Synthesis and structural analysis of novel indole derivatives by XRD, spectroscopic and DFT studies

Article abstract of DOI:10.1016/j.molstruc.2019.127438

The indole derivatives have been getting immense interest to possess diverse applications in different fields. In present investigation, four novel indole based derivatives namely; 4,6-dimethoxy-2,3-diphenyl-1H-indole 3a, 4,5,6-trimethoxy-2,3-diphenyl-1H-

Full text of DOI:10.1016/j.molstruc.2019.127438

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Synthesis and structural analysis of novel indole derivatives by XRD, spectroscopic
and DFT studies
Sobia Tariq, Abdul Rauf Raza, Muhammad Khalid, Syeda Laila Rubab, Muhammad
Usman Khan, Akbar Ali, Muhammad Nawaz Tahir, Ataualpa Albert Carmo Braga
PII:
S0022-2860(19)31547-9
DOI:
https://doi.org/10.1016/j.molstruc.2019.127438
MOLSTR 127438
Reference:
To appear in: Journal of Molecular Structure
Received Date: 26 August 2019
Revised Date: 1 November 2019
Accepted Date: 16 November 2019
Please cite this article as: S. Tariq, A.R. Raza, M. Khalid, S.L. Rubab, M.U. Khan, A. Ali, M.N. Tahir,
A.A.C. Braga, Synthesis and structural analysis of novel indole derivatives by XRD, spectroscopic and
DFT studies, Journal of Molecular Structure (2019), doi: https://doi.org/10.1016/j.molstruc.2019.127438.
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Synthesis and structural analysis of novel indole derivatives by XRD,
spectroscopic and DFT studies
1
1
2
3
Sobia Tariq, Abdul Rauf Raza, * Muhammad Khalid, * Syeda Laila Rubab,
4
1
5
Muhammad Usman Khan, Akbar Ali, Muhammad Nawaz Tahir, Ataualpa Albert
6
Carmo Braga
1
Ibn-e-Sina Block, Department of Chemistry, University of Sargodha, Sargodha-40100, Pakistan
Department of Chemistry, Khwaja Fareed University of Engineering & Information
2
Technology, Rahim Yar Khan-64200, Pakistan
3
Department of Chemistry, Division of Science and Technology, University of Education,
Lahore, Pakistan
4
Department of Applied Chemistry, Government College University, Faisalabad-38000, Pakistan
Ibn-ul-Hathim Block, Department of Physics, University of Sargodha, Sargodha-40100,
5
Pakistan
6
Departamento de Química Fundamental, Instituto de Química, Universidade de São Paulo,
Avenida Professor Lineu Prestes, 748, São Paulo 05508-000, Brazil
̃
1
*
Corresponding author E-mail address: rauf.raza@uos.edu.pk ; roofichemist2012@gmail.com
2
*
Corresponding author E-mail address: muhammad.khalid@kfueit.edu.pk; Khalid@iq.usp.br
Abstract
The indole derivatives have been getting immense interest to possess diverse applications in
different fields. In present investigation, four novel indole based derivatives namely; 4,6-
dimethoxy-2,3-diphenyl-1H-indole 3a, 4,5,6-trimethoxy-2,3-diphenyl-1H-indole-7-carbaldehyde
4
b, N-(3'''-chlorophenyl) (4,6-dimethoxy-2,3-diphenyl-1H-indol-7-yl)methanimine 6a and N-
(3'''-chlorophenyl) (4,5,6-trimethoxy-2,3-diphenyl-1H-indol-7-yl)methanimine 6b were
1
13
synthesized and characterized by H-NMR & C-NMR to resolve their molecules structures. To
provide additional spectroscopic support, FT-IR and UV–Visible techniques were executed for
characterization of entitle synthesized molecules. The X-ray diffraction (XRD) studies have been
performed to evaluate bond angles, bond lengths, unit cells and specific space groups. Ancillary,
density functional theory (DFT) study at B3LYP level of theory and 6-311+G(d,p) basis set to
investigate the optimized geometry, FT-IR vibrational analysis, frontier molecular orbital
(
FMO), molecular electrostatic potential (MEP) and nonlinear optical (NLO investigations. The
results of single crystal studies and experimental spectroscopic studies were compared with
computational insights and found in good agreement. Global reactivity parameters were
estimated using energy values of FMOs. The UV-Vis spectral analysis was executed by time

dependent DFT (TDDFT) at B3LYP/6-311+G(d,p) level of theory. Two-state model and urea
molecule comparative analysis evident that 3a, 4b, 6a and 6b comprise of fine NLO properties.
We hope that this synergistic experimental-computational study may provide new ways for the
utilization of investigated molecules for NLO associated hi-tech applications.
Keywords: Synthetic indole imines, SC-XRD, Density functional theory, Spectroscopic
data, Frontier Molecular Orbital analysis
Introduction
The diverse biological activities and pharmacological significance of indole moiety has
fascinated scientists to discover novel drugs with different modes of action. Currently, there is a
remarkable number of indole containing drugs in the market; however, a few are in clinical
evaluation. The indole alkaloids and their synthetic analogues have exhibited significant
anticancer [1], antioxidant [2], antiviral [3], antimicrobial [4], analgesic, anti-inflammatory [5],
anticonvulsant [6], antimalarial [7], antihypertensive [8], antihyperglycemic [9], antifertility [10],
anti-Parkinson’s [11] and gastroprotective [12] activities. These natural and synthetic analogues
of indoles also show some agricultural (as plant growth regulators [13], fungicidal [14],
insecticidal [15], herbicidal [16] etc.) and industrial applications (like dyes/pigments [17], food
supplements [18], essential oils [19], flavor enhancer [20], photographical materials [21] etc.).
Usual biological activities shown by heterocyclic compounds include their toxic and
pharmacological implications. Most of the pesticides, chlorinated or phosphorilated heterocyclic
hydrocarbons, a large variety of non-steroidal anti-inflammatory drugs (NSAIDs), antibacterial,
antifungal and antibiotics are also derived from synthetic or semi-synthetic heterocyclic
compounds. The marketed diazepines are completely synthetic compounds that shows a wide
range of pharmacological profile, such as, anti-HIV [22], anticancer [23], antipsychotic [24],
antischizophrenic [25], antianxiety [26], anti-inflammatory [27], antimicrobial [28], arrhythmic
[
29], anticonvulsant [30] activities. Diverse methods of synthesis have been reported for the
synthesis of a variety of natural, synthetic and semi-synthetic indoles including indole alkaloids
31-34].
[
Keeping in view all preceding significance of indole moiety and having computational as well as
synthetic study background [35-44], herein we report the synthesis of novel compounds 4,6-

dimethoxy-2,3-diphenyl-1H-indole 3a, 4,5,6-trimethoxy-2,3-diphenyl-1H-indole-7-carbaldehyde
b, N-(3'''-chlorophenyl) (4,6-dimethoxy-2,3-diphenyl-1H-indol-7-yl) methanimine 6a and N-
3'''-chlorophenyl) (4,5,6-trimethoxy-2,3-diphenyl-1H-indol-7-yl) methanimine 6b as shown in
4
(
schemes 1 and 2. Literary survey exposed that the synthetic, XRD, spectroscopic and
computational insights of compounds 3a-b, 4a-b and 6a-b are missing. Therefore, we performed
1
13
spectroscopic ( H-NMR, C-NMR, FT-IR, UV-Vis) and XRD analyses of these indole
containing derivatives. The computational calculations performed to support the structural and
spectroscopic characteristics. We also determined the frontier molecular orbital (FMO), global
reactivity parameters and molecular electrostatic potential (MEP) surfaces of 3a, 4b, 6a and 6b.
Materials and methods
All chemicals and reagents of analytical grade were purchased from Sigma-Aldrich, Fluka, Mp
Biomedicals or Merck. The pre-coated silica gel (0.25 mm thick layer over Al sheet, Merck)
TLC was used to monitor the reaction. The IR and UV/Vis spectra were recorded on Shimadzu
(Prestige 21) FT-IR spectrometer as KBr discs and Thermo Spectronic (UV-1700)
1
13
3
spectrophotometer in CHCl /MeOH respectively. The H-NMR and C-NMR were recorded in
CDCl on a Bruker AVANCE DPX300/400/500 (300, 400 or 500 MHz) spectrometer using
3
4
Me Si as internal standard. The LR ESI was recorded on Q-TOF Ultima API (Micromass) at the
Biomedical Mass Spectrometry Facility (BMSF), UNSW, Sydney (Australia). The single crystal
X-Ray data were recorded on Bruker Kappa APEX 11 CCD diffractometer at Department of
Physics, University of Sargodha (Pakistan).
Computational procedure
In present study, complete quantum chemical calculations were performed with DFT [45]
utilizing Gaussian 09 program [46] and results were visualized using GaussView [47]. The
crystal structures of investigated compounds generate the initial geometries of 3a, 4b, 6a and 6b,
which were subjected to optimization analysis, performed without any symmetry restrictions in
gas phase with conjunction of B3LYP level of theory and 6-311+G(d,p) basis set. To confirm the
stability of investigated compounds and completion of optimization analysis, frequency analysis
were performed at same B3LYP/6-311+G(d,p) functional. The absence of imaginary frequency
in all investigated compounds (3a, 4b and 6a-b) ascertains the structures are stable. The FMO

and MEP analysis were executed using 6-311+G(d,p) basis set and B3LYP level of theory. For
the estimation of photophysical properties of investigated compounds (3a, 4b and 6a-b), UV-Vis
spectral analysis were performed using TDDFT calculations at B3LYP/6-311+G(d,p) level of
theory. The GaussView 5.0 [47], Chemcraft [48] and Avogadro [49] programs were utilized to
deduce results from output files.
Experimental
Synthesis of 4,6-dimethoxy- and 4,5,6-trimethoxy-2,3-diphenyl-1H-indole (3a-b)
A mixture of 3,5-dimethoxyaniline 1a / 3,4,5-trimethoxyaniline 1b (13.1 mmol, 3 eq) and 2-
hydroxy-1,2-diphenylethanone 2 (2.8 g, 13.1 mmol, 3 eq) was heated at 120 ºC for 2 h. The
2
mixture was cooled to ambient followed by the addition of PhNH (0.41 mL, 4.4 mmol, 1 eq)
and AcOH (8.1 mL, 8.5 g, 0.141 mol, 32 eq). The resulting mixture was heated at 130 ºC for 5 h.
The resulting solution was cooled to ambient and filtered. The crude product was washed with
MeOH to afford a colorless crystalline solid in appreciable yield.
3
/
,5-dimethoxyaniline 1a (2.01 g), 3a as off white crystalline solid (2.40 g, 56%); R : 0.3 (EtOAc
f
-1
H
n-hexane, 2:3); mp: 240–242 ºC; log ε (λmax, nm): 4.62403 (325); ύ (cm ): 3343 (N–H); δ in
5
ppm (300 MHz): 3.73, 3.92 (3H each, s, OCH ), 6.26 (d, 1H, J = 1.9 Hz, H ), 6.57 (1H, d, J =
3
7
1
.9 Hz, H ), 7.22–7.45 (10H, m, 2Ph), 8.16 (1H, bs, NH); δ in ppm (75 MHz): 55.2, 55.7 (q,
C
5
7
3
3a
4΄
4΄΄
3
OCH ), 86.5, 92.5 (d, C & C ), 113.0, 115.0 (s, C & C ), 125.9, 126.9 (d, C & C ), 127.3,
2
΄
3΄
2΄΄
3΄΄
1΄
1΄΄
1
27.8, 128.5, 131.5 (all 2×, d, C , C , C & C ), 131.9, 133.0 (s, C & C ), 135.9, 137.4 (s,
2
7a
4
6
+·
· +
C & C ), 155.3, 157.8 (s, C & C ); LR EIMS (m/z, amu): 329 [M] (100%), 314 [M – Me ]
(54%); CHNS analysis: found for C H NO : C (79.9%); H (5.7%), N (4.2%), requires: C
22 19 2
(80.2%); H (5.8%); N (4.3%).
3
,4,5-(OMe) NH 1b (2.40 g), 3b as off white crystalline solid (2.40 g, 50%); R : 0.25
3
C
6
H
2
2
f
-
1
(
(
(
EtOAc / n-hexane, 1:7); mp: 218–220 ºC; log ε (λmax in nm): 2.89228 (318); ύmax (cm ): 3363
7
N–H); δ in ppm (300 MHz): 3.36, 3.72, 3.87 (3H each, s, OCH ), 6.78 (1H, s, H ), 7.23–7.48
H
3
10H , m, 2× Ph), 8.12 (bs, 1H, NH); δ
C
3
in ppm (75 MHz): 56.3, 60.9, 61.2 (q, OCH ), 90.7 (d,
7
3
3a
4΄
4΄΄
C ), 113.5, 115.8 (s, C & C ), 126.4, 127.2 (d, C & C ), 127.9, 128.0, 128.7, 131.3 (all 2×, d,
2
΄
3΄
2΄΄
3΄΄
1΄
1΄΄
2
7a
C , C , C & C ), 132.9, 133.0, (s, C & C ), 133.4, 136.6 (s, C & C ), 136.8, 146.7, 151.0
4
5
6
+•
(
all s, C , C & C ); LR EIMS (m/z, amu): 359 [M] (100%).

Synthesis of 4,6-dimethoxy- and 4,5,6-trimethoxy-2,3-diphenyl-1H-indole-7-carbaldehyde (4a-
b)
The indole 3a-b (3 mmol, 1 eq) was added to a solution of POCl (0.85 mL, 1.4 g, 9 mmol, 3 eq)
3
in DMF (20 mL). The reaction was stirred at room temperature for 2½ h before being quenched
with chilled H O (100 mL) and was basified with aq. NaOH solution (50 mL of 1 M). The
2
2
resulting precipitate was filtered, washed with chilled H O and dried over anhydrous silica in
desiccators under reduced pressure to afford aldehyde 4a-b as a yellow solid, which was
crystallized from CHCl /n-hexane to afford light yellow crystals of aldehyde 4a-b in excellent
3
yield.
Indole 3a (0.99 g), 4a (0.99 g, 92%); R : 0.18 (CHCl / n-hexane, 1:4); mp: 180–182 ºC; log ε
f
3
-1
(λ
H
max, nm): 3.59740 (372); ύ (cm ): 3298 (N–H), 1608 (C=O); δ in ppm (300 MHz): 3.81, 4.00
5
(
3H each, s, OCH ), 6.15 (1H, s, H ), 7.23–7.36 (10H, m, 2 Ph), 10.41 (1H, s, CHO), 10.59 (1H,
3
5
7
bs, NH); δ in ppm (75 MHz): 55.5, 56.4 (q, OCH ), 86.9 (d, C ), 104.2 (s, C ), 112.76, 114.7 (s,
C
3
3
3a
4΄
4΄΄
2΄
3΄
2΄΄
3΄΄
C & C ), 126.2, 127.3 (d, C & C ), 127.5, 127.9, 128.5, 131.3 (all 2×, d, C , C , C & C ),
1
΄
1΄΄
2
7a
4
6
8
1
32.2, 133.3 (s, C & C ), 135.4, 136.8 (s, C & C ), 161.7, 163.0 (s, C & C ), 188.2 (d, C );
+
·
LR EIMS (m/z, amu): 357 [M] (100%).
Indole 3b (1.08 g), 4b (0.93 g, 80%); R
f
: 0.65 (CHCl
3
/ n-hexane, 3:7); mp: 158 ºC; log ε (λmax in
-1
nm): 3.92456 (358); ύmax (cm ): 1647 (C=O), 3347 (N–H); δ in ppm (500 MHz): 3.62, 3.89,
H
4
1
.10 (3H each, s, OCH
3 2
), 7.26–7.40 (10H, m, 2Ph), 10.43 (1H, s, D O non-exchangeable, CHO),
0.45 (1H, bs, D O exchangeable, NH); δ in ppm (125 MHz): 61.5 (q, OCH ), 63.2 (2×, q,
2
C
3
7
3
3a
4΄
4΄΄
OCH ), 107.8 (s, C ), 114.3, 118.8 (s, C & C ), 126.6, 127.7 (d, C & C ), 128.0, 127.8, 128.6,
3
2
΄
3΄
2΄΄
3΄΄
1΄
1΄΄
2
7a
1
1
3
31.2 (all 2×, d, C , C , C & C ), 131.8, 132.0 (s, C & C ), 134.6, 135.2 (s, C & C ),
5
4
6
8
+•
53.1 (s, C ), 154.0 (2×, s, C & C ), 190.0 (d, C ); LR EIMS (m/z, amu): 388.3 [M + 1] (26%);
+
•
+•
87.3 [M] (100%), 372.3 [M – Me] (34%).
Synthesis of indole imines (6a-b)
A mixture of solid aldehyde 4a/4b (2.8 mmol, 1 eq) and 3-chloroaniline 5 (0.9 mL, 1.1 g, 8.4
mmol, 3 eq) was heated at 200 ºC for 36 h in a thick glass tube without stopper. The H O
2
produced as a by-product was collected at the neck of the flask. Upon the completion of reaction
the resulting product was thoroughly washed with MeOH to remove excess of aniline 5, which

was crystallized from neutralized CHCl
in excellent yield.
3
/ n-hexane to afford fast yellow crystalline solids 6a-b
N-(3'''-Chlorophenyl) (4,6-dimethoxy-2,3-diphenyl-1H-indol-7-yl)methanimine 6a: carbaldehyde
a (1.0 g), imine 6a (1.1091 g, 85%); R : 0.69 (CHCl / n-hexane, 1:1); mp: 185 ºC; log ε (λmax,
4
f
3
-1
nm): 4.02584 (379); ύ (cm ): 1566 (C=N), 3338 (N–H); δ in ppm (400 MHz): 3.79, 3.98 (3H
H
5
each, s, OCH ), 6.22 (1H, s, H ), 7.14–7.41 (m, 14H), 9.07 (1H, s, HC=N), 11.36 (1H, bs, NH);
3
5
7
3
δ
H
3
in ppm (100 MHz): 55.4, 56.6 (q, OCH
3
), 87.6 (d, C ), 101.7 (s, C ), 113.0, 114.6 (s, C &
a
2
4
6
4
4
C ), 119.8, 121.3, 125.0 (d, C , C and C ), 126.1, 126.9 (d, C & C ), 127.4, 127.8, 128.5, 131.5
2
΄
3
2
3
5
1΄
1
3
(
2×, d, C , C , C & C ), 130.5 (d, C ), 132.8, 132.9 (s, C & C ), 134.6 (s, C ), 135.9, 136.6 (s,
2
7a
1΄΄΄
8
4
6
C & C ), 151.3 (s, C ), 157.0 (d, C ), 159.3, 159.8 (s, C & C ); CHNS analysis: found for
C H ClN O : C (72.93%), H (4.56%), N ( 5.69%), requires: C (74.59%), H (4.96%), Cl
29
23
2
2
(7.59%), N (6.00%), O (6.85%).
N-(3'''-Chlorophenyl) (4,5,6-trimethoxy-2,3-diphenyl-1H-indol-7-yl)methanimine 6b:
carbaldehyde 4b (1.084 g), imine 6b (1.2499 g, 90%); R : 0.60 (CHCl / n-hexane, 1:1); mp: 149
f
3
-1
º C; log ε (λmax, nm): 4.70187 (370); ύ (cm ): 1558 (C=N), 3348 (N–H); δ in ppm (500 MHz):
H
3
.59, 3.92, 4.08 (3H each, s, OCH
3
), 7.24–7.45 (14H, m, 3 Ph), 9.02 (1H, s, HC=N), 11.28 (1H,
7
3
bs, NH); δ in ppm (125 MHz): 61.3 , 61.6, 63.0 (all q, OCH ), 108.0 (s, C ), 114.5, 118.7 (s, C
H
3
3
a
4΄΄΄
6΄΄΄
2΄΄΄
4΄
4΄΄
&
C ), 119.7, 121.3 (d, C & C ), 125.7 (d, C ), 126.5, 127.5 (d, C & C ), 127.7, 128.0,
2
΄
3΄
2΄΄
3΄΄
5΄΄΄
1΄
1΄΄
1
28.6, 131.3 (all 2×, d, C , C , C & C ), 130.3 (s, C ), 131.7, 132.5 (s, C & C ), 134.4 (s,
3
΄΄΄
2
7a
1΄΄΄
4
5
6
C ), 134.9, 135.6 (s, C & C ) 144.0 (s, C ), 151.0, 152.0, 153.4 (all s, C , C & C ), 157.6
8
(
d, C ).
Results & Discussion
The current focus of our research group is the synthesis of optically pure heterocycles applying
chiron approach. We have already reported the synthesis of a variety of enantiopure heterocycles
in appreciable yield [50-53]. We are interested in the synthesis of indole-fused-diazepines 7 for
screening their pharmacological potential (Scheme 1).

O
O
Ph
Ph
R
R
O
Ph
Ph
Ph
R
N
N
O
O
H
O
Ph
N
N
N
O
H
O
7
6
3a R = H
b R = OMe
3
Cl
Cl
Scheme 1: Retrosynthesis of targeted heterocycle (diazepine 7).
We adopted modified Bischler indole synthesis [54] to achieve 3,5-dimethoxy-2,3-diphenyl-1H-
indoles 3a and 3,4,5-trimethoxy-2,3-diphenyl-1H-indoles 3b by using commercially available
substituted anilines 1a-b and (±)-2-hydroxy-1,2-diphenylethanone 2 (commonly called benzoin).
The indole 3a-b were formylated by Vilsmeier-Haack reaction in which chlorinating agent is
basically the chloroiminium ion intermediate, which is generated by the reaction of DMF with
3
POCl under absolutely anhydrous condition [55]. Generally, the imines synthesis involves the
condensation of 1°-aromatic amines with aryl aldehydes / ketones in organic solvent and
+
normally catalyzed by H ion [56], which should be a facile reaction due to virtuous electrophilic
properties of the C=O and better nucleophillic properties of amine groups. In similar fashion the
7
-fomylindole 4a-b were condensed with 3-chloroaniline 5 in neat condition to afford novel
indole imines 6a-b (Scheme 2).
4
''
2
''
O
O
X
Ph
O
R
R
a
R
2'
c
4
'
Ph
3
5
6
O
NH2
O
N
NH
2
7
1
O
Ph
Ph
H
N
O
H
8
6a R = H
b R = OMe
1
1
a R = H
b R = OMe
2
OH
N
R
X
H
6
3
3
4
4
a H
Cl
'''
2'''
b OMe H
a H
b OMe CHO
5
b
CHO
Cl
4
'''
Scheme 2: a) 1, 2, AcOH, PhNH , 130 °C; b) POCl DMF, ambient (2½ h); c) 200 °C (36 h).
2
3,
1
13
The formation of indole 3 was verified by comparing the IR, H / C-NMR and ESI MS spectra
of synthesized compound with reported data in literature [54]. Concrete evidence was provided
by single crystal XRD studies (Figure 2). The disappearance of a singlet (6.68±0.10 ppm)
7
corresponding to H in aromatic region and the emergence of a new singlet (at 10.41±0.01 ppm),

2
which showed no signal broadening upon D O exchange, demonstrated successful formylation.
1
3
5
7
The C-NMR provided supportive proof that indicated C as a doublet and C as a quaternary
carbon in 4a. Moreover, the aldehydic (H-C=O) singlet emerged at 188.2 ppm. The downfield
7
shift of C is attributed to the –I effect of aldehydic functionality. The bathochromic shift in the
λmax of 7-formylindole 4a-b (372, 358 nm respectively) as compared to indole 3a-b (325, 318 nm
-1
respectively) and the appearance of C=O at 1608 cm inferred successful formylation. The
indoles 3a absorbs at slightly longer λ to indole 3b denying the increment due to an additional
OMe group. Same effect has also been observed between 7-formylindoles (4a and 4b). The three
OMe groups of 3b and 4b may be causing steric crowding, which would be leading to a decrease
in conjugation. The XRD studies of both indole and 7-formylindole reveals that both phenyl
groups are oriented perpendicular to the chromophore of indole ring to minimize steric repulsion
+
•
(
Figure 3). The EIMS of 7-formylindoles 4a-b exhibited [M] as the base peak; no further
+
•
fragmentation was observed due to high stability of [M] .
The successful condensation of 7-formylindoles 4a-b with aniline 5 to afford the desired imines
6
a-b was verified by various spectroscopic techniques. Primarily, the transformation was
–
1
supported by the disappearance of IR absorption of C=O of 4a-b (at 1628±20 cm ) and
–
1
emergence of new signals at 1562±4 cm indicating C=N absorptions. The λmax also indicated a
little bathochromic shift from 372 / 358 nm (4a-b respectively) to 379 / 370 nm (6a-b
respectively) due to increase in conjugation to indole chromophore. The disappearance of a
singlet of HC=O of 4a-b (at 10.42±0.01 ppm) and the appearance of a singlet corresponding to
1
HC=N at 9.04±0.03 ppm in the H-NMR confirmed the imine formation beyond any doubt
(
Figure 1). The XRD analysis finally concluded the structure of imines 6a-b (Figures 4 and 5).
The structure of our synthetic indole derivatives (6a-b) resembles the structure of a
gastroprotective agent [(S)-omeprazole 9], which shows inhibitory action (anti-inflammatorial)
with metals ions in its biological action at molecular level. We can propose that our synthetic
imines 6a-b would show good biological activities, which involves inhibitory mechanism of a
metal ion, since it has the tendency to act as good bidentate ligand very similar to omeprazole 9
(Scheme 3) [57]. The indolic N and iminic N shall act as good electron pair donors (Lewis base)
to construct coordination complexes 8a-b [58].

1
Figure 1: The H-NMR of indole imine 6a clearly showing the formation of iminic functional group
HC=NAr) from indole carbaldehyde 4a (-CHO).
(
O
Ph
R
O
O
N
N
Ph
S
N
O
M
M
N
N
8
8
a R = H
b R = OMe
9
O
Cl
2
+
1+
2+
Scheme 3: The expected chelating property of indole imines 6a-b with metal ions (Cu , Cu , Zn etc.),
similar to a standard gastroprotective agent (S)-omeprazole 9, to afford transition metal complexes 8a-b.
Crystallographic Description
The parameters of data collection along with data refinements for crystals of 3a, 4b, 6a and 6b
are presented in following Table 1.

Table 1: Crystallographic data of compounds 3a, 4b, 6a and 6b.
Crystal data
CCDC
Chemical formula
3a
4b
6a
6b
1904130
C H NO
1904129
C H NO4
24 21
1888066
C H ClN O
1888067
C H ClN O
3
22
19
2
29 23
2
2
30 25
2
M
r
329.38
387.42
466.94
496.97
Crystal system, space
group
Monoclinic, P2
1
/n
Monoclinic, P2
1
/c Monoclinic, P2
1
/n
Monoclinic, C2/c
Temperature (K)
296
296
296
296
a, b, c (Å)
11.7505 (13)
6.4434 (8)
19.436 (3)
15.891 (2)
13.0854 (17)
7.8071 (9)
23.879 (3)
25.2014 (19)
6.5585 (5)
30.899 (3)
9
1
.4790 (12)
5.9428 (19)
α, β, γ (°)
V (Å )
Z
90, 106.746 (6), 90 90, 96.225 (3), 90 90, 103.606 (8), 90 90, 98.308 (4), 90
3
1700.4 (4)
4
1978.3 (5)
4
2371.0 (5)
4
5053.4 (8)
8
Density (calculated)
F(000)
3
3
3
3
1
696
.287 Mg/m
1.301 Mg/m
816
1.308 Mg/m
976
1.306 Mg/m
2080
Radiation type
Mo Kα
0.71073 Å
0.080
Wavelength (λ)
-1
µ (mm )
0.089
0.191
0.186
Crystal size (mm)
Data Collection
Diffractometer
0.36 × 0.28× 0.26
0.40 × 0.22× 0.20 0.28 × 0.25 × 0.23
0.40 × 0.36 × 0.32
Bruker APEXII CCD diffractometer
Absorption correction
Absorption correction:multi-scan (SADABS; Bruker, 2007)
No. of measured,
independent
And observed [I> 2s(I)]
reflections
9910, 3345, 2120
13122, 4635, 2403 18030, 4662, 2388 21462, 5791, 4248
Rint
0.054
0.065
0.079
0.025
Theta range for data
collection
2.529 to 26.000°
2.461 to 27.879° 1.635 to 26.000°
1.332 to 27.518°
Index ranges
-14≤ h ≤14, -11≤ k -4≤ h ≤8, -25≤ k -16≤ h ≤13, -9≤ k
11, -17≤ l ≤ 19 ≤25, -20 ≤ l ≤20 ≤9, -29 ≤ l ≤28
0.617 0.658 0.617
-31≤ h ≤32, -8≤ k ≤
8, -40≤ l ≤39
0.650
≤
-1
(
sin
θ/λ)max (Å )
Refinement
2
2
2
R[F > 2
σ(F )], wR(F ), S 0.048, 0.133, 1.02
0.063, 0.184, 1.01 0.058, 0.138, 1.00 0.047, 0.127, 1.02
No. of reflections
No. of parameters
H-atom treatment
3345
229
4635
262
4662
312
5791
328
H-atom parameters H-atom
H atoms treated by a H-atom parameters
constrained
parameters
mixture of
constrained
constrained
independent and
constrained
refinement
-3
ꢀ
ρmax
,
ꢀ
ρmin (e Å )
0.19, -0.15
0.24, -0.20
0.18, -0.30
0.20, -0.38

4
,6-Dimethoxy-2,3-diphenyl-1H-indole 3a
In 3a (Figure 2a), the 1H-indole moiety A (C7/C8/C15-C20/N1), phenyl ring B (C1-C6) located
at C7 of A and other phenyl ring C (C9-C14) located at C8 of A are planar with r. m. s.
deviations of 0.0196, 0.0052 and 0.0054 Å respectively. The dihedral angle between A/B, A/C
and B/C is 46.45 (6)°, 79.65 (6)° and 80.07 (6)° respectively. There is N‒H····O interaction due
to which C (6) chains is formed along the crystallographic [0 1 0] direction [Table 2, Figure 2b].
Table 2: Hydrogen-bond geometry (Å, º) in 3a.
D—H····A
N1—H1A···O2
D—H
0.86
H····A
2.19
D····A
3.020 (2)
D—H····A
i
163
Symmetry code: (i) – x + 1/2, y − 1/2, − z + 1/2.
(
a)
(b)
Figure 2: (a) The ORTEP diagram of 3a with thermal ellipsoids drawn at 50 % probability level with H-
atoms drawn as small circles of arbitrary radii; (b) The H-bonding pattern showing the C (6) chain due to
N-H…O interaction.
4
,5,6-Trimethoxy-2,3-diphenyl-1H-indole-7-carbaldehyde 4b
In 4b (Figure 3a), the 1H-indole moiety A (C7/C8/C15-C20/N1), phenyl ring B (C1-C6) located
at C7 of A and other phenyl ring C (C9-C14) located at C8 of A are planar with r. m. s.
deviations of 0.0272, 0.0050 and 0.0036 Å respectively. The dihedral angle between A/B, A/C
and B/C is 39.65 (10)°, 55.90 (8)° and 55.31 (10)° respectively. The molecules are dimerized due
to N‒H····O and C‒H····O interactions (Table 3, Figure 3b). The bifurcated N‒H····O bonding
2
1
2 2
complete S (6) and R (4) loop [59]. The adjacent C‒H····O bond helps to complete a R (7)

loop. The dimers are interlinked due to C‒H····O interaction from both ends, where CH is of
benzene ring B and O of central methoxy group located at C19 of ring A (Table 3, Figure 3b).
Table 3: Hydrogen-bond geometry (Å, º) in 4b.
D—H···A
N1—H1A···O1
D—H
0.86
0.86
0.96
0.96
0.96
0.96
H···A
2.36
2.41
2.35
2.66
2.35
2.59
D···A
D—H···A
116
2.848 (3)
3.232 (3)
2.963 (4)
3.478 (4)
2.964 (4)
3.481 (4)
i
N1—H1A···O1
160
C22—H22B···O3
C22—H22C···O1
C23—H23B···O4
122
ii
144
121
iii
C24—H24A···O4
155
Symmetry codes: (i) − x, − y, − z + 1; (ii) x + 1, y, z; (iii) – x + 1, − y, − z.
(
a)
(b)
Figure 3: (a) The ORTEP diagram of 4b with thermal ellipsoids drawn at 50 % probability level with
H-atoms drawn as small circles of arbitrary radii; (b) The H-bonding pattern showing that the molecules
are dimmerized and are interlinked due to H-bonding.
N-(3'''-Chlorophenyl) (4,6-dimethoxy-2,3-diphenyl-1H-indol-7-yl)methanimine 6a
In 6a (Figure 4a), the 1H-indole moiety A (C1-C8/N1), phenyl ring B (C11-C16) located at C1
of ring A, other phenyl ring C (C17-C22) located at C2 of ring A and 3-chloroanilinic group D
(C24-C29/N2/Cl1) located at C5 of ring A are planar with r. m. s. deviations of 0.0063, 0.0018,
0
.0043 and 0.0091 Å, respectively. The dihedral angle between A/B, A/C, A/D, B/C, B/D and
C/D are 38.14 (8)°, 59.86 (8)°, 24.50(7)°, 66.13 (9)°, 49.22 (7)° and 36.58 (11)° respectively.
There is intramolecular N‒H····N interaction to complete S (6) ring. The molecules are
2
dimerized due to weaker C‒H····N interactions and complete R (18) loop (Table 4, Figure 4b).
2

There exists π····π interactions at a distance of 3.5039(15) Å [slippage 2.785 Å] and 3.7834 (15)
i
i
Å [slippage 1.581 Å] between the centroids Cg1…Cg1 and Cg2…Cg2 [i = -x, 1 - y, -z], where
Cg1 and Cg2 are the centroids of (C3-C8) and (C1-C3/C5-C8/N1) respectively (Figure 4c).
Table 4: Hydrogen-bond geometry (Å, º) in 6a.
D—H···A
N1—H1···N2
D—H
0.85 (3)
0.96
H···A
2.25 (3)
2.62
D···A
D—H···A
124 (2)
147
2.807 (3)
3.467 (4)
ii
C9—H9C···N2
Symmetry codes: (i) x − 1, y + 1, z; (ii) − x, − y + 1, − z.
(
a)
(b)
(
c)
Figure 4: (a) The ORTEP presentation of 6a with thermal ellipsoids drawn at 50 % probability level
with H-atoms drawn as small circles of arbitrary radii; (b) the H-bonding pattern showing the S (6) and
2
2
R
(18) loops; (c)
π····
π
interactions between

N-(3'''-Chlorophenyl) (4,5,6-trimethoxy-2,3-diphenyl-1H-indol-7-yl)methanimine 6b
In 6b (Figure 5a), the 1H-indole moiety A (C1-C6/C10/C11/N1), phenyl ring B (C12-C17)
located at C11 of ring A, other phenyl ring C (C18-C23) located at C10 of ring A and 3-
chloroanilinic group D (C25-C30/N2/Cl1) located at C5 of ring A are planar with r. m. s.
deviations of 0.0136, 0.0033, 0.0025 and 0.0123 Å respectively. The dihedral angle between
A/B, A/C, A/D, B/C, B/D and C/D is 37.24 (6)°, 51.38 (6)°, 6.15 (7)°, 53.69 (7)°, 31.12 (6)° and
5
1.02 (7)° respectively. There is intramolecular N‒H····N interaction to complete S (6) ring
(Table 5, Figure 5b). There exists π····π interactions at a distance of 3.8555(13) Å [slippage
i
ii
1
.279 Å] and 3.9634(12) Å [slippage 1.397 Å] between the centroids Cg1…Cg2 and Cg2…Cg3
[
i = x, 1 + y, z; ii = x, - 1 + y, z], where Cg1, Cg2 and Cg3 are the centroids of
C1/C6/C10/C11/N1), (C25-C30) and (C1-C6/C10/C11/N1), respectively.
(
Table 5: Hydrogen-bond geometry (Å, º) in 6b.
D—H···A
N1—H1···N2
D—H
0.86
0.96
0.96
0.96
H···A
2.23
2.46
2.88
2.98
D···A
D—H···A
119
2.758 (2)
3.034 (3)
3.802 (2)
3.538 (2)
C9—H9A···O2
C9—H9B···Cl1
118
i
163
ii
C9—H9C···Cl1
118
Symmetry codes: (i) x, y + 1, z; (ii) – x + 1, − y − 1, − z.
(
a) The ORTEP diagram
(b) The H-bonding pattern
Figure 5: (a) ORTEP diagram of 6b with thermal ellipsoids drawn at 50 % probability level with H-atoms
drawn as small circles of arbitrary radii; (b) The H-bonding pattern showing the S (6) loop.

Computational studies
Geometric structures
The optimized bond angles and bond lengths of 3a, 4b and 6a-b were obtained by performing
full computational optimization at DFT/B3LYP/6-311+G(d,p) level of theory. The DFT
computed results were correlated with SC-XRD findings. Atom numbering scheme of 3a, 4b and
6
a-b as shown in Figures 2a-4a and S1 (Supplementary Information) was used to calculate the
XRD and DFT structural parameters respectively. The results for XRD and DFT calculated
structural parameters of 3a, 4b and 6a-b are tabulated in Tables S1-S4 respectively. The DFT
data illustrates that calculated bond lengths and bond angles of all studied compounds show good
agreement with crystallographic data. The bond lengths in 3a, 4b and 6a-b are deviated in the
range of 0.036 ± 0.01Å, 0.029 ± 0.007Å, 0.038 ± 0.006Å and 0.025 ± 0.01Å respectively.
Deviation in the bond angles of 3a, 4b and 6a-b is observed in the range of 2.3° ± 1.8°, 2.8° ±
1
.6°, 1.4° ± 1.3° and 3.1° ± 2.9° respectively. The optimized bond lengths of C–C bond in the
benzene rings of 3a and 4b are calculated in the range of 1.38-1.41 Å, 1.39-1.41 Å (DFT) and
.39-1.4 Å, 1.36-1.44 Å (XRD) respectively. A similar trend is observed in 6a and 6b where
1
calculated bond lengths of benzene ring C–C bond are measured in the same range of 1.38-1.41
Å, 1.38-1.41 Å through DFT and 1.35-1.41 Å, 1.35-1.41 Å through XRD respectively.
The bond length between C and O atoms of methoxy (OCH ) groups calculated by DFT studies
3
is found (1.41Å and 1.42Å) in good agreement with practical values (1.41Å and 1.43Å) by XRD
studies for O(2)-C(22) and O(1)-C(21) in 3a respectively. The bond lengths of C‒O of methoxy
groups of 4b were calculated through DFT, which are found matching to same value 1.43Å
through XRD. These bond lengths are observed as 1.41Å, 1.42Å and 1.41Å for O(2)-C(22),
O(3)-C(23) and O(4)-C(24) respectively. In 6a and 6b, DFT calculated bond lengths of C‒O
methoxy groups are found to be 1.42Å for O(1)-C(9), O(2)-C(10) and 1.43Å for O(1)-C(7),
O(2)-C(8), O(3)-C(9) respectively. Conversely, XRD reveals that these bond lengths are
measured with same value of 1.42 Å for 6a and 6b. The maximum divergence of bond angle is
noticed for C(20)-O(1)-C(21) and C(8)-C(9)-C(10) in 3a as 118.8°, 121° (DFT) and 117°, 123.3°
(XRD) correspondingly. In 4b, bond angles are diverged chiefly for C(18)-O(2)-C(22) and N(1)-
C(16)-C(17) as 120.4°, 128.5° by DFT and 117.6°, 130.1° by XRD correspondingly. In 6a,
highest divergence in bond angles is estimated to be 119.6°, 122.6° (DFT) and 118.2°, 123.9°

(
XRD) for C(8)-O(1)-C(9) and N(2)-C(24)-C(25) respectively. Likewise in 6b, the DFT and
XRD measured maximum deviation of bond angle was found to be 115.8°, 122.6° and 112.9°,
25.7° for C(4)-O(3)-C(9) and N(2)-C(25)-C(26) respectively. The comparative analysis of
1
geometric data of the investigated compounds (3a, 4b and 6a-b) given in Tables S1-S4 indicate
that the optimized bond lengths and bond angles correlated well with the corresponding crystal
structural parameters.
FT-IR analysis
To investigate the modes of vibration, harmonic frequencies and intensities of the vibrational
bands present in investigated compounds 3a, 4b and 6a-b DFT analysis have been performed on
the optimized geometries in gas phase using 6-311+G(d,p) basis set and B3LYP level of theory.
Some representative calculated FT-IR results along with their detailed assignments and
experimental FT-IR results of 3a are presented in Table 6. While detail FT-IR results (calculated
and experimental) for 3a, 4b and 6a-b are mentioned in Tables S5-S8 (Supplementary
information).
-1
Table 6: Experimental and theoretical vibrational wave numbers (ύ in cm ) of indole 3a [at B3LYP/6-
3
11+G(d,p)] with proposed assignments
IR-
ύ
Unscaled
(Theo)
572
ύ
IIR
Vibrational assignments
(Exp)
5
78
75
21
52
52
87
9.241
ύ
ύ
ύ
ύ
ύ
ύ
ύ
ύ
ύ
ύ
ύ
ύ
ύ
(as) C=C–C=C–CPh
(as) C=C–C=C–CPh
6
7
7
9
9
675
711
740
953
986
1168
1244
1317
1468
1590
2949
3055
9.118
15.00
12.85
8.917
3.818
1.745
103.3
60.79
7.484
86.16
65.00
39.66
(as) C=C–C=C–C +
ύ
ύ
(w) C–HPh
(w) C–HPh
Ph
(as) C=C–C=C–C +
Ph
(as) C=C–C=C–CPh
(
(
(
(
τ
τ
τ
) C–HPh
) C–HPh
) C–HMe+
1
1
1
1
1
2
3
165
246
311
462
597
943
051
Ph
ύ (ꢀ) C–H + ύ (ꢀ) N–HInd
ꢀ
) C–H +
ύ
(as) C=C–C=C–C +
ύ
(
ꢀ
ꢀ
) N–HInd
) N–HInd
Ph
Ph
(w) C–HMe
) C–H +
(
ꢁ
Ph
ύ
(as) C=C–C=C–C +
Ph
ύ
(
+ ύ (as) C=C–C=C–CInd
(s) C–HMe
(as) C–HMe
ꢂ
= stretching;ꢃꢁ = scissoring;ꢃꢀ = rocking; w = wagging; s = symmetric; as = asymmetric; ꢄ = twisting;
Ph = benzene ring; Ind = indole ring; Me = methyl group; Exp = experimental; Theo = theoretical.

C–H vibrations
The C-H group is present at different positions in 3a, 4b and 6a-b. Literature study suggests that
-1
3
100-3000 cm is the characteristic region in which C-H vibrations of aromatic rings generally
arise [60]. Herein, pure symmetric vibrational bands are observed with wave numbers at 3188,
-
1
-1
3
3
189, 3202, 3209, 3220 cm in indole 3a, at 3192, 3201 cm in indolecarbaldehyde 4b, 3157-
-
1
-1
177, 3192 cm in imine 6a and 3189, 3203, 3206 cm in imine 6b. Vibrational bands appeared
-1
in 3a (3156, 3158, 3165, 3167, 3176, 3184 cm ), 4b (3159, 3162, 3167, 3169, 3178, 3179, 3186,
-
1
-1
3
3
189 cm ), 6a (3183-3244 cm ) and 6b (3157, 3162, 3165, 3169, 3173, 3175, 3179, 3181, 3192,
-1
201 cm ) are assigned to pure asymmetric C-H stretching vibrations (Tables 6 and S5-S8).
Methyl group vibration
-1
The characteristic region for methyl group C-H vibrations is 3000-2800 cm [61]. In 3a, pure
symmetric and asymmetric vibrational stretching modes for methyl group are computed at 2949
-1
and 3055 cm , which are in good agreement with experimental calculated values 2943 and 3051
-1
-1
cm respectively. In indolecarbaldehyde 4b, symmetric stretching mode is observed at 3026 cm
-1
comparable with experimentally calculated vibrational band observed at 3051 cm . Similarly in
-1
imine 6a, the computed vibrational band with frequency at 3059 cm exhibits good concurrence
-1
-1
with experimental band at 3053 cm . The vibrational bands in 6b at 3015, 3018, 3037 cm and
-1
3
084, 3097, 3115, 3123, 3129, 3134 cm are observed due to symmetric and asymmetric
stretching mode of methyl group C-H vibrations respectively (Tables 6 and S5-S8).
C-C stretching vibration
−
1
The literature reveals 1650-1400 cm [62] is the region in which C-C stretching modes
generally appear. Herein, C-C stretching vibrational wavenumbers is found in the span of 572-
-1
-1
-1
−1
1
655 cm , 604-1641 cm , 525-1653 cm and 575-1674 cm for 3a, 4b and 6a-b respectively.
−
1
Computed C-C bands appeared in 3a at 572, 675, 711, 750, 953 and 1317 cm are in good
−
1
harmony with experimental calculated bands appear at 578, 675, 721, 752, 952 and 1311 cm
−
1
respectively. The vibrational band computed at 690 cm shows good correspondence with
−
1
experimental band in 4b at 694 cm . Similarly in 6a and 6b, C-C stretching modes appear at
−
1
1
1
149 and 631 cm , which displays fine concurrence with experimental appeared frequency at
−
1
153 and 628 cm respectively (Tables 6 and S5-S8).

N-H band vibration
The N-H vibration is also an important stretching vibration observed in 3a, 4b and 6a-b. Pure N-
-1
H vibrational bands are appeared with wave numbers appear at 3657, 3597, 3556 and 3565 cm
for 3a, 4b and 6a-b respectively.
UV-Visible study
In order to have insight into the absorption properties, vertical transitions and charge transfer
within 3a, 4b and 6a-b, UV–Vis spectroscopic study was carried out at TDDFT/B3LYP/6-
3
11+G(d,p) functional. The results for the experimental as well as TDDFT calculated absorption
wavelengths (λmax), molecular orbital contributions, oscillator strength (f) and excitation energy
DFT
(E
) involved in 3a, 4b and 6a-b are presented in Table 7.
DFT
In indole 3a, λmax is observed at 343.52 nm with E
value 3.6090, f value 0.3265 and dominant
transition mainly originated from HOMO→LUMO (98%). The transitions in 4b are primarily
DFT
aroused from HOMO→LUMO (96%) with f , E
and λmax values observed as 0.1499, 3.1451
and 394.18 nm respectively. Similarly in 6a and 6b, maximum absorptions are observed at
04.19 and 400.95 nm with f values of 0.2878, 0.2288 and major transition aroused from
4
HOMO→LUMO (96 & 94% respectively) in both cases. The calculated λmax value (316.18 nm)
in 3a correlated in good agreement with experimental λmax value 325 nm. In 4b, computed and
experimental λmax correlated adequately with values 365.62 and 372 nm respectively. Similarly in
6
a, 379 nm is the experimental λmax value which shows good concurrence with computed λmax
value 369.33 nm. A quite similar trend is observed in 6b where computed and experimental λmax
values are observed to be 358.78 and 370 nm exhibiting good harmony. Precisely from preceding
discussion, the computed and calculated findings in investigated compounds 3a, 4b and 6a-b
correspond in good agreement to each other.
Table 7: Wave length, excitation energy and oscillator strength for 3a, 4b and 6a-b.
ꢉꢊꢋꢌ
Expt.
Cal.
Compound
f
MO contributions
ꢅꢆꢇꢈꢃ(nm) ꢅꢆꢇꢈꢃ(nm)
(eV)
3
3
2
2
43.52
16.18
96.64
91.84
3.6090
3.9211
4.1794
4.2481
0.3265
0.0043
0.0173 H-1
H
H
→
→
L(98%)
L+1(97%)
3
a
325
→
→
L(15%), H
L(12%), H
→
→
L+2(82%)
L+3(83%)
0.0031 H-1

2
2
3
3
3
3
2
2
4
3
3
3
3
2
4
3
3
3
2
4
85.08
82.49
94.18
65.62
35.86
08.39
91.53
85.22
04.19
69.33
29.00
09.02
02.51
95.65
00.95
58.78
22.47
14.40
93.12
00.95
4.3488
4.3887
3.1451
3.5870
3.6913
4.0201
4.2526
4.3467
3.0672
3.5535
3.7683
4.0119
4.0983
4.1934
3.0920
3.4555
3.8446
3.9432
4.2296
3.0920
0.2073 H-1
→L(56%), H→L+2(13%), H→L+3(14%)
0.0382
0.1499
H
H
→
→
L+4(92%)
L(96%)
0.1586 H-1
0.0076 H-4
→
→
L(89%)
L(64%), H-2
→
L(22%)
L(62%)
4b
6a
6b
372
379
370
0.2088
0.0027
H
H
→
→
L+1(96%)
L+2(91%)
0.0416 H-4
0.2878
0.4410 H-1
0.1591
0.0687 H-2
→
L(96%)
→
L+1(94%)
→
L(22%), H-2
→
H
→
L(91%)
H→
L(78%)
0.0045
0.0152
0.2288
H→
H→
H→
L+2(17%), H
L+2(71%), H
L(94%)
→
→
L+3(79%)
L+3(16%)
0.4285 H-1
0.0581 H-2
0.2073 H-2
0.0451 H-3
0.2288 H-3
→
→
→
→
→
L(92%)
L(68%), H
L(19%), H
L(62%), H
L(18%), H
→
→
→
→
L+1(23%)
L+1(73%)
L+2(10%), H
L+3(72%)
→
L+3(16%)
E = Excitation energy (eV); ꢅ=wave length (nm); f = oscillator strength; MO = molecular orbitals; H = HOMO, L =
LUMO; ꢅ (nm) Expt. = Experimental; Cal. = Calculated.
Frontier molecular orbital analysis
Frontier molecular orbitals (FMOs) comprise of two main orbitals; HOMO (highest occupied
molecular orbital) and LUMO (lowest unoccupied molecular orbital). The FMOs are significant
quantum chemistry parameters that play an important function in describing the chemical
reactivity and interaction of investigated molecule with other species [63]. Chemists and
physicists explain various electronic and optical properties, UV–Vis spectra, types of reaction in
conjugated systems and the most reactive position in π-electron systems with the help of FMOs
[64-69]. To forecast the electronic properties of 3a, 4b and 6a-b, DFT calculations were
performed at the B3LYP level of theory with 6311+G(d,p) basis set. The results for the HOMO,
LUMO and HOMO-LUMO gap energies (E ) of 3a, 4b and 6a-b are given in Table 8
gap
respectively.
The influence of one weakly deactivating chlorine (Cl) group and moderately activating methoxy
(
OCH ) groups on FMOs of investigated molecules is described in pictorial display of FMOs in
3
Figure 6. The value of least Egap is found to be 3.440 eV in 6a. On the other hand, highest Egap is
observed in 3a with 4.036 eV value. The increasing order for Egap of investigated molecule is: 6a
<
6b < 4b < 3a respectively.

Table 8: Computed energies (E) for compounds 3a, 4b and 6a-b.
3
a
∆
4b
∆
6a
6b
∆E (eV)
MO(s)
E (eV)
-5.104
-1.068
-5.946
-0.555
-6.448
-0.263
-6.733
-0.195
E (eV)
E (eV)
-5.602
-2.004
-6.159
-1.042
-6.795
-0.668
-6.958
-0.490
E (eV)
E (eV)
-5.279
-1.839
-6.074
-0.998
-6.475
-0.613
-6.704
-0.549
∆
E (eV)
E (eV)
-5.493
-2.005
-6.009
-1.059
-6.502
-0.705
-6.790
-0.608
HOMO
LUMO
4.036
5.391
6.185
6.538
3.598
5.117
6.127
6.468
3.440
3.488
4.950
5.797
6.182
HOMO-1
LUMO+1
HOMO-2
LUMO+2
HOMO-3
LUMO+3
5.076
5.862
6.155
E = energy, ∆E (eV) = ELUMO - EHOMO; HOMO = highest occupied molecular orbital; LUMO = lowest unoccupied
molecular orbital; MO = molecular orbital
3
a
4b
6
a
6b
Figure 6: Frontier molecular orbitals of indole 3a, indolecarbaldehyde 4b, imines 6a and 6b.

EHOMO, ELUMO and Egap are auxiliary utilized to depict the reactivity and stability of 3a, 4b, 6a
and 6b by anticipating the global reactivity descriptors [70-73]. First, ionization potential (I) and
electron affinity (A) were calculated in vertical manner employing equations 1 and 2.
I = E ꢍꢎ ꢏꢐ − E ꢑꢎ
(1)
(2)
ꢎ
ꢎꢓꢐ
ꢒ
A = E − E
ꢑ
The I represent the ionization potential while A indicates the electron affinity values. The E ꢍꢎ ꢏꢐ
and E ꢒꢎ ꢓꢐ factors describe the energy after losing (cation) and gaining an electron (anion)
ꢎ
respectively. The E is the basal state energy (neutral).
ꢑ
Hardness (η) and electronegativity (X), electrophilicity (ω) calculations including electron
-
+
donating (ω ) or electron accepting ability (ω ) of chemical specie and softness values (σ) are
calculated using equation 3-8 respectively.
I-A
η=
(3)
(4)
2
I+A
X=
2
2
ꢁ
ω=
(5)
(6)
(7)
(8)
2η
2
(
3I + A)
−
ω =
1
6 (I - A)
2
(
I + 3A)
+
ω =
1
6 (I - A)
1
σ
=
2η
The results obtained from equations 1-8 are presented in Table 9.
Table 9: Ionization potential (I), electron affinity (A), electronegativity (X), global hardness (
η
), chemical
-
+
potential (
ꢁ
), global electrophilicity (
ω
), electron donor capability (
ω
), electron acceptor capability (
ω
)
and global softness (σ).
-
+
I
A
X
η
ꢀ
ω
ω
ω
σ
3a
4b
6a
6b
6.28
6.52
6.32
6.50
0.04
0.89
0.92
1.10
3.16
3.70
3.62
3.80
3.11
2.81
2.69
2.70
-3.16
-3.70
-3.62
-3.80
1.60
2.44
2.43
2.67
3.57
4.64
4.58
4.91
0.41
0.93
0.95
1.11
0.16
0.17
0.18
0.18

From Table 9, it can be seen that all global reactivity parameters values of 4b is greater than 3a
due to the attendance of one extra methoxy group in 4b as compared to 3a. Similar trend is
observed in 6b which have greater values of global reactivity parameters than 6a due to the
action of one extra methoxy group. Highest and lowest I, A and X values are observed in 6b and
3
a respectively. Stability of the molecules under investigation is frequently described by
chemical potential value. Stable, less reactive are molecules holding greater chemical potential
values and vice versa. In our studied molecules, ꢀ values are found in following increasing order:
[6b (ꢀ = -3.80 eV)] < [4b (ꢀ = -3.70 eV)] < [6a (ꢀ = -3.62 eV)] < [3a (ꢀ = -3.16 eV)]
Global softness of 3a, 4b, 6a and 6b are found almost same with 0.16, 0.17, 0.18 and 0.18 eV
values respectively. Global hardness values of 3a, 4b, 6a and 6b are found to be 3.11, 2.81, 2.69
and 2.70 eV respectively. These values are found 19.43, 16.52, 14.94 and 15 times greater than
their relevant softness values. The electron donating potential of 3a, 4b, 6a and 6b are observed
-
greater than their electron accepting capability. The decreasing order of ω and ω is:
6b > 4b > 6a > 3a
Since A and I values correspond to the electron accepting and donating aptitude respectively. In
our studied molecules, A values are observed smaller as compared to I values which strengthen
+
the conclusion of their smaller electron acceptor capability (ω ) and greater electron donor
-
capability (ω ). It is evident from above discussion that studied molecules are kinetically stable
and hard compounds holding small electron accepting and greater donating capability.
Nonlinear optical (NLO) properties
To predict the NLO properties of synthesized compounds 3a, 4b, 6a and 6b, DFT calculations
were performed at B3LYP/6311+G(d,p) level of theory. The diagonal elements of equation 9 are
utilized for estimating the average polarizability (α) values.
<
α
>= 1 / 3(α xx
+
α yy
+
α zz
)
(9)
First (βtot) and second hyperpolarizability 〈ꢔ〉 values are measured utilizing equations 10 and 11
respectively.

2
2
2 1/2
(
10)
β =[(β + β + β ) +(β + β + β ) +(β + β + β ) ]
tot
xxx
xyy
xzz
yyy
xxy
yzz
zzz
xxz
yyz
1
(11)
〈
ϒ〉 =
ϒ
+ ϒyyyy + ϒzzzz + 2[ϒxxyy + ϒyyzz + ϒ ]
(
)
xxxx xxzz
5
The results for the dipole moment, linear polarizability, first hyperpolarizability and second
hyperpolarizability of 3a, 4b, 6a and 6b are tabulated in Tables 10-12 respectively.
Table 10: The dipole moment (D) and computed dipole polarizabilities for 3a, 4b, 6a and 6b.
µx
µy
µz
µ
αxx
αyy
αzz
αtotal (a.u)
295.09
331.54
432.73
449.13
3
a
-0.8492
-0.8052
2.6296
2.0870
-1.8506
3.1295
3.4750
-1.3332
-0.1580
-0.7597
-1.0585
-1.5250
2.0422
3.3195
4.4845
2.9084
389.13
434.79
569.22
586.32
318.42
364.61
483.45
498.96
177.73
195.22
245.51
262.11
4
b
6
a
6
b
Table 11: The computed first hyperpolarizability / second order NLO (a.u.) for 3a, 4b, 6a and 6b.
βxxx βxxy βxyy βyyy βxxz βyyz βxzz βyzz βzzz
βtot (a.u)
3
4
6
6
a
b
a
2206.67 -390.905 413.450 -231.792 -48.8705 -29.1349 3.68299 -42.3294 -9.49252 2708.18
966.197 12.8915 72.6561 -505.067 -106.993 -28.8447 -6.98756 66.4907 -76.0004 1136.14
-1979.62 -1250.47 195.592 -893.298 -126.766 48.8885 62.2974 -16.7848 -69.3174 2766.58
b -2175.30 1094.40 -5.22244 627.126 -338.910 -42.2391 22.7068 -4.54495 -106.005 2800.27
Table 12: The second hyperpolarizability values for 3a, 4b, 6a and 6b.
γxxxx
γyyyy
γzzzz
γxxyy
γzzxx
γyyzz
〈ꢕ〉(a.u.)
-13940.9
-17360.7
-31405.0
-33795.0
3
4
6
6
a
b
a
b
-7677.59
-9124.05
-19810.56
-19908.08
-4170.44
-5537.94
-7017.11
-8892.49
-478.745
-647.719
-872.353
-1049.37
-1749.03
-2349.68
-4321.49
-4658.37
-1458.76
-1799.25
-3408.53
-3448.14
-827.618
-978.580
-1532.30
-1756.00
Dipole moment is an important parameter that describes the interaction among atoms. It is the
product of magnitude of charges and distance between them. The values for distribution of
charges in x, y, and z-directions are listed in Table 10.
The results point out that maximum value of dipole moment is noticed as 4.4845 D in 6a. On the
other hand, 3a holds the lowest value of computed dipole moment 2.0422 D among all studied
molecules. The values of computed dipole moment are found to be in the decreasing order of 6a
>
4b > 6b > 3a. Total dipole moment of urea molecule is 1.3732 D [74] which is considered as
standard molecule for comparing dipole moment and β results. The dipole moments of 3a, 4b,
tot
6
a and 6b are calculated 1.48, 2.41, 3.26 and 2.11 times greater than urea molecule.

The results of major polarizability tensors of x, y, and z-directions and total linear polarizability
are tabulated in Table 10. The results reveal that the dipole polarizability tensors value of 6b is
found higher in all three directions as compared to polarizability tensors values of other
investigated compounds. A highest computed dipole polarizability value is found to be 449.13
(a.u) in 6b while lowest value of dipole polarizability (295.09 a.u) is observed in 3a. The
declining order of computed dipole polarizability observed in investigated compounds is:
6
b > 6a > 4b> 3a
The values of total first hyperpolarizability (second order polarizability or second order NLO;
βtot) and its contributing tensors are mentioned in Table 11. In 3a and 3b, the dominant
transitions 2206.67 and 966.197 (a.u) are observed along x-axis with positive direction, while in
6
a and 6b, dominant transitions -1979.62 and -2175.30 (a.u) are also found along x-axis but with
negative direction. Highest and lowest βtot is computed to be 2800.27 (a.u) and 1136.14 (a.u) in
b and 4b respectively. The decreasing order of β observed in studied molecules is:
6
tot
6
b > 6a > 3a> 4b
The answer to the greater NLO activity of 6b over other investigated compounds is hidden in the
basic structures of 6b. The backbone of 6b structure contains three moderately activating OCH
groups and one weakly deactivating chlorine unit. The imine 6a is at second place in terms of
NLO activity because its architecture contains two OCH and one Cl group. In 6b, the donating
3
3
effects of three OCH groups are greater in magnitude as compared to the donating effect of two
3
OCH groups in 6a. Therefore, delocalization of electrons and charge transfer increases in 6b,
3
which results in greater NLO response of 6b as compared to 6a.
Since urea molecule is used as reference material for comparative NLO analysis [74]. Therefore,
βtot values of 3a, 4b, 6a and 6b have been compared with urea molecule (βtot (urea) = 43 a.u).
The βtot values of 3a, 4b, 6a and 6b are computed 62.98, 26.42, 64.33 and 65.12 times greater
than the urea molecule respectively. The values of 〈ꢔ〉 along with their contributing tensors are
presented in Table 12. Second hyperpolarizability value along x-axis is observed greater in all
investigated compounds as compared to their y and z-axis values. The increasing order of second
hyperpolarizability observed in investigated compounds is:

6b < 6a < 4b < 3a
Two-state model was additionally used to strengthen our NLO findings. This model was
presented by Oudar and Chemla [75] and its expression is represented in equation 12.
∆
µgm fgm
β
=
.
(
12)
3
E
gm
This equation represents the connection between charge transfer transition and first hyper-
ꢙ
polarizability value. From equation 12, it can be seen that small (ꢖ ) and large f results
ꢗꢘ
gm
produce large β value. The results of fgm and ꢖꢙ for 3a, 4b, 6a and 6b are given in Table 7. The
ꢗꢘ
value of fgm for studied molecules is observed same. Consequently, only ꢖꢙ is the crucial aspect
ꢗꢘ
for the estimation of β value. The ꢖꢙ value for 3a, 4b, 6a and 6b is found 3.6090, 4.0201,
ꢗꢘ
3
4
4
6
.5535 and 3.4555 eV respectively, which results in larger β value of 6b and smaller β value of
b. The order of ꢖꢙ (6b < 6a < 3a < 4b) correspond nicely with the order of β (6b > 6a > 3a >
ꢗꢘ
b). Thus two-state model and urea molecule comparative analysis evident that 3a, 4b, 6a and
b are brilliant candidates for NLO properties associated hi-tech applications.
Molecular electrostatic potential (MEP)
To explore the reactivity of title molecules by predicting their nucleophilic as well as
electrophilic sites, MEP analysis were carried out at B3LYP/6-311+G(d,p) level of theory and
their MEP maps are displayed in Figure 7. It is observed that the most negative potential region
(red) in Figure 7 is located over oxygen atom in all investigated compounds. Thus oxygen atom
of OCH group is the most suitable spot for electrophilic attack in 3a, 4b, 6a and 6b. On the
3
other hand, blue color is mostly positioned over C and H atoms which entail that nucleophile will
likely attach on these positions. The average of the two extreme value of electrostatic potential
(red and blue) is represented by green region which is confined over hydrogen atoms mostly. The
locations of halfway potential between the extremes (red and blue) and mean (green) is indicated
by yellow color and located over aromatic ring in 3a and 3b, while on Cl atom in 6a and 6b
respectively.

3
a
4b
6
a
6b
Figure 7. Molecular electrostatic potential maps for 3a, 4b, 6a and 6b (iso value = 0.01).
Conclusion
In current study, four novel indole based derivatives namely 3a, 4b, 6a and 6b with chemical
formula of C H NO , C H NO , C H ClN O and C H ClN O respectively were
2
2
19
2
24 21
4
29 23
2
2
30 25
2
3
synthesized and their crystal structures were characterized by both experimental and
computational methods. A number of experimental techniques were performed for the prepared
1
13
compounds including H-NMR, C-NMR, FT-IR, UV-Vis and SC-XRD. X-rays analysis
revealed that 3a, 4b, 6a and 6b are crystallized in the monoclinic crystal system with space
groups P2 /n, P2 /c, P2 /n and C2/c respectively and diffused to form multi-layered structure
1
1
1
due to intermolecular hydrogen bonding (H.B). This H.B motif transformed the 3a, 4b, 6a and
b into supramolecular structures. Spectroscopic investigations were according to the proposed
6
structure. DFT based FT-IR spectra and UV-Vis absorption was in excellent agreement with the
experimental spectroscopic data. Frontier molecular orbital (FMO) analysis confirmed that studied

molecules are kinetically stable and hard compounds holding small electron accepting and
greater donating capability which might be due to H.B network. Two-state model and urea
molecule comparative analysis evident that 3a, 4b, 6a and 6b are brilliant candidates for NLO
properties associated hi-tech applications.
Acknowledgments
Abdul Rauf Raza acknowledges the Higher Education Commission of Pakistan for a research
grant (HEC-20-3873), a research fellowship to Sobia Tariq and financial support for spectral
(
NMR and MS) analyses. Muhammad Khalid thanks same funding agency for financial support
2017/1314). Ataualpa A. C. Braga, (grants # 2011/07895-8, 2015/01491-3 and 2014/25770-6) is
(
thankful to Fundação de Amparo à Pesquisa do Estado de São Paulo for financial support.
AACB (grant 309715/2017-2) also thanks the Brazilian National Research Council (CNPq) for
financial support and fellowships. This study was financed in part by the Coordenação de
Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001.
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