Crystal structure and quantum chemical calculations of (E)1-benzyl-3-((4-methoxyphenyl)imino)-5-methylindolin-2-one

Article abstract of DOI:10.1002/jhet.4284

The known Schiff base compound, (E)1-benzyl-3-((4-methoxyphenyl)imino)-5-methylindolin-2-one, was prepared as before by reacting 1-benzyl-5-methylindoline-2,3-dione with 4-methoxyaniline. The product was unambiguously characterized using elemental analysi

Full text of DOI:10.1002/jhet.4284

Crystal structure and Quantum Chemical Calculations of (E)1-benzyl-3-((4
methoxyphenyl)imino)-5-methylindolin-2-one
Hend A. A. Abdel El-wahab a, Ahmed K. Hamdy a, Carola Schulzke b, Tarek Aboul-Fadl a, Wesam S.
Qayed a
a Department of Medicinal Chemistry, Faculty of Pharmacy, Assuit University, Assuit 71526, Egypt
b Institut für Biochemie, Universität Greifswald, Felix-Hausdorff-Straße 4, 17489 Greifswald, Germany
Received: ((will be filled in by the editorial staff))
conducted in order to investigate the structures and relative
stabilities of the (E) and (Z) isomers of 1-benzyl-3-((4
methoxyphenyl).-imino)-5-methylindolin-2-one. Specific
attention was paid to the (E) isomer. The available
crystallographic experimental data for the latter ensured
also validation of the model structures computationally
derived at the theoretical B3LYP/6-31G(d,p) level.
Abstract. The known Schiff base compound, (E)1-benzyl-3-
((4-methoxyphenyl)imino)-5-methylindolin-2-one, was
prepared as before by reacting 1-benzyl-5-methylindoline-
2,3-dione with 4-methoxyaniline. The product was
1
unambiguously characterized using elemental analysis, H
and 13C-NMR spectroscopy and its new single-crystal X-ray
structural analysis. Molecular orbital calculations were
Keywords: X-ray Structural Analysis; Density Functional
Theory; Molecular Orbital Analysis; Indoline Derivative;
Schiff Base
Here, crystallographic evaluation and quantum
chemical calculation of the molecular metrical parameters
and the computational structures at the atomic level, i.e.
combined experimental and in silico studies, are reported
and discussed in relation based on a newly crystallized
known indole derivative. The structural behaviour of the
molecule as embedded in the solid crystal lattice is
compared with the corresponding gas phase structure
providing notable insights in particular with respect to the
experimentally observed formation and computed relative
stability of (E) versus (Z) isomers.
1. Introduction
1H-indole-2,3-dione and derivatives thereof are frequently
used as precursors for the synthesis of important classes of
heterocyclic drugs. According to a literature survey, Schiff
and Mannich bases of 1H-indole- 2,3-diones exhibit rather
broad and very diverse pharmacological activities
including those against cancer, bacteria, and fungi, as well
as anti-diabetic, anti-convulsant, anti-tubercular, anti-HIV,
neuroprotective [1], anti-oxidant [2], anti-glycation [3], anti-
malarial [4], anti-inflammatory, analgesic
anxiety effects [6]. Consequently, the attractive properties
of Schiff and Mannich bases, including biological ones,
and their general chemical as well as their specific
molecular structures have already been analysed for a
considerable period of time [7].
The distinct chemical structure of any molecule
profoundly affects its biological properties, irrespective of
the chemical class that it belongs to. In this context,
computational chemistry has a crucial role in the fields of
chemical, biological and material sciences. In organic
chemistry, it helps understanding concepts, e.g. regarding
the molecular structure, and explaining reaction pathways
[5]
and anti-
2. Results and Discussion
2.1. Description of the crystal structure
The unit cell of the title compound I bears sixteen
molecules while the crystal system is orthorhombic with
the space group Fdd2. All molecules are present as the
compound’s (E) isomer. The N2-C2 distance between
indole ring and bridging Schiff base nitrogen with 1.280(5)
Å falls within the range of a typical C=N double bond,
while the N2-C17 distance between the bridging nitrogen
and the phenyl ring of 1.419(4) Å clearly suggests a C–N
single bond like in other Schiff base compounds. The bond
angles involving the Schiff base nitrogen, i.e. N2-C2-C1,
N2-C2-C3 and C2-N2-C17, are 118.6(3)°, 136.0(3)° and
120.7(3)°, respectively, and they are agreeing with a sp2
hybrid character for both C2 and N2 atoms. The indole 5-
ring plane (N1, C1, C2, C3, C8) is nearly perpendicular to
the plane of the phenyl ring C11 to C16 with a torsion
angle of C1-N1-C10-C11 of -92.3(4)°. C2 of the indole
moiety is linked through the Schiff base functional group
to a second phenyl ring C17 to C22 which is twisted into
the opposite direction relative to indole with a torsion
angle of C22-C17-N2-C2 at 75.0(5)°.[6]
and chemical mechanisms through the estimation of
compounds’ geometrical properties
[8].
It may also deliver
fine details of the electronic properties of reactants,
intermediates and products as well as support and explain
various experimental observations [9, 10]. The still growing
interlocking of experimental and computational chemistry
has solved a wide range of organic chemical problems.
Computational chemistry might even encourage novel
ideas in planning unprecedented chemical reactions and
experimental mechanistic studies [1,11, 12].
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molecule itself or whether this is driven by crystal packing
effects. Therefore, in order to understand in more detail
why only the (E) isomer crystallized, a comprehensive
computational investigation into this issue was carried out.
Figure 1. The molecular structure of compound I.
Ellipsoids are shown at the 50% probability level.
Figure 2. Crystal packing of compound (I) along the c-axis.
The molecular structure exhibits a weak intra-molecular
non-classical hydrogen bond between the phenyl carbon
C16 as donor and the keto oxygen atom as acceptor (d D-H
0.95 Å; d H···A 2.68 Å, D···A 3.431 Å, < DHA 137°). In
the crystal lattice one significant inter-molecular non-
classical hydrogen bonding interaction is present (C18—
H18···N2i; (i) -x+3/2, -y+1/2, z) with distances d (D-H), d
(H···A), d (D···A) of 0.95 Å, 2.65 Å and 3.511(5) Å,
respectively, and an angle < (DHA) of 151°. This
interaction is bi-directional (푅22(8) pattern) and leads to the
formation of hydrogen bonded dimers. The dimers are
further stabilized by π-π stacking of the phenyl rings of the
indole moieties with a centroid to centroid distance of
3.672(2) Å and a slippage of 1.482 Å. Adjacent dimers in b
or in c direction are arranged in parallel orientation while
those in c direction are perpendicular. This leads to a type
of zig-zag fashion arrangement when viewed along the
crystallographic c axis (Fig. 2). All methoxy substituted
phenyl rings are arranged in the same direction with regard
to the c axis, i.e. here shown as below the rest of the
molecules/dimers (Fig. 3) and those of adjacent (in b
direction) molecules point away from each other based on
the fact that the molecules constitute (E) isomers. The
orientation of the methoxy-phenyl moiety is further
supported by the hydrogen bond involving N2 to which it
is attached plus O1 as acceptors and C6-H6 as donor. This
hydrogen bond draws an adjacent molecule near and
prevents the methoxy-phenyl moiety to bend over for a
lack of space. Based on the observed intra- and
intermolecular interactions it is certainly reasonable why
only the (E) isomer was observed crystallographically but
it is not entirely exclusive. A full interaction map (FIM;
see SI Figure S8) analysis reveals that only the hydrogen
bonding interaction of N2 and O1 as acceptors with C6-H6
as donor can be considered exemplary geometry wise and
this only indirectly involves the orientation of the
methoxy-phenyl substituent. All other inter- or
intramolecular interactions are far from geometrically ideal
compared to other structures in the Camdridge
Crystallographic Database. I.e. also with the (Z) isomer
related intermolecular interactions are presumed to be
generally possible. It is, hence, impossible based on the
crystallographic data alone to elucidate whether the
preference for the (E) isomer is an intrinsic feature of the
Figure 3. Crystal packing of compound (I) along the b-
axis.
2.2. Computational studies
DFT methods were used to calculate selected geometrical
parameters. The respective calculations were initially
based on the experimentally observed metrical parameters.
The findings of computational DFT and experimental XRD
methods are very similar showing merely minor deviations,
that may attribute to the molecular environment differences.
The experimental molecular structure of the (E) isomer of
the title compound was characterized by X-ray
crystallography, i.e. necessarily in the crystalline phase,
whereas DFT calculations of the isolated molecule and the
second isomer were performed in the gas phase.
Geometrical parameters calculated for the (E) isomer (Fig.
1) together with the experimental data of the title
compound are summarized in Tables 1–3. The observed
differences can be assigned predominantly to packing
effects and intermolecular interactions reflected in the
experimental data. Notably in the X-ray structure, the
double bonds are shorter and thereby appear to be a little
less delocalised in comparison.
Table 1. Bond lengths (Å) by X-ray and theoretical
calculations.
X-ray
B3LYP/6-31G(d,p).
(E-isomer)
1.240
O(1)-C(1)
O(2)-C(20)
O(2)-C(23)
N(1)-C(1)
N(1)-C(8)
N(1)-C(10)
N(2)-C(2)
N(2)-C(17)
C(1)-C(2)
C(2)-C(3)
C(3)-C(8)
1.225(4)
1.361(4)
1.412(5)
1.356(5)
1.411(5)
1.461(5)
1.280(5)
1.419(4)
1.515(5)
1.460(5)
1.385(5)
1.388
1.452
1.395
1.410
1.461
1.288
1.404
1.523
1.478
1.419
2
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maximum positive Mulliken charges were found on C1,
C20 and C17 with 0.510, 0.302 and 0.093, respectively,
because they are connected to more electronegative atoms.
Interestingly, the N1 atom (-0.695) exhibits the maximum
negative Mulliken charge. The generally more
electronegative oxygen atoms O2 (-0.585) atom and O1 (-
0.399) have intermediate negative Mulliken charges, while
N2 (-0.340) has the least negative one of the heteroatoms.
C5 and C8 are para-atoms of the indole’s phenyl ring
involved in the experimentally observed π-π stacking. The
rings are twisted against each other so that the particularly
positively charged atoms are not directly stacked but
interact with atoms C4 and C7. The presence of a net
positive charge on the hydrogen atom H18 (0.151) and the
still considerably negative charge on the adjacent nitrogen
atom N2 (-0.340), could facilitate a charge transfer via the
formation of the intermolecular hydrogen bond (C18—
H18···N2) which was also observed experimentally.
C(3)-C(4)
C(4)-C(5)
C(5)-C(6)
C(5)-C(9)
C(6)-C(7)
C(7)-C(8)
C(10)-C(11)
1.402(5)
1.390(5)
1.394(5)
1.501(5)
1.384(5)
1.378(5)
1.503(5)
1.397
1.407
1.406
1.513
1.402
1.390
1.520
Table 2. Bond angles (°) by X-ray and theoretical
calculations.
X-ray
DFT/B3LYP
(E-isomer)
118.876
C(20)-O(2)-C(23)
118.3(4)
C(1)-N(1)-C(8)
C(2)-N(2)-C(17)
110.7(3)
120.7(3)
110.718
127.937
N(1)-C(1)-C(2)
C(8)-C(3)-C(4)
C(5)-C(4)-C(3)
C(4)-C(5)-C(9)
C(7)-C(6)-C(5)
C(7)-C(8)-C(3)
N(1)-C(10)-C(11)
106.5(3)
119.4(3)
119.7(3)
121.4(3)
122.2(4)
122.0(3)
113.7(3)
106.340
119.251
120.348
120.520
122.119
121.513
114.266
Table 4. Mulkin charges of the (E) and (Z) isomer.
Atom
C1
Mulliken E isomer
0.510
Mulliken Z isomer
0.530
O1
-0.399
0.030
-0.413
0.064
C2
C3
0.084
0.064
Table 3. Torsion angles(°) by X-ray and theoretical
calculations
C4
-0.131
0.08
-0.139
0.085
C5
X-ray
DFT/B3LYP (E-
isomer)
C6
-0.156
-0.092
0.282
-0.157
-0.094
0.298
C7
C1-N1-C10-C11
N1-C10-C11-C12
N1-C10-C11-C16
C3-C2-N2-C17
C22-C17-N2-C2
-92.26
-123.61
56.99
8.24
111.350
128.804
-52.959
C8
N1
-0.695
-0.340
-0.115
0.118
-0.713
-0.402
-0.185
0.108
N2
9.783
C10
C11
C12
C13
C14
C15
C16
C17
C18
H18
C19
C20
C21
C22
O2
74.99
44.861
-0.166
-0.125
-0.120
-0.128
-0.142
0.093
-0.140
-0.122
-0.116
-0.125
-0.128
0.135
Mulliken atomic charges
In order to understand the electronic structure of the
molecule better, Mulliken charges were computed
[13][14]
and the results are listed in Table 4. The charge
distribution across the atoms was found to be significant in
describing donor and acceptor pairs and to obtain insights
into the overall chemical activity of the compound. The
calculations are also represented in form of the MEP
surfaces in Fig. 4. Notably in the (Z) isomer the strongly
negative charge on the carbonyl oxygen atom is less
exposed to the environment, while those carbon atoms with
a significant positive charge in both isomers appear to be
slightly less positive in the (E) isomer. Also C23 is
negative for the (E) and positive for the (Z) isomer. I.e. in
the (Z) isomer the negative charge is less and the positive
charge more localized and in the (E) isomer the opposite is
true. The computed results reveal that only C1, C2, C5, C8,
C11, C17 and C20 exhibit a positive Mulliken charge
whereas all other atoms exhibit negative charges. The
-0.090
0.151
-0.054
0.127
-0.155
0.302
-0.134
0.307
-0.134
-0.096
-0.585
-0.54
-0.153
-0.102
-0.584
0.154
C23
3
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(LUMO). The HOMO/ LUMO energy gap constitutes a
critical parameter in determining, for instance, molecular
electrical transport properties [18][19]. The global chemical
reactivity descriptors calculated for the (E) and (Z) isomer
of the title compound using DFT are: electron affinity (A),
chemical potential (μ), ionization potential (IP), chemical
hardness (η), electronegativity (χ), and electrophilicity (ɷ),
(Table 5). The calculated energy gap between HOMO and
LUMO of the (E) isomer is 0.1132 Hartree (3.0811 eV)
while for the (Z) isomer it is larger with 0.12022 Hartree
(3.2715eV) demonstrating that the (Z) isomer is harder,
more stable and less reactive than the (E) isomer. The
electron affinity (EA) reflects the change in the energy
imposed on a species by receiving one additional electron,
while the ionization potential (IP) value reflects the
propensity of losing one electron. The chemical hardness
(η) is a measure of mechanical deformation resistance, or
physical hardness. Essentially, it is the resistance measure
against change in the electron distribution in a collection of
nuclei and electrons.[21] From the global reactivity study,
the HOMO and LUMO orbital energies lead to gas phase
ionization energies (IP = −εHOMO) and electron affinities
(EA = −εLUMO) of (E) and (Z) isomers of 5.4161/2.3350
eV and 5.5477/2.2762 eV. The electronegativity (χ) is a
measure of the attraction of an atom for electrons in a
covalent bond[22]. The computed electronegativity (χ=
εHOMO + εLUMO)/2),) value for the (E) isomer is (2.708
eV) and for the (Z) isomer it is (3.911 eV) indicating that
the (Z) isomer has significantly greater electron accepting
power than the (E) isomer. The global electrophilicity
index (ω = μ2/2 η) was calculated using the electronic
chemical potential (μ) and the chemical hardness (η). The
global electrophilicity index (ω) reflects a compound's
electrophilic power which depends on thermodynamic
properties. It can be defined as the decrease in energy due
to the flow of electrons from the donor (HOMO) to the
acceptor (LUMO) in molecules. This plays an important
Figure 4. Calculated MEP surfaces of the (E) isomer (left)
and the (Z) isomer (right).
Molecule reactivity analysis by global reactivity
descriptors
Scheme 1. Chemical structures of the (E) and (Z) isomers.
The frontier molecular orbitals (FMOs) comprise the
highest energy occupied molecular orbital (HOMO) and
the lowest energy unoccupied molecular orbital (LUMO)
in a molecule and these are the most important orbitals in a
[15]
molecule as they define the compound’s reactivity
.
They are well-known indicators with respect to the
reactivity of compounds as they determine the ability of a
compound to accept an electron from (in the case of
LUMO) or donate one to (in the case of HOMO) a reaction
partner [16][17]. HOMO and LUMO orbitals of the (E) and
(Z) isomer (see Scheme 1) of the title compound were
examined and are shown in Figs. 5 and 6.
Figure 5. Plots of the frontier molecular orbitals for the (E)
isomer; left: LUMO = –0.08581 Hartree = –2.3350 eV;
right: HOMO = –0.19904 Hartree = –5.416 eV
role in determining the chemical reactivity of a system[23]
.
The electrophilicity values for the (E) and (Z) isomers are
4.871 eV and 4.677 eV, respectively, indicating that the
(E) isomer is the stronger nucleophile while the (Z) isomer
is the stronger electrophile in accordance with the
computed electronegativity[24-26]. Electrophilicity (ω) is
used to describe the stabilization energy if the system
subjected to saturation by electrons come from the external
environment. This reactivity information reveals whether
or not a molecule can donate charge. A molecule with a
low value of (ω) is a better nucleophile of higher reactivity
while higher values of (ω) indicate the presence of a good
electrophile[22]. Our findings show that the (Z) isomer has
Figure 6. Plots of the frontier molecular orbitals for the (Z)
isomer; left: LUMO = –0.08365 Hartree = –2.2762 eV;
right: HOMO = -0.20387 Hartree = -5.5477 eV
The theoretical FMOs are further used for identifying the
most likely origin and target atoms of intramolecular
electron transfer from the highest occupied molecular
orbital (HOMO) to lowest unoccupied molecular orbital
4
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lower values of (ω), indicating that it is the better
nucleophile. Consequently, the (E) isomer appears to be
the better electrophile. All of these values are substantially
distinct for the two isomers which is surprising and
highlights the importance of stereo-chemical factors for the
reactivity of compounds. Finally, the total energy of each
isomer was calculated and that of the (E) isomer (–
1148.138 Hartree) appears to be slightly higher than that of
the (Z) isomer (–1148.147 Hartree). Theoretically the (Z)
isomer is therefore more stable than the (E) isomer but the
observed difference (5.65 kcal·mol–1) is not decisive
enough to suggest that the formation of the (E) isomer is
generally precluded. However, this energy difference
contrasts the observation of the exclusive formation of the
(E) isomer in the solid state. We therefore conclude that
indeed the intermolecular interactions, in particular the
strong bifurcated hydrogen bond involving carbonyl
oxygen and amine nitrogen as acceptors comprises the
driving force for the exclusive formation of the (E) isomer
in the crystalline material.
various derivatives thereof are being explored as well as
the substantial impact crystal packing effects can have in
the solid state.
Experimental Section
2.1. Physical techniques and materials
The reagents and solvents needed for synthesis and
spectroscopic studies were commercially procured and
used as received without further purification. NMR spectra
were recorded on a Bruker spectrophotometer (400 MHz
1
for H and 100 MHz for 13C), Faculty of Pharmacy, El-
Mansoura University, El-Mansoura. Elemental analysis
was performed on a Perkin Elmer 2400 CHN elemental
analyzer, Regional Center for Mycology and
Biotechnology, Al-Azhar University, Cairo, Egypt.
2.2. Synthesis and characterization of (E)-1-benzyl-3-
((4-methoxyphenyl)imino)-5-methylindolin-2-one
The synthesis of the known Schiff base compound
(E)-1-benzyl-3-((4-methoxyphenyl)imino)-5-
methylindolin-2-one according to literature procedures is
outlined in Scheme 2. The first step involves the alkylation
of 1H-indole-2,3-dione phenylbromide in DMF in the
presence of K2CO3 as reported [27][28]. The second step
comprises a typical Schiff base preparation using p-
methoxyaniline in glacial acetic acid. These procedures
were previously reported and discussed in detail by Wang
Table 5 The calculated global reactivity properties of (E)
and (Z) isomer by B3LYP/6-31G(d,p).
Parameter
EHOMO, (eV)
ELUMO, (eV)
ΔE, (eV)
IP, (eV)
E-isomer
-5.4161eV
-2.3350 eV
3.0811
Z-isomer
-5.5477
-2.2762
3.2715
5.5477
2.2762
1.6357
3.9119
4.6778
et al.[29][30]
.
5.4161
EA, (eV)
Ƞ, (eV)
2.3350
1.5405
χ, (eV)
3.875
ω, (eV)
4.871
Conclusion
It was possible to obtain a crystal structure of the known
title compound in high quality. The metrical parameters are
to some extent influenced by crystal packing effects and
intermolecular interactions as confirmed by
a
Scheme 2
computational analysis and respective observed differences
in some distances and angles. Notably, the only
Elemental analysis for C23H20N2O2; calculated: C, 77.51;
H, 5.66; N, 7.86. Found: C, 77.28; H, 5.89; N, 7.95.
H1NMR: 7.41-7.31 (m, 2H, isatin), 7.19-7.29 (m, 2H,
phenyl), 7.06-7.09 (m, 6H, benzyl), 6.91-6.95), 6.5 (singlet,
2H, CH2-benzyl, 3.3 (singlet, 3H, OCH3), 2.5 (triplet, 3H,
aCH3)
C13NMR: 163.03 (indole C=O), 157.8 (indole C=N),
153.95 (C-OCH3), 145.04 (phenyl C-N), 143.31, 141.40,
136.48, 134.79, 131.72, 129.19, 129.15, 128.01, 127.84,
127.79 , 125.64, 123.63, 120.22, 115.96, 115.19, 113.93,
experimentally
observed
isomer
is
not
the
thermodynamically favoured one in the gas phase
according to the computational evaluation. Parameters
descriptive of the molecules’ reactivity are distinct for the
two isomers. This study, thereby, highlights the relevance
of
isomerism
which
goes
beyond
merely
geometrical/structural aspects with implications also for a
pharmaceutical context in which the title compound and
5
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110.93 (Aro C), (55.77 (OCH3), 43.29 (benzyl C-N), 20.98
(indole CH3)
unique
[R(int) = 0.0753]
99.8 %
Completeness to theta =
25.242
2.3. X-ray single crystal analysis
Absorption correction
Refinement method
None
A suitable single crystal of compound I was mounted on a
thin glass fiber which was coated with paraffin oil. X-ray
single-crystal structural data were measured at low
Full-matrix least-squares on
F2
Data / restraints / parameters 4780 / 1 / 247
Goodness-of-fit on F2
1.101
Final R indices[I>2sigma(I)] R1 = 0.0486, wR2 = 0.1091
temperature (170 K) employing
a STOE-IPDS II
diffractometer that is equipped with a normal-focus, 2.4
kW, sealed-tube X-ray source which generates graphite-
monochromated Mo Kα radiation (λ= 0.71073 Å). The
program XArea by STOE © was used for integrating the
diffraction profiles. The structure was solved by direct
methods with the programme SHELXT and refined by
full-matrix least-squares methods with the programme
SHELXL [31]. All calculations were carried out with the
WinGX system GUI, Ver 2018.3[32]. Every non-hydrogen
atom was refined anisotropically. All hydrogen atoms were
located first on the density map and then refined
isotropically on calculated positions using the typical
riding model which constrains their Uiso values to 1.5Ueq of
their pivot atoms for methyl groups and to 1.2Ueq of their
pivot atoms for all other groups. Crystallographic data
were deposited with the Cambridge Crystallographic Data
Centre, CCDC, 12 Union Road, Cambridge CB21EZ, UK.
These data can be obtained free of charge on quoting the
depository number CCDC 2058589 by FAX (+44-1223-
336-033), email (deposit@ccdc.cam.ac.uk) or, most
R indices (all data)
Absolute structure
parameter
R1 = 0.1011, wR2 = 0.1467
0.7(9)
Extinction coefficient
Largest diff. peak and hole
0.0026(3)
0.346 and -0.309 e· Å–3
2.4. Quantum chemical calculations (DFT calculations)
DFT calculations were carried out with the Gaussian 09W
and the data were analysed with various methods.[13, 14, 35,36]
For computational details (including a full list of co-
authors) please refer to the SI.
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(adamantan-1-yl)-3-[(4-chlorobenzyl)sulfanyl]-4-
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Crystal and refinement data for the structure determination
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Table 6: Crystallographic data of I crystallized as the (E)
isomer.
Empirical formula
Formula weight
Temperature
C23 H20 N2 O2
356.41
170(2) K
Wavelength
0.71073 Å
Crystal system, space group Orthorhombic, Fdd2
Unit cell dimensions
a = 48.727(10) Å,
b = 8.7971(18) Å,
c = 16.642(3) Å,
α = β = γ = 90°
7134(2) Å3
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