Antioxidant properties of ethenyl indole: DPPH assay and TDDFT studies

Article abstract of DOI:10.1039/d0nj01317j

A series of ethenyl indoles (e.g.3-(4-substituted phenylethenyl-E)-N-H-indole) with various donor or acceptor substituents have been synthesized and their antioxidant properties have been studied. Ethenyl indoles exhibit antioxidant activity in a substituent dependent manner. Ethenyls bearing strong electron withdrawing substituents show weak or no antioxidant activity, whereas ethenyls with electron donating substituents exhibit antioxidant properties comparable to vitamin E. It can be seen from a plot of the percentage of inhibitionversusthe antioxidant concentration, that the hydroxy substituted ethenyl indole exhibits good antioxidant properties (50% inhibition concentration (IC₅₀) ～ 24 μM) as compared to the other ethenyls (IC₅₀: 30-63 μM) and that it is comparable to vitamin E (IC₅₀～ 26 μM). The results are also supported by the computational data obtained through time dependent density functional theory (TDDFT) calculations. From the TDDFT and antioxidant study, it was shown that there is a correlation between the highest occupied molecular orbital (HOMO)-lowest unoccupied molecular orbital (LUMO) energy, the ground state dipole moment, optical band gap, bond dissociation enthalpy and the ionization potential of the ethenyls with the antioxidant properties. A possible hydrogen and/or electron and proton transfer mechanism is suggested for the quenching of the free radical.

Full text of DOI:10.1039/d0nj01317j

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Antioxidant properties of ethenyl indole: DPPH
assay and TDDFT studies†
Cite this:DOI: 10.1039/d0nj01317j
a
a
b
a
Jagdeep Kumar, Naresh Kumar, Nitin Sati and Prasanta Kumar Hota
*
A series of ethenyl indoles (e.g. 3-(4-substituted phenylethenyl-E)-N–H-indole) with various donor or
acceptor substituents have been synthesized and their antioxidant properties have been studied. Ethenyl
indoles exhibit antioxidant activity in a substituent dependent manner. Ethenyls bearing strong electron
withdrawing substituents show weak or no antioxidant activity, whereas ethenyls with electron donating
substituents exhibit antioxidant properties comparable to vitamin E. It can be seen from a plot of the
percentage of inhibition versus the antioxidant concentration, that the hydroxy substituted ethenyl
indole exhibits good antioxidant properties (50% inhibition concentration (IC50) B 24 mM) as compared
to the other ethenyls (IC50: 30–63 mM) and that it is comparable to vitamin E (IC50 B 26 mM). The results
are also supported by the computational data obtained through time dependent density functional
theory (TDDFT) calculations. From the TDDFT and antioxidant study, it was shown that there is a correla-
tion between the highest occupied molecular orbital (HOMO)–lowest unoccupied molecular orbital
Received 16th March 2020,
Accepted 4th May 2020
(LUMO) energy, the ground state dipole moment, optical band gap, bond dissociation enthalpy and the
DOI: 10.1039/d0nj01317j
ionization potential of the ethenyls with the antioxidant properties. A possible hydrogen and/or electron
and proton transfer mechanism is suggested for the quenching of the free radical.
rsc.li/njc
For example, stilbenoids and their derivatives, show remark-
1
. Introduction
1
1–16
ably high antioxidant activities.
Some of the synthetic
In biological systems such as cells, tissues and bio-molecules, antioxidants such as butylated hydroxy phenyl derivatives
1
7
antioxidants prevent oxidative damage by acting as scavengers BHA, BHT, TBHQ are used as food preservatives, dihydro-
1
–5
18
to reactive oxygen species (ROS). Vitamin C and vitamin E are quinoline ethoxyquin is used in the rubber industry, and
well known non-enzymatic antioxidants within normal cells organochalcogen compounds are used in biological and other
19
that interact directly with radicals such as hydroxyl and peroxyl industrial applications. Heterocyclic compounds, in particular,
intermediates and help to minimize the consequences of lipid are the most important class of molecule that show a wide range of
peroxidation in membranes. There are several natural anti- medicinal properties. Compounds based on the indole moiety are
oxidants that help reduce the risk of ROS induced human very limited, but exhibit good anti-oxidation activities with a 50%
20,21
diseases such as heart, neurodegenerative, cancer, chronic inhibition concentration (IC50) approximately 25 mM.
The
2
,3
and age related degenerative diseases. Natural antioxidants practical applications of indoles and pyrroles are heavily centered
are more suitable compared to synthetic antioxidants. However, in pharmaceutical area and thus many indole based compounds
natural antioxidants have their own merits and demerits such as have been synthesized in an effort to find substances with useful
22–25
a lack of water solubility and average antioxidant activity. Most activity in biological systems.
For example, carbazole-based
antioxidants are lipid-soluble with a lower absorption capacity, compounds exhibit radical scavenging properties (IC : 42 mM)
50
22
such as vitamin E, carotenoids, and lipoic acid. Thus, newer as well as being potential candidates for anticancer activities.
synthetic antioxidants with higher antioxidant properties are 3-Indolyl-chromene derivatives exhibit antioxidant properties com-
23
highly warranted. Many synthetic antioxidants that have been parable to vitamin C (IC50: 10–15 mM) and indole-based ethyle-
6
–10
developed recently exhibit good antioxidant properties.
nophanes show radical scavenging properties similar to those of
vitamin E (IC50: 28 mM). Another indole derivative has been found
24
a
Department of Chemistry, School of Sciences, Hemvati Nandan Bahuguna
to be a powerful antioxidant towards suspensions of graphene
25
Garhwal University, Srinagar (Garhwal), Uttarakhand 246174, India.
oxide. Thus, in a continuation of stilbene research, the antiox-
idant activity and its mechanism for a series of donor and acceptor
substituted ethenyl indoles was investigated, as shown in Fig. 1.
The results are also supported by computational data using time
dependent density functional theory (TDDFT).
E-mail: p.hota@hnbgu.ac.in; Tel: +91-1346-250646
b
Department of Pharmaceutical Sciences, School of Sciences, Hemvati Nandan
Bahuguna Garhwal University, Srinagar (Garhwal), Uttarakhand 246174, India
Electronic supplementary information (ESI) available. See DOI: 10.1039/
d0nj01317j
†
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Fig. 2 Synthetic routes and reaction conditions used to obtain the ethenyl
indoles: (a) pyridine, piperidine, 100 1C, reflux 8 h and (b) FeSO
4
, aqueous
Fig. 1 Structure of compounds 1–6, the antioxidant properties of which
NH , ethanol, 100 1C, 3 h.
3
were evaluated.
The reaction mixture was cooled to room temperature, poured
into ice-cold water and treated with 100 mL of diluted hydro-
chloric acid to remove the excess pyridine from the reaction
2
. Experimental
2.1 Materials and analytical equipment
The starting materials and reagents for the synthesis of the mixture. A brick red colored product was extracted in dichloro-
ethenyl indoles were received from local suppliers (M/s. Sisco methane and purified by column chromatography using 2–5%
Research Laboratory). Compounds were synthesized using a ethyl acetate in petroleum ether as the eluting solvent, the
Carousel 6 plus reaction station, made by Radleys. Synthetic desired compound was obtained in 31% yield. Compound 6
compounds were characterized through UV-visible (UV-Vis) was obtained through the reduction reaction of 1. For this
spectroscopy, Fourier-transform infrared (FTIR) spectroscopy, purpose, ethenyl indole 1 in ethanol was refluxed in the presence
1
13
H nuclear magnetic resonance (NMR) and C NMR, gas of aqueous ferrous sulfate and ammonia solution at 100 1C for
chromatography–mass spectrometry (GC–MS) and carbon 3 h, as shown in Fig. 2. The products were purified by column
hydrogen and nitrogen (CHN) analysis. The absorption spectra chromatography using 2–10% ethyl acetate in petroleum ether
were measured on a PerkinElmer Lambda 750 UV/VIS/near- (60–80 1C) as the eluting solvent. The compounds were char-
1
13
infrared (NIR) spectrophotometer and the fluorescence spectra acterized using UV-Vis, FTIR, H NMR and C NMR, GC-MS and
were measured on a PerkinElmer LS-55 fluorescence spectro- CHN analysis.
photometer using a red photomultiplier tubes (PMT) detector
system. The FTIR spectra in the KBr discs were recorded on an
Impact Nicolet-400 spectrophotometer. The H and C NMR
spectra, in CDCl3 as a solvent and using tetramethylsilane
2
.3 Methods used for antioxidant studies
1
13
The antioxidant studies of ethenyl indoles 1–6 were performed
36,37
using a 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay.
this purpose, varying concentrations of the ethenyl compound
0 to 400 mM) were added to a 100 mM concentration of
the DPPH solution and the quenching of the absorbance at
17 nm of the DPPH radical was monitored at regular
For
(TMS) as an internal standard, were recorded on a JEOL
500 MHz FTNMR instrument. The GC–MS spectra were recorded
(
on a GCD 1800A Hewlett Packard GC–mass spectrometer. CHN
analyses were performed on a Theoquest CE instrument 1112
series CHNS auto analyzer. Melting points were determined on a
Lab India melting point apparatus. For spectroscopic studies, UV
grade solvents were used.
5
time intervals (0–45 min). The quenching of the DPPH solution
with standard antioxidants (e.g. ascorbic acid, vitamin E)
was also used as a positive control. All of the experiments
were performed in triplicate and the average absorbance was
measured for calculating the percentage of inhibition using
eqn (1).
2.2 Synthesis of compounds 1–6
The substituted p-phenyl ethenyl-E-indoles (1–5) were synthe-
sized by the condensation of the p-substituted phenyl acetic
acid with the corresponding 3-formylindole (2 : 1 molar ratio) in
the presence of a pyridine–piperidine mixture as described
% Inhibition of the DPPH free radical
=
[(Ablank ꢀ Asample)/(Ablank)] ꢁ 100
(1)
2
6–35
previously
followed to obtain compound 1. 3-Formyl indole (1.45 g, In which Ablank represents the absorbance of the DPPH radical
.01 mol) was added to freshly distilled pyridine (10 mL), in the absence of a sample, and Asample is the absorbance of the
piperidine (0.6 mL) and p-nitrophenyl acetic acid (3.62 g, DPPH radical in the presence of varying concentrations of
.02 mol) in a round bottom flask fitted with a reflux condenser. sample. The radical inhibition concentration (IC50) of the
and the synthetic routes shown in Fig. 2 were
0
0
The reaction mixture was heated at 100 1C for 8 h. The progress ethenyls was calculated from the plot of the percentage inhibi-
of the reaction was monitored using thin layer chromatography. tion versus the sample concentration.
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2
.4 Method for calculating the bond dissociation enthalpy,
In which EAr–XH, EAr–X
ꢂ
, and E
H
ꢂ
are the enthalpies of the Ar–XH,
ꢂ
ionization potential, proton affinity, proton dissociation
enthalpy and electron transfer enthalpy
Ar–X radical, and hydrogen radical, respectively as described
3
3
previously.
Many types of anti-oxidation mechanisms are suggested in the
IP = EAr–X
ꢂ
+
H
ꢀ EAr–XH
(3)
3
8–41
literature,
such as hydrogen atom transfer (HAT), single
In which EAr–XH, and EAr–X
Ar–X H cationic radical.
ꢂ
+
H
are the enthalpies of the Ar–XH,
electron transfer (SET) or single electron transfer followed by
proton transfer (SET-PT), sequential proton loss and electron
transfer (SPLET) and so forth. It is noteworthy that the anti-
oxidation mechanism is very complex and therefore both
thermodynamic as well as kinetic studies can provide complete
information, as reported recently for the trolox molecule that
follows the HT, SET or SPLET mechanism based on the reacting
ꢂ
+
34
+
PA = EAr–X
ꢀ
+ EH ꢀ EArXH
(4)
+
In which EAr–X
ꢀ
, E
H
and EAr–XH are the enthalpies of the anion
ꢀ
+
Ar–X , H , Ar–XH.
+
PDE = EAr–X
ꢂ
+ E
H
ꢀ EArX
ꢂ
+
H
.
(5)
3
9
environment and the pH conditions. In such mechanisms,
the quenching of the free radical occurs through either hydro-
+
In which E
ꢂ
, E and EArX
ꢂ
+H are the enthalpies of the radical
Ar–X , H , Ar–X H cationic radical.
Ar–X
H
ꢂ
+
ꢂ
+
3
8–40
gen atom transfer
transfer mechanism
or electron transfer followed by a proton
(Scheme 1). Thus, thermodynamic
3
8,39,41
eꢀ
ETE = EAr–X
ꢂ
+ E ꢀ EAr–X
ꢀ
.
(6)
parameters, such as the bond dissociation enthalpy (BDE),
ionization potential (IP), proton affinity (PA), proton dissocia-
tion enthalpy (PDE) and electron transfer enthalpy (ETE),
provide the most valuable information for determining the
antioxidant capacity of a molecule.
In which EAr–X
ꢂ
, E
e
ꢀ
ꢀ
and EAr–X
ꢀ
are the enthalpies of the radical
ꢂ
ꢀ
Ar–X , electron (e ), Ar–X anion.
The difference in the energy, DBDE, DIP, DPA, DPDE and DETE
were calculated with respect to vitamin E using eqn (7)–(11).
The BDE, IP, PA, PDE and ETE of the ethenyl indoles were
calculated using TDDFT. For this purpose, various structures
DBDE = BDE ꢀ BDEvitamin E
.
(7)
(8)
DIP = IP ꢀ IPvitamin E.
(neutral, free radical, cationic radical and anion) of the ethenyl
indoles were optimized using the Avogadro and ORCA version
DPA = PA ꢀ PAvitamin E.
(9)
4
2
4.0 program package. The energy of the molecule was calcu-
DPDE = PDE ꢀ PDEvitamin E.
(10)
(11)
lated using the Becke’s three parameter hybrid exchange–
4
3
correlation, B3LYP/def2-SVP basis set. The density functional
theory (DFT) and B3LYP predicted bond dissociation energies
are the most reliable and comparable as compared to other
DETE = ETE ꢀ ETEvitamin E.
The TDDFT method was validated using standard com-
computational methods, as shown from the previously pub- pounds, such as 2,4,6-tri-tert-butylphenol, for which a BDE of
4
4–47
ꢀ1
lished literature.
The BDE, IP, PA, PDE and ETE of the 81.24 kcal mol
has been reported experimentally
4
8–50
molecules were calculated using eqn (2)–(6).
elsewhere.
radical, (E
ꢀ0.497 a.u.), the DBDE for resveratrol and 4-hydroxy stilbene
Similarly, the computed energy of the hydrogen
ꢀ
1
ꢂ
)
is ꢀ13.547 eV (ꢀ312.32 kcal mol
and
H
BDE = EAr–X
ꢂ
+ E
H
ꢂ
ꢀ EAr–XH
(2)
Scheme 1 Antioxidant mechanism through H-atom transfer, electron transfer or sequential proton loss and electron transfer followed by a proton
transfer mechanism.
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with respect to phenol is well matched with the value reported 3.2 Antioxidant properties of ethenyl indole using the DPPH
4
8
in the literature and is comparable to our experimental and assay
theoretical results.
The antioxidant properties of compounds 1–6 were studied
using a DPPH assay, in which the DPPH free radical changes
its color from purple to yellow upon the quenching of the radical
in the presence of an antioxidant (e.g. ethenyl indoles, 1–6). The
decrease in the absorbance of the DPPH radical was monitored
at 517 nm in methanol (Fig. 3) and the plot of the percentage of
inhibition versus antioxidant concentration was drawn (Fig. 4). It
can be seen that except for the nitro substituted ethenyl, all of
the other ethenyls exhibit antioxidant properties. The hydroxy
2
.5 Method for TDDFT
For the calculation of the computational parameters, the ORCA
ab initio quantum chemical software package was used. For
this purpose, TDDFT
the ground state dipole moment, the absorption wavelength
maximum (labs max), the vertical excitation energy and the
oscillator strength (f) using functional B3LYP with a def2 SVP
basis set. The minimized geometry was further confirmed by
vibrational analysis, resulting in no imaginary frequencies.
This geometry is used as the input for further calculations to
obtain the frontier molecular orbitals (FMOs), single-point
TDDFT studies (first 10 vertical singlet–singlet transitions) were
used to obtain the UV-Vis spectra using a B3LYP functional and
a def2 SVP basis set. The software multiwfn 3.6 was employed
to simulate the major portion of the absorption spectrum.
4
2
4
6,47
has been used for the calculation of
4
3
(e.g. phenolic group) substituted ethenyl indole (5) exhibits better
antioxidant properties with an IC50 of approximately 24 mM
compared to the other ethenyls 2–4 and 6 (IC50: 30–63 mM) and
comparable to those of vitamin E (IC50 B 26 mM).
3. Results and discussion
3.1 Synthesis and characterization of indolic ethenyls 1–6
The trans-olefins of 1–6 were obtained through the condensa-
tion reaction as shown in Fig. 2, with a reasonable yield
(
24–56%). All of the compounds were characterized using
1
13
H NMR, C NMR, FTIR, MS (EI+ method) and CHN analysis.
1
In H NMR, the two doublet peaks for the olefin protons appear
Fig. 3 Typical absorption spectra of 100 mM of the DPPH radical alone
near d 7.1 and 7.2 with a J coupling constant of J = 15.8–16.5 Hz and in presence of a 25 mM concentration of ethenyl indoles 1–6, vitamin E
corresponding to the trans-isomer for 4–6. In the case of and vitamin C.
compound 1–2, the two doublet peaks appear close to d 7.3
and d 7.5 ( J = 15.8–16.5 Hz). Similarly, the indole ring protons
such as –C
–H appears as a singlet near d 7.3–7.4, –C
doublet at d 7.9 ( J = 7.5–8.2 Hz) and –C –H as a doublet at
d 8.0 ( J = 6.2–7.5 Hz). In FTIR, the indole N–Hst appears close to
5
–H and C
6
–H appear as a multiplate near d 7.1–7.2,
–C
2
4
–H as a
7
ꢀ
1
ꢀ1
3
370 cm . The C–Hst appears close to 3040 cm and CQCst
ꢀ1
appears in between 1620–1636 cm . Similarly, the aromatic
CQCst and C–Cst appear close to 1520, 1488, 1455, and
ꢀ
1
1
400 cm . For compound 1, the NQO symmetrical and
asymmetrical stretching frequency appeared at 1330 and
ꢀ
1
1
520 cm . In compound 4, the O–Cst of the methoxy appeared
ꢀ1
ꢀ1
at 1244 cm . For compound 5, a broad peak at 3126 cm
corresponding to the O–Hst is observed. For compound 6, two
sharp peaks appeared at 3394 and 3341 cm corresponding to
the primary amine group. This confirmed the presence of the
functional group in the respective olefin compounds. Details of
ꢀ1
1
13
the characterization data ( H and C NMR, FTIR, CHN, GC-MS)
Fig. 4 A plot of the percentage of quenching of the DPPH radical versus
the concentration of the natural antioxidants and ethenyl indoles 1–6.
are provided in the ESI† (Fig. S1–S6).
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Upon replacement of the hydroxy group with a methoxy in
Paper
compound 5, a slight decrease in the radical quenching, but a
similar IC50 value, is observed. This suggest that the anti-
oxidation in this molecule could be caused by the hydrogen
atom transfer of the indolic NH and/or electron transfer
followed by the proton transfer mechanism. On the other hand,
in the presence of an electron withdrawing substituent, the
antioxidant activity of the ethenyl indole is decreased. For
example, as compared to 3 (IC50: 31 mM), the radical quenching
activity of compound 2, which has an electron withdrawing
chloro substituent (e.g. Cl), is reduced further (IC : 63 mM).
5
0
Ethenyl 1, which has a nitro substituent, does not show any
antioxidant activity. On the other hand, ethenyl with a donating
substituent exhibits good antioxidant properties. Thus, the
antioxidant activities could be caused by hydrogen atom trans-
fer and/or electron transfer followed by a proton transfer Fig. 6 Fluorescence spectra of compounds 1–6 in methanol.
mechanism in a substituent dependent manner. In order to
understand the antioxidant properties in detail, the optical
properties of these molecules were determined using absorp- which indicates a p - p* nature for the transition. It can be
tion, fluorescence and TDDFT.
.3 Absorption and fluorescence properties of ethenyl 1–6
seen that the absorption wavelength maximum (labs) and
fluorescence wavelength maximum (lem) are sensitive to the
substituent. Upon increasing the electron withdrawing capacity
of the substituent, a red shift in the labs and lem is observed
and a maximum of 86 nm in the labs and 194 nm in the lem was
observed for 1, whereas for 2–6, a minimal red shift was
observed. Using a Tauc plot (Fig. S7, ESI†), the optical
band gap of ethenyl indole was determined using the absorp-
tion spectrum in methanol and using the TDDFT method
3
The absorption and fluorescence spectra of 1–6 were recorded in
methanol (Table 1 and Fig. 5 and 6). For all the compounds, the
ꢀ
1
ꢀ1
extinction coefficient (e) lies between 10000–30 000 M cm
,
Table 1 IC50 values of the indolic ethenyls (1–6) for the DPPH radical in
methanol
(Fig. S8–S11, ESI†). It was found that for 1, the optical band
a
a
l
abs
l
em
e
Band gap
using Tauc plot (mM) R
IC50
gap was 1.06 eV lower as compared to other ethenyls. The large
red shift and low optical band gap suggest the involvement of a
charge transfer state for 1 with a strong electron withdrawing
nitro group. Also, ethenyl 1 is electron deficient in nature. The
ground state dipole moments of ethenyls 1–6 were computed
ꢀ1
ꢀ1
2
Compounds (nm) (nm) (M cm
)
1
2
3
4
5
6
413
335
327
327
322
324
590
395
396
404
390
405
23900
18 800
10 800
17 800
24 400
12 200
2.37
3.24
3.31
3.30
3.30
3.24
—
63
31
30
24
34
—
0.99
0.96
0.98
0.88 using the TDDFT method and the excited state dipole moments
0.98
were calculated using a Lippert–Mataga plot (Fig. S11–S13,
a
ESI†). The ground state dipole moment of 1 is 8.39 Debye with
a small optical band gap of 2.37 eV as compared to the other
ethenyls (Table 2 and Fig. S12, ESI†). Similarly, the change in
the excited state dipole moment for 1 is large compared to 2–6
Vitamin E (IC50, 26 mM), ascorbic acid (vitamin C) (IC50, 12 mM).
(for 1: B15 Debye and 6–9 Debye for 2–6) (Table S1 and
Fig. S13, ESI†). The optical band gap of vitamin E is 5.17 eV
and ethenyls 2–6 are comparable (TDDFT: 3.82–3.79 eV; Tauc
plot: 3.24–3.31 eV). On the other hand, compound 1 has an
optical band gap that is 0.8 eV lower (TDDFT: 3.06 eV; Tauc plot:
2
.37 eV) as compared to 2–6. Similarly, the ground state dipole
moments of vitamin E, compound 4 and 5 are 0.80–1.37 Debye
vitamin E: 0.80 Debye, 4: 1.05 Debye, 5: 1.37 Debye), whereas the
(
dipole moment of compound 6 is a little larger (2.44 Debye).
Therefore, the dipole moment is increased with the increasing
electron withdrawing nature of the substituent (1-NO : 8.39 Debye,
2
2-Cl: 3.99 Debye, 3-H: 2.57 Debye). Interestingly, the antioxidant
efficacy is decreased with the increasing electron withdrawing
nature of the p-phenyl substitution. The order of the antioxidant
3 2
capacity is vitamin E B 5-OH B 4-OCH 4 3-H B 6-NH 4
Fig. 5 Absorption spectra of compounds 1–6 in methanol.
2-Cl 4 1-NO . This indicates an inverse relationship between
2
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g
Table 2 TDDFT computed, ground state dipole moment (m ), optical band gap, BDE and IP of the indolic ethenyls (1–6)
ꢀ1
ꢀ1
ꢀ1
ꢀ1
Compound
m
g
(Debye)
Optical band gap (eV)
BDE (kcal mol
82.97 (–OH)
)
DBDE (kcal mol
)
IP (kcal mol
157.43
)
DIP (kcal mol
)
Vitamin E (IC50: 26 mM)
0.80
5.17
0
0
8
3
.39
.99
3.05
103.39 (–NH)
97.65 (–NH)
96.11 (–NH)
97.17 (–NH)
20.42
14.68
13.14
14.20
161.05
3.62
3.82
151.44
ꢀ5.99
2
1
1
2
.57
.05
.37
.44
3.86
3.84
3.85
3.79
150.31
144.36
145.38
140.10
ꢀ7.12
ꢀ13.07
ꢀ12.05
ꢀ17.33
9
9
8.44 (–NH)
4.10 (–OH)
15.47
11.13
9
5.79 (–NH)
12.82
22.41
2
105.38 (–NH )
the antioxidant capacity and the dipole moment of the com-
The BDE is a very important thermodynamic parameter,
pound (Table 2 and Fig. S12, ESI†). Similarly, it is shown that which is used to characterize the ability of a compound to
compound 1, with a smaller optical band gap (2.37 eV), does undergo a homolytic reaction. For ethenyl indoles, the BDEs
not show antioxidant activity, whereas compounds 3–5 with of indolic NH, aniline NH and phenol OH are 96, 105 and
ꢀ1
optical band gaps of approximately B3.30 eV exhibit an anti- 94 kcal mol respectively. Thus, the BDE of the aniline NH
ꢀ
1
oxidant activity that is comparable to that of vitamin E.
bond is 10 kcal mol higher compared to that of the indolyl
NH bond. The BDE of the indolyl NH bond is increased further
3.4 TDDFT studies of the ethenyl indoles (1–6)
in the presence of an electron withdrawing substituent (NO
In recent years, TDDFT studies have been carried out to under- Cl), whereas the BDE is reduced in the presence of an electron
stand anti-oxidation mechanisms in detail. Such activities can be donating substituent (NH , OH, OCH ). The highest BDE of
determined by calculating the chemical properties such as the 103 kcal mol for nitro compound 1 and the lowest BDE of
2
,
2
3
ꢀ
1
ꢀ
1
BDE, IP, PA, PDE and ETE of the antioxidants. In many biological 95 kcal mol for amine 6 were found. This indicates that the
systems, the antioxidant properties of the phenolic compounds electron withdrawing group stabilizes the ethenyl indole and
(
(
Ar–OH) are dependent upon the stability of the phenoxyl radical destabilizes its free radical, whereas an electron donating group
ꢂ
40,44,51–58
Ar–O ) and act through proton transfer mechanism.
It destabilizes the neutral molecule and stabilizes the radical
is known that phenol- or tryptophan-like antioxidants act via a H through the delocalization of unpaired electrons, which is well
4
1,59
58
atom transfer mechanism owing to them having low BDEs.
known in other reported amine compounds. Recently the
It is also known that these molecules have the smallest BDE radical quenching activities of the hydroxy spiroselenuranes
owing to the resonance or intramolecular hydrogen bonding were shown to have similar results. In these molecules, the
within the molecule and hence, exhibit a larger antioxidant electron withdrawing benzamide ring reduced the antiradical
4
1,59
activity.
Similarly, resveratrol-like antioxidants work through activity, whereas the electron donating aniline ring increased
the electron transfer mechanism owing to their small IP values the antioxidant properties owing to the stabilization of the
6
0
and negative DIP values as compared to phenol and its free radical. Similarly, in ethoxyquin, and dihydroquinoline
4
7
related compounds. Thus, TDDFT computation was carried compounds, the extensive delocalization of the aminyl radical
ꢀ1
out on the ethenyl indoles (1–6) and various parameters such leads to a lower BDE (B81 kcal mol ) and exhibits better
6
1,62
as the BDE, IP, PA, PDE and ETE were calculated, as shown in antioxidant properties compared to those of a-tocopherol.
Tables 2 and 3.
Thus, thermodynamic compounds with lower BDE values may
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Table 3 TDDFT computed, PDE, PA, and ETE of the indolic ethenyls (1–6)
ꢀ1
ꢀ1
ꢀ1
ꢀ1
ꢀ1
ꢀ1
Compound
PDE (kcal mol
)
DPDE (kcal mol
)
PA (kcal mol
365.34
)
DPA (kcal mol
)
ETE (kcal mol
29.19
)
DETE (kcal mol
)
Vitamin E (IC50 : 26 mM) 236.37
0
0
0
2
2
2
2
53.18
57.05
56.63
63.64
16.81
20.68
20.26
27.27
349.93
354.61
355.95
359.92
ꢀ15.40
ꢀ10.72
ꢀ9.38
ꢀ5.41
63.54
53.12
50.24
47.34
34.35
23.93
21.05
18.15
2
2
63.90
59.56
27.53
23.19
361.69
363.84
ꢀ3.64
ꢀ1.49
46.83
40.35
17.64
11.16
2
2
66.52
76.11
30.15
39.74
362.41
390.30
ꢀ2.92
43.46
25.16
14.27
ꢀ4.03
+24.96
exhibit higher antioxidant activity. In the case of ethenyl
For the SET-PT mechanism, the IP and the highest occupied
indoles, the antioxidant activity is increased with the increasing molecular orbital (HOMO) energy represent the electron donating
donating ability of the substituent with a lower BDE. Thus, capability of an antioxidant. It is known that the electron
the antioxidant activity in ethenyl indoles could be a result withdrawing substituent stabilizes the neutral molecule, which
of a thermodynamically controlled HAT mechanism. Nitro leads to a lower HOMO energy (more negative) and destabilizes
compound 1 does not show any activity. This could be a result the radical and the radical cation, which results in an increase
5
9,64
of the formation of an electron delocalized charge transfer in the IP energy.
On the other hand, the electron donating
resonating structure (Scheme 2), which is unable to donate substituent stabilizes the radical and the radical cation and
a hydrogen or electron. This type of inactivity is found in destabilizes the neutral molecule, which results in a higher
organotellurium compounds that rapidly convert to a product HOMO energy (less negative) and a decrease in the IP
5
9,65,66
which cannot act as a hydrogen donor or electron donor to a values.
peroxy radical.
In the present ethenyl indoles, a higher IP of
6
3
ꢀ1
161 kcal mol for the nitro compound 1 and a lower IP of
40 kcal mol for the amino compound 6 was found. Upon
ꢀ1
1
increasing the donating ability of the substituent, the IP is
decreased with the increasing HOMO energy. The IP order is
NO 4 Cl 4 H4 OCH B OH 4 NH . The smaller IP value in
2 3 2
the presence of a donating substituent could be a result of the
stabilization of the cationic free radical through a mesomeric
effect. There is a correlation between the HOMO and LUMO
energies of the compounds and the antioxidant efficacy. The
lowest unoccupied molecular orbital (LUMO), as well as the
HOMO energy, is gradually decreased (more negative) with the
increasing electron withdrawing nature of the substituent and
the highest negative HOMO–LUMO energy was computed for 1
(
HOMO: ꢀ5.51 eV, LUMO: ꢀ2.46 eV). On the other hand, the
Scheme 2 The lack of antioxidant activity in ethenyl indole (1) is a result
of the charge transfer and formation of a stable electron deficient
resonating structure.
highest HOMO energy was computed for the hydroxy (5) and
amino compound (6) (HOMO: ꢀ4.62 eV, LUMO: ꢀ0.83 eV).
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phenyl NH was found for the amino compound 6 and a lower
ꢀ1
PA of 349 kcal mol was found for the nitro compound 1. The
ethenyl indole with NO substitution shows the largest decrease
2
ꢀ
1
in PA by 11 kcal mol . The increasing order of PA energy is as
follows: 6 4 5 4 4 4 3 4 2 4 1 and the antioxidant capacity is
in the reverse order IC50 (e.g. 5 4 6 4 4 4 3 4 2 4 1). Thus, if
any anion is generated through proton abstraction by following
the SPLET mechanism (Scheme 4), then the indolyl anion could
be further stabilized in the presence of an electron withdrawing
substituent with a consequent decrease in the PA and an
increased in the antioxidant activity. However, in the present
ethenyl the antioxidant activity is enhanced in the presence of
an electron donating substituent. Thus, the SPLET pathway can
be ruled out.
Scheme 3 Antioxidant properties of ethenyl indole (6) through a SET-PT
mechanism via a cationic radical intermediate.
As the HOMO is related to the ionization energy, a larger
The PDE and ETE also provide useful information for the
HOMO energy for a molecule leads to a favorable ionization later step in the SET-PT and SPLET mechanisms respectively68,69
process and thus, favors the anti-oxidation process (Fig. S10, (Schemes 3 and 4). Thus, the substituent dependent BDE, PA, IP,
ESI†). Similarly, ethenyl indole with a large optical band gap PDE and ETE energy data can provide further insights into
exhibits better antioxidant properties (Fig. S11, ESI†). The the preferred thermodynamic mechanism for the antioxidant
involvement of the electron delocalization in molecule 1 leads activity for ethenyl indole. The PDE and ETE were determined
to a smaller optical band gap with a large ground state dipole and are shown in Table 2.
ꢀ
1
moment (m ) and the molecule is electron deficient in nature,
The highest PDE of 276 kcal mol for the cationic phenyl
g
ꢀ1
(
1-NO substitution, m : 8.39 Debye). This molecule exhibits no amine radical and 266 kcal mol for the cationic indolic NH
2 g
antioxidant activity (Fig. S12, ESI†). The HOMO and LUMO radical were found for the strong electron donating amine
ꢀ1
energy and the optical band gap of the neutral (NH), cationic compound 6, whereas the lowest PDE of 253 kcal mol for
ꢂ
ꢀ
(
NH+), free radical (N ) and anion (N ) groups of the ethenyls the cationic indolic NH radical was found for the strong
were computed (Fig. S13–S15, ESI†). It can be seen that the electron withdrawing nitro compound 1. This is because the
HOMO and LUMO energy of the neutral and free radical species electron donating substituent stabilizes the radical cation more
are comparable (difference 0.2–0.4 eV). The cationic radical as compared to the electron withdrawing group. Thus, the PDE
species are more stable by 4 eV as compared to the neutral is larger for the ethenyl with a strong electron donating amine
ethenyl indole. Thus, ethenyl indole with a donating substitu- substituent and it requires a higher energy for the dissociation
ent can easily give an electron and exhibits better antioxidant of the proton from the radical cation intermediate. Similarly,
ꢀ
1
properties through the SET-PT mechanism (Scheme 3).
the lowest ETE of 43 kcal mol for the indolic anion, and
ꢀ
1
The other possible mechanism is the SPLET via the anionic 25 kcal mol
for the phenyl amine anion were found for
ꢀ
1
intermediate, as shown in Scheme 4. In this mechanism the compound 6, whereas the highest ETE of 63 kcal mol was
role of PA, the reaction enthalpy, is important. The PA of found for the nitro compound 1. It is known that a more
indolic NH, phenyl amine NH and phenol OH were found to stabilized anion requires a higher energy to transfer the elec-
ꢀ
1
59,68,69
be 362, 390 and 363 kcal mol respectively. It is well known tron to the free radical.
that the electron donating group increases the PA, whereas the
Thus, in the presence of an electron-withdrawing substitu-
5
9,67
electron withdrawing group decreases the PA.
The highest ent, the indolic ethenyl shows a higher BDE, IP and ETE,
ꢀ
1
ꢀ1
PA of 362 kcal mol for indolic NH and 390 kcal mol for whereas a higher PA and PDE is found in the presence of an
electron-donating substituent. For all the ethenyl indoles, the
BDE is lower compared to the IP and PA energy, and thus, these
compounds can follow the thermodynamically controlled HAT
mechanism. It is also worth mentioning that single electron
transfer followed by proton transfer (SET-PT) could also be a
possible mechanism as per the experimental results on the
antioxidant activity. The amine and hydroxy compounds have a
lower IP energy owing to the formation of a more stable cationic
radical and thus, exhibit better antioxidant properties. On
the other hand, the SPLET mechanism is a preferred thermo-
dynamic process for the electron withdrawing substituent.
However, the nitro substituted ethenyl indole does not show
any antioxidant activity and the chloro substituted ethenyl
Scheme 4 Antioxidant properties of ethenyl indole (6) through proton
indole shows a lower activity and therefore the SPLET mecha-
nism can be ruled out.
loss followed by an electron and proton transfer via the anionic inter-
mediate, a less favorable mechanism.
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4
. Conclusion
compounds obtained from tyrosol and cinnamic acid deriva-
tives, New J. Chem., 2014, 38, 809–816.
K. Inami, Y. Iizuka, M. Furukawa, I. Nakanishi, K. Ohkubo,
K. Fukuhara, S. Fukuzumi and M. Mochizuki, Chlorine
atom substitution influences radical scavenging activity of
In summary, ethenyl indoles with various donors or acceptor
substituents were synthesized and their substituent dependent
antioxidant activity was studied using a DPPH assay and the
TDDFT method.
The ethenyl indole with an electron withdrawing nitro com-
pound does not show antioxidant properties owing to charge
transfer and the electron deficient system. Ethenyl with a
moderate electron withdrawing chloro substituted compound
show a reduced activity, whereas ethenyls with an electron
7
8
9
6-chromanol, Bioorg. Med. Chem., 2012, 20, 4049–4055.
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3 2
donating substituent (OCH , OH, NH ) show antioxidant proper-
ties comparable to those of vitamin E. From the experimental
and computed BDE, IP and PA values of the ethenyl indoles,
it is suggested that these compounds prefer HAT as well as the
SET-PT for the radical quenching process. The nature of the
substitution also plays an important role in determining
the antioxidant activities. Overall, the present indole-based
donor and acceptor ethenyls exhibit substituent dependent
antioxidant activity, which is interesting. As the anti-oxidation
mechanism is very complex, kinetic studies on these molecules
can provide further insights into the mechanism of action in
detail. These experimental and computational results, however,
provide a new direction for designing and developing novel
molecules with efficient antioxidant properties.
1
1
0 R. Han, L. Liu, J. Li, G. Du and J. Chen, Functions, applica-
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Conflicts of interest
There are no conflicts to declare.
1
4 M. Wang, Y. Jin and C. T. Ho, Evaluation of resveratrol
derivatives as potential antioxidants and identification of a
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Acknowledgements
We are thankful to the editor and reviewers for their valuable
suggestions in revising the manuscript. PKH, JK, NK are 15 N. R. Madadi, H. Zong, A. Ketkar, C. Zheng, N. R. Penthala,
thankful to the University Grants Commission, New Delhi for
the research grant (No F.30-72/2014-BSR) and research fellow-
ship. The authors acknowledged AMRC, IIT Mandi for use of
V. Janganati, S. Bommagani, R. L. Eoff, M. L. Guzman and
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the H and C NMR facility.
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