Sulfonamide molecular crystals: Structure, sublimation thermodynamic characteristics, molecular packing, hydrogen bonds networks

Article abstract of DOI:10.1021/cg400666v

The crystal structures of ten sulfonamides have been determined by X-ray diffraction. On the basis of our previous data, the obtained results and literature data crystal properties including molecular conformational states, packing architecture, and hydrogen bond networks were comparatively analyzed using graph set notations. Conformational flexibility of the bridge connecting two phenyl rings was studied. It was found out that the most frequently occurring graphs for compounds with a single hydrogen bond are infinite chains with four atoms included. The molecular packing architecture of the selected crystals may be conditionally divided into three different groups. The idea underlying such classification is the difference in structure and composition of molecular layers that can be singled out for most packings. The influence of various molecular fragments on crystal lattice energy was analyzed. A correlation between melting points and fragmental molecular interactions in the crystal lattices was obtained. The thermodynamic aspects of the sulfonamide sublimation were studied by determining the temperature dependence of vapor pressure using the transpiration method. A correlation between the Gibbs energy of the sublimation process and the melting points was found. Besides, a regression equation was derived to describe the correlation between the sublimation entropy terms and crystal density data calculated from X-ray diffraction results.

Full text of DOI:10.1021/cg400666v

Article
pubs.acs.org/crystal
Sulfonamide Molecular Crystals: Structure, Sublimation
Thermodynamic Characteristics, Molecular Packing, Hydrogen Bonds
Networks
German L. Perlovich,*,†,‡ Alex M. Ryzhakov,†,‡ Valery V. Tkachev,‡,§ Lars Kr. Hansen,∥
and Oleg A. Raevsky‡
†Krestov’s Institute of Solution Chemistry, Russian Academy of Sciences, 153045 Ivanovo, Russia
‡Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, Russia
§Laboratory of Structural Chemistry, Institute of Problems of Chemical Physics, Russian Academy of Sciences, 142432
Chernogolovka, Russia
∥Institute of Chemistry, University of Tromsø, Breivika, N-9037 Tromsø, Norway
S
* Supporting Information
ABSTRACT: The crystal structures of ten sulfonamides have been
determined by X-ray diffraction. On the basis of our previous data, the
obtained results and literature data crystal properties including molecular
conformational states, packing architecture, and hydrogen bond networks
were comparatively analyzed using graph set notations. Conformational
flexibility of the bridge connecting two phenyl rings was studied. It was
found out that the most frequently occurring graphs for compounds with a
single hydrogen bond are infinite chains with four atoms included. The
molecular packing architecture of the selected crystals may be conditionally
divided into three different groups. The idea underlying such classification
is the difference in structure and composition of molecular layers that can
be singled out for most packings. The influence of various molecular
fragments on crystal lattice energy was analyzed. A correlation between
melting points and fragmental molecular interactions in the crystal lattices
was obtained. The thermodynamic aspects of the sulfonamide sublimation were studied by determining the temperature
dependence of vapor pressure using the transpiration method. A correlation between the Gibbs energy of the sublimation process
and the melting points was found. Besides, a regression equation was derived to describe the correlation between the sublimation
entropy terms and crystal density data calculated from X-ray diffraction results.
showed that the biological activity of the sulfonamides depends
upon the conformational state of a molecule.13,14 Due to this
fact, it is of primary importance for researchers to study the
conformational preferences of compounds containing SA
groups as well as to assess the differences in energy content
of low-energy conforms.
The constantly growing database on crystalline structures
allows the most frequently occurring conformation of
sulfonamide molecules in crystals and the difference in
conformer energy content to be evaluated. Analysis of
conformational states was highlighted in works of Parkin et
al.15 and Brameld et al.16 The results obtained corroborate the
observations of Bock et al.17 that sulfonamides rarely crystallize
in their calculated low-energy structure.
INTRODUCTION
■
Sulfonamides (SA) are an important class of therapeutic agents
in modern medical science.1 The discovery of the first antibiotic
“prontosil” was followed by numerous structural modifications
of the sulfonylamide molecule to obtain preparations
possessing greater antibacterial activity and other pharmaco-
logical effects. As a result, compounds possessing anticarbonic
anhydrase, antibacterial, diuretic, hypoglycemic, and antihy-
droid properties have been produced.2−4 In addition, most of
the recently generated SA derivatives demonstrated antitumor
or antiviral activity in vitro and in vivo.3 Some of the
sulfonamide derivatives selected by careful preclinical screening
are approved preparations currently under clinical testing.5
The increase in the number of new SA derivatives made it
necessary to synthesize the compounds involved more
rationally and to study their structure/property relationships.
As a result, there appeared a number of QSAR publications
devoted to both searching for suitable models6−9 and studying
their specific biological activity.10−12 Such investigations
Received: May 10, 2013
Revised: July 13, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/cg400666v | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Article
Figure 1. Structural formulas of studied substances.
Due to the presence of donor and acceptor atoms,
sulfonamide molecules in a crystal participate in the formation
of branched hydrogen bond networks. Owing to this fact, the
compounds concerned are able to form various polymorphic
forms,18,19 as well as to become components of various
complexes20−22 of cocrystals,23−25 crystallosolvates,26−28 and
even self-assembled organic tubular structures.29 Thus, the
studies of sulfonamides are of great interest not only in terms of
using them as advanced drug compounds but also in terms of
their crystalline structure as well.
properties of the crystals and find out the relationship between
the noted parameters and the crystal structure.
EXPERIMENTAL SECTION
■
Compounds and Solvents. The chemical syntheses of SAs (XV−
XXIV) have been performed according to the procedures described
earlier30−32 by the reaction of a substituted aromatic amine with 4-
acetylaminobenzenesulfonyl chloride in dry pyridine, followed by
hydrolytic deacetylation in alkaline aqueous medium (∼ 1 M NaOH),
and precipitation of the end product by acidification (∼1 M HCl) to
pH 5. The compounds were carefully purified by recrystallizing from a
water−ethanol solution. The precipitates were filtered and dried at
room temperature under vacuum until the masses of the compounds
remained constant. The outlined procedure was repeated several times
and the product checked by NMR after each recrystallization step until
the proton NMR signal correspondence to the purity of the compound
was over 99%. N-phenyl-benzene-sulfonamide was obtained from
Sigma Chemical Co. (USA).
Our previous works30−34 studied the structures, packing
architecture, topology of hydrogen bond networks, sublimation,
solubility, and solvation characteristics of 14 sulfonamides (I−
XIV). As a continuation of the study, this work focuses on the
comparative analysis of the published compounds with new
ones: N-(2-nitrophenyl)-benzene-sulfonamide (XV), N-(2,5-
dibromophenyl)-benzene-sulfonamide (XVI), 4-amino-N-(2-
bromo-4-nitrophenyl)-benzene-sulfonamide (XVII), 4-amino-
N-(3-chloro-4-methylphenyl)-benzene-sulfonamide (XVIII), 4-
amino-N-(2-methoxy-3-chlorphenyl)-benzene-sulfonamide
(XIX), N-(2-chloro-3-pyridinyl)-benzene-sulfonamide (XX), 4-
nitro-N-(5-methyl-2-pyridinyl)-benzene-sulfonamide (XXI), 4-
amino-N-(3-methoxypyrazinyl)-benzene-sulfonamide (XXII),
4-amino-N-(3,4-dimethyl-5-isoxazolyl)-benzene-sulfonamide
(XXIII), and 4-amino-N-(5-methyl-3-isoxazolyl)-benzene-sul-
fonamide (XXIV) (Figure 1). The choice of the compounds
was dictated by the following aims. First, we aimed to analyze
the influence of substituent nature and molecular topology on
the molecule conformational state, the formation of crystal
lattice architecture, and hydrogen bond networks. Second, we
planned to study the thermodynamic and thermophysical
Single crystals of the title compounds were grown from a water−
ethanol solution (initial composition 20:1 v/v) by the vapor diffusion
of ethanol vapor into pure water.35
Methods. X-ray Diffraction Experiments. Single-crystal X-ray
measurements were carried out using a Nonius CAD-4 diffractometer
with graphite monochromated Mo Kα radiation (λ = 0.71069 Å).
Intensity data were collected at 25 °C by means of a ω-2θ scanning
procedure. The crystal structures were solved using direct methods
and refined by means of a full-matrix least-squares procedure. CAD-436
was applied for data collection, data reduction, and cell refinement.
SHELXS-97 and SHELXL-9737 were used to solve and to refine
structures, respectively.
Sublimation Experiments. Sublimation experiments were carried
out by the transpiration method as was described elsewhere.38 In brief,
a stream of an inert gas passes above the sample at a constant
temperature and at a known slow constant flow rate in order to
B
dx.doi.org/10.1021/cg400666v | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Article
Table 1. Crystal Lattice Parameters of the Substances under Investigation
a
XV
XVI
XVII
930476
XVIII
930474
XIX
CCDC code
crystal system
space group
crystal size (mm)
a (Å)
930468
triclinic
930473
triclinic
930475
monoclinic
P21/c
orthorhombic
Pna21
orthorhombic
P212121
0.30 × 0.20 × 0.10
7.599(2)
13.661 (3)
27.583(6)
90.00
P1
P1
̅
̅
0.55 × 0.20 × 0.10
0.50 × 0.35 × 0.20
8. 068(2)
5.514(1)
10.573(2)
78.51(1)
83.59(1)
71.11(1)
672.6(2)
2
0.33 × 0.25 × 0.21
14.740(4)
5.845(3)
16.093(5)
90.00
0.30 × 0.30 × 0.28
15.387(3)
6.273(1)
27.363(6)
90.00
b
8.018(2)
b (Å)
8.569(3)
9.992(3)
86.05(2)
67.05(1)
77.79(2)
617.8(3)
2
c (Å)
α (deg)
β (deg)
92.37(2)
90.00
90.00
90.00
γ (deg)
volume (Å3)
90.00
90.00
1385.3(9)
4
2641.3(9)
8
2863.4(9)
8
Z
Dcalc (g cm−3
radiation
T (K)
)
1.496
1.931
1.785
1.493
1.451
Mo Kα
293
Mo Kα
293
Mo Kα
293(2)
Mo Kα
293(2)
Mo Kα
293.1
μ (mm−1
)
0.27
6.19
3.137
0.446
0.420
Data Collection
6542
measured reflections
independed reflections
independed reflections with >2σ(I)
Rint
6121
3162
2182
0.021
30.5
2692
2588
1689
0.0525
25.57
2669
2669
2391
0.000
26.1
27680
7779
3252
0.051
30.6
3458
1533
0.037
θmax (deg)
30.5
Refinement
F2
refinement on
R[F2 > 2σ(F2)]
ωR(F2)
F2
F2
F2
F2
0.048
0.059
0.99
2204
212
0.036
0.0356
0.0894
0.962
2588
203
0.0386
0.1022
1.103
2669
343
0.0546
0.0615
1.127
3313
387
0.046
S
1.05
reflections
parameters
(Δ/σ)max
1548
172
0.019
0.16
−0.28
211.7
97.2
45.9
68.5
XX
0.021
0.000
0.620
−0.548
242.2
104.1
43.0
0.002
0.49
6.546
0.49
Δρmax (e Å−3
)
0.64
Δρmin (e Å−3
Vvdw (Å3)
)
−0.35
237.5
−0.26
234.4
95.8
−0.73
244.0
114.0
46.7
Vfree (Å3)
98.8
β = Vfree/Vvdw (%)
K = Vvdw/Vmol (%)
41.6
40.9
70.6
69.9
71.0
68.2
c
d
e
XXI
XXII
XXIII
XXIV
CCDC code
crystal system
space group
crystal size (mm)
a (Å)
930467
monoclinic
P21/n
930469
triclinic
930470
orthorhombic
Pbca
930471
orthorhombic
Pbca
930472
monoclinic
C2/c
P1
̅
0.57 × 0.49 × 0.41
10.504(2)
10.184(2)
10.638(2)
90.00
0.30 × 0.28 × 0.26
10.408(1)
11.773(1)
12.019(2)
73.41(1)
69.53(1)
71.55(1)
1283.2(3)
4
0.40 × 0.36 × 0.29
10. 912(1)
9.514(3)
24.842(3)
90.00
0.45 × 0.40 × 0.32
14.455(3)
11.514(2)
14.857(3)
90.00
0.50 × 0.30 × 0.15
16.079(6)
5.481 (2)
25.763(9)
90.00
b (Å)
c (Å)
α (deg)
β (deg)
90.41(2)
90.00
90.00
90.00
96.12(2)
90.00
γ (deg)
volume (Å3)
90.00
90.00
1132.9(4)
4
2598.5(9)
8
2472.7(9)
8
2257.4(9)
8
Z
Dcalc (g cm−3
radiation
T (K)
)
1.575
1.518
1.433
1.441
1.490
Mo Kα
293(2)
Mo Kα
293(2)
Mo Kα
293(2)
Mo Kα
293(2)
Mo Kα
293.1
μ (mm−1
)
0.511
0.270
0.259
0.226
0.143
Data Collection
5291
measured reflections
independed reflections
independed reflections with >2σ(I)
Rint
2329
2211
1839
0.019
26.00
2708
2066
1372
0.027
25.0
2605
2450
1737
0.081
26.1
6333
2875
2009
0.025
30.6
4480
3660
0.017
θmax (deg)
25.0
C
dx.doi.org/10.1021/cg400666v | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Article
Table 1. continued
c
d
e
XX
XXI
XXII
XXIII
XXIV
Refinement
refinement on
R[F2 > 2σ(F2)]
ωR(F2)
F2
F2
F2
F2
F2
0.0343
0.0950
1.046
2211
158
0.0396
0.1103
1.020
4480
371
0.0378
0.1114
1.027
2066
194
0.0442
0.1439
1.110
2450
167
0.0435
0.0496
1.057
2032
198
S
reflections
parameters
(Δ/σ)max
0.001
0.211
−0.384
202.4
80.8
0.001
0.37
0.001
0.22
0.001
0.28
0.004
0.32
Δρmax (e Å−3
)
Δρmin (e Å−3
Vvdw (Å3)
)
−0.28
221.1
99.7
−0.29
220.5
104.3
47.3
−0.32
210.5
98.6
−0.27
197.7
84.5
Vfree (Å3)
β = Vfree/Vvdw (%)
40.0
45.1
46.8
42.7
K = Vvdw/Vmol (%)
71.5
68.9
67.9
68.1
70.1
a
b
c
d
e
Ref 64. Standard deviations are presented in brackets. Ref 65. Ref 66. Ref 67.
Figure 2. A view of molecule XVII with numbering of atoms and considered angles.
achieve saturation of the carrier gas with the vapor of the substance
under investigation. The vapor is condensed at some point
downstream, and the mass of sublimate and its purity are determined.
The vapor pressure over the sample at this temperature can be
calculated by the amount of the sublimated sample and the volume of
the inert gas used.
with ΔGTsub = −RT ln(P/P0), where P0 is the standard pressure of 1 ×
105 Pa.
For experimental reasons sublimation data are obtained at elevated
temperatures. However, in comparison with effusion methods, the
temperatures are much lower, which makes extrapolation to room
conditions easier. In order to further improve the extrapolation to
298
p,cr
The equipment was calibrated using benzoic acid. The standard
value of sublimation enthalpy obtained here was ΔH0sub = 90.5 0.3 kJ
mol−1. This is in good agreement with the value recommended by
room conditions, we estimated the heat capacities (C value) of the
crystals using the additive scheme proposed by Chickos et al.40 Heat
capacity was introduced as a correction for the recalculation of the
IUPAC of ΔH0sub = 89.7
0.5 kJ mol−1.39 The saturated vapor
298
sublimation enthalpy ΔHTsub value at 298 K (ΔH value), according
sub
to the equation:40
pressures were measured 5 times at each temperature with the
standard deviation being within 3−5%. Because the saturated vapor
pressure of the investigated compounds is low, it may be assumed that
the heat capacity change of the vapor with temperature is so small that
it can be neglected. The experimentally determined vapor pressure
data may be described in (lnP;1/T) coordinates in the following way:
298
298
p,cr
ΔH = ΔHsTub + ΔHcor = ΔHsTub + (0.75 + 0.15C
)
sub
(T − 298.15)
(4)
Differential Scanning Calorimetry. Differential scanning calorim-
etry (DSC) was carried out using a Perkin-Elmer Pyris 1 DSC
differential scanning calorimeter (Perkin-Elmer Analytical Instruments,
Norwalk, Connecticut) with Pyris for Windows NT. DSC runs were
performed in an atmosphere of flowing (20 mL min−1) dry helium gas
of high purity 99.996%, using standard aluminum sample pans and a
heating rate of 10 K min−1. The accuracy of weight measurements was
0.005 mg. The DSC was calibrated with an indium sample from
Perkin-Elmer (P/N 0319-0033). The value determined for the
enthalpy of fusion corresponded to 28.48 J g−1 [reference value
ln(P) = A + B/T
(1)
The value of the sublimation enthalpy is calculated by the Clausius−
Clapeyron equation:
ΔHsTub = RT2∂(ln P)/∂(T)
(2)
whereas the sublimation entropy at the given temperature (T) was
calculated from the following relation:
ΔSsTub = (ΔHsTub − ΔGsTub)/T
(3)
D
dx.doi.org/10.1021/cg400666v | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Article
28.45 J g−1]. The melting point was 156.5 0.1 °C (n = 10). The
integral flexibility of the bridge connecting the phenyl rings. As
it has been demonstrated in our previous work34 (using a
limited number of sulfonamides), there is a correlation between
τ3 and ∠Ph1−Ph2. To confirm the discovered regularities, we
extended the range of SA, investigated by including the
structures presented in the literature (ref codes are given in
Table 2 of the Supporting Information), and analyzed their
conformational states. The results of the analysis are shown in
Figure 3. All the compounds are divided into groups,
enthalpy of fusion at 298 K was calculated by the following equation:
298
ΔH = ΔHfTus − ΔSfTus(Tm−298.15)
(5)
fus
where the difference between the heat capacities of the melt and solid
states was approximated by the fusion entropy (as an upper estimate).
This approach was used by Dannenfelser and Yalkowsky.41
Calculation Procedure. The free molecular volume in the crystal
lattice was estimated on the basis of the X-ray diffraction data and van
der Waals molecular volume (Vvdw), calculated by GEPOL42
Vfree = (V − ZVvdw)/Z
(6)
cell
where Vcell is the volume of the unit cell and Z is the number of
molecules in the unit cell.
Nonbonded van der Waals interactions of crystal lattice energy were
calculated as a sum of atom−atom interactions with the help of a
Gavezzotti et al.43 force field and cutoff radius of 16 Å.
́
The torsion angle stress energies (Etor) were obtained from the
software environment “Accelrys Materials Studio”, using the Forcite
classical molecular mechanics code as a model engine.68
RESULTS AND DISCUSSION
Crystal Structure Analysis. The results of X-ray diffraction
experiments are presented in Table 1.
■
Though most of the sulfonamides exist as amide tautomers,
there are some well-known exceptions. Imide tautomers for
crystals of sulfanylamide,44 sulfamethoxydiazine,45 sulfadox-
ine,46 sulfisoxazole,46 sulfothiazole,47,48 and sulfaguanidine49
have been revealed earlier. Three polymorphic forms of
sulpiride have been described in the works of Bar and
Bernstein,50 all of them existing in an imide form. Among
crystal structures considered, compound XXI has the form of
an imide tautomer. The compound is a heterocyclic
sulfonamide with a nitrogen atom in the ortho-position in
the second ring. Due to the competitive position of two
nitrogen atoms, the amide proton can migrate into a
heterocyclic ring. However, as one can see from the structures
of XXII and XXIV, the presence of nitrogen in the ortho
position adjacent to an amide group of the ring is not enough
for an imide tautomer to be formed.
Molecular Conformational Analysis. In order to character-
ize the conformational states of the molecules, Figure 2 shows
the view of representative molecule XVII with atomic
numbering. This numbering was used for all the compounds
under investigation. Compounds XIII, XVII, XIX, and XXI
have two molecules (A and B) in the asymmetric unit of the
crystal lattice. On the basis of the presented numbering, it is
possible to carry out the comparative analysis of conformational
states of molecules I−XXIV. The conformational states of the
molecules under investigation depend on the mobility of the
bridge, connecting two phenyl rings. In order to describe the
conformational state, we have chosen three parameters
(analogous to Parkin et al.15): the angle between the SO2
group and the phenyl motif Ph 1 (C1−C2−C3−C4−C5−C6)
∠C2−C1−S1−N1 (τ1), the angle ∠C7−N1−S1−C1 (τ2),
describing the S1−N1 bond mobility, and the torsion angle
∠C12−C7−N1−S1 (τ3), which characterizes the location of
the second phenyl ring Ph2 (C7−C8−C9−C10−C11−C12)
relative to the NH group. Moreover, we introduced an angle
between the two phenyl rings ∠Ph1−Ph2 (the acute angle
between the least-squares planes through the two phenyl rings)
(Table 1 of the Supporting Information). In addition to the
noted angles we introduced an angle, equal to the sum of the
dihedral angles (∑τi = τ1 + τ2 + τ3), which describes the
Figure 3. Plot of τ3 vs ∠Ph1−Ph2 (see Figure 2) for the compounds
studied in this work and literature data (color corresponds to the
different groups of SA; see the text).
depending on the substituents available in phenyl rings. Some
points lay over each other, which indicates the presence of
several substituents in phenyl fragments. τ3 and ∠Ph1−Ph2 are
well-correlated. So, angle τ3, making a major contribution in the
turn between two phenyl rings, is most susceptible to structural
changes of SA molecules. We would like to emphasize that all
experimental data are subdivided into a low-angle branch
[according to the ∠Ph1−Ph2 angle (black dotted line)] and a
high-angle one (red dotted line). A slight change in τ3 for the
low-angle branch results in a considerable change of the angle
between the phenyl rings. This change is far less pronounced
for the high-angle branch. Some of the investigated compounds
possess two molecules in asymmetric units. In view of this fact,
we attempted to analyze the ways in which such SAs are
distributed in the branches involved. It was found out that most
of the compounds with two molecules in the asymmetric unit
belong to the high-angle branch. Then, we determined the
percentage of these compounds within the limits of groups/
clusters, into which all SA compounds have been subdivided
(see Figure 3). It was found out that 54% of SA with NH2− and
any other group as substituents in phenyl rings are compounds
with two molecules. The results obtained for other compounds
are as follows: Cl− and any other group, −36%; Me− and any
other group, −18%; NO2− and any other group, −11%; Cl−
and Me−, 17%; only Me−, 19%; and only Cl−, 8%. Thus, SAs
with an amine group are distinguished by a maximum number
of compounds with two molecules in an asymmetric unit; it
follows from the increased number of hydrogen bonds per
molecule (as compared to compounds with other groups) and
the presence of molecular networks with a complex topological
structure (see below). One can assume that it is the compounds
E
dx.doi.org/10.1021/cg400666v | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Article
with the amine group that show a greater tendency to form
polymorphic forms as compared to the others we considered.
Our next step was to study SA with two molecules in the
asymmetric unit. Comparative analysis of the torsion angle
stress energy of molecules A and B was carried out. Conformer
A (being a high-angle one) appeared to be more relaxed (that
is, it had less torsion stress energy, Etor) in comparison with
conformer B. If we take the difference in angles between phenyl
fragments of conformers A and B as a standard distinction
between them, we will see that their values vary over a wide
range: from 1° to 47°. Figure 4 presents these values as a
plotted as β = Vfree/Vvdw versus Vvdw and Vfree versus Vvdw
(Figures 1, 2, and 3 of the Supporting Information). Figure 5
Figure 5. Plot of free volumes difference of SA studied at the
replacement locations of Me− on Cl− groups located at the same
positions (red corresponds to Cl− atoms, black to Me−). Numbering
corresponds to Scheme 1.
presents the results of changing the free volume of SA with
Me− substituted by Cl− groups in similar positions (Cl−
atoms are marked by red, Me− groups by black). The
numbering of the positions corresponds to that in Scheme 1.
For monosubstituted derivatives, replacement of methyl
groups by chlorine is accompanied by a reduction in the free
volume, the exception being the para position (a slight
increase). For disubstituted SA, substitution of two Me−
atoms by Cl− results in both a decrease in free volumes (3,5-;
2,5-; and 4,9-) and their adding (2,6- and 2,3-). Substitution of
a Me− group for Cl− in 2-, 3-, 4-, and 7- positions of the
diderivative of SA (the second Me- remaining invariably in the
9- position) causes the free volume to decrease. The pattern for
free-derivatives of SA becomes more complicated. If one of the
substituents is in position 9- in the first phenyl fragment, while
the two others are in the second fragment (3,5,9-; 2,6,9-; 3,4,9-;
and 2,3,9-), only a decrease in the free volume takes place. If
two substituents are in positions 7- and 9- in the first phenyl
fragment, while the others remain in the second phenyl ring
(4,7,9-; 5,7,9-; and 6,7,9-), the free volume only diminishes for
4,7,9-, while for 6,7,9-, it either increases or decreases. The
substitution of all methyl groups for Cl− causes a significant
free volume increase for 6,7,9-. The pattern for tetrasubstituted
SA cannot be regarded as a simple one. The substitution
reduces the free volume for three compounds (3,5,7,9-; 5,6,7,9-;
and 2,4,7,9-) and increases it for 3,4,9,11-. The substitution of
the four methyl groups by Cl− atoms in 3,4,9,11- gives a
negligible change in free volume.
Hydrogen Bond Network Analysis. The compounds
considered are able to form hydrogen bonds in crystal lattices.
Moreover, the number of hydrogen bonds in a molecule varies
remarkably and depends on the topology of a molecule and the
presence of hydrogen bond centers. Hydrogen bonds form
chains with various topological structures, which influences
thermodynamic and thermophysical characteristics, crystal
lattice energy, and as a consequence, the processes of
dissolution. The next block of our investigations consisted in
analysis of the hydrogen bond network topology, using the
terms of topological graphs introduced by Etter51 and
supplemented by Bernstein.52 Table 3 of the Supporting
Figure 4. Plot of angles difference between the phenyl rings of the
conformers A and B versus the free volume per molecule in the crystal
(numbering substituents corresponds to Scheme 1).
function of free volume values per molecule (the numbering of
a substituent position in SA molecule corresponds to that in
Scheme 1). As one can see, all dots may be arbitrarily
Scheme 1
subdivided into two groups: the first one has a greater spread in
angle values between the conformers (red ●), while the second
one has a smaller spread in contrast to the first one (blue ○).
The regularities in changes of the values discussed are as
follows: the free volume per molecule in a crystal occurs the
most; the difference in the angles between phenyl fragments of
the conformers occurs the least. Unfortunately, we failed to
identify any regularities between the structures of the
compounds of both groups. The only thing we can emphasize
is that the compounds containing amino substituents (with an
added number of hydrogen bonds per molecule) are in the
second group.
As it has already been emphasized, the literature contains
many experimental data describing crystal structure of methyl
and chlorine derivatives of SA. We adopted these data to make
it easier to study how the number, the position, and the nature
of substituents affect the density of molecular packing in a
crystal. Experimental values of the compounds involved were
F
dx.doi.org/10.1021/cg400666v | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Article
Figure 6. Distribution of frequently observed hydrogen-bond motifs of first and second levels (schematic, graph set, and number of occurrences).
Information shows the results of comparative analysis of
hydrogen bond geometrical parameters, as well as the matrix of
topological graphs describing the network topology of the
molecular crystals under study for the first (diagonal elements)
G
dx.doi.org/10.1021/cg400666v | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Article
and the second (subdiagonal elements) levels. All the
topological graphs occurring in crystals are given schematically
in Table 4 of the Supporting Information. The crystal structures
of all the compounds investigated contain 16 various graphs of
the first level (with only one type of hydrogen bond
participating) and 35 graphs of the second level (with hydrogen
bonds of two types participating). The most prevalent
hydrogen-bond motifs for both levels are given in Figure 6.
The simplest hydrogen bond network is observed for
compounds I, II, III, XI, XIV, XV, XVI, and XX, as only one
hydrogen bond participates in their formation. It is caused by
the fact that it is the sulfonamide group with an amide proton
as a bond donor that becomes the only center of the hydrogen
bond. The presence of additional acceptor groups (as for XI,
XV, and XX) does not account for the growth of hydrogen
bonds. Figure 7 shows the histograms of the most frequently
C(4)-1 graph, while compound V possesses three different
graphs: R22(16), D-2, and D-5 (Table 4 of the Supporting
Information). There is only one sinton for compound III C(4)-
1, while there are three graphs for compound IV: C(8)-1, C(8)-
2, and D-2. There is only a C(8)-3 graph available for
compound XI, while two different graphs are available for V:
C(8)-1 and C(8)-2.
For all the sulfonamides investigated, it is only amido- (N1)
and amino- (N2) protons that are donors of hydrogen bonds.
Proceeding from this fact, we attempted to evaluate the extent
of their participation in the formation of hydrogen bond
networks. The results of the analysis expressed as a percentage
ratio for two different types of donors are shown in Table 2. It
Table 2. Hydrogen-Bonding Frequency Observed for Amido
and Amino Protons
general number of HBs in
structures contained the type
of donor
number of HBs
formed by this
donor type
% of
involvement
donor
amido
82
35
42.7
(N1)
proton
amino
74
52
70.3
(N2)
proton
may be noticed that the amino proton participates about 1.5
times as often as the amido proton in the formation of
hydrogen bond networks. It is most likely to be associated with
the way hydrogen atoms are arranged: being in the outlying
part of a molecule, they are available for the formation of bonds
with adjacent molecules. Amido protons are within the
molecule and are closed down partly by other fragments. The
latter fact becomes a barrier to the process. Analysis of
hydrogen bonds of protodonor groups concerned has showed
that about 51 in 52 cases, the amino group participates in an
−NH2···SO2 bond and in about 9 in 35 cases (25.7%) it forms
an −NH−···SO2 bond. It would be interesting to emphasize
that in the above-mentioned compounds the amino group is
able to act as a hydrogen bond acceptor. The number of these
bonds amounts to 51.9% for the amido proton and corresponds
to C(8)-2 graphs.
Hydrogen bond networks of the second level (i.e., formed by
different bonds) are combinations of various graphs of the first
level. This combination of graphs is expressed in the form of
unique infinite chains as well as rings with various numbers of
atoms involved. Figure 4 of the Supporting Information shows
the most frequently occurring second level graphs.
Packing Architecture Analysis. The molecular packing
architecture of crystals depends on the molecular structure
and topology. The compounds under consideration are
structurally similar. Therefore, variations of size, nature, and
position of substituents make it possible to analyze the
influence of these factors on the packing architecture. The
molecular packing architectures of the new substances under
investigation are presented in Figure 5 of the Supporting
Information.
Figure 7. Frequency of occurrence of different topological graphs of
the first level at the presence and absence of the amino- group at the
first phenyl ring of SA studied (designations of the graphs correspond
to Table 4 of the Supporting Information).
occurring graphs of the compounds with (a) a single hydrogen
bond (sulfonamides without an amide group in the first phenyl
ring, green) and (b) an amino group (with several hydrogen
bonds, red). As one can see from Figure 6, the most frequently
occurring graphs for the compounds with a single hydrogen
bond are infinite chains with four included atoms C(4)-1.
Introducing NH2− groups (additional centers of hydrogen
bond formation) into the first phenyl ring makes topological
graphs change considerably. Only sinton C(4)-1 remains, while
6 new graphs appear with the most frequently occurring one
being C(8)-1.
Let us consider the way in which network topology changes
for comparable structures. Thus, for example, the introduction
of NH2− groups into compounds II, III, and XI (as a result, we
obtain compounds V, IV, and XII, respectively) causes the
hydrogen bond network to change remarkably. Due to adding a
new hydrogen bond center into the first phenyl ring, the
number of hydrogen bonds grows from 1 to 3.5 (7 for two
molecules in the asymmetric unit) for V, 4 for IV, and 3 for XII.
Moreover, amine-derivative compounds do not possess hydro-
gen bonds that are realized in II, III, and XI. As a result, we
obtain the following change in the topological graphs for
comparable pairs of compounds in crystals and, as an outcome,
the topology of their networks. Compound II has a single
The molecular packing architecture in the crystals of I−
XXIV compounds may be subdivided into three groups. The
division is based on the difference in structure and composition
of molecular layers to be singled out for most of the packing
(Figure 8).
The topology of the first groups is of the same character.
They include compounds I, II, III, VII, X, XI, XIV, XX, XXIII,
H
dx.doi.org/10.1021/cg400666v | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Article
Figure 8. A layout view of molecular packing and hydrogen bond networks of SA studied in the crystals [(a) compounds of I, (b) II, and (c) III
groups). Actual examples of the corresponding crystal structures for each group are shown on the right. Hydrogen bond chains with different
dimensional orientations are marked by varicolored circles and arrows.
and XXIV. The specific feature of the compounds is having
equally distant layers formed by infinite chains of hydrogen
bonds C(4), C(5), and C(8). The adjacent layers interact by
means of van der Waals forces, while the way the molecule
chains interact within the layer may vary. For the first group of
compounds (I, II, III, XI, and XIV) bonding is brought about
through van der Waals forces (Figure 8a). It would be
interesting to note that for most members of this subgroup, the
layers have the same direction in relation to the hydrogen bond
networks. For the crystals of compound XIV, the adjacent
layers are turned at the angle of 90° relative to each other. For
the second group of compounds (VII, X, XXIII, and XXIV),
the adjacent molecule chains are linked with a hydrogen bond
to form two-dimensional networks (Figure 8b).
interlayer interactions are realized in turn through a hydrogen
bond and van der Waals forces. Thus, this specific group is
distinguished by two layers formed by pairs of intertwining
(intertangling) chains of molecules. All the molecules inside of
the bilayer are linked by hydrogen bonding, while those of
various bilayers interact only through van der Waals forces.
This group includes compounds IV, V, VI, VIII, IX, XII, XVII,
XVIII, XIX, and XXII.
Samples of the compounds investigated have two dimeric
structures, XVI and XXI. Molecules of these crystals are linked
in pairs by a hydrogen bond to form graph R22(8). It should be
noted that the asymmetric crystal unit of XXI consists of two
molecules, dimers being formed between the molecules of the
same conformational state (A−A and B−B). In both
compounds, the first and second phenyl rings are in parallel
position relative to each other.
The pattern of the compounds of group III is similar to the
previous ones. The difference consists in the fact that the
I
dx.doi.org/10.1021/cg400666v | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Article
The crystals of XIII and XV have a distinctive character. A
three-dimensional network of hydrogen bonds is formed in a
crystal lattice of XIII, thereby making the architecture of the
compound molecule packing dramatically different from the
above-mentioned ones, its subdivision into layers is not
presumed. Conversely, intermolecular hydrogen bonds are
not available in compound XV. However, one cannot help but
notice their similarity to the compounds of the first group, with
the only difference between them consisting in the fact that all
interactions between their molecules are influenced by van der
Waals forces.
Literature data analysis (see Table 2 of the Supporting
Information) has shown that most of the similar structures
possess one or two hydrogen bonds of different types. As a
result, the molecules of the compounds published are packed in
a crystal lattice either in the form of dimers (2, 6, 8, 12, 15−17,
19−21, 22−44, 50, 51, 53, 54, 56−64, 69−73, 75−77, 80,
84−86, 88, 90−92, 96, 98, 100−102, and 107) or in the form
of infinite chains of the first group of compounds (1, 13, 14, 18,
45−49, 52, 55, 65, 68, 74, 78, 81, 82, 87, 89, 93−95, 97, 103,
and 106).
Figure 9. Relationship between the contributions from various
molecular fragments in the packing energy made by the nonbounded
van der Waals interactions (Ei‑i) and Vfree/Vvdw. Numbering
corresponds to Scheme 2.
In order to understand the influence of various molecular
fragments on the crystal lattice energy, we used the approach
applied by us earlier.53 The molecule was conditionally divided
into a certain number of fragments, depending on the
molecular topology. Segmentation for the six fragments (as a
common case) is shown in Scheme 2. After that, we calculated
the contribution of nonbonded van der Waals interactions to
the packing energy from different fragment pairs of adjacent
molecules.
compounds, it is the bridge connecting two aromatic rings
that interferes in the energy distribution: R4−R4 and R2−R3.
Our next step was to compare the crystal packing of different
groups of compounds and the main fragment contributions of
the compounds involved to the crystal lattice energy
stabilization. As a result, it was found out that for the
compounds of group I, the main contributions to crystal lattice
energy stabilization are the interactions between the first and
the second phenyl rings, as well as those between the bridge
and the second phenyl fragment of adjacent molecules (R2−R4
and R2−R3). For the sulfonamides of group II, the main
contributions are, in their turn, the interactions between the
second phenyl rings, as well as those between the first ring and
the bridge (R4−R4 and R2−R3). It is the interactions between
identical phenyl rings of adjacent molecules (R2−R2 and R4−
R4) that are the dominating contributions to the crystal lattice
energy of the compounds of group 3.
Scheme 2
Sublimation Characteristics. The temperature depend-
encies of saturated vapor pressure of XVI−XXIV are shown in
Table 5 of the Supporting Information. The thermodynamic
functions of drug sublimation and fusion processes are
presented in Table 3.
The results of the contributions made by the calculated
fragments to the crystal lattice energy of compounds XV−
XXIV are presented in Figure 9 in coordinates that characterize
the package density of the molecules in a crystal.
The problem constantly occupying the minds of scientists in
the literature54−57 is the determination of regularities in the
interrelations between thermodynamic (sublimation) and
thermophysical (fusion processes) characteristics and parame-
ters of crystal structures. Long ago, Kitaigorodsky58 suggested
that various physicochemical properties should be correlated
with the parameters describing molecule package density in a
crystal (Vvdw/Vmol). The parameter (β = Vfree/Vvdw) has been
slightly modified in some works,59−61 as the authors wanted to
pay special attention to the free volume (Vfree) per molecule in
a crystal. In this context, Vfree is an integral value including: (a)
free volume formed as a result of a complex topological
structure and steric hindrances from conformationally mobile
molecules in a crystal (the so-called “free volume” dependent
on molecule structure in a conformational state in a crystal) and
(b) free volume formed as a result of the molecular package in a
crystal (these being equivalent under given parameters of
crystal defects packing). It is difficult to differentiate between
the two defects, but their participation in the processes
While studying the para- and aminoderivatives of sulfona-
mides with two substituents in the second phenyl ring, we
revealed the following regularities (Figure 10). The critical
contributions stabilizing crystal lattices are interactions between
identical phenyl rings and the first phenyl ring and a bridge. It
was interesting to note that as soon as the molecule package
density in a crystal reaches a certain value (red dotted line), one
observes an inversion in the interaction contributions between
the seconds fragments (2−2) and between the second and the
third ones (2−3). The contributions of the interactions
between the first phenyl rings (2−2) of adjacent molecules to
the crystal lattice of compounds V, VII, X, and XIX are
drastically different from each other, being only 5 kJ less than
comparable (equivalent) values for VI, XVII, and XVIII. Thus,
for sulfonamides with a denser molecule packing, the critical
contributions stabilizing the crystal lattice correspond to the
interactions between identical phenyl fragments (R2−R2 and
R4−R4) of adjacent molecules. As for the rest of the
J
dx.doi.org/10.1021/cg400666v | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Article
Figure 10. Relationship between the contributions from various molecular fragments in the packing energy (Ei‑i) and Vfree/Vvdw for para-, amino-SA
with two substituents at the second phenyl ring.
Table 3. Thermodynamic Characteristics of Sublimation and Fusion Processes of the Compounds Studied
XV
XVII
72.3
XVIII
76.4
XIX
73.5
XXII
70.0
ΔG (kJ mol−1
)
)
57.1
298
sub
ΔHTsub (kJ mol−1
124.2 0.9
126.8 0.9
327.5
137.4 1.9
142.8 1.9
363.5
137.3 1.8
144.6 1.8
340.3
141.7 1.5
147.2 1.5
390.1
124.2 1.3
130.4 1.3
363.2
ΔH (kJ mol−1
)
298
sub
a
(J mol−1 K−1
)
298
C
p,cr
TΔS (kJ mol−1
)
69.7
70.5
68.2
73.7
60.4
298
sub
ΔS (J mol−1 K−1
)
234
69.0
31.0
6
236
66.9
33.1
8
229
68.0
32.0
7
247
66.6
33.4
7
203
68.3
31.7
6
298
sub
b
ςH (%)
b
ςTS (%)
Tm (K)
371.8 0.2
22.3 0.5
17.9
461.0 0.2
39.6 0.5
25.6
477.6 0.2
45.6 0.5
28.5
403.9 0.2
30.7 0.5
22.7
448.4 0.2
32.4 0.5
21.5
ΔHTfus (kJ mol−1
)
ΔH (kJ mol−1
)
298
fus
c
ΔSTfus (J mol−1 K−1
)
60.0
85.9
95.5
76.0
72.3
b
a
298
p,cr
298
C
has been calculated by Chikcos additive scheme;40 the error of the calculation procedure corresponds to a significant digit. ςH = [ΔH
/
sub
c
(ΔHs2u9b8+TΔS )]·100%; ςTS = [TΔS /(ΔH +TΔS )]·100%. ΔSTfus = ΔHfTus/Tm
298
sub
298
sub
298
sub
298
sub
occurring in crystals during sublimation and fusion is different.
For example, such effects as vacancies (i.e., free volume) are
responsible for ≪stepwise mechanism≫ of sublimation of
molecular crystals.62 In this context, we analyzed the way Vfree
influences thermodynamic functions. If we want to study the
effect of molecule topology on crystal package architecture and
thermodynamic characteristics respectively, we are to analyze
the β-parameter (or Dcal). A considerable change in molecule
conformation during crystal lattice formation results in a
nonadditive increase in the free volume per molecule in a
crystal with the van der Waals volume increasing. Vvdw is to be
used to analyze the effect of the molecule size only on the
processes under study. One can trace how much the molecule
topology influences the way the molecule is packed in a crystal
by analyzing experimental values by plotting β versus Vvdw
(Figure 11). One cannot but see that the compounds with
approximately equal van der Waals volumes possess different
package density values (I and III and V and VI). Adding
substituents into the phenyl ring of compound XIV causes
Figure 11. Plot of Vfree/Vvdw vs Vvdw for the compounds studied.
K
dx.doi.org/10.1021/cg400666v | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Article
package density of the molecules in a crystal to grow (β value
diminishes).
As the Dcal parameter is an entropy characteristic of a crystal,
additional information about crystal structure is required to
evaluate the sublimation entropy member directly from
experimental density values.
we attempted to compare these values with the entropy terms
Figure 13 shows the experimental thermodynamic functions
298
298
298
of sublimation TΔS of the compounds under study (in the
(ΔG and ΔH ) versus the molecular package density in the
sub
sub
sub
way similar to that described in our previous work31). It must
be noted that thermodynamic characteristics of sublimation for
some compounds (indicated by red) drop out of correlation
dependences with Dcal, which may be ascribed to a considerable
difference in the ratio of various contributions of the
interactions between the molecules in crystal lattices as
contrasted to the substances for which the given correlation
is observed. Figure 12 presents the experimental values. For the
crystals investigated. One cannot help but notice comparable
tendencies in their behavior: the increase in the β parameter
(i.e., diminishing in molecular package density) results in a
lowering of the Gibbs energy and sublimation enthalpy values.
Of course, there is some spread in values which may be
attributed to the great difference of hydrogen bond network
topology and structures.
It is a well-known fact that temperature and enthalpy of
crystal fusion are often used in pharmaceutics as parameters
describing (simulating) the crystal lattice. It can be exemplified
by the equation of solubility derived by Yalkowsky.63 The wide
recognition of these parameters is associated with the fact that
they are experimentally trivial and can be obtained by means of
conventional techniques of DSC experiments. The nature and
mechanisms responsible for fusion temperature values are still
under discussion in the literature.57 We attempted to find out
correlations between these temperatures and contributions of
nonbonded van der Waals interactions between various SA
fragments (included previously) to packing energy.
There is a satisfactory (approximately linear) correlation
between Tm and E4−4 for chlorine-containing sulfonamides: the
growth of interaction energy between the second phenyl
fragments of adjacent molecules makes the temperature of
fusion also rise (Figure 14). As was mentioned above, the
contribution of E4−4 to the packing energy is maximal for all the
investigated compounds in contrast to other contributions.
Hence, one can assume that the process of fusion begins with
the loss of contacts between the second phenyl fragments of
SA.
Figure 12. Correlation between the sublimation entropic terms
(TΔS2su9b8) and the calculated molecular densities (Dcal) in the crystal
lattices (numbering corresponds to Figure 1).
The analysis of enthalpies of fusion has revealed that this
thermophysical function is influenced by van der Waals
interactions between the second phenyl rings. As is shown in
Figure 15, the growth of the E4−4 contribution results in
growing of fusion enthalpy, this tendency being observed for
the following groups of compounds: chlorine derivatives
(indicated in red) and para-substituted sulfonamides (indicated
in blue).
compounds indicated by the black color, these may be
described by the following correlation equation:
298
TΔS = (−198 24) + (176 16)D
(7)
sub
cal
r = 0.955; σ = 3.21; F = 124.3; n = 14
It can be assumed that the experimentally derived density
values will correlate with the calculated ones. Therefore, no
298
298
Figure 13. Plots of (a) ΔG vs Vfree/Vvdw and (b) ΔH vs Vfree/Vvdw for the compounds studied (numbering corresponds to Figure 1).
sub
sub
L
dx.doi.org/10.1021/cg400666v | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Article
Figure 14. Relationship between the melting points and E4−4
contributions in the packing energy made by the nonbounded van
der Waals interactions.
Figure 16. Relationship between the sublimation Gibbs energies
(ΔG2su9b8) and melting points of the compounds studied (numbering
corresponds to Figure 1).
The influence of various molecular fragments on the crystal
packing energy was analyzed. When handling para-amino-
derivatives of sulfonamides in the first phenyl ring (Ph1) and
two substituents in the second one (Ph2), the following
regularities have been deduced. For SA with a much denser
molecular packing in a crystal, the main contributions
stabilizing crystal lattice conform to the interactions between
comparable phenyl fragments (Ph1−Ph1 and Ph2−Ph2) of
adjacent molecules. As for compounds with lower density
packing, it is the bridge connecting two aromatic rings that
interfere in energy distribution, Ph2−Ph2, and Ph1−Bridge.
Groups into which all the compounds under study were
conditionally subdivided according to their molecular packing
in a crystal were analyzed and compared with the basic
fragment contributions to crystal lattice energy stabilization. It
has been discovered that for the compounds of group I, the
main contributions to energy stabilization are produced by the
interactions between the first and the second phenyl rings as
well as those between the bridge and the second phenyl
fragments of the adjacent molecules. For group II sulfonamides,
the basic contributions are made, in their turn, by the
interactions between the second phenyl rings and those
between the first ring and the bridge. Prevailing contributions
to crystal lattice energy for the compounds of group III are the
interactions between identical phenyl rings of the adjacent
molecules.
298
Figure 15. Relationship between ΔH and E4−4 contributions in the
fus
packing energy made by the nonbounded van der Waals interactions.
It should be emphasized, that there is a correlation between
the Gibbs energy of sublimation and the temperature of fusion
for the investigated compounds (Figure 16). In view of the fact
that it is easy to determine thermophysical characteristics of
fusion processes by means of DSC experiments, correlation
equations become an adequate means of evaluating thermody-
namic parameters of sublimation.
The thermodynamic aspects of the sulfonamide sublimation
processes have been studied by investigating the temperature
dependence of vapor pressure by the transpiration method. A
regression equation was derived describing the correlation
between the sublimation entropy terms and the crystal density
data calculated by the X-ray diffraction results.
CONCLUSION
■
The crystal structures of ten sulfonamides (XV−XXIV) have
been solved by X-ray diffraction experiments. Comparative
analysis of molecular conformational states has been carried
out. One can observe a favorable correlation between τ3 and
∠Ph1−Ph2. Therefore, the τ3 angle appears to be the most
susceptible to structural SA molecule modifications and makes
the main contribution to the turn between the two phenyl
rings.
A quite satisfactory correlation between Tm and E4−4 is
observed for chlorine-containing sulfonamides: the increase in
interaction energy between the second phenyl fragment of
adjacent molecules raises the temperature of fusion. As it has
been demonstrated above, E4−4 contribution to packing energy
is maximal for practically all the investigated compounds, in
contrast to other contributions. That is why one can assume
that the process of fusion begins with the loss of contact
M
dx.doi.org/10.1021/cg400666v | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Article
(15) Parkin, A.; Collins, A.; Gilmore, C. J.; Wilson, C. C. Acta
Crystallogr. 2008, B64, 66−71.
between the second SA phenyl fragments. Correlations have
been established between Gibbs energy of sublimation and
fusion temperature of the investigated compounds.
(16) Brameld, K. A.; Kuhn, B.; Reuter, D. C.; Stahl, M. J. Chem. Inf.
Model. 2008, 48, 1−24.
(17) Bock, H.; Nagel, N.; Naether, C. Z. Naturforsch., B: J. Chem. Sci.
1998, 53, 1389−1400.
ASSOCIATED CONTENT
■
S
* Supporting Information
(18) Sanphui, P.; Sarma, B.; Nangia, A. Cryst. Growth Des. 2010, 10,
4550−4564.
CIF files of the XV−XXIV compounds, some parameters
describing molecular conformational states in the crystal
lattices, structural formulas and ref. codes of the crystal
structures used from the literature, hydrogen bond geometry
and graph set notations of the molecules studied, hydrogen
bond geometry and graph set notations of the molecules
studied, temperature dependencies of saturation vapor pressure
of the compounds studied, plots of Vfree/Vvdw versus Vvdw and
Vfree versus Vvdw, frequency of occurrence of different
topological graphs of the second level for SA studied, some
figures illustrated molecular packing in the crystal lattices
considered. This material is available free of charge via the
Internet at http://pubs.acs.org.
(19) 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.
(20) Katagiri, K.; Ikeda, T.; Tominaga, H.; Masu, H.; Azumaya, I.
Cryst. Growth Des. 2010, 10, 2291−2297.
(21) Zoppi, A.; Quevedo, M. A.; Derlivo, A.; Longhi, M. R. J. Pharm.
Sci. 2010, 99, 3166−3176.
́
́
(22) de Araujo, M. V. G.; Vieira, E. K. B.; Lazaro, G. S.; Conegero, L.
S.; Almeida, L. E.; Barreto, L. S.; da Costa, N. B.; Gimenez, Jr.;
Gimenez, I. F. Bioorg. Med. Chem. 2008, 16, 5788−5794.
(23) Caira, M. R. Mol. Pharmaceutics 2007, 4, 310−316.
(24) Goud, N. R.; Gangavaram, S.; Suresh, K.; Pal, S.; Manjunatha, S.
G.; Nambiar, S.; Nangia, A. J. Pharm. Sci. 2012, 101, 664−680.
(25) Ghosh, S.; Bag, P. P.; Reddy, C. M. Cryst. Growth Des. 2011, 11,
3489−3503.
AUTHOR INFORMATION
■
(26) Bingham, A. L.; Hughes, D. S.; Hursthouse, M. B.; Lancaster, R.
W.; Tavener, S.; Threlfall, T. L. Chem. Commun. (Cambridge, U.K.)
2001, 603−604.
Corresponding Author
*E-mail: glp@isc-ras.ru. Tel: +7-4932-533784. Fax: +7-4932-
336237.
(27) Aitipamula, S.; Chow, P. S.; Tan, R. B. H. CrystEngComm 2012,
14, 691−699.
Notes
(28) Pratt, J.; Hutchinson, J.; Stevens, Ch.L.K. Acta Crystallogr. 2011,
C67, o487−o491.
The authors declare no competing financial interest.
(29) Hu, Z.-Q.; Chen, Ch.-F. Chem. Commun. (Cambridge, U.K.)
2005, 2445−2447.
ACKNOWLEDGMENTS
■
This work was supported by the Russian Foundation of Basic
Research (Grant 12-03-00019) and the International Science &
Technology Centre (Projects #888 and 3777). We would like
to thank V.P. Kazachenko for assistance in preparation of some
single crystals.
(30) Perlovich, G. L.; Strakhova, N. N.; Kazachenko, V. P.; Volkova,
T. V.; Tkachev, V. V.; Schaper, K.-J.; Raevsky, O. A. Int. J. Pharm.
2007, 334, 115−124.
(31) Perlovich, G. L.; Strakhova, N. N.; Kazachenko, V. P.; Volkova,
T. V.; Tkachev, V. V.; Schaper, K.-J.; Raevsky, O. A. Int. J. Pharm.
2008, 349, 300−313.
(32) Perlovich, G. L.; Tkachev, V. V.; Strakhova, N. N.; Kazachenko,
V. P.; Volkova, T. V.; Surov, O. V.; Schaper, K.-J.; Raevsky, O. A. J.
Pharm. Sci. 2009, 98, 4738−4755.
REFERENCES
■
(1) Owa, T.; Nagasu, T. Exp. Opin. Ther. Pat. 2000, 10, 1725−1740.
(2) Abbate, F.; Supuran, C. T.; Scozzafava, A.; Orioli, P.; Stubbs, M.
T.; Klebe, G. J. Med. Chem. 2002, 45, 3583.
(33) Perlovich, G. L.; Ryzhakov, A. M.; Strakhova, N. N.;
Kazachenko, V. P.; Schaper, K.-J.; Raevsky, O. A. J. Chem. Thermodyn.
2011, 43, 683−689.
(34) Perlovich, G. L.; Ryzhakov, A. M.; Tkachev, V. V.; Hansen, L.
Kr. Cryst. Growth Des. 2011, 11, 1067−1081.
(35) Guillory, J. K. Polymorphism in Pharmaceutical Solids; Brittain, H.
G., Ed.; Marcel Dekker Inc.: New York, 1999; pp 183−226.
(36) CAD-4 Software, version 5.0; Enraf-Nonius: Delft, The
Netherlands, 1989.
(3) Scozzafava, A.; Owa, T.; Mastrolorenzo, A.; Supuran, C. T. Curr.
Med. Chem. 2003, 10, 925−953.
(4) Supuran, C. T.; Scozzafava, A. Exp. Opin. Ther. Pat. 2000, 10,
575.
(5) Sehgelmeble, F.; Janson, J.; Ray, C.; Rosqvist, S.; Gustavsson, S.;
Nillson, L. I.; Minidis, A.; Holenz, J.; Rotticci, D.; Lundkvist, J.;
Arvidsson, P. I. ChemMedChem 2012, 7, 396−399.
(6) Thakur, M.; Thakur, A.; Kkadikar, P. V.; Supuran, C. T. Bioorg.
Med. Chem. Lett. 2005, 15, 203−209.
(7) Fujita, T.; Hansch, C. J. Med. Chem. 1967, 10, 991−1000.
(8) Bell, P. H.; Roblin, R. O., Jr. J. Am. Chem. Soc. 1942, 64, 2905−
2917.
(37) Sheldrick, G. M. SHELXL97 and SHELXS97; University of
Gottingen: Germany, 1997.
̈
(38) Zielenkiewicz, W.; Perlovich, G.; Wszelaka-Rylik, M. J. Therm.
Anal. Calorim. 1999, 57, 225−234.
(39) Cox, J. D.; Pilcher, G. Thermochemistry of Organic and
Organometallic Compounds; Academic Press: London, 1970.
(40) Chickos, J. S.; Acree, W. E., Jr. J. Phys. Chem. Ref. Data 2002, 31,
537−698.
(9) Hansch, C. Il Farmaco 2003, 58, 625−629.
(10) Sethi, K. K.; Saurabh, M. V.; Prasanthi, N.; Sahoo, S. K.; Parhi,
R. B.; Suresh, P. Bioorg. Med. Chem. Lett. 2010, 20, 3089−3093.
(11) Krystek, S. R., Jr.; Hunt, J. T.; Stein, P. D.; Stouch, T. R. J. Med.
Chem. 1995, 38, 659−668.
(41) Dannenfelser, R.-M.; Yalkowsky, S. H. J. Pharm. Sci. 1999, 88,
722−724.
(12) Stein, P. D.; Floyd, D. M.; Bisaha, S.; Dickey, J.; Girotra, N. R.;
Gougoutas, J. Z.; Kozlowsky, M.; Lee, V. G.; Liu, E. C.-K.; Malley, M.
F.; McMullen, D.; Mitchell, C.; Moreland, S.; Murugesan, N.; Serafino,
R.; Webb, M. L.; Zhang, R.; Hunt, J. T. J. Med. Chem. 1995, 38, 1344−
1354.
(42) Pascual-Ahuir, J. L.; Silla, E. J. Comput. Chem. 1990, 11, 1047.
(43) Gavezzotti, A.; Filippini, G. Energetic Aspects of Crystal
Packing: Experiment and Computer Simulations. In Theoretical Aspects
and Computer Modeling of the Molecular Solid State; Gavezzotti, A., Ed.;
John Wiley & Sons: Chichester, West Sussex, U.K., 1997; Chapter 3,
pp 61−97.
(13) Senger, S.; Convery, M. A.; Chan, C.; Watson, N. S. Bioorg. Med.
Chem. Lett. 2006, 16, 5731−5735.
(14) Senger, S.; Chan, C.; Convery, M. A.; Hubbard, J. A.; Shah, G.;
Watson, N. S.; Young, R. J. Med. Chem. Lett. 2007, 17, 2931−2934.
(44) Alleaume, M.; Dkap, J. Acta Crystallogr. 1965, 18, 731−736.
(45) Shefter, E.; Sackman, P. J. Pharm. Sci. 1971, 60, 282−286.
N
dx.doi.org/10.1021/cg400666v | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Article
(46) Kalman, A.; Czugler, M.; Argay, G. Acta Crystallogr. 1981, B37,
868−877.
(47) Krueger, G. J.; Gafner, G. Acta Crystallogr. 1971, B27, 326−333.
(48) Krueger, G. J.; Gafner, G. Acta Crystallogr. 1972, B28, 272−283.
(49) Alleaume, M.; Gulko, A.; Herbstein, F. H.; KaDon, M.; Marsh,
R. E. Acta Crystallogr. 1976, B32, 669−682.
(50) Bar, I.; Bernstein, J. J. Pharm. Sci. 1985, 74, 255−263.
(51) Etter, M. C. Acc. Chem. Res. 1990, 23, 120−126.
(52) Bernstein, J.; Davis, R. E.; Shimoni, L.; Chang, N.-L. Angew.
Chem., Int. Ed. Engl. 1995, 34, 1555−1573.
(53) Perlovich, G. L.; Rodionov, S. V.; Bauer-Brandl, A. Eur. J. Pharm.
Sci. 2005, 24, 25−33.
(54) Gavezzotti, A.; Filippini, G. J. Am. Chem. Soc. 1995, 117,
12299−12305.
(55) Gavezzotti, A. J. Am. Chem. Soc. 2000, 122, 10724−10725.
(56) Osborn, J. C.; York, P. J. Mol. Struct. 1999, 474, 43−47.
(57) Li, Z. J.; Ojala, W. H.; Grant, D. J. W. J. Pharm. Sci. 2001, 90,
1523−1539.
(58) Kitaigorodsky, A. I. Molecular Crystals and Molecules; Academic
Press, Inc.: New York, 1973.
(59) Perlovich, G. L.; Proshin, A. N.; Volkova, T. V.; Cong, T. B.;
Bachurin, S. O. Mol. Pharm. 2011, 8, 1807−1820.
(60) Perlovich, G. L.; Volkova, T. V.; Proshin, A. N.; Sergeev, D.Yu.;
Cong, T. B.; Petrova, L. N.; Bachurin, S. O. J. Pharm. Sci. 2010, 99,
3754−3768.
(61) Surov, A. O.; Terekhova, I. V.; Bauer-Brandl, A.; Perlovich, G. L.
Cryst. Growth Des. 2009, 9, 3265−3272.
(62) Lebedev, Yu. A.; Miroshnichenko, E. A. Heats of Evaporation,
Sublimation and Saturated Vapor Pressure. In Thermochemistry of
Vaporization of Organic Substances; Nauka: Moscow, 1981; p 216.
(63) Yalkowsky, S. H.; Valvani, S. C. J. Pharm. Sci. 1980, 69, 912−
922.
(64) Kuz’mina, L. G.; Struchkov, Y. T.; Peregudov, A. S.; Kravtsov, D.
N. Russ. J. Struct. Chem. 1984, 25, 113−121.
(65) Bruni, B.; Coran, S. A.; Bartolucci, G.; Viara, M. D. Acta
Crystallogr. 2010, E66, o2663.
(66) Koo, C. H.; Shin, H. S.; Cho, S. I. Arch. Pharm. Sci. Res. 1982, 5,
79.
(67) Rambaud, J.; Roques, R.; Alberola, S.; Sabon, F. Bull. Soc. Chim.
Fr. 1980, 56.
(68) Delley, B. J. Chem. Phys. 2000, 113 (18), 7756−7764.
O
dx.doi.org/10.1021/cg400666v | Cryst. Growth Des. XXXX, XXX, XXX−XXX