A newly synthesized nitrogen-rich derivative of bicyclic quinoxaline—Structural and conceptual DFT reactivity study

Article abstract of DOI:10.1002/poc.4055

Novel nitrogen-rich compound featured bicyclic quinoxaline as a basic core structure has been synthesized, 1-{[1-(3-azido-2-hydroxypropyl)-1H-1,2,3-triazol-4-yl]methyl}-3-methyl-1,2-dihydroquinoxalin-2-one with formula C₁₅H₁₆N₈O₂, and their structural and chemical reactivity aspects have been comprehensively discussed. Nature, role, and relative contribution of weak noncovalent interactions in supramolecular assembly have been assessed through single-crystal analysis and computational approaches. Useful information about the global and local reactivity were obtained from Conceptual Density Functional Theory at wB97X-D/cc-pVDZ level. Studied system could act as strong electrophile and/or moderate nucleophile in polar organic reactions. We hope this study will provide deeper insight in the knowledge of the synthesis and chemistry of the quinoxaline and quinoxaline derivatives.

Full text of DOI:10.1002/poc.4055

Received: 24 August 2019
DOI: 10.1002/poc.4055
Revised: 21 December 2019
Accepted: 7 January 2020
R E S E A R C H A R T I C L E
A newly synthesized nitrogen-rich derivative of bicyclic
quinoxaline—Structural and conceptual DFT reactivity
study
Nadeem Abad1 | Melek Hajji2
| Youssef Ramli3 | Marwa Belkhiria4
|
Salima Moftah H. Elmgirhi5 | Mohamed A. Habib5 | Taha Guerfel2
Joel T. Mague6 | El Mokhtar Essassi1
|
1Laboratoire de Chimie Organique
Abstract
Hétérocyclique, Centre de Recherche des
Sciences des médicaments, URAC 21, Pôle
de Compétence Pharmacochimie, Av Ibn
Battouta, bp 1014, Faculté des Sciences,
Université´ Mohammed V, Rabat,
Morocco
2Research Unit: Electrochemistry,
Materials and Environment, University of
Kairouan, Kairouan, Tunisia
3Laboratory of Medicinal Chemistry,
Faculty of Medicine and Pharmacy,
Mohammed V University, Rabat, Morocco
4Laboratoire de Chimie Hétérocyclique,
Produits Naturels et Réactivité: L.C.H.P.N.
R, Faculté des Sciences de Monastir,
Monastir, Tunisia
Novel nitrogen-rich compound featured bicyclic quinoxaline as a basic core
structure has been synthesized, 1-{[1-(3-azido-2-hydroxypropyl)-1H-1,-
2,3-triazol-4-yl]methyl}-3-methyl-1,2-dihydroquinoxalin-2-one with formula
C15H16N8O2, and their structural and chemical reactivity aspects have been
comprehensively discussed. Nature, role, and relative contribution of weak
noncovalent interactions in supramolecular assembly have been assessed
through single-crystal analysis and computational approaches. Useful
information about the global and local reactivity were obtained from
Conceptual Density Functional Theory at wB97X-D/cc-pVDZ level. Studied
system could act as strong electrophile and/or moderate nucleophile in polar
organic reactions. We hope this study will provide deeper insight in the knowl-
edge of the synthesis and chemistry of the quinoxaline and quinoxaline
derivatives.
5Department of Chemistry, Faculty of
Education, Sirte University, Sirte, Libya
6Department of Chemistry, Tulane
University, New Orleans, LA, USA
K E Y W O R D S
DFT, chemical reactivity theory, Hirshfeld surfaces, NCI topological analysis, quinoxaline
derivatives, weak noncovalent interactions
Correspondence
Melek Hajji, Research Unit:
Electrochemistry, Materials and
Environment, University of Kairouan,
Kairouan 3100, Tunisia.
Email: melekhajji.univk@gmail.com;
melek.hajji@ipeik.u-kairouan.tn
1 | INTRODUCTION
Thus, quinoxaline and its derivatives have been exten-
sively studied. Notably, these N-heterocycles play an
In the past few decades, design and characterisations of
heterocyclic organic compounds have received consider-
able attention because of their pivotal role and wide
application in different areas of life science.[1–6] Particu-
larly, nitrogen-containing heterocyclic systems are
known to exhibit excellent pharmacological activities.[7,8]
interesting role as basic skeleton for the synthesis of
many other pharmacologically and biologically active
agents. A large number of synthetic quinoxalines have
been reported to exhibit Ant amoebic,[9] anticancer,[10]
antifungal,[11]
antiviral
and
antibacterial,[12]
antimicrobial,[13,14] antitumoral,[15] anticonvulsant,[16]
J Phys Org Chem. 2020;e4055.
wileyonlinelibrary.com/journal/poc
© 2020 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/poc.4055

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ABAD ET AL.
antidiabetic,[17]
antinomic,[9]
antioxidant,[18]
To
a
solution of 3-methyl-1-(prop-2-ynyl)-3,-
antitubercular, and antileptospiral[19] agents and neuro-
protective activity.[20,21] Also, some quinoxalines were
used in agricultural field as pesticides and chemical
controllable switches, corrosion inhibitor,[22] and insecti-
cides.[23] Additionally, conjugation of biologically active
peptides with quinoxaline analogues can lead to new
therapeutic agents possessing interesting anticancer prop-
erties.[24] Similarly, 1,2,3-triazoles have gained increased
attention in the drug-discovery field since the introduc-
tion of the “click chemistry” concept by Sharpless.[25–27]
In this context, the present research primarily focuses on
the synthesis of new N-heterocyclic quinoxaline
derivative containing 1,2,3-triazole moiety, 1-{[1-(3-azido-
2-hydroxypropyl)-1H-1,2,3-triazol-4-yl] methyl}-3-methyl-
1,2-dihydroquinoxalin-2-one and understanding their
molecular/supramolecular structure and its ability to
provide selective chemical reactivity. To get a broader
overview of the relevant structural features, single-crystal
X-ray diffraction analysis has been firstly performed,
supported by Hirshfeld surfaces and noncovalent
4-dihydroquinoxalin-2(1H)-one 2 (0.5 mmol), in ethanol
(20 mL), 1,3-diazidopropan-2-ol (0.86 mmol) was added
with sodium ascorbate and a catalytic amount of copper
sulphate (Scheme 2). The mixture was stirred under
reflux for 24 hours. After completion of the reaction
(monitored by TLC), the solution was concentrated and
the residue was purified by column chromatography on
silica gel by using a hexane/ethyl acetate (9/1) mixture as
eluent. Crystals were obtained when the solvent was
allowed to evaporate. The solid product isolated was rec-
rystallized from ethanol to afford colourless block crystals
of final compound 3, 1-{[1-(3-azido-2-hydroxypropyl)-1H-
1,2,3-triazol-4-yl]methyl}-3-methyl-
1,2-dihydroquinoxalin-2-one, in 55% yield (Scheme 2).
NMR1H (300 MHz, CDCl3) δppm: 1.73 (s, H,OH);
2.58 (s, 3H,CH3); 3.33-3.42 (d, 2H,CH2–N3, J = 3 Hz);
4.09-4.12 (m, H, CH2CHOHCH2); 4.49-4.52 (d, 2H, N–N–
CH2, J1 = 3 Hz); 5.42 (s, 2H, N–CH2); 7.59 (s, H,
CHTriazol); 7.20-7.43 (m, 4Harom).
NMR13C (75 MHz, CDCl3) δppm: 21.93 (CH3);
37.35(N–CH2); 50.08 (N–N–CH2); 55.09 (–CH2–N3); 72.06
(–CH–OH); 116.71, 124.80, 125.95, 127.53 (CHarom);
129.57Triazol, 133.35, 136.80, 139.63, 154.13 (Cq); 156.80
(C═O).
interaction-reduced
density
gradient
(NCI-RDG)
computational approaches. Global and local reactivity
behaviours have been also evaluated based on Concep-
tual Density Functional Theory (CDFT) framework.
2 | EXPERIMENTAL
2.2 | Single crystal X-ray diffraction
2.1 | Synthesis and crystallization
Crystal data, collection, and structure refinement details
are summarized in Table S1. Full crystallographic data
for compound have been deposited with the Cambridge
Crystallographic Data Centre and are freely available at
CCDC No. 1948217.
We prepared 3-methyl-3,4-dihydroquinoxalin-2(1H)-one
1 (85% yield) by condensation of 2-o-phenylenediamines
(10 mmol) with ethyl pyruvate (15 mmol) in HCl aqueous
solution for 30 minutes at room temperature (Scheme 1).
Thereafter, given the presence of more reactive sites in
the pattern of quinoxalin-2-ones, we were exclusively
interested in the reactions of N-alkylation of 1 by the
2.3 | Computational details
action of propargyl bromide. To
a
solution of
Since this research is part of an ongoing project, the com-
putational details are almost the same as our previous
work[8] and will be briefly represented here. All DFT cal-
culations were accomplished at wB97X-D/cc-pVDZ level
using Gaussian 09, Rev D.01 software package[28] and
GaussView 6.0 program.[29] RDG-NCI analysis was
performed using MULTIWFN 3.5 multifunctional
wavefunction analyser.[30] Colour-filled isosurfaces
graphs were drawn using VMD 1.9.3 molecular
3-méthylquinoxalin-2-one 1 (6.25 mmol), potassium
carbonate (8.6 mmol) and tetra n-butyl ammonium bro-
mide (0.6 mmol) in DMF (20 mL) were added propargyl
bromide (9.25 mmol). Stirring was maintained at room
temperature during 24 hours. Then the crude residue was
filtered and the solvent removed. The residue was
extracted with water. The organic compounds were
purified by column chromatography using hexane-ethyl
acetate as eluent (v/v, 1/9) (Scheme 1).
visualization
program.[31]
Three-dimensional
SCHEME 1 Synthesis pathway and chemical
structures of 1 and 2

ABAD ET AL.
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SCHEME 2 Synthesis pathway and chemical
structure of studied compound 3; 1-{[1-(3-azido-
2-hydroxypropyl)-1H-1,2,3-triazol-4-yl]methyl}-3-methyl-
1,2-dihydroquinoxalin-2-one
(3D) Hirshfeld surfaces and associating two-dimensional
(2D) fingerprint maps were drawn using the
CrystalExplorer17.5 program in conjunction with
TONTO system.[32] All global and local chemical reactiv-
ity indices were calculated by using the ideas chemical
reactivity theory.[33–36] The electrophilic Pk+ and nucleo-
philic Pk− Parr functions[37,38] were achieved through the
analysis of the Mulliken atomic spin density.
through O2–H2AꢁꢁꢁN2 hydrogen bonds, which are linked
into oblique stacks extending along the a-axis direction
by C10–H10AꢁꢁꢁO2 hydrogen bonds together with slipped
π-stacking interactions between dihydroquinoxaline units
with centroidꢁꢁꢁcentroid (CgꢁꢁꢁCg) distances alternating
between 3.7563 (8) and 3.6719 (8) Å. The stacks are fur-
ther reinforced by C9–H9CꢁꢁꢁCg3 and azideꢁꢁꢁtriazole π
interactions (centroidꢁꢁꢁcentroid = 3.199 (2) Å) (Table 1
and Figure 2). Furthermore, association of the stacks into
layers parallel to the ab plane occurs through inversion-
related C12–H12ꢁꢁꢁO1 hydrogen bonds, and the layers are
linked into the final 3D structure via inversion-related
C14–H14ꢁꢁꢁN4 hydrogen bonds (Table 1 and Figure S1).
3 | RESULTS AND DISCUSSION
3.1 | Molecular and supramolecular
features
ORTEP representation of the asymmetric unit with atom
numbering scheme is shown in Figure 1. The
dihydroquinoxaline portion shows a slight twist end-to-
end indicated by a dihedral angle of 2.02 (8)ꢀ between the
mean planes of the two six-membered rings. The substit-
uent on N1 is nearly orthogonal to the
dihydroquinoxaline unit as indicated by the C6/N1/C10/
C11 torsion angle of −83.06 (16)ꢀ. The dihedral angle
between the C1/C6/N1/C7/C8/N2 and the C11/C12/N3/
N4/N5 rings is 70.88 (8)ꢀ.
3.2 | Topological study of weak
noncovalent interactions
Identification and graphical visualization of noncovalent
interactions regions were fundamentally made by means
of the NCI-RDG approach. NCI is a recently developed
tool based on the electron density and its derivatives that
allows revealing noncovalent interactions.[39] It permits a
substantial description of van der Waals interactions,
hydrogen bonds, and steric repulsion.[40–42] The NCI
index is based on the reduced density gradient RDG (r),
Interestingly, analysis of the supramolecular arrange-
ment reveals that molecules form inversion dimers
which is defined as below[43,44]
:
FIGURE 1 ORTEP diagram of
asymmetric unit with 50% thermal
ellipsoid probability

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ABAD ET AL.
TABLE 1 Selected hydrogen-bond geometric parameters (Å, ꢀ)
D–HꢁꢁꢁA
D–H (Å)
0.84
HꢁꢁꢁA (Å)
2.13
DꢁꢁꢁA (Å)
2.9041 (19)
3.6498 (18)
3.282 (2)
D–HꢁꢁꢁA (ꢀ)
152.3
O2–H2AꢁꢁꢁN2i
C9–H9CꢁꢁꢁCg3i
C10–H10AꢁꢁꢁO2ii
C12–H12ꢁꢁꢁO1iii
C14–H14ꢁꢁꢁN4iv
0.97 (2)
0.949 (18)
0.936 (18)
1.00
2.88 (2)
2.372 (18)
2.255 (18)
2.50
137.8 (19)
160.5 (14)
150.8 (14)
158.5
3.1064 (18)
3.449 (2)
Notes. Symmetry codes: (i) − x + 1, −y + 1, −z + 1; (ii) x − 1, y, z; (iii) − x + 1, −y + 2, −z + 1; (iv) − x + 1, −y + 1, −z.
FIGURE 2 Intermolecular O–
HꢁꢁꢁN and C–HꢁꢁꢁO hydrogen bonds (red
and black dashed lines, respectively)
and the π-stacking (orange dashed lines)
and C–Hꢁꢁꢁπ (ring) interactions (green
dashed lines). The π-π interactions
between the azide and triazole moieties
are depicted by light purple dashed lines
"
#"
#
1
jrρðrÞj
RDGðrÞ =
,
ð1Þ
1=3
4=3
2ð3π2Þ
ρðrÞ
where ρ(r) and rρ(r) indicate the electron density and its
first derivative. Interestingly, 2D scatter plots of RDG
against a real space function Ω(r) [Ω(r) = sign(λ2(r)) ρ(r)],
namely, the product of sign of (λ2) and ρ(r), effectively
split attractive from repulsive noncovalent interac-
tions.[45] (λ2) means the sign of the second largest eigen-
value of electron density Hessian matrix at position r.
Moreover, when this function is mapped onto a 3D RDG
isosurfaces, we can not only know where weak
noncovalent interactions occur but also easily highlight
their nature and strength. We have drawn the colour-
coded bar for clarity and completeness.
FIGURE 3 Two-dimensional (2D) NCI-RDG scatter plot
Herein, the 2D scatter plot and 3D colour-filled RDG
isosurface for studied system are depicted in Figures 3
and 4. As observed in scatter maps, there exist spikes
(points nearly approaching bottom) at negative region of
Ω(r) (−0.02-0.0 a.u.), suggesting that this system must
comprise evident weak attractive interactions. The low-
gradient peaks appear at positive side (0.0- + 0.03 a.u.),
confirming the existence of steric repulsion. The absence

ABAD ET AL.
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FIGURE 4 Three-
dimensional (3D) colour-filled
RDG isosurfaces for selected
adjacent monomers
of pure blue-coloured spikes at very low-density clearly
indicates that the structure does not exhibit any classical
strong H-bond.
Remarkably, the type and nature of interactions are
clearer in 3D graphs (Figure 4); steric effect take place
within the six-membered rings of dihydroquinoxaline
units, because of the red colour of corresponding
isosurfaces. Additionally, the O2–H2AꢁꢁꢁN2 hydrogen
bonds are evident and could be classified weak interac-
tions, because of small green-coloured isosurfaces
between H2A atom and N2 acceptor centre. This region
corresponds to the spikes at Ω(r) ≈ −0.018 a.u. in the
scatter map. Notably, as shown in Figure 4, there
appeared green large continued RDG isosurfaces, which
should be considered as van der Waals interactions. Lat-
ter flat isosurfaces are associating to centroidꢁꢁꢁcentroid
contacts between dihydroquinoxaline units or π-π inter-
actions between azide and triazole moieties.
FIGURE 5 Visualisation of Hirshfeld surface mapped with
dnorm, showing potential hydrogen bonding (red spots)
Additionally, two deep red spots (4) and (5) detected in
dnorm surface are assigned to inversion-related C12–
H12ꢁꢁꢁO1 hydrogen bond. As displayed in Figure S2, the
π-stacking interactions in crystalline structure are also
reflected by the appearance of reciprocal red and blue tri-
angle pairs on the shape-index surface. This observation
lies in accordance to relatively short distance between
ring centroids reported by X-ray, as dCg…Cg range between
3.7563 (8) and 3.6719 (8) Å. The 2D fingerprint (di versus
de) plots are shown in Figure S3, recapitulating the indi-
vidual contribution of relevant intermolecular contacts.
As shown, the HꢁꢁꢁH contacts have the most important
contribution to the total Hirshfeld surface with 36.2%. As
can be seen, the two symmetric spikes with almost long
3.3 | Quantitative analysis of
intermolecular interactions: Hirshfeld
surfaces approach
To rationalize the contribution of significant inter-
molecular interactions in the crystalline arrangements,
Hirshfeld surface analysis was performed, and surface
mapped with dnorm is illustrated in Figure 5. Brightest
red spots, numbered (1) and (2), involving the acceptor
nitrogen atoms N2 outside the surface and oxygen donor
atoms O2 of inside fragment, are attributed to most
strong hydrogen bond O2–H2AꢁꢁꢁN2. The round mark
with lower intense red colour, noted (3), is associated to
at left and right bottom sections pointed on
ðdi + deÞ < 2:4 Å are characteristics of HꢁꢁꢁN/N … H con-
tacts, having 28.7% contribution to the total
a
weak
nonconventional
C10–H10AꢁꢁꢁO2
H-bond.
a

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ABAD ET AL.
3.4 | Chemical reactivity properties: A
conceptual DFT study
In the same way, as we have carried out in our recent
work,[8] the chemical reactivity behaviours of title com-
pound have been investigated via CDFT. The shape and
energies of HOMO and LUMO orbitals of neutral mole-
cule were predicted and displayed in Figure 6. If finite
difference approximation, together with the KID
(Koopmans' in DFT) procedure, is to be considered,[46]
the electronic chemical potential can be estimated as;
μ ≈ 1/2(ELUMO+EHOMO) ≈ 1/2(I+A), where I and A
designate the ionization potential (I = − EHOMO) and the
electron affinity (A = − ELUMO). The chemical potential
(μ) has been computed and found to be −4.4275 eV. Simi-
larly, the chemical hardness (η) is donated as
η ≈ (ELUMO − EHOMO) ≈ (I − A) and found to be 4.331 eV.
Additionally, title compound has a global electrophilicity
index (ω = μ2/2η) value of 2.2631 eV.[47] According to
Domingo's electrophilicity scale,[48] the molecule is classi-
fied as strong electrophile. The global nucleophilicity
(N) is calculated based on the HOMO ener-
gies: N = EHOMO − EHOMO(TCE); here, tetracyanoethylene
(TCE) was chosen as reference because it presents the
lower HOMO energy (−9.12 eV). Noteworthy, from the
nucleophilicity index (N),[49,50] it may be seen that stud-
ied derivative can act as moderate nucleophile in polar
organic reactions, since it shows nucleophilicity power
value (2.527 eV) in the range 2.0 to 3.0 eV.[51,52] Electro-
philic and nucleophilic reactive sites of title compound
have been assessed based on electrophilic Pk+ and nucleo-
philic Pk− Parr functions, considering atomic spin densi-
ties coming from the Mulliken population analysis. The
FIGURE 6 Electron density distribution and energy levels of
HOMO and LUMO orbitals calculated at wB97X-D/cc-pVDZ DFT
level
interactions. The C–H … O intermolecular hydrogen
bonds are evident through the narrow spike pointed on a
ðdi + deÞ≈2:4 Å attributed to close H … O/O … H interac-
tions and comprises 12.5%. Additionally, the crystal pack-
ing is maintained by H … C/C … H contacts, which cover
13.1 % of all interactions.
TABLE 2 Local electrophilic Pþk and nucleophilic Pk− Parr functions computed with Mulliken atomic spin densities
Atom (k)
O1
Pkþ
0.072815
Pk−
0.233816
Atom (k)
C4
Pkþ
0.138312
Pk−
0.009703
O2
0.000249
0.050382
0.181617
0.007346
0.027451
0.014251
−0.012902
0.052932
0.128513
−0.050734
0.142065
−0.065711
0.001563
0.132436
−0.067304
0.003076
0.007307
−0.000544
0.198885
−0.062857
0.122896
0.132304
−0.083495
0.189082
C5
0.011274
0.036604
0.086417
0.186984
−0.019809
−0.005237
−0.000777
0.003255
0.000549
0.001540
0.008737
0.021841
0.104132
N1
C6
N2
C7
−0.085194
0.121935
N3
C8
N4
C9
−0.007982
−0.010360
0.014013
N5
C10
C11
C12
C13
C14
C15
N6
N7
−0.001664
0.000968
N8
C1
0.016743
C2
−0.009938
C3
Notes: Local functions corresponding to hydrogen atoms are not reported.

ABAD ET AL.
7 of 9
FIGURE 7 Graphical illustrations of the
Mulliken atomic spin densities of radical anions
(A) and radical cations (B), along with the
electrophilic and nucleophilic Parr functions.
The blue and green colours represent the
positive and negative spin densities, respectively
obtained results for of these descriptors, estimated at
wB97X-D/cc-pVDZ level, are presented in Table 2,
Figure 7.
organic reactions. Obtained outcomes are of much
importance and could be further exploited for design
and preparation of new quinoxaline-containing
derivatives.
4 | CONCLUSIONS
ACKNOWLEDGEMENTS
The authors acknowledge all the mentioned laboratories
and departments for supporting this research. Melek
Hajji is grateful to Dr Hasan Mtiraoui and Dr Nesrine
Amiri (University of Monastir, Tunisia) for the helpful
discussions.
In summary, a new nitrogen-heterocyclic quinoxaline
derivative has been synthesized and analysed. Results
from this work can be considered from the following per-
spectives: First, we identified significant types of
structure-directing contacts. Apart from classic O–HꢁꢁꢁN
hydrogen bonding, unconventional C–HꢁꢁꢁO, C–Hꢁꢁꢁπ
(ring), and π-stacking represent these types of
intermolecular contacts. Second, we found that these
interactions provide conversion of zero-dimensional
(0D) structure into 3D assembly. Additionally,
computational assessment of global and local reactivity
descriptors indicates that studied molecule could act as
strong electrophile and/or moderate nucleophile in polar
ORCID
Melek Hajji https://orcid.org/0000-0002-6145-2858
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
How to cite this article: Abad N, Hajji M,
Ramli Y, et al. A newly synthesized nitrogen-rich
derivative of bicyclic quinoxaline—Structural and
conceptual DFT reactivity study. J Phys Org Chem.
2020;e4055. https://doi.org/10.1002/poc.4055