Formation of Ternary Inclusion Crystal and Enantioseparation of Alkyl Aryl Sulfoxides by the Salt of Urea-Modified l -Phenylalanine and an Achiral Amine

Article abstract of DOI:10.1021/acs.cgd.6b00768

Chiral supramolecular hosts comprising urea-modified l-phenylalanines and achiral primary amines were developed, which facilitated enantioselective inclusion of alkyl aryl sulfoxides (3) up to 89% ee owing to the formation of ternary inclusion crystals. F

Full text of DOI:10.1021/acs.cgd.6b00768

Article
pubs.acs.org/crystal
Formation of Ternary Inclusion Crystal and Enantioseparation of
Alkyl Aryl Sulfoxides by the Salt of Urea-Modified L‑Phenylalanine
and an Achiral Amine
Koichi Kodama,* Rina Morita, and Takuji Hirose
Graduate School of Science and Engineering, Saitama University, 255 Shimo-Okubo, Sakura-ku, Saitama 338-8570, Japan
S
* Supporting Information
ABSTRACT: Chiral supramolecular hosts comprising urea-
modified L-phenylalanines and achiral primary amines were
developed, which facilitated enantioselective inclusion of alkyl
aryl sulfoxides (3) up to 89% ee owing to the formation of
ternary inclusion crystals. From the structural optimization of
the components, the combination of N-(phenylcarbamoyl)-L-
phenylalanine (1a) and benzhydrylamine (2e) showed the best
inclusion ability among the considered supramolecular hosts.
The type of the hydrogen-bonding network of ammonium-
carboxylate salts 1a·2 was dependent on the steric bulk of
combined primary amine 2. The rigid phenylurea moiety of 1a and moderate steric bulk of 2e played an important role in their
high inclusion ability. Host 1a·2e afforded two ternary polymorphic inclusion crystals with the inclusion of acetonitrile.
Furthermore, the crystal structures of 1a·2e·3 revealed that the inclusion of 3 was assisted by hydrogen bonding to the host and
that stereoselectivity reversal occurred for larger sulfoxides, which was attributed to packing variations of one-dimensional
hydrogen-bonding networks.
materials,14,15 liquid crystals,16,17 and low-molecular-weight
INTRODUCTION
■
gelators.18−22 Moreover, because of salt-formation reproduci-
Recently, inclusion crystals have attracted significant research
bility, the combination of carboxylic acids and amines is suitable
interest for applications such as gas storage and emissive
for the assembly of supramolecular host systems.23−26
materials.1−3 In addition to classical host molecules such as urea
Recently, we have reported enantioseparation of alcohols by
the formation of ternary inclusion crystals with the salts of
and Dianin’s compound, a variety of artificial host molecules
have been designed using crystal engineering techniques.4 More
achiral primary diamines and chiral dicarboxylic acids, which
specifically, chiral host molecules derived from optically active
compounds are useful because they allow enantioselective
were derived from L-tartaric acid or L-aspartic acid.27,28 In these
inclusion crystals, one enantiomer of the alcohols was
inclusion of guest molecules.
preferentially captured in the asymmetric space by hydrogen
Although asymmetric synthesis is a powerful method to
bonding. Because the hydroxy groups of alcohols were both
obtain enantiopure compounds, separation of enantiomers
hydrogen bond donors and acceptors, the alcohols were
from a racemic mixture is a more convenient method for
incorporated by the cooperative formation of two hydrogen
laboratory and industrial-scale preparation of enantiopure
compounds.5−8 Despite the ability to give enantiopure guest
bonds with the host molecules. Here we apply this host system
to the enantioseparation of guest compounds that have only
compounds, slight modifications of the chemical structure of
hydrogen-bond-accepting sites. Enantioseparation of such guest
compounds is more challenging since there are fewer hydrogen-
bonding interactions with the host molecules. Of these
hydrogen-bond-accepting guest molecules, chiral sulfoxides
the host and/or guest molecules can change the resultant
crystal structure, which can be difficult to predict.9,10 Thus,
suitable host−guest combinations can only be found by trial-
and-error. For efficient screening of the host molecules,
supramolecular host systems consisting of chiral and achiral
are the desired target compounds since they are important
chiral auxiliaries,29−31 pharmaceutical compounds,32 etc.
components are useful because their components can be easily
Enantioseparation of alkyl aryl sulfoxides has been reported
interchanged without further synthesis of the optically active
via inclusion crystallization with BINOL, bile acids, or
compound. Such bimolecular hosts afford ternary inclusion
crystals by incorporation of guest molecules; however, the
dipeptides.33−36 We have also reported their enantioseparation
with supramolecular hosts; however, the enantiopure primary
design of ternary organic crystals is challenging, as one- or two-
component crystals can be favorably crystallized in such
processes.11−13
Received: May 22, 2016
Revised: July 25, 2016
The salts of carboxylic acids and primary amines are common
supramolecular synthons for materials such as fluorescent
© XXXX American Chemical Society
A
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amine component of the host is not a naturally occurring
compound and is expensive to purchase.37
Table 1. Enantioselective Inclusion of Phenyl Methyl
Sulfoxide (3a) with the Salts of N-(Phenylcarbamoyl)-L-
phenylalanine (1a) and Achiral Primary Amines (2a−f)
a
During the attempt to develop chiral supramolecular host
systems from inexpensive natural amino acids, chiral carboxylic
acids with a urea moiety were studied for inclusion of hydrogen
bond acceptors. Urea moieties are known as strong hydrogen
bond donors and have been used as asymmetric organo-
catalysts,38−41 host molecules,42−44 etc. In this study,
enantioselective inclusion of alkyl aryl sulfoxides was attempted
with a chiral supramolecular host consisting of an achiral
primary amine and a urea-modified chiral carboxylic acid
derived from L-amino acids.
b
c
d
EXPERIMENTAL SECTION
entry
amine
yield (%)
inclusion ratio (%)
ee (%)
■
General Methods. All the reagents and solvents were purchased
and used as received. Chiral carboxylic acids 1a−f were synthesized
from the corresponding L-amino acids and isocyanates, and acids 1g
and 1h were synthesized by the reaction of L-phenylalanine with
phenyl isothiocyanate and phenylacetyl chloride, respectively.45,46
Sulfoxides 3b−3i were synthesized from the corresponding thiols and
alkyl halides followed by oxidation with hydrogen peroxide.47,48 1H
NMR spectra were recorded at 300 MHz, 400 or 500 MHz on Bruker
AVANCE 300, AVANCE 400 or Bruker AVANCE 500 spectrometers,
respectively. Mass spectra were recorded on a Bruker Autoflex III
MALDI-TOF mass spectrometer. The enantiomeric excess was
determined by chiral HPLC analyses with a Daicel Chiralcel OD-3
column with detection at 254 nm.
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
65
92
24
20
90
20
not included
not included
not included
not included
100
45 (R)
not included
a
Crystallized from aqueous CH3CN in the presence of rac-3a (5
equiv). Yield is calculated based on the molar amount of 1a·2 salt.
Inclusion ratio of 3a was determined by H NMR analysis. ee of 3a
was determined by HPLC analysis. Absolute configuration of the
b
c
d
1
major enantiomer is shown in the parentheses.
Procedure for the Enantioseparation of Sulfoxides with the
Salts of a Chiral Carboxylic Acid and an Achiral Amine. Salt 1·2
was prepared in advance by evaporation of the methanol solution
containing equimolar amounts of 1 and 2. Salt 1·2 and guest sulfoxide
3 (5 equiv) were dissolved in acetonitrile (or aqueous acetonitrile),
and the solution was left until the solvent had evaporated. The
resulting solid deposit was collected and washed with hexane. The
inclusion ratio of the sulfoxide was determined by 1H NMR
spectroscopy measurements of the solids. The included sulfoxide
was isolated from a methanol solution of the solid by preparative-scale
thin-layer chromatography (TLC) and analyzed by HPLC to
determine the enantiomeric excess (ee).
Table 2. Enantioselective Inclusion of Phenyl Methyl
Sulfoxide (3a) with the Salts of Chiral Carboxylic Acids (1a−
a
h) and Diphenylmethylamine (2e)
Single Crystal X-ray Analyses of Solvated Diastereomeric
Salt Crystals. Single crystals suitable for X-ray diffraction analysis
were prepared by slow evaporation of the saturated solutions of the
salts. X-ray crystallographic data were collected on a Bruker Smart
APEX II diffractometer with graphite monochromated Mo Kα
radiation. Data collections were carried out at low temperatures
(150 or 200 K). The structures were solved by a direct method (SIR
2004) and refined by SHELXL-2013 programs.49,50 Crystallographic
information files have been deposited with the Cambridge Structural
Database.
b
c
d
entry
1
acid
yield (%)
inclusion ratio (%)
ee (%)
1a
1a
1b
1c
1d
1e
1f
90
80
64
39
100
100
130
15
45 (R)
89 (R)
rac.
e
2
3
4
f
e
5
e
not crystallized
RESULTS AND DISCUSSION
■
6
59
53
140
75
27 (S)
rac.
Enantioselective Inclusion of Phenyl Methyl Sulfoxide
(3a) by Salt 1a·2. First, we selected L-phenylalanine as a
natural amino acid considering our previous result that the salt
of N-(p-toluenesulfonyl)-L-phenylalanine and (R)-1-phenyl-
ethylamine cocrystallized with six-membered cyclic compounds
such as 1,4-dioxane and cyclohexane.51,52 The urea-modified
chiral carboxylic acid (1a) was directly synthesized from L-
phenylalanine and phenyl isocyanate according to the reported
procedure with some modifications.46 The enantiopurity of 1a
did not decrease, as was confirmed by HPLC analysis after
esterification. The salts of 1a and various achiral primary
amines 2 were crystallized from the aqueous acetonitrile
solution in the presence of phenyl methyl sulfoxide (3a) (Table
1). The salts of 1a and benzylamines (2a−2c) or 2-
phenylethylamine (2d) were crystallized without incorporation
7
e
8
e
1g
1h
not crystallized
115
9
53
16 (S)
a
Crystallized from aqueous CH3CN in the presence of rac-3a (5
equiv). Yield is calculated based on the molar amount of 1·2e salt.
Inclusion ratio of 3a was determined by H NMR analysis. ee of 3a
was determined by HPLC analysis. Absolute configuration of the
major enantiomer is shown in the parentheses. Crystallized from
b
c
d
1
e
f
CH3CN. Not measured.
of 3a (entries 1−4) due to the close packing of the host, which
was unsuitable for the incorporation of 3a. By increasing the
number of phenyl groups on the primary amine, the cavity was
created, and the salt of 1a and benzhydrylamine (2e) afforded
B
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ternary inclusion crystal 1a·2e·3a (entry 5). Guest 3a had an
inclusion ratio of 100% and (R)-3a was preferentially
incorporated in the crystal with a moderate enantiopurity
(45%ee). In contrast, using the sterically bulkier tritylamine
(2f), which has three phenyl groups, resulted in the loss of
inclusion ability for 3a (entry 6). These results indicate that 1a
combined with primary amine 2e, which has moderate steric
bulk, is suitable as a supramolecular chiral host.
Table 3. Enantioselective Inclusion of Alkyl Aryl Sulfoxides
(3) with the Salt of N-(Phenylcarbamoyl)-L-phenylalanine
a
(1a) and Diphenylmethylamine (2e)
Enantioselective Inclusion of Phenyl Methyl Sulfoxide
(3a) by Salt 1·2e. Next, we investigated the effects of the
crystallization solvent and the structure of chiral carboxylic
acids combined with amine 2e (Table 2). When salt 1a·2e was
crystallized from acetonitrile, the enantioselectivity of (R)-3a
drastically increased to 89% ee, while the inclusion ratio
remained unchanged (entry 2). When acid 1b prepared from
benzyl isocyanate and L-phenylalanine was used, a larger
portion of 3a was included, but both enantiomers were
included unselectively (entry 3). Diastereomeric acids 1c-d with
an additional stereocenter on the urea moiety derived from (S)-
or (R)-1-phenylethyamine decreased the inclusion ratio or
prevented crystallization of the salt (entries 4 and 5). These
results suggest that flexible substituents on the urea moiety of 1
are not conducive to the enantioselective inclusion of 3a. When
L-phenylglycine was used instead of L-phenylalanine to decrease
the structural flexibility of acid 1a and 1b, 3a was included in
the salts but with low enantioselectivity (entries 6 and 7). This
result shows that a benzyl group is preferable to a phenyl group
as the side chain structure of the amino acid, while a phenyl
group is suitable as a urea moiety. Unexpectedly, when the salt
formed with thiourea 1g was used instead of the structurally
analogous 1a, an inclusion crystal with 3a was not obtained
(entry 8). In addition, replacement of the phenyl urea moiety of
1a with a benzyl amide moiety (1h) led to lower
enantioselectivity for 3a (entry 9). Although the molecular
size of 1g and 1h was similar to that of 1a, the phenyl urea
moiety of 1a showed better inclusion ability for 3a. The most
suitable host of the series for enantioselective inclusion of 3a
was the 1a·2e salt crystallized from acetonitrile.
b
c
d
entry
sulfoxide
yield (%)
inclusion ratio (%)
ee (%)
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
80
71
61
31
100
110
110
135
89 (R)
74 (S)
70 (S)
16 (S)
not crystallized
58
58
28
69
115
105
110
115
86 (R)
79 (R)
52 (S)
3g
3h
3i
69 (S)
a
b
Crystallized from CH3CN in the presence of rac-3 (5 equiv). Yield
c
is calculated based on the molar amount of 1a·2e salt. Inclusion ratio
d
of 3 was determined by 1H NMR analysis. ee of 3 was determined by
HPLC analysis. Absolute configuration of the major enantiomer is
shown in the parentheses.
Enantioselective Inclusion of Alkyl Aryl Sulfoxides (3)
by Salt 1a·2e. Finally, the scope of enantioselective inclusion
with 1a·2e host was expanded to a variety of alkyl aryl
sulfoxides under the optimized conditions (Table 3). When the
alkyl phenyl sulfoxides (3a−3e) were used as guest molecules,
efficient inclusion was achieved for all sulfoxides except for 3e,
which had the longest alkyl chain (n-butyl group). For
sulfoxides 3b−3d with intermediate length alkyl groups, the
cavity preference for inclusion was altered, and the (S)-
enantiomers were selectively included. The enantioselectivity of
ethyl-substituted 3b was as high as 74% ee; however, the
enantioselectivity decreased as the steric bulk of the alkyl
groups increased to n-propyl-substituted 3c and isopropyl-
substituted 3d (entries 2−4). Such a decrease in enantiose-
lectivity is likely due to the size of alkyl and phenyl substituents
on sulfoxide, which are too similar to be differentiated within
the asymmetric host cavity. For the methyl tolyl sulfoxides (3f−
3h) with an additional methyl group on the aromatic ring of 3a,
all the three positional isomers were included with a high
inclusion ratio and moderate to good enantioselectivities of up
to 86% ee (entries 6−8). It is noteworthy that (S)-enantiomer
was included only in the case of methyl p-tolyl sulfoxide (3h).
For the sulfoxides with either a longer alkyl group (3b−3d) or
with a methyl group on the para-position of the phenyl group
(3h), the favored stereochemistry of the included sulfoxide was
Figure 1. Crystal structure of 1a·2d. (a) Top view of the columnar
structures. Oxygen and nitrogen atoms are represented with red and
blue balls. The dotted lines and arrows show hydrogen bonds and
CH/π interactions, respectively. (b) Schematic representation of the
columnar hydrogen-bonding network. The red and blue lines show
hydrogen bonds from ammonium-carboxylate and urea moiety,
respectively.
C
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Figure 2. Crystal structure of 1a·2f. (a) Top view of the 1D hydrogen-bonding structures. Oxygen and nitrogen atoms are represented with red and
blue balls. The dotted lines show hydrogen bonds, and the arrows show CH/π and NH/π interactions. (b) Schematic representation of the 1D
hydrogen-bonding network. The red and blue lines show hydrogen bonds from ammonium-carboxylate and urea moiety, respectively.
the (S)-enantiomer presumably due to the differences in the
molecular packing of 1a and 2e in the inclusion crystals. In fact,
1a·2e showed (S)-selectivity for sulfoxide 3i as well, which has a
longer alkyl group and a p-methyl substituent on the phenyl
group (entry 9). Thus, salt 1a·2e could be used for the
enantioselective inclusion of eight kinds of alkyl aryl sulfoxides
with various sizes and shapes.
(shown with blue lines in Figure 1), which restricted the
position of the phenyl urea moiety. The other urea hydrogen,
i.e., H2 and the carbonyl oxygen, however, were not involved in
hydrogen bonding. The Ph1 group and the phenylurea moiety
of 1a adopted the gauche conformation, which resulted in an L-
shaped molecular arrangement, as viewed from the columnar
axis. In addition, an intercolumnar CH/π interaction is present
between the Ph1 groups of 1a (the C···π plane and CH···π
plane distances were 3.47 and 2.75 Å, respectively). These
intermolecular interactions likely caused the dense molecular
packing of 1a and 2d, which hindered the incorporation of
guest molecules. Thus, primary amines 2a−2d comprising one
phenyl group are not suitable for the construction of
supramolecular hosts with 1a.
The structure of the salt of 1a and primary amine 2f (Figure
2), which also showed no inclusion ability for 3a, exhibited a
different packing arrangement from the 1a·2d salt. The
carboxylate group of 1a and the ammonium group of 2f
packed in a 1D ribbon-like hydrogen-bonding network, because
of the bulky trityl group of 2f, which shielded the ammonium
hydrogen of 2 from the network. In contrast to the 1a·2d
packing arrangement, only two of the three ammonium
hydrogens formed hydrogen bonds with the carboxylate
oxygens of 1a. The remaining hydrogen formed cationic
NH/π interaction with the Ph1 group of 1a. The resulting
motion constraints of the Ph1 group could have led to the
observed gauche conformation of Ph1 between the carboxylate
Structures and Hydrogen-Bonding Networks of the
Salt Crystals of 1a·2d and 1a·2f. To obtain detailed
information about the inclusion ability and mechanism of chiral
recognition of salts comprising 1a and achiral primary amines 2,
crystallographic analysis was performed on salts 1a·2 obtained
from acetonitrile solutions. For clarity, the two hydrogens from
the urea moiety of 1a are denoted as H1 (attached on the
nitrogen originating from L-phenylalanine) and H2 (attached on
the nitrogen originating from phenyl isocyanate). Furthermore,
the two phenyl groups of 1a are denoted as Ph1 (from L-
phenylalanine) and Ph2 (from phenyl isocyanate). The
structure of 1a·2d prepared from acetonitrile solution, which
did not show inclusion ability for 3a, is shown in Figure 1. Acid
1a and primary amine 2d showed hydrogen-bonding
interactions, which resulted in a one-dimensional (1D)
columnar structure with a 21-screw axis (shown with red lines
in Figure 1), which is the typical hydrogen-bonding network
observed in the primary ammonium-carboxylate salts.53
Another intermolecular hydrogen bond is located between
the carboxylate oxygen and the urea hydrogen (H1) of 1a
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Figure 4. Crystal structure of 1a·2e·AN2. (a) Top view of the 1D
hydrogen-bonding structures. Oxygen and nitrogen atoms are
represented with red and blue balls. The dotted lines and arrows
show hydrogen bonds and CH/π interactions, respectively. (b)
Schematic representation of the 1D hydrogen-bonding network. The
red and blue lines show hydrogen bonds from ammonium-carboxylate
and urea moiety, respectively.
Figure 3. Crystal structure of 1a·2e·AN1. (a) Top view of the 1D
hydrogen-bonding structures. Oxygen and nitrogen atoms are
represented with red and blue balls. The dotted lines and arrows
show hydrogen bonds and CH/π interactions, respectively. (b)
Schematic representation of the 1D hydrogen-bonding network. The
red and blue lines show hydrogen bonds from ammonium-carboxylate
and urea moiety, respectively.
conformation, which led to a linear molecular shape for 1a.
Both urea hydrogens H1 and H2 formed cooperative hydrogen
bonds with a carboxylate oxygen of 1a to reinforce the network.
Acetonitrile molecules were embedded in the channel between
1D structures in a 1:1 ratio without forming hydrogen bonds.
The smaller number of phenyl groups in 2e than that in 2f
allowed for the formation of a space sufficiently large for
solvent incorporation.
The other inclusion crystal, 1a·2e·AN2, was obtained by slow
evaporation of 1a·2e from acetonitrile and belonged to the P21
space group (Figure 4). Compounds 1a and 2e formed a 1D
hydrogen-bonding network, which is a counterpart of the
hydrogen-bonding network of the 1a·2d salt crystal. The 1D
structures were arranged such that a channel-like cavity formed,
where two acetonitrile molecules could be incorporated via
hydrogen bonds with an ammonium hydrogen of 2e. Acid 1a
adopted an L-shaped geometry, which is similar to the structure
adopted in 1a·2d. Three different CH/π interactions connected
the neighboring 1D structures. In addition, the efficient solvent
incorporation is attributed to another CH/π interaction
between the CH of acetonitrile and a phenyl group of 2e
(the C···π plane and CH···π plane distances were 3.72 and 2.88
Å, respectively). The formation of 1a·2e·AN suggests that the
steric demand of the two phenyl groups of primary amine 2e is
suitable for the assembly of a supramolecular host for inclusion
of the guests with a proton-accepting site in combination with
1a in the L-shaped conformation.
and urea moieties, which is the least stable conformer of 1a. To
further contrast the packing arrangement of 1a·2d, the urea
hydrogen H2 formed a hydrogen bond with the carboxylate
oxygen of 1a, which reinforced the 1D network. The dense
packing of the 1D network assisted by CH/π interactions
between the phenyl groups of 2f (the C···π plane and CH···π
plane distances were 3.42 and 2.55 Å, respectively) resulted in
crystallization without the inclusion of the guest molecules.
Although 1a·2d and 1a·2f only afforded guest-free crystals, the
ability of 1a to form hydrogen bonds with both urea hydrogens,
H1 and H2, is beneficial to reinforce the network.
Structures and Hydrogen-Bonding Networks of the
Inclusion Crystals of 1a·2e. The salt of 1a and primary
amine 2e crystallized from an acetonitrile solution afforded
ternary inclusion crystals, 1a·2e·CH3CN, which formed two
polymorphs (1a·2e·AN1 and 1a·2e·AN2) that were composi-
tionally identical but were interconnected by different hydro-
gen-bonding networks. The structure of crystal 1a·2e·AN1 that
was occasionally obtained from an acetonitrile solution in the
presence of benzyl methyl sulfoxide is shown in Figure 3. The
observed 1D ribbon-like hydrogen-bonding network of the
P212121 space group was similar to the packing arrangement
observed in 1a·2f. The hydrogen-bonding network was formed
between ammonium-carboxylate groups, involving two ammo-
nium hydrogens from 2e. The remaining ammonium hydrogen
of 2e formed a hydrogen bond with the urea oxygen of 1a. The
Ph1 group and the phenylurea moiety adopted a trans
From the acetonitrile solutions of 1a·2e and racemic
sulfoxides 3, two ternary inclusion crystals suitable for
E
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Figure 5. Crystal structure of 1a·2e·(R)-3g. (a) Top view of the 1D hydrogen-bonding structures. Oxygen, nitrogen, and sulfur atoms are
represented with red, blue, and yellow balls. The dotted lines and arrows show hydrogen bonds and CH/π interactions, respectively. (b) Side view of
the 1D hydrogen-bonding network. The dotted lines and arrows show hydrogen bonds and short CH/O contacts, respectively.
Figure 6. Crystal structure of 1a·2e·(S)-3i. (a) Top view of the 1D hydrogen-bonding structures. Oxygen, nitrogen, and sulfur atoms are represented
with red, blue, and yellow balls. The dotted lines and arrows show hydrogen bonds and CH/π interactions, respectively. (b) Side view of the 1D
hydrogen-bonding network. The red and blue lines show hydrogen bonds from ammonium-carboxylate and urea moiety, respectively.
crystallographic analysis were successfully obtained. The
structure of 1a·2e·3g is shown in Figure 5. The molecular
orientation and hydrogen-bonding network of 1a·2e were
similar to those of 1a·2e·AN2. Instead of acetonitrile, sulfoxide
(R)-3g was incorporated by a hydrogen bond between the
ammonium hydrogen of 2e and the sulfinyl oxygen of (R)-3g.
The larger molecular volume of (R)-3g than acetonitrile
disrupted the packing of the 1D network such that the channel
size accommodates one molecule of (R)-3g. The m-tolyl group
of (R)-3g interacted with the host via two CH/π interactions
between its para-CH and Ph2 group of 1a (the C···π plane and
CH···π plane distances were 3.70 and 2.76 Å, respectively) and
ortho-CH and phenyl group of 2e (the C···π plane and CH···π
plane distances were 3.68 and 2.89 Å, respectively).
Furthermore, the methyl group on the stereogenic center of
3g was positioned near two oxygens: the urea oxygen of 1a and
the sulfinyl oxygen of neighboring 3g (Figure 5b). These
intermolecular CH/O interactions (the CH···O distances were
2.64 and 2.60 Å, respectively) could enhance the enantiose-
lective inclusion of (R)-3g.54−57 It appeared that the sulfoxides
with a para-methyl substituent or a longer alkyl chain could not
be included via similar interactions to 3g because of the steric
repulsion between 3 and the host molecules. This repulsion
could have led to the reversal of stereoselectivity to the (S)-
enantiomer for sulfoxides 3b−d and 3h−i, as shown in Table 3.
In fact, the structure of 1a·2e·3i showed that (S)-3i was
preferentially included to avoid steric repulsion with the host
molecules (Figure 6). While the hydrogen-bonding network
remained unchanged, the packing of the networks expanded to
accommodate the larger substituents of 3i. The neighboring
networks were packed in an antiparallel arrangement, which
was assisted by the CH/π interactions between the para-CH of
Ph2 and π-plane of Ph1 (the C···π plane and CH···π plane
distances were 3.56 and 2.75 Å, respectively) and the meta-CH
of Ph1 and phenyl group of 2e (the C···π plane and CH···π
plane distances were 3.55 and 2.84 Å, respectively). The only
intermolecular interaction between the host and (S)-3i was an
NH···O hydrogen bond between the ammonium hydrogen of
2e and the sulfinyl oxygen of (S)-3i. It is probable that the
stereoselection of (S)-3i was a result of size recognition of the
tolyl and ethyl groups by the cavity, where the larger tolyl group
occupied the largest space and the smaller ethyl group was
accommodated into the remaining space.
F
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The urea hydrogens of 1a (H1 and H2) not only reinforced
the hydrogen-bonding network, but also restricted the
orientation of its terminal phenyl group Ph2. The resultant L-
shaped conformation of 1a contributed to the enantioselective
inclusion by 1a·2e.
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CONCLUSION
■
In this study, we have demonstrated that the salts of achiral
primary amines and chiral carboxylic acids derived from L-
amino acids successfully formed supramolecular chiral hosts for
enantioselective inclusion of alkyl aryl sulfoxides. The results of
structural optimization indicated that phenylurea and L-
phenylalanine moieties were essential for the carboxylic acid
(1a), and that benzhydrylamine (2e), which had a moderate
steric demand was a suitable achiral primary amine for the
assembly of the supramolecular host. Crystallographic analysis
of salts 1a·2 showed that the amine component affected the
arrangement of the ammonium-carboxylate hydrogen-bonding
network and the molecular conformation of 1a. Salt 1a·2e·
CH3CN afforded two ternary inclusion crystal polymorphs.
Furthermore, eight alkyl aryl sulfoxides were included in the 1a·
2e salt with high enantioselectivities of up to 89%ee. The rigid
L-shaped conformation of 1a assisted by the hydrogen-bonded
phenylurea moiety contributed to the creation of the
asymmetric cavity. Reversed stereochemistry for bulkier
sulfoxides was explained based on different packing arrange-
ments of the 1D hydrogen-bonding networks. Further
investigations of chiral supramolecular hosts for the enantio-
separation of guest compounds are now in progress.
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ASSOCIATED CONTENT
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S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.cgd.6b00768.
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Detailed synthetic procedures and characterization of 1,
summary of the crystallographic data (Table S1), 1H and
13C NMR spectra (PDF)
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Accession Codes
(27) Kodama, K.; Sekine, E.; Hirose, T. Chem. - Eur. J. 2011, 17,
11527−11534.
CCDC 1478526−1478531 contain the supplementary crystal-
lographic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
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Corresponding Author
*Fax: (+81)48-858-9548. E-mail: kodama@mail.saitama-u.ac.
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Notes
The authors declare no competing financial interest.
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