for the samples of diol 1 of different enantiomeric composition
recorded directly after the crystallization of the sample under conditions close to those of a
spontaneous separation (MTBE, ~ 15 °C) (red curves in Fig. 7). The obtained thermograms have

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been compared with thermograms for the same samples, but subjected to a procedure of
thermodynamic equilibration, i.e. slurring in hexane for about 24 hours (blue curves).
Fig. 7. DSC thermograms of equilibrium (blue lines) and metastable (red lines) samples of diol 1
of different enantiomeric composition; x = mole fraction of the dominant enantiomer.
From the figure, it is clear that immediately after crystallization a metastable solid phase is
formed which thermochemical properties significantly differ from those of equilibrium samples.
R
In particular, the thus obtained racemic sample has a lower melting point (47.6 °C vs T = 50.7
f
R
°
C), its melting enthalpy well below than that of equilibrium sample (26.3 kJ/mole vs ΔH =
f
2
7.1 kJ/mole). One could also note, that IR spectra of the racemic metastable phases do not differ
from enantiopure sample spectra and (stable) normal conglomerate. This fact, although
indirectly, indicates the isomorphic character of stable and metastable crystalline phases.
Unequivocally identify the nature of the latter only on the basis of data available is hardly
possible, and its metastable character makes it difficult to use other methods. However, certain
assumptions in this regard can be made.

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In Fig. 8 the characteristic temperatures of the DSC thermograms are imposed on the
theoretical phase diagram (built on the basis of Schroder – van Laar equation and numerical data
for enantiopure substance) under the assumption that the binary system of stereoisomers exists as
a normal racemic conglomerate. Obviously, the behavior of the equilibrated samples corresponds
well to this model, while the specimens immediately after precipitation look like metastable and
thermodynamically nonequilibrium entities.
Fig. 8. The binary phase diagram for compound 1. Solid black legs - liquidus, calculated on the
basis of Schroeder - van Laar model; dotted line - solidus. Blue and red hollow circles -
experimental values of the melting onset for equilibrium and metastable samples, respectively;
solid circles - experimental temperature values of the end of melting.
From Fig. 7 it follows, that the qualitative nature of the thermograms for the stable and
metastable systems is similar. Initially, the peak is observed, which can be identified as the
eutectic melting peak followed by post-eutectic melting process. Therefore, we can assume that
the metastable system in itself is a conglomerate. Further attention is drawn to significant
reduction, in comparison with the equilibrium model, of the eutectic melting peak on the
thermogram for the composition x = 0.91. Such system behavior can be explained if we assume
that the metastable phase is a conglomerate of limited solid solutions of enantiomers.
For a long time, the formation of solid solutions of enantiomers was considered as rare
phenomenon, represented by no more than 1% of the total number of chiral compounds [20]. In

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recent years, such solid solutions are increasingly becoming the subject of research [21-24].
Along with a simple registration of zone of solid solution in the phase diagram of chiral
substances, appear special [21,25] and generalizing [26] works, in which the mechanism of
formation of this specific phase and its genetic link with the crystal organization of enantiopure
substance and/or racemic compound are discussed. It is also shown that the ability of a chiral
substance, prone to spontaneous resolution, to form a (metastable) solid solution has a negative
effect on the results of its direct separation into individual enantiomers [27,28].
4
. Conclusions
Like other studied to date 2,6-disubstituted phenyl ethers of glycerol, 3-(2,6-
dimethoxyphenoxy)propane-1,2-diol 1 crystallizes by type of racemic conglomerate.
Nevertheless, its crystal structure differs from the previously studied terminal aromatic glycerol
ethers (TAEG) by the fact, that one of the hydroxyl groups of the glycerol moiety is involved in
the formation of a strong intramolecular hydrogen bond with the methoxy substituent and does
not participate in the formation of crystal-formative supramolecular motif. In all of the TAEG
conglomerates this motif represents a single or double helix, organized around a screw or a
simple rotation axis of symmetry. In the case of 1, the primary motive, though arranged around
the screw axis 2 , is a one-dimensional ribbon bound with zigzag sequence of intermolecular
1
hydrogen bonds.
Another feature of the phase behavior of racemic diol 1 is the formation during a kinetically
controlled crystallization of the metastable phase (presumably limited solid solution of the
enantiomers), isomorphic with normal conglomerate. Evidently, this characteristic property
complicates the process and lowers the efficiency of resolution of racemic 1 into individual
enantiomers by entrainment technique. Isomorphism of metastable solid solution and
enantiopure substance explains, firstly, the initiation of solid solution crystallization by
enantiopure seeds and, secondly, why the results of resolution are essentially independent of the
seed amount. At the same time, the initial formation of a solid solution (with smaller than for

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normal conglomerate enantiomeric purity) determines the final composition of the resultant
precipitate in the separation process. This unfavorable ratio of enantiomers in the solid solution
is preserved and subsequently, when during the process of "aging" precipitated metastable phase
is decomposed and changed into the thermodynamically stable normal conglomerate.
Acknowledgment
The authors thank Dr. A.V. Pashagin for valuable assistance with chiral HPLC analysis
and Prof. A.T. Gubaidullin for valuable help with the X-ray data.
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