Effect of a rigid sulfonamide bond on molecular folding: A case study

Article abstract of DOI:10.1021/acs.cgd.5b00424

A disulfonamide compound with bulky aromatic side chains was prepared, and its properties as a potential building block for foldamers were evaluated. Two different solvate crystal forms of the compound were identified and compared to the structures of an

Full text of DOI:10.1021/acs.cgd.5b00424

Article
pubs.acs.org/crystal
Effect of a Rigid Sulfonamide Bond on Molecular Folding: A Case
Study
Aku Suhonen, Ian S. Morgan, Elisa Nauha, Kaisa Helttunen, Heikki M. Tuononen, and Maija Nissinen*
Department of Chemistry, Nanoscience Center, University of Jyvaskyla, P.O. Box 35, FI-40014 University of Jyvaskyla, Finland
̈
̈
S
* Supporting Information
ABSTRACT: A disulfonamide compound with bulky aromatic
side chains was prepared, and its properties as a potential
building block for foldamers were evaluated. Two different
solvate crystal forms of the compound were identified and
compared to the structures of an analogous oligoamide and
related disulfonamides. The disulfonamide is unfolded in one of
the solvates, whereas in the other one, a loosely folded
conformer stabilized by an intramolecular hydrogen bond is
found. Density functional calculations indicated that the loosely
folded conformer is slightly more stable than its unfolded
isomer. The calculations also identified a third, more tightly
folded and more extensively hydrogen bonded, conformer that
is even lower in energy.
peptides, the amide-to-sulfonamide replacement has been
reported to lead to both striking differences as well as
surprising similarities in the folding patterns.8,14
INTRODUCTION
■
The crystal form, the organization of molecules in a crystalline
solid, depends on the conformational, functional, and
interaction properties of the compound as well as on the
crystallization environment, such as temperature and solvent.
On the other hand, the crystal form affects the physical
properties of crystalline materials and provides information on
conformational preferences and the interplay of intra- and
intermolecular interactions as well as their role in the formation
of crystalline materials under varying conditions.1 Molecular
conformation is especially important in the case of synthetic
compounds that adopt structures mimicking those of biological
molecules, such as peptides and proteins. These biomimetic
molecular scaffolds, called foldamers, are composed of relatively
simple repeating structural units and have, to some extent,
predictable secondary structures stabilized by weak interactions
between nonadjacent units.2,3 In addition to being artificial
models for molecular folding,4 foldamers may express enzyme-
like functions such as receptor properties and catalysis.5
The most common bond type used in the construction of
foldamers is the amide bond.6,7 This is not only due to its
analogy to peptide bonds but also because of its predictable
hydrogen-bonding properties. Another interesting, yet rarely
used, bond type is the sulfonamide bond in which the sp2
carbon of an amide is replaced with an sp3 sulfur.8,9 This leads
to differences in the preferred orientation of the C−N and S−N
bonds and in the wideness of the OXN angles (120° and 106°
for X = C and X = S, respectively). Compared to amides,
sulfonamides have different possibilities for intra- and
intermolecular hydrogen bonding,10,11 which strongly affects
their conformational properties and, hence, the propensity of
sulfonamides to form polymorphs and co-crystals.12,13 In small
Co-crystallization studies of sulfonamide compounds have
been conducted to improve their properties, such as solubility,
and to explore their potential as building blocks for new
molecular assemblies with improved pharmaceutical proper-
ties.15 Sulfonamides were the first clinically available anti-
bacterial agents,16 and they have been widely used in the design
of drug candidates.17,18 Another potential use for sulfonamide
compounds is (stereoselective) organocatalysis because of their
capacity to form fairly weak hydrogen bonds and their
increased acidity compared to the amide group.19,20
In our previous study, we focused on aromatic oligoamides as
potential foldamers and studied their conformational proper-
ties, polymorphism, and solvate formation.21,22 In order to
investigate the effect of amide-to-sulfonamide replacement on
molecular conformation and folding, we have now prepared a
sulfonamide analogue (2) of one of the previously synthesized
oligoamides (3).21 The structural properties of sulfonamide 2
were investigated in the solid state and in solution as well as by
performing density functional theory (DFT) calculations. The
results are compared and contrasted with the data of
oligoamide 3 as well as with that for other related
disulfonamides described in the literature.
Received: September 4, 2014
Revised: May 5, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.cgd.5b00424
Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Article
closed container. The sample was left to crystallize at room
temperature.
EXPERIMENTAL SECTION
■
Materials and Methods. All starting materials were commercially
available and used as such unless otherwise noted. Analytical grade
solvents and Millipore water were used for crystallizations. NMR
spectra were measured with a Bruker Avance DRX 500 spectrometer,
and chemical shifts were calibrated to the residual proton and carbon
resonances of the deuterated solvent. Melting points were measured in
open capillaries using a Stuart Scientific SMP3 melting point apparatus
and are uncorrected. ESI-TOF mass spectra were measured with a
LCT Micromass spectrometer. Elemental analyses were performed
with a Vario EL III instrument.
Syntheses. All syntheses were carried out under a N2 atmosphere.
The glassware was dried at 120 °C prior to use. Dichloromethane was
dried by distillation over CaCl2 and stored over Linde type 3 Å
molecular sieves under nitrogen gas. Compound 1 was prepared by a
published method,21 which is a slight modification of an earlier
literature procedure.23 Compound 2 was also prepared by a slightly
modified literature procedure.24
X-ray Crystallography. Single crystal X-ray diffraction data was
collected with a Bruker Nonius KappaCCD diffractometer at 173 K
using a Bruker AXS APEX II CCD detector and graphite-
monochromated Cu Kα radiation (λ = 1.54178 Å). The structures
were solved with direct methods and refined using Fourier techniques
with the SHELX-97 software package.25 Absorption correction was
performed with Denzo-SMN 1997.26 All hydrogen atoms were placed
to their idealized positions except for the N−H hydrogens, which were
located from the electron density map and included in the structure
factor calculations. Electron density of severely disordered solvent
molecules in the EtOAc solvate structure was removed with the
SQUEEZE27 routine included in the PLATON28 program in the
WinGX package.29 Full details of the crystallographic data and
refinement are presented in Table 1 and in the Supporting
Information. Graph set symbols for hydrogen bonding were assigned
and used to compare the bonding between the different crystal
structures.30,31
N-Benzoyl-2-aminoaniline 1. O-Phenylenediamine (8.97 g; 83.1
mmol) was dissolved in dry dichloromethane (350 mL). Triethyl-
amine (3.0 mL; 21.6 mmol) was added, and the solution was heated to
reflux with stirring. Benzoyl chloride (2.16 g; 20.7 mmol) dissolved in
dry dichloromethane (200 mL) was added dropwise to the solution.
The solution was allowed to reflux for 2 h. The product was separated
by column chromatography using a silica column and an ethyl
acetate−hexane (1:1) mixture as the eluent. Recrystallization from
ethyl acetate−hexane afforded the product as a white solid (yield, 3.57
g, 81%). mp. 149−151 °C; 1H NMR (500 MHz, DMSO-d6, 30 °C): δ
4.87 (s, 2H; i), 6.60 (td, JHH = 1.2 Hz, JHH = 7.6 Hz, 1H; g), 6.79
(dd, 3JHH = 1.3 Hz, 3JHH = 8.1 Hz, 1H; e), 6.97 (td, 3JHH = 1.2 Hz, 3JHH
= 7.6 Hz, 1H; f), 7.18 (d, 3JHH = 7.7 Hz, 1H; d), 7.51 (t, 3JHH = 7.4 Hz,
2H; b), 7.55−7.60 (m, 1H; a), 7.98 (d, 3JHH = 7.4 Hz, 2H; c), 9.63 (s,
1H; h) ppm; 13C NMR (126 MHz, DMSO-d6, 30 °C): δ 116.1, 116.2,
123.3, 126.4, 127.6, 128.2, 131.2, 134.6, 143.0, 165.2 ppm; MS (ESI-
TOF) m/z [M + Na]+ calcd for C13H12N2O, 212.25; found, 235.08;
Analysis calcd (%) for C13H12N2O: C, 73.6; H, 5.7; N, 13.2. Found: C,
73.8; H, 5.6; N, 13.3.
Table 1. Crystallographic Data for Solvate 2I (EtOAc) and
Solvate 2II (DCE)
solvate 2I (EtOAc)
solvate 2II (DCE)
formula
C32H26N4O6S2
626.69
C32H26N4O6S2·C2H4Cl2
725.64
MW/g mol−1
crystal system
space group
a/Å
monoclinic
C2/c
monoclinic
P21/c
3
3
24.758(2)
6.9874(5)
21.0600(12)
106.985(3)
3484.3(4)
4
13.1334(3)
22.7870(6)
11.6864(4)
104.874(10)
3380.2(2)
4
b/Å
c/Å
β/deg
V/Å3
Z
ρcalc/g cm−3
meas. reflns
ind. reflns
Rint
1.195
1.426
4899
11 132
N1,N3-Bis(2-benzamidophenyl)benzene-1,3-disulfonamide
2. N-Benzoyl-2-aminoaniline 1 (0.471 g; 2.22 mmol) was dissolved in
pyridine (15 mL). The solution was stirred, and benzene-1,3-disulfonyl
chloride (0.307 g; 1.11 mmol) dissolved in pyridine (15 mL) was
added dropwise to the mixture. The solution was refluxed for 2 h, after
which the stirring was continued for 24 h. Two molar HCl was added
to the solution, and a precipitate formed; if the precipitate did not
form, then 6 M HCl solution was added. The precipitate was filtered
and washed with water. The precipitate was then dissolved in absolute
ethanol and concentrated. The concentrated product was dissolved in
ethanol, precipitated as a pink solid by adding water, and dried in
2984
5889
0.0449
0.0427
R1 [I > 2σ(I)]
wR2 [I > 2σ(I)]
GoF
0.0469
0.0449
0.1216
0.1104
1.050
1.015
Computational Details. All calculations were performed with the
Gaussian 0932 program package using the ωB97XD density func-
tional33 and Ahlrichs’ def2-TZVP basis sets.34 The chosen density
functional includes an empirical dispersion correction term which
allows for better treat hydrogen bonding and van der Waals
interactions than many conventional density functionals such as
B3LYP. The initial geometries of conformers of 2 were taken directly
from the single-crystal X-ray diffraction data. The global minimum
conformation, 2III, was obtained via potential energy surface scans in
which the torsion angles of the sulfonamide substituents were
systematically varied while keeping the other geometry parameters
frozen. These scans were performed using a lower level basis set. The
minima found were subjected to subsequent geometry optimizations
using the same functional and basis set as those used for 2I and 2II.
Gas-phase geometry optimizations were performed for all systems, and
the nature of the located minima was confirmed by performing a full
vibrational analysis. In addition to gas-phase calculations, a polarized
continuum solvent model (IEFPCM)35 was used to determine if the
bulk properties of the solvents (EtOAc and DCE) had a significant
influence on the energetic preference of different conformers of 2. The
energy values reported in the text are enthalpy differences obtained at
298 K and 1 atm.
1
vacuum (yield, 0.37 g, 63%). mp. 213-216 °C; H NMR (500 MHz,
DMSO-d6, 30 °C): δ 6.90 (dd, 2H, 3JHH = 1.5 Hz, 3JHH = 8.1 Hz), 7.07
3
3
3
(td, 2H, JHH = 1.4 Hz, JHH = 7.8 Hz), 7.26 (td, 2H, JHH = 1.4 Hz,
3JHH = 7.8 Hz), 7.52−7.57 (m, 5H), 7.62 (tt, 2H, 3JHH = 1.5 Hz, 3JHH
7.3 Hz), 7.76−7.80 (m, 4H), 7.81−7.84 (m, 4H), 8.00 (st, 1H, 3JHH
=
=
1.8 Hz), 9.54 (s, 2H), 9.84 (s, 2H) ppm; 13C NMR (126 MHz,
DMSO-d6, 30 °C): δ 124.7 (d), 125.3 (g), 126.2 (e), 127.0 (f), 127.3
(c), 127.8 (e′), 128.5 (b), 130.6 (j), 130.8 (h), 131.8 (a), 133.2 (d′),
134.0 (c′), 140.3 (j), 165.1 (k′); HRMS (ESI+) m/z [M + Na]+ calcd
for [C32H26N4O6S2Na], 649.1191; found, 649.1186, Δ = −0.8 ppm.
Crystallizations. X-ray quality crystals were obtained from ethyl
acetate−hexane diffusion (EtOAc−Hex) and evaporation of acetoni-
trile (MeCN), 1,2-dichloroethane (DCE), or tetrahydrofuran (THF)
solutions. However, only preliminary structures could be obtained for
the MeCN and THF solvates (see Supporting Information for details).
In all evaporation crystallizations, 20 mg of compound 2 was dissolved
in 2−6 mL of the solvent. Heating and stirring were used to help the
dissolving process. After the compound had fully dissolved, slow
evaporation of the solvent was allowed at room temperature. In
diffusion crystallization, 2 mg of compound 2 was dissolved in 0.5 mL
of ethyl acetate and 2 mL of hexane was used as an antisolvent in a
B
DOI: 10.1021/acs.cgd.5b00424
Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Article
RESULTS AND DISCUSSION
■
The N1,N3-bis(2-benzamidophenyl)benzene-1,3-disulfonamide
(2) was synthesized in good yield by a nucleophilic substitution
reaction between N-benzoyl-2-aminoaniline (1) and benzene-
1,3-disulfonyl chloride (Scheme 1). The product was
1
characterized by H and 13C NMR spectroscopy including 2D
techniques (COSY, HMQC, HMBC, and NOESY; see
Supporting Information for details).
Scheme 1. Synthesis of Disulfonamide 2
Figure 1. Two conformers of disulfonamide compound 2 crystallized
from EtOAc (left, solvate 2I) and DCE (right, solvate 2II) shown as
stick (a) and space filling (b) representations. Crystal packing
highlighting intermolecular hydrogen bonding (c). Disordered solvent
molecules and non-amide/sulfonamide hydrogen atoms have been
removed for clarity.
1
The H NMR spectra of 2 in DMSO-d6 and acetone-d6 at
room temperature are consistent with a symmetric structure for
the molecular backbone, which indicates either the presence of
a single preferred conformer with a C2-symmetry axis or
multiple conformers undergoing rapid exchange on the NMR
1
time scale. Variable-temperature H NMR measurements in
bonds are on the same plane with the central aromatic ring, and
a loosely folded conformer is stabilized by two intramolecular
hydrogen bonds between neighboring amide groups (Figure
2).21
acetone-d6 showed no significant splitting of the proton signals
when the temperature was gradually lowered to −80 °C, which
confirmed that a rapid exchange process is unlikely. A NOESY
NMR spectra of 2 in acetone-d6 indicated NOEs between the
protons of the terminal phenyl substituents and the hydrogen
atoms of the sulfonamide groups, but this information was
inconclusive for a detailed conformational determination.
Crystallographic Studies. Compound 2 was crystallized as
two solvates, the ethyl acetate solvate (EtOAc, solvate 2I) and
the dichloroethane solvate (DCE, solvate 2II), which differ by
the conformation of 2 (Figure 1). Two lower-quality
preliminary structures were also obtained: an acetonitrile
(MeCN) solvate that is isomorphous with EtOAc solvate 2I
and a tetrahydrofuran (THF) solvate that is isomorphous with
DCE solvate 2II (see Supporting Information for details). In
addition, powder diffraction data collected for the samples
obtained from ethanol and methanol crystallizations of 2
suggest the existence of a third currently unknown crystal form,
since the diffraction pattern bears very little resemblance to the
patterns calculated from the single-crystal X-ray structures of
solvates 2I and 2II (see Supporting Information for details).
In both conformers, the S−N bonds are roughly
perpendicular to the plane of the central aromatic ring, which
is typical to sulfonamides. In the structure of solvate 2I, the
conformation of 2 is unfolded and symmetrical, with the S−N
bonds oriented on opposite sides of the central ring, whereas
the conformation of 2 in solvate 2II is loosely folded and
asymmetric, with the S−N bonds on the same side of the
central ring (Figure 1). In analogous oligoamide 3, the C−N
Figure 2. Loosely folded conformation of oligoamide 3.21 Non-amide
hydrogen atoms have been removed for clarity.
The conformer of solvate 2I is stabilized by two weak
intramolecular amide-to-sulfonamide N−H···N hydrogen
bonds (D···A 2.720(3) Å, ∠DHA 112(2)°) with no other
significant intramolecular interactions present. Thus, the
conformation in solvate 2I appears to be mostly influenced
by intermolecular interactions and packing effects instead of
strong intramolecular interactions. Accordingly, disulfonamide
2 forms two intermolecular N−H···OC hydrogen bonds (a
C(7) motif) involving the sulfonamide (donor) and amide
(acceptor) groups (D···A 2.793(3) Å, ∠DHA 171(3)°). The
hydrogen bonding connects the molecules into chains along the
crystallographic b-axis, giving rise to a double chain pattern
(C22(20) motif) with head-to-tail arrangement of molecules in
C
DOI: 10.1021/acs.cgd.5b00424
Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Article
the chains (Figure 1). The individual chains exhibit offset π−π
stacking interactions between the outermost phenyl rings of
neighboring molecules of 2 (see Supporting Information for
details). The packing of 2 into parallel chains creates channels
that contain severely disordered solvent molecules. This kind of
disorder is expected, as there are no restricting interactions
between the solvent and the channel walls.
structure are replaced by two strong intramolecular N−H···
OS hydrogen bonds (D···A 2.869 Å, ∠DHA 154.1°) that
result in a significantly more compact molecular geometry
(Figures 3a and 4a). This is expected, as the orientation of the
The conformation of 2 in solvate 2II reveals an intra-
molecular N−H···OC hydrogen bond between the sulfona-
mide (donor) and amide (acceptor) groups (D···A 2.774(3) Å,
∠DHA 158(3)°) that gives 2 a folded conformation (S(13)
motif). The crystal packing is dominated by intermolecular N−
H···OC hydrogen bonding (D···A 2.834(3) Å, ∠DHA
161(3)°) that results in the formation of molecular chains
along the crystallographic b-axis (C(16) motif). The chains are
further interconnected into sheet-like assemblies by two weak
N−H···OS hydrogen bonds (R22(16) motif) between the
sulfonamide groups (D···A 3.079(3) Å, ∠DHA 157(3)°). The
crystal packing of solvate 2II also reveals π−π stacking
interactions between the R22(16) bonded molecular pairs (see
Supporting Information for details). The disordered DCE
molecules are located in the solvent-accessible voids between
molecules of 2.
The primary hydrogen-bonding networks in solvates 2I and
2II can be rationalized with the tendency of 2 to maximize
interactions involving the amide carbonyls, since the amide
carbonyl oxygen is known to be a better hydrogen-bond
acceptor than the sulfonyl oxygen.11 Consequently, the sulfonyl
groups act as hydrogen-bond acceptors only between the
molecular chains in the structure of solvate 2II. This also means
that there are amide and sulfonamide NH groups in both
conformers of 2 that do not take part in the primary hydrogen-
bonding network.
The reasons why different solvents and crystallization
procedures lead to two different conformers of 2 are not
obvious. The environmental conditions (temperature, moisture,
and crystallization vessels) were kept as identical as possible for
all experiments, and there are no clear trends in the results in
relation to the physical and chemical properties of the solvents
used. It can be argued that DCE is a poor hydrogen-bond
acceptor compared to an amide carbonyl and therefore
compound 2 should form intramolecular hydrogen bonds
more willingly (solvate 2II) than when better hydrogen-bond
acceptors, such as EtOAc or MeCN, are used as solvent
(solvate 2I). However, the conformation of 2 in the THF
solvate contradicts with this interpretation, as the hydrogen-
bond acceptor properties of THF are more in line with those of
EtOAc and MeCN than with DCE, but, still, a folded,
isomorphous conformer to 2I was nevertheless obtained.36
Therefore, the likely explanation for two different conformers
of 2 is that conformers are very close in energy and the
interplay of inter- and intramolecular hydrogen bonding along
with intramolecular steric hindrance caused by the bulky phenyl
rings directs the organization of molecules to two different
structures during crystal nucleation.
Figure 3. Optimized (ωB97XD/def2-TZVPP) structures of 2I (a), 2II
(b), and 2III (c) and a dimeric pair of 2I (d). Non-amide/sulfonamide
hydrogen atoms have been removed for clarity.
amide groups in the model system, a single molecule of 2, is not
fixed by intermolecular N−H···OC hydrogen bonds whose
formation is preferred in the solid state.
Unlike structure 2I, the optimized geometry of 2II is
practically identical to the conformer in solvate 2II (Figures 3b
and 4b). The calculations reproduce well the intramolecular
N−H···OC hydrogen bond (D···A 2.842 Å, ∠DHA 155.4°)
along with all other structural features of the molecular
backbone. Only the torsional angles of the terminal phenyl
groups are different, as the rotation of these groups is the most
affected by crystal packing, which is not taken into account in
calculations.
The computational results show that the conformer in
solvate 2I does not retain its crystal structure geometry without
explicitly taking into account intermolecular interactions. Thus,
the strong hydrogen bonding between neighboring molecules
in the solid state plays a role in determining the conformation
of the molecule. This was tested computationally by optimizing
a dimeric pair of 2I in the crystal structure geometry, in which
case the intermolecular N−H···OC hydrogen bonds kept the
“tailing” molecule rather rigidly in place, whereas the geometry
of the “heading” molecule changed from an open to a more
compact form due to the formation of intramolecular N−H···
OS interactions (Figures 3d and 4c). Since the conformer of
solvate 2II was accurately reproduced even with the simplest
possible model system, it seems that the folded conformer of 2,
once formed, can effectively guide the construction of a strong
hydrogen-bonding network around it.
Computational Studies. In order to obtain more insight
into the conformational features of 2, its potential energy
surface was analyzed with DFT by optimizing the structures of
the two conformers observed in the solid state at the ωB97XD/
def2-TZVPP level of theory.
The optimized structure of 2I is similar to the conformer in
solvate 2I with major changes only in the hydrogen-bonding
network. The weak N−H···N bonds observed in the crystal
The energies of model systems 2I and 2II can also be
compared for insight. If only intramolecular steric hindrance is
considered, then the conformation of 2I would be expected to
D
DOI: 10.1021/acs.cgd.5b00424
Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Article
Figure 4. Overlay figures37 of solvate conformer 2I and calculated conformer 2I (a), solvate conformer 2II and calculated conformer 2II (b), solvate
conformer 2I and an open conformer in the optimized dimeric pair of 2I (c), and solvate conformer 2II and calculated conformer 2III (d). Crystal
structure data and calculated structures are shown in green and yellow, respectively. Non-amide/sulfonamide hydrogen atoms have been removed for
clarity.
be more favorable because of smaller repulsion between the
bulky side chains. However, the calculations indicate that
conformer 2II is lower in energy, although only by
approximately 7−11 kJ mol−1, depending on whether the
calculations were conducted in the gas phase or using a solvent
model. The energy difference between the two conformers can
be attributed to the strong intramolecular hydrogen bond in
2II. It is also possible to compare the energy of the tailing
monomer from the optimized dimeric pair of 2I, denoted 2I*,
with the optimized conformer 2II, as both of these structures
are very close to the geometries observed in the solid state
(Figure 4). This comparison reveals that 2I* is higher in energy
than 2II by 48 kJ mol−1 (approximately 35 kJ mol−1 for the
solvated system), which further supports the notion that
intermolecular interactions contribute much more to the
stability of 2I in the solid state than they do in the case of
2II. Consequently, there seems to be an energetic preference
toward structure 2II in the gas phase and in solution which is
then compensated by the external hydrogen-bonding network
in the solid state, giving 2I and 2II nearly equal energies, as
implied by the crystallization experiments. Unfortunately, the
presence of severely disordered (and different) solvent
molecules in the unit cells of solvates 2I and 2II prevents
meaningful comparisons using computational energies based on
unit cell data.
Due to extensive intramolecular hydrogen bonding, con-
former 2III is 39 kJ mol−1 more stable than 2II (25 kJ mol−1
when using a solvent model). However, conformer 2III was
neither experimentally observed in the solid state nor could its
presence in solution be identified. This could potentially be
because of the presence of large energy barriers associated with
the rotation of the bulky side chains, preventing such a folded
structure from being adopted. Additionally, the hydrogen-
bonding network in conformer 2III is easily perturbed by
appropriate solvent molecules, which could prevent its
formation altogether.
Structural Comparisons. A search through the Cambridge
Structural Database yielded only three sulfonamides related to
2 that contain a benzene-1,3-disulfonamide core with aromatic
side chains (4−6; Figure 5).24,38,39 In 4 and 5, the S−N bonds
are oriented on the opposite sides of the central ring in a
manner similar to that in solvate 2I. The rigidity of the
The potential energy surface of 2 is obviously complex with
many different possibilities for the relative orientation of the
side chains along with different secondary bonding interactions.
An exhaustive search through all alternatives is beyond the
scope of the present work. However, it was considered to be of
interest to scan through some possible conformations that
would maximize the intramolecular hydrogen bonding and
therefore the folding of 2. This led to the identification of
conformer 2III (Figures 3c and 4d) that has two N−H···OC
(D···A 2.714 Å, ∠DHA 141.4°) and two N−H···OS (D···A
3.066 Å, ∠DHA 157.6°) hydrogen bonds that collectively give
the molecule a symmetric S-shaped geometry. The terminal and
central aromatic rings in 2III adopt a mutually parallel
orientation, but the distance between the rings does not
indicate any significant π−π interactions.
Figure 5. Molecular structures and conformations of disulfonamides
4−6.24,38,39 Non-amide/sulfonamide hydrogen atoms, solvent mole-
cules, and the disorder of the tert-butyl substituents have been
removed for clarity.
E
DOI: 10.1021/acs.cgd.5b00424
Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Article
molecules and the relative position of sulfonamide groups
prohibit the formation of any intramolecular N−H···OS
hydrogen bonds. Instead, the solid-state structures of 4 and 5
exhibit intermolecular hydrogen bonds between the sulfona-
mide groups, which in the case of 5 results in the formation of
molecular chains along the crystallographic a-axis.38 In the case
of 4, the intermolecular hydrogen-bonding network involves
one of the two carbonyl oxygen atoms on the aromatic side
chains in addition to the sulfonamide groups.24 Consequently,
the conformation adopted by 4 and 5 is likely to be caused by
favorable intermolecular hydrogen bonding and by steric
hindrance associated with the bulky side chains. DFT
calculations conducted for a single molecule of 5 predict a
conformer with both aromatic side chains on the same side of
the central ring to be lower in energy by 15 kJ mol−1 (see
Supporting Information Figure S4). This supports the view that
the conformation adopted by 5 in the solid state is strongly
influenced by favorable intermolecular hydrogen-bonding
interactions.
The conformation of compound 6 is similar to that of 2 in
solvate 2II. In this case, however, there is no intramolecular
hydrogen bond to explain the orientation of the aromatic side
chains on the same side of the central ring, but the
conformation can be rationalized by the bulky isopropyl
substituents, which direct the sulfonamide groups on the same
side of the central ring. DFT calculations conducted for the two
possible conformers of 6 indicate a small, 10 kJ mol−1, energetic
preference for the geometry observed in the solid state. In
agreement with these structural features, it has been shown that
the alkoxy-substituted diarylsulfonamide moiety in 6 is a
convergent structural unit that can be used to build larger
macrocyclic oligosulfonamides with predictable conforma-
tions.38
state (see Supporting Information for details). This strongly
suggests that the folded conformation of the molecule is not
just a result of packing effects and favorable intermolecular
interactions in the solid state.
CONCLUSIONS
■
The folding of a disulfonamide compound 2 was studied both
experimentally and computationally, and the results were
compared to data reported for closely related oligoamide and
disulfonamides 3−7. Two significantly different conformers of
2 were observed in the solid state: one symmetrical and
unfolded and the other unsymmetrical and loosely folded.
Calculations at the density functional theory level showed that
the observed conformers are relatively close in energy, which
suggests that the adoption of a specific conformer during crystal
nucleation involves a delicate interplay of intra- and/or
intermolecular hydrogen bonding and steric hindrance caused
by the bulky side chains. The calculations also indicated a third
possible conformer of 2 with multiple intramolecular hydrogen
bonds, giving the molecule both an S-shaped geometry and
lower energy. The reason that this conformer was not observed
experimentally was tentatively attributed to the energy barriers
involved in the rotation of the side chains to adopt such a
folded conformation.
The results indicate that oligomers with both amide and
sulfonamide groups can easily assume at least two different
stable conformers without apparent environmental factors.
Thus, the controlled use of the sulfonamide bond as a
component in foldamers is challenging and possibly requires
synthetic modifications toward more flexible side chains or the
use of a pyridine core. In analogous oligoamides, these changes
have led to more folded structures and increased intramolecular
hydrogen bonding. However, both the number of interaction
sites in the sulfonamide derivative 2 and its ability to form
channel structures suggest that it could potentially be used as a
co-crystal host.
The Cambridge Structural Database was also searched for
molecules similar to the folded conformer 2III that was
identified by calculations. A closely related conformer has been
reported for compound 7 with a 4-methylphenol-2,5-
disulfonamide core (Figure 6).40 The conformational flexibility
ASSOCIATED CONTENT
■
S
* Supporting Information
Crystallographic data for two isomorphous preliminary
structures of compound 2 (MeCN and THF solvates); notes
on the crystallographic data; X-ray crystallographic information
files (CIF) of solvates 2I, 2IB, 2II, and 2IIB; hydrogen-bonding
parameters and relevant torsion angles (all structures); a figure
of solvent channels in the structure of solvate 2I; graphical
representations of π−π stacking interactions for solvates 2I and
2II; powder X-ray diffraction data of compound 2 (calculated
1
and measured); H, 13C, COSY, HMBC, and HMQC NMR
Figure 6. Molecular structure and conformation of disulfonamide 7
related to 2III.40 Non-amide and non-hydroxide hydrogen atoms have
been removed for clarity.
spectra of 2 in DMSO-d6, a NOESY NMR spectra in acetone-
1
d6, and H NMR spectra at 30 and −80 °C in acetone-d6;
optimized geometries (gas phase) of 2I, 2I dimeric pair, 2II,
and 2III in xyz format; energies of structures 2I, 2I*, 2II, and
2III; overlay figures of calculated and experimental structures of
compounds 5−7; and optimized structure of 5. The Supporting
Information is available free of charge on the ACS Publications
website at DOI: 10.1021/acs.cgd.5b00424. Crystallographic
information files are also available from the Cambridge
Crystallographic Data Center (CCDC) upon request (http://
www.ccdc.cam.ac.uk; CCDC deposition nos. 1022889−
1022892).
of 7 can be ascribed to the methylene linkers between the
sulfonamide groups and the terminal pyridyl rings, which, in the
absence of significant steric strain, allow the molecule to adopt
a folded S-shaped geometry in the solid state. Further
stabilization for 7 is provided by intermolecular N−H···N
and O−H···N hydrogen bonds and offset π−π stacking
interactions that organize the molecules into parallel columns
along the crystallographic a-axis. DFT calculations for molecule
7 reproduce well the S-shaped geometry observed in the solid
F
DOI: 10.1021/acs.cgd.5b00424
Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Article
(24) Koivunen, J. T.; Nissinen, L.; Kapyla, J.; Jokinen, J.; Pihlavisto,
̈
̈
AUTHOR INFORMATION
■
M.; Marjamaki, A.; Heino, J.; Huuskonen, J.; Pentikainen, O. T. J. Am.
̈
̈
Corresponding Author
*Tel: +358 50 428 0804. E-mail: maija.nissinen@jyu.fi.
Chem. Soc. 2011, 133, 14558−14561.
(25) Sheldrick, G. M. Acta Crystallogr., Sect. A: Found. Crystallogr.
2008, 64, 112−122.
Notes
(26) Otwinowski, Z.; Borek, D.; Majewski, W.; Minor, W. Acta
Crystallogr., Sect. A: Found. Crystallogr. 2003, 59, 228−234.
(27) van der Sluis, P.; Spek, A. L. Acta Crystallogr., Sect. A: Found.
Crystallogr. 1990, 46, 194−201.
(28) Spek, A. L. Acta Crystallogr., Sect. D: Biol. Crystallogr. 2009, 65,
148−155.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
B.Sc. Hel
́
en
̀
e Campos Barbosa and B.Sc. Anniina Aho are
acknowledged for their help with syntheses and crystallizations.
We thank Dr. Elina Kalenius (ESI-TOF mass spectra),
Laboratory Technician Elina Hautakangas (elemental analysis),
and Chief Laboratory Technician Esa Haapaniemi (NMR
spectroscopy). Financial support from the Academy of Finland
(project no. 2100001911, K.H. and M.N.; project nos. 136929,
253907, and 272900, I.S.M. and H.M.T.) is gratefully
acknowledged.
(29) Farrugia, L. J. J. Appl. Crystallogr. 1999, 32, 837−838.
(30) Etter, M. C.; MacDonald, J. C.; Bernstein, J. Acta Crystallogr.,
Sect B: Struct. Sci. 1990, 46, 256−262.
(31) Bernstein, J.; Davis, R. E.; Shimoni, L.; Chung, N.-L. Angew.
Chem., Int. Ed. Engl. 1995, 34, 1555−1573.
(32) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci,
B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H.
P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.;
Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.;
Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin,
K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.;
Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega,
N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.;
Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.;
Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.;
Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.;
Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.;
Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09,
revision D.01; Gaussian, Inc.: Wallingford, CT, 2009.
(33) Chai, J.-D.; Head-Gordon, H. Phys. Chem. Chem. Phys. 2008, 10,
6615−6620.
REFERENCES
■
(1) Grant, D. J. W. In Polymorphism in Pharmaceutical Solids; Brittain,
H. G., Ed.; Marcel Dekker, Inc.: New York, 1999; pp 1−34.
(2) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173−180.
(3) Hill, D. J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.; Moore, J. S.
Chem. Rev. 2001, 101, 3893−4011.
(4) Guichard, G.; Huc, I. Chem. Commun. 2011, 47, 5933−5941.
(5) Becerril, J.; Rodriguez, J. M.; Saraogi, I.; Hamilton, A. D. In
Foldamers: Structure, Properties, and Applications; Hecht, S., Huc, I.;
Eds.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany,
2007.
(6) Zhang, D.-W.; Zhao, X.; Hou, J.-L.; Li, Z.-T. Chem. Rev. 2012,
112, 5271−5316.
(34) Weigend, F.; Ahlrichs, R. Phys. Chem. Chem. Phys. 2005, 7,
3297−3305.
(35) Tomasi, J.; Mennucci, B.; Cammi, R. Chem. Rev. 2005, 105,
2999−3093.
(7) Huc, I. Eur. J. Org. Chem. 2004, 17−29.
(8) Monnee, M. C. F.; Marjne, M. F.; Brouwer, A. W.; Liskamp, R.
M. J. Tetrahedron Lett. 2000, 41, 7991−7995; Erratum. Tetrahedron
Lett. 2001, 42, 965.
(36) Marcus, Y. Chem. Soc. Rev. 1993, 22, 409−416.
(37) Overlay figures were drawn with Mercury CSD 3.5.1. Macrae, C.
F.; Bruno, I. J.; Chisholm, J. A.; Edgington, P. R.; McCabe, P.; Pidcock,
E.; Rodriguez-Monge, L.; Taylor, R.; van de Streek J.; Wood, P. A.; J.
Appl. Crystallogr., 2008, 41, 466−470.
(9) Ramesh, V. V. E.; Kale, S. S.; Kotmale, A. S.; Gawade, R. L.;
Puranik, V. G.; Rajamonahan, P. R.; Sanjayan, G. J. Org. Lett. 2013, 15,
1504−1507.
(10) Baldauf, C.; Gunther, R.; Hofmann, H.-J. J. Mol. Struct.:
̈
THEOCHEM 2004, 675, 19−28.
(38) Eagle, C. T.; Kavallieratos, K.; Bryan, J. C. J. Chem. Crystallogr.
2002, 32, 165−170.
(11) Adsmond, D. A.; Grant, D. J. W. J. Pharm. Sci. 2001, 90, 2058−
2077.
(39) He, L.; An, Y.; Yuan, L.; Feng, W.; Li, M.; Zhang, D.; Yamato,
K.; Zheng, C.; Zeng, X. C.; Gong, B. Proc. Natl. Acad. Sci. U.S.A. 2006,
103, 10850−10855.
(12) Sanphui, P.; Sarma, B.; Nangia, A. Cryst. Growth Des. 2010, 10,
4550−4564.
(13) Terada, S.; Katagiri, K.; Masu, H.; Danjo, H.; Sei, Y.; Kawahata,
M.; Tominaga, M.; Yamaguchi, K.; Azumaya, I. Cryst. Growth Des.
2012, 12, 2908−2916.
(40) Sundberg, J.; Witt, H.; Cameron, L.; Hakansson, M.; Bendix, J.;
̊
McKenzie, C. J. Inorg. Chem. 2014, 53, 2873−2882.
(14) Vijayadas, K. N.; Davis, H. C.; Kotmale, A. S.; Gawade, R. L.;
Puranik, V. G.; Rajamohanan, P. R.; Sanjayan, G. J. Chem. Commun.
2012, 48, 9747−9749.
(15) Caira, M. R. Mol. Pharmaceutics 2007, 4, 310−316.
(16) Wainwright, M.; Kristiansen, J. E. Dyes Pigm. 2011, 88, 231−
234.
(17) Supuran, C. T.; Scozzafava, A. Med. Res. Rev. 2003, 23, 535−
558.
(18) Maren, T. H. Annu. Rev. Pharmacol. Toxicol. 1976, 16, 309−327.
(19) Nakashima, K.; Murahashi, M.; Yuasa, H.; Ina, M.; Tada, N.;
Itoh, A.; Hirashima, S.-I.; Koseki, Y.; Miura, T. Molecules 2013, 18,
14529−14542.
(20) Yang, H.; Carter, R. G. Synlett 2010, 2827−2838.
(21) Suhonen, A.; Nauha, E.; Salorinne, K.; Helttunen, K.; Nissinen,
M. CrystEngComm 2012, 14, 7398−7407.
(22) Kortelainen, M.; Suhonen, A.; Hamza, A.; Pap
́
ai, I.; Nauha, E.;
Yliniemela-Sipari, S.; Nissinen, M.; Pihko, P. M. Chem.Eur. J. 2015,
̈
DOI: 10.1002/chem.201406521.
(23) Bao, X.; Zhou, Y. Sens. Actuators, B 2010, 147, 434−441.
G
DOI: 10.1021/acs.cgd.5b00424
Cryst. Growth Des. XXXX, XXX, XXX−XXX