(2024) 18:139
Adly et al. BMC Chemistry
https://doi.org/10.1186/s13065-024-01245-9

BMC Chemistry

RESEARCH

Open AccessGreen electrosynthesis of bis(indolyl)methane
derivatives in deep eutectic solvents
Mina E. Adly1, Amr M. Mahmoud2 and Hala B. El‑Nassan1*

Abstract
In this study, a new green method was developed for the synthesis of bis(indolyl)methane derivatives using electro‑
chemical bisarylation reaction in deep eutectic solvents as a green alternative to traditional solvents and electrolytes.
The effects of varying time, current, type of solvent and material of electrodes were all studied. The optimum reac‑tion conditions involved the use of ethylene glycol/choline chloride with a ratio of 2:1 at 80 °C for 45 min. Graphite
and platinum were used as cathode and anode, respectively. The newly developed method offered many advantages
such as using mild reaction conditions, short reaction time and affording high product yields with a wide rangeof substituted aromatic aldehydes bearing electron donating or electron withdrawing substituents. In addition,
the electrochemical method proved to be more effective than heating in deep eutectic solvents and afforded higher
yields of products in shorter reaction time. The mechanism of the electrochemical reaction was proposed and con‑firmed using the cyclic voltammetry study.
Keywords Bisindolylmethane, Electrochemical synthesis, Deep eutectic solvents, Green chemistry
Introduction
The 3,3ʹ-bis(indolyl)methanes (BIMs) represent an
important biologically active scaffold owing to its various
biological activities [1, 2]. Many bisindolylmethane alkaloids were isolated from marine natural sources (Fig. 1)[3, 4]. BIM derivatives were reported to exhibit anticancer [5–13], antibacterial [14–16], antifungal, antileishmanial [17], nematocidal activity [18], antioxidant [12,19], analgesic and anti-inflammatory activities [20, 21].
Additionally, BIMs displayed enzyme inhibitory activity
against human carboxylesterase (CES1 and CES2) [22].
The application of BIMs in analytical chemistry involved
their use as chemosensors for transition metal cations[23] and for ­Cu2+ ions [24]. The oxidized BIMs could act*Correspondence:
Hala B. El‑Nassan
hala_bakr@hotmail.com; hala.el-nassan@pharma.cu.edu.eg
1
Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy,
Cairo University, 33 Kasr El‑Aini Street, Cairo 11562, Egypt
2
Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy,
Cairo University, Cairo 11562, Egypt

as selective colorimetric sensors either for fluoride ionsin an aprotic solvent or for hydrogen sulfate ions in water[25].
BIMs are prepared by alkylation of indole with aldehyde or ketone. Usually, a Lewis acid or protic acid suchas HCl [5] and sulphuric acid [26] are used to catalyze
the reaction. However, the use of these acids has manyenvironmental hazards in addition to long reaction times,
low yield, and difficult reaction work-up. Therefore, manycatalysts were reported in the literature for the synthesisof BIMs aiming to shorten the reaction time and increase
the yield with minimal hazard to the environment. Examples included the use of metal salts such as R
­ uCl3 [27];nickel-iodide ­NiI2 [28], hydrated ferric sulfate [29], lithium perchlorate [30], and aluminium triflate [16]. The
reaction was catalyzed by some inorganic salts such as­NaHSO3 [20, 21], ­KHSO4 [23], tetrabutylammoniumhydrogen sulfate [31], and boric acid [32]. Other green
catalysts used include oxalic acid dihydrate and N-cetylN,N,N-trimethylammonium bromide [5], Meldrum’s
acid-induced and F­ eCl3-catalyzed domino reactions [33],© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to theoriginal author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images orother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line
to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory
regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of thislicence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/. The Creative Commons Public Domain Dedication waiver (http://​creat​iveco​
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Adly et al. BMC Chemistry(2024) 18:139

Page 2 of 11

O

O

O

O
NH
NH

NH

NH

Arundine

Vibrindole

NH

NH

NH

N

NH

NH
NH

tri(1H-indol-3-yl)methane

NH

NH

Arsindoline B

Streptindole

NH

NH

NH

NH

1,1,3-tri(1H-indol-3-yl)butane

Arsindoline A

Fig. 1 Bis(indolyl)methane derivatives isolated from natural sources

p-toluene sulfonic acid [14, 19], squaric acid [34] andcitric acid [35]. Heterogeneous catalysts like polymer
supported dichlorophosphate (PEG-OPOCl2) [6], perlitepolyphosphoric acid (EP-PPA) [36], Amberlyst-15 [26,37], silica supported-boron sulfonic acid [38], Fe-pillaredinterlayered clay (Fe-PILC) [17] and zeolite [39] were allused to catalyze the reaction.
Moreover, some green chemistry approaches wereapplied to prepare BIMs. This included the use of visible light for 3–5 h [22], and the use of microwave irradiation for 6–10 min in the presence of surfactant likesodium bis-2-ethyl hexyl sulphosuccinate [40]. The useof ultrasonication was also widely applied for the synthesis of BIMs. Examples included the use of ultrasonication either in acetic acid/water at 40 °C for 2–8 h [18]or in water and dodecylbenzenesulfonic acid catalyst
at room temperature for 10–30 min [41]. BIMs werealso prepared using the green natural catalyst taurine­(NH2CH2CH2SO3H) in water under ultrasonic irradiation [42]. The ultrasonic irradiation using p-toluene
sulfonic acid in acetonitrile was also reported [19]. Biocatalysis of the reaction involved the use of enzymes like
α-chymotrypsin [43] and lipase [44].
Ionic liquids can serve as both solvents and catalysts
to prepare BIMs [45–48]. Deep eutectic solvents (DESs)
are considered a green alternative to ionic liquids. They
are formed of H-bond donor and acceptor that interact to produce a low melting eutectic mixture. They arecharacterized by being nontoxic, easily prepared, recyclable, and eco-friendly [49–55]. The synthesis of BIM
derivatives was performed in choline chloride-urea (1:2)
at 70 °C for 4 h [56], choline chloride-SnCl2 (1:2) at room
temperature for 60–200 min [57] and l-(+)-tartaric aciddimethyl urea (3:7) at 70 °C for 2 h [58].
On the other hand, organic electrochemistry is considered a clean, atom-economic, and environment-friendly
method of synthesis. The electrochemical synthesis relieson the use of electrons as a reactant and energy source,
thereby reducing the time and energy needed for thereaction. The method was widely used in the last two
decades for the synthesis of organic compounds [59–66].
To date, two publications reported the synthesis of BIMs
under electrochemical conditions. The first was published in 2018 by Du and Huang [67] who reported thereaction of indole and ether under electrochemical conditions using ­LaCl3 as a catalyst., The authors utilized
platinum as anode and cathode and lithium perchlorate
as a supporting electrolyte. The reaction was conductedin THF-acetonitrile at room temperature under 5 mAconstant current for 6.5 h. In 2022, Jat et al. [68] reported
the BIMs synthesis using graphite as anode and cathodein acetonitrile for 90 min. Lithium perchlorate was used
as a supporting electrolyte and the reaction was conducted at room temperature under a 10 mA constantcurrent.

Adly et al. BMC Chemistry(2024) 18:139

Page 3 of 11

In continuation of our interest in developing new
methods of synthesis based on electrochemical reactions [69–72], we reported herein the first synthesisof BIM derivatives under electrochemical conditionsin DESs (Scheme 1). The method was characterized
by being atom economic and environmentally friendly.
The products were obtained in high yields in short
reaction time and the reaction tolerated a wide scopeof substrates.

Results and discussion
Reaction of indole and benzaldehyde in deep eutectic
solvents

The reaction of two molar equivalents of indole (1)and one molar equivalent of benzaldehyde (2a) in different DESs was investigated as a preliminary study.
The reaction was conducted by heating at 80 °C in awater bath. The results are presented in Table 1. The
best result was obtained upon using ethylene glycol/
choline chloride (2:1) as a solvent with a 50% yield.

Electrochemical reaction of indole and benzaldehyde
in deep eutectic solvents

The reaction of two molar equivalents of indole (1) andone molar equivalent of benzaldehyde (2a) in DESs
was studied as a model reaction. The temperature wasadjusted to 80 °C to ensure the complete dissolution of
the starting materials. Four types of DESs were examined. Choline chloride was mixed with urea, ethylene glycol, propylene glycol, or glycerol in a ratio of 1:2 to form
DESs. The reaction was conducted at 10 mA and 30 mA
at different times and using different electrode materials.
TLC was used to monitor the progress of the reaction.
The results are presented in Table 2.
The effect of the reaction time was investigated (Entry
1–5). Conducting the reaction in choline chloride/ethylene glycol for 15 min., 30 min. and 45 min. (Entry 1–3)
resulted in the production of compound 3a in yields of
31, 53 and 62%, respectively. Further increase in the reaction time to either 60 min. or 90 min. (Entry 4 and 5) did
not affect the product yield. Therefore, the optimum time
was chosen as 45 min. for subsequent experiments.
R

CHO
2
N
H

Ethylene glycol / Choline chloride (2:1)
80 oC, 30 mA
Cathode: Graphite and Anode: Platinum

+

1

2a-n

NH

R
N
H

3a-n

Scheme 1 Synthesis of bis(indolyl)methane derivatives 3a-n

Table 1 Synthesis of bisindolylmethane 3a in DESs

CHO
2
N
H

+
NH

1

2a

N
H

3a

Entry

DES

Yield

1

Ethylene glycol/choline chloride (2:1)

50%

2Propylene glycol/choline chloride (2:1)

Trace

3

Urea/choline chloride (2:1)

NR

All the reactions were conducted at 80 °C for 3h
NR no reaction

Adly et al. BMC Chemistry(2024) 18:139

Page 4 of 11

Table 2 Synthesis of bisindolylmethane 3a in DESs using electrochemical conditions

CHO
2
N
H

+
NH

1

Entry

DES

2a

Time (mins)N
H

Current (mA)

3aCathode

Anode

Yield

1

Ethylene glycol/choline chloride (2:1)

15

30

Graphite

Graphite31%2Ethylene glycol/choline chloride (2:1)

30

30Graphite

Graphite

53%

3Ethylene glycol/choline chloride (2:1)

45

30Graphite

Graphite

62%

4Ethylene glycol/choline chloride (2:1)

60

30Graphite

Graphite62%

5Ethylene glycol/choline chloride (2:1)

90

30Graphite

Graphite

62%

6

Glycerol/choline chloride (2:1)

45

30Graphite

Graphite

63%

7

Propylene glycol/choline chloride (2:1)

45

30Graphite

GraphiteNR

8

Urea/choline chloride (2:1)

45

30Graphite

Graphite

NR
N.R

9

Ethylene glycol/choline chloride (2:1)

60

10Graphite

Graphite

10

Ethylene glycol/choline chloride (2:1)

180

10

Graphite

Graphite

53%

11

Ethylene glycol/choline chloride (2:1)

45

30

Platinum

Graphite40%

12Ethylene glycol/choline chloride (2:1)

45

30Graphite

Platinum71%

13Ethylene glycol/choline chloride (2:1)

4530

CopperGraphite59%

All the reactions were conducted at 80 °C
NR no reaction

Next, the effect of varying the type of DES was examined. The results indicated that both ethylene glycol andglycerol gave comparable yields of bisindolyl methane 3a(Entry 3 and 6). However, the reaction was unsuccessful
upon using choline chloride/urea or choline chloride/
propylene glycol (Entry 7 and 8). These results were consistent with the results in Table 1 where DESs formed ofurea and propylene glycol were not efficient. Additionally,
the yield obtained under electrochemical conditions washigher (62%) than that obtained by the heating method
only (50%) and was obtained in a shorter reaction time
(45 min) than the heating method (3 h). As provided in
our previous work [69, 72], the use of DESs eliminatedthe need for supporting electrolytes and shortened thereaction time owing to their catalytic power.
Changing the constant current used from 30 to 10 mA
resulted in a lower yield and as expected the reactionneeded a longer time to be completed (3 h) (Entry 9, 10).
Finally, the effect of electrode material was investigated.
Platinum, copper, and graphite were used as electrodes.
The material of the electrode and counter electrode may
affect the yield, but the choice of the electrodes was
empirical. Therefore, the reaction was performed using

different electrodes to optimize the yield of the reaction.
The highest yield (71%) was obtained upon using graphite
as cathode and platinum as anode (Entry 12). Replacing
the graphite cathode with platinum or copper resulted ina decrease in the yield with percentages of 40% and 59%,
respectively (Entry 11 and 13). It was noteworthy that thereaction was initiated by anodic oxidation of the indole
ring as evidenced by the cyclic voltammetry studies.
The optimum reaction conditions were conducting thereaction at 80 °C at a constant current of 30 mA for 45
min in ethylene glycol/ choline chloride (2:1) deep eutectic solvent in an undivided cell fitted with platinum as
anode and graphite as cathode (Entry 12).
Electrochemical synthesis of bisindolylmethane
derivatives 3a‑n in deep eutectic solvents

The scope of the reaction was investigated using different
types of aromatic aldehydes and the results are presented
in Table 3. The reactions were conducted using the optimized conditions; Entry 12 in Table 2. All the substituted
aldehydes examined afforded higher yields (82–100%)than benzaldehyde (71%). Substitution of the benzaldehyde with electron donating or electron withdrawing

Adly et al. BMC Chemistry(2024) 18:139

Page 5 of 11

Table 3 Electrochemical synthesis of bisindolylmethane derivatives 3a–n using the optimum reaction conditions
R

2
N
H

+

Cpd

NH
2a-n

1

Entry

ArCHO

N
H

3a-n

Ar

Yield (%)

MP (oC)

References

1

3a

C6H5

71

116–118

[73]

2

3b

4-ClC6H4

92

107–108

[74]

3

3c

4-BrC6H4

100

108–110

[75]

4

3d

4-FC6H4

92

130–132

[76]

5

3e

3-OHC6H4

60

130–132

[77]

6

3f

4-OHC6H4

93

125–127

[78]

7

3g

4-CH3C6H4

83

138–140

[79]

8

3h

4-CH3OC6H4

92

130–132

[79]

9

3i

3,4-(CH3O)2C6H3

94

140–142

[80]

10

3j

3,4,5-(CH3O)3C6H2

95

141–143

[81]

11

3k

4-OH-3-CH3OC6H3

100

121–123

[82]

12

3l

2-NO2C6H4

86

125–127

[80]

13

3m

4-NO2C6H4

89

190–192

[83]

14

3n

3-indolyl

82

198–200[84]

Reaction conditions: 1 (2 mmol), 2a–n (1 mmol), in ethylene glycol/choline chloride (2:1; 10 mL) for 45 min. at 80 °C and c.c 30 mA. Graphite and platinum were used
as cathode and anode, respectively

groups gave high yields of the products. The heterocyclic
indole-3-carbaldehyde gave 82% yield. Aldehydes susceptible to electrochemical oxidation (hydroxybenzaldehydes) or reduction (nitrobenzaldydes) were also reactive
and provided products in high yields.
Compound 3c was prepared on a gram scale. The reaction was completed in 90 min resulting in 98.5% yield.
The 1H NMR spectra revealed the appearance of themethane CH proton at δ 4.77–6.05 ppm and the two NH
protons at δ 7.86–10.87 ppm. While the 13C NMR spectra revealed the appearance of the methine carbon at δ
31.38–40.58 ppm.

A comparison between the electrochemical methods
reported in the literature and the present method is illustrated in Table 4. The data presented in Table 4 proved
the efficiency of the present method in which no catalyst
or electrolyte was needed and the reaction was completed in a shorter time. The electrochemical method
developed by Jat et al. [68] used lithium perchlorate aselectrolyte which is expensive, hazardous and toxic.
Whilst, the present study relied on the use of the deep
eutectic solvent ethylene glycol / choline chloride whichis ecofriendly, more economic and served as a solvent
and a supporting electrolyte.

Table 4 The different electrochemical conditions used for the synthesis of bisindolylmethanes
Reactants

solvent

Electrolyte

Time

Temp Cathode Anode

Current (mA) Yield (%) References

1

Indole and ether

THF-acetonitrile LiClO4/LaCl3 as catalyst 6.5 h

2Indole and aldehyde Acetonitrile

LiClO4

1.5 hRTPlatinum Platinum

5

29–92

RT

Graphite

Graphite 10

49–95

3

Indole and aldehyde Ethylne glycol/
choline chlo‑
ride

none

45 min 80 °C[68]Graphite

Platinum 30

60–100Present work[67]

Adly et al. BMC Chemistry(2024) 18:139

Page 6 of 11

Investigation of the reaction mechanism

The reaction started with anodic oxidation of the indole
ring to give a radical cation I followed by a loss of a proton to afford the radical II. The latter attacked the carbonyl of the aldehyde molecule. This resulted in theformation of radical III which oxidized another moleculeof indole forming another molecule of radical II; whileradical III was reduced to the intermediate IV followedby the elimination of a water molecule. The intermediate
IV reacted with another indole radical II forming radical
VI that finally underwent a cathodic reduction to afford
the final product 3 (Fig. 2).
The cyclic voltammetry study was consistent with thispostulation. Figure 3 showed the cyclic voltammogramsof both 10 mM indole, and 10 mM 3,4,5-trimethoxybenzaldehyde at pencil graphite electrode in DES between-0.1 to 1.5 V vs Ag pseudo reference electrode at scanrate 20 mV/s. The results showed a prominent oxidation peak for indole, which started around 0.8 V, while
3,4,5-trimethoxybenzaldehyde showed initiation of oxidation at 1.3 V. These results confirmed that the reaction
started by oxidation of indole to produce a cation radicalthat reacted with the aldehyde to produce the product.
Experimental and methods

Chemicals were purchased from Sigma-Aldrich, USA.
The reaction progress was monitored by TLC using
precoated aluminum sheet silica gel MERCK 60F 254

Fig. 3 The cyclic voltammograms of 10mM indoleand 3,4,5-trimethoxybenzaldehyde in DES at PGE surface vs Ag
pseudoreference electrode(Merck, Germany) and was visualized by UV lamp. The
solvent system used was dichloromethane:ethanol [9:1].
Melting points were obtained using Stuart electrothermal
melting point apparatus SMP10 and were uncorrected.
1
H NMR spectra were conducted using a Bruker Advance
400 MHz NMR spectrometer. 13C NMR spectra were
performed using a Bruker Advance 100 MHz spectrometer. Chemical shifts were recorded in ppm on a δ scaleusing DMSO-d6 as a solvent and coupling constants wererecorded (J) in Hz. Element analyses were carried out at

Fig. 2 The proposed reaction mechanism for the formation of bisindolylmethane 3a under electrochemical conditions

Adly et al. BMC Chemistry(2024) 18:139

the Regional Center for Mycology and Biotechnology,
Faculty of Pharmacy, Al Azhar University, Egypt.
Preparation of deep eutectic solvents DESs

Choline chloride was mixed with either ethylene glycol,
propylene glycol, glycerol, or urea with a ratio of 1:2,
respectively, and heated in a water bath at 80 °C till ahomogenous liquid mixture was obtained [69].
Synthesis of compound 3a in DESs

A mixture of indole (1, 2 mmol) and benzaldehyde (1mmol) in the appropriate DES was reacted at 80 °C for
3h as presented in Table 1. The reaction was traced using
TLC. After the completion of the reaction, the mixture
was poured into distilled water (50 mL), and the solid
formed was filtered and recrystallized from an ethanol–
water mixture. The results are reported in Table 1.
Electrochemical synthesis and optimization of compound
3a in DESs

A mixture of indole (1, 2 mmol) and benzaldehyde (1mmol) in the appropriate DES was reacted in an undivided cell using two variable electrodes at 80 °C for a variable amount of time as presented in Table 2. The reaction
was traced using TLC till the reactants’ spots disappeared
and a new spot for the product appeared. After the completion of the reaction, the mixture was poured into distilled water (50 mL), and the solid formed was filteredand recrystallized from an ethanol–water mixture. The
results are reported in Table 2.
Electrochemical synthesis of bisindolyl methanes 3a‑nin DESs

A mixture of indole (1, 2 mmol) and the appropriate
aldehyde 2a–n (1 mmol) was dissolved in the deep eutectic solvent composed of ethylene glycol and choline chloride with a ratio of 2:1 (10 mL) at 80 °C. The mixture was
exposed to an electric current of 30 mA in an undivided
cell for 45 min using a platinum anode and a graphite
cathode. The reaction was monitored using TLC. The
mixture was poured into distilled water (50 mL), andthe solid formed was filtered and recrystallized from an
ethanol–water mixture to afford compounds 3a–n. The
results were reported in Table 3.
Spectral data of bisindolyl methanes 3a–n3’‑(Phenylmethylene)bis(1H‑indole) (3a)Light pink solid; IR: 3414 (NH); 1H NMR (400 MHz,DMSO-d6): δ 5.83 (s, 1H, CH), 6.82–6.87 (m, 4H, ArH),
7.01–7.05 (t, 2H, ArH, J = 8 Hz), 7.15–7.19 (t, 1H, ArH,
J = 8 Hz), 7.25–7.28 (t, 4H, ArH, J = 8 Hz), 7.33–7.37 (t,4H, ArH, J = 8 Hz), 10.81 (s, 2H, NH, ­D2O exchangeable);

Page 7 of 11

13

C NMR (100 MHz, DMSO-d6): δ 39.3, 111.9, 118.5,
118.6, 119.5, 121.3, 123.9, 126.2, 127.0, 128.4, 128.7,
137.0, 145.4; Anal. Calcd for C­ 23H18N2 (322.40): C: 85.68,
H: 5.63, N: 8.69. Anal Found: C: 85.51, H: 5.80, N: 8.95.
3,3′‑((4‑Chlorophenyl)methylene)bis(1H‑indole) (3b)Light pink solid; IR: 3410 (NH); 1H NMR (400 MHz,DMSO-d6): δ 5.86 (s, 1H, CH), 6.83–6.89 (m, 4H, ArH),
7.02–7.06 (t, 2H, ArH, J = 8 Hz), 7.26–7.28 (d, 2H, ArH,
J = 8 Hz), 7.31–7.33 (m, 3H, ArH), 7.35–7.37 (m, 3H,
ArH), 10.87 (s, 2H, NH, D­ 2O exchangeable); 13C NMR(100 MHz, DMSO-d6): δ 39.3, 112.0, 118.0, 118.7, 119.5,
121.4, 124.0, 126.9, 128.4, 130.5, 130.7, 137.0, 144.4; Anal.
Calcd for ­C23H17ClN2 (356.85): C: 77.41, H: 4.80, N: 7.85.
Anal Found: C: 77.63, H: 5.01, N: 8.12.
3,3′‑((4‑Bromophenyl)methylene)bis(1H‑indole) (3c)Buff solid; IR: 3406 (NH); 1H NMR (400 MHz, DMSOd6): δ 5.83 (s, 1H, CH), 6.83–6.85 (m, 2H, ArH), 6.87–
6.89 (t, 2H, ArH, J = 8 Hz), 7.02–7.06 (t, 2H, ArH, J = 8
Hz), 7.26–7.31 (m, 4H, ArH), 7.34–7.36 (d, 2H, ArH, J = 8
Hz), 7.44–7.46 (d, 2H, ArH, J = 8 Hz), 10.87 (s, 2H, NH,­D2O exchangeable); 13C NMR (100 MHz, DMSO-d6): δ
39.5, 112.0, 117.9, 118.7, 119.2, 119.4, 121.4, 124.1, 136.9,
131.0, 131.3, 137.0, 144.9; Anal. Calcd for C­ 23H17BrN2(401.30): C: 68.84, H: 4.27, N, 6.98. Anal Found C: 69.05,
H: 4.43, N: 7.16.
3,3′‑((4‑Fluorophenyl)methylene)bis(1H‑indole) (3d)Buff solid; IR: 3410 (NH); 1H NMR (400 MHz, C­ DCl3):
δ 5.79 (s, 1H, CH), 6.55—6.56 (m, 2H, ArH), 6.85–6.95( m, 4H, ArH), 7.07–7.11 (t, 2H, ArH, J = 8 Hz), 7.17–
7.22 (m, 2H, ArH), 7.26—7.29 (m, 4H, ArH), 7.84 ( s, 2H,
NH, ­D2O exchangeable); 13C NMR (100 MHz, C­ DCl3): δ
39.4, 111.1, 114.8, 115.0, 119.3, 119.5, 119.8, 122.0, 123.6,
126.9, 130.1, 136.7, 139.7; Anal. Calcd for C­ 23H17FN2(340.39): C: 81.16, H: 5.03, N: 8.23. Anal Found C: 80.98,
H: 5.21, N: 8.50.
3‑[Di(1H‑indol‑3‑yl)methyl]phenol (3e)Pink solid; IR: 3500–3300 (OH), 3410 (NH); 1H NMR(400 MHz, DMSO-d6): δ, 5.86 (s, 1H, CH), 6.70 (s, 1H,
OH, ­D2O exchangeable), 6.70–6.73 (m, 3H, ArH), 6.80–
6.81 (m, 1H, ArH), 6.97–7.01 (m, 2H, ArH), 7.03–7.05(m, 1H, ArH), 7.16–7.21 (m, 3H, ArH), 7.37–7.39 (m,2H, ArH), 7.41–7.43 (m, 2H, ArH), 7.94 (s, 2H, NH,­D2O exchangeable); 13C NMR (100 MHz, DMSO-d6):
δ 39.9, 111.0, 113.1, 115.6, 119.2, 119.9, 121.4, 121.9,
123.6, 127.0, 129.4, 130.9, 136.6, 146.0, 155.4; Anal. Calcdfor ­C23H18N2O (338.14) C: 81.63, H: 5.36, N: 8.28. Anal
Found C: 81.49, H: 5.53, N: 8.40.

Adly et al. BMC Chemistry(2024) 18:139

4‑[Di(1H‑indol‑3‑yl)methyl]phenol (3f)

Page 8 of 11

1

Purple solid; IR: 3500–3200 (OH), 3406 (NH); H NMR(400 MHz, DMSO-d6): δ 5.85 ( s, 1H, CH), 6.67 (s, 1H,
OH, ­D2O exchangeable), 6.75 (d, 2H, ArH, J = 8 Hz), 7.03
(t, 2H, ArH, J = 8 Hz), 7.17—7.24 (m, 5H, ArH), 7.37—
7.42 (m, 5H, ArH), 7.93 (s, 2H, NH, D­ 2O exchangeable);
13
C NMR (100 MHz, DMSO-d6): δ 39.3, 102.6, 111.0,
115.0, 119.2, 119.9, 121.9, 123.5, 127.0, 129.8, 136.3,
136.7, 153.7; Anal. Calcd for ­C23H18N2O (338.40) C:
81.63, H: 5.36, N: 8.28. Anal Found: C: 81.50, H: 5.42, N:
8.49.
3,3′‑(p‑Tolylmethylene)bis(1H‑indole) (3g)

Buff solid; IR: 3410 (NH); 1H NMR (400 MHz, DMSOd6): δ 2.31 (s, 3H, ­CH3), 5.83 (s, 1H, CH), 6.85—6.86 (m,2H, ArH), 6.90 (t, 2H, ArH, J = 8 Hz), 7.06—7.13 (m, 5H,
ArH), 7.27—7.33 (m, 3H, ArH), 7.39 (d, 2H, ArH, J = 8
Hz), 10.84 (s, 2H, NH, ­D2O exchangeable); 13C NMR (100MHz, DMSO-d6): δ 21.0, 39.3, 111.8, 118.5, 118.6, 119.5,
121.3, 123.9, 127.0, 128.6, 129.0, 135.0, 137.0, 142.4; Anal.
Calcd for C­ 24H20N2 (336.43) C: 85.68, H: 5.99, N: 8.33.
Anal Found C: 85.51, H: 6.12, N: 8.54.
3,3′‑((4‑Methoxyphenyl)methylene)bis(1H‑indole) (3h)Buff solid; IR: 3410 (NH); 1H NMR (400 MHz, DMSO-d6):
δ 3.71 (s, 3H, ­CH3), 5.77 (s, 1H, CH), 6.79–6.80 (m, 2H,
ArH), 6.82–6.87 (m, 4H, ArH), 7.03 (t, 2H, ArH, J = 8Hz),
7.25–7.28 (q, 4H, ArH, J = 6 Hz), 7.34 (d, 2H, ArH, J = 8
Hz), 10.78 (s, 2H, NH, ­D2O exchangeable); 13C NMR (100MHz, DMSO-d6): δ 39.3, 55.3, 111.8, 113.8, 118.5, 118.8,
119.6, 121.2, 123.8, 127.0, 129.6, 137.0, 137.4, 157.7; Anal.
Calcd for ­C24H20N2O (352.16) C: 81.79, H: 5.72, N: 7.95.
Anal Found C: 82.05, H: 5.68, N: 8.12.
3,3′‑((3,4‑Dimethoxyphenyl)methylene)bis(1H‑indole) (3i)Buff solid; IR: 3406 (NH); 1H NMR (400 MHz, DMSOd6): δ 3.70 (s, 3H, O­ CH3), 3.76 (s, 3H, O­ CH3), 5,82 (s, 1H,
CH), 6.86—6.87 (d, 2H, ArH, J = 2 Hz), 6.88–6.90 (m, 2H,
ArH), 6.91–6.94 (m, 2H, ArH), 7.05–7.10 (m, 3H, ArH),
7.34 (d, 2H, ArH, J = 8 Hz), 7.39 (d, 2H, ArH, J = 8 Hz),10.82 (s, 2H, NH, D­ 2O exchangeable); 13C NMR (100MHz, DMSO-d6): δ 39.3, 55.9, 111.8, 112.0, 113.0, 118.5,
118.8, 119.6, 120.6, 121.2, 123.9, 127.1, 137.0, 137.9,
147.3, 148.8; Anal. Calcd for ­C25H22N2O2 (382.45) C:
78.51, H: 5.80, N: 7.32. Anal Found C: 78.69, H: 5.94, N:
7.50.
3,3′‑((3,4,5‑Trimethoxyphenyl)methylene)bis(1H‑indole) (3j)Buff solid, IR: 3360 (NH), 1589 (C=C), 1H NMR (400
MHz, DMSO-d6): δ 3.74 (s, 6H, two C­ H3), 3.86 (s, 3H,­CH3), 5.85 (s, 1H, CH), 6.62 (s, 2H, ArH), 6.73 (s, 2H,
ArH), 7.04 (t, 2H, ArH, J = 8 Hz), 7.02 (t, 2H, ArH, J = 8
Hz), 7.38 (d, 2H, ArH, J = 8 Hz), 7.44 (d, 2H, ArH, J = 8

Hz), 7.99 (s, 2H, NH, D­ 2O exchangeable) ppm. 13C NMR(100 MHz, DMSO-d6): δ 40.5, 56.0, 60.8, 105.8, 111.0,
119.2, 119.5, 119.8, 121.9, 123.5, 127.0, 136.2, 136.7,
139.8, 152.9 ppm. Anal. Calcd for ­C26H24N2O3 (412.48)
C: 75.71, H: 5.86, N: 6.79. Anal Found C: 75.54, H: 6.02,
N: 6.85.
4‑[Di(1H‑indol‑3‑yl)methyl]‑2‑methoxyphenol (3k)

Purple solid, IR: 3610–3200 (OH), 3406 (NH), 1512
(C=C), 1H NMR (400 MHz, DMSO-d6): δ 3.69 (s, 3H,­CH3), 5.74 (s, 1H, CH), 6.59 (s, 1H, ArH), 6.74 (s, 1H,
ArH), 6.81 (s, 1H, ArH), 6.91–6.95 (m, 2H, ArH), 7.07–
7.14 (m, 4H, ArH), 7.27(s, 1H, OH, ­D2O exchangeable),
7.29—7.34 (m, 4H, ArH), 7.85 (s, 2H, NH D
­ 2O exchangeable) ppm. 13C NMR (100 MHz, DMSO-d6): δ 39.9, 55.8,
111.1, 111.5, 114.0, 119.2, 119.93, 119.96, 121.3, 121.9,
123.6, 127.0, 136.1, 136.7, 143.8, 146.4 ppm. Anal. Calcdfor ­C24H20N2O2 (368.43) C: 78.24, H: 5.47, N: 7.60. Anal
Found C: 78.51 H: 5.69 N: 7.78.
3,3′‑((2‑Nitrophenyl)methylene)bis(1H‑indole) (3l)Buff solid, IR: 3406 (NH); 1H NMR (400 MHz, DMSOd6): δ 4.77 (s, 1H, CH), 6.69–6.70 (m, 3H, ArH), 7.04 (t,3H, ArH, J = 8 Hz), 7.20 (t, 3H, ArH, J = 8 Hz), 7.35–7.40(m, 2H, ArH), 7.42–7.44 (m, 3H, ArH), 8.00 (s, 2H, NH,
D2O exchangeable) ppm. 13C NMR (100 MHz, DMSOd6): δ 34.8, 111.1, 117.6, 119.5, 119.7, 122.2, 123.8, 124.3,
126.7, 127.2, 131.0, 132.3, 136.6, 138.0, 149.8 ppm. Anal.
Calcd for ­C23H17N3O2 (367.40) C: 75.19, H: 4.66, N:
11.44. Anal Found C: 75.43, H: 4.79, N: 11.67.
3,3′‑((4‑Nitrophenyl)methylene)bis(1H‑indole) (3m)

Reddish brown solid, IR: 3410 (NH); 1H NMR (400
MHz, DMSO-d6): δ 6.04 (s, 1H, CH), 6.87–6.91 (m, 3H,
ArH), 7.06 (t, 3H, ArH, J = 8 Hz), 7.29 (d, 2H, ArH, J = 8
Hz), 7.37 (d, 2H, ArH, J = 8 Hz), 7.62 (d, 2H, ArH, J = 8
Hz), 8.15 (d, 2H, ArH, J = 8 Hz), 10.94 (s, 2H, NH, ­D2O
exchangeable) ppm. 13C NMR (100 MHz, DMSO-d6):
δ 39.2, 112.0, 117.1, 118.9, 119.3, 121.6, 123.8, 124.3,
126.8, 129.9, 137.0, 146.2, 153.6 ppm. Anal. Calcd for­C23H17N3O2 (367.40) C: 75.19, H: 4.66, N: 11.44. Anal
Found C: 75.40, H: 4.59, N: 11.63.
Tri(1H‑indol‑3‑yl)methane (3n)Buff solid, IR: 3406 (NH); 1H NMR (400 MHz, DMSOd6): δ 6.05 (s, 1H, CH), 6.85 (t, 3H, ArH, J = 7 Hz), 6.93–
6.94 (m, 3H, ArH), 7.01 (t, 3H, ArH, J = 8 Hz), 7.32 (d,3H, ArH, J = 8 Hz), 7.39 (d, 3H, ArH, J = 8 Hz), 10.71 (s,3H, NH, D­ 2O exchangeable) ppm. 13C NMR (100 MHz,DMSO-d6): δ 31.3, 111.8, 118.4, 118.7, 119.7, 121.1, 123.6,
127.2, 137.0 ppm. Anal. Calcd for ­C25H19N3 (361.44) C:
83.08, H: 5.30, N: 11.63. Anal Found C: 82.87, H: 5.46, N:
11.85.

Adly et al. BMC Chemistry(2024) 18:139

Electrochemical synthesis of compound 3c at gram‑scale

A mixture of indole (1) (1.26 g, 0.01 mol) and 4-bromobenzladehyde (2c) (1 g, 0.005 mol) was suspended
in ethylene glycol/choline chloride (2:1; 20 mL) in an
undivided cell equipped with graphite as cathode andplatinum as anode. The electrochemical reaction was
conducted at constant current (30 mA), at 80 °C for 90
min. The reaction was cooled and poured into water (250mL). The solid formed was filtered, dried, and recrystallized from ethanol. The product was obtained in 98.5%
yield (1.28 g).
Cyclic voltammetry study
Experimental setup

The study used the traditional three electrode configuration, where silver and platinum wires were employed as
quasi-reference electrode and counter electrode, respectively. While the working electrode was a Pencil graphite
electrode (PGE). The solvent was choline chloride/ethylene glycol (1:2) which also acted as a supporting electrolyte. The DES was degassed with N­ 2 for 15 min then the
study was carried out at 80 °C. The results are presented
in Fig. 3.

Conclusion
In summary, this study focused on developing a newenvironmental friendly method for the synthesis of3,3′-bis(indolyl)methanes due to their various pharmaceutical applications. Accordingly, an electrochemical
method was developed for the synthesis of bis(indolyl)
methanes in deep eutectic solvents in good to excellent yields. The use of deep eutectic solvents proved tobe easy to use, affordable, and environmentally friendly.
Moreover, the use of deep eutectic solvents eliminatedthe need for another electrolyte or catalyst which fulfilled
the atom economy principle for green sustainable chemistry. A series of aromatic aldehydes was reacted withindole successfully using the optimum reaction parameters. The newly developed method was effective acrossa wide array of substituted aldehydes with different substituents at different positions as well as heterocyclic
aldehydes. The reaction mechanism was validated using
cyclic voltammetry. Further work are currently ongoing
to examine the effect of the prepared compounds as chemosensors for the detection of ions.
Acknowledgements
None.
Author contributions
Hala B. El-Nassan: conceptualization; experimental work; writing—review andediting. Mina E. Adly: experimental work; writing—review and editing; Amr M.
Mahmoud: experimental work; writing—review and editing.

Page 9 of 11

Funding
Open access funding provided by The Science, Technology & Innovation
Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank
(EKB). This manuscript is based upon work supported by the Science, Technol‑
ogy and Innovation Funding Authority (STDF) under grant number 45569.
Data availability
All data that supports the findings of this study is available on request by theauthors.

Declarations
Competing interests
The authors declare no competing interests.
Received: 26 April 2024 Accepted: 9 July 2024

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