Polymorphism and conformerism in chalcones

Article abstract of DOI:10.1039/c5ce02591e

Herein two solid state phenomena have been observed in two chalcones. Firstly, polymorphism has been found in (E)-1-(2-aminophenyl)-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (1). This compound crystallizes with only one conformer rather than three in the

Full text of DOI:10.1039/c5ce02591e

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ARTICLE TYPE
Polymorphism and Conformerism in Chalcones
Rafael Rodrigues Ramos, Cameron Capeletti da Silva, Freddy Fernandes Guimarães and Felipe Terra
Martins*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
observed as the substitution pattern in aryl moieties of two
chalcone derivatives. First, polymorphism,11ꢀ13 the ability of a
compound to exist in more than one crystal structure, is reported
50 for (E)ꢀ1ꢀ(2ꢀaminophenyl)ꢀ3ꢀ(3,4,5ꢀtrimethoxyphenyl)propꢀ2ꢀenꢀ
1ꢀone (hereinafter compound 1, Figure 1). This compound has
crystallized here in the monoclinic space group P21/c as well as
in its antecedent crystal phase,14 even though its asymmetric unit
accommodates only one molecule rather than three ones as occurs
55 in the antecedent structure. In addition, similar conformations are
found in the two crystal forms, which exhibit a typical case of
packing polymorphism. Second, conformerism, the ability of a
compound to exist in more than one conformation into a crystal
structure, is reported for (E)ꢀ1ꢀ(3ꢀhydroxyphenyl)ꢀ3ꢀ(4ꢀ
60 nitrophenyl)propꢀ2ꢀenꢀ1ꢀone (hereinafter compound 2, Figure 1).
It has been synthesized previously,15 but its crystal structure has
not been elucidated thus far. There are three crystallographically
independent molecules in its centrosymmetric triclinic unit cell.
Two of them are similar in conformation, with a same planarity
65 feature and conformation into the chalcone openꢀchain. The third
molecule is twisted, with its phenyl ring at position 1 rotated by
ca. 60° relative to the 3ꢀphenylpropenone mean plane. Likewise,
its propenone conformation differs from that of the two other
planar molecules for a rotation of ca. 180° around the rotatable
Herein two solid state phenomena have been observed in two
chalcones. Firstly, polymorphism has been found in the (E)ꢀ1ꢀ
(2ꢀaminophenyl)ꢀ3ꢀ(3,4,5ꢀtrimethoxyphenyl)propꢀ2ꢀenꢀ1ꢀone
(1). This compound crystallizes with only one conformer
10 rather than three in the known reported structure. In the
polymorphs, the conformation of phenyl ring bonded to
carbonyl differs slightly. The intermolecular hydrogen
bonding from NH2 is the main interaction responsible for
polymorphism. Our polymorph is assembled only with weak
15 N—H●●●π interactions instead of strong N—H●●●O and
N—H●●●N ones observed in the known structure. DFT
calculations reveal that the three conformers of the known
polymorph deviate from the minimum energy conformation
which is adopted in our crystal form to compensate the
20 absence of strong intermolecular contacts. Second,
conformerism is reported for (E)ꢀ1ꢀ(3ꢀhydroxyphenyl)ꢀ3ꢀ(4ꢀ
nitrophenyl)propꢀ2ꢀenꢀ1ꢀone (2). Three crystallographically
independent molecules are found in the structure of 2: two of
them are similarly planar with an anti conformation around
25 the single bond between the carbonyl and α carbons while the
third one is twisted, with its phenyl ring bonded to carbonyl
rotated by ca. 60° besides presenting a syn conformation
around the corresponding
rotatable
bond. Both 70 bond within this openꢀchain. Furthermore, singleꢀmolecule
calculations using KohnꢀSham Density Functional Theory
(B3LYP) have helped us to understand the role of intermolecular
interactions in allowing multiple crystal structures of 1 and
variable conformations of 2.
conformational features are related to the crystal packing,
30 allowing for accommodation of twisted molecules onto the
layers made up of hydrogen bonded planar molecules.
Furthermore, our potential energy surfaces indicate that
planar and twisted conformations of phenyl ring bonded to
carbonyl are not compatible with syn and anti conformations
35 of chalcone skeleton.
75
Introduction
Chalcones are important natural compounds possessing a wide
range of bioactivities. They can be also synthetically obtained and
40 used as intermediates of analogues with improved
pharmacological profiles.1ꢀ7 Chalcone denomination indicates the
presence of a 1,3ꢀdiarylpropenone minimal framework, even
though the possibility of attaching substituents at their aromatic
rings is a recipe of getting new compounds of this class with
45 tuned biological properties.8ꢀ10
Fig. 1 Chemical representation of 1 and 2 with phenyl ring labeling
In this study, two interesting solid state behaviors have been
scheme.

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DOI: 10.1039/C5CE02591E
function (mixing Becke28 Slater exchange, LeeꢀYangꢀParr29
60 correlation functional, and exact exchange from Hartree–Fock
theory30). The diffuse Augmentated Polarization Consistent using
a valence doubleꢀζ polarizatoion quality (APC1)31 basis set,
Materials and methods
Synthesis and crystallization
optimized to DFT,
was employed in the calculations
5
Chalcone derivatives were synthesized according protocol
described previously in the literature.16 Briefly, a solution of
(DFT/B3LYP/APC1). The calculations were performed in
65 Methano cluster placed in the Laboratory of Theoretical and
Computational Chemistry at the Institute of Chemistry of the
Federal University of Goiás. The calculation of a single point on
the relaxed potential energy surface of the compound 1 was
parallelized into 6 cores in an AMD Phenom II X6 2.8 GHz
70 processor took about 5 days. Each point in the relaxed potential
curves of compound 2 took about 3 day with the jobs parallelized
into 4 cores in an Intel Core i7 2.8 GHz CPU.
3,4,5ꢀtrimethoxybenzaldehyde (392.4 mg,
2 mmol) and oꢀ
aminoacetophenone (270.5 mg, 2 mmol) was prepared in 8.0 mL
of ethanol. Next, an amount of 1.0 mL of 24% sodium hydroxide
10 in water at 10 oC was added to this solution. After stirring
overnight at room temperature, 10% HCl was added until pH 3.
The solid of 1 was filtered and recrystallized from another
isopropyl alcohol solution. After 7 days upon standing at room
temperature in the dark, blockꢀshaped single crystals of 1 in its
15 new Form II were grown on bottom and walls of the glass
crystallizer. The same procedure was carried out to synthesize
and crystallize compound 2. However, the initial solution was
prepared with 4ꢀnitrobenzaldehyde (302.4 mg, 2 mmol) and mꢀ
hydroxyacetophenone (272.5 mg, 2 mmol).
Table 1. Crystal data and refinement statistics for the crystal forms of
75 compound 1 and for compound 2.
Form I of 114 Form II of 1
2
structural formula
C18H19NO4
313.34
C18H19NO4
313.34
C15H11NO4
269.25
20
Single crystal Xꢀray diffraction analysis
fw
0.40/0.20/0.14 0.20/0.12/0.05
0.22/0.19/0.09
crystal dimensions (mm3)
Blockꢀshaped single crystals of 1 and 2 were selected and
mounted on a κꢀgoniostat of an EnrafꢀNonius KappaꢀCCD
25 diffractometer. Room temperature diffraction intensities were
collected using graphiteꢀmonochromated MoKα Xꢀray beam
through ϕꢀω scans and κ offsets. The Xꢀray diffraction frames
were recorded using the program COLLECT,17 and reduction and
scaling of the raw dataset were performed with HKL Denzoꢀ
30 Scalepack.18 The structures were solved by direct methods with
SHELXSꢀ97.19 The models were refined by the fullꢀmatrix least
squares method on F2 with SHELXLꢀ97,19 with anisotropic
thermal parameters for nonꢀhydrogen atoms. Hydrogens were
cryst syst
space group
Z
monoclinic
monoclinic
triclinic
P21/c
P21/c
Pꢀ1
6
12
4
298(2)
100
298(2)
T (K)
a (Å)
14.8537 (3)
20.5009 (4)
19.5952 (3)
12.713(16)
8.649(11)
15.231(19)
11.620(3)
13.232(3)
13.981(3)
b (Å)
c (Å)
α (°)
90
90
105.7760(10)
90.626(2)
127.043 (1) 103.798(15)
placed in idealized positions after their identification in the β (°)
35 difference Fourier map. Next, they were refined with fixed
individual isotropic displacement parameters [Uiso(H) = 1.2Ueq
(Csp2 or N) or 1.5Ueq (Csp3 or O)] using a riding model with bond
lengths of 0.82 Å (O—H), 0.86 Å (N—H), 0.93 Å (Csp2—H), or
0.96 Å (Csp3—H). Crystal data of compounds 1 (Form I14 and
40 Form II) and 2 are shown in Table 1. The programs MERCURY20
and ORTEPꢀ321 were used to generate artworks. The distribution
of the most relevant torsion angles describing conformational
features of both compounds was searched for chalcone structures
deposited in the Cambridge Structural Database (CSD,22 version
45 5.36 of November 2014 with May 2015 update) using the
ConQuest23 tool and afterwards analyzed with MERCURY.20
γ (°)
V (Å3)
90
90
1626(4)
112.7210(10)
1891.8(7)
4762.78 (16)
1.311
1.418
calculated density (Mg/m3)
absorption coefficient (mmꢀ1)
1.280
0.093
0.091
0.104
3.05 – 26.38
1.64 – 27.50 1.65 – 25.62
θ
range for data collection (°)
h range
ꢀ16 to 19
ꢀ26 to 23
ꢀ25 to 22
48,383
10,835
6,967
ꢀ11 to 15
ꢀ8 to 10
ꢀ18 to 18
9,480
ꢀ14 to 14
ꢀ16 to 16
k range
l range
ꢀ17 to 17
14,210
data collected
7,547
4,457
0.0481
97.5
3,061
unique reflections
2,187
unique reflections with I >2σ(I)
symmetry factor (Rint)
0.0479
99.0
0.0269
99.6
Theoretical calculations
θ
max completeness (%)
840
50 Full geometry optimizations were performed starting from the Xꢀ
ray structures of 1 [Form I14 and Form II (this study)] and 2.
Relaxed potential energy curves and surface scan were performed
for the most relevant molecular dihedral angles in order to
rationalize the polymorphism and conformerism found in the
55 compounds studied here. All electronic structure calculations
were performed with the GAMESS suite of programs24 using the
DensityꢀFunctional Theory (DFT)25 with the Becke, threeꢀ
parameter, LeeꢀYangꢀParr (B3LYP)26,27 exchangeꢀcorrelation
1992
664
F (000)
544
631
211
parameters refined
goodnessꢀofꢀfit on F2
R1 factor for I >2σ(I)
1.050
1.023
1.030
0.0645
0.1244
0.289
0.0402
0.1168
0.156
0.0673
0.1936
0.615
wR2 factor for all data
largest diff. peak (e/Å3)
largest diff. hole (e/Å3)
CCDC deposit number
ꢀ0.243
ꢀ0.128
1,436,382
ꢀ0.230
845,518
1,436,383

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There are slight twists between the two leastꢀsquare planes
calculated through ring A (see Figure 1 for labeling scheme of
chalcone rings) and through the propenone nonꢀhydrogen atoms.
35 These two planes form angles of 10.89(8)°, 18.90(7)° and
15.65(7)° in molecules A, B and C of Form I (according to
numbering order given by Chantrapromma, Ruanwas and Fun14)
and of 8.91(8)° in Form II. There is a still higher coplanarity
between the central mean plane and ring B. The dihedral angle
40 between them is 2.64(9)°, 7.48(6)° and 3.12(10)° in molecules A,
B and C of Form I and 5.73(5)° in Form II. The values of torsions
around C9–C10 bond axis connecting these two frameworks also
describe their coplanarity. They measure close to either 0° or
180° (Figure 3) in all molecules of the two polymorphs.
Results and discussion
Conformational analysis of 1
5
Compound
1
is known to crystallize with three
3) in a
crystallographically independent molecules (Z’
=
monoclinic lattice, space group P21/c.14 In fact, its crystal
structure has been elucidated only in 2011 and no polymorphs
thereof are known up to now. To the best of our knowledge,
10 polymorphism is rare in chalcones. Only few chalcone
compounds are known to crystallize in at least two distinct solid
state structures thus far due to an apparent conformational rigidity
of the openꢀchain framework.32ꢀ34
Here, a true polymorph of 1 has crystallized in the same space
15 group of the antecedent crystal form but with only one molecule
in its asymmetric unit (Z’ = 1) instead (Figure 2). Hereinafter,
this polymorph will be called as Form II. Its conformation does
not differ much from those of the three molecules present in the
asymmetric unit of the antecedent Form I.14 Their molecular
20 backbone is almost completely planar, except for 1) the methyl
moiety of methoxy in paraꢀposition being out of the plane
passing through phenyl ring B and 2) a slight rotation on the C1–
C7 bond axis connecting the orthoꢀaminophenyl ring to the
central propenone core. To the best of our knowledge, searches in
25 literature reveal a trend for planarity of the chalcone moiety with
an anti conformation around C7–C8 (also called sꢀcis
conformation),35ꢀ39 as found in 1.
45
Fig. 3 Distribution of chalcones in the Cambridge Structural Database
(CSD)22 for the C8—C9—C10—C11 torsion. Colored lines highlight the
values found in 1 and 2 for this torsion.
50
In order to assess these planarity features in chalcones, we
have also performed a search in the CSD restricted to compounds
bearing the 1,3ꢀdiarylpropenone moiety and compared to
structures investigated here. In this sense, the torsions C6—C1—
C7—C8 and C8—C9—C10—C11 were chosen to describe the
55 coplanarity between phenyl rings A and B and the central
propenone core of 1. In Figures 3 and 4, histograms exhibit how
607 structures of chalcones found in the CSD are distributed for
these two torsion angles. This structure number includes
chalcones with any (or without) substituent in both phenyl rings
60 (gray bars). The distribution of a subset composed with 151
structures having either N or O atoms bonded to C2 is also
displayed for torsion C6—C1—C7—C8 in Figure 4 (red bars).
It is observed that both torsions lie close to either 0° or 180°
for the most of chalcones, revealing a tendency of coplanarity
65 between phenyl rings A and B and propenone in that compounds.
However, the most of chalcones possessing a potential hydrogen
bonding donor substituent in C2 is present with C6—C1—C7—
C8 in the range from 0° to 18° (ca. 60%, 90 out of 151
structures), as occurs in all molecules of 1 known thus far (see the
70 values found in 1 in both crystal forms highlighted in Figure 4).
This torsion stays in the upper range from 162 to 180° only in ca.
16% (24 out of 151) of all those chalcones. Therefore, the
assembly of a S11(6) motif hinders the conformational freedom
around C1—C7 bond axis so that only slight bents are observed
Fig. 2 30% Probability ellipsoid plots of 1 and 2 in the crystal forms
30 elucidated in this study. Nonꢀhydrogen atoms are arbitrarily labeled and
hydrogen atoms are shown as spheres of arbitrary radii.

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in the most of these orthoꢀsubstituted chalcones. The rotation of
orthoꢀaminophenyl moiety can be slightly rotated to interact
approximately 180° is frequently hindered when N or O atoms is 30 intermolecularly with neighbors in the lattice.
bonded to C2 due to formation of such intramolecularly
hydrogenꢀbonded cycle.
Concerning conformation around the rotatable C7—C8 bond,
compound 1 adopts an anti conformation in both crystal forms,
with the torsions C1—C7—C8—C9 and O1—C7—C8—C9
measuring close to 180° and 0°, respectively. This conformation
35 is preferred over the syn one (also called s-trans conformation)
which has higher energy in most cases due to the steric hindering
between the two hydrogens at C9 and at an orthoꢀposition of ring
A.35,36 For the last torsion, 85% of all chalcones found in the CSD
(516 out of 607) are in 0ꢀ18° range, as observed for the
40 crystallographically independent molecules of 1 in its Form I and
in that of Form II. Only ca. 6% (35 out of 607) are in the 162ꢀ
180° range for O1—C7—C8—C9, which features
a syn
conformation around C7—C8. Contrary to distribution of the
torsion on C1—C7, which is affected by the presence of a N or O
45 substituent in the 2ꢀposition of phenyl ring A, this orthoꢀ
substitution is not related to either syn or anti conformations
around C7—C8. The distribution for O1—C7—C8—C9 in the
chalcones subset with either N or O atom bonded to C2 follows
that of general chalcones with any (or without) substituent in
50 phenyl rings.
At last, the conformation of the three methoxy groups is
similar among the crystallographically independent molecules of
Form I and II (Figure 5). All molecules are present with their
nonꢀhydrogen methoxy atoms in the plane crossing through the
55 ring B, except for the methyl carbon of paraꢀmethoxy group. In
fact, the conformation of the last groups differs negligibly for
molecules of 1.
5
Fig. 4 Distribution of chalcones in the CSD22 for the C6—C1—C7—C8
and O1—C7—C8—C9 torsions. Colored lines highlight the values found
in 1 for these torsions.
10
Moreover, the main intramolecular characteristic changed in
the crystallographically independent molecules of 1 is in the
rotation on the C1–C7 bond axis. Although subtle, this rotation is
responsible for different ring A conformations. If central
propenone mean plane is taken as reference, the NH2 group can
15 be either on the same (molecules B and C of Form I and that of
Form II) or on the opposite (molecule A of Form I) side of the
outꢀofꢀplane methyl moiety (Figure 5). In order to describe this
conformational feature, the values of the chosen torsion on the
C1–C7 bond axis (C6–C1–C7–C8) are shown in Figure 4. One
20 can see that this torsion in molecule A of Form I has opposite
sign of that in all other molecules of 1. Even so, the two observed
ring A conformations are compatible with the formation of the
intramolecular hydrogen bonding between amine and carbonyl
moieties. Simultaneously, the other hydrogen of NH2, which is
25 not involved in S11(6), can be directed towards a hydrogen
bonding acceptor in the lattice in both ring A conformations. In
other words, the intramolecular nonꢀcovalent contact is formed in
both conformations, assembling a S11(6) ring, meanwhile the
Fig. 5 Superposition of crystallographically independent molecules of 1
60 and 2 in the crystal forms elucidated in this study and also in the known
Form I14 of 1.

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Crystal packing analysis of 1
The importance of N—H●●●π interactions has been well
reported in organic crystal structures and biomolecules.40ꢀ48 For
instance, these nonꢀclassical hydrogen bonds are commonly
found in protein structures being responsible for their folding and
The crystal packing of 1 is stabilized only with weak
intermolecular contacts in its Form II. The amine moiety is a nonꢀ
5
classical hydrogen bonding donor to πꢀsystem of ring A, giving 35 maintenance through close packing between amine/amide and
rise to oneꢀdimensional chains along the [010] direction through
N1—H1a●●●Cg(ring A) interactions (Figure 6a). Faceꢀtoꢀedge C—
H●●●π interactions between rings A and B (C5—H5●●●Cg(ring
aromatic
side
chains.43ꢀ45
Concerning
polymorphism
phenomenon, the role of N—H●●●π interactions in the ability of
the Eꢀisomer of 2ꢀfluoroꢀN’ꢀ(3ꢀfluorophenyl)benzimidamide to
assemble different crystal forms has been recently investigated by
and C17—H17b●●●Cg(ring A)) are also responsible for the
B)
10 assembly of weakly stabilized supramolecular chains in Form II 40 Dey and Chopra.48 When one hydrogen atom of the amine group
of 1 (Figure 6b). Geometry of these contacts is shown in Table 2.
In fact, the intermolecular hydrogen bonding donation from
amine moiety is the main responsible for polymorphism in 1. All
molecules are classical hydrogen bonding donors in Form I,
is not able to interact in strong N—H●●●N interaction upon fast
evaporation from a hexane solution of the compound, N—
H●●●π contact is accessorily assembled to guarantee crystal
lattice stability. On contrary, whether the solvent is slowly
15 either to methoxy oxygens or to amine nitrogen. Molecules A and 45 evaporated, both hydrogens of NH2 are involved in classical N—
C are assembled into a centrosymmetric tetramer through
classical hydrogen bonding donation from their amine moiety to
amine nitrogen and paraꢀmethoxy oxygen of each others,
respectively. Molecules B are hydrogen bonded to themselves
H●●●N
hydrogen
bonds.48
Here,
however,
N—
H●●●π interactions are the main intermolecular contacts in
crystal Form II of 1 since neither N—H●●●N nor N—H●●●O
hydrogen bonds are found in its crystal packing. In conclusion,
20 through their amine and 5ꢀmethoxy groups (Figure 7). On the 50 these weak contacts are the primary intermolecular interactions in
other hand, in the polymorph described here, the amine moiety is
intermolecularly involved only in weak N—H●●●π interactions.
our polymorph while they work together with classical N—
H●●●N hydrogen bonds in the precedent polymorph described
by Dey and Chopra.48
55 Fig. 7 Crystal packing in the known Form I of 1 showing two hydrogen
bonded tetramers made up of molecules A and C and their intercalation
through a hydrogen bonded chain of molecules B (the framed chain grows
onto the circled region as the drawing projection). Only hydrogens
involved in the shown contacts are displayed.
60
DFT analysis of 1
Aiming to rationalize the polymorphism phenomenon of
compound 1, the minimum energy conformations were computed
65 through a relaxed potential energy surface (PES) scan for the
dihedral angles on the C1—C7 and C7—C8 bond axes (C6—
C1—C7—C8 and O1—C7—C8—C9). These two dihedral
angles were forced to assume constrained values ranging from ꢀ
20° to 20°, with variable step increments considered in the DFT
70 calculations. Computational methods have been much explored
nowadays to understand how different molecular geometries of a
compound can occur in crystal structure and which are the
Fig. 6 The crystal packing of 1 in its Form II (this study) is featured by
25 presence of chains assembled with (a) N—H●●●π and (b) C—H●●●π
interactions. The centrosymmetric dimer formed in this structure through
C—H●●●π interactions is shown in (c). The term Cg denotes the centroid
calculated through the phenyl ring carbons. The measurements refer to
hydrogen…Cg distance. Only hydrogens involved in the shown contacts
30 are displayed.

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Table 2. Geometry of classical and nonꢀclassical hydrogen bonds in compounds 1 (Form II, this study) and 2.
D—H· · ·A
N1ꢀH1b...O1
N1ꢀH1a...Cg(ring A)
D—H (Å)
H· · ·A (Å)
D· · ·A (Å)
D—H· · ·A (°)
Compound
0.86
0.86
0.93
0.93
0.82
0.82
0.82
0.93
1.97
3.18
2.88
3.48
2.03
1.90
2.04
2.97
2.612(3)
3.999(4)
3.633(4)
3.846(5)
2.848(3)
2.719(3)
2.844(2)
3.726(3)
131
160
139
105
174
176
166
139
1
i
ii
C5ꢀH5...Cg(ring B)
iii
C17ꢀH17b...Cg(ring A)
O1aꢀH1a...O2biv
O1bꢀH1b...O2aiv
O1cꢀH1c...O1bv
2
vi
C12aꢀH12a... CgC(ring A)
Symetry codes: i 2ꢀx, 0.5+y, 0.5ꢀz; ii x, 0.5ꢀy, ꢀ0.5+z ; iii 1ꢀx, 1ꢀy, 1ꢀz, iv ꢀ1ꢀx, ꢀy, ꢀz; v x, y, ꢀ1+z; vi x, ꢀ1+y, z.
5
energetic spent and barrier to their interconvertion.49ꢀ52 Besides
such knowledge, these theoretical approaches allow for the 50 slight twist around their bond axes, i. e., there are rotations on
their values but also in their signs, indicating an unsynchronized
prediction of forbidden geometries and additional minimum
energy points.53
The PES shown in Figure 8 was built by the cubic spline
10 interpolation of the electronic energies after optimization of all
such bond axes towards opposite sides of chalcone mean plane in
Form I. This differs from both minimum energy points and Form
II present with both rotations in a same direction. Such behavior
can be attributed to a competition between intramolecular and
internal coordinates at the DFT/B3LYP/APC1 level of theory, 55 intermolecular classical hydrogen bonds present in Form I, while
except those defining the two constrained dihedral angles. In this
picture, we can see two minimum energy conformers whose
energies differ for about 0.0387 kJ molꢀ1. This is a small energy
15 difference facilitating the interꢀconversion between them in gas
no deviation from global minimum energy conformation is gotten
in Form II because of the absence of intermolecular classical
hydrogen bonds in it. In other words, strong intermolecular
interactions compensate energetically the slight deviation from
phase and even in solution,50 mainly taken into account a low 60 the intramolecular minimum energy point in all molecules found
energy barrier to convert the most stable conformer into the local
minimum energy point [0.0877 kJ molꢀ1, which is the energy
difference between the global minimum and the transition state
20 (TS)]. These two minimum energy conformers are featured by the
S11(6) motif which can be slightly twisted towards opposite
sides of the overall chalcone mean plane. This is achieved
through synchronous rotations on both C1—C7 and C7—C8
bond axes, as can be seen in the similar signs and values of C6—
25 C1—C7—C8 and O1—C7—C8—C9 dihedral angles in each
minimum energy conformation (see below and in Figure 8).
Moreover, an interesting finding comes from comparison
between the two minimum energy geometries and the molecular
conformations found in its crystal forms. The global minimum
30 has C6—C1—C7—C8 and O1—C7—C8—C9 torsion angles
measuring ꢀ7° and ꢀ5°, which are values very close to the
experimental ones found in the polymorph described here (ꢀ
9.1(2)° and ꢀ10.5(3)°). In fact, Form II is remarkably similar to
the global minimum energy molecule from a conformational
35 point of view with a root mean square deviation (RMSD) for the
coordinates of their nonꢀhydrogen equivalent atoms of 0.0934 Å.
Hereinafter, all RMSD values presented refer to the coordinates
of equivalent nonꢀhydrogen atoms.
in the asymmetric unit of Form I, while in Form II this
intramolecular geometry is obligatorily adopted to compensate
the loss of strong intermolecular contacts.53
65 Fig. 8 Potential energy surface of compound 1 calculated at the
DFT/B3LYP/APC1 level of theory around two torsion angles on the
single bond axes bearing carbonyl moiety.
In summary, Form I and II are intermolecularly and
70 intramolecularly driven, respectively. Since the calculated energy
difference between the conformations found in both crystal forms
is lower than energetic gain from classical hydrogen bonds in
Form I (~20 kJ.molꢀ1 per contact) over nonꢀclassical ones in Form
II (~5ꢀ10 kJ.molꢀ1 per contact), Form I is expected to be the most
75 stable one even though deviating from global minimum energy
conformation, which is in agreement with the fact that it has been
reported earlier.
On the other hand, the three crystallographically independent
40 molecules of Form I resemble less the global minimum energy
point, with corresponding RMSD values of 0.235 Å (A), 0.163 Å
(B) and 0.134
Å (C). Except for one of these three
crystallographically independent molecules, they also do not
resemble much the local minimum energy conformer present with
45 both torsions measuring 7° (the RMSD between the molecules A,
B and C of Form I and the secondary calculated stable conformer
is 0.0886 Å, 0.2608 Å and 0.3071 Å). It is key to observe that in
Form I the signs of these two chosen torsions do not differ only in

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Conformational analysis of 2
molecules A and B of 2. Most of chalcones are featured by both
dihedral angles close to 0° or 180° (Figures 3 and 9). In addition,
Compound 2 has crystallized in the triclinic space group Pꢀ1 30 the subset having either N or O atom bonded to C3 is majorly
with three molecules in the asymmetric unit (Figure 2).
Molecules labeled as A and B are considerably planar and can be
related by pseudo translation symmetry through the lattice. The
phenyl rings A and B of molecule A form angles of 9.26(9)° and
7.06(8)° with the central propenone mean plane, respectively,
while the corresponding measurements for molecule B are
10 2.56(9)° and 1.68(10)°. These values also reveal that molecule B
is a few more planar than molecule A. Inspection of the torsion
angles around C1–C7 and C9–C10 bond axes connecting phenyl
composed with C2—C1—C7—C8 near to 180°. More than 86%
(51 out of 59) of the structures belonging to this subset are in
162ꢀ180° range (Figure 9), revealing that the metaꢀsubstituent is
preferred to be positioned in the same side of carbonyl oxygen.
However, the conformerism observed in 2 is not due to these
negligible differences between molecules A and B. If these two
molecules are taken as references, the third crystallographically
independent molecule C is present with notable rotations on the
C1–C7 and C7–C8 bond axes bearing the carbonyl group. The
5
35
rings to propenone core also shows this (Figures 3 and 9). They 40 mean planes of ring A and propenone are twisted by 64.70(12)°
are nearer to either 0° or 180° in molecule B than in A. In fact,
15 molecule B is not completely planar only due to a slight rotation
on the N1–C13 bond axis responsible for twisting the nitro group.
Nitro group of molecule A is a few less bent than that of
as a consequence of a ca. sixꢀfold rotation axis on the first bond.
Torsion angles around C1–C7 also describe such conformation.
The unusual conformation around C1—C7 of molecule C can be
viewed in the bottom histogram of Figure 9. Indeed, there are few
molecule B. There is also a small rotation on the C1–C7 bond 45 examples of general chalcones with C2—C1—C7—C8 in the
axis of molecule A of 2 similarly as occurs in all molecules of 1.
central range from 18° to 153° and this is the first report of a N or
O metaꢀsubstituted chalcone in this interval. The other rotation on
the C7–C8 bond axis is still larger. The torsions around this bond
measure near to 180° (O2—C7—C8—C9) or 0° (C1—C7—C8—
50 C9) in molecule C, while there is inversion of these values in
molecules A and B, i. e., their O2—C7—C8—C9 and C1—C7—
C8—C9 torsions are close to 0° and 180°, respectively (Figure 9).
Therefore, a rotation of ca. 180° on the C7—C8 bond axis can be
also described for molecule C when compared to the two others
55 (Figure 5). In other words, molecules A/B and C adopt anti and
syn conformations around this rotatable bond axis, respectively.
As mentioned in the conformational analysis of 1, the occurrence
of both conformations around this bond is well known,35ꢀ39 but
their simultaneous occurrence into a same crystal structure is not.
60
In the CSD, the C1—C7—C8—C9 torsion measures between
153° and 180° in almost all chalcones (ca. 93%, 566 out of 607).
All N/O metaꢀsubstituted chalcones (59) are in this range for such
torsion. Molecules A and B of 2 add to this range of values, while
molecule C deviated from this trend and is the first report of a
65 N/O metaꢀsubstituted chalcone with C1—C7—C8—C9
measuring close 0°. It is striking to observe that the presence of
metaꢀsubstituents beginning with either O or N does not affect the
distribution for this torsion. Red bars present a same distribution
profile of gray bars. At last, ring B is coplanar to propenone mean
70 plane of molecule C of compound 2, as occurs in its other
conformers and also in all molecules of 1. There is an slight angle
of 11.4(2)° between this phenyl ring and the central mean plane.
Crystal packing analysis of 2
75
In the crystal packing of 2, planar molecules A and B assemble
a pseudo centrosymmetric dimer through classical hydrogen
bonds between their hydroxyl and carbonyl groups (Figure 10).
These dimers are sideꢀtoꢀside packed onto (110) plane,
80 originating sheets which are further stacked along the [110]
direction through πꢀπ interactions. Twisted molecules C are also
accommodated into the sheets, through intercalation of two
pseudo centrosymmetric A=B dimers, but their phenyl ring A is
pointed towards the interlayer space. This packing fashion of
20
Fig. 9 Distribution of chalcones in the CSD22 for the C2—C1—C7—C8
and C1—C7—C8—C9 torsions. Colored lines highlight the values found
in 2 for these torsions.
25
The distribution for the chosen C2—C1—C7—C8 and C8—
C9—C10—C11 torsion in all chalcone structures found in the
CSD is in agreement with this planarity feature observed in
85 molecules
C has been resulted from its conformational

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Fig. 10 (a) The layered structure of 2. Observe that one molecule C is between two hydrogen bonded dimers made up of molecules A and B onto the layer.
The molecules marked with asterisks are shown in detail in (b). The term Cg denotes centroid calculated through the phenyl ring carbons. The
measurements refer to hydrogen…acceptor atom (or Cg) distance and hydrogen bonding angle. Only hydrogens involved in shown contacts are displayed.
5
adaptability and allows for simultaneous intermolecular contacts. 30 increments of 5°, followed by optimization of all atom
These include classical hydrogen bonding donation to hydroxyl
oxygen of molecule on an adjacent layer, C—
10 H●●●π interaction between its ring A πꢀsystem on an interlayer
site and an aromatic CH moiety of molecule A, and πꢀπ
coordinates except those of the four atoms from the chosen
torsion angle. Since there are two conformations in the
asymmetric unit of 2 differing for ca. 180° around C7—C8 bond
axis (syn and anti conformers), the PES curve for C2—C1—
B
interactions through the pillaring of the sheets (Figure 10 and 35 C7—C8 was calculated inputting the two distinct conformers
Table 2 for geometry of classical and nonꢀclassical hydrogen
bonds). Therefore, this set of strong (O—H●●●O) and weak
15 (C—H●●●π and πꢀπ) intermolecular contacts compensates the
energy gain from both rotations on the C1—C7 and C7—C8
(Figure 11). For both conformations, the PES scan is featured by
two minimum energy points, which are lower in the anti
conformer than in the syn one. The lowest two minimum energy
points, both of them found for the anti conformer, are present
bond axes (see in sequence). On can see the role of weak 40 with C2—C1—C7—C8 torsion angle measuring 20° and 170 °.
interactions in the crystal packing of 2. Indeed, these contacts are
well documented as stabilizers of organic crystal structures,
20 aiding or even playing the role of stronger interactions when they
are not present.22,42,54ꢀ56
These values describe almost planar conformations of the
substituted phenyl ring A relative to chalcone mean plane. Both
slight deviation from complete planarity is due to steric hindrance
between vicinal hydrogen atoms bonded to C8 and the carbon at
45 orthoꢀposition of ring A (C2 or C6 according to the rotation of ca.
180° around C1—C7 bond axis). The second value is the lowest
minimum energy point which matches well to the experimental
value in the anti conformers of 2 (172.4(2)° and 179.0(2)° for
molecules A and B). In fact, these theoretical and experimental
DFT analysis of 2
25
In order to understand how so distinct conformations can be
assumed into the same crystal form of 2, we have also calculated
PES curves for torsion angles on the same bond axes analyzed for 50 conformations are similar, with RMSD of 0.157 Å and 0.241 Å
compound 1, at the same theory level. Firstly, the C2—C1—
for crystallographically independent molecules labeled as A and
C7—C8 dihedral angle was forced to range from 0° to 180°, with
B. The highest two minimum energy points for the syn conformer

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have torsion values of 40° and 145° featuring twisted
indicating that twisted and planar ring A conformations are
adopted upon rotation around C7—C8 bond axis. This allows us
to conclude that rotation around C1—C7 bond axis defining the
phenyl ring A conformation just obeys the rotation on the C7—
conformations of phenyl ring A, which are related by a ca. 180°
rotation on the C1—C7 bond axis as occurs in the two minimum
energy points for the anti conformer. The higher energy of the
5
syn conformer have been reported previously for other 50 C8 bond axis determining either syn or anti conformation of
chalcones.39,57ꢀ59 Such twisted conformations are a consequence
of the steric hindrance between C9—H9 moiety from olefin
moiety and the CH one at orthoꢀposition of ring A (C2—H2 or
C6—H6 depending of what minimum energy point), which are
chalcone skeleton.
Taken into account the moderate energy differences53,60
between the two minimum energy points shown in Figure 12 and
between the lowest minimum energy point and the transition
10 positioned close together in the syn conformer.35,36 For this less 55 state, which are somewhat 4 and 20 kJ molꢀ1, respectively, the
stable conformer, the second dihedral angle energetically is
slightly higher than the first one. This second theoretical torsion
angle is in good agreement with that observed for the
experimental syn conformer (119.0(2)°). Likewise, their
two distinct conformations of 2 can be promptly converted into
each other with small energetic spent starting from a single
rotation on the C7—C8 bond axis. In turn, classical
intermolecular hydrogen bonds can be assembled through
15 superimposed molecular backbones are resembled (RMSD of 60 alternative positioning of the hydroxyl moiety of molecule C,
0.398 Å).
Through inspection of the PES curve for the syn conformer
allowing intermolecular accommodation even with net energetic
gain from this balance between intra and intermolecular driving
forces. In order to optimize this balance, it is known that
molecules can assume higher energy conformers in crystal
shown in Figure 11, it is possible to see that both ring A planar
conformations are not compatible with such conformation around
20 C7—C8 bond axis because of higher molecular energy values for 65 structure of up to 25 kJ mol−1 above the global minimum energy
the C2—C1—C7—C8 torsion measuring close to 0° or 180°. In
the same way, twisted ring A conformations have higher
molecular energies than planar ones in the anti conformer. One
can observe this seeing that the minimum energy points of one
25 curve are not minimal in the other.
geometry in the gas phase.53
This study adds to the field in the line that simple molecules
bearing the important chalcone scaffold can assemble into
different crystal structures, keeping its backbone a few changed,
70 or, on a contrary thought, they can be present into a same crystal
structure with very different conformations. Both phenomena
arose from the balance between inter and intramolecular energies,
being the latter probed in this study using DFT. In both cases, any
deviation from the most stable conformer is compensated by
75 intermolecular stabilization. We hope that similar correlated
experimentalꢀtheoretical investigations can be carried out with
other chalconeꢀbased compounds in order to know better the
extension of these supramolecular and conformational
adaptabilities into this compound class.
Fig. 11 Potential energy scans around C2–C1–C7–C8 torsion angle
starting from syn (blue curve) and anti (green curve) conformers of
compound 2.
30
Another interesting conclusion can be drawn from the PES
curve for a torsion on the C7—C8 bond axis. This chosen
dihedral angle was C1—C7—C8—C9, which was rotated with
steps of 5° in the 0ꢀ180° range using the experimental syn
35 conformer as starting geometry (Figure 12). This last PES was
also calculated constraining only the coordinates of atoms
enclosing the torsion angle with further optimization of all other
atomic coordinates. As result from this DFT calculation, two
minimum energy conformations have been outputted with C1—
40 C7—C8—C9 measuring 25° and 175°. These values are similar
to those of the experimental molecules with syn and anti
conformation around this bond axis. Furthermore, these two
theoretical minimum energy geometries are well superimposed to
the corresponding crystal ones (RMSD of 0.749 Å (C) and 0.119
45 Å (A) / 0.169 (B) Å for syn and anti conformers, respectively),
80
Fig. 12 Potential energy scan around C1–C7–C8–C9 torsion angle
starting from syn conformer of compound 2.
Conclusions
We have here reported two interesting solid state phenomena
85 in two chalcones. Polymorphism has been found in 1. This is not
common in compounds owning chalcone skeleton. Even though
conformation does not change much in the polymorphs, crystal
packing is completely different between them, including loss of

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8. J. Drews, Science, 2000, 287, 1960.
all classical intermolecular hydrogen bonds in the new crystal
form. This unsuitable set of intermolecular hydrogen bonds in
Form II is compensated by adopting the global minimum energy
conformation around rotatable single bonds of the carbonyl
carbon atom. This contributes to the crystal lattice stabilization in
the polymorph described here, while classical intermolecular
hydrogen bonds contribute majorly in Form I whose molecules
deviate from minimum energy points.
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Press: Oxford, 2002.
10 formed with two similar and almost completely planar molecules
and another one present with its 1ꢀphenyl ring twisted by ca. 60°.
It also differs from the two others in the conformation of the
central propenone moiety (syn or anti). In addition, our DFT
results have demonstrated that anti/planar and syn/twisted pair
15 conformations are exclusive and driven by the rotation on the
bond axis connecting carbonyl and α carbons.
Therefore, we believe to have rationalized in depth molecular
adaptations responsible for both phenomena described here,
which will be useful for further comprehension in other
20 compounds owing chalcone scaffold. The correlation between
experimental and theoretical structures seems to be a suitable
approach to probe the overall tendency of polymorphism and
conformerism in this compound class.
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