Systematic study of the fluorescent properties of cinnamaldehyde phenylhydrazone and its interactions with metals: Synthesis and photophysical evaluation

Article abstract of DOI:10.1016/j.molstruc.2020.128430

Hydrazones are organic compounds with applications in various fields of research, including fluorescent applications. In this investigation, the compound cinnamaldehyde phenylhydrazone was synthesized by condensation between cinnamaldehyde (1) and phenylh

Full text of DOI:10.1016/j.molstruc.2020.128430

Journal of Molecular Structure 1217 (2020) 128430
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: http://www.elsevier.com/locate/molstruc
Systematic study of the fluorescent properties of cinnamaldehyde
phenylhydrazone and its interactions with metals: Synthesis and
photophysical evaluation
,
*
a
b
b
a
Marco Mellado a , Rafaela Sariego-Kluge , Cesar Gonzalez , Katy Díaz , Luis F. Aguilar ,
ꢀ
ꢀ
Manuel A. Bravo a
,
**
a
ꢀ
Instituto de Química, Facultad de Ciencias, Pontificia Universidad Catolica de Valparaíso. Av. Universidad #330, Curauma, Valparaíso, Chile
Departamento de Química, Universidad Tecnica Federico Santa María. Av. Espana 1680, Valparaíso, Chile
b
ꢀ
~
a r t i c l e i n f o
a b s t r a c t
Article history:
Hydrazones are organic compounds with applications in various fields of research, including fluorescent
applications. In this investigation, the compound cinnamaldehyde phenylhydrazone was synthesized by
condensation between cinnamaldehyde (1) and phenylhydrazine (2). Furthermore, the photophysical
properties were evaluated in the presence and absence of inorganic salts, and it was found that the
fluorescence intensity selectively decays with CuCl2 in a thermodynamically spontaneous process
Received 21 March 2020
Received in revised form
8 May 2020
Accepted 9 May 2020
Available online 11 May 2020
(
D
G ¼ negative). In addition, computational approaches were used, which identified the transfer of
electrons from highest-occupied molecular orbital HOMO of compound 3 to the lowest unoccupied
molecular orbital (LUMO) of CuCl2 as the key interaction for quenching the fluorescence intensity of
cinnamaldehyde phenylhydrazone.
Keywords:
Cinnamaldehyde phenylhydrazone
Selective fluorescence quenching
Thermodynamic properties
HOMO -LUMO electron transfer
Additionally, the potential application of compound 3 as a Cu2þ chemosensor in different water
samples was evaluated. This compound was found to exhibit better recovery of Cu2þ in natural water
samples (higher than 99.3%) than in drinking water (66%).
© 2020 Elsevier B.V. All rights reserved.
1. Introduction
[24e27].
The development of organic molecules with colorimetric or
Hydrazones are known as Schiff bases that can be obtained by
condensation between hydrazines and aldehydes, exhibiting an
N]C bond [1]. These compounds have important properties for use
in various fields of research (e.g., pharmacology). Hydrazones are
used as “building blocks” for the development of bioactive mole-
cules (showing analgesic, anti-inflammatory, antioxidant, anti-
depressant, anti-convulsant, anti-acetylcholinesterase, anti-
tumour, anti-tuberculosis, and broad-spectrum antimicrobial ac-
tivities) [2e18]. Additionally, hydrazones have fluorescent
properties, so they can be used as pigments, dyes, molecular
switches, metallo-assemblies, and sensors [19e23]. Regarding its
use as a sensor, hydrazone can coordinate with various transition
metals to form stable complexes, including Cu(II), Fe(III), and Zn(II)
fluorescent chemosensor properties to detect toxic metal ions, e.g.,
Cu2þ, has received great attention [28]. This cation plays several
roles in living systems, among which it functions as a nutrient and
redox catalyst in metalloenzymes such as carbonic anhydrase,
carboxypeptidases, alkaline phosphatase and b-lactamase [29,30].
Despite the important physiological functions of this cation, vari-
ations in its concentration in the human body are associated with
Alzheimer’s, Wilson and prion diseases, as well as lateral amyo-
trophic sclerosis and others; all these diseases are related to the
production of reactive oxygen species (ROS) [30]. Due to the above
mentioned reasons, the determination of trace amounts of copper
in drinking water is becoming increasingly important. To this end,
compounds with simple chemical structures have been used as
colorimetric probes to detect Cu2þsuch as compound (I) [31], while
compounds (II) and (III) have also been used to detect Cu2þ but as
fluorescent probes (see Fig. 1) [28,32].
* Corresponding author.
** Corresponding author.
E-mail addresses: marco.mellado@pucv.cl (M. Mellado), manuel.bravo@pucv.cl
(M.A. Bravo).
To evaluate its possible application as a chemosensor, cinna-
maldehyde phenylhydrazone (3) was synthesized by condensation
between cinnamaldehyde (1) and phenylhydrazine (2) (see Scheme
https://doi.org/10.1016/j.molstruc.2020.128430
0022-2860/© 2020 Elsevier B.V. All rights reserved.

2
M. Mellado et al. / Journal of Molecular Structure 1217 (2020) 128430
Fig. 1. Hydrazones used to detect and measure Cu(II), with the Schiff base bond highlighted in red.
Scheme 1. Synthesis of cinnamaldehyde phenylhydrazone (3).
1). Its photophysical properties (UVeVis and fluorescence) were
evaluated in the absence and presence of inorganic (metal) salts, as
well as the determination of thermodynamic constants associated
2.3. Synthesis of cinnamaldehyde phenylhydrazone (3)
In a 250-mL three-neck round-bottomed flask, cinnamaldehyde
(1, 500 mg, 3.79 mmol) was dissolved in 2-propanol (50 mL), and
phenylhydrazine (2, 409 mg, 3.79 mmol) was added. The mixture
was stirred at reflux for 8 h. After this time, distilled water was
added to finish the reaction. The reaction mixture was extracted
with dichloromethane (3 ꢀ 30 mL), and the organic layer was dried
and concentrated under reduced pressure. The resulting mixture
was separated using a flash chromatography column with a hex-
ane:ethyl acetate mixture with increasing polarity as the mobile
phase. Finally, a pale yellow solid (3, 676 mg, 3.07 mmol) was ob-
with the inorganic metal-hydrazone interaction (DG, DH, and DS).
Additionally, the main chemical properties that influence the
metal-hydrazone interaction were identified by density functional
theory (DFT) calculations and with the application of multivariable
analysis. Finally, the potential application of cinnamaldehyde
phenylhydrazone (3) in the determination of Cu2þ in water samples
was evaluated.
tained as a pure compound (81% yield); MP: 161.6
1 y,
ꢁC, IR (
2. Experimental
cmꢂ1): 3441 (s, ¼NeH), 3313 (s, C]H), 1601 (s, CH Ar), 1560 (m, CH
Ar), 1517 (s, CH Ar), 1486 (w, CH Ar), 1259 (s, HeCeN), 1135(s,
2.1. Instrumentation
HeCeN); 1H NMR (400 MHz, CDCl3):
d
7.55 (1H, d, J ¼ 8.0 Hz, H-3a),
7.45 (2H, d, J ¼ 8.0 Hz, H-2 þ H-6), 7.35 (2H, m, H-3’þH-50),
7.29e7.24 (3H, m, H-3 þ H-5 þ H-2a),7.06e6.99 (3H, m, H-4þ H-
2’þH-60), 6.87 (1H, m, H-40), 6.69 (1H, d, J ¼ 16.0 Hz, H-1a); 13C NMR
The melting point was measured using a Stuart Scientific
Melting Point SMP3 (Staffordshire, UK). Infrared spectra were
recorded using aJasco FT-IR 4600 (Tokyo, Japan). 1H NMR
(400.13 MHz), 13C NMR (100.6 MHz), 2D-HSQC and 2D-HMBC
spectra were recorded on a Bruker Avance 400 Digital NMR spec-
trometer (Berlin, Germany). Tetramethylsilane was used as an in-
ternal standard. GC-MS was carried out using an Agilent
Technologies 6890 model (Santa Clara, CA, USA) with an automatic
ALS and an HP MD 5973 mass detector in splitless mode. Mea-
surement of pH was performed using a Bante Instruments Bench-
top PHS-25cw microprocessor pH/mV meter (Shanghai, China).
Absorption spectra were recorded on a Shimadzu UV-mini-1240
UVeVis spectrophotometer (Kyoto, Japan). All steady-state fluo-
rescence measurements were performed on an ISS K2 Multifre-
quency Phase Fluorometer (Champaign, IL, USA).
(400 MHz, CDCl3):
d
144.2 (C-10), 139.8 (CH-1a), 136.7 (C-1), 134.1
(CH-3a), 129.3 (2xCH, CH-5’ þ CH-30), 128.7 (2xCH, CH-3 þ CH-5),
128.0 (CH-4), 126.5 (2xCH, CH-2 þ CH-6), 125.9 (CH-2a), 120.2 (CH-
40), 112.7 (2xCH, CH-2’ þ CH-6’). MS-EI: 222 [Mþ] (100%). All
spectroscopic analyses are consistent with a previous report [1].
2.4. Evaluation of fluorescence spectroscopy parameters
Fluorescence excitation and emission spectra were obtained
using a xenon arc lamp as a light source. Fluorescence spectra were
measured at 90ꢁ in an L-format using single photon counting mode.
Data were acquired and analysed by Vinci™ software.
The relative quantum yield (
F) was determined using quinine-
sulfate as a standard (0.1 M H2SO4 at 22 ꢁC,
Fs ¼ 0.58, lex ¼ 350 nm)
[33]. Equation (1) was used to calculate the quantum yield [34].
2.2. Chemicals
Fu As n2
Fs Au
Cinnamaldehyde (1), phenylhydrazine (2), dimethylsulfoxide
(DMSO), heptane (C7H16), tetrahydrofuran (THF), acetone (Me2CO),
dimethylformamide (DMF), methanol (MeOH), HEPES sodium salt
HCl, NaOH, LiCl, NaCl, MgCl2 x 6H2O, CaCl2 x 2H2O, SrCl2 x 6H2O,
F
¼
x
x
u xFs
(Eq. 1)
ns2
where the subscripts u and s indicate the test and standard,
respectively. is the quantum yield, A is the absorbance at the
F
BaCl2 x 2H2O, AlCl3, SnCl2 x 2H2O, BiCl3, CrCl3 x 6H2O, MnCl2
x
excitation wavelength, F is the integrated emission spectrum, and n
is the refractive index of the solvent.
4H2O, FeCl3 x 6H2O, CoCl2 x 6H2O, NiCl2 x 6H2O, CuCl2 x 2H2O, CuCl,
ZnCl2, CdCl2 x 2 1/2H2O, HgCl2, Pb(NO3)2, AgNO3 and ethylenedi-
amine tetrasodic salt (EDTA), were purchased from Merck (Darm-
stadt, Germany). 2-Propanol, hexane, dichloromethane (CH2Cl2),
ethyl acetate and acetonitrile (MeCN) were purchased from J.T.
Baker (Radnor, PA, USA).
2.5. Evaluation of figures of merit
The values of the limit of detection and limit of quantification

M. Mellado et al. / Journal of Molecular Structure 1217 (2020) 128430
3
(LOD and LOQ, respectively) were calculated as reported by
2.8. Collection and preparation of water samples
Thompson et al., 2002 using the following equations [35].
The different water samples corresponding to the different wells
were collected in Casablanca Valley (Carpintero’s and Pitama’s
wells), while the drinking water was acquired from Curauma,
Valparaíso, Chile. The water samples were filtered using a Millipore
LOD ¼ 3*SD=m
(Eq. 2)
(Eq. 3)
LOQ ¼ 10*SD=m
Millex HV Hydrophilic PVDF 0.45 mm filter and then subjected to a
where SD is the standard deviation of ten blank reagent samples
and m is the slope of the calibration curve.
UCT Cleau-UP® CUC18156 cartridge. Finally, different CuCl2x2H2O
solutions were prepared using the different water samples (14, 28,
44, and 72 mM).
2.6. Computational details
3. Results and discussion
Compound 3, proposed complex 3-CuCl2, and all inorganic
compounds tested (salts) were optimized using the Gaussian 09
program [36]. To obtain the different chemical properties, a DFT-
B3LYP-LanL2DZ optimization was performed. In addition, all opti-
mized geometries were checked by frequency calculations (without
any imaginary frequencies) in their potential energy surface.
In addition, quantum reactivity descriptors such as the dipole
moment (DM), highest occupied molecular orbital (HOMO), and
lowest unoccupied molecular orbital (LUMO) were obtained from
3.1. Chemical
When mixing cinnamaldehyde (1) with phenylhydrazine (2), a
few minutes later, a yellow solid appears, corresponding to cinna-
maldehyde phenylhydrazone, by nucleophilic attack by the eNH2
group of phenylhydrazine towards the carbonyl carbon of cinna-
maldehyde as a classic 1,2-addition reaction to the carbonyl group.
After separation of compound 3 from the reaction mixture by col-
umn chromatography, the desired compound was confirmed by 1
NMR spectroscopy, showing two doublet signals (
¼ 7.27 and
H
the output file, while the chemical potential (m), hardness (h),
d
softness (S), and global electrophilic index (
the following equations.
u
) were calculated with
d
¼ 6.69 ppm) with a coupling constant J ¼ 16 Hz, characteristic of a
double bond with trans geometry. The final structure was deter-
mined by complementary NMR experiments (13C, 2D-HSQC and
2D-HMBC) and IR spectroscopy (see Supplementary Material), as
well as by comparing previous research [1].
ðELUMO þ EHOMO
Þ
Þ
m
h
¼
¼
(Eq. 4)
(Eq. 5)
(Eq. 6)
2
ðELUMO ꢂ EHOMO
3.2. Photophysical measures
2
Initially, a stock solution of compound 3 was prepared at a
concentration of 1.0 ꢀ 10ꢂ2 M in DMSO, from which a series of
dilutions were prepared for the measurement of the different
photophysical properties. For the measurement of these properties
in the absence of inorganic salts, dilutions were made using MeCN.
Additionally, the different inorganic salts were dissolved in deion-
ized water at a concentration of 1.0 ꢀ 10ꢂ2 M.
1
S ¼
2h
m2
u
¼
(Eq. 7)
2h
For the photophysical measurements associated with molecular
absorption, UVeVis spectra of compound 3 at several concentra-
tions (20, 40, 60, 80 and 100 mM) were recorded using MeCN as the
2.7. Quantitative structure-property relationship (QSPr)
solvent. The UVeVis spectra showed a maximum absorption at
labs ¼ 359 nm. The molar extinction coefficient was calculated
using the Lambert-Beer law and linear regression (ε ¼ 2928.9 mol-1
* cmꢂ1 *L, see Supplementary Material Figure S1). Subsequently,
the behaviour of the UVeVis spectrum of compound 3 in the
presence of different inorganic salts was evaluated (see Fig. 2). In
the presence of CuCl2, a new absorption band is observed to be
generated (labs ¼ 459 nm), which is attributed to the donation of
pairs of non-bonding electrons from nitrogen to the metal [40e42]
together with a hypochromic effect on the maximum absorption of
compound 3 (labs ¼ 359 nm). In contrast, the 3 þ CuCl interaction
has only a hypochromic effect at labs ¼ 359 nm.
To determine which chemical properties of the different inor-
ganic compounds (salts) produce changes in the fluorescent
properties, the quantitative structure-property relationship (QSPr)
technique was used through a multiple linear regression similar to
that of previous reports of our research group [37,38]. As a
dependent variable, the normalized fluorescence intensity (F/F0) of
compound (3) was used, while as independent variables, the pre-
viously mentioned descriptors were used in their linear and
quadratic forms (MS, MS2, MV, MV2, MW, MW2, MD, MD2, DM,
DM2, HOMO, HOMO2, LUMO, LUMO2,
using Statistica 7.0 software.
m, , h, h u )
m2 2, S, S2, , and u2
Bearing in mind the multiple fluorescent applications that have
been reported for hydrazones and to evaluate their application as
fluorescent chemosensors, compound 3 was subjected to various
tests to evaluate its photophysical properties [20]. The emission
To ensure that the established relationship is not accidental, the
cross-validation technique described by Golbraikh was used ac-
cording to the following equation [39].
and excitation spectra were recorded for compound 3 (0e100 mM).
P
2
b
ðxobs ꢂ xÞ
The emission spectrum shows that compound 3 exhibits its
maximum fluorescence intensity at lem ¼ 476 nm when excited at
lex ¼ 394 nm. The calculated Stokes shift was 82 nm, similar to that
of other hydrazones with a more complex structure [31,43]. From
the previously described results, the relative quantum yield of
q2 ¼ 1 ꢂ
(Eq. 8)
P
ðxobs ꢂ xÞ2
b
where xobs is the experimental normalized fluorescence value, x is
the calculated normalized fluorescence value and x is the average
normalized fluorescence value of all compounds. A value equal to or
greater than 0.5 is considered acceptable.
compound 3 was calculated using quinine sulfate (
f
¼ 0.58) as a
standard [33,34], obtaining a value of
f
¼ 0.018, similar to that

4
M. Mellado et al. / Journal of Molecular Structure 1217 (2020) 128430
Fig. 2. UVeVis spectrum of compound 3 (20 mM) and its interaction with different
metals (10 molar equivalents).
Fig. 3. Emission spectrum of compound 3 and its interaction with different inorganic
salts (10 eq. mol). C3 ¼ 20 M, solvent ¼ MeCN. lex ¼ 394 nm.
m
that stems from the paramagnetic nature of Cu2þ [44]. In addition,
when compound 3 interacts with Al3þ, it shows a decrease in the
fluorescence intensity, corresponding to 60% (30% lower decay than
that with CuCl2), which is consistent with that of other phenyl-
hydrazones [28,45]. In cases where fluorescence decay occurs
(CuCl2 and AlCl3), it may be associated with the interaction of the
hydrazone fragment with the metal centres of the inorganic salts.
Contrasting this information with the UVevisible spectra (see
Fig. 2), the quenching fluorescence induced by CuCl2 could be
related to coordinated bond formation, while AlCl3 quenching
fluorescence could be related to the collisional effect because there
is no charge-transfer peak.
reported for a small hydrazone-pyrene-based compound (Supple-
mentary Material Figure S2) [32].
The effect of solvent polarity and pH on the emission spectrum
was evaluated. We found that the highest emission intensity was
recorded using aprotic polar solvents. On the other hand, it is
observed that the emission spectrum has a shift at longer wave-
lengths when increasing the solvent polarity, consistent with sol-
vent effects shifting the emission to still lower energy due to
stabilization of the excited state by the polar solvent molecules
[33]. In fact, the best emission was recorded using CH2Cl2 (intensity
15177 FUA, see Supplementary Material Figure S3); however, the
incompatibility of this solvent with water makes the interaction
with inorganic salts unfeasible. Other solvents with high emission
were THF, followed by DMF, MeCN, COMe2 and DMSO. It is noted
that the emission spectrum of compound 3 using MeCN as a solvent
decreases the standard deviation of the measurement (see Sup-
plementary Material Figure S3). The influence of the water content
on the emission intensity of compound 3 was investigated, finding
that the intensity of the emission decreases proportionally as the
percentage of water increases, e.g., when using a 9:1 MeCN:water
solution, the fluorescence intensity decreases by 25.4%, while when
using only water, the fluorescence intensity decreases by 94.4%. To
evaluate the effect of pH on the emission intensity of compound 3, a
series of HEPES buffer solutions at different pH values were used.
The results show that the maximum emission intensity is obtained
between pH values of 5.0 and 7.0 (see Supplementary Material
Figure S3).
Subsequently, the quantum yield (f) of compound 3 was eval-
uated after interacting with CuCl2 and AlCl3 (see Supplementary
Material Figure S5). The compound 3þCuCl2 interaction shows a
decay of 55% (
f
¼ 0.010) due to the sharp decrease in the absorp-
tion and emission bands (see Figs. 3 and 4). However, for the
interaction of compound 3þAlCl3, the quantum yield obtained was
f
¼ 0.017 (5.6% lower than that with compound 3), which is
attributed only to a change in the emission spectrum occurring,
with the absorption spectrum varying very minimally (see Figs. 1
Because compound 3 showed an effect on its absorption spec-
trum when interacting with CuCl2 (see Fig. 1) and because it has
fluorescent properties, the effect of copper salts on the emission
spectrum of the compound was checked. First, the minimum time
required to show significant changes and stability in the interaction
of 3þCuCl and 3þCuCl2 was determined. The results show that
CuCl2 generates a 90% decay of the fluorescence intensity of com-
pound 3 at 3 min of incubation, while CuCl causes a 45% decay of
the fluorescence intensity of compound 3 at 15 min (see Material
Supplementary Figure S4). Later, the effect of inorganic salts on the
emission spectrum of compound 3 was evaluated (see Fig. 3).
Fig. 3 shows that compound 3 does not show a significant
variation in fluorescence intensity with all compounds, except
CuCl2, which generates a 90% decay of the fluorescence intensity.
This effect is due to the intrinsic fluorescence-quenching property
Fig. 4. Selective quenching of the fluorescence intensity of compound 3. C3 ¼ 20
mM,
Csalt ¼ 1.0 eq. mol, solvent ¼ MeCN, lex ¼ 394 nm, lem ¼ 476 nm, tincubation ¼ 3 min.

M. Mellado et al. / Journal of Molecular Structure 1217 (2020) 128430
5
Fig. 5. A. Titration of compound 3 with CuCl2. B. Calibration curve used for figures of merit evaluation. C3 ¼ 20
tincubation ¼ 3 min, n ¼ 3.
m
M, solvent ¼ MeCN, lex ¼ 394 nm, lem ¼ 476 nm, Tꢁ ¼ 298 K,
and 2). This last point is consistent with that mentioned above, and
AlCl3 quenching fluorescence could be related to the collisional
effect.
The results show that compound 3 interacts selectively with CuCl2,
whereby the stoichiometry of this interaction was determined.
Stoichiometry was determined by the Job plot, showing that the
ratio is 1:1 (see Fig. 6A). In addition, the association constant (K)
between compound 3 and CuCl2 was calculated by the Benesi-
Hildebrand (BH) expression [48] using linear regression between
(F0eF)ꢂ1 and 1/Cu2þ (r2 ¼ 0.963), where KBH ¼ 1.22 ꢀ 10ꢂ2 M-1 was
obtained (see Fig. 6B).
To confirm the selective interaction of compound 3 with CuCl2
shown in the previous experiments, we investigated the change in
fluorescence intensity in the presence of another inorganic salt and
the subsequent addition of CuCl2 (see Fig. 4). Fig. 4 shows that
compound 3 in the absence (blank) and presence of all inorganic
salts does not change its fluorescence intensity (F/F0 ꢃ 0.8), except
with SnCl2 (F/F0 ¼ 0.745); however, adding CuCl2 generates a sig-
nificant decrease in the fluorescence intensity (F/F0 ¼ ꢄ 0.2), except
with NaCl, CaCl2, SrCl2 and SnCl2.
As shown above, the fluorescence intensity of compound 3 de-
creases by its interaction with CuCl2, so the quenching constant was
determined by means of the Stern-Volmer equation (Eq. (9))
To obtain the performance characteristics while monitoring the
F0 = F ¼ 1 þ KSV ½Qꢅ
(Eq. 9)
interaction of Cuþ2 with compound 3, a titration was performed at
25 ꢁC using a 20
mM solution of compound 3 in MeCN and adding
Here, F0 and F are the fluorescence intensities in the absence and
presence of the quencher, respectively, KSV is the dynamic
quenching constant and [Q] is the concentration of the quencher.
Various processes can cause fluorescence quenching. The most
common processes are complex formation (static quenching) and
collisional quenching (dynamic quenching) [49]. One of the ways to
distinguish between the phenomena is temperature dependence. If
increasing amounts of CuCl2 in aqueous solution (see Fig. 5A).
Fig. 5A shows the decrease in the fluorescence intensity of
compound 3 proportionally to the increase in the CuCl2 concen-
tration. The fluorescence intensity decreased by 80% at 80
mM
CuCl2. The detection and quantification limits were calculated from
the linear segment of the titration (see Fig. 5B), obtaining
LOD ¼ 0.065
m
M (8.74 ꢀ 10ꢂ3 mg/L CuCl2), while the quantification
KSV decreases with increasing temperature, it could be considered a
limit was 0.217
m
M (2.91 ꢀ 10ꢂ2 mg/L CuCl2). These results indicate
static quenching process [50]. Therefore, the variation in the Stern-
Volmer constant was measured at 298 K and 308 K (see Fig. 7).
The results for the interaction between compound 3 and CuCl2
indicate a decrease in the Stern-Volmer constant from 1.70 ꢀ 104 to
298 K to 1.07 ꢀ 104 to 308 K (see Fig. 7), showing that there is a high
probability that the quenching phenomenon originates from the
that compound 3 could be used to monitor CuCl2 concentrations in
water samples since the detection of this metal is of interest for
both biological and environmental sciences [46]. In this sense, the
maximum copper allowed is 1.3 mg/L (20
mM) in drinking water
according to the U.S. Environmental Protection Agency (EPA) [47].
Fig. 6. A. Job plot for the compound 3-CuCl2 interaction. B. Benesi-Hildebrand plot based on the 1:1 stoichiometry of the compound 3-CuCl2 interaction. C3 ¼ 20
mM,
solvent ¼ MeCN, lex ¼ 394 nm, lem ¼ 476 nm, Tꢁ ¼ 298 K, tincubation ¼ 3 min, n ¼ 3.

6
M. Mellado et al. / Journal of Molecular Structure 1217 (2020) 128430
incubation time was used as in the previous experiments
(time ¼ 3 min). However, this phenomenon is not strange since in
other investigations, this tendency has also been shown [53].
Finally, to rule out that the quenching of the fluorescence of
compound3 is due to the water added in the test, the CuCl2 solution
was replaced by distilled water. Our results show that there is no
significant change in the fluorescence intensity when adding water
(see Supplementary Material Figure S6).
3.3. Theoretical approach
Using the Gaussian 09 program, the minimal energy structures
of compound 3 and the 3-CuCl2 complex were optimized using
DFT-B3LYP-LanL2DZ in the gas phase. The electrostatic potential
map of compound 3 (see Fig. 9A) shows an area with a negative
charge density (red colour) where it can generate the interaction
between 3 and CuCl2 through the electron lone pairs of nitrogen.
Therefore, the formation of complex 3-CuCl2is plausible through
the nitrogen atom.
Likewise, the HOMO and LUMO for compound 3 and the 3-CuCl2
complex (see Fig. 9B and C and Fig. 9E and F) were calculated
because they have important contributions to electronic photo-
excitation transitions [54]. Comparing the molecular orbitals of
compound 3 with those of the 3-CuCl2 complex, it can be seen that
Fig. 7. Determination of Stern-Volmer quenching constants (KSV) for the interaction
between compound 3 and CuCl2 at 298 K and 300 K.
formation of a complex [50]. These results agree with the CuCl2/3
charge transfer signal shown in Fig. 1 (labs ¼ 459 nm) due to the
donation of the non-bonding electron pairs of nitrogen to the metal
[40e42], forming a complex. Using the static quenching model,
from the intensity-quencher concentration relationship, the bind-
ing constant was calculated according to the following equation
[49]:
the HOMO and LUMO are mainly located on the a,b-unsaturated
imine (see Fig. 9B and C). However, when plotting the HOMO and
LUMO of the 3-CuCl2 complex, a displacement can be seen. The
HOMO is between the phenylhydrazone fragment and the chloride
substituents of CuCl2, while the LUMO is centred on the metal (see
Fig. 9E and F).
Comparing the energies associated with the HOMO-LUMO
ꢀ
ꢁ
transition (assigned by us to the
mophore), it can be seen that for compound 3, the energy associ-
ated with this transition corresponds to 3.70 eV (
¼ 335 nm),
which is consistent with the maximum absorption wavelength
measured (
¼ 359 nm). In the 3-CuCl2 complex, the energy of the
same transition is 1.97 eV (
¼ 629 nm). However, this transition is
not consistent with the CuCl2/3 charge transfer signal
¼ 459 nm, see Fig. 2). In this sense, it has been reported that
HOMO-1/LUMO transitions may be associated with
p / p* transition of the chro-
F0 ꢂ F
log
¼ logK þ nlog½Qꢅ
(Eq. 10)
F
l
Here, K is the binding constant and n is the number of binding
sites per compound 3. The binding results showed logK ¼ 8.797 at
298 K, while at 308 K, logK ¼ 5.119. In addition, the linear corre-
lation coefficients for both temperatures were larger than 0.99.
From these values, as well as the van’t Hoff equations, the ther-
l
l
(l
modynamic parameters
DG, DH, and DS were determined, ac-
cording to a previous report [49]. The results of the thermodynamic
parameters of the interaction of compound 3 and CuCl2 are shown
in Table 1.
The negative value of the Gibbs free energy change (
dicates that the interaction between compound 3 and CuCl2 is a
spontaneous process. The positive value of S is characteristic of
DG) in-
D
chelation processes, where the solvent molecules are arranged
around compound 3 and the interaction of CuCl2 causes the dis-
order of these molecules and anincrease in the configurational
entropy [51]. The positive value of the enthalpy change (DH) in-
dicates that the processes are endothermic; however, the 3-CuCl2
association is mainly affected by temperature and the entropy
change (DS), with a low contribution of the enthalpy (DH) as pre-
viously reported [52].
Moreover, fluorescence recovery was investigated through the
addition of EDTA (see Fig. 8). The 3-CuCl2 interaction was not
reversible with the addition of EDTA. In these tests, the same
Table 1
Thermodynamic parameters of the interaction of compound 3 and CuCl2.
D
G (kJ/mol)
DH (kJ/mol)
DS (J/mol)
298 K
308 K
ꢂ5.39
ꢂ4.18
41.3
156
147
Fig. 8. Fluorescence recovery from the 3-CuCl2 interaction using EDTA. C3 ¼ 20
mM,
solvent ¼ MeCN, lex ¼ 394 nm, lem ¼ 476 nm, Tꢁ ¼ 298 K, tincubation ¼ 3 min, n ¼ 3.

M. Mellado et al. / Journal of Molecular Structure 1217 (2020) 128430
7
Fig. 9. A. Map of the electrostatic potential of compound 3. B. HOMO of compound 3. C. LUMO of compound 3. D. Map of the electrostatic potential of compound 3-CuCl2. E. HOMO
of compound 3-CuCl2. F. LUMO of compound 3-CuCl2. Isovalue ¼ 0.04; density ¼ 0.0004.
photophysical phenomena [54,55]. In effect, this calculated elec-
tronic transition is nearest to the absorption band shown in the
UVeVis spectra,
Figure S7).
l
¼
459 nm (see Supplementary Material
In addition, through quantitative structure-property relation-
ship (QSPr) techniques, various correlations were evaluated be-
tween the different physicochemical properties of the inorganic
salts tested (independent variables) and the normalized variation
of the fluorescence (dependent variable). The correlation obtained
is shown in Eq. (11).
Scheme 2. Proposed fluorescence mechanism for compound 3 and its interaction with
CuCl2.
F=F0 ¼ 0:96þ0:240LUMOþ0:130
u
ꢂ0:003u2
n ¼ 18;r ¼ 0:904;r2 ¼ 0:817;SD ¼ 0:099;F ¼ 20:9;q2 ¼ 0:777
(Eq. 11)
The results are summarized in Table 2.
The measurements of CuCl2 in the different water samples
showed that the recovery of CuCl2 is similar in the well water from
Carpintero and Pitama (111.8% and 99.3%, respectively) at concen-
Eq. (11) indicates that the fluorescence quenching is related to
the energy of the LUMO and to the global electrophilic index (u) of
the different inorganic salts, which are descriptors related to the
ability to accept electrons and their stabilization [56,57]. This result
confirms that the interaction between 3-CuCl2 corresponds to an
interaction of molecular orbitals forming the corresponding com-
plex (see Supplementary Material Figure S8).
With this information obtained from the computational
approach, a fluorescence mechanism based on internal charge
transfer is proposed (see Scheme 2). The fluorescence of compound
3is decreased due to the coordination of the pairs of non-bonding
electrons of the imine nitrogen by charge transfer from the metal
to compound 3.
trations greater than 40
mM. However, for the detection and
quantification of CuCl2 at concentrations that are close to or under
current U.S.-EPA regulations for drinking water, the analyte recov-
ery rate decreases significantly (66.4% in drinking water and 72.5%
in deionized water).
4. Conclusions
Cinnamaldehyde phenylhydrazone (3) was synthesized in high
Table 2
Determination of Cu2þ using compound 3 in different water samples.
3.4. Quantitation assays of Cu2þ in water samples
Sample
Cu2þadded (
m
M) Cu2þfound (
m
M)a Recovery (%)
The potential application of compound 3 as a copper sensor in
different water samples was tested. Samples of deionized, potable
and well water (Carpintero and Pitama) were used under the same
Drinking water
Carpintero’s well water 44
Pitama’s well water
Deionized water
14
9.3 0.35
49.2 8.5
71.5 3.2
20.3 0.01
66.4
111.8
99.3
72.5
72
28
conditions applied in this investigation (C3
¼
20
mM,
a
solvent ¼ MeCN, incubation time ¼ 3 min, temperature ¼ 298 K).
Experiment carried out three times.

8
M. Mellado et al. / Journal of Molecular Structure 1217 (2020) 128430
[3] A.B.A. El-Gazzar, H.N. Hafez, G.A.M. Nawwar, New acyclic nucleosides ana-
logues as potential analgesic, anti-inflammatory, anti-oxidant and anti-
microbial derived from pyrimido[4,5-b]quinolines, Eur. J. Med. Chem. 44 (4)
(2009) 1427e1436.
[4] B.F. Abdel-Wahab, G.E.A. Awad, F.A. Badria, Synthesis, antimicrobial, antioxi-
dant, anti-hemolytic and cytotoxic evaluation of new imidazole-based het-
erocycles, Eur. J. Med. Chem. 46 (5) (2011) 1505e1511.
yield (81% yield). Its photophysical properties (UVeVis and fluo-
rescence) were evaluated in the absence and presence of various
metals, and it was found that CuCl2 causes selective quenching of
the fluorescence intensity and decay of the quantum yield in a
thermodynamically spontaneous process (DG <0).
Using quantitative structure-activity (QSAR) techniques, it was
determined that the fluorescence intensity is affected by the
transfer of electrons from HOMO of compound 3 to the LUMO of
CuCl2, quenching the fluorescence in an internal charge transfer
(ICT) process.
[5] A.E. Kummerle, M. Schmitt, S.V.S. Cardozo, C. Lugnier, P. Villa, A.B. Lopes,
N.C. Romeiro, H. Justiniano, M.A. Martins, C.A.M. Fraga, J.J. Bourguignon,
E.J. Barreiro, Design, synthesis, and pharmacological evaluation of N-Acylhy-
drazones and novel conformationally constrained compounds as selective and
potent orally active phosphodiesterase-4 inhibitors, J. Med. Chem. 55 (17)
(2012) 7525e7545.
[6] S. Bala, G. Uppal, S. Kamboj, V. Saini, D.N. Prasad, Design, characterization,
computational studies, and pharmacological evaluation of substituted-N
’-[(1E) substituted-phenylmethylidene]benzohydrazide analogs, Med. Chem.
Res. 22 (6) (2013) 2755e2767.
The quantification and detection of CuCl2 was performed using
four different water samples, and it was found that at concentra-
tions greater than 40
mM, all dissolved CuCl2 was recovered.
[7] D.D. Gaikwad, A.D. Chapolikar, C.G. Devkate, K.D. Warad, A.P. Tayade,
R.P. Pawar, A.J. Domb, Synthesis of indazole motifs and their medicinal
importance: an overview, Eur. J. Med. Chem. 90 (2015) 707e731.
[8] S. Emami, S. Dadashpour, Current developments of coumarin-based anti-
cancer agents in medicinal chemistry, Eur. J. Med. Chem. 102 (2015) 611e630.
[9] G. Roman, Mannich bases in medicinal chemistry and drug design, Eur. J. Med.
Chem. 89 (2015) 743e816.
[10] U. Abu Mohsen, B. Kocyigit-Kaymakcioglu, E.E. Oruc-Emre, Z.A. Kaplancikli,
S. Rollas, Studies on hydrazide-hydrazones derivatives as acetylcholinesterase
inhibitors, Clin Exp Health Sci 5 (1) (2015) 10e14.
[11] K. Kucukoglu, M. Gul, M. Atalay, E. Mete, C. Kazaz, O. Hanninen, H.I. Gul,
Synthesis of some Mannich bases with dimethylamine and their hydrazones
and evaluation of their cytotoxicity against Jurkat cells, Arzneim. Forsch. 61
(6) (2011) 366e371.
[12] K. Kucukoglu, H.I. Gul, R. Cetin-Atalay, Y. Baratli, A.L. Charles, M. Sukuroglu,
M. Gul, B. Geny, Synthesis of new N,N ’-bis[1-aryl-3-(piperidine-1-yl)propy-
lidene]hydrazine dihydrochlorides and evaluation of their cytotoxicity against
human hepatoma and breast cancer cells, J. Enzym. Inhib. Med. Chem. 29 (3)
(2014) 420e426.
[13] K. Kucukoglu, H.I. Gul, M. Gul, R. Cetin-Atalay, Y. Baratli, B. Geny, Cytotoxicity
of hydrazones of morpholine bearing mannich bases towards Huh7 and T47D
cell lines and their effects on mitochondrial respiration, Lett. Drug Des. Discov.
13 (8) (2016) 734e741.
[14] V. Jyothi, N. Babu, P.K. Reddy, T. Ashwini, Synthesis, characterization and
evaluation of anti-tubercular, anti-inflammatory and anti-microbial activities
of newer hydrazones, Inven. Rapid MedChem 4 (2014) 1e6, 2014.
[15] E.I. Khizhan, A.I. Khizhan, G.A. Tikhonova, V.Y. Maslova, Antioxidant activity of
arylhydrazones in sunflower oil oxidation, Russ. J. Appl. Chem. 85 (3) (2012)
460e464.
However, at concentrations below 20
m
M, the recovery rate
decreased to 66.4%. Despite these results, the information obtained
in this investigation can be applied to the design of new chemo-
sensors based on compound 3.
Declaration of competing interest
We declare that we have no conflicts of interest to this work. We
declare that we do not have any commercial or associative interest
that represents a conflict of interest in connection with the work
submitted.
Funding
This work was supported by the ANID [Fondecyt Postdoctoral
grant 3180408, Fondecyt 1190752]; and VRIEA-PUCV [37.0/2017].
Declaration of competing interest
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
[16] T.B. Chaston, R.N. Watts, J. Yuan, D.R. Richardson, Potent antitumor activity of
novel iron chelators derived from di-2-pyridylketone isonicotinoyl hydrazone
involves fenton-derived free radical generation, Clin. Canc. Res. 10 (21) (2004)
7365e7374.
CRediT authorship contribution statement
[17] X.F. Bao, Y. Xue, C. Xia, Y. Lu, N.J. Yang, Y. Zhao, Synthesis and Assessment of
novel anti-chlamydial benzylidene Acylhydrazides derivatives, Lett. Drug Des.
Discov. 15 (1) (2018) 31e36.
[18] K. Hruskova, E. Potuckova, T. Hergeselova, L. Liptakova, P. Haskova, P. Mingas,
P. Kovarikova, T. Simunek, K. Vavrova, Aroylhydrazone iron chelators: tuning
antioxidant and antiproliferative properties by hydrazide modifications, Eur. J.
Med. Chem. 120 (2016) 97e110.
[19] C.R. Li, Z.C. Liao, J.C. Qin, B.D. Wang, Z.Y. Yang, Study on 2-Acetylpyrazine
(pyridine-2 ’-acetyl) hydrazone as a fluorescent sensor for Al3þ, J. Lumin.
168 (2015) 330e333.
Marco Mellado: Conceptualization, Methodology, Software,
Investigation, Formal analysis, Funding acquisition, Resources,
Writing - review & editing. Rafaela Sariego-Kluge: Methodology,
Formal analysis. Cesar Gonzalez: Methodology, Investigation. Katy
Díaz: Methodology, Investigation. Luis F. Aguilar: Supervision,
Writing - review & editing. Manuel A. Bravo: Resources, Writing -
review & editing.
ꢀ
ꢀ
[20] X. Su, I. Aprahamian, Hydrazone-based switches, metallo-assemblies and
sensors, Chem. Soc. Rev. 43 (6) (2014) 1963e1981.
[21] S.J. Jiang, J.B. Qiu, Y.X. Chen, H.Y. Guo, F.F. Yang, Luminescent columnar liquid
crystals based on AIE tetraphenylethylene with hydrazone groups bearing
multiple alkyl chains, Dyes Pigments 159 (2018) 533e541.
[22] T. Aysha, M. El-Sedik, S. Abd El Megied, H. Ibrahim, Y. Youssef, R. Hrdina,
Synthesis, spectral study and application of solid state fluorescent reactive
disperse dyes and their antibacterial activity, Arab J Chem 12 (2) (2019)
225e235.
Acknowledgements
ꢀ
The authors thank to Agencia Nacional de Investigacion y
Desarrollo (ANID) and Vicerrectoría de Investigacion y Estudios
Avanzados of Pontificia Universidad Catolica de Valparaíso (VRIEA-
PUCV).
ꢀ
ꢀ
[23] D. Debnath, S. Roy, B.H. Li, C.H. Lin, T.K. Misra, Synthesis, structure and study
of azo-hydrazone tautomeric equilibrium of 1,3-dimethyl-5-(arylazo)-6-
amino-uracil derivatives, Spectrochim. Acta 140 (2015) 185e197.
[24] B. Samanta, J. Chakraborty, S. Shit, S.R. Batten, P. Jensen, J.D. Masuda, S. Mitra,
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://dx.doi.org/10.1016/j.molstruc.2020.128430
Synthesis, characterisation and crystal structures of
a few coordination
complexes of nickel(II), cobalt(III) and zinc(II) with N ’-[(2-pyridyl)methylene]
salicyloylhydrazone Schiff base, Inorg. Chim. Acta. 360 (7) (2007) 2471e2484.
[25] H. Jansova, J. Kubes, P. Reimerova, P. Sterbova-Kovarikova, J. Roh, T. Simunek,
2,6-Dihydroxybenzaldehyde analogues of the iron chelator salicylaldehyde
isonicotinoyl hydrazone: increased hydrolytic stability and cytoprotective
activity against oxidative stress, Chem. Res. Toxicol. 31 (11) (2018)
1151e1163.
[26] G.M. Abu El-Reash, O.A. El-Gammal, A.H. Radwan, Molecular structure and
biological studies on Cr(III), Mn(II) and Fe(III) complexes of heterocyclic car-
bohydrazone ligand, Spectrochim. Acta 121 (2014) 259e267.
References
[1] N. Giuseppone, J.L. Schmitt, E. Schwartz, J.M. Lehn, Scandium(III) catalysis of
transimination reactions. Independent and constitutionally coupled reversible
processes, J. Am. Chem. Soc. 127 (15) (2005) 5528e5539.
[2] B. Kocyigit-Kaymakcioglu, E.E. Oruc-Emre, S. Unsalan, S. Rollas, Antitubercu-
losis activity of hydrazones derived from 4-fluorobenzoic acid hydrazide, Med.
Chem. Res. 18 (4) (2009) 277e286.
[27] N.H. Al-Shaalan, Synthesis, characterization and biological activities of Cu(II),

M. Mellado et al. / Journal of Molecular Structure 1217 (2020) 128430
9
Co(II), Mn(II), Fe(II), and UO2(VI) complexes with a new Schiff base hydra-
zone: O-Hydroxyacetophenone-7-chloro-4-quinoline hydrazone, Molecules
16 (10) (2011) 8629e8645.
substituted aromatic aldehyde Schiff bases: synthesis, crystal structure, anti-
microbial activity, DNA binding and cleavage studies, J. Coord. Chem. 70 (8)
(2017) 1368e1388.
[28] X.Y. Zhu, Y.A. Duan, P. Li, H.M. Fan, T.Y. Han, X.N. Huang, A highly selective and
instantaneously responsive Schiff base fluorescent sensor for the "turn-off"
detection of iron(iii), iron(ii), and copper(ii) ions, Anal Methods-Uk 11 (5)
(2019) 642e647.
[42] S. Biju, S.S. Kumar, V. Sadasivan, Synthesis, spectral and single crystal X-ray
characterization of 5-(2-(2,3-dimethyl-5-oxo-1-phenyl-2,5-dihydro-1H-pyr-
azol-4-yl)hydrazono)pyrimidine-2,4,6(1H,3H,5H)-trione and its copper(II)
complexes, Polyhedron 144 (2018) 210e218.
[29] C. Rj, Zinc, in: F.L. Ziegler EE (Ed.), Knowledge in Nutrition, ILSI Press, Wash-
ington, DC, 1996, pp. 293e306.
[30] P.C. Dhar, A. Pal, P. Mohanty, B. Bag, Colorimetric detection of Cu(II) ion with a
[43] K. Ponnuvel, M. Kumar, V. Padmini, A new quinoline-based chemosensor for
Zn2þ ions and their application in living cell imaging, Sensor. Actuator. B
Chem. 227 (2016) 242e247.
1,3-bis-azachalcone derivative, Sensor. Actuator.
B
Chem. 219 (2015)
[44] A.K. Mahapatra, G. Hazra, N.K. Das, S. Goswami, A highly selective
308e314.
triphenylamine-based indolylmethane derivatives as colorimetric and turn-
off fluorimetric sensor toward Cu2þ detection by deprotonation of second-
ary amines, Sensor. Actuator. B Chem. 156 (1) (2011) 456e462.
[45] C.Q. Jiang, B. Tang, R.Y. Wang, J.C. Yen, Spectrofluorimetric determination of
trace amounts of aluminium with 5-bromo-salicylaldehyde salicyloylhy-
drazone, Talanta 44 (2) (1997) 197e202.
[46] X. Zheng, K.H. Lee, H. Liu, S.Y. Park, S.S. Yoon, J.Y. Lee, Y.G. Kim, A bis(pyridine-
2-ylmethyl)amine-based selective and sensitive colorimetric and fluorescent
chemosensor for Cu2þ, Sensor. Actuator. B Chem. 222 (2016) 28e34.
[47] G.Y. Lan, C.C. Huang, H.T. Chang, Silver nanoclusters as fluorescent probes for
selective and sensitive detection of copper ions, Chem Commun 46 (8) (2010)
1257e1259.
[31] C.R. Chen, G.W. Men, W.H. Bu, C.S. Liang, H.C. Sun, S.M. Jiang, A colorimetric
and fluorescent probe for multiple transition metal ions (Cu2þ, Zn2þ and
Ni2þ): fast response and high selectivity, Sensor. Actuator. B Chem. 220
(2015) 463e471.
[32] S. Mukherjee, S. Betal, Sensing phenomena, extraction and recovery of Cu2þ
followed by smart phone application using
a
luminescent pyrene based
chemosensor, J. Lumin. 204 (2018) 145e153.
[33] J.R. Lakowicz, Principles of Fluorescence Spectroscopy, second ed., Kluwer
Academic/Plenum Publishers, New York, London, Moscow, Dordrecht, 1999.
[34] K. Nawara, J. Waluk, Improved method of fluorescence quantum yield
determination, Anal. Chem. 89 (17) (2017) 8650e8655.
[35] M. Thompson, S.L.R. Ellison, R. Wood, Harmonized guidelines for single-
laboratory validation of methods of analysis, Pure Appl. Chem. 74 (5) (2002)
835e855.
[48] H.A. Benesi, J.H. Hildebrand, A spectrophotometric investigation of the
interaction of iodine with aromatic hydrocarbons, J. Am. Chem. Soc. 71 (8)
(1949) 2703e2707.
[36] M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria, M.A. Robb,
J.R. Cheeseman, G. Scalmani, V. Barone, G.A. Petersson, H. Nakatsuji, X. Li,
M. Caricato, A. Marenich, J. Bloino, B.G. Janesko, R. Gomperts, B. Mennucci,
H.P. Hratchian, J.V. Ortiz, A.F. Izmaylov, J.L. Sonnenberg, D. Williams-Young,
F. Ding, F. Lipparini, F. Egidi, J. Goings, B. Peng, A. Petrone, T. Henderson,
D. Ranasinghe, V.G. Zakrzewski, J. Gao, N. Rega, G. Zheng, W. Liang, M. Hada,
M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda,
O. Kitao, H. Nakai, T. Vreven, K. Throssell, J. Montgomery, J A, J.E. Peralta,
F. Ogliaro, M. Bearpark, J.J. Heyd, E. Brothers, K.N. Kudin, V.N. Staroverov,
T. Keith, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J.C. Burant,
S.S. Iyengar, J. Tomasi, M. Cossi, J.M. Millam, M. Klene, C. Adamo, R. Cammi,
J.W. Ochterski, R.L. Martin, K. Morokuma, O. Farkas, J.B. Foresman, D.J. Fox,
Gaussian 09 Revision A.02, Gaussian Inc., Wallingford CT, 2016.
[37] M. Mellado, A. Madrid, M. Reyna, C. Weinstein-Oppenheimer, J. Mella,
C.O. Salas, E. Sanchez, M. Cuellar, Synthesis of chalcones with antiproliferative
activity on the SH-SY5Y neuroblastoma cell line: quantitative Structure-
Activity Relationship Models, Med. Chem. Res. 27 (11e12) (2018) 2414e2425.
[38] M. Mellado, A. Madrid, U. Martinez, J. Mella, C.O. Salas, M. Cuellar, Hansch’s
analysis application to chalcone synthesis by Claisen-Schmidt reaction based
in DFT methodology, Chem. Pap. 72 (3) (2018) 703e709.
[49] H. Liu, F.X. Li, Y. Pi, D.J. Wang, Y.J. Hu, J. Zheng, Fluorescence quenching study
of 2,6-bis(5-(4-methylphenyl)-1-H-pyrazol-3-yl)pyridine with metal ions,
Spectrochim. Acta 145 (2015) 588e593.
[50] C. Wang, Q.H. Wu, C.R. Li, Z. Wang, J.J. Ma, X.H. Zang, N.X. Qin, Interaction of
tetrandrine with human serum albumin: a fluorescence quenching study,
Anal. Sci. 23 (4) (2007) 429e433.
[51] M. Calvin, N.C. Melchior, Stability of chelate compounds. IV. Effect of the metal
ion, J. Am. Chem. Soc. 70 (10) (1948) 3270e3273.
[52] K.S. Siddiqi, S. Bano, A. Mohd, A.A.P. Khan, Binding interaction of captopril
with metal ions: a fluorescence quenching study, Chin. J. Chem. 27 (9) (2009)
1755e1761.
[53] L.L. Li, H. Li, G. Liu, S.Z. Pu, A colorimetric and fluorescent chemosensor for
selective detection of Cu2þ based on a new diarylethene with a benzophe-
none hydrazone unit, Luminescence 32 (8) (2017) 1473e1481.
[54] A. Frazer, A.R. Morales, A.W. Woodward, P. Tongwa, T. Timofeeva,
K.D. Belfield, Luminescent fluorene-based bis-pyrazolyl Aniline ligand for
Aluminum detection, J. Fluoresc. 24 (1) (2014) 239e250.
[55] K. Gayathri, K. Velmurugan, R. Nandhakumar, M. Malathi, S. Mathusalini,
P.S. Mohan, R. Shankar, New pyrazolo-quinoline scaffold as
a reversible
colorimetric fluorescent probe for selective detection of Zn2þ ions and its
[39] A. Golbraikh, A. Tropsha, Beware of q(2)!, J. Mol. Graph. Model. 20 (4) (2002)
269e276.
imaging in live cells, J. Photochem. Photobiol., A 341 (2017) 136e145.
ꢀ
[56] J.E. Lopez, A.E. Ensuncho, J.R. Robles, Global and local reactivity descriptors for
[40] K.G. Rajam, M.P. Kumar, K.J. Kiran, Shivaraj, mixed ligand complexes derived
from semicarbazone Schiff base and heterocyclic ligands: structure and
antimicrobial activity, Russ. J. Gen. Chem. 88 (5) (2018) 1000e1008.
[41] M.P. Kumar, N. Vamsikrishna, G. Ramesh, N.J.P. Subhashini, J.B. Nanubolu,
Shivaraj, Cu(II) complexes with 4-amino-3,5-dimethyl isoxazole and
the design of new anticancer drugs based on cis-platinum(II), Quim. Nova 36
(9) (2013) 1308e1317.
[57] R.G. Pearson, The principle of maximum hardness, Accounts Chem. Res. 26 (5)
(1993) 250e255.