Exploring the Crystal Structure Landscape of 3,5-Dinitrobenzoic Acid through Various Multicomponent Molecular Complexes

Article abstract of DOI:10.1021/acs.cgd.0c01217

Seven new multicomponent crystals, including one hydrate, one solvate, one molecular salt, and four cocrystals, consisting of 3,5-dinitrobenzoic acid with various coformers were synthesized and presented. These coformers include 2-acetylpyridine, 3-cyanop

Full text of DOI:10.1021/acs.cgd.0c01217

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Exploring the Crystal Structure Landscape of 3,5-Dinitrobenzoic
Acid through Various Multicomponent Molecular Complexes
Matthew C. Scheepers and Andreas Lemmerer*
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ABSTRACT: Seven new multicomponent crystals, including one
hydrate, one solvate, one molecular salt, and four cocrystals,
consisting of 3,5-dinitrobenzoic acid with various coformers were
synthesized and presented. These coformers include 2-acetylpyr-
idine, 3-cyanopyridine, flufenamic acid, dimethylaminobenzophe-
none, pyridoxine, theophylline, and thiourea. Both hydrogen-
bonding and weaker intermolecular forces such as C−H···π
bonding, π-hole, and π···π contribute significantly to the overall
packing scheme of each structure. Hirshfeld surfaces were used to
identify these intermolecular forces. These structures were
compared to those in the literature using the Cambridge Structural Database (CSD). These multicomponent crystals were
characterized by single-crystal X-ray diffraction (SC-XRD) and differential scanning calorimetry (DSC).
In this work we present seven new multicomponent crystals
of dnba, which formed one solvate, one hydrate, one molecular
salt, and four cocrystals. Most of the coformers chosen consist
of N-containing heterocycles, with the rest consisting of
various functional groups. These coformers include 2-
acetylpyridine (2acp), 3-cyanopyridine (3cnp), flufenamic
acid (fa), dimethylaminobenzophenone (dmabp), pyridoxine
(pyd), theophylline (thp), and thiourea (tu) (see Scheme 1).
Two of these coformers are APIs: fa is a nonsteroidal anti-
inflammatory (NSAID) drug, while thp is used as a muscle
relaxant or vasodilator in the treatment of respiratory issues
such as asthma.17,18 pyd, also referred to as vitamin B6, is a
nitrogen-containing heterocycle with several hydroxyl groups
which can form potential hydrogen bonds with the nitro
groups of dnba. 3cnp and 2acp were chosen to explore more
crystal forms of these compounds as well, since not many
crystal structures involving these compounds have been
reported. dmabp, a derivative of benzophenone, is generally
used as a photoinhibitor.19 dmabp is structurally similar to
Michler’s ketone, which is used as an intermediate in the
synthesis of various dyes. Although various benzophenone
derivatives have been explored as potential coformers with
dnba, only dmabp formed a multicomponent crystal. The aim
INTRODUCTION
■
The search for alternative methods for improving currently
existing active pharmaceutical ingredients (APIs) with poor
properties without modifying the drug itself has become
critical. The formulation of APIs consisting of either a salt or a
cocrystal has increased in the past few decades.1−3 Cocrystals
and molecular salts often have properties which differ
significantly from those of the respective coformers. For
pharmaceutical drugs improving properties such as solubility,
tabletability, and intrinsic dissolution rates are critical, and the
use of cocrystals has achieved this.4,5 For this reason it makes
the search for new multicomponent crystals so attractive.
3,5-Dinitrobenzoic acid (dnba), the molecule of interest in
this work, consists of a carboxylic acid group and two nitro
groups, all in a positions meta to each other. Several
multicomponent crystal structures, both binary and ternary,
involving dnba have been published in the Cambridge
Structural Database (CSD),6 including those which include
various APIs.7−9 A total of 278 results of cocrystals and
molecular salts have been reported. Studies involving dnba
include high energy density related materials,10,11 short, strong
hydrogen bonding12 and the crystal engineering of APIs.13−15
Although the primary interactions will be due to the formation
of a hydrogen bond between the carboxylic acid and a suitable
hydrogen bond acceptor of the coformer, other types of weaker
interactions exist and could contribute significantly. For
example, π holes from the nitro groups can form directional
intermolecular interactions between neighboring molecules.16
Due to the strongly electron withdrawing nitro groups the ring
of dnba is relatively π-electron poor, which therefore makes
dnba a potential charge-transfer acceptor molecule.
Received: September 1, 2020
Revised: December 3, 2020
https://dx.doi.org/10.1021/acs.cgd.0c01217
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© XXXX American Chemical Society
A

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Scheme 1. Structures of dnba and the Coformers Used for This Work
Table 1. Solvent System Used to Synthesize the Respective Multicomponent Molecular Complex
coformer
2-acetylpyridine
3-cyanopyridine
diethylaminobenzophenone
flufenamic acid
pyridoxine
theophylline monohydrate
thiourea
mass used (g)
solvent system
1.08 (1 mL, 8.915 mmol)
0.049 (0.471 mmol)
0.106 (0.471 mmol)
0.133 (0.471 mmol)
0.080 (0.471 mmol)
0.093 (0.471 mmol)
0.036 (0.471 mmol)
0.049 (0.471 mmol)
ethanol
ethanol
methanol
a
ethanol/water (1/1 v/v)/ acetic acid
ethanol
ethyl acetate
ethyl acetate
ethanol
3-aminopyridine
a
It should be noted that trace amounts of water were present in the starting material for methanol. This, along with the possibility of water from the
atmosphere, resulted in the formation of the hydrate.
Powder X-ray Diffraction (PXRD). Powder X-ray diffraction data
for all compounds were measured at 293 K on a Bruker D2 Phaser
diffractometer which employed a sealed-tube Co X-ray source (λ =
1.78896 Å), operating at 30 kV and 10 mA, and a LynxEye PSD
detector in Bragg−Brentano geometry. Powder patterns for each
sample are given in the Supporting Information, where the
experimentally obtained data are compared to the calculated patterns
obtained from the SC-XRD data.
Single Crystal X-ray Diffraction (SC-XRD). A Bruker D8
VENTURE PHOTON CMOS 100 area detector diffractometer,
equipped with a graphite-monochromated Mo Kα1 sealed tube (50
kV, 30 mA), was used to collect all of the intensity data. Crystal
structures were determined at 173 K to achieve satisfactory thermal
ellipsoids. The program SAINT+, version 6.02,20 was used to
integrate the data, and the program SADABS21 was used to make
empirical absorption corrections. Space group assignments were made
using XPREP21 on all compounds. In all cases, the structures were
solved in the WinGX Suite of programs21 by direct methods using
SHELXS-9721 and refined using full-matrix least-squares/difference
Fourier techniques on F2 using SHELXL-97.21 All non-hydrogen
atoms were refined anisotropically. All carbon-bound hydrogen atoms
were placed at idealized positions and refined as riding atoms with its
of this work is to observe new supramolecular assemblies with
dnba, using a diverse range of coformers.
EXPERIMENTAL SECTION
■
All reagents used for synthesis and characterization were of analytical
grade and were purchased from Sigma-Aldrich. Reagents were used as
received, without further purification. Equimolar amounts of dnba
(100 mg, 0.471 mmol) and the respective coformers were stirred in a
heated solution of the respective solvent until no solid remained. This
solution was left loosely covered, which evaporated to yield the
respective cocrystal/salt. See Table 1 for the solvent systems used.
It should be noted that although several different solvents were
used in an attempt to obtain a multicomponent crystal in a relatively
high yield and pure form, those solvents did not yield the desired
multicomponent crystal. In addition, several molar ratios were used
(e.g. 2:1, 1:2, etc. dnba:coformer), but this yielded a mixture of the
desired multicomponent crystal (in a 1:1 ratio) with the excess
component. Heating was found to be essential in most of the cases
(the multicomponent crystals consisting of the pyridine-based
coformers did not essentially need heating, although heating helped
in acquiring complete dissolution quickly), otherwise the desired
multicomponent crystal could not be obtained.
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Uiso parameter being 1.2 or 1.5 times those of their parent atoms.
Unless otherwise stated, nitrogen-bound and oxygen-bound hydrogen
atoms were located in the difference Fourier map and their
coordinates and isotropic displacement parameters refined freely.
Diagrams and publication material were generated using ORTEP-322
and Mercury.23
Cambridge Structural Database Analysis. The Cambridge
Structural Database (CSD)6 was analyzed to determine any common
trends occurring among different multicomponent structures
consisting of dnba. A combined query using both the carboxylic
acid form of dnba and the carboxylate form was used to search for
entries. Entries were filtered using 3D coordinates and organics.
Entries containing salts with alkali or alkali-earth cations, heavily
disordered molecules, and/or solvates were not examined. Mercury23
was used to inspect the crystal structures.
Crystal structures were determined to be binary, ternary, or greater
and consist of either or both the protonated (carboxylic acid form)
and deprotonated (carboxylate) forms. In the case of a ternary or
greater structure, only the interactions involving dnba were
considered. In the case of multiple entries of the same crystal
structure, only one entry was inspected and counted.
Hirshfeld Surface Analysis. Hirshfeld surface analysis is a
computational method that can be used to explore intermolecular
interactions in molecular crystals that are weaker than hydrogen
bonds,24−26 as well as to determine the “shape” of molecular
fragments, which are key to understanding the overall packing. The
figures and fingerprint plots presented in this work were generated
using Crystal Explorer 17.5.27 All images were generated using a high
(standard) resolution.
have formed either a salt or a cocrystal with 2acp, 3cnp, pyd,
thp and tu. Table 2 gives the comparison of the results
predicted by the pKa rule vs the actual results of the crystal
structures formed. It shows that the rule works for at least
three of the five multicomponent crystal structures.
These crystals were characterized, and a description of each
crystal structure is given below (Figure 1). Crystallographic
data and hydrogen bonds are given in Tables 3 and 4,
respectively. Hirshfeld surfaces for di, de, dnorm, the shape index,
and curvedness and the respective fingerprint plots were
generated and are presented in the Supporting Information
unless stated otherwise. The discussion of each of the
Hirshfeld surfaces generated for each molecular complex are
discussed together with the description of the crystal
structures.
Crystal Structure Descriptions of Dnba Complexes.
dnba + 2acp. dnba formed a solvate with 2acp, forming
colorless plates (Figure 2). The solvate crystallizes in the P21/n
space group, with the asymmetric unit consisting of one
molecule each of dnba and 2acp. dnba forms a discrete
hydrogen bond to the pyridinium of 2acp with the carboxylic
acid group. This dimer forms 2D sheets which stack together.
The Hirshfeld surfaces generated revealed additional
intermolecular interactions present in the crystal. Red spots
on the dnorm surface indicate the presence of weak C−H···O
hydrogen bond interactions, with both the acetyl and nitro
groups being involved. The shape index shows that N−O···π
and C−O···π formed from the nitro and acetyl groups,
respectively. The shape index does not indicate the presence of
any π···π type interactions, which is normally indicated by the
presence of a red and blue triangle touching each other. These
surfaces correlate well with the observed overall packing
pattern of the crystal: the weak C−H···O hydrogen bonds
favor the formation of different “layers”, while the N−O···π
and C−O···π interactions allows the “layers” to stack together.
dnba + 3cnp. dnba formed a cocrystal with 3cnp, forming
colorless needles (Figure 3). The cocrystal crystallizes in the
P21/c space group, with the asymmetric unit consisting of one
molecule each of dnba and 3cnp. dnba forms a discrete
hydrogen bond to the pyridine of 3cnp with the carboxylic acid
group. The 3cnp and dnba molecules form alternating
columns of each molecule which then stack together with
inversion of molecules along its column.
The Hirshfeld surface revealed additional interactions. From
the dnorm red spots occurring at the cyano nitrogen (N4) and
one of the aromatic hydrogens (H10) indicates the formation
of a 3-cyanopyridine dimer, with a the graph set R22(10). Large
red spots near the nitro groups are indicative of π-hole type
interactions. Two cases exist: one where the partially positive π
system of the ring of dnba interacts with the oxygen of a nitro
group that is on a neighboring dnba and the other case one of
oxygen of the carboxylic acid interacting with the nitrogen of
the nitro group of a neighboring dnba molecule. Smaller red
spots on the dnorm indicate the presence of C−H···π type
interactions. As a result of the presence of the π-hole-type
interactions, the shape index consists of various large “bumps”
and “hollows”, as indicated by regions of large blue and red
spots, respectively, giving rise to various small regions of
“flatness”, as indicated by the curvedness. As a result, the
columns of dnba and 3cnp are held together by π-hole and
weak C−H···N interactions, respectively, while the strong
hydrogen bond between dnba and 3cnp as well as a few C−
Differential Scanning Calorimetry (DSC). Differential scanning
calorimetry data were collected using a Mettler Toledo 822e
instrument with aluminum pans under nitrogen gas (flow rate 10
mL/min). Exothermic events were shown as peaks. Samples were
heated and cooled to determine melting points as well as any
additional phase transitions. The temperature and energy calibrations
were performed using pure indium (purity 99.99%, mp 156.6 °C, heat
of fusion 28.45 J g−1) and pure zinc (purity 99.99%, mp 479.5 °C,
heat of fusion 107.5 J g−1).
RESULTS AND DISCUSSION
Seven multicomponent crystals containing dnba have been
synthesized, of which four are cocrystals, one is a hydrate, one
■
Table 2. Comparison of the Result Predicted by the pKa
Rule vs the Actual Result of the Crystal Structures Formed
a
coformer pKa of coformer
ΔpKa
result based on rule actual result
2acp
3cnp
Pyd
thp
3.00
1.78
9.63
8.60
1.44
0.33
0.23
6.86
5.83
−1.33
undetermined
undetermined
salt
salt
cocrystal
cocrystal
cocrystal
salt
cocrystal
cocrystal
tu
pKa for dnba = 2.77. Values from SciFinder.28
a
is a solvate, and one is a salt. It should be noted that for the
pyridine derivatives and theophylline it is possible for either a
salt or a cocrystal to form. A “rule of thumb” exists that if the
pKa values of both compounds are known, it is possible to
predict whether a salt or cocrystal will form. This is done by
calculating the ΔpKa, which is given by the formula,
ΔpKa = pKa(conjugate acid of base) − pKa(acid)
If the ΔpKa value is less than zero a cocrystal would form (if it
forms), whereas a value greater than 2−3 should lead to a salt.
Values between 0 and 3 can predict neither case and are 0 for
the crystal systems in question.27 For this work, dnba could
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Figure 1. Ortep diagrams for the asymmetric units for the crystal structures of (i) dnba + 2acp, (ii) dnba +3cnp, (iii) dnba + dmabp, (iv) dnba +
pyd, (v) dnba + fa, (vi) dnba + thp, and (vii) dnba + tu, which shows the atom-numbering scheme. Displacement ellipsoids are drawn at the 50%
probability level, and H atoms are shown as small spheres of arbitrary radii. The symmetry-independent hydrogen bonds are shown as dashed lines.
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Table 3. Summary of Crystallographic Data
cocrystal + salt
dnba + 2acp
dnba + 3cnp
dnba + dmabp
C22H21N3O8
455.42
173(2)
monoclinic
P21/n
dnba + fa
C21H14N3O8F3
493.35
173(2)
triclinic
empirical formula
formula wt
temp (K)
cryst syst
space group
a (Å)
b (Å)
c (Å)
α (deg)
β (deg)
C14H11N3O7
333.26
C13H8N4O6
316.23
173(2)
173(2)
monoclinic
P21/n
monoclinic
P21/c
P1
̅
8.9295(9)
13.9281(14)
11.8082(11)
90
100.347(3)
90
1444.7(2)
4
1.532
6.1678(3)
9.2276(5)
24.0942(13)
90
96.703(2)
90
1361.92(12)
4
1.542
10.0968(2)
21.2232(5)
10.3367(3)
90
101.2240(10)
90
2172.65(9)
4
1.392
7.6667(4)
10.7718(5)
13.4392(5)
70.846(2)
84.228(2)
88.073(2)
1043.11(8)
2
γ (deg)
V (Å3)
Z
density (g/cm3)
1.571
0.139
μ (mm−1
)
0.126
0.126
0.108
F(000)
688
648
952
504
crystal size (mm3)
0.512 × 0.248 × 0.248
4.566−56.922
0.347 × 0.258 × 0.159
6.652−55.984
0.213 × 0.221 × 0.268
1.919−28.335
0.142 × 0.117 × 0.052
3.222−50.998
2θ range for data collection
(deg)
no. of rflns collected
no. of indep rflns
13893
3638 (R(int) = 0.0717,
R(σ) = 0.0614)
27504
3286 (R(int) = 0.0451,
R(σ) = 0.0289)
41576
2901 (R(int) = 0.0953,
R(σ) = 0.0361)
15916
3871 (R(int) = 0.0746,
R(σ) = 0.0776)
goodness of fit on F2
final R indexes (I ≥ 2σ(I))
final R indexes (all data)
CCDC
1.022
1.037
1.015
1.098
R1 = 0.0553, wR2 = 0.1420
R1 = 0.0936, wR2 = 0.1678
2026651
R1 = 0.0473, wR2 = 0.1032
R1 = 0.0679, wR2 = 0.1124
2026652
R1 = 0.0458, wR2 = 0.0944
R1 = = 0.0759, wR2 = 0.1037 R1 = 0.1308, wR2 = 0.1636
2026653 2026654
R1 = 0.0660, wR2 = 0.1413
cocrystal/salt
dnba + pyd
dnba + thp
dnba + tu
empirical formula
formula wt
temp (K)
cryst syst
space group
a (Å)
b (Å)
c (Å)
α (deg)
C15H15N3O9
381.3
173(2)
monoclinic
P21/n
9.2152(5)
14.1356(7)
12.5534(6)
90
C14H12N6O8
392.3
173(2)
monoclinic
C2/c
18.7625(6)
15.4699(6)
12.6823(4)
90
C8H8N4O6S
288.24
173(2)
monoclinic
P21/c
13.0957(2)
9.0162(2)
9.8594(2)
90
β (deg)
γ (deg)
V (Å3)
104.378(2)
90
1584.02(14)
4
1.599
0.135
117.917(2)
90
3252.7(2)
8
1.602
0.134
92.6450(10)
90
1162.89(4)
4
1.646
0.31
Z
density (g/cm3)
μ (mm−1
)
F(000)
792
1616
592
crystal size (mm3)
0.215 × 0.436 × 0.080
0.415 × 0.401 × 0.206
5.266−55.998
36969
0.243 × 0.193 × 0.163
3.114−55.994
17130
2θ range for data collection (deg) 6.296−55.984
no. of rflns collected
36275
no. of indep rflns
3814 (R(int) = 0.0344, R(σ) = 0.0172) 3044 (R(int) = 0.0357, R(σ) = 0.0219) 2797 (R(int) = 0.0506, R(σ) = 0.0393)
goodness of fit on F2
final R indexes (I ≥ 2σ(I))
final R indexes (all data)
CCDC
1.061
1.061
1.014
R1 = 0.0405, wR2 = 0.1108
R1 = 0.0521, wR2 = 0.1227
2026655
R1 = 0.0427, wR2 = 0.1186
R1 = 0.0501, wR2 = 0.1247
2026656
R1 = 0.0368, wR2 = 0.0819
R1 = 0.0616, wR2 = 0.0933
2026657
H···π interactions allow the columns to alternate with each
other, as observed in the overall packing.
dnba + pyd. dnba and pyd formed molecular salts, which
crystallized as yellow prismatic crystals (Figure 4). The
asymmetric unit consists of one molecule each of dnba and
pyd, which crystallized in the P21/n space group. A proton
transfer occurred between the carboxylic acid of dnba and the
pyridinium of pyd. One of the hydroxyl groups forms an
intramolecular hydrogen bond with another neighboring
hydroxyl group (O8−H8···O7). dnba and pyd form several
different hydrogen bonds that form a continuous 2D lattice,
with these lattices stacking on top of each other.
E
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involved with weaker C−H···O hydrogen bonding. Although
the shape index has the presence of red and blue triangles that
are typical indicators for the presence of a π···π interaction, the
blue edges on the curvedness surface indicate otherwise. Most
likely the 2D lattices formed are stacked together by a
combination of both ionic forces and weak C−H···O
interactions.
Table 4. Hydrogen Bonds
d(D−H) d(H···A)
∠(DHA)
D−H···A
(Å)
(Å)
d(D···A) (Å)
(deg)
dnba + 2acp
O1−H1···N3
O6−H6···N3
0.98(3)
dnba + 3cnp
0.93(2)
1.73(3)
2.707(2)
171(3)
175(2)
1.74(3)
2.6684(19)
dnba + dmbp Hydrate. dnba and dmabp formed a
hydrated molecular complex and crystallized as fragile orange
plates (Figure 5). This molecular complex crystallized in the
P21/n space group with the asymmetric unit consisting of one
molecule of each dnba, dmabp, and water. dnba, dmabp, and
water form part of a dimer, where water acts as the primary
hydrogen bond donor and acceptor. In this structure, water
forms a bridge between dnba and dmabp by acting as a
hydrogen bond acceptor from dnba and as a hydrogen bond
donor to dmabp and another water molecule. These dimers
formed 2D sheets which stack to form a layered structure.
The Hirshfeld surface reveals the presence of both π-hole
and π−π stacking in addition to the hydrogen bonding present.
The bright red spots observed on the dnorm surface are related
to the previously described strong hydrogen bonding. A few
red spots appear over the nitro group O5−N1−O6 which
indicates the presence of a π-hole-type interaction to the
carboxylic acid group of an adjacent dnba molecule. The shape
index indicates the presence of several π−π stacking type
interactions due to the presence of adjacent red and blue
triangles on the surface. The first of these is between adjacent
benzene rings (C8−C13) of dmabp, while the second of these
is between the rings of dnba and the ring containing the
dimethylamino group of dmabp (C15−C20). The curvedness
shows regions which would allow for the possibility of π−π
stacking. This indicates that while hydrogen bonding yields the
formation of the 2D sheets, these sheets are held together via
π-hole and π−π stacking interactions.
dnba + dmabp
a
O1W−H1WA···O7
O1W−H1WB···O7
O1−H2A···O1W
0.92(6)
0.77(6)
1.01(7)
1.93(6)
2.02(6)
1.57(6)
2.842(5)
2.789(5)
2.558(4)
170(5)
180(6)
164(6)
dnba + fa
O1−H1···O8
0.92(5)
0.98(2)
0.98(2)
0.88(3)
0.87(3)
0.86(3)
1.72(5)
1.65(2)
2.57(2)
2.15(3)
1.76(3)
1.80(3)
2.625(4)
167(5)
174(2)
126(2)
175(2)
162(2)
147(3)
b
N3−H3···O1
N3−H3···O2
2.6269(15)
3.2529(15)
3.0239(17)
2.6019(15)
2.5685(17)
b
c
O9−H9···O4
O7−H7···O2
O8−H8···O7
dnba + thp
d
N4−H4···O8
0.98(3)
1.01(3)
1.76(3)
1.66(3)
2.7264(16)
2.6264(15)
172(2)
160(3)
O1−H1···N3
dnba + pyd
h
N3−H3···O1
0.98(2)
1.65(2)
2.57(2)
2.15(3)
1.76(3)
1.80(3)
2.6269(15)
3.2529(15)
3.0239(17)
2.6019(15)
2.5685(17)
174(2)
126(2)
175(2)
162(2)
147(3)
h
N3−H3···O2
0.98(2)
0.88(3)
0.87(3)
0.86(3)
c
O9−H9···O4
O7−H7···O2
O8−H8···O7
dnba + tu
e
N4−H4B···S1
0.89(2)
0.82(2)
0.85(2)
0.89(2)
0.88(3)
2.49(2)
2.39(2)
2.66(2)
2.66(3)
1.77(3)
2.49(2)
3.3773(18)
3.108(2)
3.4502(19)
3.470(2)
2.6524(18)
3.3773(18)
173(2)
146(2)
157(2)
152(2)
176(3)
173(2)
N3−H3A···O6
f
N4−H4A···S1
N3−H3B···S1
O1−H1···O2
N4−H4B···S1
f
g
e
0.89(2)
a
b
c
−x + 1, −y + 1, −z + 2. x − 1/2, −y + 1/2, z + 1/2. x − 1/2, −y +
d
e
f
3/2, z + 1/2. −x + 3/2, −y + 3/2, −z + 1. −x + 1, −y + 1, −z. −x +
dnba + fa. dnba formed a cocrystal with fa, which
crystallized as fragile, orange platelike crystals. The cocrystal
g
h
1, y + 1/2, −z + 1/2. −x + 2, −y, −z + 2. x − 1/2, −y + 1/2, z + 1/
2.
̅
crystallizes in the P1 space group with the asymmetric unit
consisting of one molecule of each dnba and fa. Rotational
disorder is present within the trifluoro group on the fa
molecules. Hydrogen bonding exists between the carboxylic
acids of both dnba and fa, which give the R22(8) ring dimer.
The Hirshfeld surface of the dnba + fa cocrystal reveals more
types of interactions. Red spots of various sizes appear on the
The Hirshfeld surfaces for the molecular salt of dnba + pyd
show that the hydrogen bond is the most significant
intermolecular interaction present. The large, bright red
spots present in the dnorm are involved with hydrogen bonding,
with a few smaller and dimmer set of red spots which are
Figure 2. Crystal structure of the solvate dnba + 2acp showing (i) the packing (with hydrogen atoms omitted) and (ii) the dnorm showing some of
the C−H···O interactions (surface mapped between −0.2267 and +1.0880 Å).
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Figure 3. Crystal structure of dnba + 3cnp showing (i) the packing of (with hydrogen atoms omitted) and (ii) the dnorm of dnba + 3cnp showing
the 3cnp dimer as well as the π-hole interaction between the carboxylic acid group and one of the nitro groups (surface mapped from −0.1939 to
+1.1896 Å).
Figure 4. Crystal structure of dnba + pyd showing (i) the hydrogen bonding and (ii) the packing (with hydrogen atoms omitted) and (iii, iv) the
dnorm from two different perspectives, where the brightest red spots are due to hydrogen bonding.
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Figure 5. Crystal structure of dnba + dmabp showing (i) the hydrogen-bonded “water ring”, (ii) the dnorm showing the π-hole interactions
(mapped from −0.5738 to +1.4262 Å), (iii) the shape index with circles showing possible π−π interactions, (iv) curvedness showing flat regions
that could possibly allow for π−π interactions, and (v) the packing diagram (with hydrogens omitted).
d
norm, which indicates the presence of various weak C−H···O,
the C2/c space group. The hydrogen H1 was placed
geometrically with respect to O1, since this hydrogen could
not be found accurately in the Fourier map. dnba forms a
discrete hydrogen bond between the carboxylic acid O1−H1
to nitrogen N3 of thp. thp forms part of a dimer held together
by two molecules of thp forming a ring between N4−H8···O8,
with a ring graph set of R22(10). The overall packing is made up
of several rows and columns of alternating dnba and thp
molecules.
The Hirshfeld surface shows an additional set of important
interactions. The brighter red spots that appear on the dnorm
surface correspond to the stronger hydrogen bonds described
previously, while the less bright spots represent weaker C−H
hydrogen bonds. In addition to the strong hydrogen bond
C−H···π, C−O···π and N−O···π interactions. Figure 6(ii)
shows where some of these weak interactions may be
occurring. The shape index indicates the possibility of π−π
stacking interactions, as indicated by the red and blue triangles
in Figure 6(iii) and the presence of a flat region in the
curvedness which could allow for such an interaction to exist.
This π−π stacking occurs between inverted dimers: i.e.,
between dnba and the benzoic acid portion of fa. This would
lead to a layered-type packing in the structure, with the
trifluorotoluene portion of fa separating different layers.
dnba + thp. dnba formed a cocrystal with thp, which
crystallized as colorless blocks (Figure 7). The asymmetric unit
consists of one molecule of each dnba and thp, crystallizing in
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Figure 6. Crystal structure of dnba + fa showing (i) the packing (with hydrogen atoms omitted), (ii) the dnorm showing some of the weaker
interactions present (mapped from 0.1410 to 1.4528 Å), (iii) the shape index with circles indicating the presence of some π−π stacking, and (iv)
the curvedness with arrows showing some flat regions where π−π stacking may be possible.
between dnba and thp described previously, the weak
hydrogen bond C8−H8···O2 forms. In addition, weaker
hydrogen bonds form between different neighboring dnba
molecules via C2−H2···O6 and C4−H4···O2. The presence of
red and blue triangles on the shape index on both the ring of
dnba and imidazole portion of thp, as well as the curvedness
being flat over the aforementioned regions, indicates the
presence of π···π stacking, which would dominate the overall
packing observed in this cocrystal.
dnba + tu. dnba formed a cocrystal with tu and crystallized
as pale yellow blocks (Figure 8). This cocrystal crystallizes in
the P21/c group with the asymmetric unit consisting of one
molecule each of dnba and tu. Both dnba and tu form a R22(8)
homosynthon, which forms a set of two dimers. These dimers
interact with each other via the amino group (the group not
involved in the homodimer) and one of the nitro groups. In
addition, a bifurcated hydrogen-bonded system arises between
two tu molecules related to each other via the 2-fold screw axis
through N4−H4A···S1 and N3−H3B···S1. The Hirshfeld
surfaces indicate a π-hole-type interaction in the dnorm with
the nitro group O3−N1−O4 interacting with the carboxylic
acid group of a nearby dnba molecule. The packing of this
cocrystal is made up of rows of dnba molecules alternating
with channels of tu molecules.
Cambridge Structural Database Analysis. The analysis
of the CSD indicates several trends in previously reported
multicomponent crystal structures involving dnba. The search
result of the combined query yielded 362 results. After salts
containing alkali or alkakine-earth cations, heavily disordered
molecules, and solvates were removed, 259 multicomponent
crystal structures were examined further. Some notable
examples are given in Table 5. A total of 186 of these results
were binary and 73 were ternary or greater. A total of 131
entries consisted of the protonated (carboxylic acid) form, and
186 entries consisted of the deprotonated (carboxylate) form.
At least 25 hydrates were reported. Only 5 entries show the
formation of the carboxylic acid heterodimer R22(8) ring motif
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Figure 7. Crystal structure of dnba + thp showing (i) the hydrogen bonding, (ii), the dnorm showing some of the additional weaker hydrogen bonds
(mapped from −0.5738−1.4262 Å), and (iii) the packing.
Figure 8. Crystal structure of dnba + tu showing (i) the hydrogen bonding, (ii) the packing (with hydrogen atoms omitted), and (iii) the dnorm
showing the π-hole interaction between the nitro group and carboxylic acid (mapped from −0.7297 to +1.5105 Å).
such as that observed for the dnba + fa crystal structure, which
makes the formation of this heterodimer rather rare.
4.20), which will more likely result in the formation of a salt
than of a cocrystal. Although most of the multicomponent
crystals consisting of N-containing coformers presented in this
work resulted in a cocrystal, it should be noted the
multicomponent crystals present here are more an exception,
rather than a part of the norm.
From Figures 2, 4, 7, and to some extent Figure 6 it seems
that dnba tends to favor forming a layered-type structure.
From the CSD, multicomponent structures which contain
coformers that are relatively planar tend to favor forming a
layered-type structure. This is not an absolute trend: for
One of the most common features of previously reported
structures are that many coformers contain a nitrogen atom
that can either act as a hydrogen bond acceptor or accepts a
proton as a base and becomes ionized. Out of the total number
of N-containing coformers, 66 entries include a N-containing
compound that acts as a hydrogen bond acceptor (no proton
transfer) and 140 consist of a proton transfer occurring from
dnba to the N-containing compound. This result is reasonable,
since dnba is relatively more acidic than benzoic acid (pKa =
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Table 5. Some Notable Examples of Multicomponent Crystals of dnba Presented in Other Work
refcode
COLKUL
RAVLIM
XILTAO
GAUTAM
GOBJUQ
HORWIX
comment
another benzoic acid derivative forming a carboxylic acid ring motif R22(8); also a hydrate
cocrystal formed between dnba and 4-pyridinecarboxaldehyde; has π-hole interactions; crystals are elastic29
hydrate consisting of the carboxylate of dnba and 3-aminopyridinium
cocrystal consisting of 4-dimethylaminobenzoic acid and dnba; consists of two homodimers
cocrystal consisting of dnba and indole-2-carboxylic acid; forms a heterodimer; layered structure
cocrystal consisting of carbamazepine and dnba; forms a heterodimer while a nitro group forms a hydrogen bond to amide not involved
with the ring synthon
IDUNUQ
molecular salt formed from the proton transfer of dnba to 3-hydroxypyridine; carboxylate forms a hydrogen bond between the hydroxyl
group and pyridyl nitrogen on two independent 3-hydroxypyridine groups
KIZQIT, KIZQOZ,
KIZQUF, KIZREQ
NEMSUT
series of charge transfer complexes formed between dnba and various N-substituted carbazoles; dnba formed a homodimer
cocrystal formed between the interaction of dnba and phenylurea; dnba forms a ring synthon R22(8) between the carboxylic acid and
amide group; remaining N−H groups form hydrogen bonds to nitro group
XAMHAX
molecular salt of dnba and benzimidazole; salt forms hydrogen bonds with nitro group over carboxylate
interactions, is more favorable than forming a hydrogen
bond with the nitro group.
Scheme 2. Theoretical Ring Hydrogen Bond Motif between
dnba and thp
For the cocrystal of dnba + thp, it should be noted that
dnba could have formed a heterodimer, with ring synthon
R22(9) as shown in Scheme 2. This type of heterodimer is
common with cocrystals consisting of thp and a benzoic acid
derivative, such as that occurring between thp and 4-
aminobenzoic acid (refcode HUMNEK). However, the thp
homodimer that was observed in dnba + thp is also common
in other cocrystals involving dnba and a benzoic acid
derivative, such as the thp + salicylic acid cocrystal (refcode
KIGLES). The layered type structure appears to also be a
common means of packing for such cocrystal systems, although
exceptions do arise.
Hirshfeld Surface Analysis of dnba Complexes. It
would be of interest to compare the contact contribution of
dnba between the different multicomponent crystals pre-
sented. The percentages of the contributions from different
interacting pairs is calculated by first calculating the Hirshfeld
surface of dnba by itself and then using the values obtained
from the fingerprint plots to plot a bar graph as presented in
Figure 9. From Figure 9 the largest contribution comes from
the O−H/H−O set of contacts, which naturally comes from
the main contributing hydrogen bonds formed between dnba
example, in the hydrate consisting of dnba and 4-amino-
salicylic acid (refcode COLKUL) the coformers may be
described as being relatively planar but the resulting structure
was not simply layered.
Out of the 259 structures examined for this work, only 57
entries exhibit a hydrogen bond formed with the nitro group.
In most cases, the carboxylic acid group of dnba dominates as
the major interaction with the coformer, as observed in
multicomponent crystal structures containing N-containing
heterocycles. Even in cases where multiple hydrogen bond
donors are available, it is not guaranteed that a hydrogen bond
to the nitro group will form. It is probable that the formation
of the π-hole interaction, together with other weaker
Figure 9. Percentage contribution of contacts due to dnba. For the cocrystal of dnba + fa the percentage contributions of F···H and O···F in other
are 8.5% and 5.8%, respectively.
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Figure 10. DSC curves for dnba + 2-acp.
Information. Table 6 contains the thermodynamic behavior
related to the melting of each of the multicomponent crystals.
Table 6. Thermodynamic Data for the Melting of the
Multicomponent Crystals of dnba
cocrystal/molecular
salt
onset
peak
heat of fusion ΔHfus
(°C)
(°C)
(kJ mol−1
)
CONCLUSIONS
■
Seven multicomponent crystals, of which five are cocrystals,
one is a solvate, and one is a molecular salt, consisting of dnba
were synthesized and characterized. These crystals showed
various hydrogen-bonding interactions between dnba and the
coformer. Hirshfeld surfaces show that a number of weaker
interactions exist within each crystal, which contributes to the
overall structure and packing of the molecules in the crystals.
For future work, it would be of use to determine if the
cocrystals of dnba + thp and dnba + fa have any improved
properties such as solubility over the parent API molecule.
Overall, this work shows that dnba can be a versatile molecule
to consider in the development of new multicomponent
crystals involving APIs.
dnba + thp
dnba + pyd
dnba + 2acp (solvate)
dnba + 3cnp
dnba + dmabp
hydrate
dnba + fa
dnba + tu
194.2
161.6
76.8
134.4
86.8
203.9
168.5
80.9
135.6
93.0
128.5
70.4
96.4
204.3
91.8
136.8
153.2
141.0
156.3
111.2
179.5
and its respective coformer(s). Other notable sets of contacts
include C···H and C···O. The C···O set of contacts contributes
to a large percentage toward the total, especially for the dnba +
3cnp. These arise due to the π-hole-type interactions present
across the various multicomponent crystals. The C···H
contacts arise due to the C−H···π, and its significance has
been noted before. The percentage of C−C contacts in the
cocrystal of dnba + fa and the hydrate of dnba + dmabp is
much higher than the rest due to the presence of π−π stacking
interactions. Overall the contact contributions of the different
contacts across the different multicomponents are similar to
each other to an extent.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.cgd.0c01217.
Powder X-ray diffraction data, differential scanning
calorimetry data, and the Hirshfeld surface diagrams
and fingerprint plots (PDF)
Differential Scanning Calorimetry. Differential scanning
calorimetry was carried out on all samples. In each case, the
sample was heated to 250 °C and then cooled to 40 °C twice
at a heating/cooling rate of 10 °C/min under ambient
conditions. In each case only one thermal event was
observedthe melting peak with no recrystallization. The
exceptions to this are the cocrystals of dnba + thp and dnba +
3cnp and the solvate dnba + 2acp. In these crystal systems,
upon cooling back to 25 °C, a peak corresponding to
recrystallization is observed. Upon heating and cooling a
second time, the same peaks are observed, indicating a degree
of reversibility. The DSC curves for the heating and cooling of
dnba + 2acp are represented in Figure 10, as an example of the
thermal behavior observed for dnba + thp and dnba + 2acp.
The rest of the DSC curves are available in the Supporting
Accession Codes
CCDC 2026651−2026657 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
Andreas Lemmerer − Molecular Sciences Institute, School of
Chemistry, University of the Witwatersrand, 2050
Johannesburg, South Africa; orcid.org/0000-0003-1569-
2831; Phone: +27-11-717-6711;
L
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isonicotinamide: the structural landscape in crystal engineering.
Philos. Trans. R. Soc., A 2012, 370, 2900−2915.
Email: andreas.lemmerer@wits.ac.za; Fax: +27-11-717-
6749
(14) Santiago de Oliveira, Y.; Saraiva Costa, W.; Ferreira Borges, P.;
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benzenesulfonamide−3,5-dinitrobenzoic acid (1/1). Acta Crystallogr.,
Sect. C: Struct. Chem. 2016, 72, 612−618.
Author
Matthew C. Scheepers − Molecular Sciences Institute, School
of Chemistry, University of the Witwatersrand, 2050
Johannesburg, South Africa
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.cgd.0c01217
Notes
The authors declare no competing financial interest.
́
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ACKNOWLEDGMENTS
■
We acknowledge and thank the DSI/NRF Centre of
Excellence in Strong Materials as well as the NRF for funding
the Bruker D2 Phaser diffractometer.
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