Halogen-bonding interaction stabilizing cluster-type diastereomeric salt crystals

Article abstract of DOI:10.1021/cg9010967

O-Ethyl 4-chlorophenylphosphonothioic acid (1) was newly synthesized and applied as a chiral selector for the enantioseparation of racemic l-(4-halophenyl)ethylamines (halo = F, Cl, Br, I; 2a-d) through diastereomeric salt formation. The phosphonothioic acid 1 showed an excellent chirality-recognition ability for the fluorinated and iodinated amines 2a and 2d with the dramatic switch of the absolute configuration of the enantio-enriched isomers in the deposited salts from R for the amine 2a to S for the amine 2d. The X-ray crystallographic analyses of the four pairs of diastereomeric salts revealed that halogen-bonding interaction in the salt crystals plays a very important role for the switch.

Full text of DOI:10.1021/cg9010967

DOI: 10.1021/cg9010967
Halogen-Bonding Interaction Stabilizing Cluster-type Diastereomeric
Salt Crystals
2010, Vol. 10
685–690
Yuka Kobayashi,† Jin Maeda, Tetsuo Ando, and Kazuhiko Saigo*
Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo,
Hongo, Bunkyo-ku, Tokyo 113-8656, Japan. †Present address: Waseda Institute for Advanced Study,
Waseda University, Nishi-waseda, Shinjyuku-ku, Tokyo 169-8050, Japan
Received September 9, 2009; Revised Manuscript Received October 14, 2009
ABSTRACT: O-Ethyl 4-chlorophenylphosphonothioic acid (1) was newly synthesized and applied as a chiral selector for the
enantioseparation of racemic 1-(4-halophenyl)ethylamines (halo=F, Cl, Br, I; 2a-d) through diastereomeric salt formation.
The phosphonothioic acid 1 showed an excellent chirality-recognition ability for the fluorinated and iodinated amines 2a and 2d
with the dramatic switch of the absolute configuration of the enantio-enriched isomers in the deposited salts from R for the
amine 2a to S for the amine 2d. The X-ray crystallographic analyses of the four pairs of diastereomeric salts revealed that
halogen-bonding interaction in the salt crystals plays a very important role for the switch.
Introduction
a column-type crystal or a cluster-type crystal. Although
column-type crystals are commonly observed in both less-
and more-soluble diastereomeric salts of racemic amines with
enantiopure monocarboxylic acids and in those of racemic
monocarboxylic acids with enantiopure amines/amino alco-
hols, no cluster-type crystal has been reported for diastereo-
meric salts until our discovery.6a Clusters in the cluster-type
crystals are commonly composed of four amine molecules and
four acid molecules to form a globular hydrogen-bonding
network in the center of the clusters. The alkyl and aryl groups
of the amine and phosphonothioic acid molecules surround
the surface of the clusters to make them hydrophobic. As a
result, in the cluster-type crystals, clustersbindwitheach other
by relatively weak interactions such as van der Waals and CH/
π interactions, which would mainly determine the stability of
the crystals. On the basis of these results, we considered that
upon introducing a halogen atom on both of the phenyl
groups of racemic 1-phenylethylamine and the enantiopure
phosphonothioic acid, the more tight packing of clusters
would be realized by halogen-bonding interaction as well as
van der Waals and CH/π interactions. Herein, we report the
synthesis and application of enantiopure O-ethyl 4-chloro-
phenylphosphonothioic acid (1) and the role of halogen-
bonding interaction in the stabilization of the corresponding
diastereomeric salts.
In the middle of 1960s, Schmidt and his co-workers have
pointed out that short Cl Cl contact, the so-called chloro
3 3 3
effect, plays an important role in controlling the photodimeri-
zation reaction of trans-cinnamic acid derivatives.1 On the
basis of a statistical study on a database of crystals having
Cl Cl contact(s), Desiraju and Parthasarathy have pro-
3 3 3
posed that the short Cl Cl contact is originated from
3 3 3
specific attractive intermolecular force between the chlorine
atoms.2 In contrast, Price et al. have suggested by means of
theoretical calculations that short Cl Cl contact is caused
3 3 3
by anisotropic repulsion between the chlorine atoms, depend-
ing on the C-Cl Cl angle.3 Although the physical origin of
short Cl Cl contact is still controversy at present, it has
3 3 3
3 3 3
been generally accepted that short contact frequently exists
between halogen atoms and between a carbon-bonded halo-
gen atom and an electronegative atom in molecular crystals.
For such intermolecular interactions, the terms of “halogen-
bonding interaction” is introduced, which was named after
very popular terms of hydrogen-bonding interaction.4 Halo-
gen-bonding interaction has been attracting much attention in
many fields, especially in the crystal engineering of organic
and organometallic compounds; from the viewpoint of the
construction of molecular assemblies utilizing nonbonding
interactions, halogen-bonding interaction is doubtlessly one
of the major forces to control molecular arrangement and
packing in organic and organometallic crystals today.5
On the other hand, we have recently found that there are
two types of crystals, column-type and cluster-type crystals,
for the diastereomeric salts of racemic 1-phenylethylamine
derivatives with enantiopure O-ethyl phenylphosphonothioic
acid and its analogues.6 The column-type crystals are com-
posed of 21 columns with an infinite helical hydrogen-bonding
network, while the cluster-type crystals consist of clusters with
a finite globular hydrogen-bonding network. As far as we
examined by X-ray crystallography, one of a pair of the
diastereomeric salts (less- and more-soluble salts) was either
Experimental Section
General Procedure. NMR spectra were recorded on a Varian
Mercury 300 instrument. IR spectra were recorded on a Jasco FT/
IR-480 instrument. HPLC analyses were performed on a Daicel
Chiralcel column using a Jasco PU-2080i pump, a Jasco PU-2075
UV detector, and a Hitachi D-2500 Chromato-Integrator. Melting
points were measured using a Yamato Scientific MP-21.
Racemic amines 2 were synthesized according to the procedure
previously reported.7
*To whom correspondence should be addressed. E-mail: saigo@
chiral.t.u-tokyo.ac.jp.
r
2009 American Chemical Society
Published on Web 11/20/2009
pubs.acs.org/crystal

686 Crystal Growth & Design, Vol. 10, No. 2, 2010
Kobayashi et al.
Synthesis of Racemic O-Ethyl 4-Chlorophenylphosphonothioic
Acid (Racemic 1). To a solution of 1-bromo-4-chlorobenzene
(19.9 g, 104 mmol) in dry Et2O (150 mL) was added dropwise
1.6 M butyllithium in hexane (65.0 mL, 104 mmol) at -78 °C under
argon atmosphere, and the mixture was stirred at 0 °C for 40 min.
Commercially available diethoxyphosphonothioyl chloride
(12.6 mL, 80 mmol) in dry ether (50 mL) was then added dropwise
to the mixture at -78 °C. The reaction mixture was stirred at rt for
1.5 h and then cooled with an ice bath, and H2O (30 mL) was slowly
added to the mixture. After removal of the solvent under reduced
pressure, saturated ammonium chloride solution (120 mL) was
added to the residue, and the aqueous layer was extracted
with Et2O (3 ꢀ 100 mL). The combined extracts were dried over
anhydrous Na2SO4, filtered, and concentrated under reduced
pressure to give crude O,O0-diethyl 4-chlorophenylphosphono-
thioate (22.4 g).
(d, JH-H=7 Hz, 1H), 7.72 (dd, JH-H=12 Hz, 7 Hz, 1H), 8.34 (br,
3H); 31P NMR (121 MHz, DMSO-d6) δ 64.86.
To the diastereomeric salt thus obtained was added 1 M aqueous
KOH solution (100 mL), and the solution was extracted with Et2O (4 ꢀ
50 mL). The aqueous layer was acidified with 3 M aqueous HCl
solution (40 mL) and then extracted with Et2O (4 ꢀ 50 mL). The
combined extracts were dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure to afford enantiopure 1 (3.42 g,
14 mmol, 55% yield based on a half amount of racemic 1 used) as a
colorless oil. The enantiomeric excess (ee) of 1 thus obtained was
determined by a HPLC analysis after 1 was converted into the
corresponding S-methyl ester with trimethylsilyldiazomethane (Daicel
Chiralcel OD-H; eluent, hexane/2-propanol=98:2; flow rate, 1.0 mL/
min; t1 [(R)-isomer]=18 min, t2 [(S)-isomer]=22 min; ee, >99%).
[R]D21=þ7.7° (c5.3, MeOH); IR (neat) 2984, 1584, 1482, 1390,
1124, 1089, 1034, 961, 759 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.35
(t, JH-H=7 Hz, 3H), 4.20 (dq, JP-H=10 Hz, JH-H=7 Hz, 2H), 7.43
(m, 2H), 7.83 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 138.50, 133.58,
132.16, 132.00, 128.56, 128.35, 62.76, 16.07; 31P NMR (121 MHz,
CDCl3) δ 78.75.
1H NMR (300 MHz, CDCl3) δ 1.31 (t, JH-H=7 Hz, 6H), 4.11
(m, 4H), 7.36 (m, 2H), 7.84 (m, 2H); 31P NMR (121 MHz, CDCl3)
δ 85.12.
A solution of crude O,O0-diethyl 4-chlorophenylphosphonothio-
ate (22.4 g) thus obtained in a mixture of 8 M aqueous KOH
solution (160 mL) and EtOH (160 mL) was refluxed for 20 h. After
removal of most EtOH under reduced pressure, 12 M aqueous HCl
solution (120 mL) was slowly added to the mixture at 0 °C. The
resultant solution was extracted with CH2Cl2 (7 ꢀ 80 mL), and then
the combined organic layers were extracted with 1 M aqueous KOH
solution (3 ꢀ 100 mL). The combined aqueous solutions were
further acidified with 5 M aqueous HCl solution (120 mL) and
extracted with CH2Cl2 (4 ꢀ 80 mL). Then, the combined extracts
were washed with brine (100 mL), dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure to give crude
racemic O-ethyl 4-chlorophenylphosphonothioic acid (14.3 g).
A mixture of the crude O-ethyl 4-chlorophenylphosphonothioic
acid (14.3 g) and dicyclohexylamine (10.9 g, 60 mmol) in CHCl3
(65 mL) was refluxed to give a clear solution, and then the solution
was gradually cooled to rt to give chemically pure dicyclohexyl-
ammonium O-ethyl 4-chlorophenylphosphonothioate (20.4 g) as a
white solid. The second crop from chloroform/hexane (20 mL/
10 mL) and the third crop from chloroform/hexane (15 mL/
15 mL) were 2.33 and 0.31 g, respectively. The total yield was
23.04 g (55 mmol, 53% from 1-bromo-4-chlorobenzene used).
Mp 190.5-191.0 °C. IR (KBr) 2945, 2857, 1577, 1450, 1386,
1122, 1083, 1042, 928, 751, 646 cm-1; 1H NMR (300 MHz, CDCl3)
δ 1.13 (m, 6H), 1.21 (t, JH-H=7 Hz, 3H), 1.61 (m, 10H), 2.04 (d,
Anal. calcd for C8H10ClO2PS: C, 40.60; H, 4.26. Found: C, 40.57;
H, 4.21.
A General Procedure for the Enantioseparation of Racemic 1-(4-
Halophenyl)ethylamines (2) with (R)-1. A mixture of enantiopure 1
and racemic 2 (1 equiv) in Et2O or Et2O/hexane (see Table 1) was
stirred at rt for 4 h. The deposited salt was collected by filtration using
a membrane filter (T050A047A, ADVANTEC). The yield of the salt
was evaluated on the basis of a half amount of racemic 2. A portion of
the salt thus obtained was treated with small amounts of
1 M aqueous KOH solution and Et2O, and the ethereal layer was
concentrated under reduced pressure to give a sample for the deter-
mination of theee of 2 by a HPLC analysis (Daicel Crownpak CR(þ);
eluent, HClO4 aq. (pH 2) for 2a, 2b, HClO4 aq. (pH 2)/MeOH=(95/5)
for 2c and HClO4 aq. (pH 2)/MeOH=(98/15) for 2d).
Preparation of the Single Crystals of the (R)-1 2 Salts. The single
crystals of the (R)-1 2 salts were prepared by a vapor diffusion
method. A small vial containing a solution of the (R)-1 2 salt (15
3
3
3
mg), which was obtained from (R)-1 and individually prepared
enantiopure (R)- or (S)-2,7 in ethyl acetate (3 mL) was placed in a
loosely sealed vial containing hexane (3 mL) to gradually bring into
vapor-equilibrium.
X-ray Crystallographic Analyses of the Diastereopure (R)-1 2
3
Salts. X-ray data were collected on a Mac Science DIP2000 or
RIGAKU Mercury CCD system diffractometer using Mo X-ray.
The camera length, which is the distance between the sample and the
detector, was varied from 70 to 80 mm, depending on the sample.
Crystal structures were solved and refined using the SIR 928 or
SHELX979 program. Non-hydrogen atoms were refined anisotro-
pically, and hydrogen atoms were placed in calculated positions
refined using idealized geometries and assigned fixed isotropic
displacement parameters.
J
H-H=11 Hz, 4H), 2.96 (br, 2H), 3.72 (m, 1H), 4.02 (m, 1H), 7.34
(m, 2H), 7.85 (m, 2H); 31P NMR (121 MHz, CDCl3) δ 65.57.
The salt (20.7 g, 48 mmol) was decomposed with 1 M aqueous
KOH solution (200 mL), and the aqueous solution was extracted
with CH2Cl2 (3 ꢀ 100 mL). The combined organic layers were
washed with 1 M aqueous KOH solution (100 mL). To the
combined alkaline solutions was added 3 M aqueous HCl solution
(150 mL), and the mixture was extracted with CH2Cl2 (4 ꢀ 80 mL).
The combined extracts were dried over anhydrous Na2SO4, filtered,
and concentrated under reduced pressure to give chemically pure
racemic 1 (11.8 g, 47 mmol, 98%) as a brown oil.
Results and Discussion
Synthesis and Absolute Configuration of Enantiopure
O-Ethyl 4-Chlorophenylphosphonothioic Acid (1). Racemic
O-ethyl 4-chlorophenylphosphonothioic acid (racemic 1)
could be easily prepared from commercially available 1-
bromo-4-chlorobenzene in 52% total yield through lithia-
tion, condensation, hydrolysis, ammonium salt formation,
and decomposition of the salt, as shown in Scheme 1. In
order to enantioseparate racemic 1, we tried to use enantio-
pure 1-phenylethylamine (PEA), erythro-2-amino-1,2-di-
phenylethanol (ADPE), and cis-1-amino-2-indanol (AI).
Among them, AI gave a crystalline salt with 1 upon stirring
the mixture in ether, whereas PEA and ADPE gave no crystal
under similar conditions; 1 with >99% ee was obtained in
55% yield (based on a half amount of racemic 1 used) by
applying (1S,2R)-AI as a resolving agent.
IR (neat) 2983, 1584, 1482, 1390, 1089, 1032, 959, 759 cm-1; 1H
NMR (300 MHz, CDCl3) δ 1.33 (t, JH-H=7 Hz, 3H), 4.17 (dq,
J
P-H=9 Hz, JH-H=7 Hz, 2H), 6.14 (br, 1H), 7.44 (m, 2H), 7.84
(m, 2H); 31P NMR (121 MHz, CDCl3) δ 78.87.
Synthesis of Enantiopure 1. To a solution of racemic 1 (12.5 g,
53 mmol) in AcOEt (300 mL) was added (1S,2R)-(-)-1-amino-2-
indanol (AI; 5.49 g, 37 mmol, 0.7 equiv), and the mixture was
refluxed for 2 h, gradually cooled down to -10 °C with stirring, and
then stirred at the temperature for 3 h. The deposited salt was
collected by filtration using a membrane filter (T050A047A, AD-
VANTEC). The salt was recrystallized three times from AcOEt (200
mL each) to afford diastereopure (R)-1 (1S,2R)-AI (5.81 g,
3
15 mmol, 57% yield based on a half amount of racemic 1 used).
Mp 189.5-190.0 °C. IR (KBr) 3536, 3119, 2970, 2900, 2630,
1526, 1479, 1385, 1123, 1074, 1036, 941, 821, 752, 643, 627 cm-1
;
1H NMR (300 MHz, DMSO-d6) δ 1.05 (t, JH-H = 7 Hz, 3H),
2.93 (dd, JH-H=16 Hz, 4 Hz, 1H), 3.11 (dd, JH-H=16 Hz, 6 Hz,
1H), 3.68 (m, 2H), 4.58 (m, 2H), 5.91 (br, 1H), 7.30 (m, 6H), 7.52
The elution order of the enantiomers of 1-(4-fluorophe-
nyl)ethylamine (2a) in a chiral HPLC analysis has been

Article
Crystal Growth & Design, Vol. 10, No. 2, 2010 687
correlated with their absolute configurations, as we pre-
viously reported.7 On the basis of the correlation, the abso-
lute configuration of 2a, preferentially incorporated in the
less-soluble diastereomeric salt, was deduced to be R. On the
other hand, the X-ray crystallographic analysis of the less-
soluble salt crystal revealed that the absolute configuration
of enantiopure 1 used was R (Figure 1).
Chirality-Recognition Ability of O-Ethyl (R)-4-Chlorophe-
nylphosphonothioic acid ((R)-1) for Racemic 1-(4-Halophe-
nyl)ethylamines (2). The results of the enantioseparation of
racemic 1-(4-halophenyl)ethylamines (halo = F, Cl, Br, I;
2a-d) with O-ethyl (R)-4-chlorophenylphosphonothioic
acid ((R)-1) are summarized in Table 1. The phospho-
nothioic acid (R)-1 showed an excellent chirality-recognition
ability for 2a and 2d.
meric salt crystals (less- and more-soluble crystals); with
increasing the difference, the ee value of a target acid/amine
in a salt deposited should become larger, while the ee value
should gradually reach to zero with decreasing the differ-
ence. From such a point of view, the present results are of
interest; although the amines 2b and 2c were not enriched
(12% ee and 0% ee, respectively), the amines 2a and 2d were
highly enriched (92% ee and 88% ee, respectively) with the
dramatic switch of the absolute configuration of the enantio-
enriched isomers from R for the amine 2a to S for the amine
2d. These results suggest that the (R)-1 (R)-2a crystal is
3
much less soluble than the (R)-1 (S)-2a crystal, while the
(R)-1 (R)-2d crystal is much more soluble than the (R)-
3
3
1 (S)-2d crystal, and that the solubilities of the (R)-1 (R)-
3
3
2b and (R)-1 (R)-2c crystals are comparable to those of the
3
The extent of chirality recognition by a selector via the
diastereomeric salt formation is known to strongly depend
on the difference in solubility between a pair of diastereo-
(R)-1 (S)-2b and (R)-1 (S)-2c crystals, respectively.
3
3
Factors for the Stabilization of the (R)-1 (R)-2 and (R)-
3
1 (S)-2 Crystals. In order to understand the difference in
3
stability between the (R)-1 2 crystals, we carried out X-ray
3
Scheme 1. Synthesis of Racemic 1
Table 1. Enantioseparation of Racemic 2 by (R)-1
solvent for crystallizationb
Et2O/hexane (mL/mL)
amine
yield (%)
ee (%)a
2a
2b
2c
2d
64
87
98
58
92 (R)
12 (R)
0
3.2/26.0
1.6/0
1.6/0
88 (S)
3.2/1.6
a The sign in the parentheses is the absolute configuration of the
amine. b Normalized for a 1-mmol scale.
Figure 1. Crystal structures of (R)-1 (R)-2 salts. Dotted lines indicate hydrogen bonds.
3

688 Crystal Growth & Design, Vol. 10, No. 2, 2010
Kobayashi et al.
Table 2. Crystal Data for (R)-1 (R)-2 and (R)-1 (S)-2 Salt Crystals
3
3
(Rp)-1 (R)-2b
(Rp)-1 (R)-2a
3
(Rp)-1 (R)-2c
3
(Rp)-1 (R)-2d
3
3
formula
C16H20ClFNO2PS
375.82
monoclinic
C2
22.30(3)
7.399(10)
11.91(2)
90
108.738(6)
90
1860.1(44)
4
C16H20Cl2NO2PS
392.28
monoclinic
C2
22.328(2)
7.4350(5)
13.167(2)
90
112.634(3)
90
2017.5(3)
4
C16H20ClBrNO2PS
436.73
monoclinic
C2
26.89(2)
7.463(4)
21.551(12)
90
115.103(2)
90
3917.0(36)
4
C16H20ClINO2PS
483.73
orthorhombic
P212121
7.633(3)
11.733(5)
21.156(9)
90
formula weight
crystal system
space group
˚
a/A
˚
b/A
˚
c/A
R/°
β/°
γ/°
90
90
3
˚
V/A
1894.8(14)
4
Z
crystal habit
density/g cm-3
temperature/K
reflns collected
reflns used in refinement
GOF
needle
1.342
103
4788
3599
1.309
0.0650
0.0800
needle
1.291
273
1965
1180
1.028
0.0500
0.0570
needle
1.481
103
17119
14721
0.892
0.0380
0.0520
needle
1.696
103
4998
4937
1.118
0.0301
0.0762
R
Rw
(Rp)-1 (S)-2a
3
(Rp)-1 (S)-2b
3
(Rp)-1 (S)-2c
3
(Rp)-1 (S)-2d
3
formula
C16H20ClFNO2PS
375.82
monoclinic
P21
13.209(5)
21.994(8)
13.600(5)
90
106.645(2)
90
3785.5(23)
8
prism
1.319
103
32915
23629
0.857
0.0490
0.0610
C16H20Cl2NO2PS
392.28
tetragonal
P41212
13.4500(4)
13.4500(4)
45.1410(13)
90
90
90
8166.1(4)
16
prism
1.224
296
3635
3304
1.055
0.0460
0.0600
C16H20ClBrNO2PS
436.73
tetragonal
P41212
13.4890(5)
13.4890(5)
45.241(2)
90
90
90
8231.7(4)
16
prism
1.362
103
3644
2681
1.046
0.0510
0.0590
C16H20ClINO2PS
483.73
triclinic
P1
12.788(3)
13.069(3)
25.533(6)
80.684(9)
75.203(8)
80.957(9)
4041.0(17)
8
prism
1.590
103
27641
24930
1.309
0.0538
0.0841
formula weight
crystal system
space group
˚
a/A
˚
b/A
˚
c/A
R/°
β/°
γ/°
3
˚
V/A
Z
crystal habit
density/g cm-3
temperature/K
reflns collected
reflns used in refinement
GOF
R
Rw
crystallographic analyses for all of the (R)-1 2 salts. The
crystal data are listed in Table 2.
In sharp contrast, in the (R)-1 (S)-2b-d crystals, distinct
halogen-bonding interaction between clusters is observed,
3
3
As shown in Figures 1 and 2, the (R)-1 (R)-2 crystals are
3
although there is no halogen-bonding interaction in the (R)-
1 (S)-2a crystal (Figure 2).
commonly column-type, while all of the (R)-1 (S)-2 crystals
3
3
Intercluster Cl Cl (acid-amine) contact is observed in
are cluster-type. The distances of hydrogen bonds in the
columnar hydrogen-bonding networks of the (R)-1 (R)-2
3 3 3
˚
the (R)-1 (S)-2b crystal; the distance (3.45 A) is 0.07 A
˚
3
3
shorter than the sum of van der Waals radii. In a similar
manner, in the (R)-1 (S)-2c crystal, an intercluster Cl Br
(acid-amine) contact of 3.46 A exists, which is 0.15 A
shorter than the sum of the van der Waals radii. Moreover,
crystals are similar to each other (Table 3), suggesting that
the hydrogen-bonding interactions in the (R)-1 (R)-2 crys-
3
3 3 3
3
˚
˚
tals would similarly contribute to the stabilization of the
crystals. Moreover, the case of the (R)-1 (S)-2 crystals would
3
in the case of the (R)-1 (S)-2d crystal, two kinds of halogen-
bonding interactions are observed, intercluster Cl Cl
3
be the same.
Although a column largely penetrates to the neighboring
3 3 3
(acid-acid) and I I (amine-amine) contacts; the mode
of the halogen-bonding interactions is different from those in
the (R)-1 (S)-2b,c crystals, probably due to the difference in
3 3 3
column in the case of the (R)-1 (R)-2d crystal, most likely in
3
order to avoid the formation of large voids, the molecular
arrangements in the (R)-1 (R)-2 crystals resemble each
3
3
packing mode of clusters between the (R)-1 (S)-2d crystal
3
other, indicative of the similar contribution of van der Waals
and CH/π interactions to the stabilization of the crystals.
Moreover, there is no remarkable short contact, less than the
sum of the van der Waals radii, between the halogen atoms.
As a result of the similar contribution of hydrogen-bonding,
and the (R)-1 (S)-2b,c crystals. The Cl Cl and I
I
3
3 3 3
3 3 3
˚
˚
distances (3.28 and 3.90 A) are 0.24 and 0.38 A shorter than
the sums of the van der Waals radii, respectively. These
crystal structures strongly indicate that the stability of the
(R)-1 (S)-2 crystals is highly dependent on the intercluster
3
van der Waals, and CH/π interactions, the (R)-1 (R)-2
halogen-bonding interaction, because the contributions of
hydrogen-bonding interactions in the crystals are similar to
each other as mentioned above; the stability should be in an
order of the (R)-1 (S)-2a crystal < the (R)-1 (S)-2b crystal
3
crystals might have similar stability to each other. This
estimation is strongly supported by the fact that the (R)-
1 (R)-2 crystals have almost the same melting point as shown
3
3
3
< the (R)-1 (S)-2c crystal < the (R)-1 (S)-2d crystal. This
3
in Figure 3.
3

Article
Crystal Growth & Design, Vol. 10, No. 2, 2010 689
Figure 2. Crystal structures of (R)-1 (S)-2 salts. Dotted lines indicate hydrogen bonds. Values are distances between neighboring halogen
atoms indicated by solid lines.
3
Table 3. Distances of Hydrogen Bonds in (R)-1 (R)-2 and (R)-1 (S)-2
3
3
Salt Crystals
ꢀ
ꢀ
˚
˚
O (A)
crystals
N
N
S (A)
3 3 3
3 3 3
(R)-1 (R)-2a
(R)-1 (S)-2a
2.774, 2.767
2.740, 2.763
3.301
3.332
3
3
(R)-1 (R)-2b
3
2.777,2.810
2.781, 2.825
3.295
3.260
(R)-1 (S)-2b
3
(R)-1 (R)-2c
(R)-1 (S)-2c
2.777, 2.742
2.713, 2.736
3.278
3.386
3
3
(R)-1 (R)-2d
3
2.761, 2.814
2.793, 2.793
3.286
3.313
(R)-1 (S)-2d
3
order is highly consistent with that of their melting points as
shown in Figure 3.
Figure 3. Melting points of (R)-1 (R)-2 (blue) and (R)-1 (S)-2
(green) salt crystals.
Explanation for the Dramatic Switch of the Absolute Con-
figuration of the Amines Incorporated in the Less-Soluble
Diastereomeric (R)-1 2 salts. Cylindrical assembly of organ-
3
3
3
ic molecules is known to possibly prevent the formation of
large voids between the molecules in crystals owing to
efficient van der Waals and CH/π interactions,10 suggesting
that the aggregation of cylindrical assemblies would be more
favorable than that of spherical assemblies for the creation of
stable organic crystals. This means that the column-type
crystals should be more stable than the cluster-type crystals.
crystal, owing to the contribution of strong halogen-bonding
interactions other than van der Waals and CH/π interactions
to the stabilization of the (R)-1 (S)-2d crystal.
3
On the other hand, it is widely accepted that among a pair
of diastereomeric salt crystals, a crystal with higher stability
is less soluble. Therefore, the (R)-1 (R)-2a and (R)-1 (S)-2d
3
3
crystals should be less soluble than the (R)-1 (S)-2a and
3
As a result, the stability of the (R)-1 (R)-2a crystal is higher
3
(R)-1 (R)-2d crystals, respectively, to cause the switch of the
3
than that of the (R)-1 (S)-2a crystal. In contrast, the (R)-
3
major isomer incorporated in the deposited salts from the
R-isomer for the amine 2a to the S-isomer for the amine 2d.
1 (S)-2d crystal becomes more stable than the (R)-1 (R)-2d
3
3

690 Crystal Growth & Design, Vol. 10, No. 2, 2010
Kobayashi et al.
The relative stability/solubility of the (R)-1 (R)-2 and
3
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3
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3
3
3
3
Acknowledgment. The present work was partially supported
by the Grant-in-Aid for Scientific Research from the Ministry of
Education, Science, Sports and Culture, Japan (No. 19350064).
Supporting Information Available: X-ray crystallographic infor-
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available free of charge via the Internet at http://pubs.acs.org.
€
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