Crystal Packing Modulation of the Strength of Resonance-Assisted Hydrogen Bonds and the Role of Resonance-Assisted Pseudoring Stacking in Geminal Amido Esters: Study Based on Crystallography and Theoretical Calculations

Article abstract of DOI:10.1021/acs.cgd.0c01010

A detailed experimental and theoretical investigation of a series of substituted geminal amido esters (ethyl (2E)-3-(arylamino)-2-(arylcarbamoyl)prop-2-enoate, AME-1-8) leading to the identification of a unique angularly fused pseudotricyclic (S(6),S(6),S(6)) ring system stabilized by an intramolecular resonance-assisted hydrogen bond (RAHB) and a non-RAHB are presented in addition to weak intermolecular interactions. An analysis of X-ray and theoretical models reveals that the strength of the intramolecular RAHB (N1-H1N···O1) varies in a wide range (6.9-11.4 kcal mol-1) due to crystal-packing constraints arising from different aromatic ring substitutions. However, the effect is less significant and the strength differs only in a narrow range (8.2-9.9 kcal mol-1) in the case of non-RAHB. The downfield shift (δ～12.3) observed for the N-Haniline signal in 1H NMR spectra of AME-1-8 is due to the presence of intramolecular RAHB. A PIXEL energy analysis suggests that the molecular dimer formed by stacking of RAHB pseudorings is found to be strong (Etot = -14.4 to -17.9 kcal mol-1), and this dimer forms the basic motif in most of the structures reported herein. A detailed analysis of the isostructurality suggests that the basic motif exists in most of the structural combinations. The weak intermolecular C-H···O, C-H···Cl, and C-H···πinteractions play a vital role in the stabilization of these crystal structures, as evaluated by PIXEL and Bader's quantum theory of atoms in molecules approach (QTAIM). A lattice energy analysis suggests that the Coulombic contribution and total lattice energies are higher in the para-substituted compounds (AME-2, AME-5, and AME-8) in comparison to the other isomeric compounds. Further, the crystal packing of these compounds is analyzed on the basis of the energy frameworks. It shows that most of the crystals show similar 3D topologies, suggesting that these compounds may have similar mechanical behavior.

Full text of DOI:10.1021/acs.cgd.0c01010

pubs.acs.org/crystal
Article
Crystal Packing Modulation of the Strength of Resonance-Assisted
Hydrogen Bonds and the Role of Resonance-Assisted Pseudoring
Stacking in Geminal Amido Esters: Study Based on Crystallography
and Theoretical Calculations
Perumal Venkatesan, Subbiah Thamotharan,* M. Judith Percino, and Andivelu Ilangovan*
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ABSTRACT: A detailed experimental and theoretical investigation of a series of substituted geminal amido esters (ethyl (2E)-3-
(arylamino)-2-(arylcarbamoyl)prop-2-enoate, AME-1−8) leading to the identification of a unique angularly fused pseudotricyclic
(S(6),S(6),S(6)) ring system stabilized by an intramolecular resonance-assisted hydrogen bond (RAHB) and a non-RAHB are
presented in addition to weak intermolecular interactions. An analysis of X-ray and theoretical models reveals that the strength of the
intramolecular RAHB (N1−H1N···O1) varies in a wide range (6.9−11.4 kcal mol−1) due to crystal-packing constraints arising from
different aromatic ring substitutions. However, the effect is less significant and the strength differs only in a narrow range (8.2−9.9
kcal mol−1) in the case of non-RAHB. The downfield shift (δ ∼12.3) observed for the N−Haniline signal in 1H NMR spectra of AME-
1−8 is due to the presence of intramolecular RAHB. A PIXEL energy analysis suggests that the molecular dimer formed by stacking
of RAHB pseudorings is found to be strong (Etot = −14.4 to −17.9 kcal mol−1), and this dimer forms the basic motif in most of the
structures reported herein. A detailed analysis of the isostructurality suggests that the basic motif exists in most of the structural
combinations. The weak intermolecular C−H···O, C−H···Cl, and C−H···π interactions play a vital role in the stabilization of these
crystal structures, as evaluated by PIXEL and Bader’s quantum theory of atoms in molecules approach (QTAIM). A lattice energy
analysis suggests that the Coulombic contribution and total lattice energies are higher in the para-substituted compounds (AME-2,
AME-5, and AME-8) in comparison to the other isomeric compounds. Further, the crystal packing of these compounds is analyzed
on the basis of the energy frameworks. It shows that most of the crystals show similar 3D topologies, suggesting that these
compounds may have similar mechanical behavior.
Among them, the RAHB is the most frequent concept used in
structural chemistry.6,9−14 It was first proposed by Gilli et
al.9,10 in the late 1980s. The RAHB is stronger and significantly
shorter than the conventional hydrogen bond (HB), observed
INTRODUCTION
■
Instituting novel hydrogen-bonding networks is central to
supramolecular design in organic, coordination, and organo-
metallic compounds. Since the introduction of “The Hydrogen
Bond” in 1920 by Latimer and Rodebush, 100 years have
passed and its imperative role in many areas of chemistry
continues.1 During the past few decades, different types of
hydrogen bonds (HBs), i.e. (i) charge-assisted hydrogen bonds
(CAHBs),2−4 low-barrier hydrogen bonds (LBHBs),5,6 dihy-
drogen bonds (DHBs),7,8 and resonance-assisted hydrogen
bonds (RAHBs)9,10 have been identified and investigated.11
Received: July 21, 2020
Revised: December 13, 2020
Published: December 29, 2020
https://dx.doi.org/10.1021/acs.cgd.0c01010
© 2020 American Chemical Society
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Scheme 1. Synthesis of Ethyl (2E)-3-(Arylamino)-2-(arylcarbamoyl)acrylate (AME-1−8)
among neutral molecules showing O−H···O/N−H···O inter-
actions conjugated with multiple π-bonds. The unusual
stabilization energy for the RAHB is attributed to partial
delocalization of the π-electrons along with their respective HB
systems.7 This simple and powerful concept of RAHB finds
significant use in synthetic transformations, the design of
chelating pockets for coordination, molecular recognition, the
design of molecular switches, and crystal engineering, among
many other applications in organic chemistry.1 Further, the
(R)-binol-based chiral aldehydes which form RAH-bonded
imines with amino acids have been developed and used as shift
reagents.15 In addition, the same (R)-binol-based compounds
have been used in the deracemization of amino acids whereby
RAHBs activate epimerization of the imine intermediates.16,17
Compounds (5-(benzothiazol-2-yl)-4-hydroxyisophthalalde-
hyde18 and N-(2-pyridyl)-2-oxo-1-naphthylidene methyl
amine)19 showing RAHBs have been used as chemosensors
and colorimetric agents for the detection of cyanides, even in
aqueous media.18,19 Also, the RAHB is used to improve the
mesomorphic behavior of supramolecular liquid crystals
formed from azopyridines with different linear alkyl chains20
and control of the Diaza-Cope rearrangement21−23 and the
configurational isomerization of push−pull thiazolidinone
derivatives.24
The intramolecular RAHB was successfully studied in a wide
range of systems such as β-diketone enols,9 1,3-diketone aryl
hydrazones,25 and α-enaminones.26 Similarly, an intermolecu-
lar RAHB was examined in β-diketone enols,25 anti-β-
ketoarylhydrazones, NH-pyrazoles,27 secondary enaminones,28
etc. Furthermore, both intra- and intermolecular RAHBs
showing O−H···O, N−H···O, O−H···N, and O−H···S
interactions have been investigated with the aid of
experimental and theoretical methods.29−32 The resonance-
induced charge transfer process observed in RAHBs decreases
the vibrational frequencies and shifts 1H NMR signals
downfield.33,34 On the other hand, the effect of substitution
on the strength of the RAHB existing in mono- and
disubstituted o-hydroxybenzaldehyde derivatives was ex-
plored.35 The authors also explained how different substituent
groups (π-electron-donating groups −NH2, −OH, and −F; π-
electron-withdrawing groups −NO2, −NO, and CN) influence
the stability of the RAHB in these compounds. Further, it has
been concluded that electron-donating groups at ortho/para to
the −OH group enhanced the formation of a RAHB. However,
electron-withdrawing functionalities ortho/para to the −OH
group decreased the formation of a RAHB.35 Steric and
electronic factors also interplay in strength of a RAHB in β-
ketoarylhydrazones.36,37 The studies reported above clearly
suggest the potential importance of RAHB-containing
compounds. After Gilli’s initial proposal that the formation
as well as variation in the strength of a RAHB takes place due
to π-polarization of a hydrogen-bonding CO group,38
different researchers proposed the origin of the RAHB.
Fonseca Guerra et al.39 suggested electrostatic and donor−
acceptor orbital interactions as well as movement of the donor
and acceptor groups closer in proximity due to π-resonance as
the reason for an RAHB.1,39,40 Further, computational studies
suggested that the effects of the RAHB originated from
geometric constraints of the σ-framework.1 Cole and her co-
workers described the intramolecular charge transfer and the
molecular hyperpolarizability of geminal amido esters with
different donor−π-acceptor (D−π-A) moieties on the basis of
DFT and X-ray/neutron diffraction studies.41 They also
identified that the amido ester derivative with 4-NO2 and
2,5-OMe substituents showed promising nonlinear optical
characteristics. Further, the role of intermolecular interactions
present in these structures was not explored in their studies.41
In the present study on geminal amido ester derivatives
AME-1−8 (ethyl (2E)-3-(arylamino)-2-(arylcarbamoyl)prop-
2-enoate), we have now found that, in addition to the effect of
the π-polarization of the CO group, due to the conjugated
aromatic ring and its substituent groups, the crystal packing
also contributes to the modulation of the strength of RAHBs.
An unusual angularly fused tricyclic pseudoring system has
been found. The crystal packing effect was studied on the basis
of X-ray and theoretical models with the aid of Bader’s
quantum theory of atoms in molecules (QTAIM) ap-
proach.42,43 A systematic analysis of noncovalent interactions
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Figure 1. Thermal ellipsoid plots of AME-1−8 with the ellipsoids drawn at the 50% probability level. The atom-labeling scheme and invariant
intramolecular N−H···O and C−H···O interactions are shown in dashed lines. The aniline, anilide, and ester moieties in AME-1 are shaded with
three different colors.
compounds were characterized by 1H and 13C NMR and single-crystal
with the aid of experimental, PIXEL, and QTAIM calculations
X-ray diffraction studies. A detailed synthesis procedure for all of the
was carried out to understand how the weak C−H···O and C−
individual compounds AME-1−8 and the spectral data are given in
the Supporting Information.
H···π interactions and other weak interactions participate in
the stabilization of the crystal structures of AME-1−8. A
Hirshfeld surface (HS) analysis44−46 and 2D fingerprint (FP)
analysis47,48 have been used to analyze the relative contribu-
tions of different intermolecular interactions existing in these
crystal structures to understand the effect of different
substituents.
Single-Crystal X-ray Diffraction. Single crystals of compounds
AME-1−8 were grown by a slow evaporation method (at room
temperature, 296 K) using a hexane/ethyl acetate solvent mixture (8/
2, v/v). The X-ray intensity data collections were carried out at room
temperature (296 K) on a Bruker SMART APEX II CCD
diffractometer (APEX2, SAINT, and SADABS; Bruker AXS Inc.,
Madison, WI, USA) using Mo Kα radiation (λ = 0.71073 Å). All of
the structures except AME-8 were solved by direct methods using the
program SHELXS-2014.50 The isomorphous approach was employed
for AME-8 using the coordinates of the AME-2 structure. All of the
non-hydrogen atoms were refined by full-matrix least squares on F2
using SHELXL-2018/3.50 The positions of amine H were located
from a difference Fourier map and refined freely along with their
isotropic displacement parameters. All of the remaining H atoms were
placed at calculated positions using a riding model approach. All of
the structures in the present study are ordered except for AME-7. The
ethyl group (atoms C36 and C37) of the ester moiety in AME-7 was
disordered over two orientations, and the occupancy values for the
major and minor component were refined to be 0.64(2) and 0.36(2),
respectively. The ORTEP and crystal packing diagrams were
generated using the programs PLATON51 and Mercury,52,53
respectively.
EXPERIMENTAL SECTION
■
General Procedure for the Synthesis of Diethyl
[(Arylamino)methylidene]propanedioate (DEMM-1−8). A mix-
ture of the substituted aniline (4 mmol) and diethyl ethoxymethy-
lenemalonate (4 mmol) was heated at 120 °C for 45 min under
solvent-free conditions to give the corresponding diethyl
[(arylamino)methylidene]propanedioates (DEMM-1−8, Scheme 1)
in good yield (>98%). The products were characterized by spectral
data, which are comparable with those in our earlier report.49
General Procedure for the Synthesis of Ethyl (2E)-3-
(Arylamino)-2-(arylcarbamoyl)prop-2-enoate (AME-1−8). A
mixture of diethyl [(arylamino)methylidene]propanedioate
(DEMM-1−8, 4 mmol) and the respective aniline (4 mmol) was
heated at 170 °C for 5−6 h under solvent-free conditions (Scheme 1).
After completion of the reaction, the products were purified using
column chromatography (silica gel, hexane/EtOAc, 8/2 v/v) to give
the corresponding products in 80−95% yield. All of the purified
Gas-Phase Structural Optimization. All of the quantum
chemical calculations were performed with the Gaussian16 program
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Table 1. Crystal Data and Refinement Parameters for AME-1−8
AME-1
AME-2
678846
C20H22N2O3
338.39
AME-3
655619
C20H22N2O5
370.39
AME-4
664991
C20H22N2O5
370.39
CCDC no.
empirical formula
formula wt
cryst syst
space group
a (Å)
b (Å)
c (Å)
α (deg)
665885
C18H18N2O3
310.34
monoclinic
P21/c
7.1382(14)
13.398(3)
17.100(3)
90.0
monoclinic
C2/c
18.795(4)
11.995(2)
15.567(3)
90.0
monoclinic
P21/n
9.0693(6)
16.8073(11)
13.1818(9)
90.0
monoclinic
P21/c
12.500(3)
19.953(4)
7.6459(15)
90.0
β (deg)
γ (deg)
V (Å3)
94.55(3)
90.0
1630.3(6)
4
1.264
0.087
91.66(2)
90.0
3508.0(12)
8
1.281
0.087
105.118(10)
90.0
1939.8(2)
4
1.268
0.092
97.90(3)
90.0
1888.9(7)
4
1.302
0.094
Z
calcd density (Mg/m3)
absorption (mm−1
)
F(000)
656
1440
784
784
θ (deg)
3.0−27.5
2.0−27.6
2.0−28.0
3.1−27.4
limiting indices
h
k
l
−9 ⩽ h ⩽ 8
−17 ⩽ k ⩽ 17
−22 ⩽ l ⩽ 22
15589/3724
3724/0/217
1.04
−24 ⩽ h ⩽ 24
−15 ⩽ k ⩽ 14
−20 ⩽ l ⩽ 19
14356/4011
4011/0/237
1.06
−11 ⩽ h ⩽ 11
−21 ⩽ k ⩽ 21
−17 ⩽ l ⩽ 17
22003/4563
4563/0/255
1.05
−16 ⩽ h ⩽ 16
−25 ⩽ k ⩽ 25
−9 ⩽ l ⩽ 9
18346/4271
4271/0/255
1.01
no. of collected/unique rflns
no. of data/restraints/params
goodness of fit (GOF) on F2
final R indices (I > 2σ(I))
R1
wR2
0.041
0.108
0.045
0.112
0.045
0.1250
0.059
0.117
R indices (all data)
R1
0.069
0.065
0.057
0.13
wR2
0.116
0.220/−0.098
AME-5
0.129
0.267/−0.256
AME-6
0.1340
0.173/−0.151
AME-7
0.139
0.232/−0.130
AME-8
largest difference peak/hole (e Å−3
)
empirical formula
CCDC no.
formula wt
cryst syst
space group
a (Å)
b (Å)
c (Å)
α (deg)
β (deg)
γ (deg)
V (Å3)
Z
calcd density (Mg/m3)
absorption (mm−1
C20H22N2O5
804832
370.39
monoclinic
C2/c
24.6940(6)
12.4970(2)
14.7603(5)
90.0
125.668(2)
90.0
C18H16Cl2N2O3
665886
379.23
monoclinic
P21/n
14.947(3)
7.7889 (16)
15.366(3)
90.0
91.76(3)
90.0
C18H16Cl2N2O3
804833
379.23
C18H16Cl2N2O3
804925
379.23
monoclinic
C2/c
18.6444(4)
12.0202(3)
15.6673(4)
90.0
90.224(10)
90.0
triclinic
P1
̅
7.4613(2)
15.6554(4)
15.6825(4)
84.442(2)
87.6120(10)
77.6080(10)
1780.37(8)
4
3700.56(18)
8
1.33
1788.1(6)
4
1.41
3511.16(15)
8
1.44
1.42
0.384
)
0.096
0.382
0.390
F(000)
1568
784
784
1568
θ (deg)
1.9−25.0
3.2−27.5
1.3−25.2
2.0−31.0
limiting indices
h
k
l
−29 ⩽ h ⩽ 29
−14 ⩽ k ⩽14
−17 ⩽ l ⩽ 17
30836/3237
3237/0/255
1.02
−19 ⩽ h ⩽ 19
−10 ⩽ k ⩽ 10
−19 ⩽ l ⩽ 18
16747/4045
4045/0/235
1.089
−8 ⩽ h ⩽ 8
−17 ⩽ k ⩽ 17
−17 ⩽ l ⩽ 17
25837/5013
5013/3/473
1.014
−26 ⩽ h ⩽ 26
−17 ⩽ k ⩽ 16
−22 ⩽ l ⩽ 16
20813/5508
5508/0/235
1.036
no. of collected/unique rflns
no. of data/restraints/parameters
goodness of fit (GOF) on F2
final R indices (I > 2σ(I))
R1
0.042
0.106
0.040
0.111
0.040
0.107
0.049
0.121
wR2
R indices (all data)
782
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Table 1. continued
AME-5
0.061
0.118
AME-6
AME-7
0.069
0.092
AME-8
0.081
0.138
0.399−0.350
R1
wR2
0.054
0.119
0.284/−0.236
largest difference in peak/hole (e Å−3
)
0.146/−0.184
0.309/−0.227
package.54 To study the strength of intramolecular hydrogen bonds
and to understand the crystal packing effect, we performed structural
optimization in the gas phase using the X-ray geometry as an initial
model. The M06-2X/cc-pVTZ level of theory55,56 with the
incorporation of Grimme’s D3 dispersion corrections57 was used.
Vibrational frequencies were computed for the optimized structures to
confirm the proper convergence to energy minima on their respective
potential energy surfaces.
PIXEL Calculation. The total lattice energies and intermolecular
interaction energies (Etot) for dimers of AME-1−8 were calculated by
the PIXEL method (in the CLP computer program package, version
12.5.2014).58 The electron density of the molecules for PIXEL
calculation has been obtained at the MP2/6-31G** level of theory by
using the Gaussian16 program.54 The total lattice energy and Etot are
partitioned into Coulombic (ECoul), polarization (Epol), dispersion
(Edisp), and repulsion (Erep) energy contributions. Further, the PIXEL
interaction energies (Etot) of different molecular pairs were compared
with those of interaction energies (ΔEcp) obtained from the DFT
method at the M06-2X-D3/cc-pVTZ level of theory. The basis set
superposition error (BSSE) for the interaction energies (ΔEcp) was
corrected using the counterpoise method.59
sides (Figure 1). Both rings (rings I and II) are unsubstituted
in AME-1, while AME-2−8 contain symmetrical substitutions
(4-Me, 2-/3-/4-OMe, and 2-/3-/4-Cl) on both phenyl rings
(Scheme 1 and Figure 1). All of the compounds except for
AME-7 crystallize in the monoclinic crystal system with one
molecule in the asymmetric unit. The compound AME-7
̅
crystallizes in the triclinic system (in the P1 space group) with
two crystallographically independent molecules (molecules A
and B). The crystal data and other refinement statistics are
summarized in Table 1.
The phenyl ring orientations in these structures varies due to
electron-withdrawing/-donating groups attached at different
positions on the phenyl rings concerning the unsubtituted
structure (AME-1). In the unsubstituted structure, the dihedral
angle formed between the two phenyl rings is 6.98°. In the
structures with an electron-donating methoxy group sub-
stituted at different positions, the corresponding angle is in the
order AME-3 (24.35°) < AME-5 (17.69°) < AME-4 (10.96°).
The orientation angle between two phenyl rings is greater in
isotypic structures (4-Me, AME-2, 4-Cl, AME-8) and molecule
B of AME-7 (3-Cl) in comparison to the other structures. The
dihedral angle is in the range of 47.47−51.28°. However, the
corresponding angles in 2-Cl (AME-6, 18.44°) and molecule A
of AME-7 (12.33°) are similar to those of methoxy derivatives.
These dihedral angles formed between different mean planes in
the present work are comparable with those of amido ester
structures reported earlier.41
Furthermore, the molecular twist can be measured using the
two selected torsion angles C7−N1−C1−C2 (τ1) and C9−
N2−C10−C15 (τ2) (Table S1). The molecular conformation
adopts a slightly twisted conformation in some molecules in
comparison to the unsubstituted molecule AME-1. The
enantiomerically related molecules AME-4, AME-6, and
AME-7A with respect to the unsubstituted AME-1 were
used to compare these two torsion angles. This analysis
suggests that the τ1 value is in the range of 2.4−18.5° with
respect to the molecule of AME-1, while the τ2 value is in the
range of 1.0−28.9°. These two torsion angles indicate that
different substituents cause a twist on aryl rings to various
degrees, affecting the stability of hydrogen-bridged pseudor-
ings. The structural superposition reveals aryl ring rotation
with respect to the central fragment comprising atoms H1N/
N1/C7/C8/C9/O1/N2/H2N/C16/O2 (Figure 2). Further,
we observed that two intramolecular N−H···O hydrogen
bonds and a C−H···O interaction cooperatively generate three
fused pseudo-6,6,6-membered rings at the center in all
structures (Figures 1 and 2). These intramolecular interactions
stabilize the molecular conformation. Cole and co-workers
described only two intramolecular N−H···O hydrogen bonds
in their study on amido ester derivatives,41 and the present
study identifies an invariant weak intramolecular C−H· ··O
interaction which also helps to lock the molecular
conformation.
Hirshfeld Surface (HS) Analysis. To characterize intermolecular
interactions qualitatively and to understand the substitution effects on
the crystal packing, Hirshfeld surface (HS) and decomposed 2D
fingerprint (FP) plots were used. These analyses were performed with
the program CrystalExplorer17.5.60
QTAIM Analysis. Intra- and intermolecular interactions were
quantified using topological properties with the AIMALL package.61
The crystal structure geometry with normalized hydrogen positions
was used for this calculation at the M06-2X-D3/cc-pVTZ level of
theory. The selected topological parameters such as electron density
(ρ), the Laplacian of electron density (∇2ρ), local potential energy
density (V), kinetic energy density (G), and total electronic energy
density (H = V + G) at the bond critical points (BCPs) were used to
analyze these interactions. The strength of these interactions was
assessed using the EML empirical formula.62 For all eight structures,
the topological properties for various noncovalent interactions
observed in different dimers and their molecular graphs are presented
in the Supporting Information.
RESULTS AND DISCUSSION
■
General Description of the Molecular Structure and
Conformation. The geminal amido esters, AME-1−8
(Scheme 1) have been synthesized from substituted anilines
and diethyl ethoxymethylenemalonate (DEEMM) by using the
synthesis procedures mentioned in our earlier report.41 The
synthesized compounds, AME-1−8, were characterized by
1
spectral and single-crystal X-ray diffraction studies. The H
NMR spectra indicate that the N−Hamide and N−Haniline
protons could be observed in the ranges of 10.80−11.23 and
12.29−12.40 ppm, respectively. In particular, this downfield
shift of N−Haniline might be due to the existence of an
intramolecular RAHB (N1−H1aniline···O1C9amide) interac-
tion. The structures of AME-1−8 in the present study have
common fragments such as an aniline ring (ring I), an anilide
ring (ring II), and an ester moiety as shown in Figure 1. The
vinylic double bond (C7C8) bridges these three fragments
to build the molecular structure. The molecular conformation
can be described as a distorted Y-shaped conformation in
which aniline and anilide moieties are oriented on opposite
Resonance- and Non-Resonance-Assisted Intramo-
lecular N−H···O Hydrogen Bonds. As was mentioned
earlier, the conformation of the molecular structures AME-1−
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in the above five structures show closed-shell character rather
than an intermediate bonding nature. Furthermore, there exists
an intramolecular C−H···O interaction in which the amide
carbonyl is involved as an acceptor in all structures. The
strength of this weak interaction does not vary much with
different substituents, as is evident from the dissociation energy
(3.2−3.7 kcal mol−1). As expected, this C−H···O interaction is
described as a closed-shell interaction.
Further analysis suggests that an electron-withdrawing
substituent (Cl) placed at different positions has an essential
role in stabilizing the RAHB ring. For instance, the 4-Cl
substituent deactivates the RAHB ring more than the other
substituents 2-Cl and 3-Cl do. However, the 2-Cl substituent
reduces the strength of the non-RAHB in comparison to 3-Cl
and 4-Cl substituents. It is worth noting that an electron-
donating substituent (−OMe) placed at the ortho, meta, and
para positions shows a contrasting feature in comparison to an
electron-withdrawing substituent in those different positions.
The strength of the RAHB is weakened by ∼2 kcal mol−1 for 2-
OMe substituent in comparison to the counterparts in meta
and para positions. However, meta and para isomers of −OMe
do not alter the strength of the RAHB. This variation suggests
that steric and electronic effects play an essential role in the
stabilization.
The intramolecular hydrogen-bonding geometries for H1···
O1 (RAHB) and H2···O2 (non-RAHB) interactions are
comparable with those in earlier X-ray work.41 However, the
neutron diffraction studies revealed a reduction of the distance
for a non-RAHB in comparison to a RAHB, but comparable
distance for RAHBs in X-ray and neutron structures
(unsubstituted). A contrasting feature was observed in the
case of the 4-Me structure. The bond path (Rij) values for
H1···O1 (RAHB) derived from the QTAIM framework
suggest that bond lengthening is observed in structures
containing electron-withdrawing substituents in comparison
to those of unsubstituted derivatives and those containing
electron-donating groups. A similar trend is also noted in
structures with electron-donating substituents (4-Me) and 2-
OMe. In contrast, the corresponding values are comparable in
structures with 3-OMe and 4-OMe groups. The values of Rij
and the electron density for RAHB follow the exponential
decay trend with an R2 fitting parameter value of >0.95. A
similar trend is also observed for Rij and dissociation energy
values, and the same is valid for non-RAHBs as well (Figures
S2−S4 in the Supporting Information). However, the non-
RAHBs in these structures show contracting behavior in
comparison to the RAHBs. The systems with electron-
withdrawing groups (3-Cl and 4-Cl) reduce the H2···O2
distance except in the 2-Cl structure. In contrast, the
corresponding distance increases in unsubstituted, three-
electron-donating derivatives (4-Me, 3-OMe, and 4-OMe),
except for the 2-OMe derivative. Moreover, the H2···O2
distance is greater in electron-withdrawing structures than in
electron-donating and unsubstituted structures. These features
suggest that the amide group is more acidic in electron-
withdrawing structures than in electron-donating derivatives.
In order to understand the role of crystal packing on the
strength and nature of the RAHB and the non-RAHB, we
performed a topological analysis for optimized structures as
well. The selected topological parameters for these intra-
molecular interactions in gas-phase optimized structures are
given in Table S3. The molecular graphs showing the existence
of these intramolecular interactions are depicted in Figure S1.
Figure 2. Structural overlay diagram for AME-1−8. Atoms used for
superimposition are labeled. The RAHB ring is highlighted in yellow-
green, and two non-RAHB pseudoring motifs are indicated in cyan.
(color code: AME-1, magenta; AME-2, green; AME-3, blue; AME-4,
orange; AME-5, violet; AME-6, cyan; AME-7A, yellow-green; AME-
7B, pink; AME-8, yellow).
8 is primarily stabilized by three intramolecular N/C−H···O
interactions which generate three pseudofused S(6),S(6),S(6)
motifs. The N−Haniline, N−Hamide, and one of the C−H groups
of ring II act as donors, and the oxygen atoms of carbonyl
groups (COamide and COester) act as acceptors for these
interactions (Figure 1). Among three pseudofused S(6) rings,
one of the S(6) rings (N1−H1N···O1 or N−Haniline···O
C
amide) is described as a resonance-assisted hydrogen-bridged
(RAHB) ring on the basis of the method proposed by Gilli et
al.9 These authors explained the λ value calculation from the
bond lengths of the RAHB ring. This λ value was used to
differentiate between RAHB and non-RAHB. The fully
delocalized keto form of an enol ring (RAHB) has a λ value
of 0.5, and a lower value of λ (in the range of 0.17−0.29)
indicates a non-RAHB nature (Table S2 in the Supporting
Information). Further, the hydrogen-bridged RAHB and non-
RAHB rings can also be differentiated using the π-electron
counts, and a greater number of π electrons is present in the
RAHB ring in comparison to to non-RAHB rings.
The strength and nature of the intramolecular hydrogen-
bonded motifs were fully characterized by employing Bader’s
quantum theory of atoms in molecules (QTAIM) ap-
proach.42,43 Table 2 summarizes the topological parameters
for intramolecular N/C−H···O interactions at the crystal
structure geometry with normalized H positions. It is
important to note that the strengths of the non-RAHBs, i.e.,
a N2−H2N···O2 hydrogen bond, are found to be very similar
in all eight structures. The dissociation energy for this
hydrogen bond varies from 7.5 to 9.9 kcal mol−1. The positive
value of the Laplacian (∇2ρ > 0), H < 0, and |−V/G| < 1
suggest that the non-RAHBs are closed-shell in nature (Table
3). However, the RAHB ring displays remarkable variation in
the strength and nature of bonding. The dissociation energies
are relatively higher in AME-1 (11.1 kcal mol−1), AME-4 (11.4
kcal mol−1), and AME-5 (11.3 kcal mol−1) in comparison to
the other structures. The positive value of the Laplacian (∇2ρ
> 0), H > 0, and |−V/G| > 1 suggest63 that RAHBs in these
structures show bonding character intermediate between
shared and closed-shell interactions. The other substituents
(4-Me, 2-OMe, 2-Cl, 3-Cl, and 4-Cl) reduce the strength of
the RAHB and have relatively lower dissociation energies,
varying from 6.9 to 9.4 kcal mol−1. It is also noted that RAHBs
784
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a
Table 2. Topological Parameters for Intramolecular Interactions Observed in AME-1−8
−V
G
atoms
Rij
ρ
∇2ρ
V
G
H
DEint
AME-1
N1H1···O1
N2H2···O2
H15···O1
1.853
1.938
2.424
0.2494
0.2037
0.0986
3.2112
3.1820
1.5522
−0.0353
−0.0284
−0.0104
0.0343
0.0307
0.0133
0.0010 (0.0015)
−0.0023 (0.0010)
−0.0029 (−0.0034)
11.1 (11.6)
8.9 (10.7)
3.3 (4.1)
1.03 (1.04)
0.92 (1.03)
0.78 (0.79)
AME-3
N1H1···O1
N2H2···O2
H15···O1
1.940
1.926
2.336
0.2116
0.2069
0.1100
3.4342
3.2571
1.7651
−0.0299
−0.0294
−0.0118
0.0327
0.0316
0.0151
−0.0029 (0.0000)
−0.0022 (−0.0003)
−0.0033 (−0.0035)
9.4 (10.6)
9.2 (9.7)
3.7 (4.2)
0.91 (1.00)
0.93 (0.99)
0.78 (0.79)
AME-4
N1H1···O1
N2H2···O2
H15···O1
1.850
1.906
2.381
0.2496
0.2188
0.1008
3.2970
3.3457
1.5984
−0.0364
−0.0315
−0.0106
0.0353
0.0331
0.0136
0.0011 (0.0014)
−0.0016 (0.0010)
−0.0030 (−0.0034)
11.4 (11.6)
9.9 (10.7)
3.3 (4.1)
1.03 (1.04)
0.95 (1.03)
0.78 (0.79)
AME-5
N1H1···O1
N2H2···O2
H15···O1
1.853
1.952
2.348
0.2512
0.1955
0.1101
3.3827
3.0092
1.7702
−0.0362
−0.0267
−0.0119
0.0356
0.0289
0.0151
0.0005 (0.0015)
−0.0023 (0.0009)
−0.0032 (−0.0034)
11.4 (11.7)
8.4 (10.6)
3.7 (4.1)
1.02 (1.04)
0.92 (1.03)
0.79 (0.79)
AME-6
N1H1···O1
N2H2···O2
H15···O1
1.984
2.008
2.417
0.1913
0.1757
0.1023
3.2258
3.0282
1.6191
−0.0263
−0.0240
−0.0109
0.0299
0.0277
0.0139
−0.0036 (0.0010)
−0.0037 (0.0005)
−0.0029 (−0.0036)
8.2 (11.4)
7.5 (10.3)
3.4 (4.7)
0.88 (1.03)
0.87 (1.02)
0.79 (0.80)
AME-7A
N1H1···O1
N2H2···O2
H15···O1
2.023
1.968
2.425
0.1793
0.1925
0.0995
3.0164
3.1258
1.5637
−0.0234
−0.0263
−0.0105
0.0274
0.0294
0.0134
−0.0039 (0.0015)
−0.0031 (0.0014)
−0.0029 (−0.0035)
7.4 (11.7)
8.3 (11.0)
3.3 (4.2)
0.86 (1.04)
0.90 (1.04)
0.79 (0.79)
AME-7B
N1H1···O1
N2H2···O2
H15···O1
2.012
1.970
2.362
0.1858
0.1921
0.1054
3.1695
3.1268
1.6830
−0.0248
−0.0262
−0.0112
0.0288
0.0293
0.0143
−0.0041 (0.0015)
−0.0031 (0.0014)
−0.0031 (−0.0034)
7.8 (11.7)
8.2 (11.0)
3.5 (4.1)
0.86 (1.04)
0.89 (1.04)
0.78 (0.79)
AME-2
N1H1···O1
N2H2···O2
H15···O1
1.925
1.957
2.404
0.2135
0.1949
0.0974
3.1746
3.0804
1.5295
−0.0291
−0.0267
−0.0101
0.0310
0.0293
0.0130
−0.0019 (0.0015)
−0.0026 (0.0009)
−0.0029 (−0.0034)
9.1 (11.7)
8.4 (10.6)
3.2 (4.1)
0.94 (1.04)
0.91 (1.03)
0.78 (0.79)
AME-8
N1H1···O1
N2H2···O2
H15···O1
2.051
1.951
2.364
0.1693
0.1991
0.1038
2.9577
3.1954
1.6483
−0.0221
−0.0277
−0.0109
0.0264
0.0304
0.0140
−0.0043 (0.0015)
−0.0027 (0.0013)
−0.0031 (−0.0035)
6.9 (11.7)
8.7 (10.9)
3.4 (4.2)
0.84 (1.04)
0.91(1.04)
0.78 (0.79)
a
X-ray geometry with normalized H positions. Definitions: Rij, Bond path (Å); ρ, electron density (e Å−3); ∇2ρ, Laplacian electron density (e Å−5);
V, potential energy density; G, kinetic energy density; H, total electronic density; DEint, dissociation energy = −V × 0.5 kcal mol−1. The values of V,
G, and H are expressed in au. The values in parentheses correspond to optimized structures.
In the isolated molecules, the bond path values for H1···O1
and H2···O2 interactions are significantly reduced in both
electron-donating and electron-withdrawing derivatives in
comparison to the X-ray structures and there is a marginal
variation in the unsubstituted structure. This reduction in the
bond path values for both RAHBs and non-RAHBs and the
strength and nature of these bonds are very similar irrespective
of donating and withdrawing groups. These data clearly
support that crystal packing modulates the strength and nature
of both RAHB and non-RAHB motifs but has a pronounced
effect on the RAHB motif.
PIXEL Energy Analysis: Intermolecular Interaction
Energies. PIXEL calculations were performed to identify
energetically significant dimers from the crystal structures of
AME-1−8. The interaction geometries and the interaction
energies for dimers computed by two different approximations
(M06-2X and MP2) are given in Table 3. The complete
information, including the different energy components of total
intermolecular interactions for dimers, is summarized in Table
S5. We found that the intermolecular interaction energies for
the weak dimers in these structures, which are calculated from
the PIXEL (Etot) and the counterpoise (ΔEcp) methods, are
comparable. However, for the strongest dimers formed by
resonance-assisted ring-stacking interactions, the interaction
energies are overestimated by the M06-2X-D3/cc-pVTZ level
in comparison to the MP2/6-31G** level of theory. This
overestimation could be due to the dispersion energy and the
type of interactions present in them. As was mentioned earlier,
two crystallographically independent molecules (molecules A
and B) exist in the asymmetric unit of AME-7. The dimers
formed between molecule A and its symmetry-related partners
(A···A), molecule B and its symmetry-related partners (B···B),
and between molecules of A and B (B···A/B···A) are
considered separately. For clarity, we included labels for
interacting molecules such as AA, BB, and AB with dimeric
motif numbers (Table 3 and Table S5). As amine groups are
engaged in intramolecular N−H···O hydrogen bonds with
carbonyl oxygens, the crystal structures of AME-1−8 are
stabilized by several weak C−H···O, C−H···π, C−H···Cl, and
π···π interactions. However, one of the amine groups is
785
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a
Table 3. Intermolecular Interaction Energies (in kcal mol−1) for Various Dimers in AME1−8
b
c
d
dimer
CD
symmetry code
−x, 1 − y, −z
possible interactions
geometry H···A (Å), ∠(D−H···A) (deg)
Etot
ΔEcp
AME-1
D1
D2
3.087
4.461
C7···C9
3.336(2)
3.608
3.00, 158
3.437(2)
2.62, 136
2.58, 153
−15.3
−13.3
−21.0
−15.7
CgRAHB···CgRAHB
C18−H18C···Cg2 (π)
C9···C16
C5−H5···O1C9
C12−H12···O2C16
AME-2
1 − x, 1 − y, −z
D3
D4
10.185
12.320
−x, −1/2 + y, −1/2 − z
1 − x, 1/2 + y, 1/2 − z
−4.5
−2.2
−3.3
−1.9
D1
3.334
−x, 1 − y, −z
C2−H2···O2C16
2.75, 118
3.298(2)
3.425(2)
2.71, 138
3.943
2.79, 119
2.59,131
2.54, 169
2.372(1)
2.59, 137
2.55, 134
2.70, 152
−16.9
−22.5
C7···N2
C8···C8
C11−H11···Cg1
CgRAHB···CgRAHB
C6−H6···O1C9
C6−H6··· CgRAHB
C14−H14···O1C9
C14−H14···H15−C15
C12−H12···O2C16
C3−H3···Cg2 (C14)
C19−H19A···Cg2 (C13)
AME-3
D2
D3
5.447
9.507
-x, y, 1/2-z
−11.6
−5.8
−12.6
−4.9
1/2 − x, 1/2 − y, −z
D4
D5
D6
10.983
11.148
13.250
1/2 − x, 3/2 − y, −z
x − 1/2, y − 1/2, −z
x − 1/2, −y + 1/2, z + 1/2
−5.4
−4.8
−4.0
−4.6
−6.0
−5.2
D1
5.264
1 − x, −y, −z
C8···C16
3.419(2)
2.81, 122
2.54, 131
3.022(2)
2.58, 160
3.05, 145
2.68, 146
2.87, 138
2.84, 143
−15.2
−18.3
C17−H17B···O1C9
C19−H19B···O1C9
C9 = O1···C20
C20−H20C···O4
C19−H19A···Cg1(C5)
C4−H4···O5
C18−H18A···C11
C18−H18B···C6
AME-4
D2
D3
9.141
8.951
1 − x, −y, 1 − z
−1/2 + x, 1/2 − y, −1/2 + z
−10.2
−5.7
−9.0
−6.1
D4
D5
D6
D7
11.043
9.453
9.069
2 − x, −y, 1 − z
3/2 − x, −1/2 + y, 1/2 − z
1 + x, y, z
−4.9
−4.6
−3.7
−3.2
−6.1
−4.5
−4.4
−2.3
11.334
2 − x, −y, −z
D1
D2
4.269
8.146
x, −y + 1/2, z + 1/2
1 − x, 1 − y, −z
CgRAHB···CgRAHB
C17−H17B···C15
C17−H17A···Cg2
C2−H2···H13−C13
C20−H20C···O4
C14−H14···O1C9
C19−H19B···O2C16
C20−H20C···C12
C18−H18B···C6
AME-5
4.068
−14.4
−7.5
−17.7
−5.6
2.82, 137
3.25, 117
2.304
2.82, 121
2.78, 153
2.61, 100
2.89, 131
3.02, 135
D3
D4
D5
13.697
14.361
11.925
1 + x, 1/2 − y, −1/2 + z
−x, 1 − y, −z
1 − x, −y, −z
−4.8
−3.9
−2.2
−4.2
−4.6
−1.4
D1
D2
D3
3.489
5.284
10.449
−x, −y, −z
−x, y, −z + 1/2
1/2 − x, −1/2 + y, 1/2 − z
CgRAHB···CgRAHB
C7···C7
C2−H2···O5
3.832
−15.7
−13.0
−6.8
−19.4
−15.2
−5.7
4.494(3)
261, 129
2.52, 176
2.62, 131
2.84, 124
2.76, 131
2.65, 143
2.75, 161
2.51, 159
C12−H12···O1C9
C20−H20A···O2C16
C20−H20B···C2
C19−H19C···O1C9
C20−H20C···O4
C19−H19B···Cg2 (C14)
C18−H18B··O4
AME-6
CgRAHB···CgRAHB
C7···C9
C8···C9
C1···C8
C6···C9
D4
D5
11.120
13.838
x − 1/2, −y − 1/2, z − 1/2
x + 1/2, y + 1/2, z
−5.4
−4.9
−6.5
−6.1
D6
D1
12.497
3.354
x, y+1, z
−2.1
−1.6
−x, −y, 1 − z
3.712
−17.8
−21.9
3.343(2)
3.415(2)
3.487(2)
3.464(2)
2.50, 132
2.93, 122
2.53, 144
3.07, 142
D2
D3
5.474
9.647
−x, −1 − y, 1 − z
−15.6
−4.6
−17.8
−3.9
1/2 − x, −1/2 + y, 3/2 − z
C13−H13···O1C9
C13−H13···Cl1
C3−H3···O2C16
C18−H18A···Cg2
D4
D5
10.948
10.621
−1/2 + x, −1/2 − y, 1/2 + z
−1/2 + x, −1/2 − y, −1/2 + z
−3.8
−2.9
−3.3
−3.0
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Article
Table 3. continued
b
c
d
dimer
CD
symmetry code
possible interactions
AME-6
C17−H17A···Cl2
AME-7
geometry H···A (Å), ∠(D−H···A) (deg)
Etot
ΔEcp
D6
10.892
3.600
1/2 − x, −1/2 + y, 1/2 − z
2 − x, 2 − y, −z
2.95, 136
−2.5
−1.9
D1BB
C28···C29
3.356
−17.9
−21.0
CgRAHB···CgRAHB
C28···C28
C31−H31···C26(Cg1B)
C8···C9
CgRAHB···CgRAHB
C1···C9
CgRAHB···CgRAHB
C22−H22···O5C36
C29O4···Cl2
N3−H3N···Cl2
C11−H11···C26
C24−H24···O2C16
C18−H18B···Cg2B
C17−H17A···Cl3
Cl3···Cl4
4.067
3.433(4)
3.11, 130
3.517(5)
3.876
3.402(5)
3.590
2.51, 135
3.220(2)
2.85, 142
2.87, 153
2.79, 111
2.69, 162
3.04, 114
3.492(1)
D2AA
D3AA
3.438
4.456
1 − x, 1 − y, 1 − z
2 − x, 1 − y, 1 − z
−17.3
−14.3
−21.4
−18.3
D4BB
D5AB
4.795
10.482
1 − x, 2 − y, −z
1 − x, 2 − y, 1 − z
−13.3
−6.8
−12.8
−5.8
D6AB
D7AB
D8BB
10.728
11.008
17.084
−2x, 2 − y, −z
x, y, z
−1+x, y, 1+z
−4.9
−3.5
−1.0
−4.6
−2.5
−0.7
AME-8
D1
3.573
−x, 1 − y, −z
C2−H2···O2C16
CgRAHB···CgRAHB
C8···C8
C11−H11···Cg1
C6−H6···O1 = C9
C6−H6··· CgRAHB
C14−H14···O1C9
C12−H12···O2C16
C3−H3···Cg2
2.75, 113
4.073
−17.9
−22.0
3.472(2)
2.75, 137
2.86, 118
2.66, 130
2.40, 175
2.54, 136
2.61, 131
3.857(1)
D2
5.727
−x, y, 1/2 − z
−10.9
−11.7
D3
D4
D5
D6
8.882
11.053
11.092
12.906
3/2 − x, 1/2 − y, −z
3/2 − x, 3/2 − y, −z
−1/2 + x, −1/2 + y, z
−1/2 + x, 1/2 − y, 1/2 + z
−9.8
−6.8
−4.6
−3.3
−7.5
−5.0
−5.3
−2.0
Cl1···Cg2
a
Definitions: CD, the centroid−centroid distance of the molecules in Å; CgRAHB: the center of gravity for the RAHB ring (N1−H1N···O1/C9/C8/
b
C7); Cg1 and Cg2, the centers of gravity for the phenyl rings C1−C6 (ring I) and C10−C15 (ring II), respectively. Neutron values are given for
all D−H···A interactions. PIXEL interaction energies. ΔEcp obtained from the DFT calculations at the M06-2X/cc-pVTZ level of theory.
c
d
Figure 3. Selected molecular dimers in AME-1 along with Etot values in kcal mol−1 (see Table 3).
engaged in the intermolecular N−H···Cl hydrogen bond in
AME-7. The common packing features in AME-1−8 are
discussed in a separate section. A detailed qualitative analysis
of various intermolecular interactions existing in AME-1−8
with Hirshfeld surface (HS) and 2D fingerprint plots (2D-FP)
is summarized in Figures S5−S7 in the Supporting
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Figure 4. Part of the crystal structure of AME-1, viewed down the a axis. H atoms not involved in the C−H···O interactions are omitted. The two
individual C(9) molecular chains traced with different colors and the R44(34) motif formed by C−H···O interactions in D3 and D4 are also shown.
Figure 5. Various C−H···O/C and C···O interactions forming a herringbone architecture in AME-3.
Information. Further, the quantitative molecular electrostatic
potential (MESP) analysis is presented in the ESI section
(Figure S8).
Intermolecular Interactions in AME-1. Molecules of
AME-1 form as layers along the crystallographic ac plane, and
these layers are further interconnected by a stacking (dimer
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Figure 6. Packing diagrams of AME-4 and AME-5.
D1) interaction in which adjacent resonance-assisted pseudor-
ings are involved in the π-stacking interaction. A similar kind of
interaction between two resonance-assisted hydrogen-bridged
C9···C16 (π···π) contacts and is further supported by an
intermolecular C−H···π (involving H18C and Cg2) interaction
with an Etot value of −13.3 kcal mol−1.
rings has been reported.64−68 Blagojevic and Zaric have
performed a systematic analysis to compute stacked hydro-
gen-bridged ring stabilization energies.64 The stacking
interactions occurred in different systems were analyzed, for
example, between non-RAHB rings (particularly (i) two planar
five-membered hydrogen-bridged rings64 and (ii) planar six-
membered hydrogen-bridged rings and C6-aromattc rings69)
and RAHB rings ((iii) two six-membered RAHB rings70 and
(iv) six-membered RAHB rings and C6-aromatic rings71). In
these studies, the authors demonstrated that the stacking
interactions between two six-membered RAHB rings (−4.7
kcal mol−1) and the stacking interaction between the six-
membered RAHB ring and C6-aromatic rings (−3.7 kcal
mol−1) were more robust than the normal benzene···benzene
stacking interaction (−2.7 kcal mol−1).71 In the present work,
we did not observe any stacking interactions between aromatic
rings or between aromatic and hydrogen-bridged pseudorings.
The PIXEL energy analysis revealed that there are four
energetically significant intermolecular dimers (D1−D4)
identified from the crystal packing. The intermolecular
interaction energies (Etot) range from −15.3 to −2.2 kcal
mol−1 (Table 3 and Figure 3). In all four dimers, dispersion
energies contribute more than two thirds of their stabilization
energies (Table S5). We note that the dimer D2 also forms by
The O1 and O2 atoms of carbonyl units (COamide and
COester) are involved in intermolecular C−H···O inter-
actions (C5−H5···O1C9, D3, Etot = −4.5 kcal mol−1; C12−
H12···O2C16, D4, Etot = −2.2 kcal mol−1). Each of these
interactions link the molecules into a C(9) chain, and these
chains run parallel to each other. When these two interactions
are combined, a tetrameric supramolecular sheet with the
R44(34) motif is formed, as shown in Figure 4.
́
́
Intermolecular Interactions in Methoxy-Substituted
Isomers (AME-3−5). In the crystalline state, molecules of 3-
OMe (AME-4) and 4-OMe (AME-5) pack somewhat similarly
and these two molecules form as layers. The basic motif
formed in 2-OMe (AME-3) is the stacking between adjacent
molecules (D1). This stacking motif is different from the
stacking of resonance-assisted rings observed in AME-1. The
basic dimeric motif in AME-3 is repeated along the b axis and
form as columns. The molecules in adjacent columns generate
a herringbone-like supramolecular architecture. In Table 3 and
Figures S10−S12, the important dimers observed in these
isomers are summarized. In all three isomers, the strong dimer
is formed by stacking interactions. However, molecular
stacking is different in AME-3 in comparison to AME-4 and
AME-5. In the last two structures, molecular stacking is
achieved by an adjacent intramolecular resonance-assisted
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Figure 7. (a) C−H···O/C interactions in D2, D3, and D5 forming a supramolecular sheet in AME-4. (b) C−H···O interactions in D2 and D6
forming a supramolecular sheet in AME-5.
hydrogen-bridged six-membered ring. However, there are no
stacking interactions observed between the aromatic rings
(rings I and II) in AME-4 and AME-5.
vdW radii + 0.1 Å. The Etot values for dimers D1−D7 fall in the
range of −15.2 to −3.2 kcal mol−1 (Table 3 and Figure S10).
All seven dimeric pairs are observed in AME-3 except for D2
and D3; the dispersion energies contribute more than 70%
toward the stabilization.
In AME-3, both methoxy methyl (C19 and C20) groups are
involved in the intermolecular C−H···O interactions (D2 and
D3). In one of the C−H···O interactions, molecules of AME-3
form a closed motif (D2). This D2 dimer is flanked on both
sides by dimer D3. The dimer D3 is also supported by a C
O···C (involving O1 and C20) contact in addition to a C−H···
O interaction. Interactions formed in D2 and D3 dimers act
together to link the adjacent columns, which in turn produce a
herringbone architecture (Figure 5).
The dimer D4 is stabilized by a intermolecular C−H···π
(involving H19A and the centroid of Cg1) interaction, and this
interaction helps to link the adjacent basic motifs (D1)
arranged in each column. Further, intermolecular C4−H4···O5
(D5), C18−H18A···C11 (D6), and C18−H18B···C6 inter-
actions (D7) also stabilize the herringbone architecture. It is
noted that an H4···O5 contact is established with the sum of
In AME-4, there are five dimers (D1−D5; −14.4 < Etot
>
−2.2 kcal mol−1; Figure S11) identified from the PIXEL energy
analysis. The molecules are packed as helical-like chains which
run parallel to the crystallographic b axis or form as layers
along the ac plane (Figure 6a). As was noted earlier, the strong
dimer (D1) forms by stacking between resonance-assisted rings
of adjacent molecules in an offset mode, with the separation
between them being 4.06 Å. Further stabilization is achieved
by intermolecular C−H···π interactions (the CH2 group of the
ester moiety is involved as a donor). The dimer D1 acts as a
basic motif. Dimer D2 is stabilized by two weak intermolecular
C−H···O interactions and a short H···H contact forming a
closed molecular loop.
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Figure 8. Crystal packing of chloro-substituted isomers AME-6−8 and of AME-2.
Figure 9. Part of the crystal structure in AME-6: (a) C−H···O/Cl interactions in D3 and D4 forming the molecular layers (ladderlike); (b) C−H···
Cl (D6) interactions linking the neighboring basic pattern of AME-6 into a herringbone architecture. Different molecular chains are highlighted.
For the C−H···O interactions, amide CO (O1) and
oxygen (O4) of the methoxy group are involved as acceptors.
Similarly, dimer D3 is also stabilized by a weak C−H···O
interaction (involving H19B and O2), which links the
molecules into a C(11) chain that runs parallel to the a axis.
As shown in Figure 7a, dimers D2, D3, and D5 collectively
generate a supramolecular sheet. The dimer D4 in this
structure is formed by a C20−H20C···C12 interaction. This
interaction links the molecules in the adjacent layers. For all
four dimers observed in this structure, the contribution of
dispersion energy ranges from 60 to 79% toward the
stabilization.
In AME-5, there are six dimers formed (D1−D6; −15.7 <
Etot > −2.1 kcal mol−1; Figure S12) in the crystal structure, as
revealed by the PIXEL energy analysis. As was mentioned
earlier, AME-4 and AME-5 show somewhat similar crystal
packings. The AME-4 molecules packed as a single helical-like
chain, whereas molecules of AME-5 form as double-helical-like
chains which run in the opposite direction along the ab plane
(Figure 6) or layers along the ac plane. The basic motif is
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Figure 10. Part of the crystal structure of AME-7: (a) C−H···O and Cl···Cl interactions in D4BB and D8BB generating the molecular ribbon; (b) C−
H···O/C/Cl and Cl···Cl/O interactions in D5AB, D6AB, and D8BB generating the molecular ribbon.
derived from resonance-assisted stacking between adjacent
inversion-related molecules of AME-5 (D1). The remaining
dimers are primarily stabilized with intermolecular C−H···O
interactions. The oxygens (O1 and O2) of CO groups and
oxygens (O4 and O5) of methoxy groups participate as
acceptors for these C−H···O interactions. The dimer D2 is
generated by molecular stacking in which the shortest distance
between two adjacent C7 atoms is 3.494(3) Å. The C−H···O
interactions in D3 (C2−H2···O5, C12−H12···O1C9, and
C20−H20A···O2C16) link the neighboring molecules into a
chain which runs parallel to the b axis. This dimeric motif
forms by D6 (C18−H18B··O4 interaction) generating a
supramolecular sheet along the ab plane (Figure 7b). Further,
molecules in the helical-like chain are interlinked via C19−
H19C···O1C9 (D4) and C20−H20C···O4 and C19−
H19B···π (D5) interactions (Figure 6).
Intermolecular Interactions in Chloro-Substituted
Isomers (AME-6−8) and Isomorphic Forms of 4-Cl
(AME-8) and 4-Me Derivatives (AME-2). In AME-6, there
are six dimers (D1−D6; −17.8 < Etot > −2.5 kcal mol−1; Figure
S13) extracted from the crystal structure. The crystal packing
of this structure can be described as a herringbone architecture
along the ab plane (Figure 8). The basic pattern (D1) observed
is the stacking of resonance-assisted rings, as observed in other
structures in the present study. Dimer D2 also formed by
molecular stacking in an offset mode. The shortest C···C (C1···
C8 = 3.487(2) Å and C6···C9 = 3.464(2) Å) contacts are
observed within this dimer. Further, dimers D1 and D2 are
alternately arranged and one molecule from each dimer
participates in the formation of dimers D1 and D2. Both
carbonyl oxygens (O1 and O2) are involved as acceptors for
two different intermolecular C−H···O interactions, generating
dimers D3 (Etot = −4.6 kcal mol−1) and D4 (Etot = −3.8 kcal
mol−1).
stabilized by weak intermolecular C−H···π (D5; Etot = −2.9
kcal mol−1) and C−H···Cl (D6; Etot = −2.5 kcal mol−1)
interactions (Figure 9b). Overall, the dispersion energies
contribute more than 64% toward the stabilization.
In AME-7, there are two crystallographically independent
molecules observed in the asymmetric unit. The crystal
packing is somewhat similar to those of AME-6 (Figure 8)
and AME-3. However, there are differences in the molecular
arrangements within the herringbone architectures of AME-7
and AME-3. The PIXEL energy analysis identifies a total of
eight molecular pairs (D1−D8; −17.9 < Etot > −1.0 kcal mol−1;
Figure S14) from the crystal structure of AME-7. Among the
eight dimers, two of the dimers are generated by the self-
association of molecule A and its symmetry-related partners
(D2AA and D3AA). Three dimers are produced by molecule B
and its symmetry-related partners (D1BB, D4BB, and D8BB).
Similarly, three dimers are constructed from A/B or B/A pair
of molecules (D5AB−D7AB). The dimers generated by
molecules of A and molecules of B are different. The strong
dimer D1BB is formed by molecular stacking of symmetry-
related molecules of B. This dimer is also supported by the C−
H···π interaction. Within the molecular stacking, the centroid
to centroid distance between resonance-assisted pseudorings is
4.067 Å. In contrast, dimer D2AA is formed with similar
strength in comparison to D1BB by molecular stacking in which
the centroid to centroid distance between resonance-assisted
pseudorings is 3.876 Å. Dimer D3AA is generated by molecular
stacking in which the separation between centroids of the
resonance-assisted rings is 3.590 Å. The strength of dimer D3AA
is comparable to that of D4BB, and the latter dimer is stabilized
by an intermolecular C−H···O interaction in which the ester
CO group is involved as an acceptor. This interaction
generates a closed loop that has a graph set motif of
R22(18).These neighboring closed loops are connected by a
homohalogen contact (Cl3···Cl4; D8BB; Figure 10a) in which
the shortest distance between two chlorine atoms is 3.492(1)
Å. As was noted earlier, molecules A and B generate three
dimers and these dimers are stabilized by intermolecular C−
H···O, C−H···π, N−H···Cl, C−H···Cl, and Cl···OC
The dimers D4 are also supported by a weak intermolecular
C−H···Cl contact (involving H13 and Cl1), forming a three-
centered interaction. It is noted that the interactions in D3 and
D4 interlink the basic pattern of AME-6 in the solid state
(Figure 9a). Moreover, the herringbone architecture is also
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Figure 11. C−H···O interactions in D3 and D4 linking the neighboring molecules into a molecular sheet in AME-2 and AME-8 which forms
parallel to the b axis.
interactions. The strong dimer D5AB is formed between
molecules A and B via N−H···Cl, Cl···OC, and C−H···C
interactions. The adjacent dimers of D5AB are interlinked by an
intermolecular C18−H18B···Cg2B interaction in dimer D6AB
and the Cl3···Cl4 contact in D8BB (Figure 10b). The D7AB
dimer is stabilized by an intermolecular C−H···Cl (involving
H17A and Cl3) interaction.
Moreover, the intermolecular interaction is slightly stronger for
the latter dimer in comparison to the former dimer.
Isostructurality Analysis. A structural similarity analysis
was performed for all possible pairs of structures with the XPac
2.0 program developed by Gelbrich and coauthors.73−75 This
method provides information on the degree of packing
similarity: i.e., the dissimilarity index (x) and the stretching
parameter (Table 4).
The structure of AME-8, a 4-Cl derivative, is isotypic with its
4-Me counterpart (AME-2). Although the crystal structure of
ethyl (E)-3-(4-methylanilino)-2-[(4-methylphenyl)-
carbamoyl]prop-2-enoate (4-Me derivative) has been reported
by Islor et al.,72 we used our redetermined structure of AME-2
for all analyses used in this study. In both cases, there are six
dimers identified by the PIXEL energy analysis and all of the
dimers are identical in both structures except for the least
stable dimer D6 (Figures S9 and S15). The molecules are
packed as double-helical-like chains, and each chain runs in the
opposite direction with respect to the orientation of another
chain in a double-helical-like arrangement (Figure 8). The
crystal packing of these molecules is similar to that of AME-5
(4-OMe). All of the para-substituted (4-Cl, 4-Me, and 4-OMe)
amido esters show similar packing features. In AME-8 and
AME-2, the strong dimer D1 is generated by the molecular
stacking in which resonance-assisted rings are stacking. The
molecular stacking is closer in AME-2 in comparison to AME-
8, as is evident from the centroid to centroid distance of
molecular pairs (see Table 3).
The dimer D1 is also supported by an intermolecular C−H···
O interaction, in which the ester carbonyl group acts as an
acceptor. Dimer D2 is stabilized by three-centered interactions,
one of which is a C−H···O interaction and the remaining one
is a C−H···Cg(π) interaction (Cg is the centroid of the
resonance-assisted ring). Dimers D3 and D4 are formed by
intermolecular C−H···O interactions in which both CO
groups are involved as acceptors and generate alternate closed-
loop motifs (Figure 11). The former dimer has an R22(14) ring
motif, while the latter dimer has an R22(18) ring motif. Dimer
D5 is stabilize by an intermolecular C−H···π interaction in
which the centroid of ring II is involved as an acceptor. As was
mentioned earlier, the only difference observed between the
isomorphic structures is the formation of the least stable dimer:
i.e., D6. In AME-8, this dimer is stabilized by a Cl1···π(Cg2)
interaction, whereas in AME-2 the corresponding dimer is
stabilized by an intermolecular C−H···π(Cg2) interaction.
Table 4. Structural Similarity Parameters for AME-1−8
dissimilarity
index (x)
stretching
parameter (Å)
Δa
Δp
combination
(deg)
(deg)
3D Similarity
AME-2 AME-8
AME-5 AME-8
AME-2 AME-5
1.6
13.4
11.1
0.16
0.5
7.6
5.9
1.5
11.0
9.4
2D Similarity
0.56
0.50
1D Similarity
0D Similarity
AME-1 AME-2
AME-1 AME-5
AME-1 AME-6
AME-1 AME-7
AME-1 AME-8
AME-2 AME-4
AME-2 AME-7
AME-3 AME-4
AME-3 AME-7
AME-5 AME-6
AME-5 AME-7
AME-6 AME-7
AME-7 AME-8
11.7
7.5
5.2
0.18
0.21
0.04
0.21
0.22
0.89
0.17
0.33
0.12
0.17
0.01
0.18
0.13
5.6
4.4
2.5
4.1
6.0
7.6
2.6
1.8
6.0
3.8
7.6
4.8
3.2
10.3
6.1
4.5
4.5
6.1
12.1
13.9
4.6
11.3
10.1
7.5
11.7
7.2
5.6
10.5
11.6
3.9
11.2
8.2
6.5
8.9
5.3
4.6
For each pair of structures, the XPac program identifies one
of the following structural similarities: i.e., 0D (discrete
assembly match or a dimer match), 1D (row of molecules
match), 2D (layer of molecules match), and 3D (isostruc-
tural). From the analysis, we found that most of the
combinations show an 0D structural similarity: i.e., a dimer
match. The AME-1 structure shares 0D structural similarity
with 4-Me (AME-2), 4-OMe (AME-5), 2-Cl (AME-6), 3-Cl
(AME-7), and 4-Cl (AME-8, Figure 12) This dimer is
primarily stabilized by the stacking of resonance-assisted rings.
The intermolecular interactions energies for this dimer in
different structures are comparable. The 4-Me and 3-OMe
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Figure 12. Structural 0D similarities of AME-1−8.
structures show 0D structural similarity. This dimer (D2) is
stabilized by an intermolecular C−H···O interaction (involving
amide CO as an acceptor). This dimer is slightly more stable
in 3-OMe than in 4-Me. Similarly, AME-3 and AME-4 also
share 0D structural similarity. In this case, the methyl group of
the ester moiety in each molecule of the dimer is in close
proximity (Figure S14). It is important to note that AME-2
and AME-5 share 1D structural similarity in which the adjacent
dimer D1 is arranged in an offset mode (Figure S16). A 2D
structural similarity is observed for AME-5 and AME-8. In
both structures, the basic motif formed by the molecular
stacking runs in both directions (Figure S17). Since AME-2
and AME-8 are isomorphous, they show 3D structural
similarity. Overall, this analysis helps to identify the common
motifs occurring in these derivatives and suggests that the
motif formed by molecular stacking involving resonance-
assisted rings is the most preferred choice.
Topological Analysis of Intermolecular C−H···O and
C−H···C (π) Interactions. To evaluate the strength of various
intermolecular interactions in the selected molecular dimers in
AME-1−AME-8, the topological parameters at their bond
critical points (BCPs) were calculated. The topological
parameters for intermolecular interactions and the molecular
graphs of dimers are presented in Tables S6−S13 and Figures
S18−S25 in the Supporting Information. In all eight structures,
the observed intermolecular interactions are closed-shell in
nature as evaluated using the following conditions: (i) ∇2ρ > 0,
(ii) |−V/G| < 1, and (iii) H > 0. Moreover, the electron density
values for all C−H···O interactions observed in these
structures satisfy the Koch and Popelier limit (0.013 e Å−3
<
ρ > 0.236 e Å−3) suggested for hydrogen bonds.76 The
dissociation energies for the C−H···O interactions in these
structures are in the range of 0.72−1.73 kcal mol−1. All of the
C−H···C interactions observed in these structures are closed-
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shell bonding in nature. Further, the electron density values for
the C−H···C interactions in AME-1−8 are in the range of
0.027 e Å−3 < ρ > 0.052 e Å−3 and are found to be within the
Koch and Popelier limit for hydrogen bonds and are
comparable to those in an earlier experimental charge density
analysis.77 As expected, the dissociation energies for these
interactions are in the range 0.55−1.14 kcal mol−1.
Energy Frameworks and Lattice Energy. The total
lattice energies were calculated for AME-1−8 using the PIXEL
method, and these energies along with the different energy
components are summarized in Table 5.
the order 4-Cl > 3-Cl > 2-Cl. Moreover, the stabilities of the 4-
OMe and 4-Cl derivatives are comparable. However, the
stability is reduced by ∼3 kcal mol−1 due to 4-Me substitution.
In all of the structures, the dispersion energy contributes more
than 72% toward the stabilization.
To rationalize the mechanical behavior of crystals used in
the present study at the molecular level, we determined energy
frameworks using the CrystalExplorer-17.5 program.60 Two
different cylinders (green, dispersion energy; blue, total energy;
Figure 13) with varying magnitudes are depicted in the energy
frameworks diagrams. In AME-1, the zigzag large green
cylinders correspond to dimers D1 and D2 formed by
molecular stacking and these dimers are arranged alternately
and run parallel to the a axis. The adjacent zigzag chains are
interlinked by small cylinders which represent dimer D4
formed by a weak intermolecular C−H···O interaction. The
3-OMe and 4-OMe derivatives (AME-4 and AME-5) show
similar 3D topologies of the energy frameworks in comparison
to AME-1. In AME-4, dimer D1 generates the zigzag chain,
whereas two dimers (D1 and D2) are arranged in an alternate
fashion which produces zigzag chains in AME-5. The small
cylinders interconnect the neighboring zigzag chains. The
intermolecular C−H···C and C−H···O interactions formed in
molecules of AME-4 and AME-5 are shown as small cylinders.
The topology of the energy framework for 2-Cl the
derivative is very similar to those of AME-1, AME-4, and
AME-5. The vertical zigzag chain is comprised of alternate
dimers D1 and D2. The adjacent zigzag chains are
interconnected by small cylinders. In this case, intermolecular
C−H···O and C−H···Cl interactions constitute the small
cylinders. The 3D energy topology for AME-3 is somewhat
similar to that of other structures with respect to the zigzag
chain, which is primarily generated by the first two strong
dimers (D1 and D2). Overall, this analysis suggests that the
crystals of AME-1,2,4−8 could have similar mechanical
properties irrespective of the different substituents. It also
suggests that the stacking of the resonance-assisted rings plays
Table 5. Lattice Energies (kcal mol−1) Partitioned into
Coulombic, Polarization, Dispersion, and Repulsion
Contributions for AME-1−8
compound
ECoul
Epol
Edisp (%Edisp
)
Erep
Etot
AME-1
AME-2
AME-3
AME-4
AME-5
AME-6
AME-7
AME-8
−7.96
−12.07
−11.78
−10.66
−12.69
−9.53
−3.63
−5.31
−4.78
−4.78
−4.92
−4.13
−4.28
−4.49
−38.98 (77)
−49.43 (74)
−43.19 (72)
−46.22(75)
−49.16(74)
−45.46 (77)
−47.44 (77)
−49.62 (76)
19.05
30.69
22.92
24.98
27.77
23.11
24.28
26.46
−31.52
−36.11
−36.85
−36.71
−39.01
−36.04
−37.62
−38.89
−10.18
−11.23
The results suggest that the unsubstituted, parent compound
AME-1 is weakly packed (Etot = −31.5 kcal mol−1) in the solid
state in comparison to the other crystal structures (AME-2−8;
−36.0 < Etot > −39.0 kcal mol−1). Among the methoxy isomers
(AME-3−5), the crystal structure of the 4-methoxy derivative
is found to be the most stable (AME-5, Etot = −39.0 kcal
mol−1). However, the lattice energies for the 2-OMe (AME-3,
Etot = −36.9 kcal mol−1) and 3-OMe derivatives (AME-4, Etot
= −36.7 kcal mol−1) are comparable. Similarly, the structure of
the 4-Cl (AME-8) derivative is found to be more than stable
than other two Cl isomers. The stability of the Cl isomers is in
Figure 13. Energy frameworks for the crystal structures of AME-1−8, except for AME-7. Color scheme: blue, total energy; green, dispersion
energy. All diagrams use the same cylinder scale of 80 kJ mol−1 for energies, and energies with a magnitude of less than 10 kJ mol−1 for all for the
structures except for AME-3 (a <20 kJ mol−1 cutoff was used) have been omitted for clarity.
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Article
an important role in providing the similar mechanical
properties. It is interesting to note that AME-7 shows a
completely different 3D topology of the energy framework in
comparison to the other structures. It shows a ladderlike
topology instead of zigzag chains. This feature suggests that the
crystals of AME-7 could have completely different mechanical
properties in comparison to the other crystals.
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
Subbiah Thamotharan − Biomolecular Crystallography
Laboratory, Department of Bioinformatics, School of
Chemical and Biotechnology, SASTRA Deemed University,
Thanjavur 613 401, India; orcid.org/0000-0003-2758-
6649; Email: thamu@scbt.sastra.edu
CONCLUSIONS
■
In the present study, we have systematically explored the effect
of substituents on the crystal packing and intramolecular
RAHB and non-RAHB and weak intermolecular interactions in
AME-1−8. In all structures reported herein, an angularly fused
pseudotricyclic (S(6),S(6),S(6)) ring system has been formed
by the intramolecular N−H···O and C−H···O interactions.
The weak intermolecular interactions in AME-1−8 were
quantitatively analyzed by PIXEL, DFT, and QTAIM
approaches. The PIXEL energy calculations revealed that the
strong dimer D1 was formed by the molecular stacking
involving pseudorings of RAHBs. Most of the structures shared
a 0D structural similarity, and AME-2 and AME-5 showed a
1D structural similarity. AME-5 and AME-8 displayed a 2D
structural similarity. The 3D topologies of the energy
frameworks show similar features, suggesting that they may
have similar mechanical properties. All of the weak
intermolecular C−H···O, C−H···π, and C−H ···Cl interactions
are closed-shell in nature, as evaluated by the topological
parameters derived with the QTAIM framework. The
topological analysis for X-ray and optimized structures in the
gas phase suggested differences in the natures and strengths of
intramolecular RAHBs and non-RAHBs. We found that the
strengths and the nature of these intramolecular N−H···O
hydrogen bonding were modulated by the crystal packing
effect. A pronounced effect was observed for a RAHB in
comparison to a non-RAHB. The variations in the bond path
values indicated the effect of electron-donating and -with-
drawing groups introduced in the amido ester. Moreover, the
amide group acidity is more pronounced in electron-with-
drawing structures than in the electron-donating derivatives.
Andivelu Ilangovan − School of Chemistry, Bharathidasan
University, Tiruchirappalli 620 024, Tamilnadu, India;
orcid.org/0000-0001-7240-7166; Email: ilangovan@
bdu.ac.in
Authors
Perumal Venkatesan − School of Chemistry, Bharathidasan
University, Tiruchirappalli 620 024, Tamilnadu, India;
Unidad de Polímeros y Electrónica Orgánica, Instituto de
Ciencias, Benemérita Universidad Autónoma de Puebla, San
Pedro Zacachimalpa, Puebla, México; orcid.org/0000-
0001-6134-8324
M. Judith Percino − Unidad de Polímeros y Electrónica
Orgánica, Instituto de Ciencias, Benemérita Universidad
Autónoma de Puebla, San Pedro Zacachimalpa, Puebla,
México; orcid.org/0000-0003-1610-7155
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.cgd.0c01010
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the DST-India (FIST program) for the use
of the Bruker SMART APEX II diffractometer and the 400
MHz NMR facility at the School of Chemistry, Bharathidasan
University. The authors thank the Laboratorio Nacional de
Supercoìmputo del Sureste (LNS-BUAP) for the calculation
service and the VIEP-BUAP (project 100184100-VIEP).
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