Resolution of α-phenylethylamine by its acidic derivatives

Article abstract of DOI:10.1016/S0957-4166(01)00254-3

α-Phenylethylamine was resolved by its own derivatives formed with a homologous series of dicarboxylic acids. The structure of the oxalamic acid diastereoisomeric salts was investigated by the single-crystal X-ray diffraction method.

Full text of DOI:10.1016/S0957-4166(01)00254-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1511–1518
Resolution of a-phenylethylamine by its acidic derivatives
Jo´zsef Ba´lint,a Gabriella Egri,a,* Ma´tya´s Czugler,b Jo´zsef Schindler,a Violetta Kiss,a Zolta´n Juvanczc
and Eleme´r Fogassya
aDepartment of Organic Chemical Technology, Budapest University of Technology and Economics, PO Box 91,
H-1521 Budapest, Hungary
bInstitute of Chemistry, Chemical Research Center, Hungarian Academy of Science, PO Box 17, H-1525 Budapest, Hungary
cVITUKI Plc., Kvassay J.u.1, H-1095 Budapest, Hungary
Received 18 May 2001; accepted 31 May 2001
Abstract—a-Phenylethylamine was resolved by its own derivatives formed with a homologous series of dicarboxylic acids. The
structure of the oxalamic acid diastereoisomeric salts was investigated by the single-crystal X-ray diffraction method. © 2001
Elsevier Science Ltd. All rights reserved.
1. Introduction
acid diester. The resulting monoamide-monoester was
then subjected to alkaline hydrolysis followed by
acidification in order to liberate the acids. Synthesis of
Separation of the diastereoisomeric salts of a given
compound is the main method for enantiomeric resolu-
tion.1–3 A special case is the resolution of a compound
by one of its own derivatives. The resolving agent is
prepared from one enantiomer of the target compound
to give the derivative of opposite acid–base characteris-
tics. Although this is quite a promising method which
makes use of the undesired enantiomer, so far only few
examples are known in the literature.4–7
N-(1-phenylethylamine)oxalamic
acid
has
been
reported11 by biocatalytic (Candida sp.) hydrolysis of
the ester but no analytical data were given.
The resolution experiment was carried out by applying
the resolving agent in equivalent quantity. In each case,
including literature data (n=2), resolution by the (R)-
monoamide yielded (S)-phenylethylamine. That is, the
(S,R)-diastereoisomeric salt is more stable than the
(R,R)-diastereoisomer, which indicates molecular com-
pound-like behavior of the diastereoisomeric mixture;
as in the case of molecular compounds heterochiral
interactions are stronger than homochiral ones.
a-Phenylethylamine is
a widely applied resolving
agent.8,9 It has previously been resolved by its succinic
acid monoamide.10 Our aim was to conduct a system-
atic study of some resolution processes involving
monoamides formed with dicarboxylic acids of different
chain length. We synthesized the oxalic and malonic
acid monoamide-resolving agents, while the succinic
acid monoamide has been reported previously in the
literature.10
The resolution process can be seen in Fig. 2.
The resulting diastereoisomeric salts were enantiomeri-
cally enriched by repeated recrystallization. In the liter-
2. Results and discussion
2.1. Resolution and enantiomeric enrichment
The resolving agents were synthesized (Fig. 1) by con-
densing (R)-a-phenylethylamine with the dicarboxylic
* Corresponding author. Fax: +36
@ella.hu
1 4633648; e-mail: h7622egr
Figure 1. Formation of the resolving agents.
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00254-3

1512
J. Ba´lint et al. / Tetrahedron: Asymmetry 12 (2001) 1511–1518
came from the resolving agent having the longest side
chain and thus the largest distance of the carboxylic
group from the stereogenic center.
For a better interpretation of the resolution results,
single-crystal X-ray crystal structure determinations
were undertaken for the (R)- and (S)-1-phenylethyl-
amine-(R)-1-phenylethylamine oxalamic acid mono-
amide diastereoisomeric salts (1a and 1b, respectively).
In this case both diastereoisomeric salts gave suitable
crystals for single-crystal structural studies.
For the diastereoisomeric salts of the malonamic and
succinamic acid compounds attempts at obtaining sin-
gle crystals were not successful.
2.2. X-Ray crystallography
The structure model of the (R)-salt 1a is shown in Fig.
3.
Solid state models resulting from single-crystal X-ray
structure determinations (Table 2) of 1a (Fig. 3) and 1b
(Fig. 4) indicate overall shapes of the associations of
the acid and base molecules forming the crystallo-
graphic asymmetric units. The intramolecular geometry
has bonding dimensions as expected.
Figure 2. Resolution of a-phenylethylamine by its
monoamides.
ature three steps were carried out in butan-2-one. In
our case, two recrystallizations from acetone gave good
results.
It is also apparent (Table 3) that the conformations of
both the (R)-PEA and the (S)-PEA bases are identical,
except for the sign change due to the (R)/(S) switch.
There is only one difference in the conformation of the
(R)-oxalamic acid moieties (cf. Table 3). This is a
roughly 75° rotation discrepancy around the N(1)ꢀC(7)
bond. This twist can be interpreted as a shift in the
eclipsing C and H atomic positions in the vicinity of the
amide group. C(1) eclipses with H1 and the amide C(8)
with C(7)H in 1a. In 1b the C(10)H atom turns, eclips-
ing with C(1)H. Though the amide C(8) stays eclipsed
with C(7)H in 1b it is now placed symmetrically on the
other side of C(7)H (cf. the Newman projection insets
in Figs. 3 and 4).
We found it advantageous during the workup of the
reaction to first remove the resolving agent by acidifica-
tion followed by organic solvent extraction. Using this
method, around 90% of the resolving agent can be
recovered from the organic phase. The phenylethyl-
amine is then liberated by adjusting the pH of the
aqueous phase to alkaline and isolated by straightfor-
ward extraction.
The resolution and enrichment results are summarized
in Table 1. In contrast to expectations, the best results
Table 1. Resolution and enantiomeric enrichment of a-phenylethylamine
Res. agent
Conf.
PhEA oxalamic acid
PhEA malonamic acid
PhEA succinamic acidb
Y (%)
Eea (%)
Sc
Y (%)
Eea (%)
Sc
Y (%)
OP (%)
54
Sc
EM0
EM1
EM2
EP2
R
R
S
S
83
17
4
32
14
19
98
0.27
94
16
6
61
17
67
99
0.57
110
0.56
38
0.37
56
0.55
61
100
0.61
a Ee determined by chiral GC; see Experimental section.
b Literature data source,10 OP based on optical rotatory power.
c S=Y×ee or Y×OP (efficiency of the resolution).

J. Ba´lint et al. / Tetrahedron: Asymmetry 12 (2001) 1511–1518
1513
Figure 3. X-Ray structure model of 1a with atomic displacement parameters. The Newman projection inset is along the
N(1)ꢀC(7)ꢀC(1) bonds; arrows indicate rotations to next-neighbors on the wheel.
Table 2. Summary of crystallographic data and structure model refinement for 1a and 1b
1a
1b
Empirical formula (Fw)
Temperature (K)
C
293(2)
18H22N2O3, 314.38
C18H22N2O3, 314.38
295(2)
,
,
Radiation and wavelength
Crystal system
Mo Ka, u=0.710730 A
Monoclinic
Mo Ka, u=0.710730 A
Monoclinic
Space group
P21
P21
Unit cell dimensions
,
a (A)
9.869(1)
6.750(1)
13.548(1)
101.38(1)
884.8(2)
11.478(1)
6.660(2)
11.593(1)
103.06(1)
863.3(3)
2
1.2094(4)
0.083
Colorless
Block
0.40×0.30×0.25
6873
,
b (A)
,
c (A)
i (°)
V (A )
3
,
Z
2
Dcalcd (Mg m−3
)
1.1801(2)
0.081
Colorless
Block
0.40×0.35×0.15
6973
8
Absorption coefficient, v (mm−1
Crystal color
)
Crystal description
Crystal size (mm)
Reflections collected
Decay (%)
3
Independent reflections
Reflections I\2|(I)
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
Extinction coefficient
6117 [Rint=0.011]
3576
5975 [Rint=0.023]
3386
Full-matrix least-squares on F2
6117/139/212
0.977
Full-matrix least-squares on F2
5975/1/211
0.941
–
0.0473, 0.1113
0.0937, 0.1212
0.002, 0.000
0.224/0.133
0.013(5)
Final R indices R1, wR2 [I\2|(I)]
0.0411, 0.1042
0.0843, 0.1126
0.000, 0.000
0.142/−0.133
R indices (all data) R1, wR2
Max. and mean shift (e.s.d.)
Largest diff. peak and hole (e A
−3
,
)
Intra-associate parameters show the usual bonding and
H-bonding characteristics (Table 4) as anticipated for
these types of salts. The fairly uniform hydrogen bonding
defines the salt link and an infinite one-dimensional chain
along the crystallographic {0,1,0} base vector. In essence
it can be summarized that the intra-associate conforma-
tion remains stable and the same, as far as H-bonding
between the PEA-ammonium cation and the (R)-PEA-
oxalamic anion is concerned.
packing energies of the two salts are comparable (−31.0
kJ mol−1 for 1a, −31.6 kJ mol−1 for 1b, summed12 for 96
and 98 interactions, respectively), and also show that this
approach does not reflect well upon the differing lattice
stability. To aid interpretation of the physical properties
of these two solids, their crystal packing was further
investigated. This showed some further differences.
Firstly, the small but significant differences in the calcu-
lated densities of 1a (Dc=1.1801(2) (Mg m−3)) and 1b
(Dc=1.2094(4) (Mg m−3)), reflecting the overall balance
of repulsive and attractive forces in the two crystals. Since
strong H-bonding does not show up differences between
1a and 1b, much weaker interactions should be sought
after. These are partly seen in the interesting, and yet
again very similar, pattern of CꢀH···p interactions and
aromatic ring center distances (Tables 4 and 5).
As the differing a and c cell parameters clearly indicate,
the (S)- and (R)-PEA salts of (R)-N-(1-phenylethyl-
amine)oxalamic acid monoamide are not isostructural.
Though slightly surprising, it shows that (in spite of the
similar H-bonding and the same space group symmetry)
other weaker forces define the crystal lattices. The

1514
J. Ba´lint et al. / Tetrahedron: Asymmetry 12 (2001) 1511–1518
Figure 4. X-Ray structure model of 1b with atomic displacement parameters. The Newman projection inset is along the
N(1)ꢀC(7)ꢀC(1) bonds; arrows indicate rotations to next-neighbors on the wheel.
As the packings (Fig. 5) indicate, aside from the identi-
cal H-bonding the intermolecular conformations are
somewhat different. Both 1a and 1b have two identical
C-H···p ring center distances (Table 5). One of these
comes in both cases from the same methyl group
hydrogen atom of the oxalamic anion component,
while the other is from a phenyl-hydrogen of the base.
However, these differ in that in 1a a meta-moiety acts
as the donor, while in 1b an ortho-position CꢀH acts as
the donor. All of these shortest CꢀH···p ring contacts
are virtually of equal strength. A probably more rele-
vant difference is seen in the geometry of the aromatic
ring center distances (Table 6).
longer contacts is to the base’s phenyl, while in 1b both
shorter and equal contacts are to and between the acid
aromatic rings. This pattern corroborates a somewhat
closer packing in 1b than in 1a.
3. Experimental
3.1. Materials and methods
1
The H NMR spectra were recorded at 250 MHz on a
Bruker WM250 spectrometer. Chemical shift values are
expressed in ppm values on the l scale. IR spectra of
thin film samples were taken on a Perkin–Elmer 1600
Series FTIR spectrophotometer. Optical rotations were
determined on a Perkin–Elmer 241 polarimeter. Thin-
layer chromatography was carried out using POLY-
GRAM® SIL G/UV254 sheets. Spots were visualized by
UV light or by treatment with 5% ethanolic phospho-
molybdic acid solution and heating of the dried plates.
Chemicals were products of Aldrich. All solvents used
were freshly distilled. GC analyses were done on a
Hewlett–Packard 5890/II instrument equipped with
FID at 120°C. Column was a 20×0.200 mm ID fused
silica tubing, coated with ChNEB (naphthylethylamide
chiral group containing silicone polymerxy) stationary
phase at 0.2 mm film thickness. Carrier gas was H2 with
1:100 split ratio. Samples were derivatized with tri-
fluoroacetic anhydride according to the standard
procedure.13,14
According to the two shortest such contacts for both
crystals, 1b obviously packs better. In 1a one of the two
Table 3. Essential torsion angles in the (S)-PEA 1a and
(R)-PEA 1b salts of (R)-N-(1-phenylethylamine)oxalamic
acid monoamide, with deviations greater than 20° marked
Torsion angle (°)
1a (°)
1b (°)
D\20 (°)
(R)-N-(1-PEA)-Oxalamic
acid
O(3)ꢀC(8)ꢀC(9)ꢀO(1)
O(3)ꢀC(8)ꢀC(9)ꢀO(2)
N(1)ꢀC(8)ꢀC(9)ꢀO(1)
N(1)ꢀC(8)ꢀC(9)ꢀO(2)
C(2)ꢀC(1)ꢀC(7)ꢀN(1)
C(7)ꢀN(1)ꢀC(8)ꢀO(3)
C(8)ꢀN(1)ꢀC(7)ꢀC(1)
C(9)ꢀC(8)ꢀN(1)ꢀC(7)
C(10)ꢀC(7)ꢀN(1)ꢀC(8)
−12.9
168.8
164.4
−13.9
−100.5
5.2
152.5
−172.0
−81.8
−2.0
179.6
176.8
−1.5
−116.6
3.7
77.4
−175.1
−157.4
75.1
75.6
3.2. N-(1-Phenylethylamine)oxalamic acid
(S/R)-N-(1-PhEA)
C(10)ꢀC(7)ꢀC(1)ꢀC(2)
C(12)ꢀC(11)ꢀC(17)ꢀN(2) −134.4
C(18)ꢀC(17)ꢀC(11)ꢀC(12) 102.6
135.3
119.8
138.2
−99.2
A mixture of (R)-1-phenylethylamine (35.0 g, 289
mmol) and diethyl oxalate (127.0 g, 869 mmol) was
stirred at 110°C (oil bath temperature) for 3 h. Excess
a
,
Table 4. Dimensions of hydrogen bonds (A, °) in 1a and 1b
1a/1b
DꢀH···A
1a/1b
DꢀH (A)
1a/1b
H···A (A)
1a/1b
D···A (A)
1a/1b
DꢀH···A (°)
,
,
,
N1ꢀH1···O2
0.86
0.89
0.89
0.89
0.89
2.25/2.30
1.95/1.92
2.02/2.15
2.42/2.17
1.98/1.93
2.640(2)/2.668(2)
2.814(2)/2.811(2)
2.868(2)/2.914(2)
3.024(2)/2.898(2)
2.836(2)/2.784(2)
107.8/106.0
163.1/175.2
158.5/143.4
125.6/138.9
160.7/160.2
N2ꢀH2A···O2i
N2ꢀH2B···O1
N2ꢀH2B···O3
N2ꢀH2C···O1j/k
a Translation of symmetry code to equiv. pos. i=x, −1+y, z; j=1−x, −1/2+y, 1−z; k=−x, −1/2+y, 2−z.

J. Ba´lint et al. / Tetrahedron: Asymmetry 12 (2001) 1511–1518
1515
,
Table 5. Analysis of XꢀH···Cg (p-ring) interactions (H···CgB3.0 A, kB30.0°) (distances to centers of gravities (Cg), indi-
,
cated by their acid–base type, are in A)
,
,
X···H
Cg(J)
d H···Cg (A)
XꢀH···Cg (°)
X···Cg (A)
Compound
C(10)ꢀH(10a) acid-methyl-H
C(15)ꢀH(15) base-meta-H
C(10)ꢀH(10c) acid-methyl-H
C(12)ꢀH(12) base-ortho-H
2756 base
1556 acid
2657 base
1556 acid
2.99
2.87
2.92
2.92
135
160
131
164
3.73
3.75
3.63
3.83
1aa
1a
1bb
1b
a 1a: Calculated density=1.1801(2) (Mg m−3): (2756)=2−x, 1/2+y, 1−z; (1556)=x, y, 1+z, H-bond symops: (1545)=x, −1+y, z; (2646)=1−x, −1/
2+y, 1−z.
b 1b: (2657)=1−x, 1/2+y, 2−z’j=−x, −1/2+y, 2−z; (1556)=x, y, 1+z’i=x, −1+y, z.
Figure 5. Packing motifs in the crystals of 1a and 1b with the unit cell box and with the principal H-bonding shown as broken
lines. The view is a projection near to the b axis.
diethyl oxalate was removed by distillation in vacuo.
The residue (57.8 g of oily material) was treated with
water (175 mL) and NaOH (23 g) and the resultant
mixture was stirred under reflux for 2 h. After cooling
the mixture and stirring for 1 h at 0–5°C the precipi-
tated diamide was collected by filtration. To the mother
liquor 37% aqueous HCl (55 mL) was added and the
mixture was left to crystallize for 2 h at 0–5°C. The
crystals were filtered and washed with water (3×10 mL)
and dried to afford a white crystalline solid of N-(1-
phenylethyl)oxalamic acid (31.2 g, 161 mmol, 56%); mp
128–130°C; [h]2D0=+125.7 (c 1, methanol); 1H NMR
(CDCl3): l 1.62 (d, 3H, CH3), 5.11 (m, 1H, CH),
7.33–7.41 (m, 5H, Ar), 7.61 (s, br, 1H, NH); FT-IR
(KBr, cm−1): 3304, 1764, 1680, 1544, 1436, 1360, 1352,
1304, 1240, 1176, 1116, 880, 776, 740, 696. Anal. calcd
for C18H22N2O3: C, 68.77; H, 7.05; N, 8.91. Found: C,
68.87; H, 7.06; N, 8.90%.
stirred at 145–155°C (oil bath temperature) for 3 h.
Excess diethyl malonate was removed by distillation in
vacuo. To the residue (116.5 g of brown oil), water (350
mL) and NaOH (35 g) were added and the mixture was
stirred under reflux for 2 h. After cooling and stirring
overnight at 0–5°C the precipitated diamide was col-
lected by filtration. The mother liquor was washed with
dichloromethane (4×200 mL), then 37% aqueous HCl
Table 6. Analysis of short ring interactions with Cg–Cg
,
distances B6.0 A and iB60.0°. 1a (calculated density=
1.1801(2) (Mg m−3))
,
Cg(I) type
Cg(J) type
D (A)
Compound
Acid
Acid
Acid
Acid
Acida
Baseb
Acidc
Acidd
5.118
5.084
4.704
4.704
1a
1a
1b
1b
3.3. N-(1-Phenylethyl)malonamic acid
a 1−x, 1/2+y, −z.
b x, y, −1+z.
c −x, −1/2+y, 1−z.
d −x, 1/2+y, 1−z.
A mixture of (R)-1-phenylethylamine (70.0 g, 578
mmol) and diethyl malonate (139.0 g, 868 mmol) was

1516
J. Ba´lint et al. / Tetrahedron: Asymmetry 12 (2001) 1511–1518
(80 mL) was added and the mixture was extracted with
dichloromethane (4×200 mL). The combined organic
phase was dried over Na2SO4 and the solvent was
evaporated. The oily residue crystallized on standing
The mother liquor of the second recrystallization was
evaporated. To the residue water (5 mL) and 37%
aqueous HCl (0.2 mL) were added and the mixture was
extracted with dichloromethane (3×5 mL). After adding
NaOH (0.2 g) to the aqueous phase, it was extracted
with dichloromethane (4×5 mL). The combined organic
phase was dried over Na2SO4 and the solvent was
evaporated, yielding (S)-1-phenylethylamine as an oil
(0.13 g), [h]2D0=−5.2 (c 10, ethanol).
for
3
days to
a
pink solid of N-(1-
phenylethyl)malonamic acid (63.4 g, 306 mmol, 53%);
mp 65–68°C; [h]2D0=+114.1 (c 1, methanol). The
product was suitable for use in resolution experiments
without further purification. The analytical sample was
prepared by three recrystallizations from toluene: mp
69–71°C; [h]2D0=+116.1 (c 1, methanol); 1H NMR
(CDCl3): l 1.48 (d, 3H, CH3), 3.20–3.30 (m, 2H, CH2),
5.07 (m, 1H, CH), 7.23–7.32 (m, 5H, Ar), 7.35 (d, 1H,
NH); FT-IR (KBr, cm−1): 3384, 3288, 1724, 1620, 1576,
1552, 1496, 1324, 1240, 1204, 1128, 740, 680. Anal.
calcd for C19H24N2O3: C, 69.49; H, 7.37; N, 8.53.
Found: C, 69.40; H, 7.38; N, 8.55%.
3.5. Resolution of 1-phenylethylamine by N-(1-
phenylethyl)malonamic acid
( )-1-Phenylethylamine (6.10 g, 50 mmol) and N-(1-
(R)-phenylethyl)malonamic acid (10.4 g, 50 mmol) were
dissolved in hot ethyl acetate (25 mL) and the mixture
was left to crystallize overnight. The crystals were
filtered, washed with ethyl acetate (3×2 mL) and dried
to afford product (7.46 g). The residue was recrystal-
lized twice from acetone (20 mL acetone per recrystal-
lization. Yield from first recrystallization=5.93 g),
affording product (5.34 g), [h]2D0=+49.5 (c 1, methanol),
mp 124–127°C. The diastereoisomeric salt was dis-
solved in water (20 mL), 37% aqueous HCl (1.5 mL)
was added and the mixture was washed with
dichloromethane (4×10 mL). (The organic phase con-
tains the resolving agent.) To the aqueous phase NaOH
(1.5 g) was added and it was extracted with
dichloromethane (4×10 mL). The combined organic
phase was dried over Na2SO4 and the solvent was
evaporated. The residue was distilled in vacuo, yielding
(S)-1-phenylethylamine as an oil (1.72 g), [h]2D0=−30.0
(c 10, ethanol).
3.4. Resolution of 1-phenylethylamine using N-(1-
phenylethyl)oxalamic acid
( )-1-Phenylethylamine (6.10 g, 50 mmol) and N-(1-
(R)-phenylethyl)oxalamic acid (9.70 g, 50 mmol) were
dissolved in hot acetone (25 mL) and the mixture was
left to crystallize overnight. The crystals were filtered,
washed with acetone (3×2 mL) and dried to afford
product (5.82 g). The product was recrystallized twice
from acetone (first recrystallization: 30 mL acetone;
second recrystallization: 20 mL acetone) to give the
diastereoisomeric salt as a white solid (3.62 g); mp
127–130°C; [h]2D0=+66.4 (c 1, methanol). The
diastereoisomeric salt was dissolved in water (10 mL),
37% aqueous HCl (1.5 mL) was added and the mixture
was washed with dichloromethane (3×10 mL). (The
organic phase contains the resolving agent, which can
be recovered by evaporation of the solvent.) The
aqueous phase was treated with NaOH (1.5 g) and the
mixture was extracted with dichloromethane (4×10
mL). The combined organic phase was dried over
Na2SO4 and the solvent was evaporated. The residue
was distilled in vacuo yielding (S)-1-phenylethylamine
as an oil (1.17 g), [h]2D0=−29.8 (c 10, ethanol).
The mother liquor of the resolution was evaporated. To
the residue were added water (20 mL) and 37% aqueous
HCl (3 mL) and the mixture was washed with
dichloromethane (3×20 mL). (The organic phase con-
tains the resolving agent.) To the aqueous phase NaOH
(3 g) was added and it was extracted with
dichloromethane (4×10 mL). The combined organic
phase was dried over Na2SO4 and the solvent was
evaporated. The residue was distilled in vacuo, yielding
(R)-1-phenylethylamine as an oil (2.88 g), [h]2D0=+19.0
(c 10, ethanol).
The mother liquor of the resolution was evaporated. To
the residue were added water (20 mL) and 37% aqueous
HCl (3 mL) and the mixture was washed with
dichloromethane (3×10 mL). (The organic phase con-
tains the resolving agent.) To the aqueous phase was
added NaOH (3 g) and the mixture was extracted with
dichloromethane (4×10 mL). The combined organic
phase was dried over Na2SO4 and the solvent was
evaporated. The residue was distilled in vacuo yielding
(R)-1-phenylethylamine as an oil (2.53 g), [h]2D0=+10.2
(c 10, ethanol). The mother liquor of the first recrystal-
lization was evaporated and the residue treated with
water (10 mL) and 37% aqueous HCl (0.6 mL). The
mixture was washed with dichloromethane (3×10 mL).
After adding NaOH (0.6 g) to the aqueous phase, it was
extracted with dichloromethane (4×10 mL). The com-
bined organic phase was dried over Na2SO4 and the
solvent was evaporated, yielding (R)-1-phenylethyl-
amine as an oil (0.53 g), [h]2D0=+4.0 (c 10, ethanol).
The mother liquor of the first recrystallization was
evaporated. To the residue were added water (10 mL)
and 37% aqueous HCl (0.5 mL) and the mixture was
washed with dichloromethane (3×10 mL). (The organic
phase contains the resolving agent.) After adding
NaOH (0.5 g) to the aqueous phase, it was extracted
with dichloromethane (4×10 mL). The combined
organic phase was dried over Na2SO4 and the solvent
was evaporated, yielding (R)-1-phenylethylamine as an
oil (0.49 g), [h]D20=+4.8 (c 10, ethanol).
The mother liquor of the second recrystallization was
evaporated. To the residue were added water (5 mL)
and 37% aqueous HCl (0.2 mL) and the mixture was
extracted with dichloromethane (3×10 mL). (The
organic phase contains the resolving agent.) After
adding NaOH (0.2 g) to the aqueous phase, it was
extracted with dichloromethane (3×10 mL). The com-

J. Ba´lint et al. / Tetrahedron: Asymmetry 12 (2001) 1511–1518
1517
bined organic phase was dried over Na2SO4 and the
solvent was evaporated, yielding (S)-1-phenylethyl-
amine as an oil (0.18 g), [h]2D0=−19.8 (c 10, ethanol).
crystal decay of 3% (the data were corrected for decay).
A total of 6873 reflections were collected of which 5975
were unique [Rint=0.0231, R(|)=0.0539]; intensities of
3386 reflections were greater than 2|(I). Completeness
to 2q=0.998. An empirical absorption correction was
applied to the data (the minimum and maximum trans-
mission factors were 0.934 and 1.00). The structure was
solved by direct methods. Anisotropic full-matrix least-
squares refinement on F2 for all non-hydrogen atoms
yielded R1=0.0473 and wR2=0.1113 for 3386 [I>2|(I)]
and R1=0.0937 and wR2=0.1212 for all (5975) inten-
sity data (goodness-of fit=0.941; the maximum and
mean shift/e.s.d. 0.002 and 0.000). The maximum and
3.6. X-Ray crystallography
Single crystals were obtained from their optically pure
components by crystallization from acetone.
Compound 1a. Crystal data: C18H22N2O3, Fw 314.38,
colorless block, size: 0.40×0.35×0.15 mm, monoclinic,
space group P21, a=9.869(1), b=6.750(1), c=13.548(1)
3
,
,
A, i=101.38(1)°, V=884.77(17) A , T=566(2) K, Z=
2, F(000)=336, Dcalcd=1.180 Mg m−3, v=0.081 mm−1.
A crystal of 1a was mounted on a glass fiber. Cell
parameters were determined by least-squares of the
setting angles of 25 (14.595q516.70°) reflections.
Intensity data were collected on an Enraf–Nonius
CAD4 diffractometer (graphite monochromator; Mo
minimum residual electron density in the final differ-
−3
,
ence map was 0.224 and −0.133 e A . Hydrogen
atomic positions were calculated from assumed
geometries. Hydrogen atoms were included in structure-
factor calculations but they were not refined. The
isotropic displacement parameters of the hydrogen
atoms were approximated from the U(eq.) value of the
atom they were bonded to.
,
Ka radiation, u=0.710730 A) at 293(2) K in the range
2.355q531.97° using ꢀ–2q scans. The scan width was
0.54+0.54tg(q)° in ꢀ. Backgrounds were measured 1/2
the total time of the peak scans. The intensities of three
standard reflections were monitored regularly (every 60
min). The intensities of the standard reflections indi-
cated a crystal decay of 8% (the data were corrected for
decay). A total of 6973 reflections15 were collected of
which 6117 were unique [Rint=0.0110, R(|)=0.0402];
intensities of 3576 reflections were greater than 2|(I).
Completeness to 2q=0.998. Empirical absorption
correction16 was applied. The structure was solved by
direct methods17 and subsequent difference syntheses.
Anisotropic full-matrix least-squares refinement18 on F2
for all non-hydrogen atoms yielded R1=0.0411 and
wR2=0.1042 for 3576 [I>2|(I)] and R1=0.0843 and
wR2=0.1126 for all (6117) intensity data (goodness-of-
fit=0.977; the maximum and mean shift/e.s.d. 0.000
and 0.000; extinction coefficient=0.013(5)). The maxi-
Acknowledgements
The Hungarian OTKA Foundation (Project No.
T29251) is gratefully acknowledged for financial sup-
port. J.B. and G.E. would like to thank the OTKA
(D32705 and D 29445, respectively) for Postdoctoral
Fellowships. M.C. would also like to thank the OTKA
(T25910) for partial support with the X-ray crystallog-
raphy measurements.
References
1. Sheldon, R. A. Chirotechnology; Marcel Dekker: New
York, 1993.
mum and minimum residual electron density in the final
2. Collins, A. N.; Sheldrake, G. N.; Crosby, J. Chirality in
Industry; John Wiley and Sons, 1992; pp. 69–77.
3. Jacques, J.; Collet, A.; Wilen, S. H. Enantiomers, Race-
mates and Resolution; Wiley: New York, 1981; pp. 253–
328.
4. Ba´lint, J.; Egri, G.; Vass, G.; Schindler, J.; Gaja´ry, A.;
Friesz, A.; Fogassy, E.: Tetrahedron: Asymmetry 2000,
11, 809–813.
−3
,
difference map was 0.142 and −0.133 e A . Hydrogen
atomic positions were calculated from assumed
geometries. Hydrogen atoms were included in structure-
factor calculations but they were not refined. The
isotropic displacement parameters of the hydrogen
atoms were approximated from the U(eq.) value of the
atom they were bonded to.
5. Schneider, G.; Feller, A.; Greff, Z.; Lempert, K.; Fetter,
Compound 1b. Crystal data: C18H22N2O3, Fw 314.38,
colorless block, size: 0.40×0.30×0.25 mm, monoclinic,
´
J.; Hornya´k, G.; Soha´r, P.; Fogassy, E.; Acs, M.; Ku¨rthy,
M.; Fekete, M. 2069/91 Hungarian Patent Application.
space group P21, a=11.478(1), b=6.660(2), c=
´
6. Faigl, F.; Fogassy, E.; Acs, M. Hungarian Patent 1984,
3
,
,
11.593(1) A, i=103.06(1)°, V=863.3(3) A , T=295(2)
K, Z=2, F(000)=336, Dcalcd=1.209 Mg m−3, v=0.083
mm−1. A crystal of 1b was mounted on a glass fiber.
Cell parameters were determined by least-squares of the
setting angles of 25 (17.025q519.86°) reflections.
Intensity data were collected on an Enraf–Nonius
CAD4 diffractometer (graphite monochromator; Mo
193199 (Chem. Abstr. 1984, 104, 190891).
7. Fogassy, E.; Orba´n, I.; Faigl, F.; Kiss, C. Hungarian
Patent 1984, 195174 (Chem. Abstr. 1984, 113, 23378).
8. Newman, P. Optical Resolution Procedures for Chemical
Compounds, Parts I and II; Optical Resolution Inf. Cen-
ter, Manhattan College: Riverdale, New York, 1981; Vol.
2.
9. Juaristi, E.; Escalante, J.; Leo´n-Romo, J. L.; Reyes, A.
Tetrahedron: Asymmetry 1998, 9, 715–740.
10. Felder, E.; Pitre`, D.; Boveri, S. Helv. Chim. Acta 1969,
52, 331.
,
Ka radiation, u=0.710730 A) at 295(2) K in the range
3.555q532.00° using ꢀ–2q scans. The scan width was
0.033° in ꢀ. Backgrounds were measured 1/2 the total
time of the peak scans. The intensities of 3 standard
reflections were monitored regularly (every 60 min).
The intensities of the standard reflections indicated a
11. Chapman, D. T.; Crout, D. H. G.; Mahmoudian, M.;
Scopes, D. I. C.; Smith, P. W. J. Chem. Soc., Chem.

1518
J. Ba´lint et al. / Tetrahedron: Asymmetry 12 (2001) 1511–1518
Commun 1996, 21, 2415–2416.
many, 1996.
12. Gavezzotti, A. Acc. Chem. Res. 1994, 27, 309–314.
13. Juvancz, Z.; Bradshaw, J. S.; Aggarwal, S. K.; Rouse, C.
A.; Tarbet, B. J.; Markides, K. E.; Lee, M. L. Enantiomer
1998, 3, 89.
16. (a) North, A. C.; Philips, D. C.; Mathews, F. Acta
Crystallogr. 1968, A24, 350–359; (b) Reibenspies, J. DAT-
COR Program for Empirical Absorption Correction; Texas
A&M University: College Station, TX, USA, 1989.
14. Knapp, D. R. Handbook of Analytical Derivatization
17. Sheldrick, G. M. SHELXS-97 Program for Crystal Struc-
ture Solution; University of Go¨ttingen: Germany, 1997.
18. Sheldrick, G. M. SHELXL-97 Program for Crystal Struc-
ture Refinement; University of Go¨ttingen: Germany, 1997.
Reactions; Wiley: New York, 1979.
15. Harms, K. XCAD4 Data Reduction Program for CAD4
Diffractometers; Philipps-Universita¨t: Marburg, Ger-
.