Highly functionalized N-1-(2-pyridinylmethyl)-3,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones: Synthesis, characterization, crystal structure and DFT studies

Article abstract of DOI:10.1016/j.molstruc.2020.128940

Highly functionalized N-1-(2-pyridinylmethyl)-3,5-bis[(E)-methoxy/fluorophenylmethylidene]-tetrahydro-4(1H)-pyridinones (5a and 5b) have been synthesized in good yields. The molecular structure of the synthesized compounds was elucidated by NMR spectrosco

Full text of DOI:10.1016/j.molstruc.2020.128940

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Highly functionalized N-1-(2-pyridinylmethyl)-3,5-bis[(E)-
arylmethylidene]tetrahydro-4(1H)-pyridinones: Synthesis,
characterization, crystal structure and DFT studies
Dhaifallah M. Al-thamili , Abdulrahman I. Almansour ,
Natarajan Arumugam , Sevgi Kansız , Necmi Dege ,
Saied M. Soliman , Mohammad Azam , Raju Suresh Kumar
PII:
S0022-2860(20)31265-5
DOI:
Reference:
https://doi.org/10.1016/j.molstruc.2020.128940
MOLSTR 128940
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19 July 2020
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Natarajan Arumugam , Sevgi Kansız , Necmi Dege , Saied M. Soliman , Mohammad Azam ,
Raju Suresh Kumar , Highly functionalized N-1-(2-pyridinylmethyl)-3,5-bis[(E)-
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Dhaifallah M. Al-thamili ,
Abdulrahman I. Almansour ,
arylmethylidene]tetrahydro-4(1H)-pyridinones: Synthesis, characterization, crystal structure and DFT
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Highlights

Highly functionalized α,β-unsaturated carbonyl compounds were achieved in good
yields.



Molecular structure was elucidated by NMR spectroscopic and X-ray crystallographic
studies.
Molecular packing was performed to determine different intermolecular contacts
using Hirshfeld analysis.
DFT calculations are used in order to predict the electronic properties of studied
compounds.
1

Highly functionalized N-1-(2-pyridinylmethyl)-3,5-bis[(E)-
arylmethylidene]tetrahydro-4(1H)-pyridinones: Synthesis, characterization,
crystal structure and DFT studies
1
1
1
2
Dhaifallah M. Al-thamili, Abdulrahman I. Almansour, Natarajan Arumugam, Sevgi Kansız,
3
4
1
1,*
Necmi Dege, Saied M. Soliman
,
Mohammad Azam and Raju Suresh Kumar
1
Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
Department of Fundamental Sciences, Faculty of Engineering, Samsun University, Samsun, 55420, Turkey
Department of Physics, Faculty of Arts and Sciences, Ondokuz Mayıs University, Samsun, 55139, Turkey
2
3
4
Department of Chemistry, Faculty of Science, Alexandria University, P.O. Box 426, Ibrahimia, Alexandria 21321,
Egypt
_
_____________________________________________________________________________
Abstract
Highly functionalized N-1-(2-pyridinylmethyl)-3,5-bis[(E)-methoxy/fluorophenylmethylidene]-
tetrahydro-4(1H)-pyridinones (5a and 5b) have been synthesized in good yields. The molecular
structure of the synthesized compounds was elucidated by NMR spectroscopy and further
confirmed by single crystal X-ray crystallographic studies. The Hirshfeld analysis reveals that
the molecular packing of 5a is mainly controlled by N...H (4.9%), C...H (30.6%) and H...H
(
52.4%) contacts whereas the molecules are packed by strong F...H (16.8-16.9 %), N...H (5.4%)
and O...H (5.2-5.4%) as well as weak C...C (3.9-4.5%), H...H (39.7-39.9%) and C...H (24.8-
5.8%) contacts in 5b. DFT calculations are used in order to predict the electronic properties of
2
studied compounds. The NMR data obtained experimentally correlated well with the calculated
findings.
Keywords: Functionalized -unsaturated ketones; X-ray analysis; Hirshfeld; DFT studies.
_
_____________________________________________________________________________
*
Corresponding authors: Email: sraju@ksu.edu.sa; drrajusureshkumar@gmail.com (Suresh Kumar R).
2

1
. Introduction
Heterocyclic compounds are of central importance to biological processes and are
prevalent as natural products. Heterocyclic hybrids designed and synthesized by organic
chemists are used as pharmaceuticals and play vital roles in human life. The noteworthy aptitude
of heterocyclic nuclei to serve both as biomimetics and active pharmacophores has
fundamentally contributed to their unique value as traditional key elements of several drugs
[
1,2].
Compounds possessing α,β-unsaturated carbonyl groups are the central core of several
biologically active compounds displaying fascinating biological properties [3-6]. Conjugated
unsaturated ketones have the capacity to interact favorably with thiols in contrast to amino and
hydroxyl groups present in nucleic acids. Thus, the genotoxic properties exhibited by various
alkylating agents in cancer chemotherapy may well be absent in conjugated enones [7]. Many
lead compounds have been developed due to their diverse biological properties and hence
compounds possessing α,β-unsaturated carbonyl groups have become a tool of choice both in
academia and industry.
Anticancer drug research reveals that piperidinone derivatives embedded with ,-
unsaturated group exhibit potent and promising activity against cancer cell lines [8,9].
Compounds containing two or more alkylation sites demonstrated selective toxicity towards
neoplastic cells in contrast to the corresponding normal tissues [10] and hence compounds with
two sites for thiolation are of paramount importance. It is also believed that the piperidone
derivatives with more unsaturated groups would have greater potency than the ones with less
and/or no unsaturated groups since steric impedance to attack by thiols would be less in the case
of former [9]. In particular, the 3,5-bis(arylidene)-4-piperidones demonstrate IC50 values in the
low micromolar to submicromolar range towards a number of cell lines. It is reported that these
compounds show both antitumor and fluorescent properties, and draw extensive attention as
potential fluorescent antitumor drug candidates [11,12]. Therefore, the development of series of
target compounds seemed to be judicious.
In continuation of our earlier research findings in the construction and/or biological
screening of novel heterocycles possessing piperidone structural motif [13-20], here in we
propose the synthesis of novel α,β-unsaturated carbonyl groups engrafted N-substituted
piperidones. The structural elucidation of the synthesized compounds was performed by
3

spectroscopic techniques and single crystal X-ray crystallography. Molecular packing was done
to determine the different intermolecular contacts in the crystal structure using Hirshfeld
topology analysis. Furthermore, DFT calculations were also performed to evaluate the structural
aspects and to assign the NMR chemical shifts of these compounds. In addition, the electronic
properties and reactivity descriptors were also calculated and compared.
2. Experimental
2.1. Chemistry
All reagents and solvents were purchased from commercial suppliers and used without
further purification. Reactions were monitored by thin-layer chromatography (TLC) on silica gel.
1
13
Melting points were taken using open capillary tubes and are uncorrected. H, C and two-
dimensional NMR spectra were recorded on a Jeol 500 MHz instrument in CDCl using
3
Tetramethylsilane (TMS) as internal standard. Standard Jeol software was used throughout.
Chemical shifts are given in parts per million (-scale) and the coupling constants are given in
Hertz. FT-IR spectra were recorded on a Perkin Elmer system 2000 FT-IR instrument (KBr).
Mass spectra were recorded on a DART-ToF-MS mass spectrometer. X-ray data set were
collected from STOE IPDS 2 Diffractometer and SHELXL2018/3 (Sheldrick, 2018) Program(s)
was used to refine structures.
2
.2. General procedure for the synthesis of N-1-(2-pyridinylmethyl)-3,5-bis[(E)-
arylmethylidene]tetrahydro-4(1H)-pyridinones 5(a,b)
A mixture of 3,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones (3) (1mmol) and
K
2
3
CO (3 mmol) in acetonitrile (20 mL) was stirred at room temperature for 30 min. Then 2-
(
chloromethyl)pyridine hydrochloride 4 (1.1 mmol) dissolved in acetonitrile (5 mL) was added.
The mixture was stirred and refluxed until the consumption of the starting materials was
complete. The reaction progress was monitored by TLC. After the reaction was complete (24 h),
the mixture was cooled to room temperature, the inorganic salts were filtered off on sintered
glass filter and washed with CHCl
partitioned between CHCl (20 mL) and water (10 mL). The organic phase was separated, and
the aqueous phase was washed with CHCl
Na SO
acetonitrile to afford compound 5.
3
(10 mL). The filtrate was evaporated, and the residue was
3
3
(20mL). The combined organic phase was dried
(
2
4
), filtered, and evaporated. The crude product was purified by crystallization using
4

2
.2.1. N-1-(2-Pyridinylmethyl)-3,5-bis[(E)-(2-methoxylphenyl)methylidene]tetrahydro-4(1H)-
pyridinone (5a)
Obtained as yellow solid, Yield = 85 %; mp = 120-122 °C; IR (KBr): 1670, 1614, 1586
−
1 1
cm ; H NMR (500 MHz, CDCl
3
): δ
H 3 3
3.78 (s, 3H, OCH ), 3.81 (s, 3H, OCH ), 3.82-3.83 (m,
6
3
H, 2'-CH
H, ArH), 7.43-7.46 (m, 1H, ArH), 8.06 (s, 2H, ArH), 8.44-8.45 (m, 1H, ArH). C NMR (125
2 2 2
, 6-CH ' and 7'-CH ), 6.86-6.90 (m, 4H, ArH), 7.02-7.12 (m, 3H, ArH), 7.23-7.29 (m,
1
3
MHz, CDCl
3
): δ
C
54.60, 55.19, 62.35, 110.37, 119.75, 121.78, 122.68, 124.06, 129.94, 130.11,
+
1
32.26, 132.90, 136.120, 148.80, 157.89, 158.08, 187.34. Mass: 427 [M ]. Anal. calcd for
27 26 2 3
C H N O : C, 76.03; H, 6.14; N, 6.57%; found: C, 76.24; H, 6.02; N, 6.70%.
2
.2.2. N-1-(2-Pyridinylmethyl)-3,5-bis[(E)-(4-fluorophenyl)methylidene]tetrahydro-4(1H)-
pyridinone (5b)
Obtained as yellow solid, Yield = 88 %; mp = 110–112 °C; IR (KBr): 1668, 1615, 1588
−
1 1
cm ; H NMR (500 MHz, CDCl
3
): δ
H 2 2 2
3.84-3.87 (m, 6H, 2'-CH , 6'-CH and 7'-CH ), 7.03-7.11
(
m, 5H, ArH), 7.28-7.33 (m, 5H, ArH), 7.51-7.54 (m, 1H, ArH), 7.74 (s, 2H, ArH), 8.48-8.49 (m,
1
3
1
1
4
H, ArH).
3 C
C NMR (125 MHz, CDCl ): δ 54.73, 63.23, 115.60, 115.78, 122.35, 122.99,
31.23, 131.24, 132.30, 132.77, 135.36, 136.62, 149.16, 157.62, 161.86, 163.86, 187.19. Mass:
+
03 [M ].
20 2 2
Anal. calcd for C25H F N O: C, 74.61; H, 5.01; N, 6.96%; found: C, 74.77; H, 5.14; N, 6.85%.
2
.3. X-Ray analysis
The diffraction intensity data of 5a C27
26 2 3 20 2 2
H N O and 5b C25H F N O was obtained by
using MoKα radiation with STOE IPDS 2 [21] diffractometer with graphite-monochromated
MoKα radiation (λ = 0.71073 Å) at 296 K. In the data collection and reduction processes, X-
AREA [21] and X-RED [21] programs were used, respectively. Crystal structure was resolved
using SHELXT [22] software and refined with SHELXL [23] software using direct methods,
which are included in the WinGX [24] program. The results were visualized using MERCURY
[
25] software. C–bonded hydrogen atoms were refined as riding model C—H = 0.93–0.97 Å.
Table 1. Crystal data and refinement details for 5a and 5b.
Crystal Data
(5a)
(5b)
Chemical Formula
C
27
H
26
N
2
O
3
25 20 2 2
C H F N O
5

Formula weight (a.k.b.)
Temperature (K)
Crystal system
426.5
296
Monoclinic
1
P2 /c
402.43
296
Triclinic
P-1
Space group
Unit cell parameters
a, b, c (Å)
11.6907 (10), 21.5030 (11), 9.1736 (15), 11.8482 (14),
9.8644 (7)
19.097 (3)
β (˚)
112.987 (6)
91.293 (11), 93.917 (13),
9
0.250 (12)
Crystal size (mm)
Volume, V (Å )
0.75 × 0.42 × 0.15
2282.9 (3)
4
0.42 × 0.29 × 0.16
2070.2 (5)
4
3
Z
-1
μ (mm )
0.08
0.09
F
000
904
1.241
840
1.291
3
Calculated density (Mg/m )
Data collection
Diffractometer
Wavelength (Å)
STOE IPDS 2
0.71073
STOE IPDS 2
0.71073
θ range for data collection (˚)
Index ranges
1.9 ꢀ θ ꢀ 28.9
1.7 ꢀ θ ꢀ 28.3
h
k
min, hmax
min, kmax
-10, 14
-26, 26
-12, 12
ꢁ scan
11306
4403
-10, 10
-14, 14
-22, 22
ꢁ scan
19859
lmin, lmax
Measurement method
Reflections collected
Independent reflections
7319
Observed reflections [I > 2σ(I)] 2218
Absorption correction Integration
2914
Integration
0.967, 0.994
0.101
T
min, Tmax
int
0.957, 0.990
0.075
R
Refinement
Refinement method
Parameters
SHELXL17/1
291
0.045
SHELXL17/1
542
0.076
2
2
R[F > 2σ(F )]
2
wR(F )
0.105
0.242
GooF = S
0.83
-0.17, 0.14
0.92
-0.14, 0.21
3
∆
ρ
min, ∆ρmax (e/Å )
2.4. Computational methods
6

The topology analyses of molecular packing were performed using Crystal Explorer 17.5
program [26]. Gaussian 09 software package [27,28] employing B3LYP/6-31G(d,p) method
were used for geometry optimization. Natural charge calculations were performed using NBO
3
.1 program as implemented in the Gaussian 09W [29]. The structure of both compounds was
further optimized in solution using chloroform as solvent applying the self-consistent reaction
filed (SCRF) method [30,31]. Then, the optimized structures were used to compute the NMR
chemical shifts of the protons and carbons using GIAO method [32].
3
. Results and discussion
.1. Chemistry
The highly functionalized target compounds viz, N-1-(2-pyridinylmethyl)-3,5-bis[(E)-
3
arylmethylidene]tetrahydro-4(1H)-pyridinones 5a and 5b were synthesized through the
alkylation of compounds 3a and 3b with an equivalent amount of 2-(chloromethyl)pyridine
2 3
hydrochloride in the presence of K CO (Scheme 1). The synthesis of 3,5-bis[(E)-
arylmethylidene]tetrahydro-4(1H)-pyridinones 3a and 3b was carried out according to the
method reported by Dimmock et al. in acetic acid [33]. Initially, in order to optimize the reaction
conditions, a representative reaction was performed with different solvents viz, dioxane,
acetonitrile, dimethylformamide (DMF), methanol, ethanol and chloroform (Table 2). The
reactions under dioxane, methanol, ethanol, dimethylformamide and chloroform afforded the
product only in traces even after prolonged reaction times whereas the reaction in acetonitrile
afforded the compound 5 in good yield. Hence, in a typical reaction, a mixture 3b (1 mmol) and
K
2
3
CO (3 mmol) in acetonitrile (20 mL) was stirred at room temperature for 30 min. Then 2-
(
chloromethyl)pyridine hydrochloride 4 (1 mmol) dissolved in acetonitrile (5 mL) was added.
The reaction mixture was refluxed until the complete consumption of all the starting materials as
confirmed by TLC analysis. The target α,β-unsaturated carbonyl compound 5b was obtained in
good yield. Subsequently, the other reaction was performed under this optimized reaction
condition and resulted a good yield (85 %) of the compound 5a.
7

Scheme 1. Synthesis of N-1-(2-pyridinylmethyl)-3,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-
pyridinones 5.
Table 2. Solvent optimization for the synthesis of N-1-(2-pyridinylmethyl)-3,5-bis[(E)-aryl-
methylidene]tetrahydro-4(1H)-pyridinones 5b.
a
Entry Solvents
Temp
Time (h) Yield (%)
o
(
C)
1
2
3
4
5
6
Dioxane
Methanol
Ethanol
100
60
12
12
12
24
10
24
b
b
75
b
DMF
100
60
20
b
Chloroform
Acetonitrile
80
88
a
Isolated yield
No reaction
b
A careful structural elucidation of compounds 5(a,b) was accomplished with the help of
FT-IR, NMR spectroscopic and Mass spectrometry data. As an illustrative case, structural
explanation of compound 5b is discussed here. In the IR spectrum of 5b, the main infrared
8

-
1
absorption peaks at υmax 1668, 1615 and 1588 cm are assigned to C=O and C=C groups. In its
1
2 2 2
H NMR spectrum the multiplet at 3.84-3.87 ppm is assigned to 7'-CH , 6'-CH and 2'-CH
protons. The phenylmethylidene proton, H-8' appear as a singlet at 7.74 ppm. The aromatic
1
3
protons appear as multiplets around 7.03-8.45 ppm. In the C NMR spectrum, the carbon signals
at 54.73 ppm and 63.23 ppm were due to C-2'/C-6' and C-7' respectively whilst the C-8' appeared
at 149.16 ppm. The carbonyl carbon appears at 187.19 ppm and the aromatic carbons appeared at
1
13
1
15.60-163.86 ppm. The selected H and C chemical shifts of 5b are shown in Figure 1. The
+
presence of molecular ion peak at 403 [M ] in the mass spectrum confirms the formation of 5b.
The structure of other dipolarophile 5a was also established based on similar straightforward
considerations.
1
13
Figure 1. Selected H and C NMR chemical shifts of 5b
3
.2. X-ray crystallography
The structure of the compounds 5a and 5b was further confirmed by the single crystal X-ray
analyses of [34]. The common moiety for 5a and 5b is 1-(pyridin-2-ylmethyl)piperidin-4-one.
Figures 2 and 3 show the asymmetric unit of 5a and 5b respectively. Table 1 summarizes the
experimental details (crystal data, data collection and structure refinement). Compound 5a has
one independent molecule in the asymmetric unit while 5b contains two independent organic
molecules and are not planar. In 5b, the C2–C7 benzene ring is inclined to the piperidine ring by
2
4.61(12)˚, while the corresponding angle for C14–C19 benzene ring is 54.35(9)˚ in 5a. The
piperidine and pyridine rings were twisted with respect to each other, making a dihedral angle of
7.27(7)˚. In molecule 1, (the molecule with atom numbering, O1, N1, N2, F1 and F2) the C13–
7
C18 fluorobenzene ring is inclined to the C20–C25 fluorobenzene ring by 27.8 (3)˚, while the
corresponding angle in molecule 2 is 26.1 (3)˚ in 5b. The piperidine ring is inclined to the plane
9

of the pyridine ring, the dihedral angle being 73.9 (2)˚ in molecule 1. For molecule 2, (the
molecule with atom numbering, O2, N3, N4, F3 and F4) the piperidine and pyridine rings are
twisted with respect to each other, making a dihedral angle of 74.2 (2)˚. A view of inverted
molecule 1 (red) on molecule 2 (blue), the molecule overlay illustrates the difference in the
conformations of the two molecules in Figure 4. The molecular structure is stabilized by the
intermolecular C—H···N hydrogen bond along the b-axis direction in 5a whilst the molecules in
ꢃ
ꢃ
5
b are linked by a pair of C—H···F hydrogen bonds forming inversion dimers with an ꢂ (ꢄ)
ring motif (Figures 5 and 6, and Table 3). The dimers are linked by C—H···O hydrogen bonds
forming chains along the c-axis direction. The chains are linked by very weak π-stacking
interactions, forming a three-dimensional network. In the methoxy groups in 5a, the C1—O1 and
C20—O3 bond distances are essentially equivalent, 1.423(2) Å and 1.424(3) Å, respectively.
The C11—O2 (in 5a), C9—O1 and C34—O2 (in 5b) bond lengths are typical of double bonds.
The detailed geometric parameters of 5a and 5b are given in Tables 4 and 5.
Figure 2. ORTEP diagram of 5a, showing the atomic numbering and 30% probability
displacement ellipsoids.
10

Figure 3. ORTEP diagram of 5b, with the labelling scheme and 30% probability ellipsoids.
Figure 4. A molecular overlap view of inverted molecule 1 (red) on molecule 2 (blue) in 5b.
11

Figure 5. A partial view of the crystal packing of 5a along the b-axis direction. Blue dashed
lines denote the intermolecular C24—H24···N2 hydrogen bonds.
Figure 6. A partial view of the crystal packing of 5b along the c-axis direction. Blue dashed
lines denote the intermolecular C—H···F hydrogen bonds and green ones denote C—H···O
hydrogen bonds.
12

Table 3. Hydrogen-bond geometries for 5a and 5b (Å, ˚).
D─H∙∙∙A
5a)
D─H
H∙∙∙A
D∙∙∙A
D─H∙∙∙A
(
i
C24─H24∙∙∙N2
0.93
2.68
3.563 (3)
159
(
5b)
ii
C42─H42∙∙∙F4
C29─H29∙∙∙F3
C17─H17∙∙∙F1
C4─H4∙∙∙F2
C18─H18∙∙∙O2
C43─H43∙∙∙O1
0.93
0.93
0.93
0.93
0.93
0.93
2.60
2.55
2.62
2.57
2.32
2.32
3.440 (8)
3.418 (9)
3.322 (9)
3.432 (9)
3.2058 (9)
3.2210 (8)
150
156
133
155
158
162
iii
iv
iii
iii
v
Symmetry codes: (i) x, −y+1/2, z+1/2, (ii) −x−1, −y+1, −z+2; (iii) x−1, y, z; (iv) −x, −y, −z+2; (v)
x+1, y+1, z.
Table 4. Selected geometric parameters for 5a (Å, ˚).
Geometric Parameters
X–Ray
C1─O1
C2─O1
C11─O2
C19─O3
C20─O3
C9─N1
C21─N1
C22─N1
C23─N2
C27─N2
C22─C23
C12─C13
C13─C14
C7─C8
1.423 (2)
1.360 (2)
1.224 (2)
1.358 (3)
1.424 (3)
1.461 (2)
1.460 (2)
1.472 (2)
1.327 (2)
1.337 (3)
1.498 (3)
1.333 (2)
1.468 (3)
1.460 (3)
1.344 (3)
119.1 (2)
121.0 (2)
121.0 (2)
118.6 (2)
109.7 (2)
113.0 (2)
116.8 (2)
128.0 (2)
C8─C10
C1─O1─C2
C10─C11─O2
C12─C11─O2
C19─O3─C20
C9─N1─C21
C23─C22─N1
C23─N2─C27
C12─C13─C14
13

Table 5. Selected geometric parameters for 5b (Å, ˚).
Geometric Parameters
X–Ray
C9─O1
C34─O2
C1─N1
C5─N1
C6─N2
C7─N2
C11─N2
C26─N3
C30─N3
C31─N4
C32─N4
C36─N4
C16─F1
C23─F2
C48─F3
C41─F4
C1─N1─C5
C6─N2─C7
C26─N3─C30
C31─N4─C32
C17─C16─F1
C22─C23─F2
C47─C48─F3
C41─C42─F4
1.222 (8)
1.213 (7)
1.330 (10)
1.338 (8)
1.462 (8)
1.472 (7)
1.455 (8)
1.339 (11)
1.329 (8)
1.472 (8)
1.452 (8)
1.450 (8)
1.350 (8)
1.360 (8)
1.372 (7)
1.368 (7)
117.2 (7)
109.1 (5)
115.7 (7)
109.8 (5)
119.1 (7)
118.0 (8)
117.1 (7)
118.1 (6)
3
.3. Analysis of molecular packing
We employed Hirshfeld surface analysis to compare quantitatively the different
intermolecular interactions affecting the molecular packing in the studied compounds (Figure 7).
Full Hirshfeld surfaces are given in Figures S5 and S6 (Supplementary data). The molecular
packing of 5a is mainly controlled by relatively strong N...H (4.9%), C...H (30.6%) and H...H
(
52.4%) interactions. The corresponding fingerprint plots and decomposed dnorm maps for these
interactions are shown in Figure 8. The N2...H24 (2.537 Å), C25...H20A (2.755 Å) and
H18...H22B (2.139 Å), are the shortest contacts. The results also indicated the presence of some
weak O...H (9.7%) contacts, all corresponding to C-H...O interactions. On other hand, the
molecules of 5b are packed by strong F...H (16.8-16.9 %), N...H (5.4%) and O...H (5.2-5.4%)
interactions as well as weak C...C (3.9-4.5%), H...H (39.7-39.9%) and C...H (24.8-25.8%)
14

contacts. The crystal structure of this compound comprised two molecules per asymmetric unit,
hence there are two results for each interaction in 5b. Presentation of the decomposed dnorm maps
for F...H, N...H and O...H interactions are shown in Figure 9 while the corresponding fingerprint
plots are shown in Figure 10. The F4…H42 (2.469 Å), F3…H29 (2.41 Å), N1…H47 (2.615 Å),
C42…C44 (3.375 Å), O1…H43 (2.18 Å) and O2…H18 (2.182 Å) are the shortest contacts
where all appeared as red spots in the dnorm maps and sharp spikes in the fingerprint plots.
Figure 7. Summary of the intermolecular interactions and their percentages in the crystal
structure of the studied compounds. Units 1 and 2 for 5b refer to molecular units with lower and
higher atom numbering respectively.
15

N...H
C...H
Figure 8. The decomposed fingerprint plots and dnorm maps of the N...H and C...H interactions in
5
a.
16

Figure 9. The decomposed dnorm maps of the F...H, N...H and O...H interactions in 5b.
17

Figure 10. The decomposed fingerprint plots of the F...H, N...H, O...H and C...C interactions in
5
b.
3
.4. DFT studies
Geometric parameters
The structures of 5a and 5b were optimized using B3LYP/6-31G(d,p) method. The
calculated structures matched well with the experimental X-ray structures of the studied
compounds as shown in Figure 11. The correlations between the calculated and experimental
bond distances are 0.9613 and 0.9294 for 5a and 5b, respectively (Figure 12). Full geometric
parameters were collected in Tables S1 and S2 (Supplementary data). The calculated dipole
moment values are 2.125 and 1.578 Debye, respectively indicating the higher polarity of 5a
which contains methoxy groups as substituent than 5b with the fluoro substituent. The reactivity
indices [35-43] of both compounds such as ionization potential (I), electron affinity (A),
chemical potential (μ), hardness (η), softness (S), and electrophilicity (ω) indices were calculated
18

based on the HOMO and LUMO energies and were found very close to each other (Table 6). The
HOMO-LUMO energy gap is higher for 5b (3.9307 eV) than 5a (3.8061 eV). Hence, the former
has slightly higher stability towards electron transfer than the latter. Compound 5b has higher
ionization potential and hence higher resistance towards oxidation than 5a. Furthermore, high
electron affinity for 5b suggests its higher ability to gain electron than 5a. On other hand, its
electrophilic character as indicated from the electrophilicity index (ω) is higher than 5a.
5a
5b
Figure 11. Structure matches of the optimized and calculated structures of the studied organic
compounds.
Figure 12. Correlations between calculated and experimental bond distances.
19

Table 6 HOMO and LUMO energies and the reactivity descriptors of 5a and 5b.
Parameter
5a
5b
HOMO
-5.6622 -6.1485
-1.8561 -2.2177
5.6622 6.1485
1.8561 2.2177
3.8061 3.9307
-3.7591 -4.1831
0.2627 0.2544
1.8564 2.2258
LUMO
I
A
η
μ
S
Ω
The natural charge distribution at different atomic sites were calculated and listed in Table
S3 (Supplementary data). The O-atom of the carbonyl group in both compounds has the most
negative charge. The natural charges at the carbonyl oxygen atom of 5a and 5b are -0.5753 and -
0
.5769 e, respectively. In contrast, the carbonyl carbon atoms have the highest positive charge in
both the compounds. The natural charges at these atomic sites are 0.5251 and 0.5254 e for 5a and
b, respectively. The variable charge distributions at the different atomic sites are responsible for
5
the polarity of the studied molecules. Molecular electrostatic potential (MEP) map showing the
electron density distribution as well as the dipole moment vector are shown in Figure 13. Also,
the distribution of the HOMO and LUMO orbitals are shown in the same illustration. The
distribution of these molecular orbitals sheds the light on the way by which the electron transfer
could takes place in the studied systems. The HOMO level is mainly located over the pyridine
moiety in 5a, while distributed over the pyridine and the two aryl moieties in 5b. This is
considered as the demand from which the electron transport occurs. The LUMO in both
compounds is distributed over the pyridine and the two aryl moieties which is the demand to
which the electron transfer. The energy of these intramolecular charge transfer processes are
3
.806 and 3.931 eV for compounds 5a and 5b, respectively.
20

Figure 13. HOMO, LUMO and MEP with dipole moment vector of 5a and 5b.
.5. NMR spectra
3
1
13
The H and C NMR chemical shift data were computed and the results are collected in
Table S4 (Supplementary data). There are good agreements between the results obtained from
the GIAO calculations with the experimental values measured in the same solvent where quite
good correlations were obtained (Figure 14). As can be seen from this figure, the correlations
2
1
13
coefficients (R ) are in the range of 0.965-0.990 for H NMR and 0.968-0.996 for C NMR
chemical shifts.
21

Figure 14. NMR chemical shift correlations between the calculated and experimental data.
4
. Conclusion
The synthesis of structurally interesting highly functionalized N-1-(2-pyridinylmethyl)-
,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones have been accomplished in good
3
yield. Structural elucidation of these α,β-unsaturated carbonyl compounds have been carried out
through spectroscopic studies and further confirmed by single crystal X-ray diffraction analysis.
The different intermolecular contacts control the molecular packing of 5a and 5b were predicted
quantitatively using Hirshfeld analysis. DFT calculations predicted higher polarity of 5a than 5b.
The calculated and experimental bond distances and the NMR chemical shifts correlated well.
Furthermore, different reactivity indices were also calculated and compared.
Acknowledgements
The authors extend their appreciation to the Deanship of Scientific Research at King Saud
University for funding this work through research group no RG-1438-052. This study was also
supported by Ondokuz Mayıs University under project No. PYO.FEN.1906.19.001.
22

Appendix A. Supplementary data
Supplementary data related to this article can be found at…
Credit author statement
Dhaifallah M. Al-thamili: Data curation, Visualization, Investigation
Abdulrahman I. Almansour: Visualization, Investigation and Supervision
Natarajan Arumugam: Visualization, Investigation
Sevgi Kansız: Writing- Reviewing and Editing
Necmi Dege: Visualization, Investigation
Saied M. Soliman: Writing- Original draft preparation
Mohammad Azam: Editing.
Raju Suresh Kumar: Conceptualization, Methodology, Writing- Original draft preparation,
Reviewing, Editing and Supervision.
Declaration of interest
The authors declare no conflict of interest.
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26

Graphical abstract
Highly functionalized α,β-unsaturated carbonyl compounds have been achieved in good yields.
Structural elucidation was accomplished with the help of NMR spectroscopy and X-ray
crystallographic studies. Molecular packing was performed to determine the different
intermolecular contacts using Hirshfeld topology analysis. DFT calculations were also performed
to evaluate the structural aspects of these compounds.
27