Exploring packing features of N-substituted acridone derivatives: Synthesis and X-ray crystallography studies

Article abstract of DOI:10.1016/j.molstruc.2021.131448

The title compounds include an acridone as a parent molecule in which nitrogen is linked to other nitrogen-containing heterocyclic molecules through two carbon chain alkyl linkers connected by a C—N single bond. These acridone derivatives crystallized as Triclinic, Monoclinic, Tetragonal, and Orthorhombic having space group P1, P2₁/c, I4₁/a, Pca2₁, respectively at T = 273 K. In the present work, synthesis and single-crystal X-ray crystallographic study of four novel acridone derivatives are reported from the perspective of crystal engineering. This work is based on the comprehensive analysis of Hirshfeld surfaces, 2D fingerprint plots, and DFT studies. The single-crystal structure analysis showed that compounds are connected by various intermolecular interactions such as C – H?O, C – H?C/π, and π?π (C?C) stacking interactions, which are accountable for the arrangement and amplification of molecular assembly. The DFT studies using the B3LYP functional with the 6-311++ G (d,p) basis set are employed to compare the experimental results with theoretically obtained molecular parameters. The HOMO and LUMO analyzes were used to elucidate information regarding molecular reactivity and charge transfer within the molecule.

Full text of DOI:10.1016/j.molstruc.2021.131448

Journal of Molecular Structure 1248 (2022) 131448
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
Exploring packing features of N-substituted acridone derivatives:
Synthesis and X-ray crystallography studies
Javeena Hussaina, Parul Sahrawata, Pankaj Dubeya, Sivapriya Kirubakarana,
Vijay Thiruvenkatamb,∗
a Discipline of Chemistry, Indian Institute of Technology Gandhinagar, Gandhinagar, Gujarat 382355, India
b Discipline of Biological Engineering, Indian Institute of Technology Gandhinagar, Gandhinagar, Gujarat 382355, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The title compounds include an acridone as a parent molecule in which nitrogen is linked to other
nitrogen-containing heterocyclic molecules through two carbon chain alkyl linkers connected by a C—N
single bond. These acridone derivatives crystallized as Triclinic, Monoclinic, Tetragonal, and Orthorhombic
having space group P1, P21/c, I41/a, Pca21, respectively at T = 273 K. In the present work, synthesis and
single-crystal X-ray crystallographic study of four novel acridone derivatives are reported from the per-
spective of crystal engineering. This work is based on the comprehensive analysis of Hirshfeld surfaces,
2D fingerprint plots, and DFT studies. The single-crystal structure analysis showed that compounds are
connected by various intermolecular interactions such as C – HꢀO, C – HꢀC/π, and πꢀπ (CꢀC) stacking
interactions, which are accountable for the arrangement and amplification of molecular assembly. The
DFT studies using the B3LYP functional with the 6-311++ G (d,p) basis set are employed to compare
the experimental results with theoretically obtained molecular parameters. The HOMO and LUMO ana-
lyzes were used to elucidate information regarding molecular reactivity and charge transfer within the
molecule.
Received 2 June 2021
Revised 27 August 2021
Accepted 3 September 2021
Available online 6 September 2021
Keywords:
Acridone
Crystal packing
Hirshfeld
2D Fingerprint plot
DFT studies
© 2021 Elsevier B.V. All rights reserved.
1. Introduction
DNA-metabolizing proteins [15,16]. They acquire sufficient amount
of hydrophilic and hydrophobic properties to pass through bio-
Acridones are naturally occurring alkaloids [1], which fit into
a significant group of heterocyclic molecules because of their ex-
traordinary varied activity as an innovative group of bioactive com-
pounds [2,3]. It can be considered as aza-analogs of anthrones
[4] or xanthones [5]. Acridone’s journey in pharmaceuticals sci-
ences was first discovered by Paul Ehrlich in the late 1990s [6]. The
various substituted acridone derivatives are well-established with a
different range of functional groups having several medicinal prop-
erties such as antimalarial [7], antibacterial [8], antiviral [9], an-
tileishmanial [10], antitumor [11] agents, etc. Despite of being use-
ful in many biological interests, and their derivatives have been
synthesized and evaluated for anticancer activities [12,13] also. The
planar structure of those acridones aids to work on nucleotides by
intercalating DNA and RNA strands, thereby incorporated as novel
anticancer agents [14]. Acridone derivatives are known to be chro-
mophore to intercalate DNA and cause inhibition of topoisomerase
enzymes, which further obstructs the pharmacological action of
logical membranes. It has also been well-designed to offer a va-
riety of compounds with different medicinal properties and pos-
sesses strong fluorescence emission properties [17]. Acridone has
been employed as the chromophore in many fluorescent cations
[18] or anion chemosensors [19] to observe the metabolic events
[20]. Even though there have been plenty of publications on the
properties of acridone-based materials, the research on the π-
extended acridone is reasonably limited [21]. Acridone is a tricyclic
ring with nitrogen at 10th position and carbonyl group at 9th po-
sition [22]. It includes an electron-withdrawing group (carbonyl)
and an electron-donating group (amino) in the molecule, which
is known as a basic structure of bioactive natural alkaloid. So, we
can modify it at the carbonyl group, amino group, and 2, 7- po-
sitions. Captivating these above facts into consideration, the pur-
pose of this work is to execute an experimental and computational
study on acridone derivatives, including morpholine and piperidine
group, using the single-crystal X-ray crystallography and DFT stud-
ies to assist in building further inspect on the structural properties
(Fig. 1).
∗
Corresponding author.
E-mail address: vijay@iitgn.ac.in (V. Thiruvenkatam).
https://doi.org/10.1016/j.molstruc.2021.131448
0022-2860/© 2021 Elsevier B.V. All rights reserved.

J. Hussain, P. Sahrawat, P. Dubey et al.
Journal of Molecular Structure 1248 (2022) 131448
Fig. 1. Chemical structure of compounds 1, 2, 3 and 4.
Scheme 1. General synthetic route of (1) and (2).
2. Experimental
reaction mixture was stirred for 12-15 h at ambient temperature.
Then, the solution was diluted with ethyl acetate and washed with
water. The organic layer was dried over Na2SO4 and evaporated on
a rotary evaporator. The residue was purified by silica gel column
chromatography (10-15 % ethyl acetate/hexane, as eluent) to afford
the desired product.
2.1. Chemistry: materials and methods
All the solvents and reagents were purchased from Sigma, Fi-
nar, and SD Fine. The thin-layer chromatography (TLC) on silica gel
plates (Silica Gel 60 F254 from Merck) was used to check the com-
pletion of the reaction. Perkin Elmer FTIR Spectrometer Spectrum
2 and Waters Synapt-G2S ESI-Q-TOF Mass instrument were used
to record Infrared (IR) spectra and Mass, respectively. The NMR of
the synthesized compounds were obtained using Bruker AVANCE
III 500 (1HNMR: 500 MHz, 13CNMR: 125 MHz); chemical shifts are
reported in (ppm) using the solvent peak as an internal standard,
and the multiplicity of the resonance peaks are specified as sin-
glet (s), doublet (d), triplet (t), quartet (q) or multiplet (m). Melting
points (mp) for these compounds were recorded using LAB INDIA
Visual Melting Range Apparatus (MR-Vis) instrument in an open
glass capillary.
Synthesis of 10-(2-morpholinoethyl)acridin-9(10H)-one, (1)
Yield: ∼ 46%, mp: 196 – 200 °C, IR (ν, cm−1): 1648 (C=O), 1232
(C–N), 1112(C–O), 1H NMR (500 MHz, Chloroform-d3): δ 8.60 (d,
J = 8.0 Hz, 2H), 7.76 (t, J = 7.8 Hz, 2H), 7.57 (d, J = 8.7 Hz, 2H),
7.32 (t, J = 7.6 Hz, 2H), 4.59 (m, J = 7.5 Hz, 2H), 3.71 (t, J = 4.0
Hz, 4H), 2.94 (t, J = 7.5 Hz, 2H), 2.66 (s, 4H), 13C NMR (125 MHz,
Chloroform-d3): δ 141.9, 134.0, 128.1, 122.6, 121.4, 114.4, 66.9, 55.0,
54.2, 44.2, ESI-MS: m/z, calculated for C19 H21N2O2 [M+H]+ 309.15,
found: 309.16.
General synthesis of (1) and (2)
To a solution of acridone (200 mg, 1.0 mmol) in dry N, N-
dimethyl formamide (DMF) in a round-bottomed flask, sodium hy-
dride (98.0 mg, 4.0 mmol) was added slowly under the inert condi-
tion at 0-5 °C. The reaction mixture was stirred at room tempera-
ture for 15-20 min, followed by the addition of 4-(2-chloroethyl)
morpholine hydrochloride/ 1-(2-chloroethyl)piperidine hydrochlo-
ride (189.8 mg /187 mg, 1 mmol) as shown in Scheme 1. The above
2

J. Hussain, P. Sahrawat, P. Dubey et al.
Journal of Molecular Structure 1248 (2022) 131448
Scheme 2. General synthetic route of (3) and (4).
Synthesis of 10-(2-(piperidin-1-yl)ethyl)acridin-9(10H)-one, (2)
residue was purified by silica gel column chromatography (10–25
% ethyl acetate/hexane, as eluent) to afford the desired products.
10-(2-morpholino-2-oxoethyl)acridin-9(10H)-one, (3)
Yield: ∼55%, mp: 168 – 170 °C, IR (ν, cm−1): 1633 (C=O), 1290
(C–N), 1H NMR (500 MHz, Chloroform-d3): δ 8.59 (d, J = 8.0 Hz,
2H), 7.74 (t, J = 7.8 Hz, 2H), 7.59 (d, J = 8.7 Hz, 2H), 7.31 (dd,
J = 7.7, 7.2 Hz, 2H), 4.61 – 4.48 (m, 2H), 2.87 – 2.76 (m, 2H), 2.61
(s, 4H), 1.68 (s, 4H), 13C NMR (125 MHz, Chloroform-d3): δ 142.0,
133.9, 128.0, 122.6, 121.3, 114.6, 55.3, 44.5, 25.9, 24.1, ESI-MS: m/z,
calculated for C20H23N2O [M+H]+ 307.18, found: 307.18.
Yield: 45 %, mp: 220 – 224 °C, IR (ν, cm−1): 1666 (C=O), 1250
(C–N), 1165 (C–O), 1H NMR (500 MHz, DMSO-d6): δ 8.3 (dd, J = 6.5
Hz, 2H), 7.8 (t, J = 10 Hz, 2H), 7.5 (d, J = 9 Hz, 2H), 7.3 (d, J = 7.5
Hz, 2H), 5.5 (s, 2H), 4.8 (d, J = 4.5 Hz, 4H), 3.6 (t, J = 4.5 Hz, 2H),
3.5 (s, 2H), 13C NMR (125 MHz, DMSO-d6): δ 177.2, 165.5, 145.9,
134.4, 126.9, 122.0, 121.8, 116.6, 66.6, 47.7, 45.3, 42.4, 40.6, 29.4,
ESI-MS: m/z, calculated for C19 H19 N2O3 [M+H]+ 323.13, found:
323.18.
General synthesis of 1a and 1b
To a solution of morpholine/piperidine (100 mg, 1.1 mmol) in
dry dichloromethane (5 mL) in a round-bottomed flask, triethy-
lamine (111 mg, 1 mmol) was added under an inert atmosphere.
The 2-bromoacetyl bromide (221 mg, 1 mmol) was added slowly,
stirred for 4, 5 h at 0–5 °C, and monitored by TLC. After the com-
pletion, the workup was done by dichloromethane and aqueous
NaCl solution. The organic layer was dried over Na2SO4, filtered,
and the solvent was evaporated in a rotary evaporator to obtain
the desired product, which was used as such without further pu-
rification for the next step.
10-(2-oxo-2-(piperidin-1-yl)ethyl)acridin-9(10H)-one, (4)
Synthesis of (3) and (4)
To a solution of acridone (100 mg, 0.4 mmol) in a 5 mL of
dry N, N-dimethyl formamide (DMF) in a round-bottomed flask,
sodium hydride (48 mg, 2 mmol) was added slowly under the inert
condition at 0–5 °C. The reaction mixture was stirred at room tem-
perature for 15–20 min, followed by the addition of intermediate
compound 1a and 1b (Scheme 2) for the synthesis of compound
3 and 4, respectively. The above reaction mixture was stirred for
12–15 h at room temperature. Then the solution was diluted with
ethyl acetate and washed with brine. The extraction procedure was
the same as the previously mentioned for compound 1 and 2. The
Yield: 42 %, mp: 216 – 220 °C, IR (ν, cm−1): 1654 (C=O), 1235
(C–N), 1H NMR (500 MHz, DMSO-d6): δ 8.3 (dd, J = 7.5 Hz, 2H),
7.7 (m, 2H), 7.5 (d, J = 9 Hz, 2H), 7.3 (d, J = 7.5 Hz, 2H), 5.5
(s, 2H), 3.7 (m, 2H), 3.5 (m, 2H), 1.8 (m, 4H), 1.6 (m, 2H), 13C
NMR (125 MHz, DMSO-d6): δ164.7, 143.0, 134.4, 126.9, 122.0, 121.7,
3

J. Hussain, P. Sahrawat, P. Dubey et al.
Journal of Molecular Structure 1248 (2022) 131448
Fig. 2. ORTEP diagrams with 50 % ellipsoid of compounds 1, 2, 3 and 4. Color code: Grey, C; Red, O; Blue, N. (For interpretation of the references to color in this figure
legend, the reader is referred to the web version of this article).
116.5, 47.8, 45.8, 43.1, 26.5, 25.8, 24.4, ESI-MS: m/z, calculated for
C20H21N2O2 [M+H]+ 321.15, found: 321.30.
2.4. Hirshfeld surface (HS) and 2D fingerprint plot
The CIF files for all the derivatives were uploaded in Crystal-
Explorer software (Version 17) to generate the Hirshfeld surface
(HS). It suggests the intermolecular interactions regarding the elec-
tron density of its neighboring molecule [26]. The Hirshfeld surface
analysis illustrates the percentage of contacts of strong and weak
intermolecular interactions of all the derived crystal structures. The
2D fingerprint plots are represented with di versus de pair mapped
over the Hirshfeld surface (HS), where di and de indicate the dis-
tance between the surface and the interior nucleus or exterior nu-
cleus to the surface, respectively [33]. The color scheme of dnorm
mapped with HS shows three different colors, that is white, blue,
and red. These colors have diverse meanings in terms of inter-
molecular contacts, such as the white area denotes the sum of in-
termolecular contacts that are almost equal to the sum of van der
Waals radii. In contrast, the blue area signifies longer intermolecu-
lar contacts and the red region for shorter intermolecular contacts
[29]. A surface with low curvedness assigns a flat area and may be
indicative of πꢀπ contacts in the crystal [34]. The shape index has
corresponding red (negative) and blue (positive) spots such as tri-
angles, which can be analyzed for the identification of πꢀπ stack-
ing. Here, we have studied the intermolecular interactions in the
morpholine and piperidine attached derivatives of acridone.
2.2. Single-crystal X-ray crystallography
The saturated solutions of these acridone derivatives
were obtained in appropriate solvents. The mixtures of
dichloromethane/hexane/diethyl ether were used in different
ratios (2:1:1) to get crystallized products. The solutions were
allowed for the solvent evaporation in a dust-free environment
at room temperature for overnight. After 10–12 h, compounds
were started crystallizing in a sharp needle shape form. A single
crystal of all these derivatives has been chosen and mounted onto
a crystal mounting loop to perform single-crystal X-ray diffraction
data collection. Data were recorded on a Bruker D8-Quest Single
Crystal X-ray Diffractometer with Photon 3.0 detector and a mi-
˚
crofocus X-ray source (IμS), Mo-Kα radiation (λ = 0.7107 A). The
complete crystal data and structure refinement details are shown
in Table 1. The structure was solved by direct methods using
SHELXS97 [23], and refinement was carried out by full-matrix
least-squares on F2 using the SHELXL2014 [24] program. Molecular
graphics were produced through Bruker SHELXTL, and packing
diagrams were created by Mercury CSD 4.0.0. [25]. The charac-
terization and quantification of the intermolecular interactions in
these molecules were carried out by the Hirshfeld surface(HS)
analysis and 2D (two-dimensional) fingerprint plots using the
Crystal Explorer program [26,27]. The structure input file in CIF
format was used to calculate the HS, mapped with dnorm, shape
index, and curvedness, which helps to reveal the intermolecular
interactions and the crystal packing. The 2D fingerprint plots give
a quantitative analysis of the different intermolecular interactions
[28] by using the standard values [29].
2.5. Density functional theory (DFT)
DFT has got the immediate attention of investigators owing to
their accuracy and broad applications in the last decade using the
GAUSSIAN program [35]. The CIF file of crystal structure was used
as an initial molecular geometry. The output files were visual-
ized using the help of the GAUSSVIEW software [36]. The molec-
ular structures of all the compounds in the ground state were
optimized using DFT with hybrid functional B3LYP at 6-311++G
(d,p) basis set [37–39]. The HOMO (highest occupied molecular
orbital) and LUMO (lowest unoccupied molecular orbital) are rel-
evant quantum mechanical descriptors in envisaging the chemi-
cal stability and interactions of a molecule [40]. Previous reports
suggest that the nature of electron density distribution around a
molecule and its reactivity can be understood in terms of HOMO
and LUMO [41]. The electrostatic surface potential (ESP), generated
after molecular optimization, reveals the electrophilic and nucle-
ophilic sites present in the molecules.
2.3. Cambridge structure database search
The Cambridge structure database (CSD, version 5.40) [30,31]
investigations were carried out using ConQuest version 2.0.0
[32] with all the acridone derivatives together with alkyl-
substituted acridone moiety to understand the similarities, packing
arrangement, and dominant interactions in these kinds of chemical
compounds. There were no hits similar to any of these compounds.
4

Table 1
The details of crystal data and structure refinement for the compounds 1, 2, 3 and 4.
1
2
3
4
Crystal data
Chemical formula
CCDC Number
Mr
C19H20N2O2
1976124
C20H22N2O
1976123
C19H18N2O3
2024911
C20H20N2O2
2024910
308.37
306.40
322.35
320.38
Crystal system, space
group
Triclinic, P1
Monoclinic, P21/c
Tetragonal, I41/a
Orthorhombic, Pca21
Crystal size(mm)
Temperature (K)
0.32 × 0.21 × 0.10
0.40 × 0.37 × 0.12
0.28 × 0.19 × 0.09
0.35 × 0.15 × 0.09
273
273
273
273
˚
a, b, c (A)
7.8904 (3), 9.2616 (4), 11.6148 (4)
11.3652 (12), 15.7627 (17), 9.2873 (11)
22.199 (2), 13.0600 (12)
19.4206 (13), 8.9578 (5), 9.4791 (5)
α, β, γ (°)
99.696 (1), 98.516 (1), 107.288 (1)
90, 92.361 (3), 90
90, 90, 90
6435.9 (13)
16
90, 90, 90
1649.04 (17)
4
3
˚
V (A )
780.96 (5)
2
1662.4 (3)
4
Z
Radiation type
Mo Kα
0.09
Mo Kα
0.08
Mo Kα
0.09
Mo Kα
0.08
μ (mm−1
)
Data collection
Diffractometer
Absorption correction
No. of measured,
independent and observed
[I > 2σ(I)] reflections
Rint
Bruker APEX-II CCD
Multi-scan
Bruker APEX-II CCD
Multi-scan
Bruker APEX-II CCD
Multi-scan
Bruker APEX-II CCD
Multi-scan
8971, 3883, 3164
20411, 4129, 3485
10665, 4009, 1754
12157, 3674, 2697
0.017
1.133
0.666
0.021
1.056
0.667
0.046
1.125
0.668
0.174
0.989
0.648
GooF
−1
˚
(sin θ/λ)max (A
)
Refinement
R[F2 > 2σ(F2)], wR(F2), S
0.049, 0.183, 1.38
0.061, 0.221, 1.81
0.080, 0.263, 1.21
0.061, 0.173, 0.90
No. of reflections
3797
4066
4009
3674
No. of parameters
H-atom treatment
208
208
217
217
H-atom parameters constrained
H-atom parameters constrained
H-atom parameters constrained
H-atom parameters constrained
−3
˚
ꢀρmax, ꢀρmin (e A
)
0.26, −0.18
0.33, −0.25
0.45, −0.31
0.17, −0.25

J. Hussain, P. Sahrawat, P. Dubey et al.
Journal of Molecular Structure 1248 (2022) 131448
Fig. 3. Crystal packing diagram of 1 in a unit cell viewed along b direction showing CꢀC interaction.
3. Results and discussion
S2). Their structure displays quite similar in the parent molecule,
acridone. In contrast, a very slight differences observed where
the morpholine/piperidine moiety is bent over the acridone ring,
showing a torsion angle of C7ꢀN1ꢀC14ꢀC15 is –94.45° for 1, –
94.33° for 2, –90.87° for 3, and –83.21° for 4 respectively as shown
in the Supplementary Fig. S2.
3.1. Structural description
The synthesis of new derivatives of morpholine and piperidine
ring bearing alkyl chains of the same lengths, connected to the N
atom of the heterocyclic system of acridone, was synthesized in
good or moderate yields by the same procedure [42]. Compounds
1 and 2 were synthesized by reacting 4-(2-chloroethyl) morpho-
line hydrochloride/ 1-(2-chloroethyl)piperidine hydrochloride with
acridone in the presence of sodium hydride (NaH) as a base and
N, N-dimethylformamide (DMF) as a solvent (Scheme 1). There is
two carbon chain linker in between acridone and the terminal sub-
stituents (morpholine and piperidine) in both compound 1 and 2.
Whereas, there is an introduction of the carbonyl group at one of
the carbon atom of the two carbons chain alkyl linker in both the
compounds 3 and 4, as shown in Fig. 1. Crystal structural deter-
mination revealed that 1 crystallizes in the triclinic crystal sys-
tem with the P1 space group, whereas 2 crystallized as mono-
clinic with P21/c space group. Compound 3 crystallized as tetrag-
onal with space group I41/a, and compound 4 crystallized in or-
thorhombic having Pca21 space group. The ORTEP [43] for all the
compounds are shown in Fig. 2.
To examine the influence of πꢀπ stacking on the molecu-
lar packing, an analysis of the HS mapped with shape-index and
curvedness, elaborated various interactions as shown in Supple-
mentaryFig. S3 for all the compounds. These surfaces are repre-
sented as transparent to offer visualization of the acridone deriva-
tives, in a similar orientation for all the molecular structures.
The red spots can be categorized as bright, unusually small, and
faint to associate with the strength of intermolecular interactions,
such as possible hydrogen bonds, weak or short interactions. The
electron-rich surface areas are represented as intense red-colored
spots visible on the dnorm surfaces suggesting hydrogen bond con-
tacts near the oxygen and hydrogen atoms. It indicates donors
and acceptors of a possible C–HꢀO interaction and other evident
spots are because of HꢀC/CꢀH contacts. In addition to these, other
faint red spot areas on the dnorm of all the compounds corre-
spond to C–HꢀC/π and CꢀC interactions. The varying substituting
groups such as morpholine and piperidine in the acridone parent
molecule offer both geometric and electronic contributions to fa-
cilitate C–HꢀC/π interactions in the crystal structures (1 and 2).
But in compound 3 and 4, CꢀC interactions are very low because
these moieties are oriented differently as compared to the previ-
ous molecules due to the presence of the carbonyl group into the
linker chain. The HS interaction is shown by a significant bright-
orange area in shape index, which is also visualized by a distinct
pattern of a pair of wings in the 2D fingerprint plots. The 2D fin-
gerprint plots are due to the resultants of the distribution of strong
The C=O groups were located in the same plane in the acridone
ring in all the compounds. The compounds 1, 2, 3, and 4 with the
molecular formula of C19 H20N2O2, C20H22N2O, C19 H18 N2O3, and
C20H20N2O2 are solved as a monomer with one molecule in the
asymmetric unit having Z value of 2, 4, 16, and 4 respectively.
The crystal packing is assisted by OꢀH, HꢀH, CꢀC, and CꢀH, in-
teractions playing a significant role in all the cases. However, the
acridone molecule is planar without any deviation, not more than
˚
by 0.02 A from the molecular plane (Supplementary Figs. S1 and
6

J. Hussain, P. Sahrawat, P. Dubey et al.
Journal of Molecular Structure 1248 (2022) 131448
Fig. 4. Crystal packing diagrams of 2 viewed along, c direction shows CꢀC interaction.
Table 2
the total HS area for all the four compounds 1 to 4, respectively.
It has been observed that compound 2 has a maximum contri-
bution from HꢀH contacts, i.e., 64.8% as compared to the other
three compounds due to the absence of oxygen group, which con-
tributes more to the OꢀH interactions in the rest of the molecules.
The presence of oxygen atom in the morpholine moiety of 1 and
3 is majorly responsible for the increase in OꢀH contact contri-
bution and the concomitant decrease in HꢀH contribution when
compared to 2 and 4, respectively. They are forming more C–HꢀO
bonds; hence the proportions of HꢀO/OꢀH are 21.5% and 17.6% for
3 and 4, respectively. Hence, we are highlighting the importance
of the introduction of the functional group and its effects on inter-
molecular interactions.
The relative contribution of different close contacts for the over-
all intermolecular interactions in 10H substituted phenothiazine
derivatives.
Contacts
Compounds
1
2
3
4
HꢀH (%)
CꢀH (%)
OꢀH (%)
CꢀC (%)
57.2
19.6
14.7
6.1
64.8
17.7
8.9
49.0
23.8
21.5
1.9
52.8
24.6
17.6
2.6
5.9
and weak intermolecular interactions within the crystal packing of
solid networks of both the compounds [27]. The detailed picto-
rial representation of fingerprint plots for all the interactions are
shown in SupplementaryFig. S4 and the relative contribution of
each contact as mentioned in Table 2.
3.2. Crystal packing
The weak interactions involve in self-assembly has been marked
as a constructive and useful method for the assembly of well-
defined and predesigned patterns. Hirshfeld Surface (HS) analysis
gives a simplistic way of acquiring information on approach in
crystal packing [44]. The crystal packing in all the molecules is
stabilized by an arrangement of intermolecular C–HꢀO, C–HꢀH,
C–HꢀC/π, and πꢀπ stacking interactions, which are responsible
for the formation and strengthening of molecular assembly [45,46].
The supramolecular assembly can be investigated through sub-
structures of minor dimensionality through the dimeric or trimeric
In contrast, the HꢀO interactions are denoted by a spike at
the bottom right (acceptor) region in the fingerprint. The propor-
tions of OꢀH/HꢀO interactions comprise 14.7% and 8.9% of the
total HS for each molecule of 1 and 2, respectively, which repre-
sents the oxygen atom of one molecule interacting with the hydro-
gen atom of other. Similarly, the differences in OꢀH/HꢀO interac-
tions are observed in 3 and 4 due to the presence of extra oxygen
atom in 3. The decomposition of the 2D fingerprint plot denotes
that CꢀH/HꢀC contact comprises 19.6%, 17.7%, 23.8%, and 24.6% of
7

J. Hussain, P. Sahrawat, P. Dubey et al.
Journal of Molecular Structure 1248 (2022) 131448
Fig. 5. Crystal packing diagram of 3 viewed along a direction shows CꢀC and C–HꢀO interaction.
Fig. 6. Crystal packing diagram of 4 viewed along, a direction shows CꢀC (πꢀπ) and C–HꢀO interaction.
8

J. Hussain, P. Sahrawat, P. Dubey et al.
Journal of Molecular Structure 1248 (2022) 131448
Fig. 7. The HOMO and LUMO molecular orbital surfaces of compounds 1, 2, 3 and 4, generated at B3LYP/6-311++G(d,p) level of theory.
Fig. 8. The electrostatic potential surfaces of compounds 1, 2, 3 and 4, generated using B3LYP/6-311++G(d,p) level of theory.
or tetrameric unit as the building block [47,48]. Regardless of
the two neighboring acridone rings in 1 and 2. The C–HꢀN and
C–HꢀO interactions observed among the substituents such as mor-
pholine or piperidine moiety with the acridone ring. In general, in-
termolecular hydrogen bonds and πꢀπ stacking among the adja-
cent molecules helps in building an infinite two-dimensional layer
supramolecular structure. The crystalline packing motif of com-
pounds 1 and 2 are shown in Figs. 3 and 4, respectively. A charac-
teristic herringbone motif is observed for these compounds, similar
the almost close resemblance in all the compounds in terms of
their overall constitutions and comprehensive molecular geome-
tries, there are a few significant variations in the environment of
their crystal packing arrangement.
These acridone derivatives are linked by the extensive πꢀπ
stacking interactions, which play essential roles in the crystal pack-
ing. The face-to-face πꢀπ stacked contacts are generated between
9

J. Hussain, P. Sahrawat, P. Dubey et al.
Journal of Molecular Structure 1248 (2022) 131448
Fig. 9. Experimental (left) and theoretical (right) UV–Vis spectra of compounds 1, 2, 3 and 4 in methanol. The absorption spectra were normalized at the maxima. The
theoretical spectra is simulated using the TD-DFT predicted peaks with a HWHM set to 0.09 eV.
to that of polycyclic aromatic hydrocarbons [49]. Nevertheless, we
can say that both 1 and 2 form face-to-face columnar stacks with
the acridone plane.
actions are helping in the building of the supramolecular assembly
of these compounds.
The acridone moiety in 4 is perfectly planar, and substituted
piperidine is perpendicular to the plane, as shown in Fig. 6. From
the figure, we can find that compound 4 is cross stacked, which
makes the shear sliding complex. The carbonyl groups are located
on the terminal part linked with the other three hydrogen atoms
by the moderate hydrogen bonding. It facilitates the support of
crystal packing by enhancing intermolecular interactions.
Compound 1 illustrates a sandwich herringbone pattern, in
which pairs of acridone rings of two neighboring molecules co-
facial with each other through πꢀπ interactions. There is morpho-
line moiety in a terminal group of compound 1, which has an oxy-
gen atom, which is also participating in hydrogen bonding and sta-
bilizing the crystal packing. In contrast, Compound 2 shows a layer
by layer arrangement with the molecules in each layer packed in
a β sheet-like structure of the herringbone motif. The packing di-
agram of 2 in a unit cell reveals that there exist intermolecular
hydrogen bonds in the crystal, as shown in Fig. 4. Here, also ad-
jacent molecules are mostly attached by the C = OꢀH and H–CꢀC
interactions between the oxygen atom of the carbonyl group of the
acridone ring and the hydrogen atom of the acridone ring of an-
other molecule.
3.3. DFT calculations
The effect of the terminal substituents such as morpholine
and piperidine on the electronic properties of acridone derivatives
was examined by the density DFT calculations [50] at B3LYP/6-
311++G(d,p) level of theory. The Frontier Molecular Orbital (FMO)
provides the information about the reactivity of the molecule, and
the active site can be explained by the distribution of frontier
orbital [51]. Both the HOMO and LUMO are mainly delocalized
over the acridone ring and comprise a highly delocalized π bond
(Fig. 7). The LUMOs are located at the acridone moiety with an en-
ergy level of 3.94–3.99 eV relative to HOMO (Supplementary Ta-
ble S1). The HOMO-LUMO energy gap for acridone derivatives was
compared with that of the parent molecule, whose energy gap was
computed to be - 4.02 eV. Thus, the comparison of the HOMO-
LUMO energy gap between acridone and its derivatives infers that
acridone derivatives have marginally lower kinetic stability and
higher chemical reactivity as compared to the parent molecule. The
HOMO energy level of 1 and 3 are elevated too marginally due to
the presence of the electron-donating group (oxygen atom).
˚
In the crystal packing structures, weak hydrogen bonds (2.62 A)
exist between two neighboring molecules (Supporting Figs. S17
and S18). Compound 2 has wavelike π-stacked in a crystal pack-
ing which is planar from the side view of the molecular plane as
shown in Fig. 4. The CꢀH contacts related to C–HꢀC/π interactions
vary slightly, from 19.6% in 1 to 17.7% in 2. Even though the crystal
packing in 1 and 2 relate to a C–Hꢀπ/C mediated herringbone-
like structure, whereas the crystal packing of 3 and 4 is a face-
to-side 2D structure stabilized by πꢀπ and C–HꢀC/π hydrogen
bonds having sheet-like structures. Furthermore, these structural
analyzes illustrate that the molecular interactions contribute to the
central role to advance stabilizing the structure. As shown in Fig. 5,
two neighboring molecules are mainly joined by the OꢀH and CꢀC
and CꢀH interactions between the oxygen atom of the carbonyl
group of the acridone ring and the hydrogen atom of the acridone
ring of another molecule.
3.3.1. Electrostatic potential surface
The electrostatic potential (ESP) is a very well-known tool for
identifying the electrophilic and nucleophilic reactions and inter-
molecular interactions [52]. The different colors signify the diverse
values of ESP, such as the red region indicates the possible site for
the electrophilic attack, while the blue region for the nucleophilic
attack [53]. The ESP surfaces for acridone and its derivatives were
generated at B3LYP/6-311++G(d,p) level of theory, shown in Fig. 8.
The negative and positive electron density was raised in the sites
of -2.249 × 10−2 a.u. to 2.249 × 102 a.u. The color code of ESP
lies between −0.04 a.u (intense red) and 0.04 a.u (intense blue)
for all the studied compounds. The significances of electron den-
sity increases in the subsequent order represented by color as Red
(−0.02 a.u) > Orange (−0.015 a.u) > Yellow (−0.010 a.u)> Green
(0.01 a.u) > Blue (0.02 a.u) [52]. The most intense red color was
found at the oxygen atom of the carbonyl group, representing the
Similarly, in the case of compounds 3 and 4, there is also a for-
mation of a herringbone pattern. The crystal packing diagram pro-
jected along the a-axis showed the main supramolecular interac-
tions that are intermolecular edge-to-edge πꢀπ and face to side
hydrogen bonds in both the compounds 3 and 4. Eventually, the
C–HꢀO bonds assembly can be portrayed as a herringbone shaped
arrangement of different substituents, where adjacent substituents
are connected via OꢀH hydrogen bonds from the carbonyl group
to the H atom in a second molecule along the a-axis (Fig. 5). There
˚
are the formations of four C–HꢀO ranges from 2.55–2.60 A and
˚
one CꢀC (3.27 A) bonds between the two molecules of compound
˚
3 in the crystal packing motif, whereas in 4, three C–HꢀO (2.377 A)
˚
and one CꢀC (3.37 A) (Supporting Figs. S19 and S20). These inter-
10

J. Hussain, P. Sahrawat, P. Dubey et al.
Journal of Molecular Structure 1248 (2022) 131448
Table 3
Supplementary materials
Experimental and calculated wavelengths, λ (nm) in Methanol solution for
compounds 1, 2, 3 and 4.
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.molstruc.2021.131448.
Compounds
Experimental λabs (nm)
B3LYP/6-311++G(d,p) λabs (nm)
1
2
3
4
401
231
397
265
272, 388
278, 390
270, 374
276, 403
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