Investigating the Role of Weak Interactions to Explore the Polymorphic Diversity in Difluorinated Isomeric N-Phenylcinnamamides

Article abstract of DOI:10.1021/acs.cgd.1c00422

A total of nine difluoro derivatives of N-phenylcinnamamides have been synthesized from fluoro-substituted cinnamic acids and anilines in order to investigate the formation of polymorphs arising due to the conformational flexibility around the amide and vinyl group. Among them, four compounds have been found to exist in multiple polymorphic forms, which includes concomitant polymorphism, solvatomorphism, and packing polymorphism, while the remaining five compounds display monomorphic behavior. Crystal structure analyses of all the forms belonging to these four compounds reveal that, although the molecules are primarily held by strong N-H?O hydrogen bonds, the relative interplay of weak C-H?F, C-H?O, C-H?π, and π?πinteractions allows the flexible molecules to adopt different orientations and exhibit polymorphism. These forms interestingly also display different thermal stabilities, and they have been quantified by intermolecular interaction topological analyses. The occurrence of different primary packing motifs in these crystal structures has been further investigated by the crystal structure prediction (CSP) computational method, wherein an energy landscape of an unsubstituted N-phenylcinnamamide was generated and a number of hypothetical structures were accessed with experimentally obtained crystal structures of its difluoro-substituted derivatives.

Full text of DOI:10.1021/acs.cgd.1c00422

pubs.acs.org/crystal
Article
Investigating the Role of Weak Interactions to Explore the
Polymorphic Diversity in Difluorinated Isomeric
N‑Phenylcinnamamides
Rohit Bhowal* and Deepak Chopra*
Cite This: Cryst. Growth Des. 2021, 21, 4162−4177
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: A total of nine difluoro derivatives of N-phenylcinnamamides
have been synthesized from fluoro-substituted cinnamic acids and anilines in
order to investigate the formation of polymorphs arising due to the
conformational flexibility around the amide and vinyl group. Among them,
four compounds have been found to exist in multiple polymorphic forms,
which includes concomitant polymorphism, solvatomorphism, and packing
polymorphism, while the remaining five compounds display monomorphic
behavior. Crystal structure analyses of all the forms belonging to these four
compounds reveal that, although the molecules are primarily held by strong
N−H···O hydrogen bonds, the relative interplay of weak C−H···F, C−H···O,
C−H···π, and π···π interactions allows the flexible molecules to adopt different
orientations and exhibit polymorphism. These forms interestingly also display
different thermal stabilities, and they have been quantified by intermolecular
interaction topological analyses. The occurrence of different primary packing
motifs in these crystal structures has been further investigated by the crystal structure prediction (CSP) computational method,
wherein an energy landscape of an unsubstituted N-phenylcinnamamide was generated and a number of hypothetical structures were
accessed with experimentally obtained crystal structures of its difluoro-substituted derivatives.
simultaneous crystallization of two or more forms due to their
concurrent nucleation, and their formation is controlled by both
the kinetics of crystallization and thermodynamics of crystal
packing.29−31 Packing polymorphs include crystal systems
having similar molecular conformations, differing only in the
arrangement of molecules in their crystal packing environ-
ment.32−34 The polymorphic forms of a drug may exhibit
distinct solid-state physicochemical properties such as intrinsic
dissolution rate,35,36 solubility,37 tabletability,38,39 thermal
stability,40 flowability,41 hygroscopicity,42,43 etc. and also various
drug outcomes such as drug efficacy,44 bioavailability,45 and
toxicity.46,47 Hence, it is of prime importance to conduct an in-
depth exploration into the polymorphic possibility of different
drugs and their precursors using both experimental techniques
and computational interpretations, which is one of the principal
aims of crystal engineering research.
1. INTRODUCTION
Fluorine chemistry1−3 has experienced an exponential growth,
from representing a small subfield of organic chemistry into a
major area of multidisciplinary research of drug design that
involves health and food industries.4−7 The previous few
decades have witnessed the evolution of fluorine substitution
as one of the structural trends in the world of medicinal
chemistry, where nearly 50% of all the blockbuster drug
molecules contain fluorine atoms.8−12 Peptide/protein engi-
neering relies on structure tailoring of fluorinated amino acids
and their subsequent tactical amalgamation into the peptide
chain in order to achieve a three-dimensional view of peptide−
receptor interactions.13−15 The possibility of obtaining poly-
morphism and pseudopolymorphism is quite high among active
pharmaceutical ingredients, and this phenomenon can be
considered either a blessing or a nuisance in different stages of
drug design, as it might have direct medical implications.16−21
The term “polymorphs” include those crystal systems in which a
substance can crystallize in multiple crystal structures having
different unit cell parameters, where each form displays the same
empirical formula.22−25 Solvatomorphs or pseudopolymorphs,
on the other hand, include crystal systems with different unit cell
parameters, where the unit cells differ in their elemental
composition only through the inclusion of one or more solvent
molecules.26−28 Concomitant polymorphs are defined as the
̈
Polymorphism was first discovered in benzamide by Wohler
and von Liebig in 1832,48 and since then remarkable progress
Received: April 12, 2021
Revised: June 9, 2021
Published: June 25, 2021
https://doi.org/10.1021/acs.cgd.1c00422
Cryst. Growth Des. 2021, 21, 4162−4177
© 2021 American Chemical Society
4162

Crystal Growth & Design
pubs.acs.org/crystal
Article
toward the discovery of new polymorphs of organic materials
has been accomplished. As a part of a continuous endeavor to
appreciate the solid-state diversity present in N-phenyl-
benzamides,49−51 herein we have further extended our study
to explore the polymorphic possibilities in the difluoro-
substituted N-phenylcinnamamides. A recent survey of
cinnamamide molecules in the Cambridge Structural Database
(CSD)52 has yielded only 30 hits, out of which only 3 molecules
were N-phenylcinnamamide derivatives, and no structures
exhibited any polymorphic behavior. The molecular framework
of cinnamamide derivatives has been integrated into numerous
biologically active synthetic compounds, since it promotes both
hydrophobic and hydrogen-bonding interactions originating
from the phenyl ring and the amide group, respectively, highly
suitable for interacting with the molecular target. By
introduction of a C−F group, also termed as “organic
fluorine”,53,54 it is expected to exhibit poor hydrogen bond
acceptor properties, which can be attributed to the weak
polarizability of fluorine atoms55,56 and is expected to embrace
weak C−H···F interactions. In order to quantitatively assess the
support provided by weak noncovalent interactions originating
from organic fluorine in the presence of strong N−H···O and
moderately strong C−H···O and C−H···π hydrogen bonds, we
have performed the synthesis and crystallization of a series of
nine isomeric difluorinated N-phenylcinnamamides (Scheme
1), out of which four compounds crystallized in multiple
practically an uphill task to obtain all of the plausible structures
in the landscape from crystallization experiments alone; hence,
the miscellaneous crystal packing plausibilities of N-phenyl-
cinnamamides have been computed by employing the computa-
tional CSP method within a small energy space via a crystal
lattice energy vs density plot.58 Predicting crystal structures of an
organic molecule from its molecular structure alone is of
considerable industrial importance. This is a highly complicated
venture due to the number of degrees of freedom to be explored
and the complexities arising from inter- and intramolecular
interactions, especially in our compound of interest, which has
high flexibility.59 One of the major disadvantages of this CSP
method is that it does not take into account the kinetic factors
such as nucleation dynamics, solvent effects, temperature,
pressure, and humidity affecting the crystallization pathway
and hence sometimes fails to predict experimentally obtained
crystal structures. An examination of strong and weak
intermolecular interactions via an energy framework analysis
would lead to a better understanding and comparison of the
crystal packing modes in polymorphic systems.
2. RESULTS AND DISCUSSION
In this investigation we have synthesized N-phenylcinnamamide
(ADB) and a library of nine difluoro-substituted ADB molecules
(see Scheme 1), which contain an amide group and a double
bond bridging two phenyl rings connected to organic fluorine, so
as to observe the occurrence of C−H···F−C(sp2) and related
weak intermolecular interactions acting in conjunction with
strong N−H···OC hydrogen bonds. Synthetic procedures
and purification methods for the compounds are provided in
detail in the Supporting Information. The bulk compounds were
crystallized in a wide range of solvents and solvent mixtures (for
details see Table S1) and were characterized by single-crystal X-
ray diffraction (SCXRD) experiments, which allowed the
identification of intermolecular interactions and molecular
self-assembly in the solid state. An extensive screening by
crystallization experiments of the unsubstituted and difluoro-
substituted molecules in the series has yielded three
polymorphic forms of 2ADB4 (forms I−III), one solvatomorph
(form I), and two polymorphs of 3ADB3 (forms II and III), two
concomitant polymorphs of 4ADB2 (forms I and II) and two
packing polymorphs of 4ADB4 (forms I and II) (see Table S2).
A closer inspection of the molecular structures in the series
revealed significant differences in their geometrical features (See
Tables 1 and 2). The thermal stabilities of the compounds were
determined by differential scanning calorimetry (DSC) experi-
ments, and it was found that each polymorph displayed a quite
distinct melting point, indicating the pivotal role of cooperative
noncovalent interactions. First, we have focused on only those
compounds that exhibited polymorphic behavior, and hence a
Scheme 1. Synthetic Route and Chemical Structures of N-
Phenylcinnamamide (ADB) and Its Difluoro-Substituted
Analogues
polymorphic forms. A subtle interplay of strong hydrogen bonds
and weak intermolecular interactions sometimes involving
disordered fluorine, arising from the conformational flexibility
of the difluorinated phenyl rings, has been found to exert a
substantial effect on the thermal stabilities of these polymorphs.
The occurrence of polymorphic forms of a molecule provides
the opportunity to investigate its structural landscape from
experimentally determined crystal structures.57 However, it is
Table 1. Torsion Angles (deg) for 2ADB2, 2ADB3, 3ADB2, and Three Forms of 2ADB4 and 3ADB3 Each
2ADB4
3ADB3
form II
2ADB2
2ADB3
form I
form II
form III
3ADB2
form I
form III
C7−N1−C1−C6
39.81(4)
−34.35(6)
21.37(7)
−26.54(6)
−165.33(4)
2.3
51.27(2)
9.31(2)
48.58(2)
12.84(2)
76.2
39.19(3)
51.64(2)
8.37(3)
51.61(2)
13.33(3)
75.0
155.02(10)
−171.95(2)
−6.05(3)
−42.50(2)
161.79(6)
−145.06(3)
8.80(6)
C8−C9−C10−C11
C22−N2−C16−C21
C23−C24−C25−C26
(C1−C6)/(C10−C15)interplanar
angle
150.22(3)
152.26(2)
−158.27(11)
−22.63(5)
170.79(4)
28.2
4.2
4.1
13.1
5.7
75.3
(C16−C21)/(C25−C30)
interplanar angle
4.3
76.2
78.9
25.1
4163
https://doi.org/10.1021/acs.cgd.1c00422
Cryst. Growth Des. 2021, 21, 4162−4177

Crystal Growth & Design
pubs.acs.org/crystal
Article
Table 2. Torsion Angles (deg) for 3ADB4, 4ADB3, and Two Polymorphs of 4ADB2 and 4ADB4 Each along with Unsubstituted
ADB
4ADB2
4ADB4
3ADB4
form I
form II
4ADB3
form I
form II
ADB
C7−N1−C1−C6
C8−C9−C10−C11
C22−N2−C16−C21
C23−C24−C25−C26
(C1−C6)/(C10−C15) interplanar angle
(C16−C21)/(C25−C30) interplanar angle
−159.96(16)
−17.66(3)
−41.38(13)
160.39(13)
−140.93(12)
153.24(17)
−155.67(12)
168.87(12)
−161.59(12)
170.51(13)
−156.14(16)
−18.17(3)
−20.25(6)
−6.34(7)
−40.84(5)
−7.52(6)
24.5
16.8
73.7
2.4
7.6
4.5
12.7
40.3
Figure 1. ORTEP drawings of (a) 2ADB2, (b) 2ADB3, (c) form I of 2ADB4 (orange-magenta), (d) form II of 2ADB4 (green), (e) form III of 2ADB4
(blue-purple), (f) 3ADB2, (g) form I of 3ADB3 (orange), (h) form II of 3ADB3 (magenta), (i) form III of 3ADB3 (blue-green), (j) 3ADB4, (k) form I
of 4ADB2 (orange), (l) form II of 4ADB2 (magenta), (m) 4ADB3, (n) form I of 4ADB4 (orange), and (o) form II of 4ADB4 (magenta), drawn with
50% ellipsoidal probability with the atom-numbering schemes. Different colors of carbon atoms represent the symmetry-independent positions of
molecules in the asymmetric unit in the polymorphs.
total of 10 new structures have been discussed in terms of their
conformational preferences and adaptation of complementary
supramolecular domains supported by an energetic quantifica-
tion of the intermolecular interaction topology. Thereafter, we
have also investigated the occurrence of isostructurality and
isomorphism60,61 in the entire family of difluorinated ADB
molecules, followed by an in-depth analysis of the occurrence of
different supramolecular motifs in the crystal structure land-
scape of the unsubstituted compound. This is compared with the
observed motifs in the different polymorphs of the substituted
crystal structures, which constitutes a general topological
interaction landscape via the technique of crystal structure
prediction.62
2.1. Polymorphs of 2ADB4: Forms I−III. 2.1.1. Molecular
Packing. 2ADB4 crystallizes in three polymorphic forms, where
its first form (form I) crystallizes in the triclinic crystal system
4164
https://doi.org/10.1021/acs.cgd.1c00422
Cryst. Growth Des. 2021, 21, 4162−4177

Crystal Growth & Design
pubs.acs.org/crystal
Article
Figure 2. (a) Molecular overlay of five symmetry-independent molecules (two, one, and two molecules from forms I−III of 2ADB4, respectively) at
the solid-state geometry. (b) DSC profiles of the three polymorphs of 2ADB4 at 3 °C/min of a heating−cooling cycle. (c) Overlay of experimental
PXRD patterns of 2ADB4 bulk powder and the simulated patterns of the three polymorphs. Crystal structure projections of (d) 2ADB4 (form I), (e)
2ADB4 (form II), and (f) 2ADB4 (form III) at 100 K. Energy frameworks for (g) 2ADB4 (form I), (h) 2ADB4 (form II), and (i) 2ADB4 (form III),
representing the total interaction energies in kJ/mol.
with centrosymmetric space group P1
̅
and having two molecules
Table 1), which helps in the promotion of π···π interactions
between the aromatic rings in addition to C5−H5···F1
interactions (Figure 2e). The third form (form III) of 2ADB4
crystallizes in the monoclinic crystal system with centrosym-
metric space group P21/c having two molecules (blue-purple) in
the asymmetric unit (Z′ = 2) (Figure 1e) linked by highly
directional N1−H1···O2C22 and N2−H2···O1C7 hydro-
gen bonds down the a axis (red bands in Figure 2f). These
molecular columns are diagonally bridged via C5−H5···O1
(orange-magenta) in the asymmetric unit (Z′ = 2) (Figure 1c).
The symmetry-independent molecules form a three-dimen-
sional molecular sheet along the ac plane, connected via highly
directional N1−H1···O2C22 and N2−H2···O1C7 hydro-
gen bonds (red bands in Figure 2d) along the a axis and weaker
C19−H19···F4 and bifurcated C4/C27−H4/H27···F2 inter-
actions along the c axis (Figure S2a). The molecules in form I are
further bound by C20−H20···O2C22 and C5−H5···O1
C7 R22(14) hydrogen bond synthons, both related by inversion
centers, which diagonally link the N−H···O hydrogen-bonded
molecular chains (gray bands in Figure 2d). The second form
(form II) of 2ADB4 crystallizes in the monoclinic crystal system
with noncentrosymmetric space group P21 having one molecule
(green) in its asymmetric unit (Z′ = 1) (Figure 1d). The
molecules are primarily held by bifurcated N1/C8−H1/H8···
C7 and C20−H20···O2C22 R22(14) hydrogen bond
synthons (gray bands in Figure 2f). The crystal packing in a
view along the bc plane exhibits a wavelike zigzag orientation of
molecules promoted by C20−H20···F1, C3−H3···F4, C18−
H18···F2, and C4−H4···F2 interactions (Figure S2c).
2.1.2. Thermal and PXRD Analyses. DSC experiments of all
the polymorphic forms of 2ADB4 were performed to unravel
their relative thermal stabilities (Figure 2b). All three forms
displayed smooth endotherms with sharp melting peaks, where
form I was found to exhibit the highest thermal stability with a
melting point at 145 °C (ΔH = −73.5 J/g) (orange line in Figure
2b), followed by form III, which melts at 143 °C (ΔH = −71.8 J/
O1C7 21R(6) hydrogen bond synthons down the a axis (red
zones in Figure 2e and Figure S2b), while successive molecular
chains are bridged via C3−H3···F1 and C12−H12···F2
interactions along the c axis (Figure S2b). The phenyl rings in
form II are almost coplanar with each other (2ADB4 form II in
4165
https://doi.org/10.1021/acs.cgd.1c00422
Cryst. Growth Des. 2021, 21, 4162−4177

Crystal Growth & Design
pubs.acs.org/crystal
Article
Figure 3. (a) Molecular overlay of four symmetry-independent molecules (one, one, and two molecules from forms I−III of 3ADB3 respectively) at
the solid-state geometry. (b) DSC profiles of the three polymorphs of 3ADB3 at 3 °C/min of a heating−cooling cycle, (c) Overlay of PXRD patterns of
3ADB3 bulk powder and the simulated patterns of their three polymorphs. Crystal structure projections of (d) 3ADB3 (form I), (e) 3ADB3 (form II),
and (f) 3ADB3 (form III) at 100 K. Energy frameworks for (g) 3ADB3 (form I), (h) 3ADB3 (form II), and (i) 3ADB3 (form III), representing the
total interaction energies in kJ/mol.
g) (blue line in Figure 2b) and finally form II exhibiting the
lowest thermal stability with a melting point at 140 °C (ΔH =
−86.4 J/g) (green line in Figure 2b). The relative differences in
melting points of the three forms can be explained by an energy
framework analysis of their respective IEs. Form I exhibits the
highest thermal stability due to the presence of a strong network
of electrostatically dominated N−H···O (IE = −58.9, −58.8 kJ/
mol), C−H···F and C−H···π (IE = −31.8 kJ/mol), and C−H···
O (IE = −29.9, −22.4 kJ/mol) interactions (Figure 2g). On the
other hand, form III displays a comparatively lower melting
point, evidently due to the slightly lower values of IEs in
molecular dimers connected by N−H···O (IE = −59.0, −57.8
kJ/mol), C−H···F and C−H···π (IE = −29.5 kJ/mol), and C−
H···O (IE = −23.1, −21.5 kJ/mol) interactions (Figure 2i).
Finally, the lowest thermal stability of form II can be elucidated
from the much lower values of IEs in dimers linked via bifurcated
N−H···O and C−H···O hydrogen bonds represented by vertical
tubes (IE = −56.0 kJ/mol) and supported by C−H···F and H···
H interactions represented by the diagonal tubes (IE = −19.9
kJ/mol) (Figure 2h). The experimental powder pattern of the
bulk powder of 2ADB4 has been compared with the simulated
PXRD patterns of all the polymorphic forms, and it shows that
the bulk powder is a representative of form II (Figure 2c). This
has been further proved using the powder profile fitting
refinement technique, where only form II yielded satisfactory
results (Figure S9a).
2.2. Polymorphs of 3ADB3: Forms I−III. 2.2.1. Molecular
Packing. 3ADB3 crystallizes in three polymorphic forms, where
form I is a solvatomorph crystallizing in the triclinic crystal
̅
system with the centrosymmetric space group P1 having one
3ADB3 molecule and an isopropyl alcohol solvent molecule in
the asymmetric unit (Figure 1g). Both 3-fluorobenzene rings
experience orientational disorder (sof of F1A = 0.865(2), sof of
F1B = 0.135(2), sof of F2A = 0.910(2), sof of F2B = 0.090(2),
where sof stands for site occupancy factor) and maintain a
coplanar orientation with respect to each other (3ADB3 (form
I) in Table 1), which assists in the formation of two-dimensional
molecular layers via C5A−H5A···F1A and C14A−H14A···F2A
interactions along the a axis (green belts in Figure 3d) and via a
C13A−H13A···F2A R22(8) hydrogen bond synthon related by
an inversion center along the c axis (Figure S3a). These
successive molecular sheets are further stabilized by bifurcated
C15A/C9−H15A/H9···O1 R21(6) hydrogen bonds (red bands
in Figure 3d) and π··π interactions down the b axis (blue bands
4166
https://doi.org/10.1021/acs.cgd.1c00422
Cryst. Growth Des. 2021, 21, 4162−4177

Crystal Growth & Design
pubs.acs.org/crystal
Article
Figure 4. (a) Face indexation for form I of 4ADB2 and (b) prediction of morphology for form I of 4ADB2 from BFDH calculations.63−65 (c) Face
indexation for form II of 4ADB2 and (d) prediction of morphology for form II of 4ADB2 from BFDH calculations. (e) Molecular overlay of two
symmetry-independent molecules (one molecule each from forms I and II of 4ADB2) atthe solid-state geometry. (f) Overlay of the PXRD pattern of
4ADB2 bulk powder with the simulated patterns of their concomitant polymorphs. (g) DSC profiles for the two forms of 4ADB2 at 3 °C/min for two
heating−cooling cycles. Crystal projections of (h) 4ADB2 (form I) along the bc plane and (i) 4ADB2 (form II) along the b axis at 100 K. (j) The
structural transition from form I to form II in 4ADB2 explained by an energy framework analysis representing their total interaction energies in kJ/mol.
in Figure 3d). The isopropyl alcohol molecules (demarcated in
bonds (Figure 3e). Form III crystallizes in the orthorhombic
crystal system with the noncentrosymmetric space group
P212121 having two molecules (blue-green) in the asymmetric
unit (Figure 1i), which are primarily held by an alternating
combination of highly directional N1−H1···O2C22 and
blue in Figure 3d) bridge the stacked molecular layers via an R21
(6) bifurcated N1/C8−H1/H8···O2 hydrogen bond synthon
and O2−H2···O1C hydrogen bonds (Figure S3a). Form II
crystallizes in the monoclinic crystal system with centrosym-
metric space group C2/c having one molecule (magenta) in the
asymmetric unit (Z′ = 1) (Figure 1h). The molecules are
primarily held by N1−H1···O1 hydrogen bonds along the b axis
(red belts, Figure 3e), while the oppositely tilted orientation of
both phenyl rings (3ADB3 (form II) in Table 1) allows alternate
bifurcated N2/C23−H2A/H23···O1C7 R21(6) hydrogen
bond synthons down the a axis through the 21 screw axis (red
bands in Figure 3f and Figure S3c). Interestingly here also, the 3-
fluorobenzene rings on the vinyl end of both symmetry-
independent molecules experience orientational disorder (sof of
F2A = 0.890(3), sof of F2B = 0.110(3), sof of F4A = 0.890(3),
sof of F4B = 0.110(3)), which promotes the propagation of
molecules along the c axis and occurs via 21 screw axes facilitated
by C4−H4···F2A and bifurcated C20−H20···F2A/F4A inter-
actions (Figure S3c).
regions of R21(6) bifurcated C9/C11A−H9/H11A···F1 hydro-
gen bond synthons related by the 2-fold axis (green belts in
Figure 3e and Figure S3b) and C15A−H15A···C5(π)
interactions related by an inversion center (blue belts in Figure
3e and Figure S3b). The 3-fluorobenzene ring on the vinyl end
experiences orientational disorder (sof of F2A = 0.540(3), sof of
F2B = 0.460(3)), which assists in the propagation of molecules
along the a axis and is facilitated by C4−H4···F2A hydrogen
2.2.2. Thermal and PXRD Analyses. DSC experiments have
revealed that the polymorphs of 3ADB3 have quite divergent
thermal stabilities; these have been justified from an analysis of
their energy frameworks (Figure 3b). The DSC thermogram of
4167
https://doi.org/10.1021/acs.cgd.1c00422
Cryst. Growth Des. 2021, 21, 4162−4177

Crystal Growth & Design
pubs.acs.org/crystal
Article
form I shows the expulsion of solvent isopropyl alcohol
molecules from its crystal lattice by a small endothermic peak
at 102 °C (ΔH = −21.1 J/g), followed by its melting indicated
by a sharp endothermic peak at 112 °C (ΔH = −69.7 J/g)
(orange line in Figure 3b). The DSC profile of form II exhibits a
comparatively higher melting point with an endothermic peak at
117 °C (ΔH = −72.3 J/g) (magenta line in Figure 3b), while
form III displays the highest thermal stability with a melting peak
at 127 °C (ΔH = −68.4 J/g) (green line in Figure 3b). The
lowest thermal stability of form I can be explained by the lower
values of IEs in molecules connected by N−H···O (IE = −44.2
kJ/mol, Figure 3g) and O−H···O hydrogen bonds (−30.3 kJ/
mol, Figure 3g), which bind the guest isopropyl alcohol with the
host molecules; hence, it melts immediately after solvent
expulsion. In contrast, the higher thermal stability of form II is
due to dimers connected by relatively stronger N−H···O
hydrogen bonds represented by vertical tubes (IE = −54.5 kJ/
mol, Figure 3h). The highest thermal stability of form III can be
justified by dimers linked by the strongest N−H···O hydrogen
bonds represented by vertical tubes (IE = −61.3, −57.3 kJ/mol,
Figure 3i). A comparison of experimental PXRD patterns of the
3ADB3 bulk powder with the simulated PXRD patterns of its
polymorphs shows us that the bulk powder is representative of
its thermally most stable polymorph, form III (Figure 3c), which
has been validated from a profile fitting refinement, where only
form III yielded satisfactory results (Figure S9b).
2.3. Polymorphs of 4ADB2: Forms I and II. 2.3.1. Molec-
ular Packing. 4ADB2 crystallizes concomitantly in two
polymorphic forms, where form I has a plate morphology
(4ADB2 in Figure S1), and it crystallizes in the monoclinic
crystal system with the centrosymmetric space group C2/c
having one molecule in the asymmetric unit (Z′ = 1, Figure 1k).
The molecules are primarily held by N1−H1···O1C7
hydrogen bonds down the b axis (red belts in Figure 4h).
These molecular chains connected by N−H···O hydrogen
bonds in a view along the ac plane are found to be interlinked by
distinct alternate layers of C3−H3···F2, and C12−H12···F1
interactions (green layers in Figure S4a) and C15−H15···C5/
C6(π), C5−H5···C15(π), and C6−H6···C9(π) interactions
(blue belts in Figure S4a). This is promoted by severe twisting of
aromatic rings in opposite directions with respect to each other
(4ADB2 form I in Table 2). Form II has a needle- or rod-shaped
morphology (4ADB2 in Figure S1) and it crystallizes in the
monoclinic crystal system with the centrosymmetric space
group P21/c having one molecule in the asymmetric unit (Z′ = 1,
Figure 1l), where the molecules are primarily linked via
bifurcated N1/C8−H1/H8···O1C7 hydrogen bonds (red
belts, Figure 4i). Here also the aromatic rings are severely
twisted in the same direction with respect to the bridging amide
and vinyl group (4ADB2 form II in Table 2), and this
coplanarity in turn promotes alternate columns of π···π and
C3−H3···F2A interactions (demarcated by blue and green belts,
Figure 4i). Furthermore, the propagation of molecules along the
c axis is facilitated by C12A−H12A···F2A/F1 and C13A−
H13A···F1 interactions (Figure S4b). The crystal faces of both
concomitant forms were experimentally indexed (form I, Figure
4a; form II, Figure 4c), and then the crystal habits were
compared with their morphology prediction based on Bravais,63
Friedel,64 and Donnay and Harker65 (BFDH) theory (Figure
4b,d). The BFDH method is a rapid method to identify the
crystal morphology (hkl) that is most likely to form the crystal
habit. The morphology and face indexation reveal that (100),
(001), and (−101) are the major crystal faces of form I (Figure
4a), while (001) and (100) are the major crystal faces of form II
(Figure 4c), which matches exactly with the predicted BFDH
models.
2.3.2. Thermal and PXRD Analyses. The crystals of the two
concomitant forms of 4ADB2 (optical image of the concomitant
forms of 4ADB2 (form I + II) in Figure S1) were carefully
separated by determinations of their unit cells using SCXRD
experiments, and thereafter DSC experiments were performed
in order to evaluate their individual thermal stabilities. The first
and second heating−cooling cycles of form II (green and blue
lines, respectively, in Figure 4g) show the presence of smooth
endotherms with sharp melting peaks at 146 °C (ΔH = −99.0 J/
g for the first cycle, ΔH = −101.0 J/g for the second cycle). On
the other hand, the first heating−cooling cycle of form I (orange
line in Figure 4g) displays a smooth endotherm with a single-
crystal to single-crystal phase transition (SCSC-PT) occurring at
145 °C (ΔH = −22.6 J/g) immediately followed by its melting at
146 °C (ΔH = −111.0 J/g), which is the same as the melting
point of form II, while in its second heating−cooling cycle (pink
line in Figure 4g) the endotherm perfectly resembles that of
form II, thereby indicating conversion of form I to the
thermodynamically more stable form II. This indicates a
complete structural transition from form I to form II at 145
°C and also suggests a greater thermal stability of form II over
form I. An energy framework analysis shows that the dimers
connected by N−H···O hydrogen bonds in form I have a much
lower IE of −51.0 kJ/mol (form I in Figure 4j) in comparison to
the dimers in form II linked via N−H···O hydrogen bonds with
an IE of −58.2 kJ/mol (form II in Figure 4j). The molecular
pairs linked via C−H···F interactions in form I have an IE of
−12.8 kJ/mol (form I in Figure 4j), while the dimers in form II
connected by a pair of C−H···F interactions related by an
inversion center constitute a total IE of −23.1 kJ/mol (form II in
Figure 4j), which implies that both forms have C−H···F
interactions of almost similar strengths. Hence, energy frame-
works clearly demonstrate the presence of stronger N−H···O
hydrogen bonds in form II in comparison to form I, which makes
the former more stable than the latter and hence also explains
the irreversible SCSC-PT from the less stable polymorph form I
to the thermodynamically more stable polymorph form II. The
experimental PXRD patterns of the 4ADB2 bulk powder have
been compared with the simulated PXRD patterns of both
concomitant forms, and it has been found that the experimental
pattern closely matches the simulated pattern of form I (Figure
4f), which has also been verified from a profile fitting refinement
analysis, where only form I yielded satisfactory results after
refinement (Figure S9c).
2.4. Polymorphs of 4ADB4: Forms I and II. 2.4.1. Molec-
ular Packing. 4ADB4 crystallizes in two polymorphic forms,
both crystallizing in space group P21/c, having comparable unit
cell parameters and one molecule in the asymmetric unit (Z′ = 1,
form I in Figure 1n, form II in Figure 1o) differing in their 3D
packing arrangement. Interestingly, in spite of considerable
differences in the torsion angles of the molecules (Table 2,
4ADB4 forms I and II) and crystal packing in the lattice, the
packing differences are such that both polymorphic forms adopt
the same unit cell parameters. Hence, this constitutes a
prominent example of packing polymorphism. The crystal
structure of form I illustrates that the molecules are primarily
linked by N1−H1···O1C7 hydrogen bonds, and this H-
bonded arrangement is present in both modifications along the a
axis in form I and along the b axis in form II (red bands in Figure
5d,e). However, Forms I and II differ in the way in which this
4168
https://doi.org/10.1021/acs.cgd.1c00422
Cryst. Growth Des. 2021, 21, 4162−4177

Crystal Growth & Design
pubs.acs.org/crystal
Article
Figure 5. (a) Molecular overlay of two symmetry-independent molecules (one molecule each from form I and II of 4ADB4) at the solid-state
geometry. (b) DSC profiles for the two forms of 4ADB4 at 3 °C/min of a heating−cooling cycle. (c) Overlay of PXRD patterns of 4ADB4 bulk powder
and a comparison with the simulated patterns of their packing polymorphs. Crystal projections of (d) 4ADB4 (form I) and (e) 4ADB4 (form II) at 100
K. Energy frameworks for (f) form I and (g) form II of 4ADB4 representing the total interaction energies in kJ/mol.
common hydrogen bonded molecular chain is linked to its two
neighboring units along their respective c and a axes. In form I
the propagation of molecules along the c axis is favored by the
formation of R22(8) C12−H12···F2 synthons (green zone in
Figure 5d) and C3−H3···F2 interactions supported by C4−
F1···F2−C13 Type-I (θ1= θ2 = 92°) halogen−halogen contacts
(purple ovals in Figure 5d), while in form II the translation of
molecules along the a axis is promoted by C14−H14···F1 and
C5−H5···F2 interactions (green belts in Figure 5e).
2.4.2. Thermal and PXRD Analyses. The two polymorphs
were also examined by DSC, and the appearance of smooth
baselines and sharp endothermic peaks suggests the presence of
a single phase in the crystalline material (Figure 5b). The DSC
curve of form I exhibits a melting peak at 165 °C (ΔH = −111.2
J/g) (orange line in Figure 5b), whereas the melting point of
form II is observed at 159 °C (ΔH = −96.6 J/g) (magenta line in
Figure 5b). Since form I melts at a much higher temperature and
also exhibits a considerably higher enthalpy of fusion than form
II, we can conclude from the “heat of fusion rule”66 that the two
polymorphs are monotropically related. A further confirmation
that form I is the thermodynamically stable form over the entire
temperature range can be derived from the order of their
densities, i.e., form I > form II (Table S2), in accordance with the
“density rule”,67,68 since the two forms differ mainly in the crystal
packing of identical molecular units. An energy framework
analysis shows that the N−H···O hydrogen-bonded dimers in
form I have a much lower IE of −43.1 kJ/mol (red circle, Figure
5f) in comparison to form II, where the N−H···O hydrogen-
bonded dimers are connected by a relatively higher IE of −52.3
kJ/mol (red circle, Figure 5g). This appears to be in stark
contrast with the observations from DSC experiments, but the
cumulative effect of weak C−H···F (IE = −8.1, −7.9 kJ/mol,
Figure 5f) and type I F···F (IE = −6.0 kJ/mol, Figure 4f)
interactions in form I in comparison to the much weaker C−H···
F interactions in form II (IE = −5.2, −4.7 kJ/mol, Figure 5g)
might be the reason behind the higher thermal stability of form I.
This is a prime example of the important, cooperative, and
supporting role of weak noncovalent interactions such as C−
H···F and F···F alongside strong interactions such as N−H···O
in steering the thermodynamic stability of molecular crystals. A
comparison of the experimental powder pattern of the 4ADB4
bulk powder with the simulated powder patterns of the two
packing polymorphs indicates that the bulk powder is
representative of the more thermally stable form I (Figure 5c).
This has also been verified from the satisfactory PXRD profile
fitting refinement results obtained from only form I (Figure
S9d).
4169
https://doi.org/10.1021/acs.cgd.1c00422
Cryst. Growth Des. 2021, 21, 4162−4177

Crystal Growth & Design
pubs.acs.org/crystal
Article
Figure 6. Molecular arrangements of (a) 2ADB2 and (b) 2ADB3, both along the c axis. (c) 2D supramolecular constructs obtained an from XPac
analysis of 2ADB2−2ADB3.
2.5. Isostructural Analysis. To appreciate the role of
intermolecular interactions in the design of similar molecular
arrangements having equivalent structural motifs, we have
quantitatively assessed the crystal packing similarities of
unsubstituted N-phenylcinnamamide (ADB) with its difluoro-
substituted analogues using XPac 2.0.2.69−71 Two crystals
having the same structure, i.e. similar molecular orientations and
comparable arrangements in the lattice but not necessarily the
same unit cell dimensions or chemical compositions, are said to
exhibit isostructurality.72−74 The structural similarities between
two isostructural compounds can be expressed in terms of 1D
molecular chains (a similar row of molecules), 2D molecular
layers (a similar layer of molecules), or 3D supramolecular
constructs (exactly similar arrangement or isostructural), while
two crystals with the same space groups and identical unit cell
dimensions are described as isomorphous.75,76 It has been
generally observed that isomorphous structures exhibit 3D
isostructurality.74 The extent to which two crystal structures
deviate from perfect geometrical similarity is measured in terms
of the “dissimilarity index (X)”, where lower values of X are an
indication of a better structural match. From our analysis it has
been observed that some structures display 3D crystal packing
similarity while others are related to each other via 2D packing
similarity.
the orientation of the o-fluoro-substituted benzene ring (C1 >
C6) in 2ADB3 (rotation anticlockwise by 34.35(6)° from the
vertical position). Similarly, the orientation of the second o-
fluoro-substituted benzene ring (C10 > C15) of 2ADB2
(rotation clockwise by 150.23(3)° or anticlockwise by 29.77°
from the vertical position) is also opposite with respect to the
orientation of the p-fluoro-substituted benzene ring (C10A >
C15A) of 2ADB3 (rotation clockwise by 21.37(7)° from the
vertical position). A crystal structure analysis of 2ADB2 shows
that the molecules are primarily assembled via the formation of
R21(6) N1/C8−H1/H8···O1C7 hydrogen bond synthons
supported by C2(π)···C5(π) and C11(π)···C14(π) interactions
along the a axis having an IE of −55.9 kJ/mol, while their
propagation along the c axis is promoted by C3−H3···F2
interactions with an IE of −7.5 kJ/mol (Figure 6a and Table S4).
On the other hand, in the case of 2ADB3 the propagation of
molecules along the a axis is facilitated by N1−H1···O1
hydrogen bonds supported by C12A(π)···C15A(π) interactions
having an IE of −51.7 kJ/mol, while their spread along the c axis
is promoted via C4−H4···C14A(π) interactions having an IE of
−4.1 kJ/mol (Figure 6b and Table S4). Thus, a direct
comparison of crystal packing patterns of 2ADB2−2ADB3
reveals similarity along the a and c crystallographic axes, and
both virtually resemble the twisted-ribbon-like geometry. An
XPac analysis of 2ADB2−2ADB3 reveals the presence of a 2D
supramolecular construct (SC) with a dissimilarity index value
of 6.8 (Figure 6c).
2.5.1. Comparison of 2ADB2 and 2ADB3. The single-crystal
X-ray diffraction study reveals that both 2ADB2 and 2ADB3
crystallize in the monoclinic noncentrosymmetric space group
Pn (Z = 2 for 2ADB2, Z = 4 for 2ADB3). Between these two
structures, two crystallographic parameters (a and c) are similar,
and the third (b axis) is just twice as large as the others (2ADB2)
(Table S2). The orientation of one of the 2-fluoro-substituted
benzene rings (C1 > C6) in 2ADB2 (rotation clockwise by
39.81(4)° from the vertical position) is opposite with respect to
2.5.2. Comparison of 2ADB2 and 2ADB4 (Form II). The
single-crystal X-ray data of 2ADB2 and 2ADB4 (form II) show
that, despite having crystallized in the different noncentrosym-
metric monoclinic space groups P21 and Pn, respectively, these
two compounds have almost the same unit cell parameters
(Table S2). A further comparison of their torsion angles also
4170
https://doi.org/10.1021/acs.cgd.1c00422
Cryst. Growth Des. 2021, 21, 4162−4177

Crystal Growth & Design
pubs.acs.org/crystal
Article
Figure 7. Molecular arrangements of (a) 2ADB2 and (b) 2ADB4 (form II). (c) 2D supramolecular constructs obtained from an XPac analysis of
2ADB2−2ADB4 (form II).
interestingly reveals that the orientation of one of the 2-fluoro-
substituted benzene rings in 2ADB2 (C1 > C6) (rotation
clockwise by 39.81(4)°) is the same as the orientation of the o-
fluoro-substituted benzene ring in 2ADB4 (form II) (C1 > C6)
(rotation clockwise by 39.13(3)°) (Table 1). Similarly, the
orientation of the other 2-fluoro-substituted benzene ring in
2ADB2 (C10 > C15) (rotation clockwise by 150.22(3)°) is
analogous to the orientation of the p-fluoro-substituted benzene
ring in 2ADB4 (form II) (C10 > C15) (rotation clockwise by
152.26(3)°( (Table 1). A crystal packing analysis of both
compounds interestingly reveals that the molecules share exactly
S4). A top view of the structure of 3ADB2 along the ac plane
reveals that the molecules are packed in a criss-cross fashion
interlinked via C13−H13···F2 interactions down the b axis
(Figure S6b). A structural analysis of 3ADB4 shows that
propagation of molecules along the b axis is primarily facilitated
by the formation of an R21(6) N1/C8−H1/H8···O1C8
hydrogen bond synthon supported by R21(6) C11/C12−H11/
H12···F1 interactions with an IE of −56.9 kJ/mol, while C12−
H12···C14(π) interactions link them with an IE of −10.1 kJ/mol
along the a axis (Figure S6c and Table S4). The crystal packing
of 3ADB4 in a view along the ac plane reveals that the molecules
have assembled in a criss-cross molecular architecture held
together by C12−H12···C14(π) interactions (Figure S5d).
Hence the overall crystal packing arrangements of 3ADB2 and
3ADB4 are also quite similar. An XPac analysis shows the
presence of a 3D supramolecular construct with a dissimilarity
index of 5.3 (Figure 8a).
2.5.4. Comparison of 3ADB3 (Form II) and 4ADB2 (Form I).
Single-crystal data reveal that 3ADB3 (form II) and 4ADB2
(form I) have crystallized in the same monoclinic centrosym-
metric space group C2/c, having very similar unit cell parameters
with Z = 8 (Table S2). Hence the crystal structures 3ADB3
(form II)−4ADB2 (form I) can be classified as isomorphous.
The orientation of one of the 3-fluorobenzene rings (C1 > C6)
in 3ADB3 (form II) (rotation anticlockwise by −41.50(2)°)
(Table 1) is similar to that of the 4-fluorobenzene ring (C1 >
C6) in 4ADB2 (form I) (rotation anticlockwise by
−41.38(13)°) (Table 2). Similarly, the orientation of the
other 3-fluorobenzene ring (C10 > C15) in 3ADB3 (form II)
(rotation clockwise by 161.79(6)°) (Table 1) is comparable to
that of the 2-fluoro-substituted benzene ring (C10 > C15) in
4ADB2 (form I) (rotation clockwise by 160.39(13)°) (Table 2).
Hence, a comparison of the torsion angles of these two
polymorphs shows the presence of similar molecular con-
formations. A crystal structure analysis of both 3ADB3 (form II)
and 4ADB2 (form I) shows that the molecules are primarily held
the same connectivity of R21(6) N1/C8−H1/H8···O1C7
hydrogen bond synthons supported by C2(π)···C5(π) and
C11(π)···C14(π) interactions along the a axis held by nearly
equal IEs of −55.9 and −56.0 kJ/mol in 2ADB2 and 2ADB4
(form II), respectively (Figure 7a,b and Table S4). Furthermore,
the molecules of both compounds are assembled in similar 1D
molecular chains promoted via C5−H5···F1 and C14−H14···F2
interactions in 2ADB2 having an IE of −19.1 kJ/mol (Figure 7a
and Table S4) and via C5−H5···F1 interactions and H12···H15
contacts in 2ADB4 (form II) having a similar IE of −19.9 kJ/mol
(Figure 7b and Table S4). Therefore, a detailed comparison of
the crystal packing of 2ADB2−2ADB4 (form II) reveals that
these share closely related 2D-packing motifs, and an XPac
analysis exhibits very close 2D crystal packing similarity with a
very low dissimilarity index value of 2.7 (Figure 7c).
2.5.3. Comparison of 3ADB2 and 3ADB4. The crystal
structures of 3ADB2 and 3ADB4 are isomorphous; both
compounds have crystallized in the same space group Pbca
and possess similar unit cell parameters with Z = 8 (Table S2). A
crystal structure analysis of 3ADB2 shows that the molecules are
primarily held via the formation of an R21(6) N1/C8−H1/H8···
O1C8 hydrogen bond synthon supported by R21(6) C14/
C15−H14/H15···F1 synthons along the b axis having an IE of
−54.9 kJ/mol, while C13−H13···F2 interactions connect them
with an IE of −9.4 kJ/mol along the a axis (Figure S6a and Table
4171
https://doi.org/10.1021/acs.cgd.1c00422
Cryst. Growth Des. 2021, 21, 4162−4177

Crystal Growth & Design
pubs.acs.org/crystal
Article
Figure 8. 3D supramolecular constructs obtained from an XPac analysis of (a) 3ADB2−3ADB4, (b) 3ADB3 (form II)−4ADB2 (form I), and (c)
4ADB3−4ADB4 (form I).
by N1−H1···O1 hydrogen bonds supported by π···π inter-
actions along the b axis (Figures 3e and 4h) having comparable
IEs of −54.5 and −51.0 kJ/mol, respectively (Table S4). The
highly tilted orientation of the phenyl rings in both of the
polymorphic forms facilitates alternate regions of C−H···F and
C−H···π interactions along the bc plane (Figures S3b and S4a).
In the case of 3ADB3 (form II), the molecules held by C−H···F
interactions have an IE of −14.7 kJ/mol, while molecules held
together by C−H···π interactions have IEs of −33.1 and −30.6
kJ/mol (Table S4). On the other hand, in the case of 4ADB2
(form I), molecules held by C−H···F interactions possess IEs of
−6.0 and −12.8 kJ/mol, while dimers held by C−H···π
interactions have IEs of −40.8 and −36.5 kJ/mol (Table S4).
Thus, a detailed comparison of the crystal packing of 3ADB3
(form II) with that of 4ADB2 (form I) shows that the
polymorphs share similar packing patterns along all three
crystallographic axes. An XPac analysis reveals the presence of a
3D supramolecular construct with a dissimilarity index of 5.1
(Figure 8b).
both compounds have crystallized in the centrosymmetric
monoclinic space group P21/c with nearly the same unit cell
parameters with Z = 4 (Table S2), suggesting that these two
crystal structures are isomorphous. With respect to torsion
angles, it was found that the orientation of one of the 4-fluoro-
substituted benzene rings (C1 > C6) in 4ADB3 (rotation
anticlockwise by −155.67(12)°) is similar to the orientation of
the p-fluoro-substituted benzene ring (C1 > C6) in 4ADB4
(form I) (rotation anticlockwise by −161.59(12)°). Similarly,
the orientation of the 3-fluoro-substituted benzene ring (C10 >
C15) in 4ADB3 (rotation clockwise by 168.87(12)°) is also
comparable with the orientation of the other p-fluoro-
substituted benzene ring (C10 > C15) in 4ADB4 (form I)
(rotation clockwise by 170.51(13)°) (Table 2). Hence, both
compounds display similar molecular conformations. A
comparison of their crystal structures reveals that molecules in
both compounds are primarily held by N1−H1···O1 hydrogen
bonds along the a axis having IEs of −46.5 and −43.1 kJ/mol in
4ADB3 and 4ADB4 (form I), respectively (Table S4). The
propagation of molecules along the c axis is promoted via the
2.5.5. Comparison of 4ADB3 and 4ADB4 (Form I). The
single-crystal data of 4ADB3 and 4ADB4 (form I) show that
4172
https://doi.org/10.1021/acs.cgd.1c00422
Cryst. Growth Des. 2021, 21, 4162−4177

Crystal Growth & Design
pubs.acs.org/crystal
Article
Figure 9. Lattice energy versus density plot for top 100 predicted structures on the basis of lattice energies, in various space groups of the parent
unsubstituted compound ADB, with the identification of predicted structures analogous to the experimentally obtained crystal structures along their
lowest energy rank.
Table 3. Classification of Experimental Crystal Structures of Difluoro-Substituted ADB Molecules within the Top 100 Predicted
Structures in the CSP Landscape of ADB
unit cell type
space group
group
rank
13th
predicted
exptl
compound
2ADB2
exptl
Pn
predicted
group 1
24−5−23
5−5−24
Pc
5−11−22
5−5−23
2ADB3
Pn
P21
2ADB4 (form II)
4ADB2 (form II)
3ADB2
3ADB3 (form III)
3ADB4
group 2
group 3
24th
55th
10−5−25
11−9−22
10−5−24
12−10−22
10−10−26
12−9−21
30−5−16
30−5−16
P21/c
Pbca
P212121
Pbca
C2/c
C2/c
P21/c
Pbca
group 4
81st
30−5−16
3ADB3 (form II)
4ADB2 (form I)
C2/c
formation of similar R22(8) C13−H13···F2 interactions in
detailed comparison of the crystal packing patterns of 4ADB3
with 4ADB4 (form I) reflects their isostructural behavior. An
XPac analysis further reveals the presence of a 3D supra-
molecular construct with a dissimilarity index of 4.6 (Figure 8c).
2.6. Crystal Structure Prediction (CSP). In this study, the
occurrence of different packing motifs in the crystal structures of
synthesized difluoro-substituted ADB molecules was examined
by generating the crystal structure landscape (CSL) of the
unsubstituted ADB molecule (see the ORTEP drawing of ADB
in Figure 9). The CSL of the given compound has been
generated on account of the variations in molecular con-
formation and molecular self-assembly for different packing
motifs during the crystallization process. For this purpose, the
crystal geometry of ADB was optimized by the dispersion
correction method in conjunction with assignment of electro-
4ADB3 (IE = 9.1 kJ/mol) and R22(8) C12−H12···F2
interactions in 4ADB4 (form I) (IE = −7.9 kJ/mol) on one
end of the molecule and via the formation of F1(lp)···C13(π)
interactions in 4ADB3 (IE = −5.6 kJ/mol) and a type I F1···F2
halogen−halogen contact in 4ADB4 (form I) (IE = −6.0 kJ/
mol) on the other end leading to the formation of almost
identical 1-D molecular chains (Figure 5d and Figure S7a). The
view along the bc plane reveals that molecules have assembled in
a double-herringbone fashion with the molecular dimers related
by inversion centers along the c axis. These dimers are connected
via C11−H11···O1 hydrogen bonds supported by C3−H3···F2
interactions in 4ADB3 (IE = −34.5 kJ/mol) (Figure S5a), while
those in 4ADB4 (form I) are connected via only C11−H11···O1
hydrogen bonds (IE = −26.5 kJ/mol) (Figure S7b). Therefore, a
4173
https://doi.org/10.1021/acs.cgd.1c00422
Cryst. Growth Des. 2021, 21, 4162−4177

Crystal Growth & Design
pubs.acs.org/crystal
Article
Figure 10. Supramolecular predicted structures of ADB bearing resemblance with the experimentally obtained crystal structures of difluoro-
substituted ADB molecules with their lowest energy ranks: (a) rank 13, (b) rank 24, (c) rank 55, (d, e) rank 81.
static surface potential (ESP) charges on all the atoms, which
serves as the starting point for structure prediction. The
calculations were performed using the DMol3 module followed
by Polymorph Prediction utilizing the COMPASS27 force field
incorporated in the Materials Studio 6.1 program package. We
have chosen the default setup entitled “Fine Quality” for
packing, geometry optimization, and clustering. The calculation
for structure prediction was limited to 7 experimentally observed
experimentally determined crystal packing motif of 4ADB2
(form II). The predicted structure in a view down the N/C−H···
OC hydrogen bonds displays a parallel-displaced layered
molecular stacking arrangement (Figure 10b) very similar to the
layered assembly of molecules in the crystal packing of 4ADB2
(form II) (Figure S10d). The experimentally obtained crystal
systems having orthorhombic space groups, namely 3ADB2,
3ADB3 (form III), and 3ADB4, have been collectively labeled as
group 3 and are ranked 55th in the CSL landscape of ADB (see
group 3, rank 55 in Figure 9). The molecules in this predicted
̅
space groups (P1, P21, Pc, P21/c, C2/c, P212121, and Pbca), while
only the top 100 energy-minimized predicted structures were
chosen among more than 5000 generated structures for analysis
with respect to high density, as shown in the lattice energy vs
crystal density plot in Figure 9.
structure are primarily held by R21(6) N/C−H···OC hydro-
gen bond synthons. A top view down these N−H···OC
hydrogen-bonded chains reveals a unique criss-cross molecular
assembly (Figure 10c) that is perfectly commensurate with the
criss-cross molecular architectures of 3ADB2 (Figure S6b),
3ADB3 (form III), and 3ADB4 (Figure S6d). The exper-
imentally obtained crystal systems with monoclinic space group
C2/c, namely 3ADB3 (form II) and 4ADB2 (form I), have been
labeled as group 4 and have been ranked 81st in the energy
landscape. The molecules in this predicted structure are held via
N−H···O hydrogen bonds supported by π···π interactions (see
group 4, rank 81 in Figure 9), and this pattern manifests itself in
the crystal packing of 3ADB3 (form II) (Figure S10e) and
4ADB2 (form I) (Figure S10f). The two benzene rings of ADB
in this rank are oppositely oriented and have assembled in a
columnar fashion via N−H···O hydrogen bonds (Figure 10d),
which closely corresponds with the columnar assembly in
3ADB3 (form II) (Figure 3e) and 4ADB2 (form I) (Figure 4h).
Moreover, the crystal structure of ADB in this rank displays a
brick-layered packing (Figure 10e) in a view from above the N−
H···O hydrogen bond columns; this pattern bears close
resemblance with the brick-layered molecular assembly in
3ADB3 (form II) (Figure S3b) and 4ADB2 (form I) (Figure
S4a). Hence, we have been able to identify the occurrence of
only 9 out of a total of 15 experimentally obtained difluoro-
substituted ADB crystals in the low-energy ranks of the
computed energy landscape (see Table 3) with the complete
absence of the remaining 6 unit cells in the predicted structures.
Interestingly it has been observed that the crystal structure
In our current CSP analysis, the analysis of the crystal
landscape has been carried out by classifying the experimentally
obtained crystal structures of difluoro-substituted ADB
molecules into groups on the basis of preferences of their
molecular orientations, packing motifs, and global interaction
topologies, irrespective of their unit cell parameters (Table 3).
The CSP results show that the 13th rank (−190.7 kJ/mol)
among the predicted structures with space group Pc has a
molecular packing pattern very similar to the experimentally
obtained crystal structures of 2ADB2, 2ADB3, and 2ADB4
(form II), which have been collectively labeled as Group 1. The
molecules in the predicted structure are assembled in a twisted-
ribbon-like architecture held by R21(6) N/C−H···OC hydro-
gen bond synthons (see group 1, rank 13th in Figure 9), which
bears close resemblance to the twisted-ribbon-like self-assembly
of 2ADB2 (Figure 6a), 2ADB3 (Figure 6b), and 2ADB4 (form
II) (Figure S2b). The predicted structure in a view down the N/
C−H···OC hydrogen bonds displays a wavelike herringbone
architecture (Figure 10a), which also closely matches the
herringbone crystal packing in 2ADB2 (Figure S10a), 2ADB3
(Figure S10b), and 2ADB4 (form II) (Figure S10c). The 24th
rank in the predicted structure with space group P21/c has a
linear twisted-ribbon-like molecular packing arrangement held
by R21(6) N/C−H/H···OC hydrogen bond synthons (see
group 2, rank 24th in Figure 9), which is similar to the
4174
https://doi.org/10.1021/acs.cgd.1c00422
Cryst. Growth Des. 2021, 21, 4162−4177

Crystal Growth & Design
pubs.acs.org/crystal
Article
similar to 4ADB2 (form II) (24th rank) is more stable than the
structure similar to 4ADB2 (form I) (81st rank), which perfectly
concurs with our experimental findings, where it was observed
that 4ADB2 (form I) experiences a SCSC phase transition to its
more stable form 4ADB2 (form II) (see Figure 4g). 3ADB3
(form I) is a solvatomorph, and hence its crystal-packing motif is
absent from this computed landscape, but the crystal packing
arrangements of the other two polymorphs 3ADB3 (form II)
(81st rank) and 3ADB3 (form III) (55th rank) were identified in
the landscape. The order of their lattice energies perfectly
coincides with the thermal stabilities of both forms, where it was
observed that 3ADB3 (form II) displayed a much lower melting
point (117 °C) in comparison to 3ADB3 (form III) (127 °C)
(see Figure 3b). These results suggest that, although a few
packing motifs could not be identified in the top 100 predicted
structures, CSP nevertheless has been able to correctly predict
the order of stabilities of the few polymorphs whose structures
were identified in the energy landscape.
Experimental details, including details of crystallization
screening, images of crystal morphologies, description of
SCXRD data collection and structure refinements,
additional images of molecular packing, DSC traces,
refinement of PXRD patterns, details of interaction
energy frameworks, and results from CSP calculations
(PDF)
Accession Codes
CCDC 1834349−1834358, 2075169, 2075171, 2075173, and
2075175−2075177 contain the supplementary crystallographic
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 Authors
■
Rohit Bhowal − Crystallography and Crystal Chemistry
Laboratory, Department of Chemistry, Indian Institute of
Science Education and Research Bhopal, Bhopal 462066,
Madhya Pradesh, India; Email: rohitbh@iiserb.ac.in
Deepak Chopra − Crystallography and Crystal Chemistry
Laboratory, Department of Chemistry, Indian Institute of
Science Education and Research Bhopal, Bhopal 462066,
Madhya Pradesh, India; orcid.org/0000-0002-0018-
6007; Email: dchopra@iiserb.ac.in
3. SUMMARY
In conclusion, the role of weak intermolecular interactions in a
family of unsubstituted and difluoro-substituted N-phenyl-
cinnamamides (ADB) (total of 10 molecules, See Scheme 1)
has been quantitatively analyzed by simply changing the position
of the fluorine atoms from ortho to meta to para in different
isomeric molecules and via isolation of their different
polymorphic forms by employing an extensive crystallization
strategy. Interestingly, four difluorinated derivatives of ADB
have been found to exhibit polymorphic behavior with distinct
thermal properties. The structural and energetic origins of
molecular associations in this class of molecules have been
investigated in detail, and it has been found that this unique
structural fragment is highly polymorphic in nature and hence
can be termed as a polymorphophore. The crystal structures of
these molecules have been analyzed in terms of their molecular
packing motifs, which exhibit isomorphism and isostructurality
in the solid state. The molecules have been found to exploit the
most energetically favored intermolecular N−H···OC chain
hydrogen bond synthons to build their supramolecular
assemblies, each in a different fashion to accommodate the
weaker secondary C−H···F, C−H···π, π···π, and in one case type
II C−F···F−C contacts. The cooperative interplay among these
various intermolecular interactions (strong and weak) and the
flexibilities associated with them are instrumental in the local
variations of different structural types, which enhances the
possibilities of their polymorphic outcomes. CSP calculations
have been performed on the solid-state structure of the highly
flexible unsubstituted ADB molecule, aiming to explore the large
number of possible structures for its difluorinated derivatives,
among which the experimental polymorphs were likely to be
found. Herein, the top 100 predicted structures on the basis of
their lattice energies were selected for a direct comparison of
their packing motifs with the experimentally realized crystal
structures. The results from CSP analysis demonstrate the
successful prediction of most of the experimental structures in
the computed energy landscape, which also represents an
advancement in CSP methodology.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.cgd.1c00422
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
R.B. acknowledges IISERB for research fellowship. We thank
IISER Bhopal for research facilities and infrastructure.
■
REFERENCES
■
(1) Gouverneur, V.; Seppelt, K. Introduction: Fluorine Chemistry.
Chem. Rev. 2015, 115, 563−565.
(2) Ojima, I. Exploration of Fluorine Chemistry at the Multi-
disciplinary Interface of Chemistry and Biology. J. Org. Chem. 2013, 78,
6358−6383.
(3) Berger, R.; Resnati, G.; Metrangolo, P.; Weberd, E.; Hulliger, J.
Organic fluorine compounds: a great opportunity for enhanced
materials properties. Chem. Soc. Rev. 2011, 40, 3496−3508.
(4) Meanwell, N. A. Fluorine and Fluorinated Motifs in the Design
and Application of Bioisosteres for Drug Design. J. Med. Chem. 2018,
61, 5822−5880.
(5) Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell,
N. A. Applications of Fluorine in Medicinal Chemistry. J. Med. Chem.
2015, 58, 8315−8359.
(6) Harsanyi, A.; Sandford, G. Organofluorine chemistry: applica-
tions, sources and sustainability. Green Chem. 2015, 17, 2081−2086.
(7) Xing, L.; Blakemore, D. C.; Narayanan, A.; Unwalla, R.; Lovering,
F.; Denny, R. A.; Zhou, H.; Bunnage, M. E. Fluorine in Drug Design: A
Case Study with Fluoroanisoles. ChemMedChem 2015, 10, 715−726.
(8) Han, J.; Remete, A. M.; Dobson, L. S.; Kiss, L.; Izawa, K.;
Moriwaki, H.; Soloshonok, V. A.; O’Hagan, D. Next generation
organofluorine containing blockbuster drugs. J. Fluorine Chem. 2020,
239, 109639.
ASSOCIATED CONTENT
■
sı
* Supporting Information
(9) Mei, H.; Han, J.; Fustero, S.; Medio-Simon, M.; Sedgwick, D. M.;
Santi, C.; Ruzziconi, R.; Soloshonok, V. A. Fluorine-Containing Drugs
Approved by the FDA in 2018. Chem. - Eur. J. 2019, 25, 11797−11819.
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.cgd.1c00422.
4175
https://doi.org/10.1021/acs.cgd.1c00422
Cryst. Growth Des. 2021, 21, 4162−4177

Crystal Growth & Design
pubs.acs.org/crystal
Article
(10) O’Hagan, D. Fluorine in health care: Organofluorine containing
blockbuster drugs. J. Fluorine Chem. 2010, 131, 1071−1081.
(31) Tang, W.; Sima, A. D.; Gong, J.; Wang, J.; Li, T. Kinetic
Difference between Concomitant Polymorphism and Solvent-Medi-
ated Phase Transformation: A Case of Tolfenamic Acid. Cryst. Growth
Des. 2020, 20, 1779−1788.
(32) Park, Y.; Boerrigter, S. X. M.; Yeon, J.; Lee, S. H.; Kang, S. K.; Lee,
E. H. New Metastable Packing Polymorph of Donepezil Grown on
Stable Polymorph Substrates. Cryst. Growth Des. 2016, 16, 2552−2560.
(33) Kasuga, N. C.; Saito, Y.; Satob, H.; Yamaguchi, K. Packing
polymorphism in the crystal structure of 4,5-dimethoxy-2-nitrobenzyl
acetate. Acta Crystallogr. 2015, 71, 483−486.
(34) Purdum, G. E.; Telesz, N. G.; Jarolimek, K.; Ryno, S. M.; Gessner,
T.; Davy, N. C.; Petty, A. J.; Zhen, Y.; Shu, Y.; Facchetti, A.; Collis, G.
E.; Hu, W.; Wu, C.; Anthony, J. E.; Weitz, R. T.; Risko, C.; Loo, Y.-L.
Presence of Short Intermolecular Contacts Screens for Kinetic Stability
in Packing Polymorphs. J. Am. Chem. Soc. 2018, 140, 7519−7525.
(35) Rai, S. K.; Gunnam, A.; Mannava, M. K. C.; Nangia, A. K.
Improving the Dissolution Rate of the Anticancer Drug Dabrafenib.
Cryst. Growth Des. 2020, 20, 1035−1046.
(36) Skieneh, J. M.; Sathisaran, I.; Dalvi, S. V.; Rohani, S. Co-
amorphous Form of Curcumin−Folic Acid Dihydrate with Increased
Dissolution Rate. Cryst. Growth Des. 2017, 17, 6273−6280.
(37) Nicoud, L.; Licordari, F.; Myerson, A. S. Estimation of the
Solubility of Metastable Polymorphs: A Critical Review. Cryst. Growth
Des. 2018, 18, 7228−7237.
(38) Hu, S.; Mishra, M. K.; Sun, C. C. Twistable Pharmaceutical
Crystal Exhibiting Exceptional Plasticity and Tabletability. Chem.
Mater. 2019, 31, 3818−3822.
(39) Chen, H.; Wang, C.; Sun, C. C. Profoundly Improved Plasticity
and Tabletability of Griseofulvin by in Situ Solvation and Desolvation
during Spherical Crystallization. Cryst. Growth Des. 2019, 19, 2350−
2357.
(11) Wang, J.; Sánchez-Roselló, M.; Acena, J. L.; del Pozo, C.;
̃
Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Fluorine in
Pharmaceutical Industry: Fluorine-Containing Drugs Introduced to the
Market in the Last Decade (2001−2011). Chem. Rev. 2014, 114, 2432−
2506.
(12) Inoue, M.; Sumii, Y.; Shibata, N. Contribution of Organofluorine
Compounds to Pharmaceuticals. ACS Omega 2020, 5, 10633−10640.
(13) Yoder, N. C.; Kumar, K. Fluorinated amino acids in protein
design and engineering. Chem. Soc. Rev. 2002, 31, 335−341.
(14) Berger, A. A.; Völler, J. S.; Budisa, N.; Koksch, B. Deciphering the
Fluorine Code−The Many Hats Fluorine Wears in a Protein
Environment. Acc. Chem. Res. 2017, 50, 2093−2103.
(15) Mei, H.; Han, J.; Klika, K. D.; Izawa, K.; Sato, T.; Meanwell, N.
A.; Soloshonok, V. A. Applications of fluorine-containing amino acids
for drug design. Eur. J. Med. Chem. 2020, 186, 111826.
(16) Cimarosti, Z.; Castagnoli, C.; Rossetti, M.; Scarati, M.; Day, C.;
Johnson, B.; Westerduin, P. Development of Drug Substances as
Mixture of Polymorphs: Studies to Control Form 3 in Casopitant
Mesylate. Org. Process Res. Dev. 2010, 14, 1337−1346.
(17) Marques, M. P. M.; Valero, R.; Parker, S. F.; Tomkinson, J.;
Batista de Carvalho, L. A. E. Polymorphism in Cisplatin Anticancer
Drug. J. Phys. Chem. B 2013, 117, 6421−6429.
(18) Park, Y.; Boerrigter, S. X. M.; Yeon, J.; Lee, S. H.; Kang, S. K.; Lee,
E. H. New Metastable Packing Polymorph of Donepezil Grown on
Stable Polymorph Substrates. Cryst. Growth Des. 2016, 16, 2552−2560.
(19) Blandizzi, C.; Viscomi, G. C.; Scarpignato, C. Impact of crystal
polymorphism on the systemic bioavailability of rifaximin, an antibiotic
acting locally in the gastrointestinal tract, in healthy volunteers. Drug
Des., Dev. Ther. 2014, 9, 1−11.
(20) Chemburkar, S. R.; Bauer, J.; Deming, K.; Spiwek, H.; Patel, K.;
Morris, J.; Henry, R.; Spanton, S.; Dziki, W.; Porter, W.; Quick, J.;
Bauer, P.; Donaubauer, J.; Narayanan, B. A.; Soldani, M.; Riley, D.;
McFarland, K. Dealing with the Impact of Ritonavir Polymorphs on the
Late Stages of Bulk Drug Process Development. Org. Process Res. Dev.
2000, 4, 413−417.
(21) Terada, S.; Katagiri, K.; Masu, H.; Danjo, H.; Sei, Y.; Kawahata,
M.; Tominaga, M.; Yamaguchi, K.; Azumaya, I. Polymorphism of
Aromatic Sulfonamides with Fluorine Groups. Cryst. Growth Des. 2012,
12, 2908−2916.
(40) Liu, G.; Xiong, Y.; Gou, R.; Zhang, C. Difference in the Thermal
Stability of Polymorphic Organic Crystals: A Comparative Study of the
Early Events of the Thermal Decay of 2,4,6,8,10,12-Hexanitro-
2,4,6,8,10,12-hexaazaisowurtzitane (CL-20) Polymorphs under the
Volume Constraint Condition. J. Phys. Chem. C 2019, 123, 16565−
16576.
(41) Nokhodchi, A.; Homayouni, A.; Araya, R.; Kaialy, W.; Obeidat,
W.; Asare-Addo, K. Crystal engineering of ibuprofen using starch
derivatives in crystallization medium to produce promising ibuprofen
with improved pharmaceutical performance. RSC Adv. 2015, 5, 46119−
46131.
(22) Cruz-Cabeza, A. J.; Reutzel-Edensb, S. M.; Bernstein, J. Facts and
fictions about polymorphism. Chem. Soc. Rev. 2015, 44, 8619−8635.
(23) Gentili, D.; Gazzano, M.; Melucci, M.; Jones, D.; Cavallini, M.
Polymorphism as an additional functionality of materials for
technological applications at surfaces and interfaces. Chem. Soc. Rev.
2019, 48, 2502−2517.
(42) Diniz, L. F.; Carvalho, P. S., Jr.; de Melo, C. C.; Ellena, J.
Reducing the Hygroscopicity of the Anti-Tuberculosis Drug (S,S)-
Ethambutol Using Multicomponent Crystal Forms. Cryst. Growth Des.
2017, 17, 2622−2630.
(43) Thakur, T. S.; Thakuria, R. Crystalline Multicomponent Solids:
An Alternative for Addressing the Hygroscopicity Issue in Pharma-
ceutical Materials. Cryst. Growth Des. 2020, 20, 6245−6265.
(44) Nelson, M. R.; Johnson, T.; Warren, L.; Hughes, A. R.; Chissoe,
S. L.; Xu, C.-F.; Waterworth, D. M. The genetics of drug efficacy:
opportunities and challenges. Nat. Rev. Genet. 2016, 17, 197−206.
(45) Suresh, K.; Nangia, A. Curcumin: pharmaceutical solids as a
platform to improve solubility and bioavailability. CrystEngComm 2018,
20, 3277−3296.
(24) Cruz-Cabeza, A. J.; Bernstein, J. Conformational Polymorphism.
Chem. Rev. 2014, 114, 2170−2191.
(25) McCrone, W. C. Polymorphism. In Physics and Chemistry of the
Organic Solid State; Fox, D., Labes, M. M., Weissberger, A., Eds.; Wiley
Interscience: New York, 1965; Vol. 2, pp 725−767.
(26) Nangia, A.; Desiraju, G. R. Pseudopolymorphism: occurrences of
hydrogen bonding organic solvents in molecular crystals. Chem.
Commun. 1999, 605−606.
(27) Chopra, D.; Guru Row, T. N. Solvatomorphism in 3-
Fluorobenzoylaminophenyl 3-Fluorobenzoate: A Subtle Interplay of
Strong Hydrogen Bonds and Weak Intermolecular Interactions
Involving Disordered Fluorine. Cryst. Growth Des. 2006, 6 (6),
1267−1270.
(46) Vo, A. H.; Van Vleet, T. R.; Gupta, R. R.; Liguori, M. J.; Rao, M. S.
An Overview of Machine Learning and Big Data for Drug Toxicity
Evaluation. Chem. Res. Toxicol. 2020, 33, 20−37.
(47) Dixit, V. A. A simple model to solve a complex drug toxicity
problem. Toxicol. Res. 2019, 8, 157−171.
(28) Dey, D.; Chopra, D. Solvatomorphism in (Z)-4-fluoro-N′-(3-
fluorophenyl)benzimidamide: the role of intermolecular O−H···F
interaction. CrystEngComm 2016, 18, 8291−8300.
(29) Bernstein, J.; Davey, R. J.; Henck, J. O. Concomitant
Polymorphs. Angew. Chem., Int. Ed. 1999, 38, 3440−3461.
(30) Ruggiero, M. T.; Zeitler, J. A.; Korter, T. M. Concomitant
polymorphism and the martensitic-like transformation of an organic
crystal. Phys. Chem. Chem. Phys. 2017, 19, 28502−28506.
(48) von Liebig, J.; Wöhler, F. Unter suchengen uber das Radikal der
̈
̈
Benzosaure. Ann. Pharm. 1832, 3, 249−282.
(49) Panini, P.; Chopra, D. Experimental and Theoretical Character-
ization of Short H-Bonds with Organic Fluorine in Molecular Crystals.
Cryst. Growth Des. 2014, 14, 3155−3168.
(50) Mondal, P. K.; Yadav, H. R.; Roy Choudhury, A.; Chopra, D.
Quantitative characterization of new supramolecular synthons
involving fluorine atoms in the crystal structures of di-and
4176
https://doi.org/10.1021/acs.cgd.1c00422
Cryst. Growth Des. 2021, 21, 4162−4177

Crystal Growth & Design
pubs.acs.org/crystal
Article
tetrafluorinated benzamides. Acta Crystallogr., Sect. B: Struct. Sci., Cryst.
Eng. Mater. 2017, 73, 805−819.
(75) Esteves de Castro, R. A.; Canotilho, J.; Barbosa, R. M.; Silva, M.
R.; Beja, A. M.; Paixao, J. A.; Redinha, J. S. Conformational
Isomorphism of Organic Crystals: Racemic and Homochiral Atenolol.
Cryst. Growth Des. 2007, 7, 496−500.
(76) Nath, K. N.; Nangia, A. Isomorphous Crystals by Chloro−
Methyl Exchange in Polymorphic Fuchsones. Cryst. Growth Des. 2012,
12, 5411−5425.
(51) Bhandary, S.; Gonde, S.; Chopra, D. Dissecting the Conforma-
tional and Interaction Topological Landscape of N-ethynylphenylben-
zamide by the Device of Polymorphic Diversity. Cryst. Growth Des.
2019, 19, 1072−1085.
(52) Groom, C. R.; Bruno, I. J.; Lightfoot, M. P.; Ward, S. C. The
Cambridge Structural Database. Acta Crystallogr., Sect. B: Struct. Sci.,
Cryst. Eng. Mater. 2016, B72, 171−179.
(53) Berger, R.; Resnati, G.; Metrangolo, P.; Weber, E.; Hulliger, J.
Organic fluorine compounds: a great opportunity for enhanced
materials properties. Chem. Soc. Rev. 2011, 40, 3496−3508.
(54) Chopra, D.; Guru Row, T. N. Role of organic fluorine in crystal
engineering. CrystEngComm 2011, 13, 2175−2186.
(55) Chopra, D. Is Organic Fluorine Really “Not” Polarizable? Cryst.
Growth Des. 2012, 12, 541−546.
(56) Hathwar, V. R.; Chopra, D.; Panini, P.; Guru Row, T. N.
Revealing the Polarizability of Organic Fluorine in the Trifluoromethyl
Group: Implications in Supramolecular Chemistry. Cryst. Growth Des.
2014, 14, 5366−5369.
(57) Desiraju, G. R. Approaches to crystal structure landscape
exploration. Acta Crystallogr., Sect. B: Struct. Sci., Cryst. Eng. Mater. 2017,
73, 775−778.
(58) Price, S. L. Predicting crystal structures of organic compounds.
Chem. Soc. Rev. 2014, 43, 2098−2111.
(59) Thompson, H. P. G.; Day, G. M. Which conformations make
stable crystal structures? Mapping crystalline molecular geometries to
the conformational energy landscape. Chem. Sci. 2014, 5, 3173−3182.
(60) Dey, D.; Chopra, D. Evaluation of the Role of Isostructurality in
Fluorinated Phenyl Benzoates. Cryst. Growth Des. 2017, 17, 5117−
5128.
(61) Dey, D.; Chopra, D. Occurrence of 3D isostructurality in
fluorinated phenyl benzamidines. CrystEngComm 2017, 19, 47−63.
(62) Mondal, P. K.; Chopra, D. Crystal structure landscape of
conformationally flexible organo-fluorine compounds. CrystEngComm
2016, 18, 48−53.
(63) Bravais, A. Etudes Cristallographiques; Gauthier Villars: Paris,
1866.
(64) Friedel, G. Bravais Law Studies. Bull. Soc. Fr. Mineral. 1907, 30,
326−455.
(65) Donnay, J. D. H.; Harker, D. A new law of crystal morphology
extending the Law of Bravais. Am. Mineral. 1937, 22, 446−467.
(66) Bernstein, J. Polymorphism in Molecular Crystals, 2nd ed.; Oxford
University Press: Oxford, U.K., 2020.
(67) Kitaigorodskii, A. I. Organic Chemical Crystallography; Con-
sultants Bureau: New York, 1961.
(68) Nelyubina, Y. V.; Glukhov, I. V.; Antipin, M. Y.; Lyssenko, K. A.
Higher density does not mean higher stability” mystery of paracetamol
finally unraveled. Chem. Commun. 2010, 46, 3469−3471.
(69) Gelbrich, T.; Hursthouse, M. B. Systematic investigation of the
relationships between 25 crystal structures containing the carbamaze-
pine molecule or a close analogue: a case study of the XPac method.
CrystEngComm 2006, 8, 448−460.
(70) Gelbrich, T.; Hursthouse, M. B. A versatile procedure for the
identification, description and quantification of structural similarity in
molecular crystals. CrystEngComm 2005, 7, 324−336.
(71) Fabbiani, F. P. A.; Dittrich, B.; Florence, A. J.; Gelbrich, T.;
Hursthouse, M. B.; Kuhs, W. F.; Shankland, N.; Sowa, H. Crystal
structures with a challenge: high-pressure crystallisation of ciproflox-
acin sodium salts and their recovery to ambient pressure.
CrystEngComm 2009, 11, 1396−1406.
(72) Kalman, A.; Parkanyi, S.; Argay, G. Classification of the
isostructurality of organic molecules in the crystalline state. Acta
Crystallogr., Sect. B: Struct. Sci. 1993, B49, 1039−1049.
(73) Fabian, L.; Kalman, A. Isostructurality in one and two
dimensions: isostructurality of polymorphs. Acta Crystallogr., Sect. B:
Struct. Sci. 2004, B60, 547−558.
(74) Dey, D.; Chopra, D. Occurrence of 3D isostructurality in
fluorinated phenyl benzamidines. CrystEngComm 2017, 19, 47−63.
4177
https://doi.org/10.1021/acs.cgd.1c00422
Cryst. Growth Des. 2021, 21, 4162−4177