New example of spontaneous resolution among aryl glycerol ethers: 3-(2-hydroxyphenoxy)propane-1,2-diol

Article abstract of DOI:10.1016/j.mencom.2009.07.012

The conglomerate-forming nature of 3-(2-hydroxyphenoxy)propane-1,2-diol was established by IR, DSC, and XRD methods; racemic diol could be resolved by a moderate efficiency preferential crystallization procedure.

Full text of DOI:10.1016/j.mencom.2009.07.012

Mendeleev
Communications
Mendeleev Commun., 2009, 19, 208–210
New example of spontaneous resolution among
aryl glycerol ethers: 3-(2-hydroxyphenoxy)propane-1,2-diol
Zemfira A. Bredikhina, Larisa V. Konoshenko, Dmitry V. Zakharychev,
Alexander V. Pashagin, Aidar T. Gubaidullin and Alexander A. Bredikhin*
A. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Centre of the Russian Academy of
Sciences, 420088 Kazan, Russian Federation. Fax: +7 8432 73 2253; e-mail: baa@iopc.knc.ru
DOI: 10.1016/j.mencom.2009.07.012
The conglomerate-forming nature of 3-(2-hydroxyphenoxy)propane-1,2-diol was established by IR, DSC, and XRD methods;
racemic diol could be resolved by a moderate efficiency preferential crystallization procedure.
2-Substituted 1,4-benzodioxanes 1 have been widely used in
1
the design of therapeutic agents with a pronounced effect of the
absolute configuration at the stereogenic C2 of the dioxane ring
on biological response. Popular precursors for their synthesis
are enantiomeric 2-hydroxymethyl-1,4-benzodioxanes 2, which
have been obtained through an enzyme-mediated kinetic resolu-
tions of racemate1 or from other scalemic inters,2,3 among them
3-(2-hydroxyphenoxy)propane-1,2-diols 3. Both enantiomers
of 3 have been prepared for the first time from (R)- and (S)-
glycidol derivatives.2
0
6.6%
3000
4000
1500
1000
500
n/cm–1
Figure 1 Experimental IR spectra of racemic (solid line) and scalemic
(dotted line) 3-(2-hydroxyphenoxy)propane-1,2-diols 3 as well as dif-
ference curve (beneath).
O
R
O
OH
OH
*
*
*
O
O
O
OH
Figure 1 shows the IR spectra of both racemic and highly
enantiomerically enriched solid samples of 3 along with the
normalized difference curve between individual spectra.§ Excepting
minor discrepancies, the spectra are identical. This is a good but
not definitive diagnostic for racemic conglomerate formation.
Valuable information on a chiral substance can be obtained
by differential scanning calorimetry (DSC). With a knowledge
of the temperature and enthalpy of fusion for a racemic and
enantiopure sample, it is possible to calculate for enantiomeric
3 the entropy of mixing in the liquid state ΔSlm and the free
energy of formation ΔG0 of racemic compound in the solid
state.6,7 Table 1 represents experimental and calculated thermo-
dynamic parameters for diol 3.¶ The calculated entropy of mixing
is 5.24 J K–1 mol–1, which is less but close to the ideal value of
5.77 J K–1 mol–1 (Rln 2) for conglomerates. The near-zero value
of ΔG0 points to the same crystallization peculiarity.
OH
1
2
3
Here, we consider solid state properties revealing the con-
glomerate nature of rac-diol 3, and propose a direct resolution
procedure for this valuable chiral substance.
Racemic, (R)- and (S)-3 have been prepared uniformly by
analogy with a published procedure4 through the reaction of
rac- , (S)- and (R)-3-chloropropane-1,2-diols with catechol.†,‡
†
The NMR spectra were recorded on a Bruker Avance-600 spectro-
meter in CD3CN with the signals of the solvent as the internal standard.
Optical rotations were measured on a Perkin-Elmer model 341 polarimeter.
The value of specific rotation is given in deg cm3 g–1 dm–1, and the
concentration of solutions c appears in g (100 ml)–1. Melting points for
general purposes were determined using a Boëtius apparatus and are
uncorrected. HPLC analyses of enantiomeric purity were performed on a
Shimadzu LC-20AD system controller, and a UV monitor 275 nm was
used as a detector. A Chiralcel AD-RH (0.46×15 cm) column from Daicel
was used; the column temperature was 21 °C; eluent water–isopropanol
(3:1); flow rate, 0.4 ml min–1.
§
The IR spectra of the polycrystalline samples of rac-3 and (R)- or (S)-3
in KBr pellets were recorded on a Bruker IFS-66v Fourier-transform
spectrometer. To substantiate the spectra comparison, they were subjected
to a procedure of normalization and baseline correction. For this purpose,
coefficients that minimize the difference ln (As) – [a0 + a1n + ln (Ar)a2],
where ln (As) and ln (Ar) are the extinctions (transmission logarithms)
of the scalemic and racemic samples, respectively; n is the IR radiation
frequency corresponding to A, and an are the desired regression coeffi-
cients, were selected by the least-squares method. It was reasonable to
introduce the regression terms a1n to correct the spectral differences
caused by the nonspecific (not related to particular absorption bands)
interaction of IR radiation with matter (probably, by radiation scatter on
heterogeneities of the sample). The ratio between the mean-square deviation
of the differential curves and the averaged mean-square deviation of
spectral curves for the racemate and scalemate, that is, the ratio of error
to variation (%), was used as a quantitative characteristic for differential
curves, and this namely quantity is cited in Figure 1.
‡
rac-3-(2-Hydroxyphenoxy)propane-1,2-diol (rac-3): yield 29%, mp 82–
83 °C (CH2Cl2/hexane) (lit.,5 mp 82–84 °C).
(S)-3-(2-Hydroxyphenoxy)propane-1,2-diol [(S)-3]: mp 108–109 °C
(CH2Cl2/hexane) (lit.,2 mp 106–108 °C); [a]D20 +32.8 (c 0.8, EtOH) {lit.,2
[a]D20 +42.8 (c 0.7, EtOH)}; 99.7% ee (HPLC; tR = 15.6 min). 1H NMR,
d: 2.59 (br. s, 1H, OH), 3.33 (br. s, 1H, OH), 3.64–3.71 (m, 2H, CH2O),
3.99 (dd, 1H, CH2O, J 9.4 and 6.2 Hz), 4.02–4.05 (m, 1H, CH), 4.10
(dd, 1H, CH2O, J 9.4 and 3.2 Hz), 6.80–6.83 (m, 1H, Ar), 6.87 (d, Ar,
J 9.4 Hz), 6.96 (d, 1H, Ar, J 4.1 Hz), 7.37 (br. s, 1H, OH). 13C NMR
(150.864 MHz) d: 62.87 (CH2OH), 70.79 (CH2O), 70.50 (CH), 113.83
(6-CAr), 115.34 (3-CAr), 119.97 (4-CAr), 121.99 (5-CAr), 146.54 (2-CAr),
146.70 (1-CAr).
(R)-3-(2-Hydroxyphenoxy)propane-1,2-diol [(R)-3]: mp 108–109 °C,
[a]D20 –33.0 (c 0.8, EtOH); 99.8% ee (HPLC; tR = 13.5 min).
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© 2009 Mendeleev Communications. All rights reserved.

Mendeleev Commun., 2009, 19, 208–210
Table 1 DSC measured melting point Tf and enthalpy of fusion ΔHf of
C(7A)
C(6A)
O(4A)
racemic (subscript R) and (S)-3 (subscript A), as well as calculated thermo-
dynamic characteristics of 3-(2-hydroxyphenoxy)propane-1,2-diol 3.
C(8A)
C(9A)
C(10A)
C(7B)
O(4B)
O(1B)
O(3A)
O(2A)
C(2A)
ΔHAf /
ΔHRf /
ΔG0/
ΔSml /
TAf /°C
TRf /°C
C(8B)
O(3B)
C(3B)
J mol–1
J mol–1
J mol–1
J K–1 mol–1
C(1B)
C(9B)
C(10B)
C(3A)
107.8
82.6
30790
25720
–14
5.24
C(2B)
C(1A)
From the DSC data for samples of different enantiomeric
purity, the melting temperature against composition diagram
(binary phase diagram) is depicted in Figure 2. Experimental
points in Figure 2 form an obvious single eutectic V-shape
curve typical of a racemic conglomerate.6 Figure 2 presents the
theoretical liquidus curve (solid line) deduced for conglomerate
from the simplified Schröder–Van Laar equation. Both experi-
mental and theoretical sets correlate quite well, and a calculated
value for eutectic melting point (Teu = 82.4 °C) is very close to
the experimental TRf = 82.6 °C.
O(2B)
O(1A)
Figure 3 ORTEP drawing of the symmetry independent (R)-3 molecules
in crystal.
The existence of three hydroxyls per molecule leads to the
development of the elaborated system of hydrogen bonds in
the crystals of compound 3. Owing to H-bonding of glycerol
fragments, 2D supramolecular structures arise in the crystals,
namely, endless cylinders along existing 21 screw axes parallel
with 0b axis. Alternating sequences of 3A, 3A' and 3B, 3B'
molecules form the H-bond pattern: ···O(2A)–H(20A)···O(1A')–
H(1A')···O(2B)–H(20B)···O(1B')–H(1B')···O(2A'')–H(20A'')···,
etc. In this aspect, the packing pattern of 3-(2-hydroxyphenoxy)-
propane-1,2-diol molecules is close to those of the known
chiral drug mephenesin, 3-(2-methylphenoxy)propane-1,2-diol,
investigated earlier.14 The sufficient difference between two
packing patterns consists with the presence of phenolic hydroxyl
in every molecule of 3. This group of molecule A takes part in
110
100
90
80
70
0.0
0.2
0.4
0.6
0.8
1.0
O(1A)
C(1A)
Mole fraction of (S)-enantiomer
Figure 2 Experimental (circles) and calculated (lines) melting point phase
diagram for diol 3.
C(3B)
C(3A)
O(3B)
C(5B)
C(5A)
Finaly, we studied the crystals of 3 by XRD. To unambi-
guously establish the absolute configuration for this compound,
we have used the direct Flack method for an enantiopure
sample with predetermined chiroptical characteristics.8 As we
have only a light atom structure (C,H,N,O), anomalous disper-
sion effects were small, but the situation was improved using
good quality crystals and Cu radiation. The reliability of the
absolute structure determination could also be improved using
set as many as possible of Friedel pairs in the data, in our case a
total number of 1154 was used which is a fraction of 0.68 from
possible amount. Refinement leads to good Flack parameters
with reasonable standard deviation.††
O(2B)
C(6A)
C(6B)
C(2A)
C(2B)
O(3A)
O(2A)
O(4B)
O(4A)
C(1B)
O(1B)
Figure 4 Superposition of two symmetry independent molecules of 3.
†† X-ray diffraction data. The sample of (–)-3-(2-hydroxyphenoxy)-
propane-1,2-diol, (–)-3, 99.8% ee, was crystallized from CH2Cl2 and
was characterized by mp 108–109 °C, [a]D20 –33.0 (c 0.8, EtOH); C9H12O4,
M = 184.19, monoclinic, space group P21, a = 12.2915(9), b = 4.8595(3)
and c = 15.4607(11) Å, b = 100.165(4)°, V = 908.98(11) Å3, Z = 4, dcalc
=
The sample obtained from enantiopure material forms mono-
clinic crystals, space group P21. There are two symmetry-
independent molecules in the unit cell of this compound, that
is Z' = 2; nevertheless, both chiral centres on C(2A) and C(2B)
carbons have the same absolute configuration (Figure 3). The
Flack parameter for the sample with negative sign of optical
rotation is well consistent with R-configuration of these C(2)
carbon atoms. The crystals grown from racemic 3 solution have
had the same habitus and crystallographic characteristics as
scalemic ones. Thus, the single crystal X-ray analysis confirms
the conglomerate nature of rac-3 established by IR and DSC
methods.
Having the same configurations, the independent molecules
of 3 have different conformations. If the molecule of 3B could
be characterized by sc,sc-conformation of the O(1)–C(1)–C(2)–
C(3)–O(3) fragment, then for the molecule of 3A this fragment
takes -sc,-sc-conformation (Figure 4).
= 1.35 g cm–3, m(CuKα) = 8.95 cm–1, F(000) = 392, 9903 reflections
measured, 2781 unique (Rint = 0.0445), restraints/parameters = 1/331.
Final indices R1(F) = 0.0365, wR2(F2) = 0.1029 using 2693 reflections
with I > 2s(I), and R1(F) = 0.0375, wR2(F2) = 0.1041 using all reflections.
Goodness-of-fit on F2 was 0.617, largest difference peak and hole are
0.108 and –0.149 eÅ–3. The Flack parameter is –0.0(2) (absolute structure
was established as R).
Both enantiopure and racemic diols 3 crystallize in P21 space group,
Z' = 2, having almost identical parameters of crystal unit cell.
Cell parameters and intensities for single crystals were measured at
296 K on a Bruker AXS Kappa Apex diffractometer, using CuKα radiation
with graphite monochromator. Data were corrected for the absorption
effect using the SADABS9 program. The structure was solved by a
direct method and refined by the full matrix least-squares using the
SHELXTL10 and WinGX11 programs. All non-hydrogen atoms were
refined anisotropically. The positions of the hydrogen atoms were located
from difference Fourier maps and all hydrogen atoms refined isotropically.
Data collections: images were indexed, integrated, and scaled using the
APEX212 data reduction package. All figures were made using the PLATON
program.13
¶
All thermal measurements were performed on a Perkin–Elmer Diamond
DSC model in aluminum pans using a heating rate of 10 K min–1. Mass
of the samples amounted to approximately 2.5 mg. Temperature scale
and heat flux were calibrated against the data for indium, phenol and
naphthalene.
CCDC 717487 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
For details, see ‘Notice to Authors’, Mendeleev Commun., Issue 1, 2009.
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Mendeleev Commun., 2009, 19, 208–210
References
1
(a) M. D. Ennis and D. V. Old, Terahedron Lett., 1992, 33, 6283;
(b) S. Antus, A. Gottsegen, J. Kajtár, T. Kovács, T. S. Tóth and H. Wagner,
Tetrahedron: Asymmetry, 1993, 4, 339.
2
3
A. Delgado, G. Leclerc, C. Lobato and D. Mauleon, Terahedron Lett.,
1988, 29, 3671.
C. Bolchi, L. Fumagalli, B. Moroni, M. Pallavichini and E. Valoti,
Tetrahedron: Asymmetry, 2003, 14, 3779.
4
5
6
R. R. Read and E. Miller, J. Am. Chem. Soc., 1932, 54, 1195.
G. Gellerstedt and J. Gierer, Acta Chem. Scand., 1968, 22, 2510.
J. Jaques, A. Collet and S. H. Wilen, Enantiomers, Racemates, and
Resolutions, Krieger Publishing Co., Malabar, FL, 1994, pp. 32–57.
Z. J. Li, M. T. Zell, E. J. Munson and D. J. W. Grant, J. Pharm. Sci.,
1999, 88, 337.
7
8
9
H. D. Flack and G. Bernardinelli, J. Appl. Crystallogr., 2000, 33, 1143.
G. M. Sheldrick, SADABS, Program for Empirical X-ray Absorption
Correction, Bruker–Nonius, 2004.
10 G. M. Sheldrick, SHELXTL v.6.12, Structure Determination Software
Suite, Bruker AXS, Madison, Wisconsin, USA, 2000.
11 L. J. Farrugia, J. Appl. Crystallogr., 1999, 32, 837.
12 APEX2 (Version 2.1), SAINTPlus. Data Reduction and Correction
Program (Version 7.31A, Bruker Advansed X-ray Solutions), Bruker
AXS Inc., Madison, Wisconsin, USA, 2006.
13 A. L. Spek, J. Appl. Crystallogr., 2003, 36, 7.
14 A. A. Bredikhin, A. T. Gubaidullin, Z. A. Bredikhina, D. B. Krivolapov,
Figure 5 Mutual arrangements of two independent molecules (atoms of
molecules B are shown by dark circles) of the compound 3 in the crystal,
viewed along the 0b axis.
A. V. Pashagin and I. A. Litvinov, J. Mol. Struct., 2009, 920, 377.
the above ‘cylinder’ superstructure, bonding with O(1) atom of
nearest neighbour molecule A', whereas the phenolic hydroxyl
of molecule B forms H-bond with such a hydroxyl of molecule
B', belonging to another ‘cylinder’, generating endless zigzag
succession O(4B)–H(40B)···O(4B')–H(40B')···, taking together
supramolecular cylindrical structures. Another interesting feature
of the compound 3 packing is an alternating of parallel with the
crystallographic 0ad plane layers consisting of the molecules of
only one sort: either A or B (Figure 5).
Aside from H-bonding, no other clear identifiable bonding
interactions, such as π–π and/or π···H tight contacts, for instance,
have been detected. In spite of the absence of cavities available
for guest molecules, the packing index for crystal lattice of 3 is
as low as 69.0%.
All the above-mentioned materials created solid evidence that
diol 3 crystallizes as a conglomerate. Thus, the resolution of the
racemic mixture via a classical entrainment procedure has been
tested. In this regard, the choice of a suitable solvent was
the main trouble. We have gained the purpose with a moderate
success using methylene chloride,‡‡ but it is obvious that special
search would improve the results.
Received: 29th January 2009; Com. 09/3277
‡‡ Racemic 3-(2-hydroxyphenoxy)propane-1,2-diol, rac-3 (0.79 g) and
(S)-3 (0.10 g) were dissolved in 180 ml of CH2Cl2 at 40 °C. The solution
was cooled to 25 °C and seeded with finely pulverized (S)-3 (3 mg). Chiral
HPLC was used for monitoring the resolution process. After stirring
the mixture for 120 min at 20 0.5 °C, precipitated (S)-3 was collected
by filtration (0.16 g after drying; 91% ee). The extra portion of rac-3
(0.16 g) was then dissolved in the mother liquor at 40 °C; the resulting
solution was cooled to 25 °C. After addition of (R)-3 (3 mg) as seed
crystals to the solution, and stirring the mixture for 100 min at 20 0.5 °C,
(R)-3 (0.14 g after drying; 80% ee) was collected by filtration. Further
resolution was carried out at 20 0.5 °C by adding amended amounts
of rac-3 to the filtrate in a manner similar to that described above. After
second cycle, 0.09 g of (S)-3 (92% ee) and 0.07 g of (R)-3 (84% ee)
were collected. A high degree of enantiomeric purity of collected diols
can be achieved by simple recrystallization from CH2Cl2.
– 210 –