New 3H-indole synthesis by fischer's method. Part I.

Article abstract of DOI:10.3390/molecules15042491

Methyl indolenines (4a-c) and (5a-c) were prepared in high yield by a Fischer indole synthesis reaction of o,m-tolylhydrazine hydrochlorides (1a-b) with isopropyl methyl ketone (2) and 2-methylcyclohexanone (3) in acetic acid at room temperature. o,pNitrophenylhydrazines (1c-d) were reacted with 2-methylcyclohexanone (3) in acetic acid at reflux to give nitroindolenines (5d-e), while the attempted reactions of o,pnitrohydrazines with isopropyl methyl ketone (2) in acetic acid were not successful. Compounds (1c-d) were reacted with isopropyl methyl ketone (2) in acetic acid/HCl to give 2,3,3-trimethyl-5-nitro-indolenine (4e) and 2,3,3-trimethyl-7-nitroindolenine (4d). Copyright

Full text of DOI:10.3390/molecules15042491

Molecules 2010, 15, 2491-2498; doi:10.3390/molecules15042491
OPEN ACCESS
Molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
New 3H-Indole Synthesis by Fischer’s Method. Part I.
Sami Sajjadifar 1,2,*, Hooshang Vahedi 1, Abdolhossien Massoudi 1 and Omid Louie 1
1
Department of Chemistry, Payame Noor University (PNU), P O Box 91735-433, Mashhad, Iran;
E-Mails: hooshangvahedi@yahoo.co.uk (H.V.); Massoudi_h@pnu.ac.ir (A.M.);
o_louie2001@yahoo.com (O.L.)
2
Department of Chemistry, Payame Noor University (PNU), Ilam, Iran
* Author to whom correspondence should be addressed; E-Mail: ss_sajjadifar@yahoo.com;
Tel.: +98 8412228316.
Received: 6 February 2010; in revised form: 12 March 2010 / Accepted: 19 March 2010 /
Published: 8 April 2010
Abstract: Methyl indolenines (4a-c) and (5a-c) were prepared in high yield by a Fischer
indole synthesis reaction of o,m-tolylhydrazine hydrochlorides (1a-b) with isopropyl
methyl ketone (2) and 2-methylcyclohexanone (3) in acetic acid at room temperature. o,p-
Nitrophenylhydrazines (1c-d) were reacted with 2-methylcyclohexanone (3) in acetic acid
at reflux to give nitroindolenines (5d-e), while the attempted reactions of o,p-
nitrohydrazines with isopropyl methyl ketone (2) in acetic acid were not successful.
Compounds (1c-d) were reacted with isopropyl methyl ketone (2) in acetic acid/HCl to
give 2,3,3-trimethyl-5-nitro-indolenine (4e) and 2,3,3-trimethyl-7-nitroindolenine (4d).
Keywords: 3H-indole; indolenine; Fischer’s synthesis method; acetic acid
Introduction
The Fischer indole synthesis is a chemical reaction that produces an aromatic heterocyclic indole
from a (substituted) phenylhydrazine and an aldehyde or ketone under acidic conditions. The reaction
was discovered in 1883 by Hermann Emil Fischer [1]. Today antimigraine drugs of the tryptan class
are often synthesized by this method. The choice of acid catalyst is very important. Bronsted acids
such as HCl, H2SO4, polyphosphoric acid and p-toluenesulfonic acid have been used successfully,

Molecules 2010, 15
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while. Lewis acids such as boron trifluoride, zinc chloride, iron chloride, and aluminium chloride are
also useful catalysts [2–4].
The reaction of a (substituted) phenylhydrazine with an aldehyde or ketone initially forms a
phenylhydrazone which isomerizes to the respective enamine (or 'ene-hydrazine'). After protonation, a
cyclic [3,3]-sigmatropic rearrangement occurs producing an imine. The resulting imine forms a cyclic
aminoacetal (or aminal), which under acid catalysis that eliminates NH3, resulting in the energetically
favorable aromatic indole. The accepted mechanism for Fischer’s synthesis was suggested by
Robinson [2,3]. According to Robinson mechanism, this reaction has three steps: (a) tautomeric
conversion of hydrazone to enehydrazine, (b) carbon-carbon bond formation, (c) cyclization with
ammonia, elimination and finally indole synthesis. Some researchers [5] believed that the carbon-
carbon bond formation step is the most important and rate-determining step. This step can control the
amount of indoles. The presence of different ketones for indole synthesis has been investigated.
Isotopic labeling studies show that the aryl nitrogen (N1) of the starting phenylhydrazine is
incorporated into the resulting indole [6–7].
Scheme 1. The Fischer reaction for indolenine synthesis.
R4
R3
R3
+
AcOH
AcOH
R2
NHNH2.HCl
O
R2
N
R1
R1
2
4
1
R4
R3
R2
O
N
3
R1
5
R1
a) H
b) H
c) NO
d) H
R2
H
Me
H
R3
R1
R2
R3
Me
H
H
NO
R4
a) H
b) H
c) H
d) NO
e) H
H
Me
H
H
H
2
Me
H
H
H
H
H
NO
Me
H
2
2
H
2 H
Results and Discussion
As mentioned in the Introduction, the use of different ketones for indole synthesis has been
investigated, but so far, the effects of substituent groups on the phenyl hydrazine benzene ring on the
Fischer indole synthesis have not been reported. Therefore, the presence of methyl and nitro groups in
different phenyl hydrazines and the use of isopropyl methyl ketone (2) and 2-methylcyclohexanone (3)
resulted in a new synthesis of indolenines in which the yield significantly high, mainly a single product
is obtained and it can be carried out under simple conditions.

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1H-NMR spectrum of indolenine (4a) shows a singlet at δ = 1.16 ppm corresponding to the two
methyl groups at C-3, a singlet methyl group for C-2 at δ = 2.24 ppm, and a methyl group singlet
resonance for Ar-CH3 at δ = 2.1 ppm. In the UV spectrum of (4a), two absorption bands of 217 and
262 nm were seen. After acid addition, position shifts in the band maxima was noticed which are the
result of presence of the non-bonding pair electrons in the H+ reaction. Moreover, the presence of the
donating electron methyl groups in suitable positions supported this bathochromic effect.
m-Tolylhydrazine hydrochloride (1b) reacted at room temperature with isopropyl methyl ketone (2)
at the presence of glacial acetic acid to afford two isomers - 2,3,3,4-tetramethylindolenine (4c) and
2,3,3,6-tetramethylindolenine (4b) - in 88% yield. Our efforts to separate the two isomers through TLC
and column chromatography in different solvents were fruitless.
The 1H-NMR spectrum of the two isomers displays two singlets at δ = 1.25 and δ = 1.35 ppm
corresponding to the C-3 methyl hydrogens, two methyl group of C-2 at δ = 2.33 and δ = 2.37 ppm, a
Ar-CH3 methyl group singlet at δ = 2.19 and in the aromatic region, a doublet at δ = 6.84 ppm and a
singlet at δ = 7.1. In the IR spectrum, a C=N stretching vibration is seen at 1,700 cm-1. In the UV
spectrum of this mixture, two absorption bands at 218 and 259 nm were seen and a bathochromic
effect was noticed after acid addition.
1
The H-NMR spectrum of indolenine (5a) showed a methyl group singlet at δ = 1.15 ppm which
provides strong support for the cyclization and creation of indolenine (5a). In the IR spectrum, a C=N
stretching vibration was observed at 1,700 cm-1, which indicates the absence of the N-H bond. In the
UV spectrum of (5a) two absorption bands at 212 and 263 nm were observed, which after acid addition
shifted position. This indicates the presence of non-bonding pair electrons in the reaction with H+.
m-Tolylhydrazine hydrochloride (1b) was also reacted at room temperature with 2-methyl-
cyclohexanone (3) in the presence of glacial acetic acid. After extraction, the products were passed
through a short silica gel column. Two isomers, 4a,5- and 4a,7-dimethyl-1,2,3,4-tetrahydro-4aH-
1
carbazole (5b-c), were obtained. The efforts to separate these products were fruitless. The H-NMR
spectrum of the mixture of isomers indicated two singlet for the C-4a methyl groups at δ = 1.14 and
δ = 1.24, which proves the cyclization and formtion of the indolenines (5b-c). The singlet signals of
the methyl groups in the two isomers overlap at δ = 2.21. In the IR spectrum the C=N stretching
vibration was observed at 1,695 cm-1. In the UV spectrum the maximum absorptions were noticed at
214 and 259 nm which after acid addition, a shift in the position of the band maxima was also seen,
which is indicative of the presence of non-bonding pair electrons in the reaction with H+ (bathochromic
effect).
p-Nitrophenylhydrazine hydrochloride (1d) and isopropyl methyl ketone (2) were reacted in the
presence of acetic acid and the mixture was refluxed for 1.5 h. The product, 2,3,3-trimethyl-5-
nitroindolenine (4d), was obtained in very low yield (10%). During the long reaction under reflux
conditions, the instability and sensitivity of the products led to their decomposition, oxidation and
polymerization. The reaction was also carried out in a binary mixture of acetic acid and hydrochloric
1
acid for 4 h. After extraction, the product (4e) was obtained in 30 % yield. The H-NMR spectrum of
indolenine (4e) showed a singlet signal for the two C-3 methyl groups at δ = 1.35 and a methyl group
singlet for C-2 at δ = 1.87. In the aromatic region, three hydrogens were observed.

Molecules 2010, 15
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Conclusions
It is shown that by switching from –OMe to –NO2, either the time of the reaction will be longer or
reaction conditions will be harsher, so when there is an electron-withdrawing group on the benzene
ring in the phenylhydrazine, the efficiency is lower and the reactions are much more difficult. This
research demonstrates that Robinson’s proposed mechanism is correct. The effects of the studied
groups in the indolenine formation reaction are summarized in Tables 1-2.
Table 1. Reactions with isopropyl methyl ketone (2).
+
R
R
NHNH2
O
N
R
Condition
RT
Time
20 min
2 h
0.5 h
90 h
Acid
Y %
85
>90
>90
9
p-OMe
p,o-OMe
o,m,p-Cl
AcOH
AcOH
AcOH
AcOH
RT
reflux
o,p-NO2
reflux
4 h
AcOH, HCl
31
Table 2. Reactions with 2-methylcyclohexanone (3).
+
R
R
NHNH2
O
N
R
Condition
RT
Time
20 min
1.5 h
0.5 h
24 h
Acid
Y %
>90
>90
>90
53
p-OMe
p,o-OMe
o,m,p-Cl
o,p-NO2
AcOH
AcOH
AcOH
AcOH
RT
reflux
reflux
Experimental
General
1
Melting points were recorded on a Philip Harris C4954718 apparatus and are uncorrected. H- and
13C-NMR spectra were recorded on a Bruker Avance AQS 75 MHz spectrometer. Chemical shifts δ
are in parts per million (ppm) measured in CDCl3 as solvent and relative to TMS as the internal
standard. Infrared spectra were recorded on a Thermo Nicolet-Nexus 670 FTIR instrument and
elemental analyses were carried out on an Exeter analytical model CE440 C, H and N
elemental analyzer.

Molecules 2010, 15
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2,3,3,5-Tetramethylindolenine (4a)
p-Tolylhydrazine hydrochloride (1a, 0.25 g, 1.62 mmol) and isopropyl methyl ketone (3, 0.14 g,
1.62 mmol) were added to glacial acetic acid (2 g, 0.03 mol). The mixture was refluxed for 2.25 h with
stirring. TLC indicated the end of the reaction and formation of the product. The mixture was cooled
and neutralized with 1 M NaOH then diluted with water (100 mL) and extracted with CDCl3
(3 × 100 mL). Following the drying of the organic layer over Na2SO4, the solvent was removed by
means of evaporation and the residue was passed through a short silica gel column for further
purification. A red, viscous oil of 2,3,3,5-tetramethylindolenine (4a) was obtained. TLC: RF 0.22 on
silica gel eluting with PhCH3-EtOAc (9:1); UV: (EtOH) λmax (nm) 217 (H, 2.80) 262 (H, 1.557),
(EtOH, HCl) 207 (H, 1.706), 236 (H, 1.487), 289 (H, 1.310); IR (cm-1): 2940, 1680, 1570, 1450, 1363,
1
1190, 810; H-NMR δ (ppm): 1.16 (s, 6H, 2×CH3), 2.1 (s, 3H, Ar-CH3), 2.24 (s, 3H, N=C-CH3), 6.7-
6.9 (b, 1H, Ar-H), 6.87 (s, 1H, Ar-H), 7.1-7.2 (b, 1H, Ar-H); 13C-NMR δ (ppm): 19.9, 24.6, 25.1, 37.8,
121.9, 127.6, 129.3, 136.6, 148.8, 152.7, 164.6; C12H15N, Mol. Wt: 173.2542; Elem. Anal.: C, 83.19;
H, 8.73; N, 8.08.
Reaction of (1b) with ketone (2) to produce indolenines (4b) and (4c)
m-Tolylphenylhydrazine hydrochloride (1b, 0.3 g, 1.89 mmol) and isopropyl methyl ketone
(2, 0.17 g, 1.98 mmol) were added to glacial acetic acid (3 g, 0.05 mol) and stirred for 2 h. TLC
indicated the end of reaction and formation of the product. The mixture was then cooled, neutralized
with 1 M NaOH, diluted with water (100 mL) and finally extracted with CDCl3 (3 × 100 mL).
Following the drying of the organic layer over Na2SO4, the solvent was removed by evaporation and
the residue passed through a short column of silica gel for further purification. Attempts to separate the
two isomers were not successful, but one the of isomers [2,3,3,6-tetramethylindolenine (4b)] was
isolated and separated by preparative TLC eluting with CH2Cl2-CH3COCH3 (20:1) and the data of
another isomer inferred by comparing with the data of the two isomer mixture.
2,3,3,6-Tetramethylindolenine (4b): TLC: RF 0.3 on silica gel eluting with CH2Cl2-CH3COCH3 (20:1);
UV: (EtOH) λmax (nm) 219 (H, 2.292) 261 (H, 0.684), (EtOH, HCl) 210 (H, 1.513) 227 (H, 1.088) 280
1
(H, 0.625); IR (cm-1): 2900, 1700, 1600, 1565, 1450, 1425, 1340, 1250, 1130, 800; H-NMR: 1.25 (s,
6H, 2×CH3), 2.19 (s, 3H, Ar-CH3), 2.33 (s, 3H, N=C-CH3), 6.7-6.9 (b, 2H, Ar-H), 7.1 (s, 1H, Ar-H);
13C-NMR: 19.9, 24.3, 25.1, 37.5, 123.6, 127.3, 127.4, 136.9, 149.8, 151.7, 164.6; C12H15N, Mol. Wt:
173.2542; Elem. Anal.: C, 83.19; H, 8.73; N, 8.08.
2,3,3,4-Tetramethylindolenine (4c): TLC: RF 0.1-0.35 on silicagel eluting with CH2Cl2-CH3COCH3
(20:1); UV: (EtOH) λmax (nm) 219 (H, 2.802) 259 (H, 1.007), (EtOH, HCl) 209 (H, 1.658) 235 (H,
1.234) 281 (H, 0.971); IR (cm-1) 2900, 1680-1700, 1570, 1420, 1350, 1220-1250, 800; 1H-NMR: 1.35
(s, 6H, 2×CH3), 2.19 (s, 3H, Ar-CH3), 2.37 (s, 3H, N=C-CH3), 6.7-7.2 (b, 3H, Ar-H); 13C- NMR: 18.4,
19.9, 25.4, 31.0, 119.0, 127.2, 127.3, 135.3, 142.9, 151.7, 164.6; C12H15N, Mol. Wt: 173.2542; Elem.
Anal.: C, 83.19; H, 8.73; N, 8.08.

Molecules 2010, 15
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4a,6-Dimethyl-1,3,3,4-tetrahydro-4aH-carbazole (5a)
p-Tolylhydrazine hydrochloride (1a, 0.3 g, 1.89 mmol) and 2-methylcyclohexanone (3, 0.21 g,
1.89 mmol) were added to glacial acetic acid (3 g, 0.05 mol). The mixture was refluxed for 1.5 h with
stirring until TLC indicated the end of the reaction and formation of product. The mixture was cooled
and neutralized with 1 M NaOH, then diluted with water (100 mL) and extracted with CDCl3
(3 × 100 mL). After drying the organic layer over Na2SO4, the solvent was removed by evaporation
and the residue was passed through a short silica gel column for further purification. A red, viscous oil
of 4a,6-dimethyl-1,2,3,4-tetrahydro-4aH-carbazole (5a, 0.32 g, 85%) was obtained. TLC: RF 0.2 on
silica gel eluting with PhCH3-EtOAc (9:1); UV: (EtOH) λmax (nm) 212 (H, 1.624) 263 (H, 0.709),
(EtOH, HCl) 204 (H, 1.080) 237 (H, 0.635), 290(H, 1.603); IR (cm-1): 2900, 1700, 1570, 1440, 1360,
1
1170, 810, 740. H-NMR: 1.15 (s, 6H, 2×CH3), 2.2 (s, 6H, Ar-CH3 and N=C-CH3), 1.1-2.8 (m, 8H,
aliphatic ring hydrogens), 6.7-6.9 (b, 2H, Ar-H), 7.05-7.25 (b, 1H, Ar-H); 13C-NMR: 21.9, 22.9, 24.6,
25.4, 31.2, 34.1, 54.1, 122.0, 127.6, 131.3, 136.7, 143.4, 150.8, 187.3; C14H17N, Mol. Wt: 199.2915;
Elem. Anal.: C, 84.37; H, 8.60; N, 7.03;
Reaction of (1b) with ketone (3) to produce a mixture of indolenines (5b) and (5c)
m-Tolylhydrazine hydrochloride (1b, 0.3 g, 1.89 mmol) and 2-methylcyclohexanone (3, 0.21 g,
1.89 mmol) were added to glacial acetic acid (3 g, 0.05 mol). The mixture was refluxed for 2 h with
stirring until TLC indicated the end of the reaction and formation of the product. The mixture was
cooled and neutralized with 1 M NaOH then diluted with water (100 mL) and extracted with CDCl3
(3 × 100 mL). Following drying the organic layer over Na2SO4, the solvent was removed by
evaporation and the residue passed through short silica gel column for further purification. A red
viscous oil that it is a mixture of the two isomers (5b) and (5c) is obtained. TLC: RF 0.1-0.3 on silica
gel eluting with CH2Cl2: CH3COCH3 (20: 1); UV (EtOH) λmax (nm) 214 (H, 2.398) 259 (H, 0.157),
(EtOH, HCl) 206 (H, 1.813) 235(H, 0.378) 281 (H, 0.150); IR (cm-1): 2840-2910, 1695, 1570, 1430,
1365, 1215, 1125, 965, 800, 780, 743; 1H-NMR: 1.14 (s, 3H), 1.1-2.8 (m, aliphatic ring), 1.24 (s, 3H),
13
2.21 (s, 3H), 6.4- 7.2 (m, Ar-H); C-NMR: 18.4, 21.9, 22.9, 23.2, 24.3, 25.4, 31.2, 34.1, 47.3, 53.8,
119.1, 123.7, 127.2, 127.4, 129.4, 133.6, 136.9, 137.3, 140.5, 153.7, 187.3; C14H17N, Mol. Wt:
199.2915; Elem. Anal.: C, 84.37; H, 8.60; N, 7.03.
4a-Methyl-6-nitro-1,2,3,4-tetrahydro-4aH-carbazole (5e)
p-Nitrophenylhydrazine (1d, 0.29 g, 1.89 mmol) and 2-metylcyclohexanone (3, 0.21 g, 1.89 mmol)
were added to glacial acetic acid (3 g, 0.05 mol). The mixture was refluxed for 24 h with stirring until
TLC indicated the end of the reaction and formation of product. The mixture cooled and neutralized
with NaOH 1 M then diluted with water (100 mL) and extracted with CDCl3 (3 × 100 mL). After
drying the organic layer over Na2SO4, the solvent was removed by evaporation. A yellow oil of the
product (5e) (0.24 g, 53%) was obtained and we used a short column of silica gel for further
purification. TLC: RF 0.44 on silicagel eluting with PhCH3-CH3COCH3 (10:2); UV: (EtOH) λmax (nm)
221 (H, 2.389) 304 (H, 2.413), (EtOH, HCl): 219 (H, 2.338) 302 (H, 2.370); IR: (cm-1) 2840-2920,
1
1880, 1708, 1585, 1555, 1500, 1440, 1320, 1230, 1096, 1046, 970, 830, 730; H-NMR: 1.32 (s, 3H),

Molecules 2010, 15
2497
13
1.1-2.8 (m, 8H, aliphatic ring), 7.3-7.5 (b, 1H, Ar-H), 7.85 (s, 1H, Ar-H), 7.9-8.1 (b, 1H, Ar-H); C-
NMR: 21.9, 22.9, 25.4, 31.2, 34.1, 52.8, 119.6, 123.0, 124.7, 144.4, 146.7, 159.9, 187.3; C13H14N2O2;
Mol. Wt. 230.2625; Elem. Anal.: C, 67.81; H, 6.13; N, 12.17; O, 13.90.
4a-Methyl-8-nitro-1,2,3,4-tetrahydro-4aH-cabazole (5d)
A mixture of o-nitrophenylhydrazine (1c, 0.29 g, 1.89 mmol), 2-methylcyclohexanone (3, 0.21 g,
1.89 mmol) and glacial acetic acid (3 g, 0.05 mol) was refluxed for 24 h with stirring until TLC
indicated the end of the reaction. The mixture was cooled and neutralized with NaOH 1 M then diluted
with water (100 mL) and extracted with CDCl3 (3 × 100mL). After drying the organic layer over
Na2SO4, the solvent was removed by evaporation. A red oil of (5d) (0.23 g, 51%) was obtained and a
short column of silica gel was used for further purification. TLC: RF 0.2 on silica gel eluting with
PhCH3 -CH3COCH3 (9:1); UV: (EtOH) λmax (nm) 233 (H, 1.92), 251 (H, 2.03), 440 (H, 0.66) (EtOH,
HCl), 233 (H, 1.87), 251 (H, 1.94), 440 (H, o.64); IR (cm-1): 2820-2940, 1690, 1600, 1560, 1490,
1400, 1320, 1260, 1020, 740; 1H-NMR: 1.3 (s, 3H), 1.1-2.8 (m, 8H, aliphatic ring) 6.5-7.8 (b, 3H, Ar-
H); 13C-NMR: 21.9, 22.9, 25.4, 31.2, 34.1, 52.8, 119.6, 128.0, 135.6, 141.7, 143.9, 144.4, 187.3;
C13H14N2O2; Mol. Wt. 230.2625; Elem. Anal.: C, 67.81; H, 6.13; N, 12.17; O, 13.90.
2,3,3-Trimethyl-5-Nitroindolenine (4d)
A mixture of o-nitrophenylhydrazine (1c, 0.29 g, 1.89 mmol), 2-methylcyclohexanone (3, 0.21 g,
1.89 mmol), and glacial acetic acid (3 g, 0.05 mol) was refluxed for 24 h with stirring until TLC
indicated the end of the reaction. The mixture was cooled and neutralized with 1 M NaOH, then
diluted with water (100 mL) and extracted with CDCl3 (3 × 100 mL). After drying the organic layer
over Na2SO4, the solvent was removed by evaporation. A red oil of (5d) (0.23 g, 51%) was obtained
and we used a short column of silica gel for additional purification. TLC: RF 0.2 on silica gel eluting
with PhCH3-CH3COCH3 (9:1); UV: (EtOH) λmax (nm) 233 (H, 1.92), 251 (H, 2.03), 440 (H, 0.66):
(EtOH, HCl), 233 (H, 1.87), 251 (H, 1.94), 440 (H, 0.64); IR (cm-1): 2820-2940, 1690, 1600, 1560,
1
1490, 1400, 1320, 1260, 1020, 740. H-NMR: 1.3 (s, 3H), 1.1-2.8 (m, 8H, aliphatic ring), 6.4-6.6
(b, 3H, Ar-H); 13C-NMR δ: 19.9, 25.1, 36.5, 119.6, 122.7, 122.9, 146.6, 153.7, 157.9, 164.6;
C11H12N2O2; Mol. Wt: 204.2252; Elem. Anal.: C, 64.69; H, 5.92; N, 13.72; O, 15.67.
Acknowledgements
The authors are grateful to the Payame Noor University (PNU) of Mashhad for financial support of
this work.
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