Crystal structure of a hybrid salt-cocrystal and its resolution by preferential crystallization: ((±)trans-N,N′- dibenzyldiaminocyclohexane)(2,3-dichlorophenylacetic acid)4

Article abstract of DOI:10.1039/c1ce05484h

trans-N,N′-Dibenzyldiaminocyclohexane (B) crystallizes with 2,3-dichlorophenylacetic acid (AH); the crystal structure, resolved by using crystal X-ray diffraction, revealed an odd stoichiometry composed of H ₂B²⁺, two A^- a

Full text of DOI:10.1039/c1ce05484h

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PAPER
Crystal structure of a hybrid salt–cocrystal and its resolution by preferential
0
crystallization: ((± ±trans-N,N -dibenzyldiaminocyclohexane±(2,3-
dichlorophenylacetic acid±4†
Julien Mahieux, Silvia Gonella, Morgane Sanselme and G ꢀe rard Coquerel*
Received 22nd April 2011, Accepted 30th August 2011
DOI: 10.1039/c1ce05484h
0
trans-N,N -Dibenzyldiaminocyclohexane (B) crystallizes with 2,3-dichlorophenylacetic acid (AH); the
crystal structure, resolved by using crystal X-ray diffraction, revealed an odd stoichiometry composed
ꢀ
2+
of H B , two A and two AH forming an unexpected hybrid salt–cocrystal. As this compound is
2
2+
a stable conglomerate (i.e. every single crystal contains the enantiomerically pure cation H B , RR or
2
SS), several preferential crystallization attempts (AS3PC) were performed in methanol and in THF and
gave unexpected final enantiomeric excesses greater than 20% for the entrainment in methanol. These
results suggest that the crystal growth mechanism preferentially involves building units composed of
2+
ꢀ
2
[H B ; 2A and 2AH] or reconstruction of some crystal interfaces rather than a layer by layer
construction.
Introduction
ref. 14–16 for counter-examples associated with metastable
conglomerates). That is to say the racemic mixture of crystals is
composed of enantiomerically pure solid particles even if partial
solid solutions might exist without impairing preferential crys-
The demand for chiral compounds is steadily increasing both in
academic research and for industrial applications. Although
efficient routes of asymmetric syntheses are now available, chiral
resolutions of racemic mixtures keep being the preferred options
in many large-scale applications. These processes can be run by
17
tallization. Thus the screening of conglomerates corresponds to
the identification of crystallized phases providing full chiral
discrimination. When the molecule to be resolved contains an
acidic or a basic function, this is usually performed by numerous
attempts to crystallize salts. At the top of that, in order to spot
1
chromatography on chiral stationary phases, biocatalytic
2
processes (involving enzymes or microorganisms) and crystal-
3
lization. This latter mode offers several possibilities to resolve
18
conglomerates of solvated or heterosolvated salts, it is recom-
a racemic mixture: diastereomeric entities (by formation of salts
mended to make a screening with different solvents or mixture of
solvents for every counter-ion.
4,5
in the Pasteur resolution or the enantioselective encapsulation
6
into a chiral macrocycle in the host–guest association ), prefer-
7
ential nucleation, simultaneous crystallization, symmetry
The conglomerates can be spotted by using various methods.
8
The detection of the Second Harmonic Generation (SHG)
19
effect is a pre-screening technique, which has recently proved to
9,10
3
and preferential crystallization (PC). PC itself can
breaking
be subdivided into several variants according to the nature of the
be fast, cheap and efficient. Nevertheless, complementary anal-
yses are necessary to confirm the existence of a conglomerate by,
for instance, comparisons of spectroscopic data such as X-ray
powder diffraction (XRPD) or IR or ss-NMR or Raman
patterns of the pure enantiomer and of the racemic mixture.
This article aims at showing that odd stoichiometries can
sometimes provide the full chiral discrimination in the solid state,
necessary for the application of PC. Therefore no a priori
restriction should be considered in the screening of associations
between partners of crystallization.
11
crystallization process (e.g. seeding procedures: SIPC (Seeded
Isothermal Preferential Crystallization), S3PC (Seeded Poly-
1
2
thermic Programmed Preferential Crystallization) and AS3PC
(
Auto-Seeded Polythermic Programmed Preferential Crystalli-
13
zation)) and the possibility or not of in situ racemisation, SOAT
(
Second Order Asymmetric Transformation). Whatever those
variants, the pre-requisite condition for application of preferen-
11
tial crystallization is the existence of a stable conglomerate (see
SMS laboratory, University of Rouen, rue Lucien Tesni eꢁ re, Mont Saint
Aignan, 76130, France. E-mail: gerard.coquerel@univ-rouen.fr; Fax: +33
0
The molecule to be resolved is the diamine trans-N,N -diben-
zyldiaminocyclohexane (compound B) (see the Syntheses section
and Fig. 15) synthesized in our laboratory. This diamine crys-
tallizes as a conglomerate with 2,3-dichlorophenylacetic acid
(0)2 35 52 29 59; Tel: +33(0)2 35 52 29 27
†
Electronic supplementary information (ESI) available: FT-IR spectra
of hybrid salt–cocrystal and 2,3-dichlorophenylacetic acid. CIF-file
including crystallographic data (excluding structure factors) of hybrid
salt–cocrystal (CCDC 818797) and 2,3-dichlorophenylacetic acid
(
compound AH) (see the Screening of conglomerate section and
Fig. 16). It belongs to a series of resolution agents, easy to obtain,
(CCDC 818798). See DOI: 10.1039/c1ce05484h
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CrystEngComm, 2012, 14, 103–111 | 103

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and cheap, that are being developed within the European project:
IntEnant.‡ An alternative process consists of synthesizing the
pure enantiomer of compound B from the pure enantiomer of
trans-1,2-diaminocyclohexane. The pure enantiomer of trans-
Table 1 Crystal data of the hybrid salt–cocrystal
2
+
Chemical formula
[C
6
H10–(NH
2
–CH
2
–C
6
H
5 2
) ] ,
ꢀ
2
2
[C
[C
6
H
H
3
Cl
Cl
2
–CH
–CH
2
–COO] ,
–COOH]
6
3
2
2
1
,2-diaminocyclohexane ((ꢁ) DACH) can be resolved by two
CSD number
Molecular weight/g mol
Crystal system
CCDC 818797
1114.54
Monoclinic
25.444(2)
8.0222(7)
13.4912(12)
106.581(1)
2640.2(4)
1.402
C2 (no. 5)
2, 0.5
0.481
10 636
5364
0.0202
4681
0.0657
0.1713
0.0739
0.1802
1.029
ꢀ
1
20
distinct methods: preferential crystallization or formation of
21
diastereomeric salt. These resolutions circumvent the asym-
ꢂ
a/A
metric synthesis of (+) or (ꢀ) DACH. Moreover, DACH being
b/Aꢂ
ꢂ
c/A
b/
Unit cell volume/A
2 2
simultaneously CO , O , hn and moisture sensitive, it is prefer-
ꢂ
20
ably stored as a salt (e.g. citrate monohydrate ).
ꢂ
3
ꢀ
3
Calculated density/g cm
Space group
No. of formula per unit cell, Z, Z
Absorption coefficient/m mm
No. of reflections measured
Results and discussion
0
ꢀ
1
Single crystal structural description
No. of independent reflections
R
The complete structure of the phase between B and AH was
determined by single crystal X-ray diffraction. Despite numerous
attempts on different single crystals, the R-factors remained
greater than 5% probably due to the poor crystal quality (Fig. 1).
Nevertheless, the reliability of the results is high enough for an
error free determination of the stoichiometry. Crystallographic
data are summarized in Table 1.
int
No. of reflections with I > 2sI
Final R value (I > 2sI)
Final wR value (I > 2sI)
Final R value (all data)
Final wR value (all data)
Goodness on fit
1
2
1
2
The asymmetric unit is composed of one molecule of acid
ꢀ
(
AH), one molecule of deprotonated acid (A ) and one half
2
+
molecule of base H
2
B
(Fig. 2). Therefore, the 2-fold axis
2+
regenerates a building unit (Fig. 3) composed of a single H
ꢀ
2
B
and two pairs of AH and A that are tightly connected through
strong ionic interactions (Table 2).
The oxygen atoms, O(1A) and O(2A), from the carboxylate
ꢀ
function of A establish strong ionic bonds with the two
hydrogen atoms of the protonated amine moiety, N(1B)H2.
Molecule AH is involved in a second ionic interaction through
the hydroxyl group, O(2)H, of the carboxylic moiety with the
ꢀ
oxygen atom O(2A) of A .
ꢀ
For molecule A , the carbon–oxygen bond lengths are similar
whereas for molecule AH these lengths exhibit an unambiguous
difference (Table 3). Furthermore, the IRFT spectrum confirms
the presence of protonated and deprotonated carboxylic
Fig. 2 Asymmetric unit with ellipsoidal contribution at room temper-
ature (50% of probability). Molecule of the dibase is depicted in grey and
white (to illustrate the symmetry generated part), the molecule of
deprotonated acid is presented in purple and the full protonated acid is
featured in yellow. Symmetry used to generate the equivalent atom: *
(
ꢀx, y, 2 ꢀ z).
Fig. 1 SEM picture of a single crystal of a hybrid salt–cocrystal obtained
by smooth evaporation in methanol. Defects at the extremities can be
observed on many single crystals.
2+
Fig. 3 The building unit formed by one molecule of H
2
B
(grey), two
ꢀ
molecules of A (purple) and two molecules of AH (yellow). The ionic
bonds are depicted in dashed green lines or pink dashed lines regarding
molecules involved.
‡
www.intenant.com
1
04 | CrystEngComm, 2012, 14, 103–111
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Table 2 Ionic interactions
The comparison between the experimental and the calculated
24
morphologies by using the geometrical BFDH method clearly
shows that the main growth axis is [010] (Fig. 6). The fibrous
aspect corresponds well to the rows spreading along b (Fig. 7).
In order to see if AH exhibits special structural features, its
crystal structure was also investigated. The crystallographic data
and details of the resolution are summarized in Table 4.
ꢀ
2+
Molecule A to molecule H
A/H–D
2
B
a
O(2A)/H(1B2)–N(1B)
1.81
O(1A) /H(1B1)–N(1B)
1.91
ꢂ
d(H/A)/A
ꢂ
ꢂ
(
<
D/A)/A
DHA/
2.708(3)
172.1
Molecule A to molecule AH
2.738(3)
152.6
ꢀ
A/H–D O(2A)/H(2)–O(2)
ꢂ
The asymmetric unit (Fig. 8) is composed of a single molecule
of 2,3-dichlorophenylacetic acid. The molecules are tightly linked
by the usual centrosymmetric hydrogen bonds between their
d(H/A)/A
1.81
2.568(4)
153.9
ꢂ
(
D/A)/A
ꢂ
<
DHA/
a
ꢂ
Symmetry used to generate equivalent atoms: (1 ꢀ x, y, ꢀz).
acidic moieties O(2)/O(1), d ¼ 2.67(1) A (Fig. 9). During the
last steps of the structure refinement, high electronic density was
ꢂ
located at almost 1 A to the oxygen atom O(2); therefore it was
Table 3 Bond lengths within the carboxylic/carboxylate moieties
attributed to the hydrogen atom of the carboxylic moiety.
ꢀ
Molecule AH
Molecule A
ꢂ
ꢂ
C(8)–O(1)
C(8)–O(2)
1.195(5) A
C(8A)–O(1A)
C(8A)–O(2A)
1.233(4) A
ꢂ
1.289(6) A
ꢂ
1.255(4) A
moieties. Indeed, the representative vibrational band of the C]
ꢀ1
O at 1750–1700 cm is split, with equal intensity, into two bands,
ꢀ1
ꢀ1
one at 1700 cm and the other at 1630 cm . This latter can be
attributed to the carboxylate moiety.
According to these results, a proton transfer occurs between
ꢀ
2+
2
the two acids A and the base H B , whereas no proton
exchange occurs within the other acid molecules AH. Therefore,
the title compound is at the same time a salt because of the
proton transfer and a cocrystal because the carboxylic moiety is
Fig. 5 Projection along the b axis, (200) layers are stacked along the
a axis with d200 thickness and (003) layers are stacked along the c axis.
The symmetry elements are depicted in black.
22,23
not altered and remains neutral.
The building units are aligned along the b direction and thus
formed rows in this direction (Fig. 4). Every building unit
interacts with equivalent elementary blocks from adjacent rows
along the c axis. These interactions are established between
ꢀ
aromatic rings of molecules AH from one row to molecules A of
adjacent rows; the distance between the centroids of these phenyl
ꢂ
groups is circa 3.6 A.
Therefore, the building units are stacked through p–p inter-
actions and give rise to slices parallel to the (bc) plane with d200
thickness. Moreover, two types of subslices exist along the c axis:
ꢂ
the first composed of molecules AH with d003 (¼4.31 A) thickness
2
+
ꢀ
and the second containing chiral ions: H B and 2A with 2d
2
003
ꢂ
(
¼8.62 A) thickness (Fig. 5).
Fig. 6 Comparison between the experimental and the calculated
morphologies.
Fig. 4 Representation of the building unit stacking. The p–p interac-
tions are represented in dashed blue lines. The 2-fold axes along the b axis
are represented in black.
Fig. 7 SEM picture of a single crystal of a hybrid salt–cocrystal. A
fibrous aspect can be observed on the single crystals.
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Table 4 Crystallographic data of 2,3-dichlorophenylacetic acid
Chemical formula
CSD number
6 3 2 2
[C H Cl –CH –COOH]
CCDC 818798
205.03
Monoclinic
4.8955(5)
12.3245(12)
14.5030(14)
94.270(2)
872.6(15)
1.561
ꢀ
1
Molecular weight/g mol
Crystal system
ꢂ
a/A
ꢂ
b/A
ꢂ
c/A
b/
Unit cell volume/A
ꢂ
ꢂ
3
ꢀ
3
Calculated density/g cm
Space group
No. of formula per unit cell, Z, Z
Absorption coefficient/m mm
No. of reflections measured
P2
4, 1
1
/c (no. 14)
0
Fig. 10 Projection along the a axis. Between the pseudo-chains the
cohesion is ensured by van der Waals interactions. The symmetry
elements are depicted in black.
ꢀ
1
0.695
6796
1774
0.0186
1523
0.0477
0.1307
0.0542
0.1362
1.058
No. of independent reflections
R
int
Preferential crystallization (AS3PC±
No. of reflections with I > 2sI
Final R value (I > 2sI)
Final wR value (I > 2sI)
Final R value (all data)
Final wR value (all data)
Goodness on fit
1
The main data of four consecutive batches in methanol are
summarized in Table 5. The productivity is defined as the mass of
pure enantiomer harvested per hour and per litre of solvent. This
preferential crystallization exhibits a good reproducibility and
a mean optical purity of ꢃ87% for the crude product obtained
without washing or recrystallization. Moreover, the final enan-
tiomeric excess of the mother liquors (e.e.final) appeared repro-
ducibly greater than 20%.
2
1
2
The main data of three consecutive batches in THF are
summarized in Table 6. Compared with methanol, the produc-
tivity and the optical purity are similar; however e.e.final is halved.
25
Ideally, Meyerhoffer’s rule gives amol ¼ Smol(ꢁ)/Smol(+) ¼ 2
for covalent compounds, and amol ¼ O2 for (1–1) stoichiometric
salts. For this hybrid salt–cocrystal, even if the concentration in
THF is circa twice as that in methanol, the preferential crystal-
lization performances remained roughly the same in both
Fig. 8 Asymmetric unit with thermal ellipsoid representation (50%
probability) and with atom labels.
a
Table 5 Principal data of batches carried out in methanol
Pure
Raw
mass/g purity (%) mass/g
Optical
enantiomer e.e.final
(%)
Batch
Duration
1
2
3
4.77
5.49
5.31
5.20
5.19
86
ꢀ83
90
4.10
4.56
4.78
4.58
4.51
52.80
ꢀ20.20 55 min
22.80 45 min
ꢀ20.64 50 min
20.73 55 min
21.10 51.25 min
Fig. 9 Centrosymmetric dimers interacting through p–p stacking along
the a axis. These interactions are represented in dashed pink lines. The
hydrogen bonds are represented in dashed blue lines.
4
Average
ꢀ88
87
Productivity/
ꢀ1
ꢀ
1
g L
h
However, the bond lengths observed within the carboxylic
moiety of the 2,3-dichlorophenyl acetic acid are similar, C–O(1)
ꢂ ꢂ
.231(3)A and C–O(2) 1.267(3)A. Therefore the proton of the
1
a
Table 6 Principal data of batches carried out in dry THF
carboxylic moiety probably exhibits a disordered behaviour.
These bonds give rise to centrosymmetric dimers that is
a common feature when protonated carboxylic functions are
involved. The dimers are interconnected by p-stacking spreading
along the [100] direction (Fig. 9 and 10).
Pure
Raw
mass/g purity (%) mass/g
Optical
enantiomer e.e.final
(%)
Batch
Duration
1
2
6.16
6.80
6.79
6.58
84
ꢀ81
89
5.17
5.51
6.04
5.57
ꢀ8.42 70 min
ꢂ
Two consecutive aromatic rings are at a distance of 3.7 A from
9.55 70 min
ꢀ11.53 55 min
9.83 65 min
carbon atoms C(4)–C(3) to carbon atoms C(6)–C(7) from the
adjacent ring, respectively. These interactions lead to pseudo-
chains, along the a axis. The cohesion between these pseudo-
chains is ensured by van der Waals interactions.
3
Average
84.7
Productivity/
ꢀ
51.42
1
ꢀ1
g L
h
a
The values of the optical purity correspond to the enantiomeric excess
of the harvested solid without further purification. e.e.final stands for the
enantiomeric excess in the final mother liquor.
The crystal structure of the 2,3-dichlorophenylacetic acid is
thus totally different with regard to the AH subslice of the phase
between B and AH.
1
06 | CrystEngComm, 2012, 14, 103–111
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solvents. These results come from the molar a ratio which is more
favourable in methanol (amol ¼ 1.20, Table 7) than in dry THF
(
amol ¼ 1.52, Table 8). This is consistent with the ability of
methanol to be a better solvent for ionic species than pure THF.
Furthermore, the metastable zone width (MSZW assessed by b ¼
S(ꢁ) at T
B
/S(ꢁ) at T ) is much wider in methanol (b ¼ 1.55) than
F
in dry THF (b ¼ 1.23) confirming the important role of the
solvent in the performances of preferential crystallization.
Fig. 11 and 12 illustrate the projection of the solution point
trajectory during an entrainment (AS3PC mode) in methanol
and THF, respectively. Based on experimental results, it seems
that the stereoselective crystallizations persist up to F points
which means up to circa 23% in methanol and circa 10% in THF.
These F points are located on the tie-lines which connect the
antipode hꢀi to the racemic liquid at T
F
. They correspond to the
boundaries between the three phase domain: h+i, hꢀi and
racemic solution and the biphasic domain: hꢀi and saturated
solution.
Fig. 11 Projection of the solution point trajectory (red line) during
entrainment in methanol. The initial and final isothermal sections of the
ternary system (+)-(ꢀ)-MeOH are drawn in black and in blue,
respectively.
Prior to testing PC, the crystal structure features raised some
concerns about the possibility to keep on with stereoselective
crystallization while the two antipodes are supersaturated.
Considering the (001) orientation and assuming that AH could
be the protruding units in solution, the non-chiral AH layers
might induce a loss of transmission of chirality from underneath
2+
ꢀ
(
H B –A layers) depending on the growing mode of the
2
2
crystal (Fig. 13 and 14). This alternation of subslices forms
a hybrid salt–cocrystal. This dual character has, even more
surprisingly, been observed in the crystal structure of a (1–1)
0
26
phase with Z ¼ 3/2 containing phthalazine and fumaric acid.
One possible hypothesis consistent with all the results is that
this crystal growth does not proceed by 2D nucleation on the
27
(
001) surface but by assemblage of chiral building units
Fig. 14).
(
In this case, a full pre-assemblage in the vicinity of the growing
surfaces might prevail and therefore allow the high efficiency in
chiral discrimination in the solid state. That is to say, 2AH and
2+
ꢀ
2
A and H
2
B
could be linked (building unit) prior to docking
onto the growing surface. Thus, the necessary transmission of
Table 7 Solubilities in MeOH of conglomerate
Solubilities in methanol
Fig. 12 Projection of the solution point trajectory (red line) during the
entrainment in dry THF. The initial and final isothermal sections of the
ternary system (+)-(ꢀ)-THF are drawn in black and in blue, respectively.
ꢂ
Temperature/ C
Solubilities (ꢁ) (% mass)
25
7.5
6.3
0.23
0.19
1.20
30
8.9
7.4
0.28
0.23
1.22
40
11.6
9.8
0.37
0.31
1.19
Solubilities (ꢀ) (% mass)
2
2
Solubilities (ꢁ) (molar fraction) ꢄ 10
Solubilities (ꢀ) (molar fraction) ꢄ 10
chirality throughout the crystal growth could be kept without
any epitaxy of the antipode. The fibrous aspect along the b axis of
single crystals together with large defects at the tips of the crystals
obtained in methanol under smooth conditions seems consistent
with this hypothesis. Another hypothesis could also involve an
extensive reconstruction of this surface.
a
mol
Table 8 Solubilities in THF of conglomerate
Solubilities in THF
ꢂ
Temperature/ C
Solubilities (ꢁ) (% mass)
30
22.5
15.8
1.84
1.2
1.53
35
25
17.9
2.11
1.39
1.52
40
27.7
20.2
2.42
1.61
1.50
Experimental section
Solubilities (ꢀ) (% mass)
2
2
Analytical techniques
Solubilities (ꢁ) (molar fraction) ꢄ 10
Solubilities (ꢀ) (molar fraction) ꢄ 10
NMR spectra were recorded on a Bruker Advance-300 instru-
1 13
ment (300 MHz for H NMR and 75 MHz for C NMR) using
a
mol
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Fig. 13 Growth by two-dimensional nucleation mode. Alternate achiral subslices of molecule AH thickness d003 and chiral subslices of thickness 2d003
ꢀ
2+
B
of ions: H
2
and A .
Fig. 14 Illustration of the crystal growth by assemblage of solvated chiral building units.
CDCl3 or DMSO-d6 as solvent; d values are quoted in ppm
downfield from TMS using the residual proton signal of the
solvent as reference.
A solution of benzaldehyde (2.05 eq., 75.02 g, 707 mmol) in
methanol (400 mL) was added rapidly dropwise to a solution of
trans-1,2-diaminocyclohexane ((ꢁ) DACH) (39.38 g, 345 mmol)
in methanol (1 L) at room temperature. The reaction mixture was
X-Ray powder diffraction measurements were carried out on
a SIEMENS D5000 Matic diffractometer (Bruker analytical X-
ray Systems, D-76187 Karlsruhe, Germany) with a Bragg
Brentano geometry, in theta/2-theta reflection mode. The
instrument is equipped with a copper anticathode (40 kV, 40 mA,
stirred for 6 hours at room temperature and then cooled down to
ꢂ
0 C, followed by a slow addition of NaBH
4
(1.5 eq., 19.5 g, 515
mmol). After stirring the reaction mixture overnight at ambient
temperature, the solvent was removed under vacuum. After
addition of dichloromethane, the organic layer (300 mL) was
ꢂ
Ka1 radiation: 1.540 A, K radiation: 1.544 A) and a scintilla-
ꢂ
a2
tion detector. The diffraction patterns were collected by steps of
ꢂ
washed with water (2 ꢄ 200 mL) and dried (MgSO ).
4
ꢂ
0
.04 (in 2-theta) over the angular range 3–30 , with a counting
Dichloromethane was evaporated and the pure harvested
product was a yellow oil (88.2 g, 299 mmol). The total yield was
time of 4 s per step.
Polarimetric measurements were performed with a Perkin-
ꢂ
87%. dH (300 MHz, CDCl
3
), 1.10 (2H, t, J ¼ 10.56 Hz), 1.25 (2H,
Elmerꢀ 341 (l ¼ 436 nm, T ¼ 25 C, l ¼ 10 cm).
d, J ¼ 7.02 Hz), 1.74 (2H, d, J ¼ 7.02 Hz), 2.17 (2H, d, J ¼ 10.56
Hz), 2.30 (2H, br s), 3.68 (2H, d, J ¼ 13.2 Hz), 3.92 (2H, d, J ¼
Scanning electron microscopy (SEM) pictures were obtained
with a JEOL JCM-5000 NeoScope instrument (secondary scat-
tering electron) at an accelerated voltage of 15 kV. Samples were
stuck on an SEM stub with gloss carbon and coated with gold to
reduce electric charges induced during analysis with a NeoCoater
MP-19020NCTR.
3
13.2 Hz), 7.23–7.28 (10H, m). dC (75 MHz, CDCl ) 25.1, 31.5,
50.8, 60.9, 127.0, 128.2, 128.5, 140.8.
The enantiomeric product was synthesized from the starting
chiral material (+ or –) DACH citrate monohydrate obtained
from a preferential crystallization previously carried out in the
20
Infrared spectra were measured on a Bruker Alpha-P FT-IR
instrument in the ATR geometry with a diamond ATR unit.
laboratory.
Syntheses
All reagents and solvents were purchased from Acros Organics
and were used without further purification.
0
trans-N,N -Dibenzyldiaminocyclohexane (compound B) was
2
8
0
trans-N,N -dibenzyl-
prepared according to Jones and Mahon, which was applied
with modifications (Fig. 15).
Fig.
15 Reaction
of
formation
of
diaminocyclohexane.
1
08 | CrystEngComm, 2012, 14, 103–111
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A suspension of K CO (2.5 eq., 532 mg, 3.85 mmol) and
2
3
DACH citrate monohydrate (500 mg, 1.54 mmol) was prepared
in methanol (20 mL) then a solution of benzaldehyde (2.11 eq.,
3
44 mg, 3.25 mmol) in methanol was added dropwise. After
stirring the reaction mixture overnight at ambient temperature,
the solvent was removed under vacuum. After addition of
dichloromethane (15 mL), the organic layer was washed with
water (2 ꢄ 5 mL) and dried (MgSO
4
). Dichloromethane was
evaporated under vacuum. The crude product was dissolved in
ꢂ
methanol (20 mL) then the solution was cooled at 0 C, and
Fig. 17 X-Ray powder patterns of the racemic salt (bottom), the
enantiomer salt (middle) and the calculated salt (top) from the single
crystal diffraction data.
NaBH (1.6 eq., 93 mg, 2.46 mmol) was added slowly. After
4
stirring the reaction mixture overnight at ambient temperature,
the solvent was removed under vacuum. Dichloromethane
The AS3PC process is briefly recalled below (Fig. 19).
A small amount of pure (+) enantiomer was added to
a methanol saturated solution of racemic mixture at the initial
(
15 mL) was added and then the organic layer was washed with
). Dichloromethane was
water (2 ꢄ 5 mL) and dried (MgSO
4
evaporated and the pure got back was a yellow oil (372 mg, 1.26
mmol). The results of NMR analyses were the same as that of the
racemic oil. The final yield was 82%.
temperature, T
remained at circa 10%. A cooling ramp was applied to the system
with a controlled rate, down to T in order to induce a dual
B
, so that the initial enantiomeric excess (e.e.)
F
enantioselective effect: secondary nucleation and crystalline
growth of the (+) enantiomer. The crystallization of this enan-
tiomer was maintained beyond the thermodynamic limit (i.e. e.e.
¼ 0) due to the entrainment effect. Therefore the mother liquor
became supersaturated in the counter-enantiomer (i.e. no spon-
taneous nucleation of the (ꢀ) enantiomer occurred for a given
Screening of conglomerate
A screening of salts was carried out in order to spot stable
conglomerates with compound B. All salts were prepared by
using the same protocol; only the nature of the acid introduced
varied. This screening allows access to all kinds of stoichiome-
29
tries that lead to the possible conglomerate.
period of time). This slurry had to be filtered at T before the
F
A methanol solution of pure acid was added slowly to
a methanol solution of compound B at room temperature.
Solutions were prepared so that the ratio of acidic/basic func-
tions was respected. After a few minutes, the spontaneous crys-
tallization of salt occurred at room temperature. The resulting
suspension was filtered on the glass filter (porosity 4). The
recovered salts were analyzed by SHG and in the case of positive
results, pure enantiomeric salts were also crystallized. The X-ray
powder patterns of these two salts were compared to confirm, or
not, the existence of a conglomerate forming system.
primary nucleation of the (ꢀ) enantiomer began. At this time, the
system was a solution enriched in (ꢀ) enantiomer, but depleted in
matter, so a compensation in the racemic mixture and solvent
was made, and this prior to each new cycle. By means of
continuous recycling of the mother liquor, every odd operation
gave the (:) enantiomer, and every even operation gave the (+)
enantiomer.
The filtration cakes were neither washed nor recrystallized.
The enantiomeric purities of the crops were determined by
polarimetry. For each batch, the final composition of the mother
liquor was measured (mass concentration and e.e.final ¼ enan-
tiomeric excess of the mother liquor at the end of a run).
In our case, the conglomerate exhibits good solubility in
methanol (Table 7) and in THF (Table 8), so that these solvents
were chosen for the preferential crystallization by the AS3PC
method.
Only the 2,3-dichlorophenylacetic acid (Fig. 16) in methanol
gave rise to a conglomerate with compound B (Fig. 17).
As the main condition for preferential crystallization was
fulfilled, AS3PC was tested.
Resolution by preferential crystallization
The first entrainments were performed with 10.4 g of racemic
mixture in 100 mL of methanol and with 34 g in 100 mL of THF
and led to the main AS3PC parameters, listed in Table 9.
Preferential crystallizations using the Auto-Seeded variant
12
(
AS3PC) were performed in a flask equipped with a magnetic
stirrer. Temperature was accurately controlled by a cryo-ther-
mostat (Huber_polystat CC240). The course of the entrainment
was monitored by off-line polarimetric measurements of the
mother liquor (l ¼ 436 nm). The presence of very small particles
requires a filtration prior to measurement with disposable Gel-
manꢀ Acrodiscs media (0.45 mm). Simultaneously, the clear
mother liquor was sampled to determine its global composition
(
mass concentration) by refractometry (Fig. 18).
Fig. 18 Evolution of the refractive index of the solution versus the mass
Fig. 16 Structure of 2,3-dichlorophenylacetic acid.
concentration of the hybrid salt–cocrystal (in methanol).
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weighted agreement factors of R ¼ 0.0698, wR ¼ 0.1649 for
1
2
3
171 reflections with I > 2sI and R ¼ 0.1165, wR ¼ 0.1888 for
1
2
all data (see Table 1). Simulated morphology, calculated from
the structural data with the geometric method published by
24
Bravais, Friedel, Donnay and Harker (BFDH), was deter-
mined, thanks to the Material Studio molecular modelling
33
software.
For 2,3-dichlorophenylacetic acid, the final cycle of full-matrix
2
least-square refinement on F was based on 1774 observed
reflections and 110 variable parameters and converged with
unweighted and weighted agreement factors of R1 ¼ 0.0476,
wR ¼ 0.1334 for 1523 reflections with I > 2sI and R ¼ 0.0537,
2
1
wR ¼ 0.1334 for all data (see Table 3).
2
Conclusion
Fig. 19 Principle of the AS3PC. Two consecutive temperature cycles are
represented: the enantiomeric excess at T engenders a preferential
secondary nucleation and crystal growth during the cooling ramp. At T
B
2+
B )
An unexpected hybrid salt–cocrystal between the dibase (H
2
F
,
ꢀ
and four monoacids (2AH and 2A ) has been characterized. It
crystallizes as a stable conglomerate. The stoichiometry of this
compound emphasizes the importance of enlarging the ‘‘classic’’
stoichiometries when screening conglomerates.
the suspension is filtered and the crop obtained is pure enantiomer,
whereas the solution is enriched in the counter-enantiomer (solid parts
and liquid parts of the system are depicted in dark and in light colours,
respectively).
The resolutions in methanol and in THF reveal that the
entrainment effect, at its best, persists up to 22% e.e.final in the
counter-enantiomer for a global concentration of 13% in meth-
anol. Furthermore these results prove that the non-chiral
protonated acid subslices do not induce any loss in the chiral
selectivity of the self-assembling process (i.e. the stereoselective
crystallization). The morphology of crystals and the high
performance of AS3PC suggest that the crystal growth proceeds
During these first tests, the aD of the mother liquor was
measured by off-line polarimetry. The filtration time was deter-
mined according to the monitoring of the a
D
of the mother
liquor.
2+
Single crystal X-ray structural determination
by direct incorporation of building units composed of H B ,
2
ꢀ
2
A , 2AH or reconstruction of some surfaces of the crystal might
0
A suitable single crystal of the title compound, (trans-N,N -
occur.
dibenzyldiaminocyclohexane) (2,3-dichlorophenylacetic acid) ,
1
4
was obtained by slow evaporation of a saturated solution in
methanol at room temperature. A single crystal of 2,3-dichlor-
ophenylacetic acid was obtained by slow evaporation of a satu-
rated solution in dichloromethane at room temperature.
Acknowledgements
We are grateful for financial support to the European collabo-
rative project: ‘‘IntEnant’’ FP7-NMP2-SL-2008-214219.
The crystal structures were determined by single crystal
diffraction on a SMART APEX diffractometer (with MoKa1
ꢂ
radiation: l ¼ 0.71073 A). The structures were solved by direct
3
0
Notes and references
methods (SHEL-XS ). Anisotropic displacement parameters
3
1
were refined for all non-hydrogen atoms using SHEL-XL
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Chichester, England, New York, 1998.
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/ C
/ C
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ꢂ
F
ꢂ
ꢀ1
Cooling rate/ C min
ꢂ
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