Polymorphism in secondary benzene sulfonamides

Article abstract of DOI:10.1021/cg100845f

The role of about 20 different solvents in the crystallization of polymorphs for 13 N-phenyl benzene sulfonamides was studied. Five compounds (1, 2, 3, 7, and 11) are dimorphic, and one is trimorphic (6). All the crystalline solids were characterized by p

Full text of DOI:10.1021/cg100845f

DOI: 10.1021/cg100845f
Polymorphism in Secondary Benzene Sulfonamides
2010, Vol. 10
4550–4564
Palash Sanphui, Bipul Sarma, and Ashwini Nangia*
School of Chemistry, University of Hyderabad, Prof. C. R. Rao Road, Gachibowli,
Central University P.O., Hyderabad 500046, India
Received June 25, 2010; Revised Manuscript Received August 3, 2010
ABSTRACT: The role of about 20 different solvents in the crystallization of polymorphs for 13 N-phenyl benzene sulfonamides
was studied. Five compounds (1, 2, 3, 7, and 11) are dimorphic, and one is trimorphic (6). All the crystalline solids were
characterized by powder and single crystal X-ray diffraction, thermal analysis, hot stage microscopy, and IR and Raman
spectroscopy. The phase transition from a metastable form to the stable form was examined visually for two compounds (1, 11)
on a HSM and confirmed by differential scanning calorimetry and X-ray diffraction. The N-H O hydrogen bond catemer
3 3 3
(chain) and dimer (cyclic) motifs of the sulfonamide group were analyzed as the main difference between polymorphs of 1, 3, and
6. Weaker C-H O interactions differentiate the molecular packing of other polymorphic systems. Accordingly, these crystal
3 3 3
structures are referred to as synthon polymorphs. The occurrence of N-H O catemer and dimer synthon in secondary
3 3 3
sulfonamides is compared with crystal structures in the Cambridge database. The nearly equal probability of the dimer and
catemer motifs for secondary sulfonamides (∼19%) is attributed to the possibility of making the catemer synthon via both anti
and syn oxygen atoms of the SO2NH group, with the former acceptor being preferred in two-thirds of the cases.
Introduction
sublimation, additives, cocrystal formers, polymer-induced
heteronucleation, etc.5 We used common laboratory solvents
for the crystallization of polymorphs along with melting and
sublimation techniques. However, the solvent-free method
did not afford a new crystalline form because these com-
pounds did not sublime and melting afforded the stable
Sulfonamides continue to attract the attention of structural
and pharmaceutical chemists because of their druglike pro-
perties.1 A thorough screening for all possible polymorphs is
considered an essential step in the pharmaceutical industry to
select the best drug formulation.2 Gelbrich, Hursthouse, and
Threlfall3 reported a comparative study of molecular packing
and hydrogen bonding in one hundred phenylbenzene sulfon-
amides having the para-para substitution on the the N-Ph
and Ph-SO2 moieties. They classified the 133 crystal struc-
tures into 56 different structure types. We have synthesized 13
N-phenyl benzenesulfonamides of ortho-meta-para substi-
modification of solution crystallization. N-H O dimer
3 3 3
and catemer between the sulfonamide group are possible
hydrogen bond motifs in these crystal structures (Figure 1).
Structural Analysis. Molecule 1 crystallized as two differ-
ent polymorphs, forms I and II, by slow evaporation of
methanol and p-xylene, respectively. The first form matches
with the crystal structure reported recently by Gowda et al.6
The crystal structure of form I (in the P21/n space group,
Table 2) has one-dimensional tapes of molecules connected
tution. The formation of different N-H O hydrogen bond
3 3 3
synthons4 between the sulfonamide group, namely dimer and
catemer, is the main focus of this study. Changes in molecular
conformation and weak intermolecular interactions such as
via a catemeric N-H O hydrogen bond (N1-H1 O1,
3 3 3
3 3 3
˚
2.21 A, 162.5ꢀ) along [100] (Figure 2). These tapes are
C-H O, C-H π, π-π stacking, etc. afforded different
3 3 3
3 3 3
connected via C-H π interaction cross-links to form a
crystalline polymorphs. The role of the crystallization solvent
(polar vs nonpolar) to give one or another polymorph, or
mixtures in some cases, is discussed.
3 3 3
sheet parallel to the (001) plane. C-H O interaction
3 3 3
˚
(C5-H5 O2, 2.48 A, 126.2ꢀ, Table 3) between these
parallel sheets sustains the overall packing. The sulfonamide
3 3 3
˚
dimer (N1-H1 O1, 2.00 A, 170.2ꢀ) is present in the crystal
Results and Discussion
3 3 3
structure of form II (Figure 3). Close packing of the dimeric
units in the P21/c crystal system completes the molecular
arrangement. The basic difference between these two poly-
morphs comes from the catemer and dimer motif of
N-Phenyl benzenesulfonamides were prepared by the con-
densation of the substituted benzenesulfonyl chloride with the
appropriate aniline (Scheme 1). After confirming the com-
pound homogeneity and purity by 1H NMR and FT-IR, they
were crystallized from about 20 different solvents (Table 1).
Six of the 13 compounds studied are polymorphic. These solvent
screens give an idea of the solvent effect on the polymorphic
outcome (or absence of polymorphism) in crystallization
experiments. In general, a variety of experimental methods
are practiced to crystallize new polymorphs, for example,
solvent/antisolvent evaporation, slurry crystallization, melting,
N-H O hydrogen bonds of the sulfonamide group.
3 3 3
Molecule 2 is also dimorphic. Form I crystallized in the
P21/c space group whereas form II is in the P1 space group.
The sulfonamide dimer synthon is present in both poly-
morphs, with the difference being the C-H O interaction
3 3 3
leading to different packing arrangements. In form I, the SO2
oxygen acceptor that is not involved in the sulfonamide
homodimer makes a C-H O chelate motif7 (Figure 4a).
3 3 3
In form II, the sulfonamide dimer units extend through a
˚
C-H O interaction along [001] (C11-H11 O2 2.68 A,
3 3 3
3 3 3
*To whom correspondence should be addressed. E-mail: ashwini.nangia@
gmail.com.
150.8ꢀ) (Figure4b).Thedifferencebetweenthesetwopolymorphs
r
pubs.acs.org/crystal
Published on Web 08/25/2010
2010 American Chemical Society

Article
Scheme 1. (a) Synthetic Procedure for the Preparation of
Crystal Growth & Design, Vol. 10, No. 10, 2010 4551
Secondary Sulfonamides 1-13. (b) A Single CPh-S-N-CPh
Torsion Angle Defines Much of the Shape of N-Phenyl
Benzenesulfonamide Molecules
can be understood by their C-H O interactions. They
3 3 3
may be classified as synthon polymorphs at the secondary
level, because the strong hydrogen bonding is the same but
there are differences at the weak interactions level.8 The
graph set notation9 of the hydrogen bond motifs for the
N-H O dimer, N-H O catemer, C-H O chelate,
3 3 3
3 3 3
3 3 3
and C-H O dimer are R22(8), C(4), R21(6), and R22(16).
Changes in molecular conformation are listed as torsion
3 3 3
angles in Table 4.
For molecule 3, polymorph I contains the sulfonamide
N-H O dimer units, which are connected via type II
3 3 3
Cl Cl10 (Cl1-Cl2: 3.44 A, 113.5ꢀ and 164.7ꢀ) and
˚
3 3 3
C-H O interactions (Figure 5a). In form II, catemer
3 3 3
3 3 3
N-H O chains are connected through C-H O inter-
3 3 3
actions (Figure 5b). Thus, sulfonamide dimer and catemer
are the main difference between these two polymorphs. This
set as well as molecule 1 structures differing in the strong
N-H O motifs are primary synthon polymorphs.4c,11
3 3 3
Molecules 4 and 5 have the sulfonamide N-H O dimer
3 3 3
as the common synthon (Figure 6). Both structures exhibit
similar kinds of molecular arrangements and graph sets
R22(8) and R22(16) along [010]. In structure 4, π-π interaction
˚
˚
(3.47 A), whereas in structure 5 π-π (3.47 A) and Cl
π
3 3 3
˚
interactions (3.53 A), contributes to the weaker interactions
in the crystalline lattice.

4552 Crystal Growth & Design, Vol. 10, No. 10, 2010
Sanphui et al.
Molecule 6 is trimorphic in the monoclinic crystal system.
Forms I and II have a catemer N-H O chain (Figure 7a,b)
3 3 3
that is connected by C-H O interaction. However, form
3 3 3
III has the sulfonamide dimer motif (Figure 7c) together with
a π-stacking interaction. The molecular packing of form III
is similar to that of 12 and 13, which are discussed later in
the paper.
Molecule 7 is dimorphic. Form I crystallized in the P21/c
space group with two molecules in the asymmetric unit.
Sulfonamide N-H O catemer forms a helical structure
3 3 3
along [010] (Figure 8a). A difference between the catemer
motif in this crystal structure compared to previous ones is
that the syn O of sulfonamide is the acceptor here compared
to the more common anti O in previous structures. Form II in
the P21/n space group also has two symmetry-independent
molecules. One molecule makes a catemer via anti O along
[010], and the second molecule fills the voids between
b-translated molecules connected by N-H O and C-
3 3 3
˚
Cl O (3.19 A) interactions (Figure 8b).
3 3 3
Molecule 8 has similar molecular packing to form II of 7
with two symmetry-independent molecules in the P21/n
space group (Figure 9). One molecule (ball and stick model)
Figure 1. Dimer and catemer hydrogen bond synthons of the
sulfonamide group. The chain motif formed with anti and syn O
acceptor atoms.
makes an N-H O catemer along [010] using the anti O
3 3 3
Table 2. Crystallographic Parameters of Structures 1-13
compound
polymorph
1
2
3
4
form I
form II
form I
form II
form I
form II
empirical formula
formula weight
crystal system
space group
C14H15NO2S
261.33
monoclinic
P21/n
5.2133(16)
17.989(5)
14.052(4)
90
91.659(5)
90
1317.3(7)
1.318
0.239
1.84 to 26.14
4
C14H15NO2S
261.33
monoclinic
P21/c
7.6844(6)
23.9322(17)
8.0899(6)
90
115.0690(10)
90
1347.62(17)
1.288
0.234
1.70 to 26.01
4
C15H17NO2S
275.36
monoclinic
P21/c
8.2222(8)
8.1697(8)
21.715(2)
90
95.0480(10)
90
1453.0(2)
1.259
0.220
2.49 to 25.91
4
C15H17NO2S
275.36
triclinic
P1
7.954(3)
8.367(3)
12.305(5)
81.347(5)
87.854(6)
64.361(6)
729.5(5)
1.254
C13H11Cl2NO2S
316.19
monoclinic
P21/n
9.495(5)
12.260(6)
12.154(6)
90
97.162(7)
90
1403.7(12)
1.496
0.607
2.37 to 26.15
4
C13H11Cl2NO2S
316.19
monoclinic
P21
4.9650(8)
17.550(3)
8.1488(13)
90
102.245(3)
90
693.88(19)
1.513
0.614
2.32 to 19.06
2
C14H14ClNO2S
295.77
monoclinic
P21/n
8.290(3)
12.476(5)
13.885(5)
90
98.192(6)
90
1421.5(9)
1.382
0.412
2.20 to 25.99
4
˚
a (A)
˚
b (A)
˚
c (A)
R (deg)
β (deg)
γ (deg)
3
˚
V (A )
Dcalcd (g cm-3
)
μ (mm-1
θ range
Z
)
0.219
2.73 to 25.88
2
range h
range k
range l
reflections collected
observed reflections
total reflections
R1 [I > 2 σ(I)]
wR2 (all)
-6 to þ6
-22 to þ22
-17 to þ22
13267
2295
2626
-9 to þ9
-29 to þ29
-9 to þ9
13863
2245
2641
-10 to þ10
-10 to þ10
-26 to þ26
14612
2342
2870
-9 to þ9
-10 to þ10
-15 to þ14
7467
2485
2835
-11 to þ11
-15 to þ15
-14 to þ15
13065
2463
2809
-6 to þ6
-21 to þ21
-10 to þ9
7110
2175
2703
-10 to þ10
-15 to þ15
-14 to þ17
10926
2185
2836
0.0738
0.1829
0.0424
0.1160
0.0478
0.1329
0.0434
0.1224
0.0358
0.1054
0.0544
0.1015
0.0663
0.1513
goodness-of-fit
T (K)
1.181
298
1.039
298
1.029
298
1.055
298
1.056
298
1.057
298
1.079
298
compound
polymorph
5
6
7
form I
form II
form III
form I
form II
empirical formula
formula weight
crystal system
space group
C13H11Cl2NO2S
316.19
monoclinic
P21/n
8.2137(8)
12.4688(12)
14.0076(14)
90
101.5720(10)
90
C12H9Cl2NO2S
302.16
monoclinic
P21/n
5.0633(11)
17.083(4)
15.300(3)
90
90.485(3)
90
C12H9Cl2NO2S
302.16
monoclinic
P21/n
5.0326(6)
14.4315(13)
18.120(2)
90
99.251(10)
90
C12H9Cl2NO2S
302.16
monoclinic
P21/c
9.4444(10)
12.2349(12)
12.3344(12)
90
111.4710(10)
90
C13H12ClNO2S
281.75
monoclinic
P21/c
19.9753(18)
6.1903(5)
22.208(2)
90
97.165(2)
90
C13H12ClNO2S
281.75
monoclinic
P21/n
11.083(2)
10.184(2)
24.045(5)
90
102.907(3)
90
˚
a (A)
˚
b (A)
˚
c (A)
R (deg)
β (deg)
γ (deg)
3
˚
V (A )
1405.4(2)
1.494
0.606
1323.3(5)
1.517
0.640
1298.9(2)
1.545
0.652
1326.3(2)
1.513
0.638
2645.2(9)
1.415
0.439
2724.6(4)
1.374
0.426
Dcalcd (g cm-3
)
μ (mm-1
θ range
)
2.21-26.08
2.38-26.00
3.04-26.37
2.32-25.14
2.18-24.59
3.42-20.13

Article
Crystal Growth & Design, Vol. 10, No. 10, 2010 4553
Table 2. Continued
compound
polymorph
5
6
7
form I
form II
form III
form I
form II
Z
range h
range k
range l
reflections collected
observed reflections
total reflections
R1 [I > 2 σ(I)]
wR2 (all)
4
4
4
4
8
8
-10 to þ10
-15 to þ15
-17 to þ17
14048
2716
2777
0.0627
0.1385
1.336
298
-6 to þ6
-21 to þ21
-18 to þ18
13467
2269
2596
0.0416
0.1013
1.082
-6 to þ6
-18 to þ18
-22 to þ22
5880
2657
1684
0.0399
0.0931
0.924
-11 to þ11
-14 to þ14
-14 to þ14
11728
2138
2366
0.0447
0.1141
1.074
298
-13 to þ13
-12 to þ12
-29 to þ29
26763
3610
5236
0.0502
0.1335
1.023
298
-23 to þ23
-7 to þ7
-26 to þ26
24906
3153
4803
0.0647
0.1492
1.060
goodness-of-fit
T (K)
298
298
298
compound
polymorph
8
9
10
11
12
13
form I
form II
empirical formula
formula weight
crystal system
space group
C14H15NO2S
261.33
monoclinic
P21/n
11.1556(8)
10.1380(7)
24.1724(17)
90
103.0230(10)
90
2663.5(3)
1.303
0.236
2.25-26.01
8
C12H9Cl2NO2S
302.16
orthorhombic
Pbca
15.6409(15)
7.4161(7)
23.015(2)
90
90
90
2669.6(4)
1.504
0.634
2.60-25.57
8
C13H12ClNO2S
281.75
monoclinic
P21/c
10.400(5)
10.989(4)
11.639(5)
90
98.942(7)
90
1314.1(10)
1.424
0.442
2.56-25.96
4
C13H12FNO2S
265.30
monoclinic
P21/n
8.716(6)
9.834(7)
15.410(11)
90
100.176(12)
90
1300.1(16)
1.355
0.254
2.47-23.14
4
C13H12FNO2S
265.30
monoclinic
P21/c
9.485(5)
13.752(8)
9.822(6)
90
90.881(10)
90
1281.0(13)
1.376
0.258
2.55-20.39
4
C14H14FNO2S
279.32
triclinic
P1
8.518(6)
9.045(7)
9.189(7)
87.020(9)
77.933(11)
76.759(11)
674.0(9)
1.376
C14H14ClNO2S
295.77
triclinic
P1
8.566(2)
9.226(2)
9.307(3)
84.940(3)
75.128(4)
79.458(4)
698.2(3)
1.407
˚
a (A)
˚
b (A)
˚
c (A)
R (deg)
β (deg)
γ (deg)
3
˚
V (A )
Dcalcd (g cm-3
)
μ (mm-1
θ range
Z
)
0.249
2.27-26.14
2
0.419
2.25-25.81
2
range h
range k
range l
reflections collected
observed reflections
total reflections
R1 [I > 2 σ(I)]
wR2 (all)
-13 to þ13
-12 to þ12
-29 to þ29
25971
4529
5251
-18 to þ18
-8 to þ8
-27 to þ27
23822
1706
2360
-12 to þ12
-13 to þ13
-14 to þ14
12619
2418
2561
-10 to þ9
-11 to þ11
-19 to þ18
10579
1676
2511
-11 to þ11
-16 to þ16
-11 to þ11
12074
1856
2259
-10 to þ10
-11 to þ11
-11 to þ11
6858
2282
2657
-10 to þ10
-11 to þ11
-11 to þ11
7044
2381
2660
0.0471
0.1285
0.0528
0.1371
0.0671
0.1450
0.0636
0.1503
0.0455
0.1195
0.0515
0.1395
0.0395
0.1079
goodness-of-fit
T (K)
1.062
298
1.008
298
1.275
298
1.054
298
1.071
298
1.059
298
1.043
298
Figure 2. (a) Catemeric N-H O hydrogen bond along [100] in form I of 1. (b) Herringbone motif C-H π interaction connecting the
linear tapes.
3 3 3
3 3 3
while the second molecule (capped stick model) fills the voids
between screw axis related molecules by connecting via a
interchange is somewhat surprising because normally such
3
isosteric Me/Cl substitution (20, 24 A volume) is expected to
˚
N-H O hydrogen bond to the second sulfonyl oxygen
give identical crystal structures.12
Molecule 11 crystallized in two different forms. Both
3 3 3
acceptor. The difference comes from the exchange of the Cl
atom by a methyl group. Molecule 9 has a catemer chain
along [010] using the syn O but now with only one molecule
in the crystal structure in the Pbca space group (Figure 10).
Molecule 10 has the sulfonamide dimer synthon along with
forms I and II have the sulfonamide dimer of N-H
O
3 3 3
hydrogen bonds. These dimeric units extend in the plane
parallel to (202) via C-H O interaction involving the free
3 3 3
O of the sulfonamide group and a ring hydrogen donor. The
basic difference between the two forms is the type of C-
˚
π-π stacking of aromatic rings at 3.49 A (Figure 11).
The only difference in crystal structures 7-10 is the
exchange of methyl with a chloro group. A change in the
H
O interaction between the dimer units. A ring hydrogen
3 3 3
is involved in form I whereas a methyl group donor makes
strong N-H O synthon from dimer to catemer by this
3 3 3
the C-H O interaction in form II (Figure 12). They are
3 3 3

4554 Crystal Growth & Design, Vol. 10, No. 10, 2010
Table 3. Hydrogen Bonds in Crystal Structures (Neutron-Normalized Distance)
Sanphui et al.
˚
A/A
˚
A/A
crystal form
interaction
H
D
—D-H A/deg
symmetry code
3 3 3
3 3 3
3 3 3
1_form I
N1-H1 O1
2.21
2.48
2.41
3.188(3)
3.236(5)
2.906 (5)
162.5
126.2
106.4
-1 þ x, y, z
3 3 3
C5-H5 O2
1/2 þ x, 3/2 - y, 1/2 þ z
3 3 3
C13-H13A N1
intramolecular
3 3 3
1_form II
2_form I
2_form II
N1-H1 O1
2.00
2.52
2.46
3.004(2)
2.916(3)
3.129(3)
170.2
127.3
118.6
2 - x, 1 - y, 1 - z
intramolecular
1 þ x, y, z
3 3 3
C6-H6 O2
3 3 3
C14-H14A O2
3 3 3
N1-H1 O1
1.96
2.63
2.69
2.945(2)
3.489(2)
3.466(2)
165.8
153.7
138.3
1 - x, -y, -z
3 3 3
C10-H10 O2
1 - x, 1/2 þ y, 1/2 - z
3 3 3
C15-H15 O2
1 - x, 1/2 þ y, 1/2 - z
3 3 3
N1-H1 O1
1.98
2.32
2.68
2.963(2)
3.349(3)
3.524(3)
161.9
157.7
150.8
-x, 1 - y, 1 - z
3 3 3
C7-H7B O2
-1/2 þ x, 1/2 - y, 1/2 þ z
3 3 3
C11-H11 O2
1 - x, -y, -z
3 3 3
3_form I
N1-H1 O1
1.99
2.32
2.963(2)
3.349(3)
161.9
157.7
-x, 1 - y, -z
3 3 3
C7-H7B O2
-1/2 þ x, 1/2 - y, 1/2 þ z
3 3 3
3_form II
N1-H1 O2
1.95
2.52
2.60
2.955(5)
2.913(6)
3.682(5)
173.9
100.4
177.3
1 þ x, y, z
3 3 3
C2-H2 O1
intramolecular
-1 þ x, y, z
3 3 3
C6-H6 Cl1
3 3 3
4
N1-H1 O2
1.99
2.44
2.49
2.54
2.975(4)
3.401(4)
2.885(4)
3.128(6)
165.2
147.5
100.1
113.3
2 - x, 2 - y, 1 - z
-1 þ x, y, z
3 3 3
C4-H4 O1
3 3 3
C6-H6 O1
intramolecular
intramolecular
3 3 3
C13-H13A O1
3 3 3
5
N1-H1 O1
2.02
2.47
2.42
2.968(4)
2.873(4)
3.353(5)
155.5
100.7
144.1
2 - x, 1 - y, 1 - z
intramolecular
-1 þ x, y, z
3 3 3
C2-H2 O2
3 3 3
C4-H4 O2
3 3 3
6_form I
6_form II
6_form III
7_form I
N1-H1 O2
2.05
2.27
2.62
3.026(3)
3.253(4)
3.682(3)
162.5
148.9
167.6
1 þ x, y, z
3 3 3
C5-H5 O1
-1/2 þ x, 1/2 - y, -1/2 þ z
3 3 3
C6-H6 Cl2
-1 þ x, y, z
3 3 3
N1-H1 O1
2.04
2.61
2.34
3.039(6)
3.693(8)
3.305(8)
169.7
174.8
174.2
-1 þ x, y, z
3 3 3
C6-H6 Cl1
1 þ x, y, z
3 3 3
C9-H9 O2
-1/2 þ x, 1/2 - y, -1/2 þ z
3 3 3
N1-H1 Cl2
2.81
2.22
2.56
3.022(2)
2.914(3)
2.920(4)
100
158
103.2
intramolecular
1 - x, 1 - y, z
intramolecular
3 3 3
N1-H1 O1
3 3 3
C2-H2 O2
3 3 3
N1-H1 O4
1.92
1.91
2.41
2.56
2.924(4)
2.921(4)
3.476(5)
3.123(3)
177.3
176.6
166.9
111.57
x, 1 þ y, -1 þ z
x, 1 þ y, z
3 3 3
N2-H2A O2
3 3 3
C12-H12 O1
x, 1 þ y, z
3 3 3
C19-H19 O3
intramolecular
3 3 3
7_form II
N1-H1 O1
2.12
1.97
2.45
2.45
2.37
2.44
2.44
2.39
3.091(4)
2.980(3)
3.405(4)
2.868(3)
3.059(4)
2.869(4)
3.086(4)
3.450(4)
159.8
178.9
145.8
101.4
119.7
101.64
117.0
166.9
1/2 - x, -1/2 þ y, 1/2 - z
1/2 - x, 1/2 þ y, 1/2 - z
1/2 - x, -1/2 þ y, 1/2 - z
intramolecular
3 3 3
N2-H2A O2
3 3 3
C2-H2 O1
3 3 3
C6-H6 O1
3 3 3
C12-H12 O1
intramolecular
intramolecular
intramolecular
3 3 3
C19-H19 O3
3 3 3
C21-H21 O3
3 3 3
C22-H22 O3
1 - x, -y, -z
3 3 3
8
N1-H1 O4
1.98
2.07
2.45
2.38
2.43
2.46
2.46
2.27
2.36
2.980(2)
3.040(2)
2.873(3)
3.442(3)
3.087(3)
3.416(3)
2.870(3)
3.304(4)
3.050(3)
170.0
160.9
101.4
167.4
117.7
147.1
100.9
158.7
119.6
3/2 - x, 1/2 þ y, 1/2 - z
3/2 - x, -1/2 þ y, 1/2 - z
intramolecular
3 3 3
N2-H2A O3
3 3 3
C6-H6 O2
3 3 3
C12-H12 O2
2 - x, 1 - y, -z
intramolecular
3 3 3
C13-H13 O2
3 3 3
C16-H16 O3
3/2 - x, -1/2 þ y, 1/2 - z
3 3 3
C20-H20 O3
intramolecular
x, -1 þ y, z
3 3 3
C21-H21C O1
3 3 3
C23-H23 O3
intramolecular
3/2 - x, -1/2 þ y, z
3 3 3
9
N1-H1 O2
2.08
2.49
2.48
2.66
247
2.996(3)
2.891(4)
3.286(4)
3.681(3)
3.004(4)
149.2
100.3
130.2
156.2
108.7
3 3 3
C6-H6 O2
intramolecular
x, -1 þ y, z
3 3 3
C9-H9 O1
3 3 3
C11-H11 Cl1
1/2 - x, -1/2 þ y, 1/2 - z
intramolecular
3 3 3
C12-H12 O1
3 3 3
10
N1-H1 O1
1.98
2.39
2.972(4)
3.063(4)
166.8
118.6
2 - x, 2 - y, 1 - z
intramolecular
3 3 3
C12-H12 O2
3 3 3
11_form I
N1-H1 O1
1.97
2.44
2.49
2.39
2.980(4)
3.526(4)
2.903(4)
3.090(5)
173.9
176.7
101.0
121.0
2 - x, 1 - y, 1 - z
-1/2 þ x, 1/2 - y, -1/2 þ z
intramolecular
3 3 3
C3-H3 O2
3 3 3
C6-H6 O2
3 3 3
C9-H9 O2
intramolecular
3 3 3
11_form II
N1-H1 O2
1.91
2.30
2.44
2.912(3)
3.036(3)
3.491(4)
173.6
123.1
162.0
-x, 1 - y, -z
intramolecular
3 3 3
C9-H9 O1
3 3 3
C12-H12 O2
-x, -1/2 þ y, 1/2 - z
3 3 3
12
13
N1-H1 O1
1.90
2.33
2.906(4)
3.034(4)
171.1
121.3
1 - x, 1 - y, -z
intramolecular
3 3 3
C9-H9 O2
3 3 3
N1-H1 O2
1.90
2.32
2.910(2)
3.032(3)
175.4
121.3
2 - x, -y, -z
intramolecular
3 3 3
C13-H13 O1
3 3 3

Article
Crystal Growth & Design, Vol. 10, No. 10, 2010 4555
Table 4. C-S-N-C Torsion Angle (see Scheme 1) in Molecules 1-13
crystal form
torsion angle
molecule 1_form I
molecule 1_form II
molecule 2_form I
molecule 2_form II
molecule 3_form I
molecule 3_form II
molecule 4
78.15
78.21
75.33
71.26
77.19
83.86
68.65
molecule 5
70.81
82.49
83.56
84.83
Figure 3. (a) N-H O hydrogen bond dimer in form II of 1.
molecule 6_form I
molecule 6_form II
molecule 6_form III
molecule 7_form I
molecule 7_form II
molecule 8
molecule 9
molecule 10
molecule 11_form I
molecule 11_form II
molecule 12
3 3 3
(b) The dimeric units are connected through a C-H O hydrogen
3 3 3
˚
bond (2.46 A, 118.6ꢀ) along [100].
66.92, 62.09
64.42, 54.45
54.88, 65.35
69.40
56.05
52.21
57.58
61.26
59.27
molecule 13
metastable form(s). The solution concentration will be dif-
ferent depending on the polarity of the solvent, which plays a
role in supramolecular aggregation via strong and/or weak
hydrogen bonds. In less polar or nonpolar solvents, intra-
molecular hydrogen bonds are expected to be strong, and the
converse is true in polar solvents.13b
Several common laboratory solvents were used to screen
for the crystallization of different polymorphic phases
(Table 1). All six sulfonamide molecules that are poly-
morphic afforded the stable polymorph from a more polar
solvent; for example, stable form I of molecule 1 was crystal-
lized from MeOH but metastable form II crystallized from
p-xylene. The packing fraction (Table 6), density, and phase
transition of form II suggest that form I is the stable
modification. Similarly, polymorphs I, II, and III of mole-
cule 6 were crystallized from p-xylene, MeOH, and hexane,
respectively. Their stability order is form II (most stable),
form I (intermediate), and form III (least stable), as con-
firmed by packing fraction, density, and heat of fusion (see
Table 9 discussed later). So molecule 6 also follows the same
trend that the most stable form was crystallized from a polar
solvent and the least stable from a nonpolar solvent.
Another trend regarding solvent polarity and crystal
structure is that, in general, polar or hydrogen bonding sol-
vents afforded a polymorph with the catemer chain whereas
nonpolar or less polar solvents gave a structure of dimer
motif (dimer/catemer motifs for polymorphic structures are
listed in Table 1). There is a similar precedent in at least one
system: in situ IR spectroscopy showed the presence of
Figure 4. (a) Bifurcated C-H O motif connects sulfonamide
dimer units along [001] in form I of 2. (b) Sulfonamide dimers
3 3 3
extend through the C-H O dimer motif in form II.
3 3 3
synthon polymorphs at the secondary level; the N-H
O
3 3 3
hydrogen bond is the same, but the C-H O interaction is
3 3 3
different.
Molecules 12 and 13 were prepared to compare the effect
of halogen exchange on crystal packing. These Cl/F analo-
gues have a similar molecular arrangement in the crystal
lattice mediated via a sulfonamide N-H O dimer, π
π
3 3 3
3 3 3
stacking, and C-H F/C-H Cl interaction (Figure 13).
3 3 3 3 3 3
There are minor conformational differences (Figure 14)
among the sulfonamide polymorphs (selected torsion angles
are listed in Table 4). The main torsion angle which defines
the molecular shape (Scheme 1) varies from 55 to 85ꢀ in 1-13
while the variation within a polymorph set is smaller (2-5ꢀ).
Lattice energies for the polymorphic systems calculated in
Cerius2 are within 0.5-1.0 kcal mol-1 (except for 3, Table 5),
and so it is difficult to identify the stable polymorph from
energy values.
tetrolic acid dimers in CHCl3 solution and O-H O cate-
3 3 3
mer in EtOH.4c
IR and Raman Spectroscopy. FT-IR and FT-Raman
spectroscopy14 are popular analytical methods for studying
polymorphism in pharmaceuticals. In the spectra of solid-
state samples, asymmetric and symmetric N-H stretching
vibrations are observed in the range 3390-3323 cm-1 and
3279-3229 cm-1, respectively, due to intermolecular hydro-
gen bonding; however, these absorptions appear at higher
frequencies for dilute solution samples (3520-3400 cm-1) in
the absence of hydrogen bonding. Primary sulfonamides
Role of Solvent in Polymorph Crystallization. Ostwald’s
rule of stages13a states the least stable polymorph appears
first followed by more stable states and finally the thermo-
dynamic modification. Solvent-mediated transformations
can proceed in three steps: (1) dissolution of the metastable
form; (2) nucleation of the stable form; (3) crystal growth of
the thermodynamic phase. Generally, slow crystallization
from dilute solution produces the stable form, whereas rapid
crystallization from concentrated solution generates the
show strong N-H stretching bands at 3390-3330 cm-1
,
and secondary sulfonamides absorb near 3265 cm-1. Asym-
metric and symmetric SdO stretching vibrations appear as
strong absorption peaks in the range 1344-1317 cm-1 and

4556 Crystal Growth & Design, Vol. 10, No. 10, 2010
Sanphui et al.
Figure 5. (a) C-H O and Cl Cl type-II interactions connect sulfonamide dimers along [010] in form I of molecule 3. (b) Catemeric
3 3 3 3 3 3
N-H O H bond along [100] and C-H O interactions in form II.
3 3 3 3 3 3
97.5 ꢀC and then melts at 153.1 ꢀC. The melting of form I is
sharp (Tonset 151.5 ꢀC, Tpeak 152.0 ꢀC). From the crystal
structure, form II has the N-H O dimer and form I is
3 3 3
sustained by the catemer chain. This solid to solid transition
was visualized on a hot stage microscope. A phase transition
of the plate shaped crystal of form II occurs at 97-98 ꢀC, and
it then melts at 152-154 ꢀC, matching with the melting point
of form I. A small difference between the Tonset of the original
solid and that obtained after phase transformation happens
due to different contact surfaces. The transformation of form
II to I was confirmed by X-ray diffraction (unit cell check).
A similar behavior is shown by form II of compound 11,
wherein the first endotherm appears at 80 ꢀC and the melting
endotherm at 111 ꢀC in DSC, which corresponds to the newly
transformed form I. These events were visualized on HSM
(Figure 18) and confirmed by X-ray diffraction. Compounds
2, 3, 6, and 7 do not show any phase transition up to 20-
30 ꢀC beyond their melting temperature. The monotropic and
enantiotropic behavior of polymorphs was established by
calculating the enthalpy of melting from DSC plots (Table 9)
and using Burger and Ramberger’s16a,b heat-of-fusion rule.
If the higher melting polymorph has the higher heat of
fusion, then it is a monotropic system (no phase transition
in the given temperature range); if the higher melting poly-
morph has a lower heat of fusion, then it is an enantiotropic
system (phase transition before melting). Another important
guide is the heat-of-transition rule (Grunenberg et al.16c and
Burger-Ramberger16a,b): If an endothermic phase change is
observed at a particular temperature, then the two poly-
morphs are enantiotropically related; if an exothermic phase
transition is observed, the two polymorphs are monotropi-
cally related or the transition point is higher and they are
enantiotropically related. These well-known rules to under-
stand the thermodynamics of polymorphs are summarized
elsewhere.16d
Figure 6. Sulfonamide dimer extends via C-H O dimer in struc-
tures 4(a) and 5(b).
3 3 3
1187-1147 cm-1, respectively. Sulfonamides exhibit S-N
stretching vibrations at 924-906 cm-1. Solid-state IR and
Raman spectra (Figures 15 and 16) show differences in
hydrogen bonding. For example, molecules 1 and 6 have
N-H O hydrogen bonds of different strengths (due to
3 3 3
dimer/catemer synthons) in their polymorphs. The N-H
stretch is at higher frequency for form I (3304.8 cm-1
)
compared to form II (3255.7 cm-1), indicating a weaker
N-H OdS hydrogen bond in form I of 1, which is con-
3 3 3
˚
sistent with the hydrogen bond distance (2.21 vs 2.00 A,
Table 3). Similarly, the Raman spectra of the two poly-
morphs of molecule 1 show higher stretching frequency for
the N-H group in form I, which suggests stronger N-H and
consequently weaker N-H O hydrogen bond. Spectral
CSD Analysis of Dimer/Catemer Synthons. The sulfona-
mide group is capable of making dimer and catemer motifs of
3 3 3
parameters for N-H stretch, N-H bend, and SdO sym-
metric/asymmetric stretch are summarized in Table 7
(IR stretching) and Table 8 (Raman shift). Such a correlation
in red/blue shift of IR frequency and short/long hydrogen
bond distance is absent for polymorphs of 6.
N-H O hydrogen bonds. Yet, sulfonamide polymorphs
3 3 3
have not been studied or classified according to dimer/catemer
synthons. We surveyed the Cambridge Structural Database17
(version 5.31, ConQuest 1.12, May 2010) to tabulate the
frequency of dimer and catemer synthons (Figure 1) in
primary and secondary sulfonamides (Table 10). Out of
1054 secondary sulfonamides, 204 contain the dimer motif
and 196 have the catemer chain. Similarly, the numbers for
186 primary sulfonamides are 32 and 36. The near equal
probability of dimer and catemer motifs in secondary sulfo-
namides of ∼19% came as a surprise because the situation is
very different in carboxamides and carboxylic acids. The
dimer motif is overwhelmingly favored, and the catemer is
Phase Transitions. Polymorphs exist only in the solid-
state. Melting or dissolution destroys any distinctions be-
tween them. The presence of solvent or moisture can speed
up interconversion between polymorphs. Compounds 1 and
11 show phase transition15 by differential scanning calori-
metry (differential scanning calorimetry (DSC) plots are
shown in Figure 17). Form II converts to form I as the
temperature is raised, and form I is the thermodynamically
stable polymorph. Form II of 1 shows a small exotherm at

Article
Crystal Growth & Design, Vol. 10, No. 10, 2010 4557
Figure 7. (a and b) N-H O chain and C-H O cross-link in polymorphs I and II of molecule 6. (c) N-H O dimer in polymorph III.
3 3 3 3 3 3 3 3 3
Figure 8. (a) N-H O helix via the syn O of symmetry-independent molecules along [010] in form I of molecule 7. (b) N-H O catemer via
3 3 3 3 3 3
the anti O along [010] with the second molecule making N-H O and Cl O interactions in form II.
3 3 3 3 3 3
Figure 9. N-H O catemer via the anti O of two crystallographic
molecules in structure 8.
3 3 3
Figure 10. Catemer N-H O chain using the syn O along [010]
with only one crystallographic molecule of 9. This seems to be a rare
situation in sulfonamide structures.
3 3 3
very rare in acids and amides.4c,d,11a We sought a reason for the
equal probability of dimer and catemer motifs in sulfonamides.1i
In carboxylic acids and amides the NH or OH hydrogen
can reside syn or anti to the CdO oxygen, and of these two
orientations the syn conformation is energetically preferred.
Thus, the dimer is the default motif. The fact that the dimer

4558 Crystal Growth & Design, Vol. 10, No. 10, 2010
Sanphui et al.
motif occurs across the inversion center, the most preferred
crystallography symmetry element in crystal structures, is an
additional favorable factor. The situation is different in
sulfonamides because there are two O atoms here. Hence,
the question is: which of these is involved in dimer/catemer
hydrogen bonding? The dimer motif can be made only with
syn O (to NH), but the catemer can form via either syn or anti
O. CSD statistics show that there is a >2:1 preference for
anti O compared to syn O in the catemer N-H O chain:
3 3 3
137/59 for secondary sulfonamides and 25/11 for primary
sulfonamides. In the polymorphic systems studied by us,
the anti O catemer is present in molecule 1_formI, mole-
cule 3_formII, molecule 6_formI, molecule 6_formII, and
Table 5. Lattice Energy (kcal mol-1) Calculated in Cerius2
(Compass Force Field)
molecule
form I
form II
form III
1
2
3
6
7
11
-30.031
-30.973
-30.696
-30.534
-30.745
-29.243
-30.040
-30.583
-33.264
-31.626
-31.119
-29.186
-30.403
Figure 11. Sulfonamide dimers are connected via π π stacking of
Cl-Ph rings (3.49 A) in 10.
3 3 3
˚
Figure 12. (a) Dimer sulfonamide units are connected through aromatic C-H O interaction in form I of 11. (b) Sulfonamide dimers are
3 3 3
connected by the methyl C-H O in form II.
3 3 3
Figure 13. Sulfonamide dimer along with π-stacking in structures 12 (a, left) and 13 (b, right).
Figure 14. Overlay of molecular conformations: form-I = red; form II = blue; form III = magenta for 1, 2, 3, 6, and 11. For 7, form I = red,
blue and form II = green, brown (two symmetry-independent molecules). There is not much variation in these molecular conformations and
orientation of aromatic rings in the crystal structures.

Article
Crystal Growth & Design, Vol. 10, No. 10, 2010 4559
Table 6. Density, Packing Fraction, and Melting Onset of Sulfonamide Polymorphs
sulfonamide polymorphs
density (g cm-3), packing fraction (%), and melting onset (ꢀC)
form I
form II
form III
molecule 1
molecule 2
molecule 3
molecule 6
molecule 7
molecule 11
1.318, 67.3, 151.5
1.259, 65.1, 120.8
1.496, 66.8, 168.9
1.517, 66.0, 155.3
1.371, 64.3, 93.6
1.355, 64.7, 111.86
1.286, 65.4, 97.5a
1.243, 64.5, 124.3
1.507, 67.2, 168.5
1.548, 67.2, 156.5
1.415, 66.5, 91.6
1.376, 65.7, 80.27a
1.513, 66.0, 155.87
a Phase transition temperature.
Figure 15. IR spectra of polymorphs of molecules 1 (a) and 6 (b).

4560 Crystal Growth & Design, Vol. 10, No. 10, 2010
Sanphui et al.
Figure 16. Raman spectra of polymorphs of molecules 1 (a) and 6 (b).
Table 7. IR Resonances (cm-1) of Sulfonamide Polymorphs
Table 8. Raman Resonances (cm-1) of Sulfonamide Polymorphs
molecule
N-H stretch
N-H bend
SdO asym/sym stretch
molecule
N-H stretch
N-H bend
SdO asym/sym stretch
1 form I
1 form II
2 form I
2 form II
3 form I
3 form II
6 form I
6 form II
6 form III
7 form I
7 form II
11 form I
11 form II
3304.8
3255.7
3261.1
3261.2
3249.1
3251.5
3271.1
3259.4
3240.8
3215.5
3215.7
3243.3
3245.2
1472.0
1473.0
1473.8
1473.8
1478.5
1477.8
1445.6
1447.9
1447.0
1463.7
1463.5
1498.0
1497.7
1327.6/1161.5
1329.6/1162.0
1331.2/1158.6
1331.0/1158.1
1340.8/1157.4
1339.6/1157.5
1336.8/1168.5
1341.0/1168.7
1343.0/1166.1
1334.7/1157.7
1341.9/1157.7
1333.2/1163.8
1328.8/1162.9
1 form I
1 form II
2 form I
2 form II
3 form I
3 form II
6 form I
6 form II
6 form III
7 form I
7 form II
11 form I
11 form II
3308.0
3249.4
3257.4
3252.2
3249.0
3249.8
3271.9
3278.9
3269.7
3220.3
3214.6
3239.8
3237.9
1584.7
1587.0
1593.4
1597.4
1575.4
1575.2
1583.3
1580.5
1582.1
1580.8
1581.5
1597.5
1597.4
1325.5/1160.8
1325.3/1150.7
1321.5/1145.4
1326.4/1145.1
1333.2/1165.2
1334.0/1154.5
1336.7/1164.6
1336.7/1163.3
1333.4/1162.6
1336.5/1157.1
1336.3/1157.2
1332.4/1154.4
1331.8/1154.2

Article
Crystal Growth & Design, Vol. 10, No. 10, 2010 4561
Table 9. Thermal Parameters from DSC for Sulfonamide Polymorphs
sulfonamide
T
m (ꢀC), ΔHfus (kJ mol-1
)
stable polymorph
relationship and rule applied
form I
form II
form III
molecule 1
151.5, -38.32
97.5, þ1.99
form I
monotropic, heat-of-transition
153.1, -30.11
124.3, -25.79
167.3, -107.09
156.5, -99.33
91.6, -18.16
80.3, -1.14
molecule 2
molecule 3
molecule 6
molecule 7
molecule 11
120.8, -15.91
168.2, -115.37
155.3, -88.27
93.6, -26.44
111.9, -18.61
form II
form I
form II
form I
form I
monotropic, heat-of-fusion
monotropic, heat-of-fusion
monotropic, heat-of-fusion
monotropic, heat-of-fusion
enantiotropic, heat-of-atransition
155.9, -79.99
111.2, -18.83
Figure 17. Differential scanning calorimetry of sulfonamides 1 and 11. Remaining thermograms are shown in Supporting Information.
molecule 7_formII, whereas syn O catemer is in molecule
7_formI only. N-H O hydrogen bond synthon and graph
set notation in sulfonamides 1-13 is summarized in Table 11.
Surprisingly, the presence of sulfonamide dimer in one
3 3 3

4562 Crystal Growth & Design, Vol. 10, No. 10, 2010
Sanphui et al.
polymorph and catemer in another polymorph is quite a
rare situation. CSD Refcodes FIBKUW01/FIBKUW0218a
(secondary sulfonamide) and SULAMD07/SULAMD0818b
(primary sulfonamide) are the only sulfonamide pairs where
the basic difference in structures is the SO2NH dimer vs
catemer motif. We add three structure pairs of dimer and
catemer motif in polymorphs: molecules 1, 3, and 6. The
reason for the near equal probability of dimer and catemer
N-H O motifs in sulfonamides is the ease with which the
3 3 3
catemer chain can form using the anti O of the SO2NH
group, a conformation that is predisposed to extend the
hydrogen bond chain. There are no tangible differences
between the conformations of molecules (Figure 14) in
crystal structures containing dimer or catemer synthon.
Conclusion
Hydrogen bonding of the sulfonamide group as N-H
O
3 3 3
dimer and catemer synthons is systematically studied in
polymorphic crystal structures. The relatively rare occurrence
of the dimer motif in one polymorph and the catemer in
another structure is shown to occur in three systems among
with the 13 sulfonamides studied. The frequency of dimer and
catemer synthons is about the same for the sulfonamide
group. The greater frequency for the catemer motif in sulfo-
namides, compared to carboxamides and carboxylic acids, is
attributed to the anti O participating inthe infinite chain motif
twice as often as syn O. The crystallization solvent is impor-
tant to obtain a particular polymorph, with polar solvents
giving the stable polymorph while nonpolar solvents afforded
a metastable state.
Experimental Section
The phenyl benzenesulfonamides listed in Scheme 1 were synthe-
sized by the condensation of the appropriate aniline with a substi-
tuted sulfonyl chloride (1:1 molar ratio) in the presence of pyridine
base. All starting materials were purchased from Sigma-Aldrich and/
orLancaster. Molecules 1-13werepurifiedand crystallizedusing the
Figure 18. Hot Stage microscope snapshots of compounds 1 and 11
to study phase transitions.
Table 10. CSD Statistics on Sulfonamides
no. of secondary sulfonamides after removing all duplicates
no. of primary sulfonamides after removing all duplicates
no. of secondary sulfonamides that are polymorphic
no. of primary sulfonamides that are polymorphic
1054
186
17 (Refcodes list is given in Supporting Information)
5 (Refcodes list is given in Supporting Information)
1 (SULAMD02 and SULAMD07)
1 (FIBKUW01 and FIBKUW02)
204 (19.3%)
196 (18.6%)
137 (Refcodes list is given in Supporting Information)
59 (Refcodes list is given in Supporting Information)
32 (Refcodes list is given in Supporting Information)
36 (Refcodes list is given in Supporting Information)
25 (Refcodes list is given in Supporting Information)
11 (Refcodes list is given in Supporting Information)
primary sulfonamide having dimer/catemer synthon in polymorphs
secondary sulfonamide polymorphs containing dimer/catemer synthon
no. of secondary sulfonamides containing dimer motif
no. of secondary sulfonamides containing catemer motif
no. of secondary sulfonamide catemer motifs with anti O
no. of secondary sulfonamide catemer motifs with syn O
no. of primary sulfonamides containing dimer motif
no. of primary sulfonamides containing catemer motif
no. of primary sulfonamide catemer motifs with anti O
no. of primary sulfonamide catemer motifs with syn O
Table 11. Summary of N-H O Hydrogen Bond Synthon and Graph Set Notation in Sulfonamides 1-13
3 3 3
compound
crystal polymorph, synthon, graph set
classification
form I
form II
form III
1
2
3
4
5
6
7
8
catemer, anti O C(4)
dimer, syn O R22(8)
dimer, syn O R22(8)
dimer, syn O R22(8)
dimer, syn O R22(8)
catemer, anti O C(4)
catemer, syn O C(4)
catemer, anti O C(4)
catemer, syn O C(4)
dimer, syn O R22(8)
dimer, syn O R22(8)
dimer, syn O R22(8)
dimer, syn O R22(8)
dimer, syn O R22(8)
dimer, syn O R22(8)
catemer, anti O C(4)
synthon polymorphs, primary
synthon polymorphs, secondary
synthon polymorphs, primary
no polymorph
no polymorph
catemer, anti O C(4)
catemer, anti O C(4)
dimer, syn O R22(8)
synthon polymorphs, primary
synthon polymorphs, secondary
no polymorph
no polymorph
no polymorph
synthon polymorphs, secondary
no polymorph
no polymorph
9
10
11
12
13
dimer, syn O R22(8)

Article
Crystal Growth & Design, Vol. 10, No. 10, 2010 4563
solvents listed in Table 1. All products were characterized by
1H NMR (δ ppm, J Hz) and FT-IR spectroscopy and finally by
single crystal X-ray diffraction. The N-H asymmetric and sym-
metric stretching vibrations absorb at 3390-3323 cm-1 and 3279-
3229 cm-1, and the asymmetric and symmetric SO2 stretches at
1344-1317 cm-1 and 1187-1147 cm-1. Sulfonamides exhibit S-N
stretching absorption at 924-906 cm-1. All polymorphic structures
were confirmed and differentiated by single crystal and powder
XRD, FT-IR (KBr and ATR modes), FT-Raman, and DSC.
General Synthesis Procedure. Phenyl benzenesulfonamides were
prepared by mixing equivalent amounts of aniline (1 mmol) and
benzensulfonyl chloride (1 mmol) in 20 mL of freshly distilled
acetone under inert atmosphere. Pyridine (2 mL) was added drop-
wise and the reaction mixture was refluxed at 60 ꢀC for 2-3 h.
Finally the product was washed with water and the colorless pro-
duct was filtered. The product was purified by crystallization from
acetone.
(2H, d, J = 8), 6.57 (2H, d, J = 8), 6.32 (2H, d, J = 8), 6.13 (1H, d,
J = 8), 2.35 (3H, s), 1.98 (3H, s).
Molecule 13: Yield 74%. Mp 141-144 ꢀC. IR (KBr, cm-1) 3235,
2928, 2868, 1597, 1510, 1474, 1406, 1333, 1271, 1167, 1116, 1090,
1
966, 901, 810, 679. H NMR (CDCl3) δ 7.65 (2H, d, J = 8), 7.26
(1H, s), 7.24 (1H, d, J = 8), 7.06 (2H, d, J = 8), 6.88 (1H, d, J = 4),
6.71 (1H, s), 2.39 (3H, s), 2.28 (3H, s).
X-ray Crystallography. Reflections were collected on a Bruker
˚
SMART CCD diffractometer. Mo KR (λ = 0.71073 A) radiation
was used to collect X-ray reflections on all crystals (1-13). Data
reduction was performed using Bruker SAINT software.19 Struc-
tures were solved and refined using SHELX20 with anisotropic
displacement parameters for non-H atoms. Hydrogen atoms on O
and N atoms were experimentally located in all crystal structures.
All C-H atoms were fixed geometrically. A check of the final CIF
file with PLATON21 did not show any missed symmetry. All N-H
and O-H hydrogens were located in difference electron density
maps. Packing diagrams were prepared in X-Seed.22 Crystallo-
graphic .cif files (CCDC Nos. 781569-781588) are available at
www.ccdc.cam.ac.uk/data_request/cif or as part of the Supporting
Information.
Molecule 1: Yield 78%. Mp 151-153 ꢀC. IR (KBr, cm-1) 3306,
2928, 1586, 1471, 1451, 1393, 1327, 1194, 1161, 1090, 899, 825, 777,
1
762, 742, 719, 688. H NMR (CDCl3) δ 7.58 (2H, d, J = 8), 7.44
(1H, t, J = 8), 7.32 (2H, t, J = 8), 6.94 (1H, t, J = 8), 6.86 (2H, d,
J = 8), 5.94 (1H, s), 1.89 (6H, s).
X-ray Powder Diffraction. Powder XRD of all samples was
recorded on a PANlytical 1830 (Philips Analytical) diffractometer
Molecule 2: Yield 76%. Mp 127-129 ꢀC. IR (KBr, cm-1) 3262,
3059, 2926, 1474, 1398, 1381, 1333, 1157, 1097, 910, 829, 791. H
˚
1
using Cu KR X-radiation (λ = 1.54056 A) at 40 kV and 30 mA.
Diffraction patterns were collected in the 2θ range 5-50ꢀ at the scan
rate 1ꢀ min-1. Powder Cell 2.323 was used for Rietveld refinement.
Vibrational Spectroscopy. A Nicolet 6700 FT-IR spectrometer
with a NXR FT-Raman Module was used to record IR and Raman
spectra. IR spectra were recorded on samples dispersed in a KBr
pellet. Raman spectra were recorded on samples contained in
standard NMR tubes or on compressed solids placed on a gold-
coated sample holder.
Thermal Analysis. DSC was recorded on Mettler Toledo DSC
822e module. A sample of 4-6 mg was placed in a crimped but
vented aluminum pan, and the temperature was increased from
30 to 250 at 2 ꢀC min-1. A stream of nitrogen flow at 150 mL min-1
purged the sample.
NMR (CDCl3) δ 7.51 (1H, s), 7.50 (1H, d, J = 8), 7.38-7.32 (2H,
m), 7.08 (1H, t, J = 8), 6.99 (2H, d, J = 8), 5.88 (1H, s), 2.35 (3H, s),
2.03 (6H, s).
Molecule 3: Yield 65%. Mp 167-168 ꢀC. IR (KBr, cm-1) 3252,
2928, 1586, 1468, 1450, 1408, 1392, 1327, 1273, 1161, 1140, 1090,
897, 866, 826, 777, 761, 742, 717, 688.
1H NMR (CDCl3) δ 7.65 (1H, s), 7.62 (1H, d, J = 8), 7.40-7.32
(4H, m), 7.16 (1H, t, J = 8), 6.32 (1H, s), 2.40 (3H, s).
Molecule 4: Yield 75%. Mp 140-142 ꢀC. IR (KBr, cm-1) 3270,
3084, 2917, 1460, 1373, 1331, 1161, 1080, 907, 837, 789, 772, 671.
1H NMR (CDCl3) δ 7.67 (1H, s), 7.52 (1H, d, J = 8), 7.47 (1H, d,
J = 8), 7.34 (1H, t, J = 8), 7.03 (1H, t, J = 8), 6.95 (2H, d, J = 8),
6.00 (1H, s), 1.99 (6H, s).
Molecule 5: Yield 56%. Mp 102-104 ꢀC. IR (KBr, cm-1) 3260,
2961, 1456, 1383, 1339, 1261, 1167, 1080, 907, 872, 793, 773, 671.
1H NMR (CDCl3) δ 7.60 (1H, s), 7.48 (1H, d, J = 8), 7.46 (1H, d,
J = 8), 7.30 (1H, t, J = 8), 7.16 (1H, d, J = 2), 7.09-7.03 (2H, m),
6.02 (1H, s), 2.48 (3H, s).
Acknowledgment. B.S. and P.S. thank CSIR and UGC for
fellowships. We thank the DST for research funding (SR/S1/
RFOC-01/2007 and SR/S1/OC-67/2006) and DST (IRPHA)
and UGC (PURSE and UPE grants) for providing instru-
mentation and infrastructure facilities.
Molecule 6: Yield 39%. Mp 153-156 ꢀC. IR (KBr, cm-1) 3259,
3085, 1567, 3259, 1567, 1448, 1341, 1167, 1088, 779, 753. 1H NMR
(CDCl3) δ 7.85 (2H, d, J = 8), 7.62 (2H, t, J = 8), 7.52 (2H, t, J = 8),
7.28 (2H, d, J = 8), 7.21 (1H, t, J = 8), 6.45 (1H, s).
Molecule 7: Yield 70%. Mp 91-93 ꢀC. IR (KBr, cm-1) 3217,
3040, 2917, 2861, 1464, 1397, 1337, 1298, 1159, 997, 914, 828, 795,
673. 1H NMR (CDCl3) δ 1.98 (6H, s), 6.00 (1H, s), 6.95 (2H, d, J =
8), 7.02, 10.20 (1H, s), 8.31 (1H, s), 7.72 (1H, d, J = 6), 7.69 (1H, d,
J = 6), 7.64 (1H, t, J = 6), 7.04 (2H, d, J = 8), 6.95 (2H, d, J = 8),
2.19 (3H, s).
Supporting Information Available: PXRD patterns, DSC, refcodes,
and CIF files. This material is available free of charge via the
Internet at http://pubs.acs.org.
References
(1) (a) Kruger, G. J.; Gafner, G. Acta Crystallogr. 1971, B27, 326.
(b) Gelbrich, T.; Hughes, D. S.; Hursthouse, M. B.; Threlfall, T. L.
CrystEngComm 2008, 10, 1328. (c) Koo, C. H.; Lee, Y. J. Arch.
Pharm. Res. 1979, 2, 99. (d) Bar, I.; Bernstein, J. Eur. Cryst. Meeting
1982, 7, 182. (e) Basak, A. K.; Chaudhuri, S.; Mazumdar, S. K. Acta
Crystallogr. 1984, C40, 1848. (f) Bernstein, J. Acta Crystallogr. 1988,
C44, 900. (g) Bar, I.; Bernstein, J. J. Pharm. Sci. 1985, 74, 255.
(h) Ajibade, P. A.; Kolawole, G. A.; O'Brien, P.; Helliwell, M.; Raftery,
J. Inorg. Chim. Acta 2006, 359, 3111. (i) Roy, S.; Nangia, A. Cryst.
Growth Des. 2007, 7, 2047. (j) Ko, S.-K.; Jin, H. J.; Jung, D.-W.; Tian,
X.; Shin, I. Angew. Chem., Int. Ed. 2009, 121, 7949.
(2) (a) Knapman, K. Mod. Drug Discovery 2000, 3, 53. (b) Hilfiker, R.;
Blatter, F.; von Raumer, M. Relevance of Solid-state Properties for
Pharmaceutical Products. In Polymorphism In the Pharmaceutical
Industry; Hilfiker, R., Eds.; Wiley-VCH: Weinheim, 2006.
(3) Gelbrich, T.; Hursthouse, M. B.; Threlfall, T. L. Acta Crystallogr.
2007, B63, 621.
(4) (a) Nangia, A.; Desiraju, G. R. Top. Curr. Chem. 1998, 198, 57.
(b) Desiraju, G. R. Angew. Chem., Int. Ed. Engl. 1995, 34, 2311.
(c) Parveen, S.; Davey, R. J.; Dent, G.; Pritchard, R. G. Chem.
Commun. 2005, 1531. (d) Florence, A. J.; Shankland, K.; Gelbrich,
T.; Hursthouse, M. B.; Shankland, N.; Johnston, A.; Fernandesa, P.;
Leec, C. K. CrystEngComm 2008, 10, 26. (e) Takasuka, M.; Nakai, H.;
Shiro, M. J. Chem. Soc., Perkin Trans. 1982, 2, 1061.
Molecule 8: Yield 74%. Mp 98-100 ꢀC. IR (KBr, cm-1) 3270,
1
2922, 2856, 1456, 1338, 1298, 1219, 1153, 914, 818, 687. H NMR
(CDCl3) δ 7.44 (1H, s), 7.40 (2H, d, J = 8), 7.18-7.12 (2H, m), 6.89
(2H, d, J = 8), 6.80 (2H, d, J = 8), 2.21 (3H, s), 2.14 (3H, s).
Molecule 9: Yield 65%. Mp 92-94 ꢀC. IR (KBr, cm-1) 3283,
3088, 1489, 1447, 1410, 1389, 1335, 1294, 1219, 1163, 1125, 1107,
1
1076, 1011, 941, 908, 883, 847, 785, 717, 675. H NMR (CDCl3)
δ 7.69 (1H, s), 7.50 (1H, d, J = 8), 7.45 (1H, d, J = 8), 7.32 (1H, t,
J = 8), 7.17 (2H, d, J = 8), 6.93 (2H, d, J = 8), 6.40 (1H, s).
Molecule 10: Yield 87%. Mp 82-84 ꢀC. IR (KBr, cm-1) 3256,
2916, 2849, 1491, 1452, 1385, 1329, 1223, 1153, 1082, 1013, 910, 843,
1
781, 698. H NMR (CDCl3) δ 7.59 (1H, s), 7.54 (1H, d, J = 7),
7.36-7.31 (2H, m), 7.19 (2H, d, J = 8), 7.01 (2H, d, J = 8), 6.84
(1H, s), 2.37 (3H, s).
Molecule 11: Yield 80%. Mp 108-111 ꢀC. IR (KBr, cm-1) 3250,
2897, 1497, 1408, 1329, 1273, 1163, 1140, 1090, 917, 897, 818, 773,
685. 1H NMR (CDCl3) δ 7.66 (1H, s), 7.23-7.21 (2H, m), 7.14 (1H,
t, J = 8), 6.77 (2H, d, J = 8), 6.73 (2H, d, J = 8), 2.36 (3H, s).
Molecule 12: Yield 82%. Mp 156-158 ꢀC. IR (KBr, cm-1) 3235,
2924, 1609, 1495, 1458, 1389, 1329, 1287, 1260, 1227, 1161, 1088,
1049, 931, 889, 812, 702, 683. 1H NMR (CDCl3) δ 9.17 (1H, s), 6.99

4564 Crystal Growth & Design, Vol. 10, No. 10, 2010
Sanphui et al.
(5) (a) Babu, N, J.; Cherukuvada, S.; Thakuria, R. Cryst Growth Des.
ꢀ
(14) (a) Tudor, A. M.; Church, S. J.; Hendra, P. J.; Davies, M. C.; Melia,
ꢁ
2010, 10, 1979. (b) Lopez-Mejías, V.; Kampf, J. W.; Matzger, A. J.
C. D. Pharm. Res. 1993, 10, 1772. (b) Vrecer, F.; Vrbinc, M.; Meden,
J. Am. Chem. Soc. 2009, 131, 4554. (c) Parmar, M. M.; Khan, O.;
Seton, L.; Ford, J. L. Cryst. Growth Des. 2007, 7, 1635. (d) Sarma, B.;
Roy, S.; Nangia, A. Chem. Commun. 2006, 4918. (e) Roy, S.; Matzger,
A. J. Angew. Chem., Int. Ed. 2009, 121, 8657.
A. Int. J. Pharm. 2003, 256, 3. (c) Chesalov, Y. A.; Baltakhinov, P.;
Drebushchak, T. N.; Boldyreva, E. V.; Chukanov, N. V.; Drebushchak,
V. A. J. Mol. Struct. 2008, 891, 75.
(15) (a) Roy, S.; Bhatt, P. M.; Nangia, A.; Kruger, G. J. Cryst. Growth
Des. 2007, 7, 476. (b) Kimura, K.; Hirayama, F.; Uekama, K. J. Pharm.
Sci. 1999, 88, 385. (c) Long, S.; Parkin, S.; Siegler, M. A.; Cammers,
A.; Li, T. Cryst. Growth Des. 2008, 8, 4006.
(6) Gowda, B. T.; Foro, S.; Babitha, K. S.; Fuess, H. Acta Crystallogr.
2008, E64, o1691 [CSD Refcode HODWED].
(7) Jeffrey, G. A. An Introduction to Hydrogen Bonding; Oxford
University Press: New York, 1997.
(8) Babu, N. J.; Reddy, L. S.; Aitipamula, S.; Nangia, A. Chem. Asian
(16) (a) Burger, A.; Ramberger, R. Mikrochim. Acta 1979, II, 259.
(b) Burger, A.; Ramberger, R. Mikrochim. Acta 1979, II, 273.
(c) Grunenberg; Henck, J.-O.; Siesler, H. W. Int. J. Pharm. 1996,
129, 147. (d) Bernstein, J. Polymorphism in Molecular Crystals;
Clarendon Press: Oxford, 2002; pp 28-42.
J. 2008, 3, 1122.
(9) (a) Bernstein, J.; Davis, R. E.; Shimoni, L.; Chang, N. L. Angew.
Chem., Int. Ed. Engl. 1995, 34, 1555. (b) Etter, M. C.; Macdonald, J. C.
Acta Crystallogr. 1990, B46, 256. (c) Grell, J.; Bernstein, J.; Tinhofer,
G. Acta Crystallogr. 1999, B55, 1030.
(17) Cambridge Crystallographic Data Center, Cambridge, U.K.,
www.ccdc.cam.ac.uk.
(10) (a) Bui, T. T. T.; Dahaoui, S.; Lecomte, C.; Desiraju, G. R.;
Espinosa, E. Angew. Chem., Int. Ed. 2009, 121, 3896. (b) Desiraju,
G. R.; Parthasarathy, R. J. Am. Chem. Soc. 1989, 111, 8725.(c) Saha,
B. K.; Nangia, A.; Nicoud, J.-F. Cryst. Growth Des. 2006, 6, 1278.
(11) (a) Braun, D. E.; Gelbrich, T.; Kahlenberg, V.; Tessadri, R.;
Wieser, J.; Griesser, U. J. J. Pharm. Sci. 2009, 98, 2010. (b) Nagel,
N; Bock, H.; Eller, P. Acta Crystallogr. 2000, B56, 234. (c) Florence,
A. J.; Shankland, K.; Gelbrich, T.; Hursthouse, M. B.; Shankland, N.;
Johnston, A.; Fernandesa, P.; Leech, C. K. CrystEngComm 2008, 10, 26.
(d) Gajda, R.; Katrusiak, R.; Crassous, J. CrystEngComm 2009, 11, 2668.
(12) (a) Kitaigorodskii, A. I. Molecular Crystals and Molecules;
Academic Press: New York, 1973. (b) Desiraju, G. R.; Sarma, J. A.
R. P. Proc. Ind. Acad. Sci. (Chem. Sci.) 1986, 96, 599.
(18) (a) Nagel, N.; Bock, H.; Eller, P. Acta Crystallogr. 2000, B56,
234 [FIBKUW01/02]. (b) Hursthouse, M. B.; Threlfall, T. L.; Coles,
S. J.; Ward, S. C. Crystal Structure Report Archive; University of
Southampton: 1998; [SULAMD07/08].
(19) SAINT Plus (version 6.45); Bruker AXS Inc.: Madison, WI, 2003.
(20) SMART (version 5.625) and SHELX-TL (version 6.12); Bruker AXS
Inc.: Madison, WI, 2000.
(21) (a) PLATON, A Multipurpose Crystallographic Tool; Spek, A. L.
Utrecht University: Utrecht, Netherland, 2002. (b) Spek, A. L. J. Appl.
Crystallogr. 2003, 36, 7.
(22) Barbour, L. J. X-Seed, Graphical Interface to SHELX-97
and POV-Ray; University of Missouri;Columbia: Columbia, MO,
1999.
(13) (a) Ostwald, W. F. Z. Phys. Chem. 1897, 22, 289. (b) Trifkovic, M.;
Rohani, S. Org. Process. Res. Dev. 2007, 11, 138.
(23) Powder Cell, A program for structure visualization, powder pattern
calculation and profile fitting, www.ccp14.ac.uk.