Diastereomeric resolution of p-chloromandelic acid with (R)-phenylethylamine

Article abstract of DOI:10.1002/chir.20695

The optical resolution of p-chloromandelic acid using (R)-α- phenylethylamine as resolving agent was presented. The effect of solvents, molar ratio of racemate to the resolving agent, filtration temperature as well as the amount of solvent on resolution w

Full text of DOI:10.1002/chir.20695

CHIRALITY 22:16–23 (2010)
Diastereomeric Resolution of p-Chloromandelic Acid
with (R)-Phenylethylamine
QUAN HE,1 YANG-FENG PENG,2 AND SOHRAB ROHANI
3
*
1Department of Chemical Engineering, Ningbo University of Technology, Ningbo 315016, China
2Department of Chemical Engineering, East China University of Science and Technology, Shanghai 200237, China
3Department of Chemical and Biochemical Engineering, The University of Western Ontario, London, Ontario, Canada
ABSTRACT
The optical resolution of p-chloromandelic acid using (R)-a-phenylethyl-
amine as resolving agent was presented. The effect of solvents, molar ratio of racemate
to the resolving agent, filtration temperature as well as the amount of solvent on resolu-
tion was investigated by orthogonal experimentation. The binary melting point phase
diagram and crystal structure analysis of diastereomeric salts rationalized the success
C
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of the resolution. Chirality 22:16–23, 2010.
2009 Wiley-Liss, Inc.
KEY WORDS: p-chloromandelic acid; phenylethylamine; resolution; diastereomeric salt;
crystal structure; binary melting point phase diagram
INTRODUCTION
fusion was much more stable than the more soluble salt,
(R)-PEAÁ(S)-p-ClMA. Examining the crystal structures
reveals that the less soluble salt and more soluble salt
have similar infinite hydrogen-bonding network perpendic-
ular to c-axis in which ammonium cations and carboxylate
anions form columnar hydrogen-bonding around a twofold
screw axis. The columnar hydrogen-bondings are inter-
linked by other hydrogen bonds formed between carboxy-
late oxygens and hydroxyl hydrogens. However, the crys-
tal packing between hydrogen-bonding layers in two salts
are significantly different. The less soluble salt has very
planar boundary surface among the hydrophobic layers,
which is believed to enhance the salt stability by van der
Waals interations and thus realize close packing mode.
The more soluble salt does not possess this kind of even
boundary surface. Therefore, we suggest that van der
Waals interaction contribute much to the stability differ-
ence of the two salts. The results of the investigation are
consistent with the chiral discrimination mechanism in
resolutions of mandelic acid, p-methoxymandelic acid, p-
methylmandelic acid, and 2-naphthylglycolic acid by PEA.
In the latter case, the characteristics of hydrogen-bonding
patterns and van der Waals interactions in a pair of diaster-
eomeric salts play the most important role in successful
resolution of primary amine and mandelic acid deriva-
tives.14–16
Enantiopure (R)-p-chloromandelic acid (hereafter (R)-p-
ClMA) is a significant chiral intermediate, and has been
used to synthesize pharmaceuticals.1 It is also an efficient
resolving agent for chiral amines resolutions.2,3 Usually, it
is the racemic p-chloromandelic acid (hereafter p-ClMA)
to be obtained by regular chemical synthesis process.
Enantiopure (R)-p-ClMA has to be obtained through enan-
tioseparation. Xu and coworkers4 prepared (R)-p-ClMA
with optical purity 99% e.e. by enantioselective degradation
of racemates with a new isolate Pseudomonas putida;
Yamaguchi et al.5 carried out the optical resolution of race-
mic organic acids using optically active 4-amino-2-methyl-
butan-1-ol as resolving agent in isopropanol solvent; Honda
et al.6 prepared (R)-p-ClMA by optical resolution of man-
delic acid derivatives with amino acid hydrazide as resolv-
ing agent in 2-propanol.
However, there are some drawbacks such as low yield
and high cost of the resolving agent in the aforementioned
methods. Herein, optical resolution process of p-ClMA
with resolving agent (R)-a-phenylethylamine (hereafter
(R)-PEA), which is commercially available and inexpen-
sive, was investigated. The molecular structure of race-
mate and resolving agent are shown in Figure 1. Experi-
mental results indicated that PEA was an efficient re-
solving agent for p-ClMA and the resulting pair of
diastereomeric salts had significant differences in solubil-
ities which led to an efficient resolution.
To get insight to the chiral discrimination mechanism of
this resolution system, we further investigated the charac-
teristic differences between the thermodynamic properties
and crystal structures of the pair of diastereomeric salts.
This approach is widely used to clarify the chiral recogni-
tion in diastereomeric salt resolution.7–16
Contract grant sponsor: Ningbo Nature Science Fund; Contract grant
number: 2005B100085
*Correspondence to: Sohrab Rohani, Department of Chemical and Bio-
chemical Engineering, The University of Western Ontario, London,
Ontario N6A 5B9, Canada. E-mail: srohani@uwo.ca
Received for publication 6 October 2008; Accepted 1 December 2008
DOI: 10.1002/chir.20695
Our investigation indicated that the less soluble salt,
Published online 9 February 2009 in Wiley InterScience
(R)-PEAÁ(R)-p-ClMA with higher melting point and heat of (www.interscience.wiley.com).
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2009 Wiley-Liss, Inc.

DIASTEREOMERIC RESOLUTION OF P-CHLOROMANDELIC ACID
17
193.48C, specific rotation of [a]2D2 5 234.38 (c 5 1,
C2H5OH). The yield of 97.4% was calculated based on (R)-
PEAÁ(R)-p-ClMA in starting salt and the resolution effi-
ciency was 69.3%.
Resolution processes in other solvents are similar to the
above described process.
Fig. 1. Structures of (R)-p-chloromandelic acid and (R)-a-phenyl-
ethylamine.
Preparation of ( R)-p-Chloromandelic Acid by Resolution
To a solution of racemic p-ClMA (28 g, 0.15 mol) in 180-
mL 95% ethanol, (R)-PEA (19 mL, 0.15 mol) was added.
The mixture was heated to reflux for 15 min to dissolve
the solid crystals and then slowly cooled to 208C. The pre-
cipitated crystalline salt was collected by filtration to give
crude diastereomeric salt (22.6 g), mp: 187.6–193.48C, spe-
cific rotation [a]2D2 5 234.58 (c 5 1, C2H5OH).
EXPERIMENTAL
p-ClMA with 99% purity was purchased from Alfa Aesar,
A Johnson Matthey Company (Ward Hill, MA). PEA with
optical purity of 99% ee was purchased from Sigma-Aldrich
Canada (Oakville, ON) and used without further purifica-
tion. Specific rotations of salts were measured by Autopol
IV Digital Polarimeter Rudolph America (Hackettstown,
NJ) at 589 nm, equipped with a quartz cell of 100 mm path
length. Optical purity of (R)-p-ClMA was determined by
Chiral HPLC using (R, R) Whelk-O2 column (250 mm 3
The crude diastereomeric salt (22 g) was recrystallized
from 95% ethanol (150 mL) to afford a white needle crystal
salt (15.9 g). mp: 191.8–195.48C, specific rotation [a]D22
245.28 (c 5 1, C2H5OH).
5
Above salt was recrystallized in 95% ethanol (130 mL)
1
again to give (R)-PEAÁ(R)-p-ClMA (12.6 g), mp: 193.8–
4.6 mm) from Regis Tech. (Morton Grove, IL). H NMR
195.48C, specific rotation [a]D22
5 248.58 (c 5 1,
spectra were recorded at 500 MHz on AVANCE DRX500
(BRUKER, US) in DMSO solution with tetramethylsilane as
an internal standard. IR spectra were recorded on NICO-
LET 5SXC spectrometer (NICOLET, US) by KBr pellets.
The elemental analysis was performed on Elementar Vario
EL (Elementar Analysensysteme, Hanau, Germany).
C2H5OH). The salt was verified by NMR, IR, as well as ele-
mental analysis, and the analytical data are presented as
follows:
1H NMR(500 MHz, DMSO) d: 1.408(d, 3H, CH3),
4.291(m, 1H, CHNH2), 4.531(s, 1H, CHOH), 7.272–7.439
(m, 9H, Ph 1 PhCl); IR (KBr) m(cm21): 3301, 3036, 2535,
1610, 1576, 1531, 1383, 1193, 1072, 776, 705, 553, 478, 446;
Optical Resolution of p-ClMA
A standard resolution process example listed as entry 3 Element analysis: Calcd for C16H18NO3Cl (FW307.77) C:
in Table 1 is as follows:
62.40, H: 5.85, N: 4.55; Found C: 62.71, H: 6.26, N: 4.48.
To a solution of racemic p-ClMA(5.6 g, 0.03 mol) in 48-
The above (R)-PEAÁ(R)-p-ClMA salt (12 g, 0.039 mol)
mL 95% aqueous ethanol, (R)-PEA (3.8 mL, 0.03 mol) was was dissolved in H2O (80 mL), and the resulting solution
added. The mixture was heated to 728C by water bath to was acidified with hydrochloric acid (2 N, 0.045 mol) to
dissolve the solid crystals. The solution was kept at 728C pH 5 1. The liberated acid was extracted by ethyl acetate
for 15 min and then slowly cooled to 158C. After standing three times (30 mL, 20 mL, and 20 mL, respectively). The
at 158C for 15 min, the precipitated crystalline salt was col- combined extract was dried over Na2SO4. Upon removal
lected by filtration and washed with cold 95% ethanol (2 3 of solvent under reduced pressure, (R)-p-ClMA was
8 mL) to afford diastereomeric salt (4.5 g), mp: 190.8– obtained as white solid (7.0 g, 50% yield based on (R)-p-
TABLE 1. The effect of solvent on resolution
Diasteromeric salt (R)-PEAÁ(R)-p-ClMA
Entry
Solvent
Yield %
Melting point/8C
Specific rotation/8
Diastereomeric purity d.p./%
Resolution efficiency %
1
2
3
4
5
6
7
8
9
Watera
114
64.9
97.4
96.3
184.9
192.1
190.8
190.3
191.2
188.0
174.9
179.6
170.8
164.0
24.6
38.2
34.3
33.7
33.1
28.3
8.72
18.2
7.4
50.7
79.1
71.1
69.8
68.7
58.7
17.8
37.8
14.8
1.5
57.8
51.3
69.3
67.2
67.7
66.1
28.3
51.4
23.4
2.6
Methanola
95% Ethanola
Ethanola
Propanola
98.5
2-Propanolb
Ethyl acetateb
Butyl actateb
Tolueneb
112.6
159.0
136.0
152.6
174.3
10
Chloroformb
20.7
ap-ClMA 5 0.03 mol, (R)-PEA 5 0.03 mol, solvent 5 48 ml.
bp-ClMA 5 0.03 mol, (R)-PEA 5 0.03 mol, solvent 5 68 ml.
Filtration temperature: 158C; yield is calculated based on a half amount of p-ClMA; diastereomeric purity is the ratio of specific rotation of obtained salt
from resolution to the specific rotation of enantiopure diastereomeric salt; the specific rotation of pure (R)-PEAÁ(R)-p-ClMA is 48.58 (c 5 1, 95% ethanol);
Resolution efficiency S is the product of yield and optical purity.
Chirality DOI 10.1002/chir

18
HE ET AL.
TABLE 2. Orthogonal experiment design
RESULTS AND DISCUSSION
Solvent Screening and Resolution Condition
Determination
Filtration
95%
Entry
p-ClMA: (R)-PEA
temperature/8C
ethanol/mL
Attempted experiment proved that (R)-PEA was able to
resolve the p-ClMA. Because solvent plays an important role
in resolution process, screening suitable solvents is of im-
portance. In this work, the resolution of p-ClMA by (R)-PEA
was performed respectively in water, ethyl acetate, alcohols,
and other solvents as shown in Table 1. Diastereomeric sep-
arations took place in all the cases. However, the resolution
efficiency varied significantly in different solvents. The reso-
lution results were evaluated by resolution efficiency S,
which was calculated as the product of yield and diastereo-
meric purity of diastereomeric salts obtained. Experimental
results indicated that the diastereomeric purity of salts was
high in several alcohol solvents but quite low in chloroform
and toluene. Taking the resolution efficiency as well as the
cost and toxicity of the solvents into consideration, 95%
aqueous ethanol was chosen as the most suitable solvent.
Once the optimum choice of solvent was made, the
other factors affecting the resolution process including
molar ratio of p-ClMA to (R)-PEA, the amount of 95% etha-
nol solvent, and filtration temperature were investigated.
1
2
3
4
5
6
7
8
9
1
1
1
0.85
0.85
0.85
0.7
0.7
0.7
25
20
15
25
20
15
25
20
15
48
36
42
36
42
48
42
48
36
ClMA in starting racemate), mp: 118.5–121.28C; specific
rotation [a]2D2 5 2133.38 (c 5 0.3, C2H5OH). The enantio-
meric purity of (R)-p-ClMA was determined to be 99% ee
by HPLC analysis on chiral column (Regis (R, R)-Whelk-
O2). The mobile phase was H2O/CH3OH (70/30) with
0.1% acetic acid and flow rate was 0.8 mL/min under
detection wavelength of 225 nm.
Binary Phase Diagram of Diastereomeric Salts
The preparation of pure salts (R)-PEAÁ(R)-p-ClMA and To reduce the experimental work, the three-factor and
(R)-PEAÁ(S)-p-ClMA has been introduced in our previous three-level factorial experimental design, 23, shown in Ta-
work focused on single X-ray crystallographic analysis.17,18 ble 2 was used. The experimental results are summarized
A weighed amount of pure (R)-PEAÁ(R)-p-ClMA and (R)- in Table 3. In the optical resolution via diastereomeric salts
PEAÁ(S)-p-ClMA were mixed and crushed in a mortar to formation, with the increase of diastereomeric salts yield,
obtain a uniform mixture with different diastereomeric the diastereomeric purity of diasteromeric salts usually
composition. The resolution of the electronic balance was decreases. The comparison between entry 2 and 5 in Table
0.00001 g. The binary melting point phase diagram was 3 shows that when the yield decreased from 101.9% to
developed using Mettler Toledo DSC 822e differential 80.2%, the diastereomeric purity increased slightly only
scanning calorimeter (Greifensee, Switzerland) by meas- from 70.5% to 71.8%. In addition, reduction in the amount
uring the temperature at the beginning and the end of of solvent and decrease in the temperature increased the
fusion of diastereomeric salt mixture. The samples (3–12 yield of salt. The lower the ratio of p-ClMA to (R)-PEA
mg) were prepared in a covered aluminum crucible having resulted in lower yield and higher diastereomeric purity.
pierced lids to allow the escape of volatiles. The sensors Therefore, according to the results of factorial experi-
and samples were under nitrogen purge of flow rate of ments, the optimal resolution conditions were determined
50 ml/min during the experiments. The temperature cali- as follows: the ratio of p-ClMA to PEA was 1.0, the filtra-
bration was carried out using melting point of highly pure tion temperature of 208C and the amount of solvent was
indium in a medium temperature range. Heating rates of 120 ml 95% ethanol/0.1mol p-ClMA. Furthermore, the re-
3, 5, 108C/min were used. The heating rate did not affect solution was performed under this optimal condition. The
the results. The heating rate of 58C/min was used.
TABLE 3. Resolution results in various conditions
Diasteromeric salt (R)-PEAÁ(R)-p-ClMA
diastereomeric salt was recrystallized twice in 95% ethanol
Entry
Quantity/g
Yield/%
Melting point/8C
Specific rotation/8
Diastereomeric purity d.p./%
Resolution efficiency %
1
2
3
4
5
6
7
8
9
4.3
4.7
4.3
3.9
3.7
3.9
2.8
3.5
3.3
93.2
101.9
93.2
84.6
80.2
84.6
60.7
73.8
71.5
191.1
190.6
190.8
188.5
191.6
191.6
192.1
191.3
189.6
34.0
34.0
33.2
33.5
34.6
34.6
37.1
36.4
35.1
70.5
70.5
68.9
69.5
71.8
71.8
77.0
75.5
72.8
65.7
71.8
64.2
69.1
67.8
71.4
46.7
55.7
52.1
p-ClMA 5 0.03 mol in all cases.
Chirality DOI 10.1002/chir

DIASTEREOMERIC RESOLUTION OF P-CHLOROMANDELIC ACID
19
TABLE 4. Thermodynamic properties
of diastereomeric salts
eomeric-salt mixtures are classified into three types: a
eutectic conglomerate, a 1:1 addition compound, and a
solid solution.21 The type of diastereomeric salt mixture
can be identified on the basis of the binary melting point
phase diagram. The formation of eutectic conglomerate is
the primary condition for resolution. Figure 2 shows bi-
nary melting point phase diagrams for a mixture of (R)-
PEAÁ(R)-p-ClMA and (R)-PEAÁ(S)-p-ClMA constructed by
detailed DSC analysis of mixture with different composi-
tion of XR, which is the molar fraction of less soluble salt
(R)-PEAÁ(R)-p-ClMA. The system was a eutectic mixture,
and the eutectic composition Xe was 0.1 from experimental
results, which was in good agreement with the Xe of 0.09
calculated theoretically from thermodynamic Schro¨der-van
Laar equation.21 The fact that the system is a eutectic mix-
ture indicates that the resolution efficiency primarily
depends on the difference in stability between the less and
more soluble salts.
Melting
Heat of
Diastereomeric salt
point/8C fusion/Jg21 Solubilitya/g
(R)-PEA (R)-p-ClMA (less)
(R)-PEA (S)-p-ClMA (more) 141.76
194.60
223.73
105.41
2.0
18.2
aWeight (g) of the solute dissolved in 100 g of 95% ethanol at 228C.
and high purity (R)-PEAÁ(R)-p-ClMA was obtained. The
(R)-p-ClMA was liberated from the diastereomeric salt to
give white powder solid with optical purity of 99% ee and
yield of 50%. Detailed description is presented in experi-
mental section 2.2.
Thermodynamic Properties of Diastereoemric Salts
The above efficient resolution is presumed to be due to
the large difference in physicochemical properties of the
pair of diastereomeric salts, (R)-PEAÁ(R)-p-ClMA and (R)-
PEAÁ(S)-p-ClMA. It is mostly common that efficient separa-
tion can be expected when the difference of melting point
of diastereomeric salt is larger than 208C, and the trend of
solubilities difference between distereomeric salts paral-
lels that of difference in melting point and heat of
fusion.19,20 Table 4 lists some of the physical properties of
(R)-PEAÁ(R)-p-ClMA and (R)-PEAÁ(S)-p-ClMA. As shown in
Table 4, the conditions for efficient resolution are fulfilled
in this system. The melting point of less soluble salt
exceeds that of the corresponding more soluble salt by
548C. The solubility ratio of more soluble salt to less soluble
salt is 9.1, which is very large. It is strongly suggested that
the less soluble salt is thermodynamically more stable than
the corresponding more soluble salt. Consequently, such
large stability difference leads to an efficient resolution.
Furthermore, we established the binary melting point
phase diagram of diastereomeric salts. In general, diaster-
For
a better interpretation of stability difference
between disatereomeric salts, we then focused on the crys-
tal structures of the less and more soluble salts to find
which property of the diastereomeric salt crystal is corre-
lated to the difference in stability.
Crystal Structures of Diastereomeric Salts
Fortunately, both well-formed single crystals of less and
more soluble salts were obtained for X-ray crystallographic
analysis although the single crystal of (R)-PEAÁ(S)-p-ClMA
was not easy to prepare due to its high solubility. Crystals
of (R)-PEAÁ(R)-p-ClMA are colorless rod crystallized in
orthorhombic P212121 space group and unit cell contains
four (R)-p-ClMA anion and (R)-PEA cation. Crystals of (R)-
PEAÁ(S)-p-ClMA are colorless plate crystallized in mono-
clinic P21 space group and unit cell contains two (S)-p-
ClMA anion and (R)-PEA cation. Detailed crystal data
have been reported in authors’ previous work.17,18 It is
generally believed that pattern of hydrogen-bonding and
crystal packing mode account the chiral discrimina-
tion.8,12,13,15,16 Therefore, special attention was paid to the
characteristics of hydrogen-bonding network in the crystal
structures.
In the crystal of less soluble salt, the typical packing
structure were acid–base salt structure containing (R)-p-
ClMA anions and the (R)-PEA cations, supported by elec-
trostatic interaction, hydrogen-bonding, and van der Waals
interactions. All the hydrogen bonds are listed in Table 5.
TABLE 5. Hydrogen-bonding geometry of (R)-PEAÁ(R)-p-
˚
ClMA [A and 8]
D-HÁÁÁA
d(D-H)
d(HÁÁÁA)
d(DÁÁÁA)
<(DHA)
O9-H9AÁÁÁO11a
0.82
0.89
0.89
0.89
2.09
2.00
1.99
2.04
2.848 (2)
2.863 (2)
2.869 (3)
2.878 (3)
154
157
167
156
N13-H13AÁÁÁO12
N13-H13BÁÁÁO11b
N13-H13CÁÁÁO12c
Fig. 2. Binary melting point phase diagram of diastereomeric salts.
The solid curves represent calculated values based on Schro¨der-van Laar
equation; Circle and diamond represent the temperatures of the beginning
and the end of fusion. [Color figure can be viewed in the online issue,
which is available at www.interscience.wiley.com.]
Symmetry transformations used to generate equivalent atoms:
ax 2 1/2, 2y, 15/2, 2z.
bx 2 1/2, 2 y 1 3/2, 2z.
cx 1 1/2, 2y 1 3/2, 2z.
Chirality DOI 10.1002/chir

20
HE ET AL.
Fig. 3. Atomic-numbering molecule schemes. The dashed lines represent the hydrogen bond. (a) less solule salt (R)-PEAÁR-(p)-ClMA; (b) more solu-
ble salt (R)-PEAÁ(S)-p-ClMA. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]
The atomic-numbering schemes are graphically illustrated
in Figure 3a. The ammonium hydrogen formed three
hydrogen bonds, namely N13-H13A-O12, N13-H13B-
O11(ii), and N13-H13C-O12(iii) with carboxylate oxygens
of adjacent (R)-p-ClMA. Thus, a columnar hydrogen-bond-
ing network was formed around a twofold screw axis by
ammonium hydrogens and carboxylate oxygens. Sche-
matic illustration of 21 column structure is shown in Figure
4. Additionally, there was another hydrogen bond O9-H9A-
O11(i) between hydroxy hydrogen of (R)-p-ClMA and car-
boxylate oxygen of another (R)-p-ClMA which interlinked
the neighboring 21 columns. These hydrogen bonds
formed 2-dimentional network perpendicular to c-axis,
extending infinitely. This characteristic 2-dimentional
hydrogen-bonding network was commonly observed in
other salts of primary amine and mandelic acid derivatives
investigated by Kinbara et al.15,16 who proposed that for a
successful resolution, it was necessary to form this kind of
hydrogen-bonding layer, consisting of stable 21 columns
and having planar boundary surfaces in the less soluble
salts crystals. The crystals with this kind of hydrogen-
bonding structure are considered to be stabilized from the
viewpoint of both their hydrogen-bonding and van der
Waals interactions. Crystal structure of (R)-PEAÁ(R)-p-
ClMA has these two features shown in Figure 5. 21 col-
umn hydrogen bonds along a-axis were formed between
Fig. 4. Schematic illustration of 21 column hydrogen-bonding pattern.
[Color figure can be viewed in the online issue, which is available at
carboxylate oxygens and ammonium hydrogens. Neigh- www.interscience.wiley.com.]
Chirality DOI 10.1002/chir

DIASTEREOMERIC RESOLUTION OF P-CHLOROMANDELIC ACID
21
In the crystal of more soluble salt, there were more
complicated hydrogen bonds as listed in Table 6. The
atomic-numbering schemes are graphically illustrated in
Figure 3b. The ammonium hydrogen formed three hydro-
gen bonds, namely N13-H13A-O12(ii), N13-H13B-O11, and
N13-H13C-O12(iii) with carboxylate oxygens of adjacent
(S)-p-ClMA. Additionally, there are hydrogen bonds O9-
H9A-O11 (i) between hydroxy hydrogen of (S)-p-ClMA
and carboxylate oxygen of another (S)-p-ClMA as well as
O9-H9A-O9(i) between hydroxy hydrogen of (S)-p-ClMA
and hydroxy oxygen of another (S)-p-ClMA. All these
Fig. 5. Crystal structure of less soluble salt. (a) viewed from c-axis; (b)
viewed from a-axis; (c) viewed from b-axis. The dashed lines represent
hydrogen bonds. [Color figure can be viewed in the online issue, which is
available at www.interscience.wiley.com.]
boring 21 columns were interlinked by hydrogen bond
between the hydroxy hydrogen of one (R)-p-ClMA mole-
cule and the carboxylate oxygen of another (R)-p-ClMA
molecule. Viewed from a-axis and b-axis directions, this
hydrogen-bonding layer had planar boundary surfaces as
shown in Figures 5b and 5c, respectively, which could be
efficiently stabilized by van der Waals interactions
between layers. As a consequence, close packing was real-
ized in this crystal, which was believed to be important to
the stability of the solid salt.
Fig. 6. Crystal structure of more soluble salt. (a) Viewed from c-axis;
(b) viewed from a-axis; (c) viewed from b-axis. The dashed lines represent
hydrogen bonds. [Color figure can be viewed in the online issue, which is
available at www.interscience.wiley.com.]
Chirality DOI 10.1002/chir

22
HE ET AL.
TABLE 6. Hydrogen-bonding geometry of (R)-PEAÁ(S)-p-
CONCLUSIONS
˚
ClMA [A and 8]
p-Chloromandelic acid was resolved by (R)-a-phenyl-
ethylamine via diastereomeric salt formation. The suitable
resolution conditions were determined. This successful re-
solution was realized by significant stabilities difference
between the less and more soluble salts. The 21 column
hydrogen-bonding network and van der Waals interactions
between planar boundary surface in the less soluble (R)-
PEAÁ(R)-p-ClMA crystal, commonly found in less soluble
salts of PEA and other mandelic acid derivatives reported
in literature,15,16 is believed to dramatically stabilize the
less soluble salt. Thermodynamic and crystal structure
studies in this article provide a good interpretation to chi-
ral discrimination mechanism in p-ClMA and (R)-PEA
resolution system.
D-HÁÁÁA
d(D-H)
d(HÁÁÁA)
d(DÁÁÁA)
<(DHA)
O9-H9AÁÁÁO9a
0.84
0.84
0.91
0.91
0.91
2.26
2.09
1.89
1.83
1.88
2.939 (2)
2.826 (2)
2.798 (2)
2.731 (2)
2.779 (2)
139
146
172
169
171
O9-H9AÁÁÁO11a
N13-H13AÁÁÁO12b
N13-H13BÁÁÁO11
N13-H13CÁÁÁO12c
Symmetry transformations used to generate equivalent atoms:
a2x 1 1, y 1 1/2, 2z 1 1.
bx, y 2 1, z.
c2x 1 2, 2y 2 1/2, 2z 1 1.
hydrogen bonds also formed an infinite 2-dimentional
network perpendicular to c-axis as shown in Figure 6.
The pattern of this hydrogen-bonding network was dif-
ferent from the one in the corresponding less soluble
salt. Although similar 21 column structures were also
observed as shown in Figure 6a, but interlinks
between 21 columns were different. Except the hydro-
gen-bonding between hydroxy hydrogen and carboxy-
late oxygen, there were zig-zag hydrogen-bonding lines
formed between hydroxy hydrogens and hydroxy oxy-
gens. It is noteworthy that the hydrogen acceptor was
hydroxy oxygens in this hydrogen bond, which were
less favorable than carboxylate oxygens. This fact was
not in accordance with the rule of hydrogen bonding
proposed by Etter22 that the best hydrogen donor will
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