Polymorphism of aromatic sulfonamides with fluorine groups

Article abstract of DOI:10.1021/cg300098q

N-(2-Phenoxyphenyl)benzenesulfonamide (1) and fluorine-substituted N-(2-phenoxyphenyl)benzene sulfonamides (2-5) were designed to examine the effect of a fluorine group in the polymorphism of aromatic sulfonamides. Single-crystal X-ray analysis revealed that those with a fluorine (2-5) afforded polymorphs or pseudopolymorphs while the sulfonamide without fluorine (1) did not. From the differential scanning calorimetry measurements, stable (2a-5a) and metastable (2b-5b) crystalline forms were identified. The sulfonamide 1 formed a dimer through hydrogen bonds (H-bonds), which were aligned into two-dimensional (2D) layers via π/π and CH/π interactions. In 2b, 3b, and 4a, the sulfonamide constructed a dimer through H-bonds, which formed 2D layers via CH/F interactions. The sulfonamides 4 formed a one-dimensional (1D) straight chain via H-bonds, which were arranged into 2D layers via CH/F, CH/O, and CH/π interactions in 4b. The sulfonamide 5 either formed a dimer through H-bonds, which formed 2D layers via CH/O and π/π interactions in 5a, or formed a 1D straight chain via CH/O and π/π interactions, which were arranged into 2D layers via F/F and CH/F interactions in 5b. In the pseudopolymorph 5c, the sulfonamide 5 formed a 1D zigzag chain via CH/F interactions and was assembled into 2D layers via π/π interactions.

Full text of DOI:10.1021/cg300098q

Article
pubs.acs.org/crystal
Polymorphism of Aromatic Sulfonamides with Fluorine Groups
Sho Terada, Kosuke Katagiri, Hyuma Masu,† Hiroshi Danjo,‡ Yoshihisa Sei,§ Masatoshi Kawahata,
Masahide Tominaga, Kentaro Yamaguchi, and Isao Azumaya*
Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, 1314-1 Shido, Sanuki, Kagawa 769-2193, Japan
S
* Supporting Information
ABSTRACT: N-(2-Phenoxyphenyl)benzenesulfonamide (1) and fluorine-
substituted N-(2-phenoxyphenyl)benzene sulfonamides (2−5) were designed
to examine the effect of a fluorine group in the polymorphism of aromatic
sulfonamides. Single-crystal X-ray analysis revealed that those with a fluorine
(2−5) afforded polymorphs or pseudopolymorphs while the sulfonamide
without fluorine (1) did not. From the differential scanning calorimetry
measurements, stable (2a−5a) and metastable (2b−5b) crystalline forms
were identified. The sulfonamide 1 formed a dimer through hydrogen bonds
(H-bonds), which were aligned into two-dimensional (2D) layers via π/π and
CH/π interactions. In 2b, 3b, and 4a, the sulfonamide constructed a dimer
through H-bonds, which formed 2D layers via CH/F interactions. The
sulfonamides 4 formed a one-dimensional (1D) straight chain via H-bonds,
which were arranged into 2D layers via CH/F, CH/O, and CH/π interactions in 4b. The sulfonamide 5 either formed a dimer
through H-bonds, which formed 2D layers via CH/O and π/π interactions in 5a, or formed a 1D straight chain via CH/O and π/
π interactions, which were arranged into 2D layers via F/F and CH/F interactions in 5b. In the pseudopolymorph 5c, the
sulfonamide 5 formed a 1D zigzag chain via CH/F interactions and was assembled into 2D layers via π/π interactions.
polymorphism of two or more crystal systems.11 These
polymorphs and pseudopolymorphs are comprised of various
types of molecular network structures through noncovalent
interactions. However, the effects of fluorine groups on
INTRODUCTION
Polymorphism and pseudopolymorphism of organic com-
pounds have attracted significant attention in medicinal
chemistry and materials science because compounds exhibit
■
polymorphs and pseudopolymorphs of aromatic sulfonamides
are rarely reported. Here, we describe the syntheses and
characterization of the crystal structures of a series of aromatic
sulfonamides that have fluorine groups: N-(2-phenoxyphenyl)-
benzenesulfonamide (1), 2-fluoro-N-(2-phenoxyphenyl)benzene-
sulfonamide (2), 3-fluoro-N-(2-phenoxyphenyl)benzenesulfon-
amide (3), 4-fluoro-N-(2-phenoxyphenyl)benzenesulfonamide
(4), and 2,3,4,5,6-pentafluoro-N-(2-phenoxyphenyl)benzene-
sulfonamide (5). All of these aromatic sulfonamides with
fluorine groups exhibited polymorphism in contrast to a
compound that did not have fluorine groups. The crystal
arrangements were constructed by intermolecular hydrogen
bonds, CH/F, CH/O, and CH/π interactions, and π/π
interactions between the component units.
various types of physical and chemical properties due to the
different packing types of the component molecules.1
Generally, most polymorphisms and pseudopolymorphisms
occur for organic molecules and are derived from multiple
intermolecular weak noncovalent interactions such as hydrogen
bonds,2 CH/π interactions,3 aromatic−aromatic interactions,4
and others,5 where solvent,6 temperature,7 and other factors8
are involved in the crystal-growth process. Especially, poly-
morphism of organic molecules bearing a fluorine group are
important because a large number of drugs contain fluorine
groups on their organic skeleton, and they are important for the
drugs’ specific pharmacological activities. Thus, comparisons
between polymorphs offer fundamental and valuable informa-
tion on the relation between the alignment of individual
molecules and their properties in the solid state. In addition,
the fluorine group shows unique and specific chemical
properties including F/π, F/F, and donor−acceptor inter-
molecular interactions.9 Thus when fluorine groups are
introduced into organic molecules that previously did not
show polymorphism, we expect that these unique interactions
may result in the fluorine-substituted compounds having a
higher probability of demonstrating polymorphism.
EXPERIMENTAL SECTION
■
General. Benzenesulfonyl or fluorobenzenesulfonyl chloride (2.0
mmol) was added dropwise to a solution of 2-phenoxyaniline (2.2 mmol)
in pyridine (50 mL) with stirring under an Ar atmosphere. After being
stirred at room temperature for 3 h, the reaction mixture was poured
into ice and extracted with chloroform. The organic layer was
successively washed with 2 M HCl (30 mL), saturated aqueous
Previously, we reported polymorphism and pseudopoly-
morphism of aromatic bis-phenyl and macrocyclic molecules
containing sulfonamide parts.10 Recently, Nangia et al. also
reported that several substituted aromatic sulfonamides yield
Received: January 23, 2012
Revised: April 11, 2012
© XXXX American Chemical Society
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Scheme 1. Synthetic Procedure for the Preparation of
Sulfonamides 1−5
Figure 1. Comparison between polymorphs and pseudopolymorph of
the crystals (a) 2, (b) 3, (c) 4 and (d) 5. Black dotted lines show
H-bonds, CH/O interactions, and aromatic−aromatic interactions.
NaHCO3 (30 mL), and brine (30 mL) and dried over Na2SO4. The
solvent was evaporated, and the crude product was recrystallized from
20 different types of mixed solvents to give a pure product.
N-(2-Phenoxyphenyl)benzenesulfonamide, 1. Yield 0.60 g, 87%.
1
Mp 110−111 °C. IR (KBr) ν 1149, 3242 cm−1. H NMR (400 MHz,
CDCl3, 25 °C): δ 7.83 (dt, J = 2.0, 8.0 Hz, 1H), 7.63 (dd, J = 2.4, 8.0
Hz, 1H), 7.49 (m, 1H), 7.38 (s, 1H), 7.27 (m, 3H), 7.17 (dt, J = 0.8,
B
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Table 2. Conformational Parameters of Sulfonamides 1−5
torsion angle C1−S1−N1−C7
dihedral angle Ph1−Ph2
crystal
(deg)
(deg)
1
66.9(1)
66.9(2)
69.9(1)
66.4(1)
62.1(3)
67.9(2)
72.4(2)
71.0(1)
71.6(2)
74.6(7)
82.9(7)
83.5(8)
72.1(9)
86.8(8)
75.9(2)
68.4(2)
62.7(1)
68.7(1)
71.1(1)
78.8(6)
2a
2b
3a
3b
4a
4b
5a
5b
5c
Figure 3. Hydrogen bond motifs of the sulfonamides.
Figure 2. Thermal ellipsoid models of the crystal structures of
sulfonamides (a) 1, (b) 2a, (c) 2b, (d) 3a, (e) 3b, (f) 4a, (g) 4b, (h)
5a, (i) 5b, and (j) 5c. Ellipsoids of all non-hydrogen atoms are drawn
at the 50% probability.
7.6 Hz, 1H), 7.12 (dt, J = 1.2, 8.4 Hz, 1H), 7.0 (m, 3H), 6.75 (m, 3H)
ppm. 13C NMR (100 MHz, CDCl3): δ 116.91, 117.11, 117.78, 118.47,
122.46, 123.81, 124.00, 124.15, 124.19, 125.78, 127.31, 129.86, 130.78,
135.28, 135.36, 147.53, 155.97, 160.26 ppm. MS (FAB): m/z = 343.0
[M]+. Elemental Anal. Calcd for C18H15O3NS: C, 62.96; H, 4.11; N,
4.08. Found: C, 62.83; H, 3.84; N, 4.17.
Figure 4. Crystal structure of the sulfonamide 1 in a ball and stick
model: (a) arrangement of dimeric units through intermolecular π/π
interactions; (b) arrangement of dimeric units through CH/π
interactions. Black dotted lines and red dotted lines show H-bonds
and aromatic−aromatic interactions, respectively.
2-Fluoro-N-(2-phenoxyphenyl)benzenesulfonamide, 2. Yield 0.60
1
g, 87%. Mp 110−111 °C. IR (KBr) ν 1149, 3242 cm−1. H NMR
(400 MHz, CDCl3, 25 °C): δ 7.83 (dt, J = 2.0, 8.0 Hz, 1H), 7.63 (dd,
C
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Figure 5. Crystal structure of the sulfonamide 2a as a ball and stick
model: (a) arrangement of the dimeric units through intermolecular
π/π interactions; (b) arrangement of dimeric units through CH/π
interactions. Black dotted lines and red dotted lines show H-bonds and
aromatic−aromatic interactions, respectively.
Figure 6. Crystal structure of the sulfonamide 2b as a ball and stick
model: (a) arrangement of the dimeric units through intermolecular
CH/F and CH/π interactions; (b) arrangement of dimeric units
through π/π and CH/π interactions. Black dotted lines and red dotted
lines show H-bonds and aromatic−aromatic interactions, respectively.
J = 2.4, 8.0 Hz, 1H), 7.49 (m, 1H), 7.38 (s, 1H), 7.27 (m, 3H), 7.17
(dt, J = 0.8, 7.6 Hz, 1H), 7.12 (dt, J = 1.2, 8.4 Hz, 1H), 7.0 (m, 3H),
6.75 (m, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ 116.91, 117.11,
117.78, 118.47, 122.46, 123.81, 124.00, 124.15, 124.19, 125.78, 127.31,
129.86, 130.78, 135.28, 135.36, 147.53, 155.97, 160.26 ppm. MS
(FAB): m/z = 343.0 [M]+. Elemental Anal. Calcd for C18H14O3NSF:
C, 62.96; H4.11; N, 4.08. Found: C, 62.83; H, 3.84; N, 4.17.
3-Fluoro-N-(2-phenoxyphenyl)benzenesulfonamide, 3. Yield 0.58
g, 85%. Mp 109−110 °C. IR (KBr) ν 1152, 3242 cm−1. 1H NMR (400
MHz, CDCl3): δ 7.69 (dt, J = 2.0, 8.0 Hz, 1H), 7.53 (m, 1H), 7.44 (m,
1H), 7.36 (m, 1H), 7.25 (t, J = 16.0 Hz, 3H), 7.07 (m, 4H), 6.70 (dd,
J = 2.4, 8.0 Hz, 1H), 6.62 (m, 2H) ppm. 13C NMR (100 MHz,
CDCl3): δ 114.58, 114.83, 117.87, 118.40, 120.10, 120.31, 122.67,
123.08, 123.12, 124.01, 124.18, 126.12, 127.33, 129.95, 130.66, 130.74
ppm. MS (FAB): m/z = 343.0 M+. Elemental Anal. Calcd for
C18H14O3NSF: C, 62.96; H, 4.11; N, 4.08. Found: C, 62.63; H, 4.06;
N, 4.08.
4-Fluoro-N-(2-phenoxyphenyl)benzenesulfonamide, 4. Yield 0.61
g, 90%. Mp 114−115 °C. IR (KBr) ν 1142, 3240 cm−1. 1H NMR (400
MHz, CDCl3): δ 7.72 (m, 3H), 7.25 (t, J = 16.0, 2H), 7.05 (m, 6H),
6.70 (dd, J = 2.0, 8.0 Hz, 1H), 6.62 (dd, J = 2.2, 8.4 Hz, 2H) ppm. 13C
NMR (100 MHz, CDCl3): δ 116.02, 116.07, 118.02, 118.28, 122.81,
124.04, 124.09, 126.04, 127.58, 129.92, 129.96, 130.05, 147.56, 155.77
ppm. MS (FAB): m/z = 343.0 M+. Elemental Anal. Calcd for
C18H14O3NSF: C, 62.96; H, 4.11; N, 4.08. Found: C, 62.92; H, 3.78;
N, 4.32.
C18H10O3NSF5: C, 52.05; H, 2.43; N, 3.37. Found: C, 52.30; H, 2.44;
N, 3.24.
Crystallization. The sulfonamides were dissolved with chloroform,
ethyl acetate, or tetrahydrofuran as good solvents. Each solution was
put into microtubes that included chloroform, ethyl acetate, toluene,
hexane, methanol, acetone, acetonitrile, and tetrahydrofuran as poor
solvents. (See Supporting Information).
Measurement. X-ray data of the crystals were collected on a CCD
diffractometer with graphite-monochromated Mo Kα (λ = 0.71073 Å)
radiation. Data collection for crystals of 3b was carried out at room
temperature. For other crystals, data collections were carried out at
low temperature (150−100 K) using liquid nitrogen. The crystal
structures were solved by the direct method SHELXS-97 and refined
by full-matrix least-squares SHELXL-97.12 All non-hydrogen atoms
were refined anisotropically, and hydrogen atoms were included at
their calculated positions.
Differential scanning calorimetry (DSC) was measured at a heating
rate of 10 K/min. Samples weighing 2−3 mg were heated in open
aluminum pans under a nitrogen gas flow of 20 mL/min.
Thermogravimetric analysis (TGA) experiment was measured at a
heating rate of 10 °C/min. Sample of 5c (4.591 mg) was heated in
open aluminum pan from 30 to 500 °C.
RESULTS AND DISCUSSION
Aromatic sulfonamides (1−5) were prepared by the reaction of
the substituted sulfonyl chloride with 2-phenoxyaniline
■
2,3,4,5,6-Pentafluoro-N-(2-phenoxyphenyl)benzenesulfonamide,
5. Yield 0.67 g, 81%. Mp 122−123 °C. IR (KBr) ν 1145, 3250 cm−1.
1H NMR (400 MHz, CDCl3): δ 7.71−7.67 (m, 1H), 7.49 (brs, 1H),
7.31 (t, J = 8.4 Hz, 2H), 7.18−7.12 (m, 3H), 6.88−6.84 (m, 1H), 6.78
(d, J = 8.0 Hz, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ 155.97,
147.73, 129.98, 127.38, 126.08, 124.53, 124.13, 124.06, 118.72, 117.51
ppm. MS (FAB): m/z = 416.3 [M+H]+. Elemental Anal. Calcd for
1
(Scheme 1). After confirmation of their purities by H NMR,
13C NMR, and mass spectrometry (FAB), they were crystallized
from 24 combinations of solvents (Table S3, Supporting
Information). Two types of solvent-free polymorphs of the
crystal for compounds 2−5 and a pseudopolymorph of 5 were
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Figure 7. Crystal structure of the sulfonamide 3a as a ball and stick
model: (a) arrangement of the dimeric units through intermolecular
π/π interactions; (b) arrangement of dimeric units through tilted CH/π
interactions. Black dotted lines and red dotted lines show H-bonds and
aromatic−aromatic interactions, respectively.
obtained (Figure 1). Crystal data and conformational
parameters of 1−5 are shown in Tables 1 and 2. In the all
crystal structures, the sulfonamide bonds of all compounds exist
in synclinal conformation (Figure 2). The torsion angles of the
sulfonamide moiety [C1−S1−N1−C7] ranged from 62.1(3)° to
74.6(7)°, and the dihedral angles of Ph1 and Ph2 ranged from
62.7(1)° to 86.8(8)° (Table 2). The intermolecular H-bond
motifs of the sulfonamide in the crystal structure were classified
as dimer, straight chain, and zigzag chain (Figure 3).
Furthermore, the dimer motif was subdivided into type A or
type B depending on whether the dimeric structure was
stabilized by aromatic−aromatic interactions. A straight chain
motif via H-bonds between the sulfonyl oxygen and amide
nitrogen was classified as type C, a straight chain motif via CH/O
interactions between the sulfonyl oxygen and phenyl carbon
was classified as type D, and a zigzag chain motif via CH/F
interactions was classified as type E.
Compound 1 crystallized in a monoclinic system, space
group P21/n, and included four molecules in the unit cell. This
crystal is classified as Type A and has the sulfonamide dimer
motif (N1−H1···O2, 2.933(2) Å, 163.2°, Table S1, Supporting
Information) together with an offset π/π stacking interaction.
The ring center−ring center distance of two phenyl groups
(Ph1 and Ph3) is 3.979(2) Å (Table S2, Supporting
Information). As shown in Figure 4a, the dimeric units extend
along the a axis through π/π stacking interactions to form 1D
polymers (Ph1−Ph1 = 3.768(2) Å). Furthermore, the 1D
polymers associate along the b axis through the tilted T-shaped
aromatic−aromatic (CH/π) interaction (Figure 4b). The ring
center−ring center distance of the two phenyl groups (Ph1 and Ph2)
Figure 8. Crystal structure of the sulfonamide 3b as a ball and stick
model: (a) arrangement of the dimeric units through CH/F
interactions; (b) arrangement of the dimeric units through π/π
interactions. Black dotted lines and red dotted lines show H-bonds and
aromatic−aromatic interactions, respectively.
is 4.909(2) Å, and the angle between two phenyl groups (Ph1
and Ph2) is 72.53°.
The sulfonamide 2 crystallized as two different polymorphs,
2a and 2b, by slow evaporation of CHCl3/hexane or CHCl3/
THF solution, respectively (Figure 1a). Crystal 2a crystallized
in a monoclinic system, space group P21/n, and included four
molecules in the unit cell. The sulfonamide 2 forms an NH/O
dimer motif with a π/π interaction. The ring center−ring center
distance of the two phenyl groups (Ph1 and Ph3) is 4.012(1) Å
(Table S2, Supporting Information). The molecular packing of
this molecule is similar to that of 1, which is classified as type A
(Figure 5). As shown in Figure 5a, the dimeric units extend
along the a axis through aromatic−aromatic interactions to
form the 1D network (Ph1−Ph1 = 3.805(1) Å). Furthermore,
the sulfonamide 2 associates along the b axis through the CH/π
interaction (Figure 5b). The ring center−ring center distance of
the two phenyl groups (Ph1 and Ph2) is 4.828(2) Å, and both
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Figure 9. Crystal structure of the sulfonamide 4a as a ball and stick
model: (a) arrangement of the dimeric units through CH/π
interactions; (b) arrangement of the dimeric units through π/π and
CH/π interactions. Black dotted lines and red dotted lines show
H-bonds and aromatic−aromatic interactions, respectively.
Figure 10. Crystal structure of the sulfonamide 4b as a ball and stick
model: (a) arrangement of the straight chain units through CH/F
interactions; (b) arrangement of the straight chain units through CH/
O and CH/π interactions. Black dotted lines show H-bonds. Red
dotted lines show CH/O and CH/π interactions.
angles between the two phenyl groups (Ph1 and Ph2) are
73.31° (Table S2, Supporting Information). Crystal 2b forms a
dimer motif without π/π interactions in the P1 space group. As
̅
shown in Figure 6a, the sulfonamide 2 associates along the a
axis through CH/F interactions (C(11)−F(1) = 3.216(2) Å,
Table S1, Supporting Information). Furthermore, the dimeric
units extend along the c axis through π/π and CH/π interac-
tions (Ph1−Ph1 = 3.670(2) Å, Ph2−Ph3 = 4.851(2) Å,
Figure 6b).
Furthermore, the sulfonamide 3 extends in the bc plane through
π/π interactions (Ph1−Ph3 = 4.176(5) Å, Figure 8b).
The sulfonamide 4 crystallized as two different polymorphs,
4a and 4b, by slow evaporation of CHCl3/n-hexane or CHCl3/
THF, respectively (Figure 1c). Crystal 4a forms a dimer motif
without π/π interactions in the P1 space group. The molecular
̅
The sulfonamide 3 crystallized as two different polymorphs,
3a and 3b, by slow evaporation of THF/n-hexane or CHCl3/
n-hexane, respectively (Figure 1b). Crystal 3a crystallized in a
monoclinic system, space group P21/n, and included four
molecules in the unit cell. The sulfonamide 3a forms a dimer
motif with π/π stacking. The ring center−ring center distance
of the two phenyl groups (Ph1 and Ph3) is 3.919(1) Å (Table
S2, Supporting Information). The molecular packing of this
molecule is similar to that of 1 and 2a, which is classified as
type A. As shown in Figure 7a, the dimeric units extend along
the a axis through π/π interactions to form the 1D network
(Ph1−Ph1 = 3.943(1) Å). Furthermore, the sulfonamide 3
associates along the b axis through the CH/π interactions
(Figure 7b). The ring center−ring center distance of Ph1 and
Ph2 is 4.928(2) Å, and the angle between Ph1 and Ph2 is
74.05° (Table S2, Supporting Information). In contrast, 3b
forms a dimer motif without π/π interactions in the P21/n
space group. Type B dimeric units extend in the ac plane
through CH/F interactions (C(2)−F(1) = 3.236(6) Å, Figure 8a).
packing of sulfonamide 4a is similar to that of 2b, which is classified
as type B. As shown in Figure 9a, the sulfonamide 4 associates along
the a axis through CH/π interactions (the ring center−ring center
distance of Ph2 and Ph3 is 5.035(3) Å, and the angle between Ph2
and Ph3 is 88.25°, Table S2, Supporting Information). Furthermore,
the dimeric units extend along the c axis through π/π and CH/π
interactions (Figure 9b). The ring center−ring center distances of
the two phenyl groups (Ph1−Ph1, Ph2−Ph3) are 3.897(2) and
4.857(2) Å, respectively. On the other hand, the sulfonamide 4b
forms a straight chain motif via H-bonds, which is classified as type C.
Crystal 4b crystallized in a monoclinic system, space group
P21/c, and included four molecules in the unit cell. The straight
chain units are bridged by CH/F interactions (C(5)−F(1) =
3.409(3) Å, Figure 10a). Furthermore, the straight chain units
extend along the a axis through CH/O interactions and along
the c axis through CH/π interactions (O(1)−C(15) = 3.365(3)
Å, Ph2−Ph3 = 4.989(2) Å, Figure 10b).
The sulfonamide 5 crystallized as two different polymorphs
and a pseudopolymorph, 5a, 5b, and 5c by slow evaporation of
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Figure 12. Crystal structure of the sulfonamide 5b as a ball and stick model:
(a) straight chain units via CH/O and π/π interactions; (b) arrangement of
the straight chain units through F/F interactions. Black dotted lines show
H-bonds. Red dotted lines show CH/O, π/π, and F/F interactions.
Figure 11. Crystal structure of the sulfonamide 5a as a ball and stick
model: (a) arrangement of the dimeric units through CH/O
interactions; (b) arrangement of the dimeric units through π/π
interactions. Black dotted lines show H-bonds. Red dotted lines show
CH/O and π/π interactions.
CHCl3/n-hexane, toluene/MeOH, or CHCl3/THF, respec-
tively (Figure 1d). Crystal 5a forms a dimer motif without π/π
interactions in the P21/n space group. As shown in Figure 11a,
the sulfonamide 5 associates along the c axis through CH/O
interactions (O(1)−C(10) = 3.416(2) Å, Figure 11a).
Furthermore, the dimeric units extend along the a axis through
π/π interactions (Ph1−Ph3 = 3.749(2) Å, Figure 11b). The
sulfonamide 5b crystallized in a monoclinic system, space group
P21, and included two molecules in the unit cell. Crystal 5b
forms a straight chain motif via CH/O and π/π interactions,
which is classified as type D (C(9)−O(1) = 3.134(3) Å, Ph1−
Ph3 = 4.026(2) Å, Figure 12a). The straight chain units
associate along the b axis through F/F interactions (F(1)−F(5) =
2.888(3) Å, F(2)−F(4) = 2.874(3) Å, Figure 12b).
Furthermore, the straight chain units extend along the c axis
through CH/F interactions (C(15)−F(3) = 3.356(4) Å, Figure
S28, Supporting Information). In contrast, the solvent-included
pseudopolymorph was obtained from THF by slow evapo-
ration. The sulfonamide 5c crystallized in a monoclinic system
and space group P21/n. The unit cell contained four molecules
of 5 and four molecules of THF. Crystal 5c forms a zigzag
chain motif via CH/F interactions, which is classified as type E
(C(18)−F(2) = 3.269(8) Å, Figure 13a). Furthermore, the
sulfonamide 5 associates along the a axis through π/π
interactions (Ph1−Ph3 = 3.701(4) Å, Figure 13b).
Figure 13. Crystal structure of the sulfonamide 5c as a ball and stick
model: (a) zigzag chain units via CH/F interactions; (b) arrangement
of sulfonamide units through π/π interactions. THF molecules are
omitted for clarity. Red dotted lines show CH/F and π/π interactions.
Using differential scanning calorimetry (DSC) measurements, we
examined the melting points and enthalpies of fusion for all crystals
(Table 3 and Supporting Information). The crystals 2a, 3a, and 5a
have higher melting points and larger enthalpies than those of 2b,
3b, and 5b, respectively. In the case of the sulfonamide 4, the crystal
packing of 4a is similar to that of the metastable forms (2b and 3b),
and 4b has higher density than that of 4a; nevertheless, the
crystallization reproducibility of 4b was not observed.
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Present Addresses
Table 3. Thermodynamic Parameters of Crystals 1, 2a, 2b,
3a, 3b, 4a, 5a, and 5b
†Chemical Analysis Center, Chiba University, 1-33 Yayoi-cho,
Inage-ku, Chiba-city, Chiba 263-8522, Japan.
‡Department of Chemistry, Faculty of Science and Engineering,
Konan University, 8-9-1 Okamoto, Higashinada-ku, Kobe 658-
8501, Japan.
melting point (°C)
ΔHfus (kJ mol−1
)
1
102.0
108.9
88.59
87.27
86.42
113.7
109.5
98.09
30.84
33.38
28.60
30.75
21.30
31.16
29.36
24.30
2a
2b
3a
3b
4a
5a
5b
§Center for Advanced Materials Analysis, Technical Depart-
ment, TIT, Tokyo Institute of Technology University, 4259
Nagatsuda-cho, Midori-ku, Yokohama, Kanagwa 226-8503,
Japan.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The molecules in the two polymorphs are conformationally
similar, and an overlay diagram of the polymorphs shows that
the conformers of the sulfonamides differ only in the diphenyl
ether moiety but not the benzenesulfonyl moiety (Figure S31,
Supporting Information). In contrast, both exist with different
crystal packing depending on the intermolecular behavior of the
fluorine group. The introduction of fluorine groups into the
aromatic sulfonamides gave rise to the polymorphism due to
additional intermolecular CH/F interactions.
■
We gratefully acknowledge the financial support of Houansha
foundation (I.A.) and Tokushima Bunri University Research
Grant for Collaborative Research.
REFERENCES
■
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CONCLUSION
■
We demonstrated that the aromatic sulfonamides containing a
fluorine group on the benzenesulfonyl moieties showed
polymorphs and pseudopolymorphs by crystallization from usual
solvents. In crystal 1 without the fluorine group, the sulfonamide
formed a dimer through H-bonds, which are assembled into 2D
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Sulfonamide 1 did not afford a different crystalline form. In the
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chains via CH/F interactions, which are assembled into 2D layers via
π/π interactions. We believe that the introduction of a fluorine atom
into crystalline compounds will affect the appearance of the
polymorphs, and the results obtained from these investigations will
lead to the development of methodology for controlling the potential
for polymorphism of pharmaceutical compounds.
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ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectroscopic data, the DSC charts of 1, 2a,
2b, 3a, 3b, 4a, 5a, and 5b, and all crystallographic data and
crystallographic information files (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Tel: +81-87-894-5111, ext 6308. Fax: +81-87-894-0181.
E-mail: azumayai@kph.bunri-u.ac.jp.
■
H
dx.doi.org/10.1021/cg300098q | Cryst. Growth Des. XXXX, XXX, XXX−XXX

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