Co-crystal of (R,R)-1,2-cyclohexanediol with (R,R)-tartaric acid, a key structure in resolution of the (±)-trans-diol by supercritical extraction, and the related ternary phase system

Article abstract of DOI:10.1016/j.tca.2009.09.001

A novel co-crystal of trans-(R,R)-1,2-cyclohexanediol and (R,R)-tartaric acid (with 1:1 molar ratio, 1) has been found to be a key crystalline compound in the improved resolution of (±)-trans-1,2-cyclohexanediol by supercritical fluid extraction. The molecular and crystal structure of this co-crystal, which crystallizes in orthorhombic crystal system (space group P2₁2₁2₁, a = 6.7033(13) A?, b = 7.2643(16), c = 24.863(5), Z = 4), has been solved by single crystal X-ray diffraction (R = 0.064). The packing arrangement consists of two dimensional layers of sandwich-like sheets, where the inner part is constructed by double layers of tartaric acids which hydrophilicity is "covered" on both upper and bottom side by cyclohexanediols with the hydrophobic cyclohexane rings pointing outward. Thus, a rather complex hydrogen bonding pattern is constructed. The relatively high melting point (133 °C) observed by both simultaneous TG/DTA and DSC, and the main features of FTIR-spectrum of 1 are explained by the increased stability of this crystal structure. DSC studies on binary mixtures of co-crystal 1 with (R,R)-1,2-cyclohexanediol or (R,R)-tartaric acid, revealed eutectic temperatures of T_eu = 100 or 131 °C, respectively. Between (S,S)-1,2-cyclohexanediol and (R,R)-tartaric acid a eutectic temperature of T_eu = 85 °C have also been observed. The phase relations have been confirmed by powder X-ray diffraction, as well.

Full text of DOI:10.1016/j.tca.2009.09.001

Thermochimica Acta 497 (2010) 129–136
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Co-crystal of (R,R)-1,2-cyclohexanediol with (R,R)-tartaric acid, a key structure in
resolution of the ( )-trans-diol by supercritical extraction, and the related
ternary phase system
Paul Thoreya, Petra Bombiczb, Imre Miklós Szilágyic,d, Péter Molnára, György Bánsághia,
Edit Székelya, Béla Simándia, László Párkányib, György Pokold, János Madarászd,∗
a Department of Chemical and Environmental Process Engineering, Budapest University of Technology and Economics, H-1521 Budapest, Hungary
b Institute of Structural Chemistry, Chemical Research Center, Hungarian Academy of Science, H-1525 Budapest, Hungary
c Material Structure and Modeling Research Group, Hungarian Academy of Sciences, H-1111 Budapest, Hungary
d Department of Inorganic and Analytical Chemistry, Budapest University of Technology and Economics, H-1521 Budapest, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 June 2009
Received in revised form 2 September 2009
Accepted 7 September 2009
Available online 13 September 2009
A novel co-crystal of trans-(R,R)-1,2-cyclohexanediol and (R,R)-tartaric acid (with 1:1 molar ratio, 1) has
been found to be a key crystalline compound in the improved resolution of ( )-trans-1,2-cyclohexanediol
by supercritical fluid extraction. The molecular and crystal structure of this co-crystal, which crystallizes
in orthorhombic crystal system (space group P212121, a = 6.7033(13) Å, b = 7.2643(16), c = 24.863(5), Z = 4),
has been solved by single crystal X-ray diffraction (R = 0.064). The packing arrangement consists of two
dimensional layers of sandwich-like sheets, where the inner part is constructed by double layers of tar-
taric acids which hydrophilicity is “covered” on both upper and bottom side by cyclohexanediols with the
hydrophobic cyclohexane rings pointing outward. Thus, a rather complex hydrogen bonding pattern is
constructed. The relatively high melting point (133 ◦C) observed by both simultaneous TG/DTA and DSC,
and the main features of FTIR-spectrum of 1 are explained by the increased stability of this crystal struc-
ture. DSC studies on binary mixtures of co-crystal 1 with (R,R)-1,2-cyclohexanediol or (R,R)-tartaric acid,
revealed eutectic temperatures of Teu = 100 or 131 ◦C, respectively. Between (S,S)-1,2-cyclohexanediol
and (R,R)-tartaric acid a eutectic temperature of Teu = 85 ◦C have also been observed. The phase relations
have been confirmed by powder X-ray diffraction, as well.
Keywords:
Chiral resolution
(
)-Trans-1,2-cyclohexanediol
(R,R)-Tartaric acid
Single crystal and powder X-ray diffraction
(XRD)
Crystal structure determination
FTIR spectroscopy
Differential scanning calorimetry (DSC)
Simultaneous TG/DTA
Binary melting phase diagrams
Eutectic compositions and temperatures
Structure–property relationship
© 2009 Elsevier B.V. All rights reserved.
1. Introduction
co-crystallization, as (+)-tartaric acid (TA) is a good hydrogen bond
acceptor and donor. This opened the way for the resolution of com-
Enantiopure products take a growing importance in the field
of fine chemistry and pharmaceutical industry. Most enantiomers
(in 1992 about 65% [1]) are prepared by classical resolution: stere-
oselective crystallization with an optically active resolving agent.
Generally a salt is formed by an exchange of proton between a base
and an acid. For instance (+)-tartaric acid (TA) has been widely
used as an acidic resolving agent [1,2]. The use of tartaric acid
is not restricted to the resolution of bases. Indeed, in some cases
where the existence of a salt was expected, IR spectroscopy did
not show an exchange of proton, and the formed compound was a
complex or co-crystal rather than a salt [3]. Not ionic interaction,
but a strong system of hydrogen bonds was responsible for the
pounds without basic properties with (+)-tartaric acid derivatives.
Chiral alcohols were screened for the resolution with TA deriva-
tives. Whereas O,Oꢀ-dibenzoyl-(2R,3R)-tartaric acid afforded good
enantiomeric excesses [4–6], the resolution with O,Oꢀ-di-p-toluoyl-
(2R,3R)-tartaric acid was less successful [7] and impossible with TA
[8].
(
)-Trans-1,2-cyclohexanediol (CHD), an important building
block for the pharmaceutical industry [9–11], is a good candidate
for resolution with TA followed by supercritical fluid extraction.
The method was presented in our previous work [12] and based on
three steps [13,14] (see Fig. 1):
•
The sample preparation: the stereoselective co-crystallization
of (R,R)-trans-1,2-cyclohexanediol with (R,R)-tartaric acid (TA)
forming the co-crystal TA-(R,R)-CHD 1:1 (1), while (S,S)-trans-
1,2-cyclohexanediol ((S,S)-CHD) remains free or “uncocrystal-
lized”.
∗
Corresponding author. Fax: +36 1 463 3408.
E-mail address: madarasz@mail.bme.hu (J. Madarász).
0040-6031/$ – see front matter © 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.tca.2009.09.001

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P. Thorey et al. / Thermochimica Acta 497 (2010) 129–136
Fig. 1. Scheme of the resolution of ( )-CHD by co-crystal formation followed by an extraction in CO2 [12].
Table 1
preferentially. This method gave (S,S)-CHD of an optical purity
of 67% and the extraction yield was 36.5% based on the racemic
compound (for an optical purity of 100% the maximum extraction
yield is 50%). The structure of the co-crystal between (S,S)-CHD
and (R,R)-1,2-cyclohexanediamine was established and discussed
in [16–18]. Other co-crystals were found between (R,R)-CHD and
(R,R)-2,3-diaminobutane [17] or N-methylmorphine-N-oxide [19].
These structures reveal an inner core based on hydrogen bonds
between the diamine and diol moieties, which are responsible for
the stereoselectivity of the crystallisation and the geometry of the
crystal, and an outer region formed of the hydrophobic groups.
Crystal and molecular structure of the co-crystal (1) between
(R,R)-CHD and TA, on which the successful supercritical resolution
is based, has been solved by single crystal X-ray diffraction and
presented here. This key compound has also been characterized
by differential scanning calorimetry (DSC), as well as simultane-
ous thermogravimetry and differential thermal analysis (TG/DTA),
To explore the (in)compatibility of racemic diol with enantiomeric
tartaric acid, the various binary phase relations in the ternary
(R,R)-TA-(R,R)-CHD-(S,S)-CHD system has been studied by DSC
and powder X-ray diffraction (XRD). Based on related eutectic
calculations, a schematic ternary phase diagram has also been
constructed.
Summary of crystallographic data, data collections, structure determination and
refinement for CHD-TA co-crystal (1).
Formula
C6 H12 O2, C4 H6 O6
266.24
Orthorhombic
P212121 (No. 19)
6.7033(13) 7.2643(16) 24.863(5)
1210.7(4)
4, 1
1.461
0.128
568
Formula weight
Crystal system
Space group
a, b, c [Å]
V [Å3]
Z, Zꢀ
D (calc.) [g/cm3]
ꢀ (Mo-K␣) [mm−1
F(000)
]
Crystal size [mm]
Temperature [K]
Radiation [Å]
Theta min–max
Dataset
Tot., uniq. data, R(int)
Observed data [I > 2.0ꢁ(I)]
Nref, Npar
0.55 × 0.55 × 0.34
295
Mo-K␣ 0.71073
3.2, 26.4
−8:8, −9:9, −31:31
25,226, 2468, 0.121
2216
2468, 170
0.0640, 0.1369, 1.05
0.00, 0.00
R, wR2, S [*]
Max. and Av. shift/error
Flack x
Min. and max. resd. dens. [e/Å3]
0(1)
−0.26, 0.28
*w = 1/[ꢁ2(Fo2) + (0.0222P)2 + 1.1376P] where P = (Fo2 + 2Fc2)/3.
•
The separation, from co-crystal (1), of (S,S)-CHD which is
extracted.
2. Experimental
•
The recovery of (R,R)-CHD by decomposition of 1, in this case, by
a basic treatment.
2.1. Starting materials and sample preparations
(+)-Tartaric acid (>99.5%, Aldrich Ref. No. 251380) was
purchased from Sigma–Aldrich. (S,S)-CHD (>99% for sum of enan-
tiomers, Ref. No. 29003) and (R,R)-CHD (>99%, Ref. No. 421790)
were obtained from Fluka and Aldrich, respectively. Ethanol
(>99.5%) was purchased from Reanal Ltd. (Budapest, Hungary).
The transparent single crystals of the co-crystal (1) of TA and
(R,R)-CHD were grown by a slow evaporation of the solvent from
The optimization of extraction pressure and temperature led to
an improved enantiomeric excess of 62% (yield 50.6%) and 81.9%
(yield 33.7%)% for (S,S)-CHD and (R,R)-CHD, respectively [12].
In the work of Kawashima and Hirayama the CHD was
resolved [15] by reacting with an other resolving agent (R,R)-
1,2-cyclohexanediamine that formed a co-crystal with (S,S)-CHD
Fig. 2. ORTEP diagram [25] of the CHD-TA co-crystal (1), represented at 50% probability level, heteroatoms are shaded. The chiral centers are C2 R, C3 R, C21 R and C26 R,
respectively.

P. Thorey et al. / Thermochimica Acta 497 (2010) 129–136
131
Table 2
Intermolecular interactions in the crystal structure of CHD-TA co-crystal (1).
D–H. . .A
D–H [Å]
H. . .A [Å]
D. . .A [Å]
D–H. . .A [◦]
Symmetry operation
O2–H2O. . .O12
O3–H3O. . .O41
O12–H12O. . .O21
O26–H26O. . .O11
0.820
0.820
0.820
0.820
2.300
2.380
1.770
2.130
2.615(3)
2.707(3)
2.593(3)
2.923(3)
104
105
176
162
Intra
Intra
Within asym. unit
Within asym. unit
O2–H2O. . .O26
O3–H3O. . .O41
O21–H21O. . .O3
O26–H26O. . .O41
O42–H42O. . .O26
0.820
0.820
0.820
0.820
0.820
2.100
2.020
1.970
2.500
1.990
2.873(3)
2.740(4)
2.786(3)
2.882(3)
2.773(3)
157
146
171
109
160
x, −1 + y, z
(1/2) + x, −(1/2) − y, −z
(1/2) + x, (1/2) − y, −z
(1/2) + x, (1/2) − y, −z
−1 + x, −1 + y, z
C2–H2. . .O21
0.980
2.390
3.280(4)
150
−1 + x, y, z
Fig. 3. The two-dimensional infinite hydrogen bonded sheet of the CHD-TA co-crystal (1) [26]. Views from the a, b crystallographic axis, respectively, are side views, while
view from the c crystallographic axis is a perpendicular view to the sheet. TA is colored red, while CHD is blue. Hydrogen atoms are omitted for clarity.

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P. Thorey et al. / Thermochimica Acta 497 (2010) 129–136
Fig. 4. The inner TA layer of the sheet presenting [26] its hydrogen bonding system
of co-crystal 1. View from the c crystallographic axis. Hydrogen atoms are omitted
for clarity.
Fig. 6. DSC melting peak of the pure CHD-TA co-crystal (1) in sealed Al-pan at
10 ◦C/min (mass 2.59 mg).
an equimolar solution of TA and (R,R)-CHD in 1:1 (v/v) water and
ethanol solvent mixture at room temperature.
the Flack x parameter [24] is not reliable. The O–H hydrogen atomic
positions could be located in the difference Fourier maps. Hydrogen
atoms were included in structure factor calculations but they were
not refined. The isotropic displacement parameters of the hydro-
gen atoms were approximated from the U(eq) value of the atom, to
which they were bonded.
Crystallographic data (excluding structure factors) for the co-
crystal structure of 1 have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication num-
ber CCDC 728882.
The samples of the binary mixtures of TA and enantiomeric CHDs
were prepared by evaporation of the solvent from the ethanolic
solutions of CHD and TA at reduced pressure (about 160 Torr) and
40–45 ◦C.
2.2. Single crystal X-ray diffraction
The selected transparent crystal of 1 for single crystal X-ray
diffraction measurement had the size of 0.55 mm × 0.55 mm ×
0.34 mm. 1 was mounted on a loop with parathon oil. Cell parame-
ters were determined by least-squares of all reflections in the whole
measured ꢂ range. Intensity data were collected on a Rigaku Raxis-
Rapid diffractometer (graphite monochromator; Mo-K␣ radiation,
ꢃ = 0.71073 Å). Empirical absorption correction was applied to the
data. The structure was solved by direct methods [20]. Anisotropic
full-matrix least-squares refinements [21,22] on F2 for all non-
hydrogen atoms were performed. Neutral atomic scattering factors
were taken from the International Tables for X-ray Crystallography
[23]. Crystallographic data, parameters of data collection, structure
solution and refinement can be found in Table 1. Since there are no
strong anomalous scattering centres in the constituents and the
diffraction measurement was performed using Mo-K␣ radiation,
2.3. Further analytical methods
FTIR spectra of co-crystal (1) was measured by Excalibur Series
FTS 3000 (Biorad) FTIR spectrophotometer in KBr between 700 and
4000 cm−1
.
Powder X-ray diffraction patterns were recorded with a PANa-
lytical X’pert Pro MDP X-ray diffractometer using Cu-K␣ radiation
and Ni filter.
Differential scanning calorimetry (DSC) measurements were
performed using a Modulated DSC 2920 device (TA Instruments).
The samples (1–2 mg) were measured in sealed Al-pans at a heat-
Fig. 5. FTIR spectrum of the CHD-TA co-crystal (1).

P. Thorey et al. / Thermochimica Acta 497 (2010) 129–136
133
ing rate of 10 K/min. For temperature and enthalpy calibration of
the DSC instrument pure In metal standard was applied. Simultane-
ous thermogravimetry and differential thermal analysis (TG/DTA)
tests were conducted using an STD 2960 Simultaneous TG/DTA
equipment (TA Instruments), a heating rate of 10 K/min, open Pt
crucibles and an air purge of 130 ml/min. The build-in temperature
calibration of TG/DTA was accepted and applied.
3. Results
3.1. The crystal structure of the co-crystal of (+)-tartaric acid and
(R,R)-CHD 1:1 (1)
The co-crystal 1 crystallizes in the orthorhombic crystal sys-
tem, space group P212121 (No 19), having one TA and one CHD
molecules in the asymmetric unit (Z = 4, Zꢀ = 1) (Fig. 2). Detailed
crystallographic data, the parameters of data collection, structure
determination and refinement are presented in Table 1. As the
configuration of the starting material (2R,3R)-tartaric acid was
known (C2 and C3 are R), consequently the configuration of CHD is
(R,R)-1,2-cyclohexanediol (C21 and C26 are R) in the crystal struc-
ture. Both alcoholic oxygen atoms in the CHD are in equatorial
positions.
The two molecules forming the co-crystal present 4 alcohol and
2 carboxylic acid moieties so the co-crystal contains six donors and
eight acceptors for the hydrogen bonds. Thus, a rather complex
hydrogen-bonding pattern (Table 2) is constructed in the crystal
structure (Fig. 3) A two-dimensional sheet is formed in the ab crys-
tallographic plane with the width of c/2. The 2D hydrogen bonded
sheet is like a “double sandwich”. The inner part is constructed
from a double layer of TA-s (Fig. 4). It is “covered” on both upper
and lower sides by the polar moities, the hydroxyl groups of CHD
(Fig. 3a and b) while the cyclohexane moieties points outward. Thus
the inner part is hydrophilic, the outer coat is hydrophobic.
There are two intramolecular hydrogen bonded loops
in TA stabilizing the conformation of the molecule:
Fig. 7. Simultaneous TG/DTA curves of the pure CHD-TA co-crystal 1 (open Pt cru-
cible, air flow of 130 ml/min, heating rate 10 ◦C/min, mass 8.68 mg).
theless its H42 proton is kept also relatively strongly, based on
donor–acceptor distances (Table 2). The latter band (at 1698 cm−1
)
should belong to C1O11O12H12 carboxylic group, whose O11 oxy-
gen is involved only in one weak hydrogen bond, meanwhile the
H12 proton is also loosely kept and very intensely shared with O21
oxygen of O21H21 hydroxyl group of CHD. This quasi-anionic fea-
ture (which is stabilized by the strong intramolecular hydrogen
bond of O12–O2 of O2H2 hydroxyl group absorbing at 1919 cm−1
)
· · ·O12–C1–C2–O2–H2O· · ·
and
· · ·O41–C4–C3–O3–H3O· · ·,
results in large decrease of carbonyl frequency. Our assignments of
the relative strength of hydrogen bonds are based simply on the
donor acceptor distances.
The DSC analysis of CHD-TA co-crystal (1) in sealed Al-pan
showed a melting point at 133.2 ◦C and its enthalpy of fusion was
56.7 kJ/mol (Fig. 6).
According to simultaneous TG/DTA measurement in an open Pt
crucible (Fig. 7), the co-crystal 1 shows nearly same melting point
(133 ◦C). Mass loss of 3% in the TG curve shows partial sublimation
of CHD starting from 100 ◦C till the melting point. A further evap-
oration of CHD seems to be overlapping with the decomposition
process of tartaric acid above 171 ◦C.
both are S(5) by the graph set analysis [27]. Within
the asymmetric unit the two constituents are hydro-
gen
bonded
forming
a
R22(9)
homodromic
loop:
fur-
· · ·O11 C1–O12–H12O· · ·O21–C21–C26–O26–H26· · ·.
A
ther hydrogen bonded loop exists between CHD and TA:
· · ·H21O–O21–C21–C26–O26–H26O· · ·O41 C4–C3–O3· · ·, which
is heterodromic R22(10). In the inner part of the “sandwich” the
TA molecules are connected by strong intermolecular interaction
to each other (Fig. 4) and to CHD molecules. There is no hydro-
gen bond between CHD molecules. One TA molecule within the
sheet is connected to four other TA-s, to three TA-s directly, to
one TA via a CHD. One TA molecule is connected to four CHD
molecules with six hydrogen bonds. The hydrogen bond loops
3.3. Differential scanning calorimetry (DSC) and powder X-ray
diffraction (XRD) study of the various binary mixtures in the
ternary system of solids
are:
· · ·H3O–O3–C3–C2–O2–H2O· · ·O26–H26· · ·O41· · ·
R23(9)
and · · ·O41–C4–C3–O3–H3O· · ·O41 C4–O42–H42· · ·O26–H26· · ·
R33(11). Finally, there is a weak C-H· · ·O type interaction also, i.e.
C2–H2· · ·O21 within the sheet.
Attempt has been made to study in details the phase relations
of the three basic components ((R,R)-CHD, (S,S)-CHD, and (R,R)-TA),
in order to support the resolution of ( )-trans-1,2-cyclohexanediol.
The available thermal and structural information on the racemic
and enatiomeric trans-1,2-cyclohexanediol isomers are summa-
rized in a recent study of Lloyd et al. [28]. The corresponding
structural reference data obtained from previous X-ray diffraction
studies [18,28–34] are listed in the Supplementary material.
Earlier, CHD was the subject of several publications because of
its industrial importance and also different features very interest-
ing to a theoretic point of view. The pure enantiomers crystallized
in two different forms that melted at 382.5 K and 352.8 K, and the
3.2. Characterization of the 1:1 co-crystal of (+)-tartaric acid and
(R,R)-CHD (1) by FTIR, DSC and simultaneous TG/DTA
The FTIR spectrum of the co-crystal (1) presents an interesting
feature (Fig. 5), i.e. a splitting of the single carbonyl C O stretch-
ing vibration (at 1740 cm−1) of pure TA. Indeed, there are two C
O
bands at 1738 and 1698 cm−1 in the spectrum of co-crystal 1. The
former band (1738 cm−1) belongs certainly to the C4O41O42H42
carboxylic group, despite its carbonyl oxygen O41 is involved
in three relatively strong hydrogen bonds as acceptor. Never-

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P. Thorey et al. / Thermochimica Acta 497 (2010) 129–136
Table 3
Melting point and enthalpy of fusion of the chemicals applied in the study of binary systems.
Initial chemicalsa
Tfus observed by DSC K (◦C)
ꢄHfus measured by DSC (kJ/mol)
Reference Tfus (K)
Refs.
(
)-CHD
372 (99) (small pre-melting endothermic peak at 87 ◦C, as well)
381 (108)
377 (104)
34.4
18.0
15.0
376.4
382.5
Ibid.
[36]
[36]
Ibid.
(R,R)-CHD
(S,S)-CHD
(R,R)-tartaric acid
Co-crystal (1)
444 (171) (decomposes)
406 (133)
22.4 (estimated)
56.7
[38–40]
This work
a
Chemicals listed in the experimental part were used without further purification, and their experimentally measured parameters were involved in the calculations.
Table 4
DSC and XRD data of binary mixtures in the ternary system.
Binary mixtures
Molar ratio
Eutectic temperature Teu (K/◦C)
Liquidus temperature Teu (K/◦C)
Crystalline phases present (XRD)
1
2
3
4
5
(R,R)-CHD:(R,R)-TA
(R,R)-CHD:(R,R)-TA
(S,S)-CHD:(R,R)-TA
(S,S)-CHD:(R,R)-TA
(S,S)-CHD:(R,R)-TA
2:1
1:2
3:1
1:1
1:3
373.3/100.2
404.7/131.6
359.7/86.6
358.6/85.5
257.2/84.1
Ca. 396/123
Ca. 433/160
–
Ca. 410/137
Ca. 427/154
(R,R)-CHD and co-crystal (1)
Co-crystal (1) and (R,R)-TA
(S,S)-CHD and (R,R)-TA
(S,S)-CHD and (R,R)-TA
(R,R)-TA and (S,S)-CHD
crystal were generally a mixture of the two forms whose difference
in melting could be observed [35]. Only the stable polymorph’s
structure was determined [18,28]. The racemic compound (( )-
CHD) of (R,R)- and (S,S)-1,2-cyclohexanediol is present under two
polymorphic forms, as well. The stable polymorph’s structure was
determined in [28,31,32] and the metastable’s in [28].
eutectic temperature of (1) and TA or (1) and (R,R)-CHD. This indi-
cates that no co-crystal is formed between (S,S)-CHD and (R,R)-TA.
This result is corroborating with the XRD profile of the samples for
the binary mixtures of (R,R)-TA and (S,S)-CHD of 1:3, 1:1, and 3:1
molar ratio, presenting only patterns of (R,R)-tartaric acid (PDF No.
00-033-1883; 00-020-1901; 00-031-1911) and (S,S)-CHD (PDF No.
02-093-3042), and no other reflections occurred.
After the eutectic melting the elongated dissolution of the excess
phase continued, as it is shown for both mixture of the 1:1 molar
ratio of (R,R)-CHD and co-crystal (1) or (S,S)-CHD and (R,R)-TA in
Fig. 8a and b, respectively. In case of 3:1 molar ratio of (S,S)-CHD
and (R,R)-TA, only the single eutectic melting effect occurred, i.e. it
represents almost a eutectic composition between (S,S)-CHD and
(R,R)-TA.
The solid–liquid melting phase diagram for mixtures of (R,R)-
CHD and (S,S)-CHD was investigated by DSC method [36]. This
binary system resembled a type of melting phase diagram includ-
ing a racemic compound [37], but had an unusual feature. Usually,
a racemic compound, as a co-crystal of both enantiomers, can form
a eutectic mixture, i.e. crystal conglomerate with one of the enan-
tiomers. Actually, in this case, eutectic compositions were found
at about molar fractions of xSS-CHD = 0.2 and 0.8. Furthermore the
corresponding eutectic temperature of Teu = 371 K was observed
in the composition ranges 0 < xSS-CHD < 0.2 and 0.8 < xSS-CHD < 1, but
in intermediate composition, 0.2 < xSS-CHD < 0.8, no eutectic melting
endothermic heat effect occurred at all [33]. This phenomenon was
explained by Leitao et al. as solid solution formation for compo-
sitions within the latter wide range around the 1:1 molar ratio.
A metastable phase was also found below eutectic temperature
(xSS-CHD < 0.2 and xSS-CHD > 0.8), as the continuation of the liquidus
curve of solid solution [36].
Now, we have investigated both binary systems between (R,R)-
TA and (R,R)-CHD or (S,S)-CHD with DSC and powder X-ray
diffraction, with help of samples prepared at representative 1:3,
1:1, and 3:1 molar ratios. The melting point and enthalpy of fusion
of the initial chemicals applied in preparation and calculation of
binary mixtures are listed in Table 3, while the temperatures of
the observed thermal heat effect(s) and the initial crystalline phase
composition of various mixtures at room temperature are summa-
rized in Table 4.
The experimental powder X-ray diffraction pattern of sample
with 1:1 molar ratio of (R,R)-CHD and (R,R)-TA has been checked
with comparison with the simulated powder diffraction pattern
of co-crystal CHD-TA (1) generated from the single crystal data
presented above: the agreement was perfect.
The XRD profile of the samples formed from the 1:2 and 2:1
binary mixtures of (R,R)-CHD and (R,R)-TA corresponded to the 1:1
mixtures of co-crystal (1) and (R,R)-CHD or (R,R)-TA, respectively.
These samples showed eutectic melting behavior, eutectic tem-
peratures were found lower than the melting point of co-crystal
(1) by DSC. The first eutectic is found between (R,R)-CHD and co-
crystal (1) at 100 ◦C (Fig. 8a); and the second between co-crystal
(1) and (R,R)-TA at 131.6 ◦C. DSC showed, in all the cases of the
binary (S,S)-CHD–(R,R)-TA system, a constant eutectic temperature
of 84–86 ◦C. It is lower than the melting point of (S,S)-CHD and the
Fig. 8. DSC curve of binary mixtures corresponding to 1:1 molar ratio of -a) (R,R)-
CHD and co-crystal (1) and b) (S,S)-CHD and (R,R)-TA, both exhibiting eutectic
melting behavior.

P. Thorey et al. / Thermochimica Acta 497 (2010) 129–136
135
Table 5
Calculated eutectic compositions, calculated and measured eutectic temperatures of binary and ternary mixtures (based on experimental DSC data of used chemicals and
assumption of validity of Schöder–van Laar equation).
Components
Calculated eutectic
molar fractions
Calculated eutectic temperature (K, ◦C)
Measured eutectic
temperature (K, ◦C)
x(1) = 0.184
369, 96
373, 100
Co-crystal (1)/(R,R)-CHD
xRR-CHD = 0.816
x(1) = 0.553
392, 119
404, 131
Co-crystal (1)/(R,R)-TA
xRR-TA = 0.447
xRR-TA = 0.148
xSS-CHD = 0.852
xRR-CHD = 0.222
x( )-CHD = 0778
x(1) = 0.134
365, 92
359, 86
(R,R)-TA/(S,S)-CHD
371, 98
(R,R)-CHD (or (S,S)-CHD)/racemic-CHD
Co-crystal (1)/racemic-CHD
Co-crystal (1)/(R,R)-TA/(S,S)-CHD
366, 93 (Prigogine-Defay equation also applied)
363, 90
353, 80
Not measured
Not measured
x( )-CHD = 0.866
x(1) = 0.077
xRR-TA = 0.206
xSS-CHD = 0.717
x(1) = 0.051
345, 72
Co-crystal (1)/(R,R)-CHD (or (S,S)-CHD)/racemic-CHD
Not measured
xRR-CHD = 0.542
x( )-CHD = 0.405
Estimation of eutectic molar fraction, eutectic temperature,
and liquidus curves of binary eutectic phase diagrams have also
been calculated numerically [41,42] based on the temperature and
enthalpy of fusion of pure crystalline phases (listed in Table 3)
assuming the validity of simplified Schröder–van Laar equation,
and in case of racemate also of Prigogine–Defay–Mauser equa-
tion [37]. Beyond the results on various binary subsystems, the
calculated eutectic parameters for ternary eutectic subsystems,
with assumption of incompatibility of (R,R)-TA and racemic CHD,
and according to the Schröder–van Laar equation [43] are also
reported in Table 5. A schematic diagram of phase relation of the
three-component ((R,R)-CHD, (S,S)-CHD, and (R,R)-TA) system, that
allows the required resolution, is exhibited in Fig. 9.
and complexed CHD liberation): enantiomeric excess of 85%
(yield 45%) and 88.9% (yield 50.2%) for (S,S)-CHD and (R,R)-CHD,
respectively.
4. Conclusion
The structure of 1, 1:1 co-crystal of (R,R)-TA and (R,R)-CHD
(orthorhombic crystal system, space group P212121) has been
determined by single crystal X-ray diffraction. The crystal structure
is made of layers, each formed of four sheets, CHD-TA-TA-CHD. The
inner part of the layer is polar (alcoholic and carboxylic groups of TA
and alcohol groups of CHD) whereas the outside is apolar (cyclohex-
ane rings of CHD). The co-crystal melts at 133 ◦C and its sublimation
starts at 100 ◦C. In the case of the binary mixtures between (R,R)-
CHD and TA, two different eutectic temperatures were found, the
first one between (R,R)-CHD and co-crystal (at 100 ◦C) and the
second between co-crystal and TA (at 131 ◦C), whereas, in the
case of the binary (S,S)-CHD-TA, the constant eutectic tempera-
ture (84–86 ◦C) helps to conclude that no co-crystal was formed,
which result was corroborated by powder X-ray diffraction. Further
improvement of resolution technique by supercritical carbondiox-
ide based on the explored phase relations is under completion.
Based on the result presented above, resolution experiments
were performed with (R,R)-TA: (S,S)-CHD: (R,R)-CHD = 2:0.5: 0.5
molar ratio. Results showed significant improvement of the pro-
cess, in one single resolution step (including sample preparation,
supercritical carbon dioxide extraction at optimal conditions
Acknowledgements
This research work was financially supported through a Euro-
pean Community Marie Curie Fellowship (Project MEST-CT-2004-
007767, for further information: http://www.cordis.lu/improving)
and by the Hungarian Scientific Research Fund (OTKA 72861). P.B.
and L.P. acknowledge the National Science and Technology Office
for an X-Ray diffractometer purchase grant (MU-00338/2003). J.M.,
Sz.I.M., and G.P. also thank for the purchase grant of a new HT-XRD
apparatus supported by the EU and the Hungarian government
(GVOP-3.2.1.-2004-0224, KMA). The authors thank Prof Mátyás
Czugler for giving the opportunity to carry out the single crystal
XRD measurement that allowed the determination of the structure.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tca.2009.09.001.
Fig. 9. Schematic three-component T–x phase diagram for trans-1,2-
cyclohexanediols and (R,R)-tartaric acid, drawn from the data shown in Table 5.
Schematic T–x diagrams for each pair of components are also shown. (1) corre-
sponds to the co-crystal of (R,R)-1,2-cyclohexanediol and (R,R)-tartaric acid (1:1).
No phase containing (S,S)-1,2-cyclohexanediol and (R,R)-tartaric acid is known.
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