Diverse structural assemblies of a series of ninhydrin derivatives: Quantitative analyses from experimental and theoretical studies

Article abstract of DOI:10.1016/j.molstruc.2020.128920

Three ninhydrin derivatives (2–4) have been synthesized where the reaction of ninhydrin with Meldrum's acid yielded [3.3.3] propellanoid (2) and ethyl 2,2-bis (1,3-dioxo-2,3-dihydro-1H-inden-2-yl)acetate (3) while with malononitrile yielded a spiroindenopyran (4). The products being crystalline in nature and are characterized by single crystal X-ray diffraction in addition to other spectroscopic studies. X-ray crystallography reveals that solid-state structure of the title compounds exhibits C?H···π, π?π and lone-pair(l.p)···π interactions in building supramolecular assemblies. Indeed, compound (2) was stabilized through extended supramolecular C?H···π/π?π/π···H?C network whereas compounds (3) and (4) are stabilized through lone-pair (l.p)···π and π?π interaction respectively. The diverse intermolecular interactions via Hirshfeld surface analysis enables quantitative contributions to the crystal packing that exposes the similarities and differences in the interactions experienced by each compound. The distinctive energy frameworks have been calculated for individual molecules and the interaction energies suggest that the contacts are largely dispersive in nature. The binding energies associated with the non-covalent interactions observed in the crystal structures have been calculated using theoretical DFT calculations. Finally, the interplay between the interactions have been characterized by Bader's theory of “atoms-in-molecules” (AIM).

Full text of DOI:10.1016/j.molstruc.2020.128920

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Diverse structural assemblies of a series of ninhydrin derivatives:
Quantitative analyses from experimental and theoretical studies
Yeshwinder Saini , Sheena Mahajan , Kamal K. Kapoor ,
Geeta Hundal , Saikat Kumar Seth
PII:
S0022-2860(20)31245-X
DOI:
Reference:
https://doi.org/10.1016/j.molstruc.2020.128920
MOLSTR 128920
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15 July 2020
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Highlights





Newer ninhydrin derivatives have been studied.
Supramolecular self-assembly of the X-ray structure were explored in detail.
Hirshfeld surface and Energy framework analysis were performed.
DFT calculation were performed to explore the energetic features.
Bader‟s theory of “atoms-in-molecules” (AIM) have been performed.
1

Diverse structural assemblies of a series of ninhydrin derivatives:
Quantitative analyses from experimental and theoretical studies
a
a
a,
b
Yeshwinder Saini, Sheena Mahajan, Kamal K. Kapoor, * Geeta Hundal, Saikat Kumar
Seth, *
c,
a
Department of Chemistry, University of Jammu, Jammu-180 006, India
b
Department of Chemistry, Guru Nanak Dev University, Amritsar-143 005, India
c
Department of Physics, Jadavpur University, Kolkata 700032, India
Corresponding author(s) E-mail:
k2kapoor@yahoo.com (K.K. Kapoor) and
saikatk.seth@jadavpuruniversity.in (S.K.S)
Abstract: Three ninhydrin derivatives (2–4) have been synthesized where the reaction of
ninhydrin with Meldrum‟s acid yielded [3.3.3] propellanoid (2) and ethyl 2,2-bis (1,3-dioxo-2,3-
dihydro-1H-inden-2-yl)acetate (3) while with malononitrile yielded a spiroindenopyran (4). The
products being crystalline in nature and are characterized by single crystal X-ray diffraction in
addition to other spectroscopic studies. X-ray crystallography reveals that solid-state structure of
the title compounds exhibits C‒H···π, π‒π and lone-pair(l.p)···π interactions in building
supramolecular assemblies. Indeed, compound (2) was stabilized through extended
supramolecular C‒H···π/π‒π/π···H‒C network whereas compounds (3) and (4) are stabilized
through lone-pair (l.p)···π and π‒π interaction respectively. The diverse intermolecular
interactions via Hirshfeld surface analysis enables quantitative contributions to the crystal
packing that exposes the similarities and differences in the interactions experienced by each
compound. The distinctive energy frameworks have been calculated for individual molecules and
the interaction energies suggest that the contacts are largely dispersive in nature. The binding
energies associated with the non-covalent interactions observed in the crystal structures have
been calculated using theoretical DFT calculations. Finally, the interplay between the
interactions have been characterized by Bader‟s theory of “atoms-in-molecules” (AIM).
2

Keywords: Ninhydrin derivatives; Supramolecular self-assembly; Hirshfeld surface; Energy
Framework; DFT calculation; „atoms-in-molecules‟ (AIM).
1
.
Introduction
Propellanes constitute a unique class of polycyclic hydrocarbons possessing two more or
less inverted tetrahedral carbon atoms common to three bridging rings. Among these,
smaller entities have significantly weakened central single bond between the two
bridgeheads leading to unusual reactivity of these structurally fascinating propeller-like
molecules. Various biologically active natural products such as modhephene (1A)[1],
hasubanan alkaloids(1B)[2], merrilactone A (1C)[3] and periglaucine A (1D)[4] contain
propellanoid motif (Fig. 1) and so are the molecules with spiro framework having
applications as organic light-emitting diode (OLED)[5], as fluorescent probe
[
fluorescamine(1E)] (Fig. 1) for peptides, proteins and primary amines [6], anti-
bacterial[7], anti-influenza[8] and inhibitory agents against enzymatic activity of tRNA
synthetase[9]. Synthesis of propellanes and spiro compounds poses an extraordinarily
challenge for the researchers [10]. As a part of research in developing newer
methodologies for the unprecedented synthesis of newer oxygen containing heterocyclic
compounds[11], reaction of ninhydrin with active methylenes has been utilized. To
further explore the potential of this chemistry, reaction of ninhydrin with Meldrum‟s acid
and malononitrile was conceived to access propellanes and spiro heterocycles.
Fig. 1 Some significant compounds 1(A-E) containing propellane and spiro moieties.
The detailed understanding of weak interactions are essential to develop new application
in supramolecular chemistry across a variety of fields [12-15]. The properties of a crystalline
3

solid intensely depend on how the molecules are organized and the control over this organization
directs the functional properties of the material. Crystals are assembled in spontaneous process
and the recognition between set of molecules is the consequence of the mutual interaction
through various forces. Hydrogen bonding is the non-covalent interaction that usually dominates
the crystal packing due to directionality and strength [16-18]. Though hydrogen bonding has
been widely employed in crystal packing, other weaker forces involving aromatic rings are also
important players in crystal engineering [19]. For instance, C‒H···π [20], π‒π [21-24], anion···π
[
25-28] and lone-pair(l.p)···π [29-32] are commonly used to explore solid-state networks [33].
Herein, we report the X-ray characterization of three ninhydrin compounds by exploring their
supramolecular assemblies involving weak forces. The solid-state structures are described in
detail; the binding energies of the networks have been calculated using theoretical DFT
calculations. Finally, the non-covalent interactions have been characterized by using Bader‟s
theory of “Atoms in molecules” (AIM).
2
2
2
.
Experimental sections
.1. Experimental
.1.1. General procedures
All the experiments were performed in an oven dried glass apparatus. All the
commercially available reagents were purchased from Aldrich and were used without further
purification. Ultrasonication was performed on 2510 Branson Ultrasonicator. The progress of
reaction was monitored by thin layer chromatography (TLC) using silica gel pre-coated
aluminium sheets (60 F254, Merck). Visualization of spots was effected by exposure to
ultraviolet light (UV) at 365 nm and 254 nm, iodine vapours and 2% 2,4-dinitrophenylhydrazine
in methanol containing few drops of H SO and draggendroff reagent.
2
4
2
2
.1.2. Syntheses
.1.2.1. Procedure for the synthesis of (2) and (3)
A mixture of ninhydrin (0.89g, 5 mmol) and Meldrum‟s acid (2.16g, 15 mmol) was
ultrasonicated in ethanol (30 ml). After three hours ethanol was removed and the residue was
subjected to column chromatography to yield three products i.e. malonic acid (0.21g, 40%), (2)
(0.187g, 13%) and (3) (0.282g, 30%) respectively. (2) and (3) were further purified by
recrystallization with ethanol.
4

2
.1.2.2.
Procedure for the synthesis of (4A) and (4)
0.89g (5 mmol) of ninhydrin and 0.99g (15 mmol) of malononitrile were added to 70 ml
of distilled water and the mixture was stirred and boiled for 20 minutes. The solid
separated was filtered, dried and recrystallized from acetonotrile to yield two types of
crystalline products, interestingly distinguishable by color (orange and yellow). The
products were isolated manually, thereby, avoiding the use of column chromatography.
The products could also be isolated by column chromatography using gradient mixture of
ethyl acetate and petroleum ether.
2
2
.2. Characterization
.2.1. Measurements
Melting points (°C) were measured in open glass capillaries using Perfit melting point
-1
apparatus and are uncorrected. IR spectra (ν, cm ) were recorded on Perkin-Elmer FTIR
1
13
spectrophotometer using KBr discs. H and C NMR were recorded on Bruker AC-400
1
13
spectrometer operating at 400 MHz for H and 100 MHz for C with tetramethylsilane (TMS) as
13
an internal standard. All the C NMR spectra are proton decoupled. The chemical shifts are
expressed in δ (ppm) downfield from TMS. J values are given in Hertz (Hz). The abbreviations
1
s, d, t, q and m in H NMR spectra refer to singlet, doublet, triplet, quartet and multiplet
respectively. ESI-MS were recorded on Micro Mass VG-7070 H mass spectrometer. Commercial
grade solvents were dried as per established procedure before use [34]. Elemental analysis was
performed on Leco CHNS 932 analyzer. Solvents were removed using Heidolph rotary vapour.
2
.2.2. Spectroscopic measurements
2-Ethoxy-2-methyl-2H-3a,8b-(epoxyethano)indeno[1,2-b]furan-4,10(3H)-dione(2)
1
White crystalline solid (0.187g, 13% yield); Mp 295°C; H NMR (400 MHz, CD OD) δ
3
7.95-7.77 (m, 3H), 7.68- 7.60 (m, 1H), 4.17-4.07 (q, J = 8 Hz, 2H), 3.46-3.40 (d, J = 16
Hz, 1H), 3.17-3.08 (d, J = 20 Hz, 1H), 2.82-2.75 (d, J = 12 Hz, 1H), 2.49-2.42 (d, J = 12
1
3
Hz, 1H), 1.52-1.48 (s, 3H), 1.34-1.23 (m, 3H); C NMR (100 MHz, CD OD) δ 196.04,
3
1
4
73.62, 152.72, 136.83, 130.30, 125.09, 124.78, 110.61, 94.64, 89.12, 56.27, 48.26,
-
1
2.33, 21.30, 13.68. IR(KBr)ν /cm : 3400.40, 2923.71, 1795.99, 1730.98, 1046.66,
max
5

1
019.79; Anal. calcd. for C H O : C, 66.66; H, 5.59; found C, 66.42; H, 5.66; ESI-
16 16 5
+
MS(m/z): [M+H] = 289.
Ethyl 2,2-bis(1,3-dioxo-2,3-dihydro-1H-inden-2-yl)acetate (3)
1
White crystalline solid (0.282g, 30% yield); Mp 198-200 °C; H NMR (400 MHz, CDCl ) δ
3
8
.06-7.98 (d, J = 7.4 Hz, 2H), 7.94-7.74 (m, 6H), 4.23-4.19 (t, 1H, J = 4 Hz), 4.18-4.10 (q, 2H, J
13
=
8 Hz), 3.72-3.65 (d, 2H, J = 4 Hz) 1.16-1.08 (t, 3H, J = 8 Hz); C NMR (100 MHz, CDCl ) δ
3
1
1
4
3
98.24, 196.62, 170.68, 142.48, 141.47, 135.75, 135.27, 123.36, 123.24, 62.01, 51.35, 40.43,
-1
3.72.IR(KBr)ν /cm : 3443.45, 1748.25, 1711.22; Anal. calcd. for C H O :C, 70.21; H,
max
22 16
6
+
+
+
.29; found C, 70.35; H, 4.19; ESI-MS(m/z) : [M+H] = 377, [M+Na] = 399, [M-COOEt] =
03.
2
-(1,3-Dioxo-1H-inden-2(3H)-ylidene)malononitrile (4A). Yellow colored crystalline solid
1
0(d) 1
(
0.74g, 71% yield): mp 267-268°C (lit. 267-268°C) ; H NMR (400 MHz, DMSO-d ) δ 8.07-
6
1
3
7
1
6
.98 (m, 4H); C NMR (100 MHz, DMSO-d ) δ 182.47, 152.51, 141.75, 137.91, 128.34,
6
-
1
-1
24.55, 110.42, 88.80; IR(KBr)ν /cm : 1705.05, 1618.90 cm ; Anal. calcd. for C H N O :C,
max
12
4
2
2
9.24; H, 1.94; N, 13.46; O, 15.37; found C, 69.35; H, 1.85; N, 13.52; O, 15.21; ESI-MS (m/z) :
+
[
M+H] , 209.
2
'-Amino-1,3,5'-trioxo-1,3-dihydro-5'H-spiro[indene-2,4'-indeno[1,2-b]pyran]-3'-carbonitrile
1
3 1
(
4). Orange colored crystalline solid (0.16g, 18% yield): mp 259°C (lit. 255-260°C) ; H NMR
(
400 MHz, DMSO-d ) δ 8.14 (d, J = 6.6 Hz, 2H), 8.02 – 7.87 (m, 4H), 7.73 (d, J = 8.6 Hz, 2H),
6
1
3
6
1
1
.95 (d, J = 8.6 Hz, 12H), 3.79 (s, 2H); C NMR (100 MHz, DMSO-d ) δ 194.80, 189.97,
6
77.03, 150.72, 147.46, 138.22, 134.06, 132.37, 131.57, 131.11, 130.81, 130.48, 129.26, 127.88,
-
1
26.79, 126.07, 125.94, 125.04, 124.65, 75.36, 57.03; IR(KBr)ν /cm : 3435.90, 1635.83;
max
Anal.calcd. for C H N O :C, 71.19; H, 2.84; N, 7.91; O, 18.06; found C, 70.35; H, 2.38; N,
2
1
10
2
4
+
7
.46; O, 17.95; ESI-MS (m/z) : [M+H] , 355.
2
.2.3. X-ray crystal structure determination
Single crystal X-ray data of compounds (2–4) were collected on a Bruker Kappa Apex-II
diffractometer at room temperature with Mo-Kα radiation ( = 0.71073 Å). Data reduction was
carried out using the program Bruker SAINT [35] and an empirical absorption correction was
applied based on the multi-scan method [36]. The structures of the title compounds were solved
6

2
by the direct method and refined by the full-matrix least-square technique on F using the
programs (SHELXS-14) [37] and (SHELXL-18) [38] respectively. All the non-H atoms were
treated anisotropically and all H atoms were attached geometrically. The summary of crystal data
and relevant structure refinement parameters of the title compounds are given in Table 1. CCDC
1
900911, 1900913 and 1900912 contain the supplementary crystallographic data of compounds
(2‒4) respectively.
Table 1. Crystal data and structure refinement parameters for the title compounds.
7

Structure
(2)
(3)
22 16
(4)
21 10
Empirical formula
Formula Weight
Temperature (K)
Wavelength (Å)
Crystal system
space group
C H O
C H O
C H N O
16
16
5
6
2
4
288.29
295(2)
0.71069
376.36
296(2)
0.71073
354.31
296(2)
0.71073
Monoclinic
Monoclinic
Monoclinic
P2 /c
P2 /n
P2 /c
1
1
1
a, b, c (Å)
11.997(3), 7.549(4), 13.561(5), 9.021(4), 10.2703(7),
16.365(5)
14.700(7)
16.8077(9),
.5361(6)
9
α, β, γ (°)
90, 109.597(5), 90
1396.3(9)
4 / 1.371
90, 94.872(15), 90
1791.8(13)
4 / 1.395
90, 104.813(2), 90
1591.41(17)
4 / 1.479
3
Volume (Å )
Z / Density (calc.)
3
(
Mg/m )
Absorption coefficient
0.102
0.102
0.105
-
1
(
mm )
F(000)
608
784
728
3
Crystal size (mm )
Limiting indices
0.15 × 0.12 × 0.08
-14<=h<=14,
0.13 × 0.11 × 0.06
-16<=h<=16,
-10<=k<=10,
-17<=l<=17
20077 / 3250
0.14 × 0.08 × 0.06
-13<=h<=13,
-15<=k<=22,
-10<=l<=12
14597 / 3753
-
8<=k<=7,
-
18<=l<=19
Reflections collected /
unique
Completeness to θ (%)
Absorption correction
8890 / 2488
98.6
98.9
99.8
Semi-empirical from Semi-empirical from Semi-empirical from
equivalents
0.998 and 0.978
equivalents
0.998 and 0.979
equivalents
0.999 and 0.976
Max. and min.
transmission
Refinement method
Full-matrix least-
Full-matrix least-
Full-matrix least-
2
2
2
squares on F
squares on F
squares on F
Data / parameters
Goodness-of - fit on F
Final R indices [I > 2σ(I)] R = 0.0378, wR =
2488 / 190
0.909
3250 / 254
3753 / 0 / 250
1.040
2
0.968
R = 0.0702, wR =
R = 0.0427, wR =
1
2
1
2
1
2
0.0874
0.1856
0.1032
R indices (all data)
R = 0.0641, wR =
R = 0.1650, wR =
R = 0.0593, wR =
1
2
1
2
1
2
0.1053
0.2906
0.1138
Largest diff. peak and
0.148 and -0.190
0.485 and -0.431
0.238 and -0.245
-3
hole (e.Å )
2
2 2
2 2 1/2
2
2
o
2
R = ∑||F |–|F ||/∑|F |, wR = [∑{(F –F ) }/∑{w(F ) }] , w = 1/{σ (F ) + (aP) + bP}, where a =
1
o
c
o
2
o
c
o
0
=
.0441 and b = 0.9039 for (2), a = 0.1499 and b = 0.0000 for (3) and a = 0.0556 and b = 0.3000 for (4). P
(F + 2F )/3 for all structures.
o c
2 2
2
.2.4. Hirshfeld surface analysis
Molecular Hirshfeld surface [39-42] is generated based on the electron distribution of the
molecule and that have been calculated as the sum of spherical atom electron densities [43-44].
Hirshfeld surface is unique for a given crystal structure and a set of spherical atomic electron
densities [45]. The normalized contact distance (dnorm) is based on d , d and the vdW radii of the
e
i
atom. The distance d is defined as the distance from the point to the nearest nucleus external to
e
8

the surface, and d is the distance to the nearest nucleus internal to the surface. The 2D
i
fingerprint plot (based on d and d ) provides summary of intermolecular contacts in the crystal
e
i
[
45-47]. To explore the intermolecular interaction topology, we have performed the “energy
framework analysis” using Crystal Explorer program [48]. The energy framework was
constructed based on the crystal symmetry, in which we have used B3LYP/6-31G(d,p) molecular
wave functions to estimate the interaction energies. The pair-wise interaction energy within the
crystal have been calculated by summing up the electrostatic (E ), polarization (E ), dispersion
ele
pol
(
E ) and exchange-repulsion (E ) terms based on the scaling factors. The sum of the energy
dis rep
components (E ) for the investigating molecules are scaled following the energy model [49].
tot
Other information like rotational symmetry operations (Symop), centroid-to-centroid distance
(R) and number of pair(s) of interacting molecules (N) are also calculated for colour-coded
interaction mapping. The individual energy components of the energy framework are depicted
as cylinders where the radius of the cylinders are proportional to the magnitude of the interaction
energy [50]. The energy components corresponding to electrostatic (E ), dispersion (E ) and
ele
dis
total energy (E ) are represented in red, green and blue color-codes respectively.
tot
2
.2.5. Theoretical Methods
The binding energies of the title compounds included herein were performed using
Gaussian 09 calculation package [51] at the B3LYP level with a large basis set 6-311++G(d,p).
The visualization of the results are accomplished with GaussView 6.0. The crystallographic
coordinated have been used for the theoretical analysis of the non-covalent interactions present
in the solid-state structures of (2‒4). The Bader‟s "Atoms in molecules" theory [52] has been
used to investigate the interactions studied herein by means of the AIMall calculation package
[
(
53]. The topological properties of the charge density (ρ(r)) characterized by their critical points
2
CPs) and its Laplacian which is expressed in terms of L(r) = – ∇ (ρ(r)) were calculated using
the Atom In Molecule (AIM) theory [54]. It is noted that electron density is concentrated where
2
2
∇
(ρ(r)) < 0 and it is depleted where ∇ (ρ(r)) > 0. Gaussian09 calculation package [51] has been
used for wave function analysis.
3
.
Results and discussion
3
.1. Reaction of ninhydrin with Meldrum's acid
9

In continuation to our earlier work [11] that yielded unprecedented products by the
reaction of ninhydrin with active methylenes on ultrasonic-irradiation, we wished to carry out the
reaction of ninhydrin with Meldrum's acid. Ninhydrin was reacted with Meldrum‟s acid under
ultrasonic-irradiation in ethanol. After 5 hours all the ninhydrin was consumed. Ethanol was
removed and the residue after column chromatography gave three products (Scheme 1). The
most polar product was found to be malonic acid. The remaining two products were obtained in
crystalline form after recrystallization with ethanol. The less polar product was found to be ethyl
2
,2-bis(1,3-dioxo-2,3-dihydro-1H-inden-2-yl)acetate (3) whereas the third polar product was
found to be 2-ethoxy-2-methyl-2H-3a,8b-(epoxyethano)indeno[1,2-b]furan-4,10(3H)-dione (2)
as revealed by X-ray data.
Scheme 1. Ultrasound-assisted reaction of ninhydrin with Meldrum‟s acid.
3
.2. Reaction of ninhydrin with malononitrile
The reaction of ninhydrin with malononitrile is known to yield the single Knoevenagel
product (4A) [55]. When we carried out a reaction between ninhydrin and malononitrile (1:3
ratio) using water as solvent, in addition to the Knoevenagel product (4A) (71%), we obtained
an unexpected spiroindenopyran (4) (18%) (Scheme 2). The two products were obtained in
crystalline form - the crystals of product (4A) were large block shaped and yellow in colour
whereas crystals of product (4) were small and slightly orange in colour (Fig. S1). In our first
attempt, the products were isolated manually using a spatula and forceps based on colour
distinction, thus avoiding column chromatography. However, in our second attempt the products
were successfully isolated by column chromatography.
1
0

Scheme 2. Reaction between ninhydrin and malononitrile
.3. X-ray structural description of the title compounds
3
3
.3.1. Structural description of (2)
The molecular view of compound (2) is included in Fig. 2a with atom numbering scheme.
The solid-state structure of (2) is stabilized through C‒H···π and π‒π interactions (Tables 2, 3).
No classical hydrogen bonding interaction is observed for the title compound. The molecular
packing in (2) is such that the π‒π stacking between the aryl rings of adjacent parent and partner
molecules are optimized [21-24].The aryl rings (C1‒C6) of the molecule at (x, y, z) and (-x, -y,
1
-z) are essentially parallel, with an interplanar spacing of 3.795(1)Å, and a ring centroid
separation of 4.181Å, corresponding to a ring offset of 1.753Å. The combination of
intramolecular C‒H···π and intermolecular π‒π stacking interactions generates C‒H···π/π‒
π/π···H‒C network in (2) (Fig. 2b).
Fig. 2 (a) ORTEP view and atom numbering scheme of compound (2) with the displacement
ellipsoid at the 30% probability level; (b) Cooperativity of weak interactions in building
extended supramolecular network in (2).
1
1

3
.3.2. Structural description of (3)
Despite the similarity between compounds (2) and (3) in terms of their overall
constitutions and molecular geometries, there are some significant differences in the nature of
their supramolecular aggregation. The molecular view of compound (3) is depicted in Fig. 3a.
Compound (3) is stabilized through C‒H···O hydrogen bonds and lone-pair(l.p)···π interactions.
Due to the self-complementary nature, the carbon atom C(8) acts as donor to the carbonyl
2
oxygen atom O(3) in the molecule at (2-x, -y, 2-z), so generating a centrosymmetric R (12)
2
dimeric ring centered at (1, 0, 1) (Fig. S2). Additional reinforcement between C15 and O4 in the
molecule at (x, y, z) and (3/2-x, -1/2+y, 3/2-z) leads the molecules to generate a two-dimensional
supramolecular framework in (110) plane (Fig. S2). In another substructure, the centrosymmetric
dimeric rings are interconnected through C(21)‒H(21)···O(6) hydrogen bonds to generate
another supramolecular layered assembly in (101) plane (Fig. S3). In another substructure, the
carbonyl oxygen atom is oriented towards the π-face of aryl ring (C1-C6) in the molecule at (2-x,
1
3
-y, 2-z) with a separation distance of 3.844(5)Å, suggesting lone-pair(l.p)···π interaction [30-
1]. Due to the self-complementarity, two molecules are juxtaposed through lone-pair(l.p)···π
interaction by generating a centrosymmetric synthon. Moreover, another carbonyl oxygen atom
O(6) is also interacting with the π-face of aryl ring at (3/2-x, 1/2+y, 3/2-z). Therefore, the
additional reinforcement of lone-pair(l.p)···π interactions leads the molecules to generate a
supramolecular layered assembly (Fig. 3b).
Table 2. Relevant hydrogen bonding parameters.
D–H···A
D–H
H···A
D···A
D–H···A
Symmetry
Compound (2)
C(14)–H(14C)∙∙∙Cg(4)
0.93
2.99
3.841(4)
148
x, y, z
Compound (3)
C(8)–H(8)···O(3)
C(8)–H(8)···O(3)
C(15)–H(15)···O(4)
C(21)–H(21)···O(6)
0.98
0.98
0.98
0.93
2.59
2.45
2.33
2.59
3.249(6)
125
152
141
137
x, y, z
2-x, -y, 2-z
3/2-x, -1/2+y, 3/2-z
1/2+x, 1/2-y, -1/2+z
3.350(6)
3.154(6)
3.324(7)
Compound (4)
N(1)–H(1A)···O(1)
N(1)–H(1B)···O(4)
C(20)–H(20)∙∙∙O(4)
0.84
0.86
0.93
2.252
2.178
2.59
3.0833(17)
3.0271(18)
3.428(2)
170
170
151
1-x, -1/2+y, 1/2-z
x, 1/2-y, -1/2+z
2-x, 1-y, 1-z
Cg(4) is the centroid of (C1‒C6) ring.
1
2

Fig. 3 (a) ORTEP view and atom numbering scheme of compound (3) with the displacement
ellipsoid at the 30% probability level; (b) Perspective view of the supramolecular network
generated through lone-pair(l.p)···π interactions in (3).
Table 3. Geometrical parameters (Å, °) for π-stacking interactions.
a
b
c
d
e
f
g
Rings i‒j
Compound (2)
Rc
R1v
-3.7952(10) -3.7952(10)
-3.3619(6) -3.3619(6)
R2v
α
β
γ
Slippage
1.753
(i)
Cg(4)‒Cg(4)
Compound (4)
Cg(5)‒Cg(5)
4.181(3)
4.144(1)
0.00
0.00
24.79 24.79
35.78 35.78
(ii)
2.423
a
[
Symmetry code: (i) (-x, -y, 1-z); (ii) (x, ½-y. -1/2+z)] Cg(4) and Cg(5) are the centroids of the (C1−C6)
and (C14/C15/C17−C20) rings, respectively. Centroid distance between ring i and ring j. Vertical
distance from ring centroid i to ring j. Vertical distance from ring centroid j to ring i. Dihedral angle
between the first ring mean plane and the second ring mean plane of the partner molecule. Angle between
b
c
d
e
f
g
centroids of first ring and second ring mean planes. Angle between the centroid of the first ring and the
normal to the second ring mean plane of the partner molecule.
1
3

3
.3.3. Structural description of (4)
The molecular view of compound (4) is shown in Fig. 4a. We have re-determined the X-
ray structure [56] to quantify the non-covalent interactions in the context of crystal engineering.
The title structure is stabilized through N‒H···O, C‒H···O hydrogen bonds, π‒π interactions
(Tables 2-3). The aryl ring carbon atom C(20) acts as donor to the carbonyl oxygen atom O(4) in
2
the molecule at (2-x, 1-y, 1-z), so generating a centrosymmetric R (10) dimeric ring centered at
2
(1, ½, ½) (Fig. S4). In both side of this dimeric ring, the amine nitrogen atom N1 acts as donor to
the carbonyl oxygen atom O1 at (1-x, -1/2+y, 1/2-z); thus generating a two-dimensional
supramolecular framework in (110) plane (Fig. S4). In another substructure, the dimeric ring
motif leads the molecules to generate an infinite chain along [001] direction (Fig. S5). Due to the
self-complementarity, the parallel chains are interconnected through hydrogen bonding
interaction where the amine nitrogen atom acts as donor to the carbonyl oxygen atom of the
centrosymmetric ring motif. Therefore, another two-dimensional supramolecular framework is
generated in the (011) plane (Fig. S5). Finally, the molecules are juxtaposed through weak π‒π
stacking interactions. The aryl rings (C14/C15/C17−C20) of the molecule at (x, y, z) and (x, ½-y,
-1/2+z) are juxtaposed, with an interplanar spacing of 3.362(1)Å, and a ring centroid separation
of 4.144Å, corresponding to a ring offset of 2.423Å (Fig. 4b).
1
4

Fig. 4 (a) ORTEP view and atom numbering scheme of compound (4) with the displacement
ellipsoid at the 30% probability level; (b) Partial view of the X-ray solid-state structure of
compound (4).
3
.4. Hirshfeld surface
The pattern of the intermolecular interactions of the solid-state structure of compounds
2‒4) prompted us to explore and quantify the contribution of the non-covalent interactions. In
(
the present study, we have evaluated the contacts that are responsible in building supramolecular
assembly. The Hirshfeld surface of the title compounds are illustrated in Fig. 5 showing surfaces
that have been mapped over dnorm [in the ranges (-0.025 to 1.504Å) in (2); (-0.268 to 1.221Å) in
(3) and (-0.446 to 1.324Å) in (4)] and shape-index [-1.000 to 1.000Å for all compounds]. The
intermolecular interactions summarized in Tables 2‒3 are mostly evident by the Hirshfeld
surfaces. For instance, the distinct circular depressions on the dnorm surface indicates the
hydrogen bonding contacts whereas other small visible spots are due to short contacts. The π‒π
stacking has been examined and verified by the shape-index surface. The intermolecular
interactions involved within the structures are also visible on the 2D fingerprint plots that can be
decomposed to quantify individual contributions of intermolecular interactions (Figs. S6‒S8).
The distinct spikes in the full fingerprint plot of all compounds designates O···H and H···O
contacts. The percentage of contacts of O···H/H···O interactions of the title compounds varies
from 23.0% in (4) to 37.4% in (2). The spikes in the (d , d ) region of (1.417Å, 1.121Å),
i
e
(1.282Å, 0.966Å) and (1.171Å, 0.831Å) designate the O···H/H···O interaction in (2‒4)
respectively.
The C···H/H···C interactions appears as spoon like tips and comprises 4.3%, 18.7% and
4.2% of the total Hirshfeld surface area of (2‒4) respectively (Figs. S6‒S8). The spoon like tips
in (2), sharp edged spike in (3) and spike in (4) in the (d , d ) region of (1.697Å, 1.557Å),
2
i
e
(
1.763Å, 1.517Å) and (1.833Å, 1.552Å) designates C···O/O···C interactions which comprises of
.8%, 6.5% and 5.3% to the total Hirshfeld surface area of the molecules (Figs. S6‒S8). In
compound (4), the N···H and H···N interactions are appeared in the (d , d ) region of (1.432Å,
1
i
e
1
.071Å) of the fingerprint plot (Fig. S8).
1
5

Fig. 5 Hirshfeld surfaces mapped with dnorm (left column) (a‒c) and shape-index (right
column) (d‒f) of the title compounds ( 4).
2
‒
The adjacent red and blue triangles (highlighted by red circles) on the shape-index figures
(Fig. 5) of compound (2) and (4) indicates that the molecules are related to one another by π‒π
stacking interactions [57-59]. The red and blue triangles on the shape index figures characterized
the face-to-face π-stacking interaction and in agreement with the geometrical parameters
obtained from X-ray structural studies. The scattered points in the breakdown fingerprint plot
show that the π‒π stacking interactions comprises 3.2%, 1.4% and 4.7% in (2‒4) to the total
Hirshfeld surface area of the molecules. In (3), the breakdown fingerprint plot shows that π‒π
stacking comprises only 1.4% but there is no signature on the shape-index surface. Therefore, it
can be concluded that the contributions comes from C···C close-contacts only. The scattered
points that are displayed as blue/green colour on the diagonals of the fingerprint plots (Figs. S6‒
S8) at around d =d = 1.697Å, d =d = 1.818Å and d =d = 1.692Å in (2‒4) respectively. The d
i
e
i
e
i
e
norm
surfaces are also decomposed corresponding to various interactions involved within the
structures of (2‒4) that are included in Figs. S9‒S11. Another significant contribution comes
from H···H contacts that contributed 52.9%, 39.6% and 21.3% to the total Hirshfeld surface area
of in (2‒4) respectively. The difference between the molecular interactions due to H···H contacts
1
6

are reflected in the distribution of scattered points of the fingerprint plots (Figs. S6‒S8), which
spread only up to d =d = 1.136Å, d =d = 1.086Å and d =d = 1.232Å in (2‒4) respectively.
i
e
i
e
i
e
Fig. 6 The colour-coded interaction mapping for the clusters within 3.8 Å of the compounds (2-
) (a–c) and the parameters for lattice energy calculations are illustrated in (d–f) for compounds
2-4) respectively (CHANGE COMPOUND CODES IN THE FIGURE).
4
(
1
7

Fig. 7 Energy framework of compounds (2–4) (a-c) as viewed down b-axis showing the
electrostatic potential force (left column), dispersion force (middle column) and total energy
(right column) diagrams. The cylindrical radii are proportional to the relative strength of the
corresponding energies and they were adjusted to the same scale factor of 80 with a cut-off value
of 5 kJ/mol within 2 × 2 × 2 unit cells.
For better understanding of the molecular contacts that are involved within the structures,
we have calculated the interaction energies by mapping the structure-cluster within 3.8 Å in a
colour-coded molecular cluster related to the specific interaction energy (Fig. 6a-c). The
interaction energies of the available contacts i.e., the energy components (E , E , E and E )
ele
pol
dis
rep
in addition to the sum of energy components (E ) for the interactions relative to the reference
tot
molecule (based on the colour scheme) for compounds (2–4) are included in Fig. 6 (d-f).
Moreover, other parameters for lattice energy calculations such as rotational symmetry
1
8

operations with respect to the reference molecule (Symop), intercentroid distance between the
reference molecule and interacting molecules (R), number of pair(s) of interacting molecules
with respect to the reference molecule (N) have been included in Fig. 6(d-f). We have performed
the energy frameworks to investigate the overall topology of the energy distribution of (2‒4) by
using the scale factor 80 with a cut-off energy value of 5 kJ/mol (Fig. 7). In all compounds, the
dispersion force dominates the electrostatic potential force. The dispersion forces in compounds
(2) and (3) dominate the calculation shows that the electrostatic force attributed to the weak H-
bonds. In compound (4), the electrostatic force attributed to the strong N–H···O interactions and
are also dominated by the dispersion forces. The dispersion force co-exists with the main energy
framework due to π–π interactions that facilitated to endure the molecular packing of the title
compounds. The energy frameworks (Fig. 7) indicates their overall participation in distinct
modes of supramolecular association.
3
.5. Theoretical calculations
To analyze the non-covalent interactions described above for compounds (2‒4), we have
performed theoretical DFT study focusing on the energetic features of the interactions. For the
calculations, the crystallographic coordinates have been used and the fragments are modified to
evaluate the contributions of different interactions. Following the self-assembled structure (Fig.
2
b) of compound (2), we have shown two simplified models (see the red arrow in Fig. S12). The
first theoretical model is simplified to avoid intramolecular C‒H···π interaction and to evaluate
the formation energy only. In first model, the binding energy corresponding to weak π‒π
stacking interaction is ΔE = -0.2 kcal/mol (Fig. S12).
1
For compound (3), we have prepared three simplified models (see red arrows in Fig. 8) to
evaluated weak hydrogen bonds and lone-pair(l.p)···π interaction. In the second model (Fig. 8a)
the interaction energy for C(15)–H(15)···O(4) bond is ΔE = -1.3 kcal/mol. In another model, we
2
have estimated the formation energy of the centrosymmetric dimer generated through the
hydrogen bond C(8)–H(8)···O(3). The interaction energy of the dimeric unit is ΔE = -3.6
3
kcal/mol (Fig. 8b). Therefore, the formation energy corresponding to one C(8)–H(8)···O(3)
hydrogen bond is ΔE ʹ = -3.6/2 = -1.8 kcal/mol which is more favourable than C(15)–
3
H(15)···O(4) hydrogen bond (ΔE = -1.3 kcal/mol). The formation energy corresponding to lone-
2
pair(l.p)···π interaction is ΔE = -1.0 kcal/mol (Fig. 8c).
4
1
9

Fig. 8 Theoretical models of compound (3) and their interaction energies. Distances in Å.
In Fig. 9, we show the theoretical models to estimate the binding energies in compound
(
4). The binding energy of the C‒H···O bonded centrosymmetric dimer is ΔE = -4.5 kcal/mol
5
and is more favorable than the dimer formed in compound (3) (ΔE = -3.6 kcal/mol). We also
3
calculated the formation energies for N‒H···O hydrogen bonds where an amine nitrogen atom is
in contact with two carbonyl oxygen atoms and the models are included in Figs. 9b and 9c
respectively. The interaction energy corresponding to the models are -4.1 kcal/mol and -2.9
kcal/mol. Therefore, the N‒H···O hydrogen bond of the theoretical model (Fig. 9b) is much
more favorable compare to the model included in Fig. 9c.
2
0

Fig. 9 Theoretical models of compound (4) and their interaction energies. Distances in Å.
We have further analyzed the self-assembled dimers of compounds (2‒4) using Bader‟s
theory of “atoms in molecules” (AIM), to provide additional insight on the non-covalent
interactions. The AIM analysis provides an unambiguous definition of chemical bonding and
therefore used to visualize and characterize non-covalent interactions following the distribution
of bond paths and bond critical points (CPs) [52]. Following the X-ray structure described above,
the C‒H···π interaction is characterized by the CP (ρBCP = 0.0037 a.u.) and the bond path
connecting the methyl hydrogen and carbon atom of the aryl ring (Fig. 10a). Again in Fig. 10a,
the CP(ρBCP = 0.0030 a.u.) and the bond path connecting the carbon atoms of the aryl rings of
parent and partner molecule characterizes π‒π stacking interaction in (2). In compound (3), the
lone-pair···π interaction is characterized by the bond path connecting carbonyl oxygen and aryl
ring carbon atoms (Fig. 10b) and the CP (ρBCP = 0.0025 a.u.). Finally, the face-to-face π‒π
stacking in (4) is characterized by the CP (ρBCP = 0.0067 a.u.) and bond path connecting two
carbon atoms of the aryl rings of parent and partner molecules (Fig. 10c).
2
1

Fig. 10 AIM analysis of the self-assembled dimers retrieved from the X-ray structure of
compound (2) (a), compound (3) (b) and compound (4) (c). Red and yellow spheres represent the
bond and ring critical points, respectively. The bond path connecting the bond critical points are
represented by dashed lines. The values of the ρ(r) at the bond critical points are given in atomic
units (a.u.).
4
.
Conclusions
In summary, three new ninhydrin derivatives have been synthesized and structurally
characterized by single-crystal X-ray diffraction. They participate in unprecedented cooperative
C–H···π, π‒π and lp···π interactions that generates extended supramolecular frameworks. A
comparison of the Hirshfeld surfaces of the title compounds have been presented which reveals
that more than two-third of the close contacts are associated with weak noncovalent interactions.
The interaction energy calculations showed that the contacts between the molecules are largely
2
2

dispersive in nature and that are verified by the energy framework of the molecules. The
intermolecular interactions have been evaluated using theoretical calculations and AIM analyses
that confirm the existence of the interactions. Furthermore, the computational study estimated the
contribution of noncovalent interaction to the self-assembly process by providing individual
energy values to them. These π-facial interactions in ninhydrin derivatives might have potential
importance in the field of drug design and supramolecular chemistry.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
S. K. Seth gratefully acknowledges the financial support from SERB (NewDelhi) India,
for Research Project (EEQ/2019/000384). The financial support from the RUSA 2.0
programme of Jadavpur University is also acknowledged.
Supplementary information
CCDC 1900911, 1900913 and 1900912 contain the supplementary crystallographic data
of compounds (2‒4) respectively. These data can be obtained free of charge via
http://www.ccdc.cam.ac.uk/conts/retrieving.html, or from the Cambridge Crystallographic Data
Centre,12 Union Road, Cambridge CB21EZ, UK; fax: (+44) 1223-336-033; or E-
mail:deposit@ccdc.cam.ac.uk. The full and breakdown fingerprint plots are included as
supplementary data.
Credit Author Statement
Kamal K. Kapoor gave the planning of the synthesis of the compounds, Yeshwinder Saini and
Sheena Mahajan synthesized the compounds and other physico-chemical experiments. Geeta
Hundal solved the structures. Saikat Kumar Seth, Yeshwinder Saini and Kamal K. Kapoor
analyzed the data. Saikat Kumar Seth contributed performing the theoretical calculations; Saikat
Kumar Seth and Yeshwinder Saini wrote the paper.
2
3

Declaration of Interest Statement.
The authors declare no competing financial interest.
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