Substitution effect on a hydroxylated chalcone: Conformational, topological and theoretical studies

Article abstract of DOI:10.1016/j.molstruc.2017.01.076

The effect of substituents on two hydroxylated chalcones was studied in this work. The first chalcone, with a dimethylamine group (HY-DAC) and the second, with three methoxy groups (HY-TRI) were synthesized and crystallized from ethanol on centrosymmetric

Full text of DOI:10.1016/j.molstruc.2017.01.076

Journal of Molecular Structure 1136 (2017) 69e79
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: http://www.elsevier.com/locate/molstruc
Substitution effect on a hydroxylated chalcone: Conformational,
topological and theoretical studies
a
b
c
a
Jean M.F. Custodio , Wesley F. Vaz , Fabiano M. de Andrade , Ademir J. Camargo ,
c
a, *
Guilherme R. Oliveira , Hamilton B. Napolitano
Ci ^e ncias Exatas e Tecnol oꢀ gicas, Universidade Estadual de Goi aꢀ s, An aꢀ polis, GO, Brazil
Instituto Federal de Educaç a~ o, Ci ^e ncia e Tecnologia de Mato Grosso, Lucas do Rio Verde, MT, Brazil
Instituto de Química, Universidade Federal de Goi aꢀ s, Goi a^ nia, GO, Brazil
a
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 October 2016
Received in revised form
The effect of substituents on two hydroxylated chalcones was studied in this work. The first chalcone,
with a dimethylamine group (HY-DAC) and the second, with three methoxy groups (HY-TRI) were
synthesized and crystallized from ethanol on centrosymmetric space group P2 /c. The geometric pa-
1
25 January 2017
rameters and supramolecular arrangement for both structures obtained from single crystal X-ray
diffraction data were analyzed. The intermolecular interactions were investigated by Hirshfeld surfaces
with their respective 2D plot for quantification of each type of contact. Additionally, the observed in-
teractions were characterized by QTAIM analysis, and DFT calculations were applied for theoretical
vibrational spectra, localization and quantification of frontier orbitals and potential electrostatic map.
The flatness of both structures was affected by the substituents, which led to different monoclinic
crystalline packing. The calculated harmonic vibrational frequencies and homo-lumo gap confirmed the
stability of the structures, while intermolecular interactions were confirmed by potential electrostatic
map and QTAIM analysis.
Accepted 27 January 2017
Available online 30 January 2017
Keywords:
Hydroxylated chalcone
Hirshfeld surface
DFT
©
2017 Elsevier B.V. All rights reserved.
1
. Introduction
stress. Furthermore, these compounds could be involved in various
physiological processes such as defense against bioaggressors,
redox homeostasis and dissipation of excess excitation energy [22].
As biological agents, Hofmann et al. [23] state that a minimum of
three hydroxyl groups was a requirement of effective xanthine
oxidase inhibition. In addition, two hydroxyl groups at neighboring
positions on at least one phenyl ring were responsible for effective
radical scavenging, which makes hydroxylated chalcones inter-
esting candidates as possible agents for the treatment of hyper-
uricemia. A QSAR study made by Silva et al. [24] shows that the
presence of a hydroxyl group in ortho position increased activities
against S. mutans, while its absence or OH in meta position
decreased the activity.
Chalcones have attracted much attention in the scientific com-
munity due to their multifunctional basic skeleton. Basically, they
are formed by an olefin portion and a carbonyl group that bind two
substituted aromatic rings, providing a delocalized
p system [1e4].
The broad features of these compounds, such as materials applied
to environmental science [5e9] and biological activities [3,10e17],
are results of their natural origin which allows for a wide range of
chemical compositions derived from this basic skeleton. Further-
more, the understanding of the structure-activity relationship has
motivated the synthetic production of chalcones that possess the
desired chemical, physical and biological properties [18].
As a result, hydroxylated chalcones have been thoroughly
studied, and many results show desirable properties related to this
group [19e21]. As environmental agents, these chalcones would act
as defense against UV radiation and as protection against oxidative
However, unlike previous studies that assessed the effect of the
chemical composition on the biological activities, we propose a
comparative structural study of two hydroxylated chalcones in
order to relate the chemical, physical and biological properties of
these compounds to structural factors, such as flatness, bond angles
and intermolecular interactions. The first,
a dimethylamine-
hydroxychalcone, is used as a ratiometric fluorescent probe for
the detection of alkaline phosphatase (ALP), an indicator of several
*
Corresponding author.
E-mail address: hbnapolitano@gmail.com (H.B. Napolitano).
http://dx.doi.org/10.1016/j.molstruc.2017.01.076
022-2860/© 2017 Elsevier B.V. All rights reserved.
0

70
J.M.F. Custodio et al. / Journal of Molecular Structure 1136 (2017) 69e79
diseases, such as hepatitis, prostate cancer, osteoporosis and bone
tumor [25e28]. The second chalcone is trimethoxy-
various atoms. Then, the electron density of an atomic fragment can
be defined as
a
hydroxychalcone with chemical composition similar to the first,
excepting only the substituents of the second ring, which enabled
this study. We synthesized both chalcones and studied their
structures from single crystal X-ray diffraction. In addition, we
performed theoretical calculations in order to assess the vibrational
frequencies, nucleophilic attack sites and chemical stability for both
structures.
mol
r
aðrÞ ¼ w
a
ðrÞr
ðrÞ
(2)
mol
where
r
ðrÞ indicates the molecular electron density. Crystal
Explorer 3.1 [32] software has been widely used to obtain several
properties that can be viewed in HS. Among these properties we
e i
have the distance of atoms external (d ) and internal (d ), to the
surface. This information can be represented in 3D or 2D histo-
grams known as fingerprints. The Crystal Explorer 3.1[32] program
normalizes these distances (dnorm) using the van der Waals radius
of the appropriate internal and external atom of the surface [36].
2
. Methodology
2.1. Synthesis and crystallization
ꢀ
ꢁ.
ꢀ
ꢁ.
vdw
vdw
i
vdw
vdw
d
norm
¼
di ꢁ ri
r
þ d
e
ꢁ re
r
(3)
To a solution of aromatic aldehyde (2 mmol) and aromatic ke-
e
tone (2 mmol) in 8.0 mL of ethanol, an amount of 1.0 mL of 24%
The graphical representation of dnorm allows us to identify a
ꢀ
sodium hydroxide in water at 10 C was added. After stirring
particular intermolecular interaction via a color coding system. Red
and blue colors in the HS are associated with shorter and longer
distances than van der Waals intermolecular contacts, respectively
overnight at room temperature, the reaction medium was
neutralized with 10% HCl. The solid was filtered and recrystallized
from ethanol.
[
37]. The surfaces were mapped for HY-DAC and HY-TRI as a func-
tion of d and d by Crystal Explorer 3.1 [32] software, and for the
fingerprint we used the standard 0.6e2.8ꢁA view of d vs. d
e
i
2.2. Crystallographic characterization
e
i
.
A single crystal of each compound was carefully selected under
polarizing microscope in order to perform its structural analysis by
X-ray diffraction. The crystals were collected at room temperature
2
.4. Computational procedure
The start geometries for HY-DAC and HY-TRI optimizations in
using
a Bruker APEX II CCD diffractometer with graphite-
gas phase were taken from X-ray data as described before. All
computation procedures present in this work were carried out
using the Gaussian09 [38] package of programs. The hybrid func-
tional of Truhlar and Zhao, M06-2X [39], with 6e311 þ g (d) basis
set and B3LYP [40] exchange-correlation functionals with 6e311 g
monochromated MoKa radiation (
l
¼ 0.71073 Å). The structure
was solved by direct methods and refined by full-matrix least
2
squares on F using SHELXL2014 software [29]. HY-DAC crystallized
in the monoclinic crystal system and space group P21/c [30] with
the following unit cell metrics: a ¼ 12.124 Å, b ¼ 10.275 Å,
(d,p) [41,42] basis set were applied to calculate the geometric and
ꢀ
ꢀ
ꢀ
3
c ¼ 12.506 Å;
a
¼ 90 ,
b
¼ 115.87 ,
g
¼ 90 and V ¼ 1401.8 Å . HY-
electronic properties of the compounds. The M06-2X functional is a
nonlocal functional parametrized for nonmetals with double the
amount of nonlocal exchange [39]. This functional is recommended
TRI also crystallized in the monoclinic crystal system and space
group P21/c [30] with the following unit cell metrics: a ¼ 12.687 Å,
ꢀ
ꢀ
ꢀ
b ¼ 8.586 Å, c ¼ 15.349 Å;
a
¼ 90 ,
b
¼ 107.99 ,
g
¼ 90 and
for noncovalent interaction such as CeH/O and CeH$$$p [43e45].
3
V ¼ 1549.9 Å . In both structures, H atoms connected to aromatic
carbon atoms were placed at calculated positions and refined as
riding, with CeH ¼ 0.94 Å and Uiso(H) ¼ 1.2Ueq(C). H atoms
The optimizations of geometric parameters were carried out
without constraint and to confirm if the optimized geometry found
in local minimum analytic harmonic frequency calculations had
been carried out using the same level of theory. With the support of
potential energy distribution (PED) analysis in Veda 4 [46] software
and the animation option of Gaussview [47], the assignments of the
vibrational frequencies were made.
3
attached to N and O atoms, and CH group, were located reliably on
difference Fourier maps, and their positions were refined as riding
on their parent atoms, with Uiso(H) 1.2Ueq(N) and
Uiso(H) ¼ 1.5Ueq (C or O). Mercury [31] and Crystal Explorer 3.1
32] were used to generate molecular representations, tables and
¼
[
pictures. The possible intermolecular interactions and hydrogen
bond were checked by PARST software [33] and studied from the
Hirshfeld surface. The crystallographic information files of
3
. Results and discussion
3.1. Crystallographic structure
17 17 5
C H17NO (HY-DAC) and C18H O (HY-TRI) molecule were depos-
ited in the Cambridge Structural Database [34] under the codes
CCDC 1507796 and 1507797, respectively.
Our crystallographic data collected for (E)-3-(4-(dimethyla-
mino)phenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one (HY-DAC) are
very similar to those found by Zhiqiang Liu and coworkers [28],
2
.3. Hirshfeld surface analysis
with monoclinic crystal system, P2 /c space group and unit cell
1
ꢀ
parameters a ¼ 12.124 Å, b ¼ 10.275 Å, c ¼ 12.506 Å and
b
¼ 115.87 ,
The potential intermolecular interactions of HY-DAC and HY-TRI
showing one molecule per asymmetric unit. Similarly, (E)-1-(2-
hydroxyphenyl)-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (HY-
TRI) also crystallized with a single molecule per asymmetric unit in
were visualized and interpreted using Hirshfeld surface (HS)
analysis. The idea for HS appeared from an attempt to define the
space occupied by a molecule in a crystal intending to partition the
crystal electron density into molecular fragments [35]. F. L. Hirsh-
feld defined a weight function for each atom in a molecule as
a P2 /c space group and monoclinic crystal system, with metrics
1
ꢀ
a ¼ 12.687 Å, b ¼ 8.586 Å, c ¼ 15.394 Å and
b
¼ 15.394 , like those
found by Hui Wu, Zhou Xua and Yong-Min Liang [48]. Complete
data for HY-DAC and HY-TRI are shown in Table 1, followed by Ortep
representations and an atom-numbering scheme for HY-DAC
.
at
a
X
w
a
ðrÞ ¼
r
ðrÞ
at
i
(1)
r
ðrÞ
(Fig. 1a) and HY-TRI (Fig. 1b):
i2molecule
Excepting the substituted region, both structures are very
similar in bond lengths and angles, as can be seen in Fig. 2a. Major
at
i
where
r
ðrÞ are spherically averaged electron densities of the

J.M.F. Custodio et al. / Journal of Molecular Structure 1136 (2017) 69e79
71
Table 1
Crystal data and structure refinement for HY-DAC and HY-TRI.
HY-DAC
HY-TRI
Empirical formula
Formula weight
C
17
H
17NO
18 17 5
C H O
313.32
267.31
Temperature
293 (2) K
Wavelength
0.71073 Å
Crystal system, space group
Unit cell dimensions
Monoclinic, P2
a ¼ 12.124 Å
b ¼ 10.275 Å
c ¼ 12.506 Å
1
/c
Monoclinic, P2
a ¼ 12.687 Å
b ¼ 8.586 Å
c ¼ 15.394 Å
1594.9 Å3
1
/c
ꢀ
¼ 90ꢀ
a
b
g
¼ 90
a
b
g
ꢀ
ꢀ
¼ 115.87
¼ 107.99
¼ 90ꢀ
ꢀ
¼ 90
3
Volume
1401.8 Å
3
3
Z, Calculated density
Absorption coefficient
F (000)
Theta range for data collection
Reflections collected/unique
Completeness to theta ¼ 25.242
Refinement method
Data/restraints/parameters
Goodness-of-fit on F^2
Final R indices [I > 2sigma(I)]
R indices (all data)
4, 1.267 Mg/m
0.083 mm
568
4, 1.305 Mg/m
ꢁ
1
ꢁ1
0.095 mm
660
1.688e25.385
ꢀ
ꢀ
1.867e25.360
7962/2568 [R (int) ¼ 0.0202]
9745/2932 [R (int) ¼ 0.0210]
100.0%
99.8%
Full-matrix least-squares on F2
2568/0/186
2932/0/212
1.037
1.040
R1 ¼ 0.0376, wR2 ¼ 0.1002
R1 ¼ 0.0373, wR2 ¼ 0.0904
R1 ¼ 0.0523, wR2 ¼ 0.1115
R1 ¼ 0.0528, wR2 ¼ 0.1011
discrepancies are observed in angles C10eC15eC14 and
electronic density and decrease the angles of meta-position,
compared to HY-DAC. In addition, molecular planarity evidences
the structural differences. HY-DAC is flatter than HY-TRI, with the
largest deviations from planarity involving the dihedral angles
C11eC10eC9eC8 and O2eC7eC8eC9, present in the carbonyl and
ꢀ
ꢀ
ꢀ
C10eC11eC12 (122.76 and 122.30 for HY-DAC and 120.30 and
ꢀ
1
20.13 for HY-TRI). Electronic effects explain this difference: HY-
DAC has an activating group (N(CH
tial charge around the C15 and C11 atom. Although HY-TRI also has
an activating group (OCH ), the orto-substitution increases the
3 2
) ), resulting in a positive par-
ꢀ ꢀ
olefin regions (2.97 and 3.81 , respectively). Comparing only the
3
Fig. 1. The ORTEP diagram of ellipsoids at 50% probability level with the atomic numbering scheme for HY-DAC (a) and HY-TRI (b).

72
J.M.F. Custodio et al. / Journal of Molecular Structure 1136 (2017) 69e79
Fig. 2. Overlapping of HY-DAC and HY-TRI (a); Representation of dihedral angles formed by planes of aromatic rings of HY-DAC (b) and HY-TRI (b).
q
1
¼ 10.24ꢀ and
q
2
¼ 15.22ꢀ.
regions in common of HY-DAC and HY-TRI, the dihedral angles
molecular structural study, because it involves the arrangement of
the molecular units in the crystalline environment. We evaluated
the neighborhood pattern by Hirshfeld surface analysis. The first
C5eC4eC7eO2, C3eC4eC7eC8, O2eC7eC8eC9 are evidence of
ꢀ
ꢀ
ꢀ
low planarity of HY-TRI, with values of ꢁ4.62 , ꢁ6.92 and ꢁ6.94 .
Fig. 2 also shows the angle formed by planes of aromatic rings of
HY-DAC (Fig. 2b) and HY-TRI (Fig. 2c). In the presence of the
approach involves distances between components of crystal: d
the distance from an external molecule to the Hirshfeld surface,
while d is the distance from an internal nucleus to the Hirshfeld
surface [49]. Hence, high values for d indicate donor regions of
intermolecular contacts and high values for d indicate acceptor
e
is
dimethylamine substituent, aromatic rings has
a
deviation
i
ꢀ
ꢀ
q
1
¼ 10.24 , increased to
q
2
¼ 15.22 when methoxy groups are
i
bonded at positions 3, 4 and 5 of the phenyl ring. In total, changes in
the substitution pattern are responsible for an angular difference
e
regions of intermolecular contacts [35]. Intermolecular interactions
of HY-DAC are presented in Fig. 4a, followed by intermolecular
interactions of HY-TRI, in Fig. 4b and c. Such surfaces are composed
of a color scale where blue indicates low intensity and red indicates
high intensity of contacts. In Fig. 4 a, (1) and (2) are the places with
ꢀ
between the aromatic rings of HY-DAC and HY-TRI equal to 24.84 .
Regarding inter/intramolecular interactions, the HY-TRI com-
pound has more interactions than HY-DAC. The crystal packing of
HY-DAC is stabilized by one strong intramolecular H-bond
involving O1eH18/O2 and one non-classical intermolecular
interaction involving C3eH3/O1, which contributes to the zigzag
repetition in the direction of the c axis. In addition to the strong H-
bond O1eH19/O2, the spatial arrangement of HY-TRI also re-
sembles a zigzag chain along the b axis, involving CeH/O and
CeH/C interactions. While only one interaction contributes to this
chain in HY-DAC, HY-TRI is stabilized by C9eH9/C6, C1eH1/O2,
C3eH3/O5 and C3eH3/C14 interactions. Two factors explain the
HY-TRI interactions: the increased electron density caused by the
three methoxy substituents in HY-TRI allows the C3eH3/C14 and
C3eH3/O5 interactions, and the angular difference between the
aromatic rings of HY-DAC and HY-TRI brings HY-TRI molecules
closer together and allows C9eH9/C6 and C1eH1/O2 in-
teractions, causing an increase in the calculated density for HY-TRI.
Information about distance, angles and the symmetry code of total
interactions of HY-DAC and HY-TRI is shown in Table 2, followed by
a representation of interactions and packing, in Fig. 3.
i e
high intensity of d and d of C3eH3/O1 interaction. In contrast,
for HY-TRI, donor regions of C9eH9/C6, C1eH1/O2, C3eH3/O5
and C3eH3/C14 interactions are recognized as the red points in
(3), (6), (9) and (10), while (4), (5), (7) and (8) represent acceptor
regions of these interactions. Note that the red points (8) and (10)
are higher than other points of HY-TRI, indicating that C3eH3/C14
interaction is stronger than C9eH9/C6, C1eH1/O2 and
C3eH3/O5 interactions.
Hirshfeld surfaces are a very effective tool for the recognition of
intermolecular interactions by evaluating not only classical and
non-classical hydrogen bond, but also hydrophobic interactions
(p$$$p and CeH$$$p interactions). These interactions are impor-
tant for the three-dimensional arrangement of the compounds
studied here and have characteristic features in the Hirshfeld sur-
face shape index. We evaluated the
crystal packing of HY-DAC and HY-TRI, and the results are illus-
trated in Fig. 5. HY-DAC is stabilized by both $$$ and CeH$$$
interactions (Fig. 5a). The $$$ interaction, involving only Cg1 (the
p interactions involved in the
p
p
p
The topological analysis of crystal is as important as the
p
p
gravity center of the aromatic ring formed by C10, C11, C12, C13 and
C15 atoms) is separated by a distance of 4.014 Å and recognized by
two triangular shapes above the aromatic ring, indicating the place
where two molecules meet (Fig. 5b). Fig. 5c shows the effect of
Table 2
Total intra/intermolecular interactions for HY-DAC and HY-TRI.
ꢀ
CeH$$$p interactions involving Cg1 and Cg2 (gravity center of ar-
D-H$$$A
d (D-H)Å d (H$$$A)Å d (D$$$A)Å d (DH$$$A) ( ) Type
omatic ring formed by C1, C2, C3, C4, C5 and C6 atoms) in the
HY-DAC
Hirshfeld surface shape index:
p
systems involved in
O1eH18/O2
C3eH3/O1 (i)
HY-TRI
O1eH19/O2
C9eH9/C6 (i)
C1eH1/O2 (ii)
C3eH3/O5 (iii)
0.961
0.931
1.613
2.665
2.509
3.523
153.31
153.73
Intra
Inter
ꢀ
C16eH16B$$$Cg1 [H16B$$$Cg1 ¼ 3.383 Å, D-H$$$A ¼ 104.79 ] and
ꢀ
C17eH17C$$$Cg2 [H16B$$$Cg1 ¼ 3.105 Å, D-H$$$A ¼ 113.12 ] cause
0.944
0.930
0.931
0.930
1.643
2.872
2.648
2.687
2.802
2.523
3.736
3.381
3.546
3.503
153.40
155.11
136.15
153.91
133.01
Intra
Inter
Inter
Inter
Inter
large depressions above the aromatic ring, seen as large red regions
of concave curvature [50,51]. In contrast, HY-TRI is stabilized by
only one CeH$$$p involving Cg3 (the gravity center of the aromatic
C3eH3/C14 (iii) 0.930
ring formed by C10, C11, C12, C13 and C15 atoms), C2 and H2 atoms
ꢀ
[
H2$$$Cg3 ¼ 2.838 Å, D-H$$$A ¼ 142.69 ] (Fig. 5d). The same
(
i) ¼ x,1/2-y,1/2 þ z; (ii) ¼ x,1/2-y,-1/2 þ z; (iii) ¼ x,3/2-y,-1/2 þ z.

J.M.F. Custodio et al. / Journal of Molecular Structure 1136 (2017) 69e79
73
Fig. 3. Representation of total interactions and crystal packing of HY-DAC (a) and HY-TRI (b).
features already discussed for the CeH$$$
were observed for HY-TRI.
p
interactions of HY-DAC
and d provides
various pieces of information about the system studied [52]. This
combination is called a fingerprint and summarizes all interactions
in a 2D plot created by binning (d , d ) pairs in intervals of 0.01 Å
i e
The combination of distance functions d
i
e
Fig. 4. Hirshfeld surfaces indicating intermolecular interactions of HY-DAC (a) and HY-TRI (b) e (c). Interactions are represented by dotted blue lines.

74
J.M.F. Custodio et al. / Journal of Molecular Structure 1136 (2017) 69e79
Fig. 5. Representation of
teractions and HY-TRI, revealing the CeH$$$
p
$$$
p
and CeH$$$
p
p
interactions of HY-DAC (a) and HY-TRI (b). Hirshfeld surface shape index of HY-DAC evidencing the
(e) interaction.
p$$$p (c) and CeH$$$p (d) in-
and coloring each bin of the resulting 2D histogram as a function of
the fraction of surface points in that bin, in a color scale from blue
to techniques with the same purpose, is the non-restriction of
origin of the electron density of the evaluated system. This means
that QTAIM does not depend only on electron densities calculated
by ab initio or DFT methodologies, but can be grounded in elec-
tronic systems experimentally obtained via X-ray diffraction
[38,55,56]. Qualitatively, a chemical bond/interaction is defined in
(
few points) through green to red (many points) [51,53,54]. Fig. 6a
shows the percentage of each contact for HY-DAC and HY-TRI, fol-
lowed by their respective fingerprint plots in Fig. 6b and c.
Due to the substitution pattern, HY-TRI has more O/H contact
than HY-DAC. This difference is noted as a higher intensity region
terms of the electron density
r and its gradient vector Vr. The
with d
e
and d
i
ranging from 1.2 to 2.0 Å in Fig. 6c. Generally, O/H
gradient vector represents the direction of greater variation of the
electron density, and when its value is zero at one point, it is said
that there is a maximum electron density at that point, called the
critical point [57]. Based on this assumption, we confirm the exis-
tence of intermolecular interactions already discussed by the
contacts are represented by two peaks in fingerprints, where the
upper peak (d
lower peak (d
C9eH9/C6 interaction in HY-TRI is responsible for the main dif-
ference between H/H contacts of both structures. It is recognized
e
> 1.4 Å and d
< 1.4 Å and d
i
< 1.4 Å) is the donor regions and the
i
> 1.4 Å) is the acceptor regions. The
e
location of the Bond Critical Point (BCP) by Laplacian electron
2
as blue points with coordinates d
z 1.1 Å; d z 1.3 in the HY-TRI fingerprint. For both structures,
C/H contacts have a wing shape in fingerprints and are related to
CeH$$$ interactions. This shape is very similar to HY-DAC and HY-
TRI, except for two peaks in d z 1.8e2.0 Å; d z 1.2 Å and
z 1.2 Å; d z 1.8e2.0 Å in HY-TRI, caused by C2eH2$$$Cg3
interaction. Finally, totally absent in HY-TRI, the HY-DAC fingerprint
shows an intensity in d z d z 1.8 Å, indicating the place where
the aromatic rings of $$$ interaction overlap.
e
z 1.3 Å; d
i
z 1.1 Å and
density V
r
[58ꢁ61]. Although Hirshfeld surfaces indicate the
d
e
i
C3eH3/C14 interaction in HY-TRI, this interaction is not found by
QTAIM analysis. The bond critical points found for HY-DAC and HY-
TRI are represented in Fig. 7a and Fig. 7b, respectively:
p
e
i
Besides the distance, another parameter that classifies an
interaction as weak, strong or very strong is its energy. By studying
the energy of a hydrogen bond [XeH$$$O (X ¼ C, N, O)], Espinosa,
Molins, and Lecomte [62] determined that
d
e
i
e
i
p
p
ꢀ
ꢁ
The Quantum Theory of Atoms in Molecules (QTAIM) is a
quantitative and qualitative approach by which hosteguest in-
teractions can be easily analyzed. QTAIM represents an advance in
the evaluation of molecular properties in chemical compounds
independent of their nature. One of its advantages, when compared
V r
bcp
EHB
¼
(4)
2
where EHB ¼ Energy hydrogen bond and V (rbcp) ¼ Energy Density
potential in the corresponding BCP. Each BCP has a value for the

J.M.F. Custodio et al. / Journal of Molecular Structure 1136 (2017) 69e79
75
Fig. 6. Quantifying the different types of contacts in HY-DAC and HY-TRI (a) followed by fingerprints for HY-DAC (b) and HY-TRI (c).
potential energy density calculated by the Multiwfn program [63],
which provides calculation of the hydrogen bond energy by
replacing it in Equation (4), resulting in Table 3:
point classifies the HY-DAC and HY-TRI interactions as closed-shell
type.
Note that the intramolecular H bond is stronger in HY-TRI than
HY-DAC. This decrease in energy is caused by the C3eH3/O1
interaction that acts on the oxygen involved in intramolecular
interaction. Finally, the positive values for the Laplacian critical
3
.2. Theoretical characterization
Our major aim in the theoretical analysis in this work was to
quantify the effect of substituting the three methoxy groups from
Fig. 7. Representation of bond critical points of HY-DAC (a) and HY-TRI (b).

76
J.M.F. Custodio et al. / Journal of Molecular Structure 1136 (2017) 69e79
Table 3
Topological parameters calculated by quantum theory of atoms in molecules (QTAIM). BCP ¼ Bond critical point; V (rbcp) ¼ Potential energy density; EHB ¼ Bond energy; V [2]
r
ꢁ
1
Laplacian critical point; au ¼ atomic units ¼ 627.5095 kcal mol
.
BCP
V (rbcp) (au)
E
HB (Kcal/mol)
V
2r (au)
Interaction
HY-DAC
HY-TRI
1
2
3
4
5
6
ꢁ0.072207325800
ꢁ0.009417884996
ꢁ0.003756927443
ꢁ0.003787432061
ꢁ0.002299879157
ꢁ0.058952248280
ꢁ22.65539039
ꢁ2.954906014
ꢁ1.178753775
ꢁ1.188324744
ꢁ0.721597976
ꢁ18.49654705
0.013277360211
0.013737317860
0.022182122460
0.023234850860
0.015578557070
0.179433609100
O1eH18/O2
C3eH3/O1
C3eH3/O5
C1eH1/O2
C9eH9/C6
O1eH19/O2
Fig. 8. Overlapping of experimental and theoretical (M062X) structures of HY-DAC (a) and HY-TRI (b).
HY-TRI by the amine group from HY-DAC. We studied the effect of
the molecular interactions theoretically, in solid state, in the geo-
metric parameters of HY-DAC. Since optimized geometry was car-
ried out in gas phase, we can conclude that the structural variations
observed between optimized and experimental structures are a
consequence of the molecular interactions in the solid state phase.
Structurally, the largest deviations from planarity between the solid
and the gas phase of HY-DAC are shown in the dihedral angles
involving C4eC5eO1eH18, C14eC13eN1eC17, C8¼C9eC10eC11
and C9¼C8eC7 ¼ O2. For HY-TRI, deviations from planarity are
observed near to carbonyl-olefin, olefin-hydroxylated aromatic,
methoxyl and hydroxyl regions. Fig. 8 shows graphically the main
differences between theoretical and experimental structures by
overlapping the models, while Table S1 (Supplementary
Information) shows bond lengths and bond angles:
experimental results, we applied in the theoretical values a scaling
factor of 0.947 [64] for M062X/6-311 þ g (d,p) and a scaling factor of
0.966 [65] for the results obtained at B3LYP/6-311 g(d) level of
theory. This procedure corrects the systematic overestimation of
the vibrational frequencies that is characteristic of the DFT methods
and, besides, makes it easier to carry out the assignments of the
vibrational modes.
Experimentally, the OH stretching vibration mode, for phenols,
ꢁ
1
shows strong centering bands ranging from 3400 cm
to
ꢁ
1
3300 cm . The DFT calculations (M062X) give that band at
ꢁ
1
ꢁ1
3216 cm and 3236 cm for HY-DAC and HY-TRI, respectively.
These theoretical values, lower than expected, can be explained by
the fact that, experimentally, the intermolecular hydrogen bonding
weakens the OeH bond, thereby shifting the band to lower fre-
quency [66]. The strong CeOH single-bond stretching vibrations
are observed in the range from 1260 cm to 1000 cm ; phenols
give that absorption at about 1220 cm because of conjugation of
the oxygen with the ring, which shifts the band to higher energy
ꢁ1
ꢁ1
Based on the values in S1, we calculated the roots of the mean
squared errors (RMSE) for bond lengths and bond angles parame-
ters, obtained with M062X functional, for both molecules. HY-DAC
ꢁ1
ꢀ
ꢀ
ꢁ1
ꢁ1
presents a RMSE of 21.70 (11.37 with B3LYP) for the bond angles
[66]. The bands at 1282 cm and 1285 cm , to HY-DAC and HY-
TRI, respectively, in DFT calculations, are assigned as stretching
CeOH mode. The carbonyl group absorbs strongly in the range from
and 0.0027 Å (0.0032 Å with B3LYP) for bond lengths, while HY-TRI
ꢀ
ꢀ
presents 7.65 (10.34 with B3LYP) and 0.0030 Å (0.0038 Å with
B3LYP), respectively, for the same parameters. This shows that HY-
TRI has a better agreement with bond angles, whereas for bond
lengths, HY-DAC has the closest values. Hence, although containing
more interactions, the conformation in gas phase of HY-TRI is less
affected by intermolecular interactions in solid state than HY-DAC.
ꢁ1
ꢁ1
1850 cm
to 1650 cm . In chalcones we must consider the
conjugation effects that increase the single bond character of the
C]O and C]C bonds in the resonance hybrid and hence lower
their force constants, resulting in a lowering of the absorption
ꢁ
1
ꢁ1
frequencies. Generally, this effect results in a 25 cm to 45 cm
lowering of the carbonyl frequency [66]. These calculated fre-
ꢁ1
ꢁ1
quencies are 1643 cm for HY-DAC and 1651 cm for HY-TRI.
Silver and Boykin [67] studied the effect of the substituents on
the carbonyl stretching frequency of chalcones and observed that
when there is the p-dimethylamine group, just like in HY-DAC, the
3.3. Vibrational assignments
Table 4 shows the theoretical vibrational frequencies for the
proposed compounds. For the sake of clarity, we decided to discuss
only the values for the main absorbing groups. As can be seen in
Table 4, these values are in line with each other and between the
expected experimental values, according to the literature. In order
to make a better comparison between theoretical and expected
ꢁ1
value of this stretching is 1558 cm . For chalcones with methoxy
group, just like in HY-TRI, C]O stretching occurs, on average,
ꢁ1
around 1585 cm . The stretching modes of the vinyl group occur at
ꢁ1
ꢁ1
,
1
660 cm -1600 cm
but conjugation often moves C]C

J.M.F. Custodio et al. / Journal of Molecular Structure 1136 (2017) 69e79
77
Table 4
Vibrational assignments, experimental and calculated wavenumbers in cm of HY-DAC and HY-TRI.
ꢁ
1
IR Assignments
B3LYP unscaled IR freq.
(a)3292.73
M062X unscaled IR freq.
B3LYP scaled IR freq.
M062X scaled IR freq.
B3LYP I
M062X I
n
n
n
n
n
n
OH
(a) 3396.26
(b) 3418.05
(a) 1354.77
(b) 1356.91
(a) 1646.08
(b) 1674.43
(a) 1734.99
(b) 1743.51
3180.78
3205.84
1300.50
1284.81
1546.59
1635.63
1630.13
1553.31
2904.60
2921.06; 2910.33; 2909.54
3039.22
3055.98; 3038.04; 3038.55
1325.63
911,95; 1225.14
995.41e1127.85
3216.26
3236.89
1282.97
1285.00
1558.84
1585.68
1643.03
1651.10
494.99
418.43
13.74
621.90
529.87
19.32
(
b)3318.68
(a)1346.27
b)1330.03
(a) 1601.03
b) 1693.20
(a)1687.50
b)1607.98
(a) 3006.83
b)3023.88; 3012.77; 3011.95
(a)3146.19
b)3136.55; 3144.97; 3145.50;
CeOH
C]O
(
292.07
840.97
316.97
273.62
392.48
119.11
225.76
56.02
140.56
23.37
345.01
201.79
54.08
494.67
417.79
312.30
261.40
67.65
56.51
30.90
24.28
47.25
(
C]C
(
symCH3
asymCH3
(a) 3023.76
2863.50
(
(b) 3041.27; 3043.20; 3058.93
(a) 3034.64; 3082.10
(b) 3113.93; 3133.34; 3168.42
(a) 1379.84
(b) 975.11; 1307.09
(b)1077.03e1208.13
2880.08; 2881.91; 2896.80
2873.80; 2918.75
2948.89; 2967.27; 3000.49
1306.71
923.42; 1238.19
1019.94e1144.09
(
n
n
n
CeN
O-CAryl
OeC
(a) 1372.29
(b)944.05; 1268.27
(b)1030.45e1167.55
232.04
223.80
stretching into lower frequencies, that increases the intensity [66].
Fig. 9. The MEP contour map shows the negative red regions are
more concentrated at the oxygen atoms on the electrophilic sites of
both molecules. The positive blue regions are concentrated over the
hydrogen atom attached to the nitrogen atom, for HY-DAC, and the
methyl group, for HY-TRI, positioned on nucleophilic sites. The
green region represents the zero potential of the title molecules.
Thus, Fig. 9 confirms the existence of intra and intermolecular in-
teractions of the title molecules in solid state. The dipole moment of
the compound is another parameter that predicts the polarized
nature of the molecule [75]. The theoretical study has shown that
HY-DAC (7.8249D) has the highest values of dipole moments, thus it
is more polarized, compared to those obtained for HY-TRI
(3.1244D), while with B3LYP calculations these values are 8.2098
D and 3.5622 D, respectively. Through Mulliken atomic charges, we
can see that the electron density on the carbonyl oxygen of HY-TRI
ꢁ
1
The calculated wavenumbers for this mode are 1643 cm and
ꢁ
1
1
651 cm for HY-DAC and HY-TRI, respectively. The OeC stretching
ꢁ
1
3
vibration of the OeCH group appears in the wide 975 ± 125 cm
region with an intensity varying from weak to strong [68,69]. A
methoxy group attached to an aromatic ring gives the asymmetric
ꢁ
1
stretching in the range 1310e1210 cm and symmetric stretching
ꢁ1
in the range 1050e1010 cm [69]. The ab initio calculations give
ꢁ ꢁ1
1
1
019 cm and 1144 cm as asymmetric and symmetric methoxy
stretching vibrations, respectively. Electronic effects such as back-
donation and induction, mainly caused by the presence of an ox-
ygen atom adjacent to the methyl group, can shift the position of
CH stretching mode. In aromatic methoxy compounds the asym-
ꢁ
1
metric mode is expected in the region 2985 ± 20 cm
and
ꢁ
1
2
2
955 ± 20 cm , and the symmetric mode in the region
ꢁ1
845 ± 15 cm [69]. For HY-DAC, the computed wavenumbers of
ꢁ
1
asymmetric stretching of the CH
2
3
group appear in 2873 cm and
ꢁ
1
ꢁ1
918 cm , while the band in 2863 cm is assigned as symmetric
stretching mode. For HY-TRI, the computed wavenumbers of
ꢁ
1
ꢁ1
asymmetric stretching of the CH
3
group are 2948 cm , 2967 cm
ꢁ1
ꢁ1
ꢁ1
and 3000 cm , while the bands in 2880 cm , 2881 cm ; and
896 cm are assigned as symmetric stretching mode. The CeN
ꢁ
1
2
absorption occurs at a higher frequency in aromatic amines
because resonance increases the double-bond character between
the ring and the attached nitrogen atom, so aromatic amines absorb
ꢁ
1
ꢁ1
ꢁ
from 1350 cm to 1250 cm [70]. Brouwer and Wilbrandt [71]
1
found an IR band in 1344 cm for CeN stretching in N,N-Dime-
thylaniline. Substitution in ring A with basic groups, N(CH and
OCH , containing an unshared -electron, result in bathochromic
shifts of the longer wave length absorption band, and this effect is
higher than for N(CH to OCH . This is understandable on the
3 2
)
3
p
3
)
2
3
basis of partial electron withdrawal from the nitrogen. This pro-
pensity is offset by the inductive effect of the methyl group. The
overall effect is that there is some lowering in the resonance
contribution of the nitrogen lone pair towards the benzene ring of
the chalcone molecule [72]. In this study, the CeN stretching occurs
ꢁ1
ꢁ1
in 1306 cm for HY-DAC and 923 cm for HY-TRI.
3.4. Electrostatic potential surface
The molecular electrostatic potential (MEP) has been employed
in characterizing various properties of chemical and biological
systems. The electrostatic potential is a well-defined quantum-
mechanical quantity, emphasizing the charge distribution of mol-
ecules three-dimensionally. It can also be explored experimentally
through X-ray diffraction investigations [73,74]. The MEP surface
with Mulliken atomic charges of HY-DAC and HY-TRI is shown in
Fig. 9. Potential electrostatic surface calculated at M062X/6-311 þ g (d,p) for HY-DCA
(
a) and HY-TRI (b) with Mulliken atomic charges. Electrostatic potential regions are
represented in red while positive electrostatic potential areas are shown in dark blue.
For interpretation of the references to colour in this figure legend, the reader is
referred to the web version of this article.)
(

78
J.M.F. Custodio et al. / Journal of Molecular Structure 1136 (2017) 69e79
Fig. 10. The HOMO and LUMO distribution of HY-DCA (a) and HY-TRI (b) in gas-phase by using M062X.
(
ꢁ7.86 eV) is slightly higher than that on HY-DAC (ꢁ8.13 eV). The
hardness (
transfer. The chemical softness (
atom or group of atoms to receive electrons [78], and both pa-
rameters were calculated in this work. The for HY-DAC is 2.662 eV
and the is 0.3756 eV, while the for HY-TRI is 2.861 eV and the s
is 0.3495 eV. Thus, we conclude that HY-DAC has a higher capacity
to receive electrons, while HY-TRI has a higher capacity to resist a
charge transference (i.e, resistance to changing its electronic
configuration).
h
) is a measure of the resistance of an atom to a charge
negative charge on the oxygen atom of the hydroxy group in HY-
s
) describes the capacity of an
DAC (ꢁ8.27 eV) is also lower compared to that of HY-TRI
(
ꢁ7.97 eV). On the other hand, it is observed that the positive
h
values on the carbon atoms of the ring system in HY-TRI lead to a
redistribution of electron density. Because of these strong positive
charges, the carbon atoms of the HY-TRI ring where the oxygen
atom is connected accommodate higher positive charges and
become more acidic.
s
h
4. Conclusions
3.5. Frontier molecular orbitals
Due to the smaller number of intermolecular interactions, HY-
The Highest Occupied Molecular Orbital (HOMO) is the molec-
DAC is more planar than HY-TRI, which can be measured by the
angle formed between the planes of the aromatic rings. Hence, the
twists present in HY-TRI added to the electron density of the
methoxy groups provide a closer contact between their molecules
when compared to HY-DAC. In contrast, the planar character of HY-
DAC allows its stability through p$$$p and CeH$$$p interactions.
Geometry optimization was carried out using the DFT (M062X
and B3LYP) method of the Gaussian 09 software package with 6-
ular orbital of highest energy that has electrons in it. The Lowest
Unoccupied Molecular Orbital (LUMO) is the molecular orbital of
lowest energy that does not have electrons in it. The energy dif-
ference (Gap) between the HOMO and the LUMO is related to the
minimum energy needed to excite an electron in the molecule [76].
The band gap energy (i.e., the energy difference between the ELUMO
and EHOMO) calculated for HY-DAC is 5.324 eV and 5.722 eV for HY-
TRI. According to the frontier molecular orbital theory, chemical
reactivity is strongly determined by the interaction of the HOMO
and the LUMO of the reactants. The energy of HOMO is often
associated with the electron donating ability of a molecule, and a
higher HOMO energy value indicates a higher tendency of the
molecule to donate electron(s) to the appropriate acceptor mole-
cule with low energy and an empty/partially filled molecular
orbital [77]. The HOMO/LUMO graphical surfaces of the studied
compounds, calculated using M062X/6-311 þ G (d,p) for HY-DAC
and HY-TRI, are shown in Fig. 10. HY-TRI has a large HOMO-LUMO
gap, which implies a high kinetic stability and low chemical reac-
tivity, compared to HY-DAC. In all the structures, the HOMO is
strongly delocalized on ring A and the double bond corresponding
3
11 þ G (d,p) and 6-311G(d) basis sets. The calculated harmonic
vibrational frequencies confirm the stability of the structures, and
the main absorbing groups are characterized. RMSDs for bond an-
gles and bond lengths in HY-DAC and HY-TRI are, respectively,
ꢀ ꢀ
1.70 , 0.0027 Å, 7.65 and 0.0030 Å. MEP confirms the existence of
2
intra and intermolecular interactions of the title molecules in solid
state. HY-TRI has a large HOMO-LUMO gap, which implies a high
kinetic stability and low chemical reactivity, compared to HY-DAC.
Analyzing the Hardness and Softness, we conclude that HY-DAC has
a higher capacity to receive electrons, while HY-TRI has a higher
capacity to resist changing its electronic configuration.
to the sites with the highest electron density. Absolute hardness (
and softness ( ) are properties that also facilitate the analysis of the
molecular reactivity and selectivity; a hard molecule has a large
while a soft molecule has a small E [77]. The global chemical
h
)
Acknowledgements
s
DE
The authors are grateful to Conselho Nacional de Desenvolvi-
mento Científico e Tecnol oꢀ gico (Grant no. 313070/2014-8) and
D

J.M.F. Custodio et al. / Journal of Molecular Structure 1136 (2017) 69e79
79
Coordenaç ~a o de Aperfeiçoamento de Pessoal de Nível Superior for
financial support and to Prof. Felipe Terra Martins, of the Depart-
ment of Chemistry of the Federal University of Goias, for the X-ray
data collection.
[38] M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria, M.A. Robb,
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H. Nakatsuji, M. Caricato, X. Li, H.P. Hratchian, A.F. Izmaylov, J. Bloino,
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