Hansch’s analysis application to chalcone synthesis by Claisen–Schmidt reaction based in DFT methodology

Article abstract of DOI:10.1007/s11696-017-0316-3

Chalcones are bioactive compounds obtained from either natural sources or synthetic procedures and widely used due to their several biological properties. The most common experimental methodology in obtaining these compounds is Claisen–Schmidt reaction, which is a particular type of aldolic condensation. In this work, we have synthesized 23 chalcones and by density functional theory (DFT) calculation, we have studied the difference in reactivity of the several benzaldehydes and their effects on the yield of this reaction. From molecular orbital descriptors were obtained two quantitative structure–reactivity relationship (QSRR) models based on Hansch’s analysis. The results of this study showed that, for the most benzaldehydes (15 of 23 compounds), their reactivity was correlated with LUMO energy and global Electrophilicity Index (ω) values, which are determined in the first step of Claisen–Schmidt condensation mechanism (nucleophilic addition). Likewise, for the smallest group of benzaldehydes, their reactivity was related to their HOMO and ΔL???H (LUMO???HOMO) energies, which were determined in the second step of the mechanism (trans-elimination). This is the first report of a QSRR model analyzing the yield of chalcone synthesis based on DFT methodology.

Full text of DOI:10.1007/s11696-017-0316-3

Chem. Pap.
DOI 10.1007/s11696-017-0316-3
ORIGINAL PAPER
Hansch’s analysis application to chalcone synthesis
by Claisen–Schmidt reaction based in DFT methodology
4
Marco Mellado1,2 Alejandro Madrid3 Ursula Martınez Jaime Mella5
´
•
•
•
•
´
Cristian O. Salas6 Mauricio Cuellar7
•
Received: 7 April 2017 / Accepted: 7 October 2017
Ó Institute of Chemistry, Slovak Academy of Sciences 2017
Abstract Chalcones are bioactive compounds obtained
from either natural sources or synthetic procedures and
widely used due to their several biological properties. The
most common experimental methodology in obtaining these
compounds is Claisen–Schmidt reaction, which is a partic-
ular type of aldolic condensation. In this work, we have
synthesized 23 chalcones and by density functional theory
(DFT) calculation, we have studied the difference in reac-
tivity of the several benzaldehydes and their effects on the
yield of this reaction. From molecular orbital descriptors
were obtained two quantitative structure–reactivity
relationship (QSRR) models based on Hansch’s analysis.
The results of this study showed that, for the most ben-
zaldehydes (15 of 23 compounds), their reactivity was cor-
related with LUMO energy and global Electrophilicity Index
(x) values, which are determined in the first step of Claisen–
Schmidt condensation mechanism (nucleophilic addition).
Likewise, for the smallest group of benzaldehydes, their
reactivity was related to their HOMO and
DL - H (LUMO - HOMO) energies, which were deter-
mined in the second step of the mechanism (trans-elimina-
tion). This is the first report of a QSRR model analyzing the
yield of chalcone synthesis based on DFT methodology.
Electronic supplementary material The online version of this
article (doi:10.1007/s11696-017-0316-3) contains supplementary
material, which is available to authorized users.
Keywords Chalcones Á Claisen–Schmidt condensation Á
QSRR Á DFT
& Marco Mellado
marco.mellado@pucv.cl
Introduction
1
´
Instituto de Quımica, Facultad de Ciencias, Pontificia
Universidad Catolica de Valparaıso, Av. Universidad 330,
´
´
Chalcones (or 1,3-diaryl-2-propen-1-one, IUPAC name)
are obtained from either natural sources or synthetic pro-
cedures and correspond to the main group of bioactive
compounds because these have several pharmacological
applications, such as anti-inflammatory, anti-pyretic, anti-
fungal, anti-bacterial, anti-mutagenic, anti-leishmanial,
anti-cancer, anti-HIV, and anti-oxidant properties (Anto
et al. 1994; Kamal et al. 2011; Luo et al. 2012; Pilatova
et al. 2010; Alegaon et al. 2014; Zhuang et al. 2017). These
compounds can be synthesized through the condensation of
acetophenone (1) with benzaldehyde (2) in the presence of
a base or an acid to form the respective chalcone (4) with
high chemoselectivity (see Scheme 1). This reaction is
generally known as Claisen–Schmidt condensation, and
therefore, this a specific type of aldolic condensation and in
the reaction mechanism, an intermediary product known as
´
Valparaıso, Chile
2
3
´
´
Departamento de Quımica, Universidad Tecnico Federico
Santa Marıa, Av. Espan˜a 1680, Valparaıso, Chile
´
´
´
Departamento de Quımica, Facultad de Ciencias Naturales y
Exactas, Universidad de Playa Ancha, Avda. Leopoldo
´
Carvallo 270, Valparaıso, Chile
4
5
´
Colegio Nueva Era Siglo XXI, Av. Cardenal Samore 1850,
´
Valparaıso, Chile
´
Instituto de Quımica y Bioquımica, Facultad de Ciencias,
Universidad de Valparaıso, Av. Gran Bretan˜a 1111, Playa
´
Ancha, Casilla 5030, Valparaıso, Chile
´
´
6
7
´
Departamento de Quımica Organica, Pontificia Universidad
Catolica de Chile, Avda. Vicun˜a Mackenna 4860, Macul,
´
´
Santiago, Chile
´
Facultad de Farmacia, Universidad de Valparaıso, Av. Gran
´
Bretan
˜a 1093, Valparaıso, Chile
123

Chem. Pap.
O
O
O
OH
O
+
H
Aldol
trans-
Elimination
R
R1
R
R1
R
R1
Condensation
2
4
1
3
Scheme 1 General Claisen–Schmidt reaction
aldol (3) is formed. To obtain bioactive chalcone deriva-
tives, usually alkaline conditions are more appropriated and
efficient. (Akansksha, 2007; Bhagat et al. 2006; Jeon et al.
2012; Li et al. 2010; Liu et al. 2011; Narender and Reddy
2007; Patil and Bhanage 2013; Petrov et al. 2008;
Sivakumar et al. 2001; Sugamoto et al. 2011; Narender
et al. 2011). Likewise, it is well known that the substitution
patterns of both 1 and/or 2 are important to achieve in a
successful way this reaction, since which can influence the
yield of this transformation.
Experimental
General
Melting Point was measured in Fischer Scientific appara-
tus. Infrared spectra were recorded in Buck Scientific
M500. Recorded range 600 cm-1–4000 cm-1, all samples
were registered on ATR system (attenuated total reflec-
tance). 1H NMR, 13C NMR, 2D-HSQC and 2D-HMBC
spectra were recorded on a Bruker Avance 400 Digital
1
On the other hand, several computational methodologies
have been used to study the mechanism of reactions. Some
analysis of structural relationships such as quantitative
structure–property relationships or quantitative structure–re-
activity relationships (QSPR and QSRR, respectively) have
emerged as a useful tool to find relevant physicochemical
descriptors to get some insight into the underlying mecha-
nisms of reaction. These mathematical models are based on
Hansch’s analysis and on the assumption that structurally
similar compounds have similar activities or properties (Yee
and Wei 2012). The QSPR and QSRR can also be used in the
analysis of structural descriptors that capture different con-
stitutional, topological, geometrical, or electronic features of
molecular structures in relation to properties of interest (Du-
chowicz and Castro 2009; Yee and Wei 2012). These
molecular descriptors can be readily calculated through
mathematical formulae derived from several theories, e.g.,
quantum mechanics and other similar theories, which have
been proven to function quite well for the wide spectra of
properties/activities (Duchowicz and Castro 2009). In this
context, density functional theory (DFT) is an important
method in designing bioactive compounds, obtaining satis-
factory results based on accuracy and reliability (Carloni et al.
2006). Furthermore, this methodology has been used in
understanding chemical system reactivity (De Vleeschouwer
et al. 2007; Moens et al. 2007). In fact, through DFT, it is
possible to calculate different reactivity descriptors, such as
electronic chemical potential (l), Pearson’s hardness and
softness (g and S, respectively), and global Electrophilicity
Index (x), all of which led to understanding reactivity in
organic molecules (Chermette 1999; Li et al. 2010).
NMR spectrometer, operating at 400.13 MHz for H and
100.6 MHz for 13C, respectively. Chemical shifts are
reported in d (ppm downfield from the TMS resonance)
and coupling constants (J) are given in Hz. GC–MS was
carried out Agilent Technologies 6890 model with auto-
matic ALS, mass detector HP MD 5973 in spitless mode.
Chemicals
To a stirred solution of 4-methoxyacetophenone (5)
(250 mg, 2.08 mmol) and the appropriate benzaldehydes
(6a–w; 2.29 mmol) in EtOH (2.5 mL) was added saturated
ethanolic NaOH (20 mL). The mixture was stirred for 48 h at
room temperature. After reaction time, the reaction mixture
was neutralized with HCl 5% solution until pH & 7 and
extracted with ethyl acetate (3 9 50 mL). Later, the organic
phase was dried, concentrated and purified by flash column
chromatography using EtOAc: Hexane mix (0:1–1:1) as
eluent, obtaining the corresponding chalcones (7a–w).
Computational details
All compounds considered in this study (acetophenone (5),
benzaldehydes (6a–w) and aldol-intermediate structures),
were subjected to the following computational procedure.
Full unconstrained geometry optimizations of these com-
pounds were carried out using Gaussian 03 program (Frisch
et al. 2004). The most widely used exchange–correlation
function suggested exchange potential by Becke with gra-
dient-corrected correlation provided by Lee, Yang and Parr
(B3LYP) with Gaussian basis set triple-Z 6-311G double-
polarized and d orbital expansion was necesary for
obtained chemical properties of all compounds. Optimized
geometries were verified by frequency calculations and
characterized as minimum structure (no imaginary fre-
quency) in their potential energy surfaces. The reactivity
Herein, a quantitative structure–reactivity relationship
(QSRR) model was developed to explain the different
yields observed in Claisen–Schmidt condensation to obtain
several chalcones, in alkaline conditions. The uses of this
methodology should be useful for other similar reactions.
123

Chem. Pap.
descriptors: Mu¨lliken’s Charge on carbon and oxygen of
carbonyl benzaldehyde, highest-occupied molecular orbital
(HOMO), lowest unoccupied molecular orbital (LUMO),
electronic chemical potential (l), hardness (g), softness
(S) and Electrophilicity Global Index (x) were calculated
with the following equations:
The difference in the yields in this reaction is probably
related to the substitution patterns of benzaldehydes, in
terms of structural features and position of these groups. If
considered 7a as a reference compound to evaluate the
effect of chemical modifications over Claisen–Schmidt
reaction, some tendency is possibly observed. One of these
is the acidic hydrogen of hydroxyl–benzaldehydes (OH
group) generated decreased yield (except 7q, 80% yield)
(see Scheme 2). On the other hand, strong electron donor p
groups on R3’ position (7g and 7h) decrease the chalcone
yield, however, a few electronic donor as methyl group
generate to increase the chalcone yield. Likewise, when the
replacement of the hydrogen atom is in R4’ positions of
benzaldehydes, is observed the best results for each group
in particular (7j–l), except to 7n. In the case of the poly-
substitution (7o–w), the behavior is unclear, because of the
yield of this reaction depended on both, the position and
feature of these groups. However, a Hansch’s analysis
model gives an even more precise explanation of the yield
differences of the studied compounds, which was devel-
oped in the next section.
ðELUMO þ EHOMO
Þ
l ¼
g ¼
S ¼
ð1Þ
ð2Þ
ð3Þ
2
ðELUMO À EHOMO
Þ
;
2
1
2g
l2
x ¼
ð4Þ
2g
Hansch’s analysis
Hansch’s analysis was performed using multiple linear
regressions, which has been attempted to relate the struc-
tural features of these benzaldehydes on the yield of
reactions. In this analysis, different descriptors previously
calculated were selected: HOMO and LUMO energies,
energy difference between LUMO and HOMO (DL - H),
electronic chemistry potential (l), hardness (g), softness
(S), global electrophilicity (x), Mulliken’s charge (on CO
and O of carbonyl groups) of benzaldehydes. Statistica 7.0
Package Software carried out model optimization.
The chemical structures of the target compounds were
established based on their spectral properties (IR, 1H NMR,
13C NMR and MS, see the Experimental part and Sup-
plementary Material). Infrared spectra of all obtained
chalcones (7a–w) showed absorption peaks characteristic
of conjugated carbonyl groups (t = 1665 cm-1) by reso-
nance effects (Silverstein et al. 2005). Furthermore, these
peaks are characteristic of aromatic systems, with angle
deformations of t & 1600, 1550, and 1500 cm-1
.
The 1H-NMR spectra recorded in deuterated chloroform
(CDCl3) of all compounds shows two coupled hydrogens
with geometry trans to the down field (d & 7.88 and
7.56 ppm, J & 15.6 Hz), corresponding to a and b
hydrogens, respectively. 13C-NMR and 2D-HSQC spectra
Cross-validation QSRR model
Cross-validation of QSRR model was carried out by Gol-
braikh method (Golbraikh and Alexander 2002). Accept-
able q2 values are equal or greater than 0.5. q2 values are
obtained by the following formula:
show two carbons correlated to hydrogens
a
P
(d & 122 ppm) and b (d & 143 ppm). Finally, with 2D-
HMBC experiments, quaternary carbons that link the two
aryl systems (see Scheme 3a) were determined. The EIMS
of all compounds showed three key fragments: M?-15 (lost
CH3 from methoxy group), M?-131 (lost cinnamic frag-
ment from a carbonyl rupture), and M?-103 (lost styrene
fragment from a carbonyl rupture) (see Scheme 3b).
2
ðyobs À ycalc
Þ
q2 ¼ 1 À
ð5Þ
P
2
ðyobs À yave
Þ
where yobs is pYield observed, ycalc is pYield calculated by
QSPR model and yave is pYield average of all compounds
in the training set.
Hansch’s analysis
Results and discussion
Chemistry
Quantum chemical calculations are an attractive source for
new molecular descriptors, which can express all of the
electronic and geometric properties of molecules and their
interactions. Indeed, many recent Hansch’s analysis
(QSAR/QSRR/QSPR studies) have employed quantum
chemical descriptors alone or in combination with con-
ventional descriptors, such as atomic charges, orbital
The preparation of the chalcones 7a–w is described in
Scheme 2. 4-methoxyacetophenone (5) was treated with dif-
ferent benzaldehydes (6a–w) in ethanolic NaOH to give 23
chalcones(7a–w), withmediumtoexcellentyields(40–98%).
123

Chem. Pap.
O
O
O
2'
5'
2'
5'
3'
NaOH / EtOH
r.t.
3'
H
R
+
R
4'
48
MeO
7a-w
h,
4'
MeO
5
6a-w
R=
68%
R=
R=
R=
R=
R=
R=
4'-NMe 98%
7a,
7b,
7c,
7d,
7e,
7f,
7g,
7h,
7i,
H;
;
(
2
7m,
7n,
7o,
7p,
(
)
)
R=
R=
R=
R=
R=
R=
R=
R=
R=
R=
R=
80%
44%
H
;
13
4'-OC6
-
47%
)
2'-Me;
(
(
)
)
(
71%
2'-OH;
;
2',5'
2',5'
(OMe)2
(
)
-
49%
H
(OC6 )
13 2
50%
)
2'-OMe;
;
(
)
(
H
(
(
2'-OC6
3'-Me;
69%
)
2'-OH-3'
80%
)
;
-OMe;
(
) 7q,
(
(
9123%
3'-OMe-4'
63%
)
7r,
-OH;
-
40%
7s R=
41%
3'-OH;
,
;
3',4'
)
(OMe)2
(
)
-
50%
R=
3'4'
91%
3'-OMe;
7t,
(
)
(OCH2O); (
)
(
H
3'-OC6
4'-Me;
43%
R=
H
;
3'-OMe-4'-OC6
55%
)
;
7u,
(
)
13
13
-
98%
R=
90%
'-Br;
63%)
(
;
7v,
7w,
7j,
7k,
7l,
2',4',5'
2',5'
(
)
(OMe)3
(OMe)2
(
)
-
62%
R=
-4
4'-OH;
(
)
98%
4'-OMe;
(
)
Scheme 2 Synthesis of chalcone 7a–w by Claisen–Schmidt reaction
electron density, dipole moments, and polarity indices,
among others (Karelson and Lobanov 1996).
pYield ¼ À0:639ðÆ0:329Þ À 336ðÆ46:7ÞLUMO
À 174ðÆ24:8Þx
There are several descriptors to understand chemical
reactivity. The most widely used are that of the
molecular orbital (MO), e.g., highest-occupied molecu-
lar orbital (HOMO) and lowest unoccupied molecular
orbital (LUMO), equivalent to Lewis base and acid,
respectively (Ege 2000). HOMO and LUMO values can
be used to calculate other reactivity descriptors, such as
DLH (LUMO–HOMO), electronic chemical potential
(l), Pearson’s hardness and softness (g and S, respec-
tively) and global Electrophilicity Index (x). Electronic
chemical potential (l) is, at the physical level, electron
donation capacity from HOMO to LUMO. Hardness can
be understood as resistance to charge transfer. In
addition, the global Electrophilicity Index (x) is a
concept of measure for energy stabilization, such as
when systems receive additional electronic charges from
underground (Lopez et al. 2013; Pearson 1993).
ð6Þ
n ¼ 15; r ¼ 0:918; r2 ¼ 0:843; SD ¼ 0:063;
F ¼ 29:5; q2 ¼ 0:821
The first model (Eq. 6) shows that Claisen–Schmidt
condensation is related to LUMO and global Elec-
trophilicity Index (x) values of the benzaldehydes, which
could be connected to their capacities to accept two elec-
trons (Lopez et al. 2013; Parr et al. 1999; Pearson 1993).
This point is pivotal in the first step in the Claisen–Schmidt
reaction mechanism, which involves nucleophilic attack
from enolate through benzaldehyde, to obtain the respec-
tive addition intermediate (see Scheme 4).
Furthermore, in optimizing this Hansch’s analysis
model, eight outlier compounds with no significance in this
model were identified. All outlier compounds have a
common feature: OH or O-alkyl groups, in positions 2 and/
or 4, which could influence the stereo-electronic properties
of these benzaldehydes. For explaining different features of
outlier compounds and chalcone yield relationship, all
descriptors calculated were correlated with pYield again,
found a significant correlation (p \ 0.05) with HOMO,
DLH, g, S and l descriptors. Furthermore, a new Hansch’s
analysis statistical depuration showed that HOMO and
DLH are the only descriptors that can explain reactivity
differences with 99.99% of certainity (p \ 0.0001). In
second, the Hanch’s analysis (outlier model), two non-
correlated compounds were found (6q and 6t). Despite
efforts by reactivity understanding of this compounds using
Hansch’s analysis, into two models have no contribution
statistical. Variables involved in the Hanch’s analysis
According to previously mentioned descriptors, the
values of these parameters were calculated for ben-
zaldehydes under investigation and those that elicited a
statistical significance (p B 0.05), then were correlated
with the respective reaction yields (pYield). The
descriptors considered were: Mu¨lliken charge of the
carbon in the carbonyl group (CO), LUMO, electronic
chemical potential (l), and global Electrophilicity Index
(x). However, when finished Hansch’s analysis statisti-
cal depuration, only LUMO and x were the descriptors
that can explain reactivity differences with 99.99% of
certainity (p \ 0.0001) (see Eq. 6 and Table 1 Supple-
mentary Material).
123

Chem. Pap.
Scheme 3 a Most important 2D-HMBC correlations for chalcone 7m. b Common fragmentation pattern observed for chalcones 7a–w
HO-
O
O
O
OH
O
-OH
R
R
trans-
H
MeO
MeO
elimination
MeO
MeO
H2O
O
Pivotal step
O
O
+
H
R
R
Scheme 5 The pivotal step in Claisen–Schmidt reaction for outliner
benzaldehydes, observed from Hansch’s analysis
MeO
MeO
Pivotal step
pYieldout ¼ À4:03ðÆ0:264Þ À 11:5ðÆ2:55ÞHOMO
Scheme 4 The pivotal step in Claisen–Schmidt reaction for some
benzaldehydes, observed from Hansch’s analysis
À 2:8ðÆ2:64ÞDLH
ð7Þ
n ¼ 6; r ¼ 0:982; r2 ¼ 0:964; SD ¼ 0:030;
(outlier model) were thus HOMO and DLH (see Eq. 7 and
Table 2 supplementary material), which correspond to
reactivity descriptors related to electron-donating capacity
(Lopez et al. 2013; Pearson 1993).
F ¼ 40:1; q2 ¼ 0:999
123

Chem. Pap.
Fig. 1 HOMO diagrams for
aldol intermediates: a 7a and b
7c. DFT-B3LYP-6-
311G ??(d) calculated.
Isovalue: 0.035; Density:
0.0004
reaction and would be used in other chemical reactions to
explain the same experimental aspects.
Equation 7 shows that HOMO is the most important
descriptor (up to four times more important than DLH),
related to electron-donating capacity or the behavior as
Lewis base of the outliner benzaldehydes (Ege 2000;
Lopez et al. 2013; Pearson 1993). If Claisen–Schmidt
reaction mechanism is considered, these electronic features
are important for the second step of the reaction, the trans-
elimination (see Scheme 5). To confirm this hypothesis,
HOMO and DLH values of aldols were calculated and the
values of these descriptors were correlated with the cor-
responding benzaldehydes, which shows r2 C 0.9. These
results could indicate that in the Claisen–Schmidt reaction
mechanism, the reactivity of outlier compounds was
determined by the second step of the reaction, the trans-
elimination (see Scheme 5).
´
Acknowledgements The authors thank the Direccion de Investi-
gacion y Postgrado (DGIP) of Universidad Tecnica Federico Santa
´
´
´
Marıa; scientific initiation project 2015 (PIIC-MM), CONICYT
Programa Formacion de Capital Humano Avanzado 21130456;
´
´
Proyecto VRIEA-PUCV ‘‘37.0/2017’’ and Dr. Guillermo Dıaz
Felming of Laboratorio de Espectroscopia Atomica y Molecular of
´
Universidad de Playa Ancha.
References
Akansksha AK (2007) Zirconium chloride catalyzed efficient syn-
thesis of 1,3-diaryl-2-propenones in solvent free conditions via
aldol condensation. J Mol Catal A Chem 274:212–216. doi:10.
1016/j.molcata.2007.05.016
Alegaon SG, Alagawadi KR, Vinod D, Unger B, Khatib NA (2014)
Synthesis, pharmacophore modeling, and cytotoxic activity of
2-thioxothiazolidin-4-one derivatives. Med Chem Res
23:5160–5173. doi:10.1007/s00044-014-1087-9
Anto RJ, Kutaan G, Kuttan R, Sathyanarayana K, Rao MNA (1994)
Tumor-reducing and antioxidant activities of sydnone-substi-
tuted chalcones. J Clin Biochem Nutr 17:73–80. doi:10.3164/
jcbn.17.73
Bhagat S, Sharma R, Sawant D, Sharma L, Chakraborti A (2006)
LiOHÁ H2O as a novel dual activation catalyst for highly
efficient and easy synthesis of 1, 3-diaryl-2-propenones by
Claisen–Schmidt condensation under mild conditions. J Mol
Catal A Chem 244:20–24. doi:10.1016/j.molcata.2005.08.039
Carloni P, Alber F, Mannhold R, Kubinyi H, Folkers G (2006)
Quantum medicinal chemistry, vol 17. Wiley-VCH, Alemania
Chermette H (1999) Chemical reactivity indexes in density functional
theory. J Comp Chem 20:129–154. doi:10.1002/(Sici)1096-
987x(19990115)20:1\129:Aid-Jcc13[3.0.Co;2-A
Figure 1 shows HOMO diagrams for aldol intermediates
of 7a and 7c. Figure 1b demonstrates that 20-OH substitu-
tion increases electronic population in the ring near OH-
aldol, behavior not observed for aldol intermediate of 7a.
This effect producing smaller stability on the addition
intermediate, which can be related to the HOMO values in
Hansch’s analysis outlier model (All HOMO plots of aldols
outlier model are in Fig. 1 Supplementary Material).
Conclusions
In summary, a series of 23 chalcones were synthesized
through Claisen–Schmidt condensation using alkaline
media and structural characterization several spectroscopic
techniques (IR, NMR, and MS). Through DFT calculus
with B3LYP exchange-correlated basis set and
6-311G ??(d) calculus level, was possible obtained
quantum descriptors for Hansch’s analysis. The Hansch’s
analysis indicated that, for 15/23 compounds (65%), the
yield to obtain the respective chalcone, were related to the
nucleophilic attack from enolate to the carbonyl group of
the respective benzaldehyde. On the other hand, for 6/23
compounds (26%), the yield of this reaction was deter-
mined for aldol dehydration process. In two models,
developed descriptors were correlated with 99.9% certainty
(p \ 0.001). Finally, this is the first report of Hansch’s
analysis use to explain different yields in Claisen–Schmidt
De Vleeschouwer F, Van Speybroeck V, Waroquier M, Geerlings P,
De Proft F (2007) Electrophilicity and nucleophilicity index for
radicals. Org Lett 9:2721–2724. doi:10.1021/ol071038k
Duchowicz PR, Castro EA (2009) QSPR studies on aqueous
solubilities of drug-like compounds. Int
10:2558–2577. doi:10.3390/ijms10062558
J
Mol Sci
´
Ege S (2000) Reacciones Concertadas Quımica Organica Estructura y
Reactividad, vol TOMO 1. Editorial Reverte, Espan˜a,
´
`
pp 1297–1356
Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA,
Cheeseman JR, Montgomery JA, Vreven T, Kudin KN, Burant
JC, Millam JM, Iyengar SS, Tomasi J, Barone V, Mennucci B,
Cossi M, Scalmani G, Rega N, Petersson GA, Nakatsuji H, Hada
M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M,
Nakajima T, Honda Y, Kitao O, Nakai H, Klene M, Li X, Knox
JE, Hratchian HP, Cross JB, Bakken V, Adamo C, Jaramillo J,
Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R,
123

Chem. Pap.
Pomelli C, Ochterski JW, Ayala PY, Morokuma K, Voth GA,
Narender T, Reddy KP (2007) A simple and highly efficient method
for the synthesis of chalcones by using borontrifluoride-etherate.
Tetrahedron Lett 48:3177–3180. doi:10.1016/j.tetlet.2007.03.
054
Narender T, Venkateswarlu K, Nayak BV, Sakar S (2011) A new
chemical access for 30-acetyl-40-hydroxychalcones using boron-
trifluoride–etherate via a regioselective Claisen–Schmidt con-
densation and its application in the synthesis of chalcone
hybrids. Tetrahedron Lett 52:5794–5798. doi:10.1016/j.tetlet.
2011.08.120
Parr RG, Von Szentpaly L, Liu SB (1999) Electrophilicity index.
J Am Chem Soc 121:1922–1924. doi:10.1021/Ja983494x
Patil AB, Bhanage BM (2013) Novel and green approach for the
nanocrystalline magnesium oxide synthesis and its catalytic
performance in Claisen–Schmidt condensation. Catal Commun
36:79–83. doi:10.1016/j.catcom.2013.03.012
Pearson RG (1993) The principle of maximum hardness. Acc Chem
Res 26:250–255. doi:10.1021/Ar00029a004
Petrov O, Ivanova Y, Gerova M (2008) SOCl2/EtOH: catalytic system
for synthesis of chalcones. Catal Commun 9:315–316. doi:10.
1016/j.catcom.2007.06.013
Pilatova M, Varinska L, Perjesi P, Sarissky M, Mirossay L, Solar P,
Ostro A, Mojzis J (2010) In vitro antiproliferative and antian-
giogenic effects of synthetic chalcone analogues. Toxicol
In Vitro 24:1347–1355. doi:10.1016/j.tiv.2010.04.013
Silverstein RM, Webster FX, Kiemle DJ (2005) Spectrometric
identification of organic compounds, Seventh edn. Wiley, USA
Sivakumar PM, Prabhakar PK, Doble M (2001) Synthesis, antioxidant
evaluation, and quantitative structure–activity relationship stud-
ies of chalcones. Med Chem Res 20:482–492. doi:10.1007/
s00044-010-9342-1
Salvador P, Dannenberg JJ, Zakrzewski VG, Dapprich S,
Daniels AD, Strain MC, Farkas O, Malick DK, Rabuck AD,
Raghavachari K, Foresman JB, Ortiz JV, Cui Q, Baboul AG,
Clifford S, Cioslowski J, Stefanov BB, Liu G, Liashenko A,
Piskorz P, Komaromi I, Martin RL, Fox DJ, Keith T, Al-Laham
MA, Peng CY, Nanayakkara A, Challacombe M, Gill PMW,
Johnson B, Chen W, Wong MW, Gonzalez C, Pople JA (2004)
Gaussian 03, Revision C.02. Gaussian, Inc, Wallingford
Golbraikh A, Alexander T (2002) Beware of q2! J Mol Graph Model
20:269. doi:10.1016/S1093-3263(01)00123-1
Jeon JH, Kim SJ, Kim CG, Kim JK, Jun JG (2012) Synthesis of
biologically active chalcones and their anti-inflammatory effects.
Bull Korean Chem Soc 33:953–957. doi:10.5012/bkcs.2012.33.
3.953
Kamal A, Prabhakar S, Janaki Ramaiah M, Venkat Reddy P, Ratna
Reddy C, Mallareddy A, Shankaraiah N, Lakshmi Narayan
Reddy T, Pushpavalli SN, Pal-Bhadra M (2011) Synthesis and
anticancer activity of chalcone-pyrrolobenzodiazepine conju-
gates linked via 1,2,3-triazole ring side-armed with alkane
spacers. Eur J Med Chem 46:3820–3831. doi:10.1016/j.ejmech.
2011.05.050
Karelson M, Lobanov VS (1996) Quantum-chemical descriptor in
QSAR/QSPR studies. Chem Rev 96:1027–1043. doi:10.1021/
cr950202r
Li W, Xu K, Xu L, Hu J, Ma F, Guo Y (2010) Preparation of highly
ordered mesoporous AlSBA-15–SO3H hybrid material for the
catalytic synthesis of chalcone under solvent-free condition.
Appl Surf Sci 256:3183–3190
Liu Z, Lee W, Kim SN, Yoon G, Cheon SH (2011) Design, synthesis,
and evaluation of bromo-retrochalcone derivatives as protein
tyrosine phosphatase 1B inhibitors. Bioorg Med Chem Lett
21:3755–3758. doi:10.1016/j.bmcl.2011.04.057
Lopez JM, Ensuncho AE, Robles JR (2013) Global and local
reactivity descriptors for the design of new anticancer drugs
based on cis-platinum(II). Quim Nova 36:1308–1317. doi:10.
1590/S0100-40422013000900006
Sugamoto K, Matsusita YI, Matsui K, Kurogi C, Matsui T (2011)
Synthesis and antibacterial activity of chalcones bearing prenyl
or geranyl groups from Angelica keiskei. Tetrahedron
67:5346–5359. doi:10.1016/j.tet.2011.04.104
Yee LC, Wei YC (2012) Statistical modelling of molecular descrip-
tors in QSAR/QSPR. In: Dehmer M, Varmuza K, Bonchev D
(eds) Statistical modelling of molecular descriptors in QSAR/
QSPR, vol 2. Wiley, Weinheim
Luo Y, Song R, Li Y, Zhang S, Liu ZJ, Fu J, Zhu HL (2012) Design,
synthesis, and biological evaluation of chalcone oxime deriva-
tives as potential immunosuppressive agents. Bioorg Med Chem
Lett 22:3039–3043. doi:10.1016/j.bmcl.2012.03.080
Moens J, Geerlings P, Roos G (2007) A conceptual DFT approach for
the evaluation and interpretation of redox potentials. Chem Eur J
13:8174–8184. doi:10.1002/chem.200601896
Zhuang C, Zhang W, Sheng C, Zhang W, Xing C, Miao Z (2017)
Chalcone: a privileged structure in medicinal chemistry. Chem
Rev 117:7762–7810. doi:10.1021/acs.chemrev.7b00020
123