An unexpected Cu(II) complex of oxidized 1,4-dydropyridine derivative: Synthesis, characterization and DFT calculations

Article abstract of DOI:10.1016/j.molstruc.2021.130057

A Cu(II) complex of 4-phenyl-3,5-dicarboxylic-pyridine (HL₂), [Cu(HL₂)Py], was isolated unexpectedly during studying coordination reaction of 3,5-dicarboxylic-1,4-dihydropyridine-4-phenyl ligand (HL₁) with copper(II) nitra

Full text of DOI:10.1016/j.molstruc.2021.130057

Journal of Molecular Structure 1232 (2021) 130057
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
An unexpected Cu(II) complex of oxidized 1,4-dydropyridine
derivative: Synthesis, characterization and DFT calculations
Qiangwen Fan a,c, Guorong Wub,c,∗, Yong Chenc, Yanling Hec, Longwei Zhuc, Huijun Renc,
Hailu Linc,∗
a State Key Laboratory of Nuclear Resources and Environment (East China University of Technology), Nanchang 330013, Jiangxi, China
b Jiangxi Province Key Laboratory of Polymer Micro/Nano Manufacturing and Devices (East China University of Technology), Nanchang 330013, China
c School of Chemistry, Biology and Materials Science, East China University of Technology, Nanchang 330013, Jiangxi, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A Cu(II) complex of 4-phenyl-3,5-dicarboxylic-pyridine (HL2), [Cu(HL2)Py], was isolated unexpectedly
during studying coordination reaction of 3,5-dicarboxylic-1,4-dihydropyridine-4-phenyl ligand (HL1) with
copper(II) nitrate by solvothermal method. Crystal structure of the [Cu(HL2)Py] was determined by single-
crystal X-Ray diffraction and its phase purity and thermal stability was evaluated by PXRD and TGA, re-
spectively. Furthermore, to shed more light on structural properties of the [Cu(HL2)Py], its geometrical
and electronic structure was investigated experimentally and theoretically. Finally, the oxidative mecha-
nism of HL1 was investigated by DFT calculations.
Received 16 December 2020
Revised 24 January 2021
Accepted 25 January 2021
Available online 5 February 2021
Keywords:
1,4-dydropyridine
Cu(II) complex
© 2021 Elsevier B.V. All rights reserved.
Structural characterization
Oxidative mechanism
DFT calculations
1. Introduction
unexpectedly during the study of improving biological activities of
the nitrendipine, wherein the 1,4-dihydropyridine scaffold of the
1,4-dihydropyridines (1,4-DHPs) are often used as calcium
channel antagonists in clinical for the treatment of cardiovascular
diseases, such as hypertension and angina pectoris, due to their ca-
pacity in relaxing vascular smooth muscle and lowing blood pres-
sure [1–6]. 1,4-DHPs also exhibit extensive bioactivities includ-
ing antitubercular, antitumor, antimicrobial, analgesic, and anticon-
vulsant [7–11]. In addition, 1,4-dihydropyridine scaffold is usually
used as model compound of nicotinamide adenine dinucleotide for
investigating acting mechanism of the reducing coenzyme [12].
On the other hand, intensive endeavors have been devoted to
investigate chemical reactivity of 1,4-DHPs, for example, ring con-
traction [13,14], [3+2] cycloaddition [15], [2+2] photocycloaddition
[16,17], oxidation [18]. In contrast, limited efforts have been spent
on studying coordinated reactivity of 1,4-DHPs. Suen et.al. reported
that structure of the complex formed by nitrogen-containing aryl
substituted 1,4-DHPs and Ag(I) salts was affected by counteran-
ions and solvents, wherein the anions play determined roles in
controlling the formation of 3D supramolecular structures [19–21].
Bontchev et.al. synthesized a near flat square Cu(II) complex of
nifedipine and investigated its optical and magnetic property [22].
Williams et.al. obtained a Cu(II) complex of oxidative nitrendipine
nitrendipine was oxidized to pyridine [23]. However, all these stud-
ies were focused on hantsch-type 1,4-DHPs (Scheme 1), of which
the C2- and C6-position was substituted with methyl group, the co-
ordinated reactivity study of non-hantsch-type 1,4-DHPs has never
been reported before.
Our previous studies have demonstrated that the two types
1,4-DHPs showed distinct physicochemical properties [24]. For in-
stance, strong fluorescence emission can be detected for the non-
hantsch-type 1,4-DHPs, but not for the hantsch-type 1,4-DHPs. Ad-
ditionally, in terms of their photochemical property, oxidation re-
action was predominant for the former, while [2+2] cycloaddition
was more favorable for the latter. With these in mind, as a contin-
uous work for revealing intrinsic chemical properties of 1,4-DHPs,
herein we investigated the coordinated reactivity of non-hantsch-
type 1,4-DHPs with Cu(II) for the first time.
2. Experimental section
2.1. Materials and instruments
All chemicals were purchased from commercial sources and
used without further purification. Thin-layer chromatography (TLC)
was conducted on silica-gel 60 F254 plates (Merck KGaA). Melt-
ing points were measured using an XT-5A digital apparatus with-
∗
Corresponding authors.
E-mail addresses: ecutwugr@163.com (G. Wu), hllin@ecut.edu.cn (H. Lin).
https://doi.org/10.1016/j.molstruc.2021.130057
0022-2860/© 2021 Elsevier B.V. All rights reserved.

Q. Fan, G. Wu, Y. Chen et al.
Journal of Molecular Structure 1232 (2021) 130057
was placed in a Teflon line stainless steel vessel (20 mL), and to the
solution added pyridine (0.1 mL). The reaction system was heated
to 85 °C with increasing rate of 10 °C/min and kept for 24 hours,
subsequently the reaction was cooled naturally to room tempera-
ture. Green pillar-type crystals [Cu(HL2)Py] were obtained in 90%
yields (based on HL1). The crystal structure can be accessed in
CCDC (No: 2050699). Element analysis (%) for C18 H12CuN2O4, calc:
C: 56.32, H: 3.15, Cu: 16.55, N: 7.30, O: 16.67, found: C: 56.04, H:
2.98, Cu: 16.80, N: 7.21, O: 16.96.
Scheme 1. Two types of 1,4-DHPs defined in current study.
2.3. Computational details
out correction. The NMR spectra were recorded on a Bruker AV400
spectrometer (400 MHz) at ambient temperature (25 °C) with TMS
as an internal standard. Infrared spectra in the region of 4000-500
cm−1 were recorded on a Thermo Scientific Nicolet IS5 spectrom-
eter. TGA was performed on a TGA Q500 thermal analyses system
with a heating rate of 10 °C/min from 25 to 800 °C under N2 atmo-
sphere. Element analysis was performed on a PE 2400II analyzer.
Mass spectra were recorded on a Bruker Esquire 6000 mass spec-
trometer, equipped with an electrospray ionisation source. The X-
ray diffraction data were collected on a Bruker-AXS SMART Breeze
CCD diffractometer at 293 K using graphite-monochromatized Mo
Structural optimization of crystal [Cu(HL2)Py] was performed
at the B3LYP/6-31G(d) theoretical level, wherein the SDD basis
set was used for the Cu atom. Wavefunction analysis were per-
formed by the Multiwfn 3.7 program and all graphic visualiza-
tion of electronic structures was realized by the VMD program [26,
27]. Calculations of all stationary points involved in the oxidation
of HL1 were performed at the B3LYP-D3/6-31G(d) theoretical level
and frequency analysis were also performed at the same level to
verify the located stationary points as minima (no imaginary fre-
quency) or transition states (only one imaginary frequency) and
obtain thermodynamic correctional data. All Single-point energy
calculations were performed at the B3LYP-D3/def2-TZVP level. All
calculations were finished by Gaussian 16 package [28]. Cartesian
coordinates of all the stationary points can be found in supporting
information.
˚
Kα radiation (λ=0.71073 A).
2.2. Synthesis
Synthesis
of
3,5-dicarboxyl-1,4-dihydropyridine-4-phenyl
(HL1): The ligand HL1 was prepared by hydrolysis of its corre-
sponding ester (1) (Scheme 2), wherein the compound 1 was
prepared by one-pot multicomponent reaction of benzaldehyde,
ethyl propiolate and ammonium acetate [25].
3. Results and discussion
3.1. Description of crystal structure [Cu(HL2)Py]
Specifically, benzaldehyde (10 mmol), ammonium acetate (10
mmol), ethyl propilate (20 mmol) were dissolved with ethanol (40
ml) in a 100 mL round bottom flask and then added acetic acid (0.1
mL). The resulting solution was refluxed at 80 °C until totally con-
version of benzaldehyde (detected by TLC). Thereafter, the organic
solvent was removed under reduced pressure, and the residues
were crystallized in ethyl acetate and n-hexane (v/v = 1:3) to af-
fording the desired products (1). Subsequently, compound 1 (3.01
g, 10 mmol) was dissolved in THF (25 mL) and MeOH (25 mL) in
another 100 mL round bottom flask and then concentrated NaOH
aqueous solution (10 M, 10 mL) was dropped into the solution.
The resulting mixture was refluxed at 100 °C until complete con-
version of 1 (detected by TLC). Thereafter, organic solvents were
removed under vacuum. The pH of the obtained solution was ad-
justed to 2-3 by HCl (1 mol/L), meanwhile white powders precipi-
tated from the solution. After filtrating and drying the precipitates,
target compound HL1 was obtained (2.45 g, 100 %). m.p. 250–252
°C; 1H NMR(DMSO-d6): δ = 4.69 (s, 1H, -C H), 7.09-7.30 (m, 6H, =C
H), 9.01 (t, 1H, -N H), 11.6 (br, 2H, -COO H); δ = HRMS (ESI-TOF),
m/Z calcd: 254.0688 for C13H11 NO4, found: 255.0686 for [M+H]+.
Synthesis Cu(II) complex [Cu(HL2)Py]: HL1 (12.3 mg, 0.05
mmol), Cu(NO3)2•3H2O (12.1 mg, 0.05 mmol) were dissolved in
deionized water (1 mL) and ethanol (1 mL), the resulting solution
X-Ray single crystal diffraction of Cu(HL2)Py reveals that the
crystal exhibits a polymeric structure and crystallizes in the mon-
oclinic system, space group P21/n. The asymmetric unit con-
tains one deprotonated HL2 ligand generated by oxidation of the
HL1(The mechanism was discussed following), one molecular pyri-
dine (Py) and a Cu atom, wherein the HL2 and Py are bridged by
a Cu atom through Cu-N and Cu-O coordination bonds (Fig. 1a).
Detailed examination of coordination sphere of the Cu atom shows
that the Cu atom is a six-coordinate distorted octahedron, which
binds with three HL2 ligands and one molecular pyridine (Fig. 1b).
As shown in Fig. 1b, four coordinative sites of the Cu atom are
occupied by carboxyl groups from two HL2 ligands, the remaining
two coordinative sites are occupied by N atom of the third HL2 lig-
and and one molecular pyridine through the Cu-N1 and Cu-N2 co-
ordination bond, respectively. Furthermore, the Cu(HL2)Py exhibits
a zigzag packing mode with infinite extension along the Cu site
(Fig. 1c) and small size cavities formed by three HL2 ligands and
three Cu atoms can be observed (Fig. 1d). Besides, the phenyl at-
tached at C4-position of HL2 stretches into the pores, which leads
these small pores are less accessible for guest molecules.
Table 1 lists selected bond lengths and bond angles around
the Cu atom as well as corresponding calculated values. The atom
Scheme 2. Synthetical route for preparing compound HL1.
2

Q. Fan, G. Wu, Y. Chen et al.
Journal of Molecular Structure 1232 (2021) 130057
Fig. 1. Crystal structure of Cu(HL2)Py. (a) asymmetric unit; (b) coordination sphere of Cu atom; (c) crystal packing mode; (d) pores formed between ligands HL2 and Cu
atoms.
Table 1
o
˚
Selected experimental and calculated bond lengths (A) and angles ( ) of Cu(HL2)Py.
Para.
Exp.
Calc.
ꢀV
Para.
Exp.
Calc.
ꢀV
Cu-N1
2.115
2.015
2.689
1.911
1.936
2.586
116.70
54.10
55.31
85.90
99.31
2.064
2.372
2.867
1.956
2.022
2.209
94.22
51.25
62.11
98.28
104.06
0.051
-0.357
-0.178
-0.045
-0.086
0.377
22.48
2.85
N1-Cu-O3
91.25
81.89
77.17
75.38
78.63
80.85
104.61
150.10
164.30
95.04
73.96
93.97
90.94
91.97
78.45
79.18
77.62
101.43
175.35
176.62
93.50
87.20
-2.72
-9.05
-14.8
-3.07
-0.55
3.23
Cu-N2
O1-O4-O3
Cu-O1
O2-O4-O3
Cu-O2
O1-N1-O3
Cu-O3
O2-N1-O3
Cu-O4
O3-N2-O2
N1-Cu-N2
O1-Cu-O2
O3-Cu-O4
N1-Cu-O1
N1-Cu-O2
N1-Cu-O1-O2
N1-Cu-O3-O4
N2-Cu-O2-O1
N2-Cu-O4-O3
O1-O2-O3-O4
3.18
-25.25
-12.32
1.54
-6.8
-12.38
-4.75
-13.24
numbers were showed in Fig. 1c. As shown in Table 1, the bond
3.2. Thermal and PXRD element analysis
˚
˚
length of Cu-N1 (2.115 A) was larger than that of Cu-N2 (2.015 A),
indicating stronger coordination interaction of the former, which
might be ascribed to the decrease of electron density of the N1
atom caused by the presence of carboxyl groups in HL2. According
to the bond lengths of Cu-O, inequivalent bond strength could also
Thermal stability of the Cu(HL2)Py were investigated by ther-
mal gravimetric analysis (TGA) and its phase purity were as-
sessed by PXRD and element analysis. As shown in the TGA curve
(Fig. 2a), the Cu(HL2)Py was thermal stable before 185 °C, after
that the crystal began to lost weight. The first weightlessness point
corresponded to the loss of the coordinated pyridine molecule at
212 °C, the weight loss found of 22.26% (calcd. 20.57 %). The fol-
lowing weight loss corresponded to the combustion of organic HL2
ligand and only CuO remained at last as indicated by the remain-
ing weight (found: 21.31%, calcd. 20.83%). Fig. 2b showed that the
PXRD pattern of as-synthesized sample in well agreement with the
simulated spectrum, indicating the phase of the bulk sample was
pure, which would also be supported by the element analysis re-
sult of the Cu(HL2)Py (See synthesis section).
˚
be observed. To be specific, the strength of Cu-O2 (1.911 A) and
˚
˚
Cu-O3 (1.936A) was much stronger than that of Cu-O1 (2.689 A)
˚
and Cu-O4 (2.586 A) as indicated by shorter lengths of the formers.
The result suggested that the two HL2 ligands exhibited different
coordination affinities with the Cu atom, which could also be con-
firmed by different angles between O atoms of carboxyl groups and
the Cu atom, for instance, the angle of O1-Cu-O2 (54.10o) and O3-
Cu-O4 (55.31o). From the angles of O1-O4-O3 (81.89o) and O1-N1-
O3(75.38o), one could readily conclude that the octahedron formed
between O, N and Cu atoms is distorted due to the values deviated
from the standard angles(109o).
On the other hand, as can be seen from the Table 1, calculated
bond lengths were in well agreement with the experimental ones
3.3. Vibrational spectroscopy analysis
˚
as the largest value of ꢀV was no more than 0.4 A. Although the
Solid state FT-IR spectra of the Cu(HL2)Py were recorded in
the region of 4000-500 cm−1 and the spectrum were presented
in Fig. 3. Additionally, frequency calculation of the Cu(HL2)Py was
carried out for assisting assignment of its vibrational bands in the
IR spectrum.
calculated angles exhibited a big difference with the experimental
ones with the maximum of ꢀV reaching to 25.25o, such result may
attribute to that the geometrical optimization of Cu(HL2)Py was
performed in gas state, wherein molecular interactions and lattice
energies were not taken into consideration during the calculations
(Overlap of experimental and calculated structures can be found in
Fig. S1 as well as the calculated RMSD).
As shown in Fig. 3, typical stretching vibrations of saturated C-
H bond that usually present at above 3000 cm−1 was disappeared
in the spectrum, suggesting disappearance of the H atom at C4-
3

Q. Fan, G. Wu, Y. Chen et al.
Journal of Molecular Structure 1232 (2021) 130057
Fig. 2. TGA curve (a) and PXRD pattern (b) of Cu(HL2)Py.
Fig. 3. FT-IR spectrum of Cu(HL2)Py.
Table 2
intensity and the assignments of major vibrational bands. An em-
pirical scaling factor of 0.963 was used to correct the theoretical
frequencies as basis set incompleteness can lead to systematic er-
ror.
The
experimental
and
theoretical
vibrational
wavenumbers(cm−1
) for Cu(HL2)Py as well as as-
signments of major IR bands.
Exp.
Calc.
|ꢀR|
Intensity
Assignments
asCOO−
νsCOO−
νC=C
Rb-Py
βC-H
βPy
1593
1348
1221
1132
1074
1014
616
1619
1330
1231
1117
1051
1009
606
26
18
10
15
23
5
285.64
75.95
14.08
46.59
14.61
8.84
ν
3.4. Electronic structure analysis
To investigate structural characteristics of the Cu(HL2)Py in ex-
cited state, electron-hole analysis was carried out on the founda-
tion of electronic wavefunction generated by TDDFT calculations.
To achieve this goal, the Cu(HL2)Py was divided into five frag-
ments (Fig. 4a), wherein three HL2 ligand molecules were denoted
as Frag.1, Frag.2 and Frag.4, and the pyridine molecule and Cu atom
were denoted as Frag.3 and Frag.5, respectively. Excited-state pa-
rameters including D, Sr, H, t, HDI and EDI indexes of the five low-
est excited-states for the Cu(HL2)Py were presented in Fig. 4b-f as
well as the corresponding electronic transition maps.
10
1
6.75
νC-N
γ -Py
581
582
9.46
aThe absolute difference between experimental and cal-
culated values; ν: stretching; β: in plane bending; γ :
out of plane bending; Rb.: Ring breathing; s: symmet-
ric; as: asymmetric; Py: Pyridine Ring.
position in 1,4-dihydropyridine skeleton of HL1, which were also
supported by X-Ray single-crystal diffraction of the Cu(HL2)Py. The
IR absorption peaks for carboxyl groups that should be observed
at near 1710 cm−1 were replaced by two peaks at 1593 and 1348
cm−1 that attributed to antisymmetric and symmetric stretching
vibrations of deprotonated carbonyl, indicating the presence of co-
ordination interaction between O atoms and the Cu atom. Addi-
tionally, the peaks at 581 and 616 cm−1 can be assigned to the
ring wagging vibration of the pyridine scaffold of HL2 ligand in
the complex and the stretching vibration of the Cu–N bond, re-
spectively [22,29].
As shown in the Fig. 4b, in terms of transition S0→S1, the D
˚
index was only 0.20 A and the t index was -0.66, suggesting insuf-
ficient separation of electron and hole distributions. Indeed, over
half of the distributions were overlapped as indicated by the Sr,
which reached to 0.64 (upper limit:1.0). These results revealed that
the transition S0→S1 was a local excitation process. Besides, the
large values of HDI (53.42) and EDI (47.30) demonstrated strong
locality of electron and hole. In other words, the distribution re-
gion of them was narrow. Just as displayed in Fig. 4b, the distribu-
tions of both electron (Purple) and hole (Green) predominantly lo-
cated on the Cu atom. Obviously, electron-hole transition map fur-
ther confirmed the transition S0→S1 was a local excitation process.
Transition S0→S2 showed a distinct different behavior with the
S0→S1. It was readily to concluded that the electron and hole of
the transition S0→S2was separated sufficiently according to the
It is readily to conclude that the simulated IR spectra in well
agreement with the experimental one due to small difference (ꢀR)
of their IR absorption peaks, therefore, assignments of vibrational
bands based on the calculated results were reasonable and ac-
ceptable. Table 2 summarized the experimental IR bands for the
Cu(HL2)Py, corresponding theoretical vibrational wavenumbers, IR
˚
˚
values of D (4.21 A) and t (2.87 A) and the value of Sr (0.26)
illustrated only 26% distributions of the electron and hole was
4

Q. Fan, G. Wu, Y. Chen et al.
Journal of Molecular Structure 1232 (2021) 130057
Fig. 4. Electron-hole analysis of the lowest five excited states of of the Cu(HL2)Py and relevant excited parameters. isoface = 0.003 a.u. aD: Centroid distance between
electron and hole; bSr: Overlap of electron and hole; cH: Overall mean distribution extent of electron and hole; dt: Separation of electron and hole; eHDI: Hole delocalization
index; fEDI: Electron delocalization index.
Fig. 5. Contribution of each fragment to electron and hole as well as the corresponding heat map.
overlapped. Compared with the HDI value (53.42) of S0→S1, the
lower value (12.84) of S0→S2 suggested distribution of the hole
was wider, which totally distributed on pyridine ring of Frag.4 and
the attaching carboxyl groups, while the electrons mainly located
on the Cu atom with slight distributions appearing on carboxyl and
N atom of the HL2 ligand. These results showed that the transition
S0→S2 was a charger transfer excitation process.
excitation due to the large overlap of electron and hole. Similarly,
the excited state S0→S5 was also regarded as a local excitation de-
˚
spite that the t index was above zero (0.84 A) and the D index
˚
reached 2.70 A.
Furthermore, contribution of each fragment to electron and
hole were calculated for quantitatively analyzing the electronic
transition characteristics. As shown in Fig. 5, contribution of the
five fragments to electron showed no big difference for the five
excited states, wherein the frag.5 contributed the most to electron,
accounting for about 69%, the least contribution (only 0.2 %) came
from the frag.3. While contributions of the five fragments to holes
of the five excited states was different. For the transition S0→S1,
82.16% contribution came from the frag.5, while for the transition
S0→S2, the major contribution was from frag.4, which accounted
for 93.34%. For the remaining three excited states, both frag.4
and frag.5 exhibited contributions to holes. Specifically, for the
transitions S0→S3 and S0→S4, major contributions to holes origi-
nated from the frag.5, which were 58.93% and 70.79%, respectively,
As for the excited states S0→S3 and S0→S4, they exhibited sim-
ilar electronic transition behavior with the S0→S1 (0.20, -0.66) due
˚
to their similar values of Sr and t, which were 0.57, -0.33 A for
˚
the S0→S3 and 0.59, -0.52 A for the S0→S4, respectively. How-
ever, large difference of hole distributions were present as indi-
cated by the HDI index (31.32 and 33.49), which were much lower
than that of the S0→S1.To be specific, only small amounts of hole
was found to locate on carboxyl groups of frag.4 (Fig. 4c-d). In this
sense, both S0→S3 and S0→S4 showed electron transfer character-
istic, while such characteristic was not observed for the transition
S0→S1. Nevertheless, the two excited states were ascribed to local
5

Q. Fan, G. Wu, Y. Chen et al.
Journal of Molecular Structure 1232 (2021) 130057
Fig. 6. The IFCT analysis of the five lowest excited states of Cu(HL2)Py.
Scheme 3. Synthetical route for preparing crystal Cu(HL2)Py.
whilst the situation was reversed for the transition S0→S5, where
contributions of the frag.4 was over the frag.5, which was 52.74%
and 43.27%, respectively. All these results were in well agreement
with observations in Fig. 4.
In addition, the interfragment charge transfer (IFCT) method
was used further to quantitatively analyze the electronic excita-
tions based on analytic results described above. The results were
presented in Fig. 6.
As shown in Fig. 6, for the S0→S1 excitation, the maximum
interfragment charge transfer was only 0.112 e, which was ob-
served between the frag.1 and frag.5, while the electronic trans-
fer in frag.5 reached to 0.499 e, which suggested that local exci-
tation played a dominant role in the S0→S1 electronic transition.
In terms of S0→S2, the charge transfer played a dominant role as
0.442 e transferred from the frag.4. to the frag.5 and 0.106 e to the
frag.1. The S0→S3 and S0→S4 exhibited a similar electron transfer
behavior. For example, about 0.44 e of them was excited within
frag.5 and about 0.1e was transferred from frag.4 to frag.5. Obvi-
ously, the two excited states were dominated by local excitation.
For the S0→S5, 0.273 e was excited within frag.5 and 0.243 e was
transferred from frag.4 to frag.5. In this sense, dominate electronic
transition mode was absent for current excitation.
Scheme 4. Plausible oxidative mechanism of HL1.
alyze reduction reactions. Based on these facts, the plausible oxida-
tive mechanism of HL1 was proposed and presented in Scheme 4.
Scheme 3
3.5. Oxidative mechanism of HL1
As shown in Scheme 4, two H-releasing processes were in-
volved in the oxidation of HL1. The reaction enthalpies (ꢀHr) and
Gibbs free energies (ꢀGr) were calculated as -16.44 and -17.71
kcal/mol (Detailed thermodynamic data can be found in support-
ing information), indicating this transformation was kinetically and
thermodynamically favorable. The first process was C4-H bond fis-
To reveal oxidative mechanism of HL1, kinetics and thermody-
namic parameters for this process were evaluated by DFT calcu-
lations. Wang et.al revealed that 1,4-dihydropyridine was a pow-
erful antioxidant with high H-atom-donating ability [30]. Besides,
1,4-dihydropyrine derivatives were usually used as H source to cat-
6

Q. Fan, G. Wu, Y. Chen et al.
Journal of Molecular Structure 1232 (2021) 130057
sion induced by O2, generating hydroperoxyl radical (HOO•) and
RN1 radical. This process was endothermic with ꢀHr1 of 28.08
kcal/mol. Besides, the energy barrier(ꢀGTS1) of this step was calcu-
lated as 40.42 kcal/mol. The newly formed RN1 radical rearranged
to RN2 radical, which released the second H through fission of N-
H bond induced by hydroperoxyl radical (HOO•), generating HL2
and hydrogen peroxide. Unlikely to the first step, this step was an
exothermic process with ꢀHr2 of -43.39 kcal/mol, and energy bar-
rier (ꢀGTS2) for the H-releasing was 38.97 kcal/mol. Obviously, the
rate determining step for the oxidation of HL1 was the C4-H re-
leasing process.
Acknowledgement
We acknowledge the open-end foundation of State Key Labo-
ratory of Nuclear Resources and Environment of East China Uni-
versity of Technology (No. NRE1925); Research Foundation for
Advanced Talents of East China University of Technology (No.
DHBK2019141); Science and Technology Research Project of Jiangxi
Provincial Department of Education (No. GJJ190381), Science and
Technology Research Project of Jiangxi Provincial Department of
Education (No. GJJ150587), National Natural Science Foundation of
China(No. 22008028), the opening Project of Jiangxi Province Key
Laboratory of Polymer Micro/Nano Manufacturing and Devices (No.
PMND202003).
4. Conclusions
In summary, a new Cu(II) complex, denoted as Cu(HL2)Py, was
obtained unexpectedly during studying coordination reaction of
1,4-dihydropyridine derivative (HL1) and Cu(II). X-ray single-crystal
diffraction reveals that the crystal crystallizes in the monoclinic
system, space group P21/c and exhibits a zigzag packing mode.
The asymmetric unit contains one ligand HL2, one molecular pyri-
dine (Py) and one Cu atom, and the Cu atom is six-coordinated.
FT-IR analysis of the complex indicates that the oxidization of lig-
and HL1 to HL2 leads to the disappearance of stretch vibration
peaks for saturated C-H bond and N-H bond, which usually present
above 3000 cm−1. Besides, The IR absorption peaks for carboxyl
groups that should appear at near 1710 cm−1 are observed at 1593
and 1348 cm−1, which are assigned as antisymmetric and sym-
metric stretching vibrations of deprotonated carbonyl. TGA analy-
sis reveals the complex is stable up to 185 °C and its PXRD spectra
in well agreement with the experimental one. DFT calculations of
the five lowest electronic excitations for the complex reveal that
the S0→S1 is a local excitation involving d-d transition of the Cu
atom, while the S0→S2 is dominated by electronic transfer transi-
tion with electrons transferring from frag.4 to frag.5. For the upper
excited states, the S0→S3 and S0→S4 excitations are dominated by
local excitation and mixed with small amount of electronic trans-
fer transition, while the S0→S5 excitation shows no dominated
electronic transition mode. DFT calculations reveal that the oxida-
tion of HL1 is both kinetically and thermodynamically favorable,
where two H-releasing processes are involved and the C4-H re-
leasing process is the rate determining step with energy barrier of
40.42 kcal/mol.
Supplementary materials
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.molstruc.2021.130057.
References
[1] D.J. Triggle, 1,4-dihydropyridines as calcium channel ligands and privileged
structures, Cell. Mol. Neurobiol. 23 (2003) 293–303.
[2] S. Goldmann, J. Stoltefuss, 1,4-dihydropyridines: effects of chirality and confor-
mation on the calcium antagonist and calcium agonist activities, Angew. Chem.
Int. Ed. 30 (1991) 1559–1578.
[3] C. Safak, R. Simsek, Fused 1, 4-dihydropyridines as potential calcium modula-
tory compounds, Mini-Rev. Med. Chem. 6 (2006) 747–755.
[4] A. Kumar, R.A. Maurya, S. Sharma, M. Kumar, G. Bhatia, Synthesis and bio-
logical evaluation of N-aryl-1,4-dihydropyridines as novel antidyslipidemic and
antioxidant agents, Eur. J. Med. Chem. 45 (2010) 501–509.
[5] R. Peri, S. Padmanabhan, A. Rutledge, S. Singh, D.J. Triggle, Per-
manently
of L-type calcium channels. Synthesis and pharmacological char-
acterization of methyl (ω-trimethylalkylammonium) 1,4-dihy-
charged
chiral
1,4-dihydropyridines:
molecular
probes
dro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate iodide, calcium
channel antagonists, J. Med. Chem. 43 (2000) 2906–2914.
[6] SA Khedkar, PB Auti, 1, 4-dihydropyridines: a class of pharmacologically im-
portant molecules, Mini-Rev. Med. Chem. 14 (2014) 282–290.
[7] P.S. Kharkar, B. Desai, H. Gaveria, B. Varu, R. Loriya, Y. Naliapara, A. Shah,
V.M. Kulkarni, Three-dimensional quantitative structure-activity relationship
of 1, 4-dihydropyridines as antitubercular agents, J. Med. Chem 45 (2002)
4858–4867.
[8] K. Sirisha, G. Achaiah, V.M. Reddy, Facile synthesis and antibacterial, antituber-
cular, and anticancer activities of novel 1,4-dihydropyridines, Arch. Pharm. 343
(2010) 342–352.
[9] Y. Murthy, A. Rajack, M.T. Ramji, C. Praveen, K.A. Lakshmi, Design, solvent free
synthesis, and antimicrobial evaluation of 1, 4 dihydropyridines, Bioorg. Med.
Chem. Lett. 22 (2012) 6016–6023.
Supporting information
[10] N. Tripathi, in: Study of Synthesis and Biological Importance of 1, 4-Dihydropy-
ridines Derivatives, in: Advances in Water Pollution Monitoring and Control,
Springer, 2020, pp. 79–84.
Detailed crystallographic data of Cu(HL2)Py were listed in Ta-
ble S1; The crystal have been deposited with the Cambridge Crys-
tallographic Centre, CCDC No 2050699; Overlap of experimental
and calculated structures (Fig. S1). Solid-state UV-Vis spectrum of
Cu(HL2)Py(Fig. S2). Cartesian coordinates of Cu(HL2)Py and ther-
modynamic data (Table S2) of all located stationary points in-
volved in oxidation of HL1 as well as their Cartesian coordinates
[11] M. Faiza, H. Shafaroodi, S. Nezamoleslami, M. Zubair, M. Sheibani, V. Nikoui,
M. Ghazi-khansari, A.R. Dehpour, Involvement of nnos, and α1, α2, β1, and β2
subunits of soluble guanylyl cyclase genes expression in anticonvulsant effect
of sumatriptan on pentylenetetrazole-induced seizure in mice, Iran. J. Pharm.
Res. (2020) in Press http://10.22037/IJPR.2020.112594.13844 .
[12] S.G. Ouellet, A.M. Walji, D.W. Macmillan, Enantioselective organocatalytic
transfer hydrogenation reactions using Hantzsch esters, Acc. Chem. Res. 40
(2007) 1327–1339.
[13] J. Bielmann, H. Callot, Ring contraction in the 1, 4-dihydropyridine series, J.
Chem. Soc. D: Chem. Commun. 4 (1969) 140–140.
[14] Q. Fan, R. Sun, Z. Zhao, H. Yan, Synthesis and theoretical study of pyrrole
formiate derivatives through ring contraction of 1,4-dihydropyridines, Tetrahe-
dron 74 (2018) 7457–7465.
[15] A. Alvarez, E. Ochoa, Y. Verdecia, M. Suárez, M. Solá, N. Martín, Theoretical
study of the highly diastereoselective 1,3-dipolar cycloaddition of 1, 4-dihy-
dropyridine-containing azomethine ylides to [60]fullerene (Prato’s reaction), J.
Org. Chem. 70 (2005) 3256–3262.
Declaration of Competing Interest
The authors declared that they have no competing financial in-
terests or personal relationships that could have appeared to influ-
ence the work reported in this paper.
[16] C. Wang, Z. Lu, Intermolecular [2+2] cycloaddition of 1, 4-dihydropyridines
with olefins via energy transfer, Org. Lett. 19 (2017) 5888–5891.
[17] Q. Fan, H. Tan, P. Li, H. Yan, Hetero-intermolecular [2+ 2] photocycloaddition of
1, 4-dihydropyridines: a combined experimental and DFT study, New J. Chem.
42 (2018) 16795–16805.
[18] M. Nasr-Esfahani, M. Moghadam, S. Tangestaninejad, V. Mirkhani, A.R. Momeni,
Rapid and efficient oxidation of Hantzsch 1,4-dihydropyridines with sodium
periodate catalyzed by manganese (III) Schiff base complexes, Bioorg. Med.
Chem. 14 (2006) 2720–2724.
CRediT authorship contribution statement
Qiangwen Fan: Conceptualization, Project administration, Fund-
ing acquisition, Writing - original draft. Guorong Wu: Writing -
review & editing. Yong Chen: Investigation. Yanling He: Investiga-
tion. Longwei Zhu: Investigation. Huijun Ren: Data curation. Hailu
Lin: Writing - review & editing.
7

Q. Fan, G. Wu, Y. Chen et al.
Journal of Molecular Structure 1232 (2021) 130057
[19] M.-C. Suen, C.-W. Yeh, Y.-W. Ho, J.-C. Wang, Self-assembly of two-dimen-
sional coordination polymers from AgX (X= BF4−, ClO4−, NO3− and PF6−) and
2,6-dimethyl-3,5-dicyano-4-(6-methyl-2-pyridyl)-1,4-dihydropyridine, New J.
Chem. 33 (2009) 2419–2425.
[25] Q. Zhong, Q. Fan, H. Yan, Synthesis of 2, 3-dihydropyrroles by photo rearrange-
ment of Hantzsch 1, 4-dihydropyridines with high diastereoselectivity, Tetra-
hedron Lett. 58 (2017) 1292–1295.
[26] T. Lu, F. Chen, Multiwfn: a multifunctional wavefunction analyzer, J. Comput.
Chem. 33 (2012) 580–592.
[27] W. Humphrey, A. Dalke, K. Schulten, VMD: visual molecular dynamics, J Mol.
Graph. Model. 14 (1996) 33–38.
[28] M. Frisch, G. Trucks, H. Schlegel, G. Scuseria, M. Robb, J. Cheeseman, G. Scal-
mani, V. Barone, G. Petersson, H. Nakatsuji, in, Gaussian, Inc. Wallingford, CT,
2016.
[29] L.-Q. Chai, Y.-X. Li, L.-C. Chen, J.-Y. Zhang, J.-J. Huang, Synthesis, X-ray structure,
spectroscopic, electrochemical properties and DFT calculation of a bridged din-
uclear copper (II) complex, Inorg. Chim. Acta 444 (2016) 193–201.
[30] L.F. Wang, H.Y. Zhang, L. Kong, Z.W. Chen, J.G. Shi, DFT calculations indicate
that 1, 4-dihydropyridine is a promising lead antioxidant, Helv. Chim. Acta. 87
(2004) 1515–1521.
[20] C.-W. Yeh, C.-H. Tsou, H.-A. Tsai, H.-T. Lee, W.-H. Yao, M.-C. Suen, Structural di-
versity in the self-assembly of silver (I) complexes containing 2, 6-dimethyl-3,
5-dicyano-4-(4-quinolinyl)-1, 4-dihydropyridine, Inorg. Chim. Acta. 427 (2015)
1–12.
[21] P.-N. Wang, C.-W. Yeh, C.-H. Tsou, Y.-W. Ho, S.-C. Lin, M.-C. Suen, Struc-
tural diversity in the self-assembly of Ag (I) complexes containing 2,
6-dimethyl-3, 5-dicyano-4-(3-pyridyl)-1, 4-dihydropyridine, New J. Chem. 38
(2014) 1079–1091.
[22] P.R. Bontchev, D.R. Mehandjiev, B.B. Ivanova, R.P. Bontchev,
A mononuclear
complex of copper (II) with a calcium channel antagonist nifedipine. Synthesis,
properties, crystal structure, Transit. Metal. Chem. 28 (2003) 745–748.
[23] N. Jori, P.A. Quispe, M.S. Islas, O.E. Piro, G.A. Echeverría, E.G. Ferrer,
P.A. Williams, Unexpected oxidation of nitrendipine. Properties of oxidized ni-
trendipine and its Cu (II) complex, J. Mol. Struct. 1177 (2019) 199–203.
[24] Q. Fan, P. Li, H. Yan, Photophysical properties of 2, 6-unsubstituented 1, 4-dihy-
dropyridines: experimental and theoretical studies, J. Photoch. Photobio. A 358
(2018) 51–60.
8