Insights into supramolecular assembly formation of diethyl aryl amino methylene malonate (DAM)derivatives assisted via non-covalent interactions

Article abstract of DOI:10.1016/j.molstruc.2019.04.114

The crystal structures of four derivatives of diethyl 2-(((aryl)amino)methylene)malonate (DAM)have been studied by single crystal X-ray diffraction. The molecular structures of all the four derivatives were found to be in co-planar conformation. The detailed analysis of molecular conformation in four derivatives reveals the presence of a common strong intramolecular N–H?O hydrogen bonding, forming a ring of graph-set motif S₁ ¹ (6). The effect of chloro and nitro substitution on their relative strengths of hydrogen bonding are analyzed here. Particularly, in compound 1, additional intramolecular hydrogen bonding between –NO₂ and N–H was observed that results in the formation of another six-membered chelate ring. On the other hand in case of compound 3, we have observed type-I Cl?Cl interaction for the first time in this class of compounds. Further, Hirshfeld surface has been generated that is mapped with d_norm shape index and curvedness to summarize the weak interactions and examine the molecular shapes in all four derivatives. Effect of nitro (1 and 2)and chloro (3 and 4)substitution on the C?H, N?O and C?O interaction is highlighted in molecular contour and 2D fingerprint plots.

Full text of DOI:10.1016/j.molstruc.2019.04.114

Accepted Manuscript
Insights into supramolecular assembly formation of diethyl aryl amino methylene
malonate (DAM) derivatives assisted via non-covalent interactions
Althaf Shaik, Deekshi Angira, Vijay Thiruvenkatam
PII:
S0022-2860(19)30525-3
DOI:
https://doi.org/10.1016/j.molstruc.2019.04.114
MOLSTR 26486
Reference:
To appear in: Journal of Molecular Structure
Received Date: 8 January 2019
Revised Date: 25 April 2019
Accepted Date: 26 April 2019
Please cite this article as: A. Shaik, D. Angira, V. Thiruvenkatam, Insights into supramolecular assembly
formation of diethyl aryl amino methylene malonate (DAM) derivatives assisted via non-covalent
interactions, Journal of Molecular Structure (2019), doi: https://doi.org/10.1016/j.molstruc.2019.04.114.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Insights into supramolecular assembly formation of diethyl aryl amino methylene malonate (DAM)
derivatives assisted via non-covalent interactions
Althaf Shaik a, Deekshi Angira a, Vijay Thiruvenkatam* b
aDiscipline of Chemistry, Indian Institute of Technology Gandhinagar, Ahmedabad, India-382355
bDiscipline of Biological Engineering, Indian Institute of Technology Gandhinagar, Ahmedabad, India-
382355
* Corresponding Author: vijay@iitgn.ac.in
Abstract
The crystal structures of four derivatives of diethyl 2-(((aryl)amino)methylene)malonate (DAM) have
been studied by single crystal X-ray diffraction. The molecular structures of all the four derivatives
were found to be in co-planar conformation. The detailed analysis of molecular conformation in four
derivatives reveals the presence of a common strong intramolecular N—H···O hydrogen bonding,
forming a ring of graph-set motif S11 (6). The effect of chloro and nitro substitution on their relative
strengths of hydrogen bonding are analyzed here. Particularly, in compound 1, additional
intramolecular hydrogen bonding between -NO2 and N-H was observed that results in the formation of
another six-membered chelate ring. On the other hand in case of compound 3, we have observed
type-I Cl···Cl interaction for the first time in this class of compounds. Further, Hirshfeld surface has
been generated that is mapped with dnorm shape index and curvedness to summarize the weak
interactions and examine the molecular shapes in all four derivatives. Effect of nitro (1 and 2) and
chloro (3 and 4) substitution on the C···H, N···O and C···O interaction is highlighted in molecular
contour and 2D fingerprint plots.

ACCEPTED MANUSCRIPT
1. Introduction
The formation of a crystal and molecular aggregation is based on molecular recognition phenomena
that are complex events attained through the different types of non-covalent interactions [1], [2], [3].
The nature of non-covalent interactions (strong and weak) such as C—H···O/N, N—H···O/N, O—
H···N/O, π··· π, lone pair (lp)··· π, halogen···halogen (X···X), N···O interactions and their role is
extremely important in supramolecular chemistry, medicinal chemistry and crystal engineering [4], [5],
[6], [7], [8], [9], [10], [11]. The nature of strong intermolecular interactions (e.g. N—H···O/N, O—
H···N/O) are well-studied and they turn out to be the most reliable in the molecular recognition
mechanism and hence, these are found to be the main structure directing interactions in crystal
packing [2], [5]. The present focus in supramolecular chemistry is shifted towards the understanding
of the nature and capability of weak interactions such as halogen···halogen (X···X), N···O π ··· π, and
lp···lp in the formation of molecular self-assembly, ladders, two dimensional sheets, etc. and it’s effect
on the material properties [4], [6], [7], [8], [10], [12], [13]. Over the past few years, many studies have
attempted to rationalize the nature of X···X interactions in halogenated compounds because of their
essential role in molecular self-assembly in crystals and in supramolecular and bio-molecular
systems [6], [10], [14]. The study of X···X contacts has been classified into three types based on C—
X···X angles: contacts with 0° ≤ |θ1 − θ2| ≤ 15° represent close packing of halogen atoms in
geometrical model and are classified as type I, those with 30° ≤ |θ1 − θ2| represent chemical model
and are classified as type II, while those with 15° ≤ |θ1 − θ2| ≤ 30°are classified as quasi type I/type
II interactions [6], [8], [12], [14], [15], [16], [17].
Further, crystallographic study of nitro substituted chemical compounds helps in better understanding
the nature and role of N···O interactions on physico-chemical properties. Nitro functional group plays
a very important yet diverse role in the mechanism of action of several drugs [18] due to its ability to
form inter and intramolecular hydrogen bonds and at the same time, it is strong electron withdrawing in
nature [19]. Nitroaromatic drugs are known to treat several diseases and disorders like Parkinson’s
disease, insomnia, giardiasis, amoebiasis and several other infections [20]. Importance of nitro group
has also been established in cancer treatment, where, the presence of electron withdrawing nitro
group is considered essential for the anti-cancer effect of niclosamide according to its SAR studies

ACCEPTED MANUSCRIPT
[21]. Also, a similar study reported that the anti-proliferative effect of nitro substitution, as studied in
THP-1 and MCF -7 cancer cell lines, exhibited a descending pattern from para to meta to ortho,
where, para showed maximum anti-proliferative activity while ortho derivative failed to elicit any kind of
such property [22]. On the contrary, in another study, ortho-substituted thiosemicarbazones displayed
more inhibition against MCF-7, T98G, and U87 cell lines as compared to it’s para and meta analogs
[23].
In the view of above interest, we focused on the nature of weak and strong interactions in substituted
diethyl aryl amino methylene (DAM) derivatives to illustrate the changes in the crystal packing and
interaction energies in this class. DAM derivatives are important intermediates in the synthesis of
various substituted quinoline derivatives in organic synthesis [24]. These quinoline derivatives have
diverse chemical and pharmacological properties. Quinoline derivatives have been used immensely
for the development of potent antimalarial, antimycobacterial, antimicrobial, and anticonvulsant
activity [24], [25], [26], [27]. However, DAM derivatives itself have anti-proliferative properties as
enhancers of TGFβ induced smad2/3 nuclear translocation, reduced microfilament remodeling with
D50 of 1-4 mM [26], [28], [29]. Even though DAM derivatives have wide applications, the
crystallographic studies of diethyl aryl amine methylene malonate derivatives are limited. There are
only four reports of DAM in Cambridge structural database (CSD) [30], [31], [32]. Considering these
facts, we are interested in the 3D structure determination of DAM derivatives with the aim of getting a
general understanding on the nature of intermolecular interactions (N···O, Cl···Cl, C—H···O/N, π ··· π,
and lp··· lp) in compound 1-4 (Fig. 1).
Fig. 1. Structures of investigated -NO2 and –Cl substituted DAM derivatives

ACCEPTED MANUSCRIPT
The synthesis of these derivatives was carried out by the well-known Gould-Jacobs reaction [33]
Scheme 1. Hirshfeld surface and 2D decomposition plots were generated with the help of Crystal
explorer 3.1 software [34], [35]. Hirshfeld surfaces are mapped with dnorm, shape index and
curvedness. Further, 2D fingerprint plots for four DAM derivatives have been generated for
visualization of various weak interactions [1], [36]. Interestingly, Hirshfeld surface and 2D fingerprint
analysis of chloro DAM derivative highlighted the presence of type I Cl···Cl (3.533Å) interaction only
in 3.
2. Experimental section
2.1 Material and methods
The starting materials 2-Nitroaniline, 4-Nitroaniline, 4-Chloroaniline, 3,4-Dichloroaniline and diethyl
ethoxy methylene malonate were purchased from Sigma Aldrich. Toluene was obtained from Merck
Chemicals. All the derivatives were confirmed by NMR spectroscopy. 1H NMR spectra were recorded on a
BrukerAvance 500 (500 MHz) spectrophotometer using TMS δ= 0 ppm as an internal standard with
chloroform-D as a solvent. 13C NMR spectra were taken on a BrukerAvance 500 (126 MHz); chemical shifts
are expressed in δ values (ppm) using the solvent peak as an internal standard; multiplicity of resonance
peaks is indicated as singlet (s), doublet (d), triplet (t), quartet (q) and multiplet (m). Fourier transform
infrared spectra for all the derivatives were recorded using Perkin Elmer spectrometer with diamond
prism (4000–550 cm−1; number of scans: 250; resolution: 1 cm−1).
2.1.0 Synthesis of -NO2 and -Cl DAM derivatives
All the derivatives were prepared by the well-known and reported Gould-Jacobs reaction. The
corresponding anilines (1g, 3.2 mmol) were taken in a sealed tube and added toluene (5 ml) at room
temperature followed by addition of diethoxy methylene malonate (3.2 mmol) at the same temperature.
After the completion of addition, the reaction vessel was closed and allowed to stir at 150°C for 3 hr s.
The progress of the reaction was monitored on TLC (10 % ethyl acetate and hexane). After the

ACCEPTED MANUSCRIPT
completion of the reaction, an excess of toluene was removed under reduced pressure. To the resulting
residue, hexane was added and washed several times to remove the traces of toluene. The resulting
residue was evaporated under reduced pressure to afford corresponding derivatives as solid in good
yield (80-85% yield).
Scheme 1. Synthesis of DAM derivatives 1-4.
Analytical data for Diethyl 2-(((2-nitrophenyl)amino)methylene)malonate(1)
1H NMR (500 MHz, Chloroform-d) δ 12.58 (d, J = 12Hz, 1H), 8.53(d, J =12.5Hz, 1H), 8.26 (d, J = 8Hz,
1H), 7.70 (m, 1H), 7.51 (d, J = 8.5Hz, 1H), 7.27-7.20 (m, 1H), 4.41-4.28 (m, 4H), 1.41-1.339 (m, 6H).
13C NMR (126 MHz, Chloroform-d) δ 166.74, 166.59, 148.28, 137.11, 136.10, 135.85, 126.81, 123.32,
116.75, 99.48„ 60.95, 60.72, 14.35, 14.33. IR Data (cm-1): 3185, 3090, 2990, 2910, 1685, 1650, 1575,
1200, 745, 685.
Analytical data for Diethyl 2-(((4-nitrophenyl)amino)methylene)malonate (2)
1H NMR (500 MHz, Chloroform-d) δ 11.21 (d, J = 13Hz, 1H), 8.52 (d, J = 13Hz, 1H), 8.29 (d, J = 8.5Hz,
2H), 7.24(d, J = 8.5Hz, 2H), 4.37-4.28 (m, 4H), 1.42-1.35 (m, 6H).13C NMR (126 MHz, Chloroform-d) δ
168.54, 165.07, 149.66, 144.58, 143.92, 125.99, 116.35, 97.48, 60.95, 60.64, 14.35, 14.19.
IR Data (cm-1): 3175, 3090, 2980, 2905, 1680, 1575, 1235, 1020, 825, 750.
Analytical data for Diethyl 2-(((3,4 -dichlorophenyl)amino)methylene)malonate (3)
1H NMR (500 MHz, Chloroform-d) δ 11.00 (d, J = 12.5 Hz, 1H), 8.40 (t, J = 17.2 Hz, 1H), 7.45 (d, J = 8.3
Hz, 1H), 7.27 (s, 1H), 7.00 (d, J = 8.4 Hz, 1H), 4.32 (m, 4H), 1.37 (m, 6H).13C NMR (126 MHz, CDCl3) δ
168.81, 165.37, 150.95, 138.87, 133.90, 131.40, 128.17, 118.75, 116.37, 95.32, 77.27, 77.21, 77.01,

ACCEPTED MANUSCRIPT
76.96, 76.76, 60.66, 60.37, 14.39, 14.34, 14.23. IR data (cm-1): 3374.16, 2980.97, 1677.46, 1614.29,
1495.29, 1436.65, 1225.85, 1086.89, 1028.46, 817.66, 805.02, 508.16, 426.84.
Analytical data for Diethyl 2-(((4-chlorophenyl)amino)methylene)malonate (4)
H NMR (500 MHz, Chloroform-d) δ 11.02 (d, J = 13.5 Hz, 1H), 8.48 (dd, J =13.5, 3.4 Hz, 1H), 7.37 (dd, J
= 8.8, 3.3 Hz, 2H), 7.10 (dd, J = 8.7, 3.3 Hz, 2H), 4.31 (m, 4H), 1.38 (m, 6H). 13C NMR (126 MHz, CDCl3)
δ 168.97, 165.57, 151.54, 137.97, 130.10, 129.90, 118.33, 116.20, 94.31, 77.26, 77.01, 76.75, 60.49,
60.21, 14.40, 14.27. IR data (cm-1): 3247.04, 2384.13 1679.82, 1585.87, 1436.65, 1258.219, 1223.48,
1089.26, 846.87, 797.133, 677.91, 479.74.
2.2 SCXRD Data collection, structure solution and refinement
2.2.1 Data collection, structure solution and refinement for compound 1 and 2
Crystal data, data collection and structure refinement details are summarized in Table 1. All hydrogens
were placed in geometrically idealized positions and constructed to ride on their parent N or C atoms,
with N–H = 0.86 Å, C–H = 0.93 Å and Uiso(H) = 1.2Ueq(N,C), for the aromatic and amine hydrogens,
and with C–H = 0.96 Å and Uiso(H) = 1.5Ueq(C) for methyl H atoms.
Table 1: SCXRD Data of 1 and 2
o-Nitro(1)
C14H16N2O6
308.29
p-Nitro (2)
C14H16N2O6
308.29
3,4-Dichloro (3)
C14H15Cl2NO4
332.17
p-Chloro (4)
C14H16ClNO4
297.73
Chemical formula
Mr
Crystal system, space Monoclinic, P21/C
Monoclinic, P21
Monoclinic, P21/C
Monoclinic, P21
group
Temperature (K)
293
293
293
293
a, b, c (Å)
18.7594 (15), 4.7213 9.1462 (8), 6.6350 12.1193 (19), 9.0232 9.0669 (14), 6.3688
(4), 15.6380 (12)
93.351 (3)
(6), 12.3627 (10)
103.832 (3)
(8), 14.785 (2)
108.843 (16)
(10), 13.481 (2)
106.611 (4)
b (°)

ACCEPTED MANUSCRIPT
V (Å3)
1382.67 (19)
4
728.47 (11)
1530.2 (4)
746.0 (2)
Z
2
4
2
F(000)
162
162
688
312
Radiation type
m (mm-1)
Crystal size (mm)
Diffractometer
Mo Ka
Mo Ka
Mo Ka
Mo Ka
0.12
0.11
0.44
0.27
0.4 × 0.25 × 0.25
Bruker APEX-II CCD
Multi-scan
0.42 × 0.20 × 0.20
Bruker APEX-II CCD
Multi-scan
0.26 × 0.25 × 0.24
Xcalibur, Eos, Nova
Multi-scan
0.49 × 0.20 × 0.20
Rigaku SCX mini
Absorption
correction
Empirical
(using
SADABS;
(Bruker, SADABS;
(Bruker, CrysAlis PRO, Agilent intensity
2014/5)
2014/5)
Technologies,
measurements)
Version 1.171.37.35 SADABS;
Empirical absorption 2012/1)
(Bruker,
correction
spherical harmonics,
implemented in
SCALE3 ABSPACK
using
scaling algorithm.
0.208, 1.000
Tmin, Tmax
0.580, 0.746
0.614, 0.745
0.390, 0.923
No. of measured, 36729, 3054, 2382
independent and
6895, 2494, 2107
5436, 2694, 1122
7561, 3382, 1564
observed [I > 2s(I)]
reflections
Rint
0.113
0.044
0.075
0.058

ACCEPTED MANUSCRIPT
(sin q/l)max (Å-1)
0.643
0.596
0.594
0.649
Range of h, k, l
h = -24 ->24, k = -6- h = -10->10, k = -7->7, h = -14->13, k = -10- h = -11->11, k = -8->8,
>6, l = -20->20
l = -14->14
>10, l = -10->17
l = -17->17
R[F2 > 2s(F2)], wR(F2), 0.050, 0.145, 1.01
0.041, 0.154, 0.65
0.093, 0.144, 1.02
0.055, 0.166, 0.88
S
No. of reflections
No. of parameters
Δρmax, Δρmin (e Å-3)
CCDC Submission
3054
2494
2694
3382
201
201
196
183
0.25, -0.26
1495651
0.21, -0.24
1528606
0.24, -0.24
1471905
0.24, -0.22
1477440
Table 2:
Hydrogen-bond geometry (Å, °) for o-Nitro (1)
D—H···A
D—H
0.86
0.86
0.93
H···A
2.01
1.99
2.62
D···A (Å)
D—H···A (°)
130.4
N1—H1···O3
N1—H1···O5
C3—H3···O6i
2.6507 (19)
2.6396 (19)
3.5250 (2)
131.1
163.5
Symmetry code: (i) -x+1, -y+3, -z.
Table 3. Hydrogen-bond geometry (Å, °) for p-Nitro (2)
D—H···A
D—H
0.86
0.93
H···A
1.96
2.36
D···A (Å)
2.626 (4)
3.244 (4)
D—H···A (°)
133.7
N1—H1···O3
C6—H6···O1i
158.4

ACCEPTED MANUSCRIPT
C2—H2···O3ii
0.93
0.97
2.45
2.53
3.264 (4)
146.8
168.9
C10—H10A···O1iii
3.483 (4)
Symmetry codes: (i) -x+1, y-1/2, -z; (ii) -x+2, y-1/2, -z+1; (iii) -x+1, y+1/2, -z.
Table 4. Hydrogen-bond geometry (Å, º) for 3,4-Dichloro (3)
D—H···A
D—H
0.860
0.992
H···A
2.044
2.451
D···A (Å)
2.675 (7)
3.361 (1)
D—H···A (°)
129.61
N1—H1···O3
C6—H6···O1i
152.28
Symmetry code: (i) x, -y+3/2, z+1/2.
Table 5. Hydrogen-bond geometry (Å, °) for p-Chloro (4)
D—H···A
D—H
0.86
0.93
0.93
H···A
1.93
2.45
2.51
D···A (Å)
2.602 (6)
3.320 (7)
3.201 (6)
D—H···A (°)
134.0
N1—H1···O3
C6—H6···O1i
C2—H2···O3ii
155.8
131.6
Symmetry codes: (i) -x+1, y+1/2, -z+1; (ii) -x+1, y+1/2, -z+2.
2.3 Hirshfeld surface and 2D fingerprint plot analysis
Crystal explorer 3.1 was used to perform Hirshfeld analysis, wherein, with the help of graphical
representation in color code, we can study the intermolecular interactions of the atoms with the
neighboring species [34], [35], [36]. The relative contribution of each contact for the molecule of
interest is depicted in the form of 2D fingerprint plot, thereby, making it a very important platform for
comparative studies with respect to short contacts or weak interactions [36], [37]. Other properties of
the molecule of interest can also be studied using curvedness and shape index [35], [34].

ACCEPTED MANUSCRIPT
3. Results and discussion
3.1.1 Molecular structure and packing of -NO2 DAM derivatives (Compound 1 and Compound 2)
Crystal structure of 1 was solved and refined in centrosymmetric monoclinic crystal system with
P21/C space group (Fig. 2a), while the structure 2 was solved in the non-centrosymmetric space
group P21 (Fig. 2b). Molecular conformation in 1 is stabilized by a strong intramolecular N—H···O
1
hydrogen bonding (graph-set S1 (6)) between amino and carbonyl ester. The amino methylene
moiety and malonate moiety are in the planar conformation as shown by the torsional angle N1—
C7—C8—C9 = -178.76° (2). On the other hand, the ary l group attached to the amino methylene
group slightly deviates from the plane as indicated by C7—N1—C1—C2 torsional angle of 168.26°
(2). The nitro group attached to the aryl ring also displayed a small deviation from the plane as
specified by the torsional angle O6—N2—C2—C1= -166.59° (2), forming strong intramolecular N—
H···O hydrogen bonding (N1— H1···O5, 1.994 Å) with amino group, creating another six-membered
1
chelate ring with graph-set motif S1 (6). Further, molecules are linked via a pair of C3—H3···O6
2
interaction forming inversion dimers with ring motif R2 (10).
Importantly, a rare π -hole interaction (an interaction between anion-π and lone pair-π) of N···O is
observed in 1, which in itself is a non- conventional covalent bond of the nitro group. Lewis acid nature
of the nitro group in the o-nitro DAM interacts favorably with electron rich oxygen atom by means of π
-hole that is located above or below the C—N bond. This N···O interaction (N2···O6, 2.946 Å) which
is less than the sum of the van der Waals radii 3.070 Å, plays a significant role in crystal packing and
creating stacking interactions to generate final 3D architecture.
Similar to 1, the molecular conformation in 2 is also stabilized by intramolecular N—H···O hydrogen
1
bonding (S1 (6)) bringing the co-planar conformation. As compared to 1, in compound 2, the aryl
group is in the same plane of the methylene malonate moiety as indicated by the torsional angle of
C2—C1—N1—C7 = -179.6° (4). Nitro group is also in the same plane of the aryl moiety, with the
torsional angle of O5—N2—C4—C3 = 174.34°(3). In th e crystal structure, molecules are packed via
a network of C—H···O hydrogen bonding (C2—H2···O3, 2.446 Å, C6—H6···O1, 2.362 Å & C10—
H10A···O1, 2.526) along with N2—O6…C13 (Symmetry code: 2-x, -½+y, 1-z) and N2—O6…C4

ACCEPTED MANUSCRIPT
(Symmetry code: 1-x, -½+y, 1-z) generating 3D network (Table 3).
Fig. 2 ORTEP diagram with 50% ellipsoid probability of a) 1 with atom labeling b) 2 with atom labeling.
Hydrogen bonding is represented as dotted lines
3.1.2 Molecular structure and packing of —Cl DAM derivatives (Compound 3 and Compound 4)
The crystal structure of 3 was solved and refined in centrosymmetric monoclinic space group (P21/C)
while 4 was solved in non-centrosymmetric space group P21. ORTEP diagram for 3 and 4 with the atom
labeling is shown in Fig. 3. The molecular structure in them was stabilized by intramolecular N1—
H···O3 hydrogen bond interaction, which led to the formation six-membered (N1/C7/C8/C12/O3/H1)
1
ring (graph-set notation S1 (6)) like other reported DAM derivatives. The bond length and bond angles
were observed to be within the range. Both the compounds are in coplanar conformation a s
indicated by C6—C1—N1—C7 torsional angle of -176.81° (5) in 3 and C2—C1—N1—C7 torsional
angle of -172.72° (5) in 4 between the aryl and ami no methylene moieties. Also, as indicated by N1—
C7—C8—C9 torsional angle of -179.58° in 3 and N1—C7—C8—C9 torsional angle of -175.23° (5) in 4.
Further, molecular packing in 3 was stabilized by a pair of intermolecular C—H···O hydrogen bonding
between aromatic C6—H6 and oxygen of carbonyl ester C9=O1 and C10—H10A···O1 between CH2 and
oxygen of carbonyl ester. Further, molecules are stacked by a pair of weak C9···C12 (3.351 Å) contacts
between carbonyl moiety, generating a 3D network. While in 4, molecular packing was stabilized by
C6—H6…O1, 2.45 Å, and C2—H2…O3, 2.51 Å.

ACCEPTED MANUSCRIPT
Fig.3 ORTEP diagram with 50% ellipsoid probability of a) 3 with atom labeling b) 4 with atom labeling.
Hydrogen bonding was represented as dotted lines
3.2 Hirshfeld surface and fingerprint plot analysis
3.2.1 Hirshfeld surface and 2D fingerprint plot analysis -NO2 DAM derivatives (Compound 1 and
Compound 2)
Hirshfeld surface was generated for both 1 and 2 and was further examined, studied and analyzed for
intermolecular contacts (Fig. 4). 1 showed a higher percentage of C···H contact (14.1%) as compared to 2
that had a lower contribution of the similar contacts (8.6%). On the other hand, C···O contacts that
show a 3.1% contribution in 1 have a major contribution of 8.1% in 2. Other interactions like H···H,
O···H or C···C are at par with each other in 1 and 2. Specifically in case of 1, the network of C2—N2···O3
and C2—N2···O6 having a bond length of 2.896 Å and 2.946 Å respectively appear as prominent dark
and red spots, which supports the presence of rare π hole interaction in this class. Other red spots in the
Hirshfeld surface of 1 correspond to carbon and hydrogen contact between C14—H14···C12 with a bond
length of 2.609 Å. It has a relative percentage contribution of C···H contact (14.1%) as compared to its
para analog (2) that had a lower contribution of the similar contacts (8.6%). Besides this, few mild red
spots can also be seen due to C3—H3···O6, and C5—H5···O3 interaction having a bond distance of
2.477 Å and 2.494 Å respectively. These contacts play a major role in crystal packing as already
discussed in the paper. Considering 2, contrary to 1, the only major interactions dominating here as
depicted by red spots in Hirshfeld surface are strong hydrogen bonds in the form of O···H contacts,
wherein C6—H6···O1 and C10—H10A···O1 show a bond length of 2.220 Å and 2.413 Å (Fig. S13). O1

ACCEPTED MANUSCRIPT
forms bifurcated contact with both H10A and H6 at the same time. Also, C2—H2···O3 forms a bond with
a distance of 2.322Å. A trifurcated but weak hydrogen bond is also seen in O6 and H14B—C14, H13B—
C13 and H13A—C13 with bond lengths of 2.759Å, 2.791Å and 2.873Å respectively.
The two-dimensional fingerprint plots (plotted as di versus de) being derivedfrom Hirshfeld surface depict
the relative contribution of each contact in the form of colored points ranging from blue to green and then
red in the ascending order of highest contact fraction. As shown in Fig. 5, fingerprint plot for 1 has two
sharp spikes corresponding to the strong hydrogen bond between oxygen and hydrogen. As already
mentioned, the color depicts the considerable contribution O···H contacts as compared to other minor
interactions in the molecule. Similarly, in the case of 2, identical spots can be observed corresponding to
O···H contacts which explains the importance of O···H bonding in the packing of both the derivatives. A
small area covering the middle part of the fingerprint plot as laid out in Fig. S13 illustrates the
contribution of N···O contacts present in 1 which is negligible in case of 2. The detailed pictorial
representation of fingerprint plots for all the interactions and the relative contribution of each contact can
be observed in Fig. 5and Fig. 6.
Fig. 4 Hirshfeld surface mapped with dnorm, curvedness, shape index A) compound 1 B) compound 2

ACCEPTED MANUSCRIPT
Fig. 5 A) 2D decomposition plots for 1 B) 2D decomposition plots for 2
Fig. 6 Relative contribution of each interaction in the Hirshfeld surface for compound 1 and 2
3.2.2 Hirshfeld surface and 2D fingerprint plot analysis for -Cl DAM derivatives (Compound 3
and Compound 4)
Similar to 1 and 2, Hirshfeld surface for both the chloro derivatives (3 and 4) was mapped with dnorm
shape index and curvedness (Fig. 7). The dark red spots in the dnorm surface are due to weak Ar—
C—H···O=C interaction. The H···O contacts correspond to 13.4% in 3 and 18.1% in 4. In the
Hirshfeld surface, H···H contacts contribute to the highest percentage of 35.5 % and 44.6% in 3 and 4
respectively. Compound 3 shows type-I Cl···Cl interaction at a distance of 3.533 Å with θ1 = 130.58°
θ2 =130.58°. The type-I class of Cl ···Cl contacts are highlighted by mapping curvedness on Hirshfeld
surface Fig. 7 and Fig. 10.
The 2D decomposition plots for 3 and 4 are represented in Fig. 8. The contacts involving Cl atoms and
Cl···H contacts were also quantified in both the derivatives. The percentage of contribution towards
these contacts along with other contacts (H···H, O···H, C···C etc.) are shown in Fig. 9. The Cl···H

ACCEPTED MANUSCRIPT
contributes about 26.2% in 3 and 12.3% in 4.
Fig. 7 Hirshfeld surface mapped with dnorm, curvedness, shape index and selective highlighting of C-H…O
contacts a) compound 3 b) compound 4
Further, the molecular conformation in both the derivatives was stabilized by C···C interplanar contacts
and this can be visualized from shape index with the pattern of red and blue colored triangles. The
C···C contacts in 3 were found to be 3.399 Å and contribute to 6.4 % of the surface (Fig. 9). But the
C···C contacts in 2 has 3.850 Å and contributes only to 2.3 % of the total Hirshfeld surface. The
changes in the interaction can be attributed to the presence of a strong electronegative group at the 3rd
position in 4 which creates an electron deficiency in the ring and thereby the electron-rich alkenyl (—
C=CH) π electrons of adjacent molecule interact with the electron deficient aromatic π system, bringing
the changes in the crystal packing.

ACCEPTED MANUSCRIPT
Fig. 8 a) 2D decomposition plots for 3 b) 2D decomposition plots for 4
Fig.9 Relative contribution of each interaction in the Hirshfeld surface for compound 3 and 4

ACCEPTED MANUSCRIPT
Fig.10 Hirshfeld surface mapped with curvedness and highlighting the type I Cl…Cl interaction in
compound 3.
4.0 Conclusion
In conclusion, the four DAM derivatives are synthesized and characterized using SCXRD. It is observed
that all the four derivatives are stabilized by intramolecular N—H···O=C interactions and the molecular
conformation is stabilized by the aryl C—H···O=C interactions. In the case of nitro derivatives (1 and 2),
non-covalent N···O contact in 1 helps in crystal packing, whereas, no significant N···O interaction is
observed in case of 2. In 3, we have observed the type I Cl···Cl (3.5 Å) interactions for the first time in
the class of DAM derivatives. The Hirshfeld surface and 2D decomposition plots highlight the relative
contribution of intermolecular H···H, C···C, N···O, H···O, Cl···H and C···H contacts in four derivatives.
Hirshfeld surface also highlights the presence of weak intermolecular C···C interaction between aromatic
π system and alkenyl system of the adjacent molecule in them. In view of the diverse application of these
classes of compounds, these analyses give us an insight into the details of the intermolecular interaction
in crystal packing which will aid in the better understanding of DAM derivatives. It will also help in
attaining knowledge about the role of weak interactions in molecular packing that may have implications
in crystal engineering and supramolecular chemistry.

ACCEPTED MANUSCRIPT
Acknowledgments
The authors thank the Indian Institute of Technology Gandhinagar for support and facilities. VT thanks
SERB for the financial support and IISc Bangalore for single crystal X-ray facility. We acknowledge Prof.
Kirubakaran for her support and proofreading.
Author contribution: AS & VT developed the project. AS and DA performed all the experiments and the
data was analyzed by VT, AS and DA. VT wrote the manuscript with the inputs from AS and DA.
Associated content
The authors declare no competing financial interest
Supporting data
CIF is attached.
References
[1]
[2]
[3]
[4]
G.R. Desiraju, The C-H.cntdot..cntdot..cntdot.O hydrogen bond in crystals: what is it?, Acc. Chem.
Res. 24 (1991) 290–296. doi:10.1021/ar00010a002.
C.B. Aakeröy, N.R. Champness, C. Janiak, Recent advances in crystal engineering,
CrystEngComm. 12 (2010) 22–43. doi:10.1039/B919819A.
C. V Krishnamohan Sharma, R.D. Rogers, Perspectives of crystal engineering, Mater. Today. 1
(1998) 27–30. doi:https://doi.org/10.1016/S1369-7021(98)80010-2.
S. Sarkhel, G.R. Desiraju, N-H...O, O-H...O, and C-H...O hydrogen bonds in protein-ligand
complexes: strong and weak interactions in molecular recognition., Proteins. 54 (2004) 247–259.
doi:10.1002/prot.10567.
[5]
[6]
[7]
G.R. Desiraju, Hydrogen Bridges in Crystal Engineering:ꢀ Interactions without Borders, Acc. Chem.
Res. 35 (2002) 565–573. doi:10.1021/ar010054t.
P. Metrangolo, G. Resnati, Halogen Bonding: Where We Are and Where We Are Going, Cryst.
Growth Des. 12 (2012) 5835–5838. doi:10.1021/cg301427a.
B.K. Saha, A. Nangia, M. Jaskólski, Crystal engineering with hydrogen bonds and halogen bonds,

ACCEPTED MANUSCRIPT
CrystEngComm. 7 (2005) 355–358. doi:10.1039/B501693B.
[8]
M. V Vener, A. V Shishkina, A.A. Rykounov, V.G. Tsirelson, Cl...Cl interactions in molecular
crystals: insights from the theoretical charge density analysis., J. Phys. Chem. A. 117 (2013)
8459–8467. doi:10.1021/jp405119x.
[9]
A. Anthony, G.R. Desiraju, R.K.R. Jetti, S.S. Kuduva, N.N.L. Madhavi, A. Nangia, R. Thaimattam,
V.R. Thalladi, Crystal Engineering: Some Further Strategies, Mater. Res. Bull. 33 (1998) 1–18.
[10]
R. Wilcken, M.O. Zimmermann, A. Lange, A.C. Joerger, F.M. Boeckler, Principles and applications
of halogen bonding in medicinal chemistry and chemical biology., J. Med. Chem. 56 (2013) 1363–
1388. doi:10.1021/jm3012068.
[11]
[12]
J.D. Dunitz, A. Gavezzotti, How molecules stick together in organic crystals: weak intermolecular
interactions, Chem. Soc. Rev. 38 (2009) 2622–2633. doi:10.1039/B822963P.
F.F. Awwadi, R.D. Willett, K.A. Peterson, B. Twamley, The Nature of Halogen···Halide Synthons:ꢀ
Theoretical and Crystallographic Studies, J. Phys. Chem. A. 111 (2007) 2319–2328.
doi:10.1021/jp0660684.
[13]
[14]
S.K. Nayak, M.K. Reddy, T.N. Guru Row, D. Chopra, Role of Hetero-Halogen (F···X, X = Cl, Br,
and I) or Homo-Halogen (X···X, X = F, Cl, Br, and I) Interactions in Substituted Benzanilides,
Cryst. Growth Des. 11 (2011) 1578–1596. doi:10.1021/cg101544z.
N. Ramasubbu, R. Parthasarathy, P. Murray-Rust, Angular preferences of intermolecular forces
around halogen centers: preferred directions of approach of electrophiles and nucleophiles
around carbon-halogen bond, J. Am. Chem. Soc. 108 (1986) 4308–4314.
doi:10.1021/ja00275a012.
[15]
[16]
M. Capdevila-Cortada, J. Castelló, J.J. Novoa, The nature of the C–Cl⋯Cl–C intermolecular
interactions found in molecular crystals: a general theoretical-database study covering the 2.75–
4.0 Å range, CrystEngComm. 16 (2014) 8232–8242. doi:10.1039/C4CE00505H.
T.T.T. Bui, S. Dahaoui, C. Lecomte, G.R. Desiraju, E. Espinosa, The nature of halogen...halogen
interactions: a model derived from experimental charge-density analysis., Angew. Chem. Int. Ed.

ACCEPTED MANUSCRIPT
Engl. 48 (2009) 3838–3841. doi:10.1002/anie.200805739.
[17]
S. Tothadi, S. Joseph, G.R. Desiraju, Synthon Modularity in Cocrystals of 4-Bromobenzamide with
n-Alkanedicarboxylic Acids: Type I and Type II Halogen···Halogen Interactions, Cryst. Growth
Des. 13 (2013) 3242–3254. doi:10.1021/cg400735f.
[18]
[19]
[20]
[21]
M.J. Strauss, The nitroaromatic group in drug design. Pharmacology and toxicology (for
nonpharmacologists), Ind. Eng. Chem. Prod. Res. Dev. 18 (1979) 158–166.
N.A. Meanwell, Synopsis of Some Recent Tactical Application of Bioisosteres in Drug Design, J.
Med. Chem. 54 (2011) 2529–2591. doi:10.1021/jm1013693.
S. Patterson, S. Wyllie, Nitro drugs for the treatment of trypanosomatid diseases: past, present,
and future prospects, Trends Parasitol. 30 (2014) 289–298. doi:10.1016/j.pt.2014.04.003.
C.L. Walters Haygood, R.C. Arend, A. Gangrade, S. Chettiar, N. Regan, C.J.I.I. Hassmann, P.-K.
Li, B. Hidalgo, J.M.J. Straughn, D.J. Buchsbaum, Niclosamide Analogs for Treatment of Ovarian
Cancer, Int. J. Gynecol. Cancer. 25 (2015).
https://journals.lww.com/ijgc/Fulltext/2015/10000/Niclosamide_Analogs_for_Treatment_of_Ovaria
n.7.aspx.
[22]
[23]
T. Kauerova, J. Kos, T. Gonec, J. Jampilek, P. Kollar, Antiproliferative and Pro-Apoptotic Effect of
Novel Nitro-Substituted Hydroxynaphthanilides on Human Cancer Cell Lines, Int. J. Mol. Sci. . 17
(2016). doi:10.3390/ijms17081219.
M.A. Soares, J.A. Lessa, I.C. Mendes, J.G. Da Silva, R.G. Dos Santos, L.B. Salum, H.
Daghestani, A.D. Andricopulo, B.W. Day, A. Vogt, J.L. Pesquero, W.R. Rocha, H. Beraldo, N(4)-
Phenyl-substituted 2-acetylpyridine thiosemicarbazones: cytotoxicity against human tumor cells,
structure-activity relationship studies and investigation on the mechanism of action., Bioorg. Med.
Chem. 20 (2012) 3396–3409. doi:10.1016/j.bmc.2012.04.027.
[24]
S. Bawa, S. Kumar, S. Drabu, R. Kumar, Structural modifications of quinoline-based antimalarial
agents: Recent developments., J. Pharm. Bioallied Sci. 2 (2010) 64–71. doi:10.4103/0975-
7406.67002.

ACCEPTED MANUSCRIPT
[25]
[26]
V.R. Solomon, H. Lee, Quinoline as a privileged scaffold in cancer drug discovery., Curr. Med.
Chem. 18 (2011) 1488–1508.
B. d’A. Lucero, C.R.B. Gomes, I.C. de P.P. Frugulhetti, L. V Faro, L. Alvarenga, M.C.B. V de
Souza, T.M.L. de Souza, V.F. Ferreira, Synthesis and anti-HSV-1 activity of quinolonic acyclovir
analogues, Bioorg. Med. Chem. Lett. 16 (2006) 1010–1013.
doi:https://doi.org/10.1016/j.bmcl.2005.10.111.
[27]
M.M. Ghorab, F.A. Ragab, H.I. Heiba, W.M. Ghorab, Design and synthesis of some novel
quinoline derivatives as anticancer and radiosensitizing agents targeting VEGFR tyrosine kinase,
J. Heterocycl. Chem. 48 (2011) 1269–1279. doi:10.1002/jhet.749.
[28]
[29]
[30]
M.P. de Caestecker, E. Piek, A.B. Roberts, Role of Transforming Growth Factor-β Signaling in
Cancer, JNCI J. Natl. Cancer Inst. 92 (2000) 1388–1402. http://dx.doi.org/10.1093/jnci/92.17.1388.
J.L. HUPPATZ, J.N. PHILLIPS, B.M. RATTIGAN, Cyanoacrylates. Herbicidal and Photosynthetic
Inhibitory Activity, Agric. Biol. Chem. 45 (1981) 2769–2773. doi:10.1271/bbb1961.45.2769.
A. Ilangovan, P. Venkatesan, R. Ganesh Kumar, Hydrogen bonding due to regio{\-}isomerism and
its effect on the supra{\-}molecular architecture of diethyl 2-[(2/4-hy{\-}droxy{\-}anilino)methyl{\-
}idene]malonates, Acta Crystallogr. Sect. C. 69 (2013) 70–73. doi:10.1107/S0108270112047257.
[31]
[32]
Z.-Q. Feng, X.-L. Yang, Y.-F. Ye, T. Dong, H.-Q. Wang, Diethyl 2-[(4-bromo-anilino)methyl-
idene]malonate., Acta Crystallogr. Sect. E. Struct. Rep. Online. 66 (2010) o3119.
doi:10.1107/S1600536810045150.
B. Garudachari, A.M. Isloor, M.N. Satyanarayan, T. Gerber, E. Hosten, R. Betz, Diethyl 2-{[2-
(trifluoro-meth-yl)anil-ino]methyl-idene}propane-dioate, Acta Crystallogr. Sect. E. Struct. Rep.
Online. 68 (2012) o514–o515. doi:10.1107/S1600536812002590.
[33]
[34]
R.G. Gould, W.A. Jacobs, The Synthesis of Certain Substituted Quinolines and 5,6-
Benzoquinolines, J. Am. Chem. Soc. 61 (1939) 2890–2895. doi:10.1021/ja01265a088.
J.J. McKinnon, D. Jayatilaka, M.A. Spackman, Towards quantitative analysis of intermolecular
interactions with Hirshfeld surfaces, Chem. Commun. (2007) 3814–3816. doi:10.1039/B704980C.

ACCEPTED MANUSCRIPT
[35]
[36]
M.A. Spackman, D. Jayatilaka, Hirshfeld surface analysis, CrystEngComm. 11 (2009) 19–32.
M.A. Spackman, J.J. McKinnon, Fingerprinting intermolecular interactions in molecular crystals,
CrystEngComm. 4 (2002) 378–392. doi:10.1039/B203191B.

ACCEPTED MANUSCRIPT
Highlights:
Insights into supramolecular assembly formation of diethyl aryl amino methylene malonate
(DAM) derivatives assisted via non-covalent interactions
Althaf Shaik a, Deekshi Angira a, Vijay Thiruvenkatam* b
aDiscipline of Chemistry, Indian Institute of Technology Gandhinagar, Ahmedabad, India-382355
bDiscipline of Biological Engineering, Indian Institute of Technology Gandhinagar, Ahmedabad, India-
382355
* Corresponding Author: vijay@iitgn.ac.in
Hirshfeld surface mapped with curvedness and highlighting the type I Cl…Cl interaction in compound
3.