Characteristic Hydrogen Bonding Observed in the Crystals of Aromatic Sulfonamides: 1D Chain Assembly of Molecules and Chiral Discrimination on Crystallization

Article abstract of DOI:10.1021/acs.cgd.9b00159

N-Phenylbenzenesulfonamides exist preferentially in (+)- or (-)-synclinal conformations, which place the aromatic rings at both ends in the same direction with a twist. We have systematically analyzed the crystal structure of secondary aromatic sulfonamides bearing methyl, ethyl, and/or methoxy groups on the benzene rings. Intermolecular hydrogen bonding between the sulfonamide protons and sulfonyl oxygens was observed in 81 out of 85 crystals. The intermolecular hydrogen-bonding patterns could be classified into four types, i.e. Dimeric, Zigzag, Helical, and Straight patterns, with retention of the synclinal conformation of the sulfonamide moiety. We investigated the relationship between the hydrogen-bonding pattern and the proportion of the compounds that show chiral crystallization. On the basis of our classification of the intermolecular hydrogen bonds of aromatic sulfonamides, the crystals with Dimeric and Zigzag patterns, which both have enantiomeric synclinal conformers, intrinsically become achiral, except for kryptoracemates. In contrast, a high proportion of compounds with Helical or Straight patterns in the crystals showed chiral crystallization. Our classification is useful for discussion regarding the chirality of molecular assemblies, on the basis of the conformational chirality of the molecules in the crystal.

Full text of DOI:10.1021/acs.cgd.9b00159

Article
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Cite This: Cryst. Growth Des. 2019, 19, 2936−2946
Characteristic Hydrogen Bonding Observed in the Crystals of
Aromatic Sulfonamides: 1D Chain Assembly of Molecules and Chiral
Discrimination on Crystallization
Shoko Kikkawa,† Hyuma Masu,‡ Kosuke Katagiri,§ Misaki Okayasu,† Kentaro Yamaguchi,∥
Hiroshi Danjo,§ Masatoshi Kawahata,⊥ Masahide Tominaga,∥ Yoshihisa Sei,# Hidemasa Hikawa,†
and Isao Azumaya*,†
†Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan
‡Center for Analytical Instrumentation, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
§Department of Chemistry, Faculty of Science and Engineering, Konan University, 8-9-1 Okamoto, Higashinada, Kobe, Hyogo
658-8501, Japan
∥Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, 1314-1 Shido, Sanuki, Kagawa 769-2193,
Japan
⊥Showa Pharmaceutical University, 3-3165, Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, Japan
#Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, 4259 Nagatsuta,
Midori-ku, Yokohama 226-8503, Japan
S
* Supporting Information
ABSTRACT: N-Phenylbenzenesulfonamides exist preferen-
tially in (+)- or (−)-synclinal conformations, which place the
aromatic rings at both ends in the same direction with a twist.
We have systematically analyzed the crystal structure of
secondary aromatic sulfonamides bearing methyl, ethyl, and/
or methoxy groups on the benzene rings. Intermolecular
hydrogen bonding between the sulfonamide protons and
sulfonyl oxygens was observed in 81 out of 85 crystals. The
intermolecular hydrogen-bonding patterns could be classified
into four types, i.e. Dimeric, Zigzag, Helical, and Straight
patterns, with retention of the synclinal conformation of the
sulfonamide moiety. We investigated the relationship between
the hydrogen-bonding pattern and the proportion of the
compounds that show chiral crystallization. On the basis of our classification of the intermolecular hydrogen bonds of aromatic
sulfonamides, the crystals with Dimeric and Zigzag patterns, which both have enantiomeric synclinal conformers, intrinsically
become achiral, except for kryptoracemates. In contrast, a high proportion of compounds with Helical or Straight patterns in the
crystals showed chiral crystallization. Our classification is useful for discussion regarding the chirality of molecular assemblies,
on the basis of the conformational chirality of the molecules in the crystal.
pounds),20 S-aryl 2-benzoylbenzothionates (3 of 7 com-
INTRODUCTION
■
pounds),25 simple benzophenone derivatives (13 of 55
The chiral crystallization of an achiral compound is of great
compounds), and 1,3-indanedione derivatives (11 of 54
interest in terms of the generation of optical activity simply by
compounds)22 have been found to show chiral crystallization
crystallization,1−3 and chiral crystals have been used as chiral
precursors in asymmetric synthesis4−11 and are associated with
in higher proportions in comparison to other achiral
the origin of life.12−15 We have previously reported that some
compounds.
aromatic amides,16−18 aromatic sulfonamides,19,20 and a
Aromatic sulfonamides display conformational chirality,
benzene-1,3,5-tricarboxylic acid derivative21 show chiral
which is derived from the synclinal conformation in which
the sulfonamide bond connecting the two benzene rings
crystallization phenomena. This type of crystallization,
(Figure 1a) exists in a twisted manner. Consequently, there are
however, does not occur very frequently: only 5−10% of
achiral compounds can be crystallized as chiral crystals,22−24
and the mechanism of the crystallization is still unknown.
However, several groups of compounds with common
skeletons, including aromatic sulfonamides (4 of 12 com-
Received: February 1, 2019
Revised: April 1, 2019
Published: April 22, 2019
© 2019 American Chemical Society
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stronger than the other intermolecular interactions, such as
CH−π, CH−lone pair, aromatic−aromatic, and other hydro-
gen-bonding interactions.19,20,27−34 Herein, we focused on the
effect of noncovalent interactions, such as hydrogen bonding,
in the crystals of secondary aromatic sulfonamides that have
simple substituents, such as methyl, ethyl, and ethoxy groups at
the ortho, meta, and para positions on the aromatic rings.
Recently, several groups have reported classifications based on
the hydrogen-bonding pattern of sulfonamides: graph set
analysis (Adsmond et al.),28 graph set analysis and supra-
molecular synthons (Nangia et al.),29,30 graph set and topology
(Perlovich et al.),31,32 and supramolecular constructs (XPac
program, Gelbrich et al.).33,34 We classified the hydrogen
bonding into four patterns, that is, “Dimeric”, “Zigzag”,
“Helical”, and “Straight” patterns, according to the sign of
the synclinal conformation. Our concept of classification is
relatively uncomplicated and is easy to relate to the chiral
crystallization (chirality of the crystals). We synthesized and
crystallized 85 aromatic sulfonamides and analyzed them by
single-crystal X-ray diffraction. Of the analyzed sulfonamides,
the compounds with the Helical and Straight types of
hydrogen-bonding patterns in the crystals showed chiral
crystallization in anomalously high proportions.
EXPERIMENTAL SECTION
■
General Comments. All of the starting materials, except for 2-
methoxybenzenesulfonyl chloride (S5), and solvents were purchased
from Sigma−Aldrich Japan (Tokyo, Japan), FUJIFILM Wako Pure
Chemical Co. (Osaka, Japan), nacalai tesque, INC. (Kyoto, Japan),
and TCI Co., Ltd. (Tokyo, Japan). All commercially available reagents
and solvents were used without further purification. S5 was
synthesized according to a modified procedure based on a literature
report (see the Supporting Information).
Synthesis and Crystallization. The synthesis and crystallization
of compounds were carried out according to the procedures described
below. Full details of the synthetic and characterization data of 53 new
compounds and 16 previously reported compounds are described in
the Supporting Information.
Typical Procedure for Synthesis (TP-S). A mixture of the
requisite sulfonyl chloride (2.0 mmol), the corresponding aniline (2.2
mmol), and anhydrous pyridine (6.0 mmol) in anhydrous dichloro-
methane was stirred under an argon atmosphere. After approximately
3 h, the reaction mixture was washed with 1 M HCl(aq),
NaHCO3(aq), and brine. The organic layer was dried over Na2SO4
and concentrated under reduced pressure. The crude product was
purified by recrystallization from chloroform/n-hexane to afford the
required sulfonamides S1A1−S7A10.
Typical Procedure for Crystallization (TP-C). Purified
sulfonamide (20 mg) was dissolved (with heating if necessary) in
solvent A (2.0 mL). Solution A (200 μL) was dispensed into a glass
vessel, and solvent B (200 μL) was layered onto solution A. Storage of
the solution mixture at room temperature for several days resulted in
crystals (see the Supporting Information).
Single-Crystal X-ray Diffraction Analysis. A single crystal was
mounted on a loop for the X-ray measurements. Diffraction data were
collected on a X-ray diffractometer (Rigaku XtaLAB P200) equipped
with a rotating anode X-ray source (Mo Kα, λ = 0.71075 Å or Cu Kα,
λ = 1.54187 Å) and a hybrid photon-counting detector (PILATUS
200K). The frame data were integrated, and absorption correction
was calculated using the Rigaku CrystalClear program package. The
structures were solved by SHELXS2013 and SHELXT2014, and
refined by full-matrix least-squares fitting on F2 (SHELXL2013,
SHELXL Version 2014/7).35,36 All non-hydrogen atoms were refined
anisotropically. All N−H hydrogen atoms were found by difference
Fourier synthesis. The other hydrogens (aromatic and methyl
hydrogens) were located on the calculated positions or found by
difference Fourier synthesis. Crystallographic data have been
Figure 1. (a) Various conformations of aromatic N-substituted
benzenesulfonamides. The position of the substituent (R = H,
secondary sulfonamide; R = alkyl, tertiary sulfonamide) is slightly
distorted out of the sulfonamide plane (S−N−C(aniline)). The pale
red sectorial areas show the range of the N−R bond which depends
on the Ph−N−R bond angle. (b) (+)- and (−)-synclinal
conformations of aromatic sulfonamides.
(+)- and (−)-synclinal conformations (Figure 1b), which are
enantiomeric to each other. In solution, aromatic sulfonamides
exist in fast equilibrium between both the enantiomeric
synclinal conformations. In the crystalline state, because the
conformation is fixed, each synclinal conformational enan-
tiomer can be discriminated. Aromatic sulfonamides without
any fixed chiral elements, such as chiral carbon atoms, usually
crystallize as optically inactive crystals that include an equal
amount of both enantiomeric synclinal conformers in the unit
cell. However, if a single crystal that includes only one kind of
enantiomeric conformer is obtained, the crystal will be
conglomerate,26 that is, optically active,19,20 indicating that
the sulfonamide shows chiral crystallization. Although the
structural requirements for chiral crystallization and the
mechanism for the formation of conglomerates remain
unknown, the mechanism must be closely related to the
shape of the molecule and to the intermolecular interactions
between the molecules in the crystals.
In the crystals of secondary aromatic sulfonamides, the
intermolecular hydrogen bonds between the sulfonamide
proton and the O atom of the sulfonyl group are generally
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deposited with the Cambridge Crystallographic Data Center as
supplementary publication numbers CCDC 1894011−1894091 and
1894104. These data can be obtained free of charge from the
Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/
data_request/cif.
RESULTS AND DISCUSSION
■
Crystal Structures of Functionalized Benzenesulfo-
namides. We synthesized 70 aromatic sulfonamides, including
some with crystal structures already reported (1S1A−7S10A),
which have functional groups such as methyl, ethyl, and
methoxy groups, on the benzene rings. Fourteen compounds
were polymorphs or pseudopolymorphs, and we eventually
analyzed 85 crystal structures of 69 compounds. We analyzed
53 new compounds (53 crystals, 9 crystal polymers, and 1
pseudopolymorph) and 16 reported compounds37 (5 new
crystal polymorphs, 14 reported crystals that we reanalyzed,38
and 3 reported crystals which we could not reproduce38). The
crystallographic parameters measured are given in Table S1 in
the Supporting Information.
Conformation of Sulfonamides in the Crystals. First,
we examined the conformation of the sulfonamides. As
expected, all compounds had slightly distorted (+)- or
(−)-synclinal conformations in appearance. Figure 2b shows
the representative compound S1A2, which formed a slightly
distorted (+)-synclinal conformation. In this study, the
sulfonamide hydrogen atoms were located in a difference
map and their coordinates were refined. Although accurately
determining the position of hydrogen atoms by X-ray analysis
is difficult because the electron density of H atoms is poor, all
of the observed amide protons were obviously distorted out of
the S1−N1−C1 plane (shown in violet, C1 is part of the
aniline ring; Figure 2c). The sums of the angles around N1
were less than 360° for all compounds; for instance, in S1A2
this sum was 346° (=111.9° + 119.1° + 115.0°; see Table S2).
The sulfonamide hydrogen atom was placed away from the
oxygen atom (Figure 2c). We defined this conformation as a
slightly distorted synclinal conformation. We observed
intermolecular hydrogen bonding networks between this
sulfonamide hydrogen and the sulfonyl oxygen in the crystals
of 81/85 compounds. Then, we focused on determining
common characteristic hydrogen bond networks, as these are
the most important intermolecular interactions that determine
the crystal structures, including any chiral properties of the
crystals.
Figure 2. Chemical structure and conformation of a representative
aromatic sulfonamide. (a) Synthetic scheme of S1A2. (b) Thermal
ellipsoid view of one molecule of compound S1A2. (c) Diagram
showing the distortion of the N−H bond and the Newman projection
of the stable synclinal conformation. Colors of atoms: C, gray spheres;
O, red spheres; N, violet spheres; S, orange spheres; H, light gray
spheres. Colors of planes: S1−N1−C1 plane and centroid, violet;
N1−S1−C7 plane and centroid, yellow.
Table 1. Four Patterns of Hydrogen-Bonding Networks
Intermolecular Interactions: Classification of Hydro-
gen Bonds. Hydrogen bonding is commonly observed as a
preferential interaction in the crystals of aromatic sulfona-
mides. Therefore, we postulated that the packing of the
molecules in the crystal should depend on the hydrogen-
bonding pattern, and consequently the hydrogen bonding
determines the chirality of the crystals. We classified the
intermolecular hydrogen bonding patterns into the following
four patterns (Figure 3, Table 1): (1) Dimeric, (2) Zigzag, (3)
Helical, and (4) Straight. In addition, the Zigzag and Helical
patterns were subdivided into two types depending on which
of the two sulfonyl oxygen atoms: that is, the anti oxygen (O1
in Figure 3, type 1) or the syn oxygen (O2 in Figure 3, type 2)
was used for hydrogen bonding. An overview of the
classification is shown in Figure 3. The details of each pattern
are described in the following section.
space groups of crystalline sulfonamides and the types of
hydrogen-bonding patterns for 85 crystals (our 82 crystal
structures and 3 previously reported crystal polymorphs39) are
shown in Table 2. The rows and columns of the table
correspond to the starting materials of the sulfonamides:
sulfonyl chlorides (S1−S7) and anilines (A1−A10). Each cell
shows the space group and the hydrogen-bonding pattern.
Divided cells represent the existence of a polymorph. The
hydrogen-bonding pattern is indicated by the background
Adaptation of the Classification of Hydrogen Bond-
ing Patterns to Functional Benzenesulfonamides. The
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a
Table 2. Hydrogen-Bonding Pattern and Space Group of Functionalized Benzenesulfonamides
a
The background color indicates the hydrogen bonding pattern: Dimeric, green; Helical, blue; Straight, red; Zigzag, yellow; others, gray. The term
in the cells describes the space group, and the second or third line indicates the existence of a polymorph (the upper right Roman numeral in the
cell indicates the number of polymorphs). Bold-framed cells indicate chiral crystals. The letters indicate the following: (a) two, (b) three, and (c)
four symmetry-independent molecules in the asymmetric unit; (d) the molecules were connected alternately via 1D chains formed with both O1
and O2; (e) the conformations contained side chains (spacer molecules); (f) intramolecular N−H···OMe bonds were observed; (g) the crystal
lattice contained solvent H2O molecules; (h) the data were in agreement with the reported data;38 (i) reported data (crystal polymolph);39 (j)
molecules related by pseudosymmetry; (k) not crystallized.
color in Table 2: Dimeric, green (44 crystals); Helical 1 and 2,
blue (15 crystals); Straight, red (11 crystals); Zigzag 1 and 2,
yellow (11 crystals); others, gray (4 crystals). The bold-framed
cells represent the crystals that belong to the space groups
(Sohncke type space groups) P41212 and P43212 (which are
enantiomeric to each other) and P21 and P212121: that is,
compounds that crystallized as chiral crystals.40 Thus, 11 out of
the 85 crystals of the synthesized sulfonamides showed chiral
crystallization.
Hydrogen Bonding Classification 1: Dimeric Pattern
(Figures 3a and 4). This pattern had a 0D ring structure of
the hydrogen-bonding network (graph set analysis:41 R22(8);
Figure 4a). The crystals consisted of a racemic pair of (+)- and
(−)-synclinal conformers: in other words, these crystals are
intrinsically racemic compounds, except for kryptoracemates.42
The center of the pairs of molecules was connected by an
inversion center or pseudoinversion center (Figure 4b). In fact,
all the compounds were Dimeric, except for S1A7-I, which
formed optically inactive crystals (see below). A Dimeric
pattern was observed in 44 out of the 85 crystals (52%). We
demonstrated that secondary aromatic sulfonamide groups are
predisposed to form racemic dimer structures. These racemic
dimer structures appear to array themselves depending on the
steric features of the substituents on the aromatic rings, and no
other structural features in the arrangement were found
(Figure 4c,d). The crystal of S7A3-I showed an expanded
Dimeric pattern: that is, the second O atom of molecule A
acted as an acceptor for the amide proton of another molecule,
molecule B. Molecules B formed dangling side chains that
attached to the dimeric motif of molecules A (Table S3).
Hydrogen Bonding Classification 2: Zigzag Pattern
(Figures 3b and 5). This pattern had a 1D structure of the
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Figure 3. Four patterns of hydrogen-bonding networks with symmetry operations: (a) Dimeric; (b) Zigzag and subcategories; (c) Helical and
subcategories, (d) Straight. The elemental hydrogen bond units were shown along with the structural formulas. Circled “+” and “−” indicating (+)-
and (−)-synclinal conformations, respectively.
atom (O1) of the sulfonyl group, and Zigzag-2, where the
chains were connected via the syn oxygen atom (O2). The
Zigzag pattern was observed in 11 of the 85 crystals (13%).
Figure 5 shows the crystal structures of S3A1 (Figure 5a-2,b-
2,c-2) and S1A5 (Figure 5a-2, 4b-2, 4c-2) as representative
Zigzag-1 and -2 patterns, respectively. Structures on the left
(Figure 5a-1,b-1,c-1) show S3A1 (Zigzag-1), and those on the
right (Figure 5a-2,b-2,c-2) show S1A5 (Zigzag-2).
Hydrogen Bonding Classification 3: Helical Pattern
(Figures 3c and 6). This pattern had a 1D structure of the
hydrogen-bonding network (graph set analysis: C11(4)). The
1D polymeric chains formed through hydrogen bonds
consisted of single enantiomers ((+)- or (−)-synclinal)
associated with a 2-fold screw axis (or pseudo-2-fold screw
axis). These crystals may become conglomerate. This type of
crystals was able to be subdivided into two subcategories:
Helical-1, where the chains were connected via the anti oxygen
atom (O1) of the sulfonyl group, and Helical-2, where the
chains were connected via the syn oxygen atom (O2). A
Helical pattern was observed in 15 of the 85 crystals (18%).
Figure 4. Dimeric pattern of hydrogen-bonding networks. (a) Crystal
Figure 6 shows the crystal structures of 2S1A (Figure 6a-1,b-
structure of the Dimeric hydrogen bonding pattern (S4A1-I as a
1,c-1) and S3A7 (Figure 6a-2,b-2,c-2) as representative
representative structure). (b) Pattern diagram and Newman
Helical-1 and -2 patterns, respectively. In the crystals that
projection. Packing structure of S4A1-I (c) and S4A2 (d). Colors
displayed this pattern, each hydrogen-bonding 1D chain
consisted of conformers with a single sign of synclinal
conformation: that is, the chain was homochiral. If a crystal
consists of the homochiral assembly of homochiral 1D helical
chains, the crystal is optically active, which means the
compound will crystallize as a conglomerate: that is, show
chiral crystallization (Figure 6c-1). A crystal that consists of a
heterochiral assembly of homochiral 1D helical chains will be
optically inactive, which means that the compound will
crystallize as a racemic compound (Figure 6c-2). The
of atoms: C, gray spheres; O, red spheres; N, violet spheres; S, orange
spheres; H, light gray spheres.
hydrogen-bonding network (graph set analysis: C11(4)). The
1D polymeric chains formed through hydrogen bonds
consisted of (+)- and (−)-synclinal conformers alternately
associated with glide (or pseudoglide): in other words, these
crystals were also intrinsically racemic compounds. These types
of crystals were able to be subdivided into two subcategories:
Zigzag-1, where the chains were connected via the antioxygen
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Figure 5. Crystal structures of S3A1 and S1A5 as representative
Zigzag-1 and -2 patterns, respectively. The left side shows Zigzag-1
(S3A1: a-1, b-1, c-1), and the right side shows Zigzag-2 (S1A5: a-2, b-
2, c-2). The yellow circles and columns show the 1D zigzag chains.
(a) Top view of the Zigzag hydrogen-bonding motif. The dashed line
on the Newman projection shows the glide plane. (b) Side view of the
Zigzag hydrogen bonding motif. (c) View along the c axis. The
(+)-synclinal chain is shown in red, and the (−)-synclinal chain is
shown in blue; the zigzag 1D chain runs along the c axis. Colors of
atoms: C, gray spheres; O, red spheres; N, violet spheres; S, orange
spheres; H, light gray spheres.
Figure 6. Crystal structures of S2A1 and S3A7-ΙΙ as representative
Helical-1 and -2 patterns, respectively. The left side (a-1, b-1, c-1)
shows Helical-1 (S2A1), and the right side (a-2, b-2, c-2) shows
Helical-2 (S3A7-ΙΙ). The blue circles and columns show 1D helical
chains. (a) Top view of the Helical hydrogen-bonding motif. (b) Side
view of the Helical hydrogen-bonding motif. (c) View along the b axis
(for Helical-1) and the a axis (for Helical-2): The helical 1D chain
runs in the direction vertical to the paper surface. Colors of atoms: C,
gray spheres; O, red spheres; N, violet spheres; S, orange spheres; H,
light gray spheres. Colors of space-filling diagrams: (+)-synclinal
chain, red or pink; (−)-synclinal chain, light blue.
proportions of the compounds showing chiral crystallization
that showed Helical-1 and Helical-2 type patterns were 2/8
and 2/6, respectively; the crystals of S2A7 displayed both
patterns and could not be classified into a single type. The
optical activity of the crystals in this pattern (the combination
of the chirality of the homochiral chains in the assembly) did
not depend on the oxygen that is associated with the hydrogen
bonding (whether O1 or O2). The crystal of S2A7 showed an
expanded Helical pattern: that is, the molecules were
connected alternately via both O1 and O2 and formed a 1D
chain (shown as Helical-1 + 2 in Table 2; see the Supporting
Information). Furthermore, three crystals (S1A4, S3A4, and
S7A7-II; Table S3) showed other expanded Helical patterns.
These structures had multiple independent molecules in the
asymmetric unit, and the independent molecule A formed 2-
fold screw axis related 1D helical chains. Additionally, the
second O atom of molecule A acted as an acceptor for the
amide proton of another molecule, molecule B. Molecules B
(and C, if it exists) formed dangling side chains that attached
to the 1D helical chains of molecules A, and the SO2 moieties
of molecules B (or C) were not involved in any hydrogen-
bonding interactions. The crystal of S1A3, which consists of a
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(+)-helical chain and a (−)-helical chain, crystallized as a
kryptoracemate in the orthorhombic space group P212121 (Z =
8, Z′ = 2; Table S3).
conformation: that is, the chain was homochiral. In the case
of the Straight pattern, as well as the Helical pattern, if a crystal
consisted of a homochiral assembly of homochiral 1D straight
chains, the crystal will be optically active, while if a crystal
consisted of a heterochiral assembly of homochiral 1D straight
chains, the crystal will be optically inactive.
Hydrogen Bonding Classification 4: Straight Pattern
(Figures 3d and 7). In this pattern, a 1D C11(4) chain is
formed by hydrogen bonding between translation-related
molecules. These 1D polymeric chains formed through
hydrogen bonds consisting of single enantiomers ((+)- or
(−)-synclinal) associated by translation. This type of crystal
also may become conglomerate similarly to the Helical pattern.
The molecules composing the 1D chains were always
connected via the anti oxygen atom (O1) of the sulfonyl
group. The Straight pattern was observed in 11 of the 85
crystals (13%). Figure 7 shows the crystal structures of S4A10
(Figure 7a-1,b-1,c-1,d-1) and S1A10 (Figure 7a-1,b-1,c-1,d-1)
as representative of the Straight pattern. In the crystals
belonging to this pattern, each hydrogen-bonding 1D chain
consisted of conformers with a single sign of synclinal
Structural Features and Intermolecular Interactions
Observed in the Crystals. On comparing the crystal
structures of 69 aromatic sulfonamides, we found that there
were some common structural characteristics. First, para-
substituted compounds tended to form Helical and Straight
patterns (18 out of 44, see Table 2). In particular, compounds
containing p-methoxy groups (S7 and A10 derivatives)
preferred to form chiral crystals with a Straight pattern (9 of
21 compounds). Another characteristic intramolecular inter-
action, N−H···OMe, a hydrogen bond in the broad sense,43
was observed in o-methoxybenzenesulfonyl compounds (S5
derivatives). Although hydrogen bonding was not observed in
the three crystals (S5A8-I and -II and A10S7), there were
intermolecular N−H···OMe bonds. Additionally, solvated
crystals were obtained only by crystallization of S7A8 as the
pseudopolymolph S7A8-II, which contained hydrogen bonds
between N−H and the oxygen of a water molecule.
The absolute values of the torsion angles of the sulfonamide
bond (C1(Ar)−N−S−C7(Ar), θ) and dihedral angles of the
two benzene rings (φ) are shown in Table S2. The θ values
were in the range of 47−81°. This result indicated that all of
the compounds formed synclinal conformations.44
Conglomerates of Functionalized Benzenesulfona-
mides. We found that 9 of the 85 crystals of the aromatic
sulfonamides analyzed showed chiral crystallization owing to
having only the same sign of synclinal conformation in a single
crystal (the percentage of compounds showing chiral
crystallization was 10.6%), and two crystallized as kryptor-
acemates. Of the crystals that displayed Helical and Straight
patterns, 3 of 15 compounds (20%) and 6 of 11 compounds
(55%), respectively, were obtained as conglomerates: that is,
showed chiral crystallization. The Dimeric and Zigzag patterns
intrinsically do not form conglomerates because these two
patterns contain synclinal conformations of both signs in equal
amounts. In fact, among the compounds that displayed
Dimeric and Zigzag patterns, only the crystal of S1A7-I
(Dimeric) showed optical activity, which was because of the
unidirectional distortion of an enantiomeric pair of synclinal
conformations: that is, a kryptoracemate.42 Thus, our
classification is well-suited for discussions regarding the
chirality of molecular assemblies based on the conformational
chirality of the molecules in the crystal. If a crystal adopts a
Helical or Straight pattern in the assembly, the crystal has the
potential to be optically active. Whether the crystal is optically
active, that is, shows chiral crystallization or not, depends on
how the 1D chains assemble in the 3D space.45−47 In the
Helical or Straight pattern of crystals, each hydrogen-bonding
1D chain always consisted of molecules that formed synclinal
conformations with a single sign to give a “homochiral 1D
chain”. Thus we have succeeded in associating the generation
of the chirality of the crystal with the symmetry of the
molecular array in the 3D space: that is, the space group.
Specifically, in the Helical pattern, we obtained crystals that
belonged to the space groups P21, P212121, P41212, and P43212
Figure 7. Crystal structures of S4A10 and S1A10 as representative of
the Straight pattern. The left side (a-1, b-1, c-1) shows chiral S4A10
(space group P21), and the right side (a-2, b-2, c-2) shows achiral
S1A10 (space group: P21/c). The red columns and circles show 1D
straight chains. (a) Top view of the Straight hydrogen-bonding motif.
(b) Side view of the Straight hydrogen bonding motif. (c, d) View
along the b axis: the straight 1D chain runs along the b axis. Colors of
atoms: C, gray spheres; O, red spheres; N, violet spheres; S, orange
spheres; H, light gray spheres. Colors of space-filling diagrams in (d):
(+)-synclinal chain, red or pink; (−)-synclinal chain, blue or light
blue.
(which are Sohncke type space groups) and P21/c and P1
̅
(which represent achiral crystals). In the construction of the
crystals, first, a homochiral 1D chain is formed around a 2-fold
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Figure 8. Assembly of chiral-21 columns in the Helical pattern according to the relationship of the symmetry operations and the resulting space
○
groups: P21 (a); P212121 (b); P41212 (c); P21/c and P21/n (d); P-1 (e). Graphical symbols: half arrow, 2-fold screw axis; “ ”, inversion center.
Colors of columns: (+)-synclinal, pink; (−)-synclinal, purple. Selected symmetry elements are omitted for clarity.
screw axis (chiral-21 column; Figure 8). This 1D helical chain
extends into 2D sheets and 3D structures, through self-
assembly with adjacent chiral-21 columns in relation to
symmetry operations. The space group depended on the
symmetry operation that relates to these chiral-21 columns.
When a crystal belonged to space group P21, one chiral-21
column parallel to the b axis was in the unit cell and was
related to an adjacent chiral-21 column by translation. Hence,
the direction of the column and the synclinal conformation of
the structures was the same, allowing formation of a
conglomerate. Similarly, crystals with the space group
P212121 had chiral-21 columns parallel to the unit cell, and
two parallel chiral-21 columns in the same direction were
related by the 21 axis parallel to the columns. The resulting
homochiral layer was also associated with the opposite layer by
the 21 axis perpendicular to the columns. In addition, in
crystals with the space group P41212 (and P43212), four
orthogonal chiral-21 columns were related by the 4-fold (41 or
43) screw axis. In the cases of the space groups P212121, P41212,
and P43212, although the directions of the columns were
different, the crystals were conglomerate because both the
columns consisted of the same synclinal conformation. In
contrast, crystals with the space group P21/c (P21/n) had
chiral-21 columns parallel to the b axis in the unit cell, and two
parallel chiral-21 columns in the same direction and with the
same synclinal conformations were related by the 21 axis
parallel to the columns. The resulting homochiral layer was
also associated with the inversion-related layer; hence, the
̅
crystals were racemic compounds. The space group P1, which
is a slightly special case, had two chiral-21 columns (Z’ = 4) in
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Figure 9. Assembly of chiral-t columns in the Straight pattern according to the relationship of the symmetry operations and the resulting space
○
groups: P21 (a); P212121 (b); P21/c and P21/n (c). Graphical symbols: half arrow, 2-fold screw axis; “ ”, inversion center. Colors of columns:
(+)-synclinal, pink; (−)-synclinal, purple.
the unit cell. These columns were related by inversion. The
synclinal conformations in the columns were inversed by the
symmetry operation; thus, the resulting crystals become
achiral.
contrast, crystals with the space group P21/c (P21/n) had four
chiral-t columns parallel to the a axis (case A) or b axis (case
B) in the unit cell. The chiral-t columns that had the same
synclinal conformation had the 21 axis perpendicular (case A)
or parallel (case B) to the columns, and the resulting
homochiral layer was also associated with the inversion-related
layer. The synclinal conformations in the column were inverted
by the symmetry operation; therefore, the resulting crystals
become achiral.
In the Straight pattern, we obtained crystals that belonged to
the space groups P21, P212121, and P21/c. In the construction
of the crystals, first, molecules were associated by translation to
give a homochiral 1D chain (chiral-t column, Figure 9). Similar
to the Helical pattern, in the crystals with the space group P21,
the two chiral-t columns in the unit cell, which were parallel to
the b axis, were related by the 21 axis parallel to the columns.
The resulting chiral column pair was associated by translation.
When the space group is P212121, two chiral-t columns parallel
to the b axis were in the unit cell and were related by the 21 axis
parallel to the columns. The resulting homochiral layer was
also associated with the opposite layer by the 21 axis
perpendicular to the columns. In the cases of the space
group P21 and P212121, the crystals were conglomerate. In
CONCLUSION
■
We analyzed 85 crystal structures of 69 secondary
benzenesulfonamide derivatives, some of which showed chiral
crystallization. On the basis of the results of single-crystal X-ray
diffraction analysis, we proposed a new classification system
based on the intermolecular hydrogen bond network pattern in
the crystals focusing on the synclinal conformation of the
sulfonamide bond. The crystals were classified according to
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Article
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whether Dimeric, Zigzag, Helical, or Straight patterns were
formed. The analyzed crystals displayed one of these four
patterns, with the exception of a very few examples. This
classification is superior to other methods, especially for
discussing the relationships between the molecular arrange-
ments and the chiral crystallization phenomenon of sulfona-
mides. In the Helical pattern, the 1D helical chain extends into
2D sheets through self-assembly with adjacent 1D helical
chains by weak intermolecular interactions. When the sign of
the synclinal conformation in an adjacent HB 1D chain was
same as that of the first 1D helical chain, a homochiral 2D
sheet was obtained. Furthermore, if a homochiral 2D sheet was
assembled with other 2D sheets with the same sign, a
homochiral 3D crystal (conglomerate crystal) was obtained.
The percentage of these 69 compounds that showed chiral
crystallization was 10.6%, and on the basis of our classification
system, Dimeric and Zigzag patterns intrinsically resulted in
achiral crystals. In contrast, Helical and Straight patterns
produced a high proportion of conglomerate crystals (20% and
55%, respectively).
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.cgd.9b00159.
■
S
Details of synthesis, crystallographic data, and additional
crystal structure (PDF)
(11) Soai, K.; Kawasaki, T.; Matsumoto, A. Asymmetric
Autocatalysis of Pyrimidyl Alkanol and Its Application to the Study
on the Origin of Homochirality. Acc. Chem. Res. 2014, 47 (12), 3643−
3654.
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Walker, D. C., Ed.; Elsevier: Amsterdam, The Netherlands, 1979;
Chapter 14.
Accession Codes
CCDC 1894011−1894091 and 1894104 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing 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.
(13) Mason, S. F. Origins of Biomolecular Handedness. Nature
1984, 311 (5981), 19−23.
(14) Kawasaki, T.; Suzuki, K.; Hakoda, Y.; Soai, K. Achiral
Nucleobase Cytosine Acts as an Origin of Homochirality of
Biomolecules in Conjunction with Asymmetric Autocatalysis. Angew.
Chem., Int. Ed. 2008, 47 (3), 496−499.
AUTHOR INFORMATION
Corresponding Author
*I.A.: e-mail, isao.azumaya@phar.toho-u.ac.jp; fax, +81-47-
472-1585; tel, +81-47-472-1589.
■
(15) Feringa, B. L.; van Delden, R. A. Absolute Asymmetric
Synthesis: The Origin, Control, and Amplification of Chirality. Angew.
Chem., Int. Ed. 1999, 38 (23), 3418−3438.
ORCID
Shoko Kikkawa: 0000-0002-9390-5671
Kosuke Katagiri: 0000-0002-3871-619X
Kentaro Yamaguchi: 0000-0002-2629-716X
Hiroshi Danjo: 0000-0001-9850-8301
Masahide Tominaga: 0000-0003-3199-1882
Hidemasa Hikawa: 0000-0002-7819-3012
Isao Azumaya: 0000-0002-6651-2768
(16) Azumaya, I.; Yamaguchi, K.; Okamoto, I.; Kagechika, H.;
Shudo, K. Total Asymmetric Transformation of an N-Methylbenza-
mide. J. Am. Chem. Soc. 1995, 117, 9083−9084.
(17) Azumaya, I.; Okamoto, I.; Nakayama, S.; Tanatani, A.;
Yamaguchi, K.; Shudo, K.; Kagechika, H. A Chiral N-Methylbenza-
mide: Spontaneous Generation of Optical Activity. Tetrahedron 1999,
55, 11237−11246.
(18) Azumaya, I.; Okamoto, I.; Takayanagi, H. Spontaneous Optical
Resolution of 1,2-Bis(Formylamino)Benzene in Crystals. Anal. Sci.: X-
Ray Struct. Anal. Online 2003, 19, x3−x4.
Notes
The authors declare no competing financial interest.
(19) Azumaya, I.; Kato, T.; Okamoto, I.; Yamasaki, R.; Tanatani, A.;
Yamaguchi, K.; Kagechika, H.; Takayanagi, H. Absolute Helical
Arrangement of Sulfonamide in the Crystal. Org. Lett. 2003, 5 (21),
3939−3942.
(20) Kato, T.; Okamoto, I.; Tanatani, A.; Hatano, T.; Uchiyama, M.;
Kagechika, H.; Masu, H.; Katagiri, K.; Tominaga, M.; Yamaguchi, K.;
Azumaya, I. Spontaneous Resolution of Aromatic Sulfonamides:
Effective Screening Method and Discrimination of Absolute Structure.
Org. Lett. 2006, 8 (22), 5017−5020.
(21) Azumaya, I.; Uchida, D.; Kato, T.; Yokoyama, A.; Tanatani, A.;
Takayanagi, H.; Yokozawa, T. Absolute Helical Arrangement of
Stacked Benzene Rings: Heterogeneous Double- Helical Interaction
Comprising a Hydrogen-Bonding Belt and an Offset Parallel
ACKNOWLEDGMENTS
■
I.A. is supported by the Research Encouragement Grants from
Asahi Glass Foundation and JSPS KAKENHI Grant Number
16590011 and 25670006. We are deeply grateful to Emeritus
Professor Mikiji Miyata (Osaka University) for valuable
discussions.
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