Electrochemical oxidation of 4-morpholinoaniline in aqueous solutions: Synthesis of a new trimer of 4-morpholinoaniline

Article abstract of DOI:10.1016/j.electacta.2011.02.030

Electrochemical oxidation of 4-morpholinoaniline has been studied in various pHs using cyclic voltammetry and controlled-potential coulometry. The electrochemical trimerization of 4-morpholinoaniline is described and its mechanism has been studied in aqueous solution. This method provides a green, reagent-less, and environmentally friendly procedure with high atom economy, for the synthesis of "4-morpholinoaniline-trimer" using a carbon electrode in an undivided cell in good yield and purity.

Full text of DOI:10.1016/j.electacta.2011.02.030

Electrochimica Acta 56 (2011) 3899–3904
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Electrochimica Acta
journal homepage: www.elsevier.com/locate/electacta
Electrochemical oxidation of 4-morpholinoaniline in aqueous solutions:
Synthesis of a new trimer of 4-morpholinoaniline
Roya Esmaili, Davood Nematollahi∗
Faculty of Chemistry, University of Bu-Ali Sina, Mahdiyeh St., Hamedan, Zip Code 65178-38683, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Electrochemical oxidation of 4-morpholinoaniline has been studied in various pHs using cyclic voltam-
metry and controlled-potential coulometry. The electrochemical trimerization of 4-morpholinoaniline
is described and its mechanism has been studied in aqueous solution. This method provides a green,
reagent-less, and environmentally friendly procedure with high atom economy, for the synthesis of
“4-morpholinoaniline-trimer” using a carbon electrode in an undivided cell in good yield and purity.
© 2011 Elsevier Ltd. All rights reserved.
Received 14 November 2010
Received in revised form 29 January 2011
Accepted 4 February 2011
Available online 2 March 2011
Keywords:
4-Morpholinoaniline
Electrochemical trimerization
Cyclic voltammetry
Quinone-diimine
Green synthesis
1. Introduction
such as doxopram, molindone or timolol have a morpholine group
in their structures [12]. On the other hand, some drugs such as
The electrochemical oxidation of aromatic amines is quite com-
plex, leading to a variety of products depending on their structure
and electrolysis conditions. Products may vary largely by using
aqueous or non-aqueous, neutral, acidic or basic conditions [1,2].
Adams and Bacon [3] have published several papers on the voltam-
metric oxidation of 4-substituted anilines, which are accounted as
classical works nowadays. They have established that the first step
of electrooxidation in acidic aqueous solution is the formation of a
radical cation arising from the starting aniline, which dimerizes via
‘head-to-tail’ coupling. Desideri et al. studied the electrochemical
oxidation of anilines in basic aqueous solution. They found that
‘head-to-head’ coupling (azobenzene type compounds) occurred
beside the ‘head-to-tail’ one [4–6]. Previously unknown oxida-
tion products were detected and identified with electrochemical
mass spectrometry in the case of aniline, N-alkyl-anilines, N,N-
dialkyl-anilines and triphenylamine [7–11]. Oxidation products
of p-toluidine are 4-amino-2,5-toluquinon-bis-p-tolylimine and/or
the oxidized form of 5-methyl-Nꢀ-p-tolylbenzen-1,2-diamine, in
the whole pH range explored [6]. In this direction, the development
of a simple synthetic route for the synthesis of a unique organic
compound from readily available reagents is the major tasks in
this paper. The results of a literature survey show that some drugs
a mefenamic acid have diphenylamine portion in their structures
[12]. With due attention to our experiences on electrochemical
synthesis of organic compounds [13–17], we thought that synthe-
sis of an organic compound with both structures of morpholine
and diphenylamine may be useful from the point of view of phar-
maceutical properties. This idea prompted us to investigate the
electrochemical oxidation of 4-morpholinoaniline (1) and repre-
sents a facile and one-pot electrochemical method for the synthesis
of a new trimer (5) of 4-morpholinoaniline in a good yield and
purity (Fig. 1).
2. Experimental
2.1. Apparatus
Cyclic voltammetry, controlled-potential coulometry and
preparative electrolysis were performed using an Autolab model
PGSTAT 20 potentiostat/galvanostat. The working electrode used
in the voltammetry experiment was a glassy carbon disc (1.8 mm
diameter) and platinum wire was used as counter electrode. The
working electrode used in controlled-potential coulometry and
macroscale electrolysis was an assembly of four carbon rods (6 mm
diameter and 4 cm length) and a large stainless steel gauze consti-
tute the counter electrode. The working electrode potentials were
measured versus SCE (all electrodes from AZAR electrode).
∗
Corresponding author. Tel.: +98 811 8282807; fax: +98 811 8257407.
E-mail addresses: nemat@basu.ac.ir, dnemotallahi@yahoo.com (D. Nematollahi).
0013-4686/$ – see front matter © 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.electacta.2011.02.030

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R. Esmaili, D. Nematollahi / Electrochimica Acta 56 (2011) 3899–3904
NH2
H
N
N
O
N
NH2
O
N
O
N
H
N
1
5
O
Fig. 1. The structures of 4-morpholinoaniline (1) and synthesized trimer 5.
0.55
A1
O
NH
NH2
O
N
NH
dE/dpH = 54 mV
R2 = 0.9997
10
8
0.5
0.45
0.4
6
0.35
0.3
4
dE/dpH = 31 mV
R2 = 0.9942
0.25
0.2
2
0.15
0.1
0
0
2
4
6
8
10
-2
-4
-6
-8
pH
O
Fig. 4. The potential-pH diagram of 4-morpholinoaniline (1).
NH
The peak current ratios (IpC1/IpA1) were determined using the
following equation given in Ref. [18].
O
N
NH
NH2
C1
(Ipc
)
(Isp)
0
Ipc
Ipa
0
0.15
0.35
0.55
E vs SCE/V
0.75
=
+ 0.485
Ipa
and (Isp) are cathodic peak current and “switching
0
+ 0.086
Ipa
where (Ipc
)
0
Fig. 2. Cyclic voltammogram of 1 mM 4-morpholinoaniline (1) at glassy carbon
electrode, in phosphate buffer solution (pH = 2.0, c = 0.2 M). Scan rate: 100 mV/s.
potential” current respect to the zero current, respectively. Ipc and
Ipa have their usual meanings.
t = 25
1
◦C.
2.2. Electro-organic synthesis of 5
Phosphate buffer solution (80 ml, c = 0.2 M, pH = 7.0) containing
0.25 mmol of 4-morpholinoaniline (1) was subjected to electroly-
sis at 0.45 V versus SCE, in an undivided cell. The electrolysis was
terminated when the current decayed to 5% of its original value.
The process was interrupted during the electrolysis and the carbon
anode was washed in acetone in order to reactivate it. The precipi-
tated solid was collected by filtration and was washed several times
with water (isolated yield 53%), M.p = 160–162 ◦C. IR(KBr) = 3446,
16
11
6
d
c
b
a
2954, 2346, 1602, 1554, 1502, 1233, 1115, 924, 599 cm−1 1H NMR
.
(90 MHz, CDCl3): 3.13 (t, 12H), 3.75 (t, 12H), 4.5 (br), 5.77 (s, 1H),
-2e -2H+
1
NH2
NH2
NH
NH
O
O
NH
1H+
O
O
N
(1)
(2)
pH<5.65
1a
-4
-9
-2e -H+
N
N
N
pH > 5.65
1a
1
-0.05
0.15
0.35
0.55
Scheme 1.
Scheme 2.
E vs SCE/V
+ H+
Fig. 3. Cyclic voltammograms of 1 mM 4-morpholinoaniline (1) at glassy carbon
electrode, in buffer solution with various pHs. pH from a to d are: 2.0, 5.0, 7.0 and
9.0. Scan rate: 100 mV/s. t = 25 1 ◦C.
NH2
NH2
O
O
NH

R. Esmaili, D. Nematollahi / Electrochimica Acta 56 (2011) 3899–3904
3901
5.91 (s, 1H), 6.86 (m, 8H). MS: m/e (relative intensity); 530 (M•+
100), 471 (37.5), 265 (34.3), 251 (37.5), 177 (31.25), 163 (75), 119
(42.5), 105 (65), 77 (27.5), 45 (62.5), 29 (50).
This method also, can be useful for the synthesis of similar com-
pounds by electrooxidation of other related starting molecular in
appropriate applied potential (Eapp).
be related to the occurrence of coupling of 1 with quinone-diimine
1a (dimerization reaction), under the experimental conditions [6].
This reaction is pH dependent and enhanced by increasing pH. In
acidic solutions because of protonation of 1 and its subsequent inac-
tivation towards a Michael addition, this reaction is avoided and the
peak current ratio (IpC1/IpA1) becomes nearly unity.
Also, it was found that the potential for peak A1 (EpA1) shifted to
the negative potentials by increasing pH. This is expected because
of the participation of proton(s) in the oxidation of 1 to quinone-
diimine 1a.
3. Results and discussion
3.1. The effect of pH
1(or 1H+) ꢀ 1a + mH+ + 2e−
Fig. 2 shows cyclic voltammogram of 1 mM protonated 4-
morpholinoaniline (1H+) in aqueous phosphate buffer solution
(pH = 2.0). The voltammogram shows an anodic peak (A1) in the
positive-going scan and a cathodic counterpart peak (C1) in the neg-
ative going scan which corresponds to the transformation of 1H+
to p-quinone-diimine 1a and vice versa within a quasi-reversible
two-electron process [19]. A peak current ratio (IpC1/IpA1) of nearly
unity, particularly during the repetitive recycling of potential can
be considered as a criterion for the stability of p-quinone-diimine
1a produced at the surface of electrode under the experimental
conditions.
Fig. 3 shows the cyclic voltammograms of 4-morpholinoaniline
(1) in various pHs. As can be seen, with increasing pH, the peak
current ratio (IpC1/IpA1) becomes less than unity and decreases
with increasing pH as well as decreasing potential sweep rate. This
cathodic peak C1 disappears in basic solutions. These changes can
where m is the number of protons involved in the reaction. The
half-wave potential (E1/2), is given by [20]:
ꢀ
ꢁ
2.303 mRT
2F
E1ꢀ /2 = E1/2
−
pH
where E1/2 is the half-wave potential at pH = 0.0, R, T, and F
have their usual meanings. The half-wave potentials (E1/2) were
calculated as the average of the anodic and cathodic peak poten-
tials of the cyclic voltammograms {(Epa + Epc)/2} [20, page 229]. A
potential-pH diagram is constructed for compound 1 by plotting
the calculated E1/2 values as a function of pH (Fig. 4). The Eꢀ1/2-pH
diagrams comprise two linear segments with different equations
and slopes around of pH = 5.65.
-2e- - H+
O
O
O
N
N
N
NH2
NH2
NH2
O
N
NH
1
1
1a
O
N
O
NH2
NH
O
N
NH
H
- H+
NH
O
N
NH
+
N
O
1a
N
2
3
-2e- - H+
O
N
NH
NH
NH
N
N
3
3a
O
N
O
NH2
H
N
H
N
O
NH2
+
O
N
O
NH
NH
O
N
O
N
O
1
NH
4
- H+
NH2
N
3a
H
O
N
N
NH
N
O
N
5
O
Scheme 3.

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R. Esmaili, D. Nematollahi / Electrochimica Acta 56 (2011) 3899–3904
I/μA
I
/
μA
Ι/μΑ
A1
Ipc/Ipa
0.6
40
35
30
25
20
15
10
5
40
35
30
25
20
15
10
5
40
35
30
25
20
15
10
5
d
0.5
A1
0.4
1
a
2
3
c/mmol l-1
b
c
0
0
0
C1
0.15
C1
0.25
-5
0.05
-5
0.05
-5
0.05
0.25
0.35
0.15
0.35
0.15
0.25
0.35
E vs SCE/V
E vs SCE/V
E vs SCE/V
Fig. 5. Cyclic voltammograms of 4-morpholinoaniline (1) in aqueous solution containing phosphate buffer (pH = 7.0, c = 0.2 M), at glassy carbon electrode, in various con-
centrations. Concentration from a to c are: 3.0, 2.0 and 1.0 mM, respectively. Scan rate: 100 mV/s; t = 25
1
◦C. Curve d: variation of peak current ratio (IpC1/IpA1) versus
concentration.
In pHs < 5.65:
forward scan and reduction of 1a to 1H+ in reverse scan (Scheme 1,
Eq. (1)). Whereas, the electrode surface reaction at pH > 5.65, corre-
sponds to the two-electron, one-proton process (Scheme 1, Eq. (2)).
Also, the pKa obtained in this work for acid/base equilibrium
shown in Scheme 2 is: 5.65.
E1ꢀ /2 = 0.55 − 0.054 pH or slope = −54 mV/pH
In pHs > 5.65:
ꢀ
E1ꢀ /2 = 0.42 − 0.031 pH or slope = −31 mV/pH
3.2. Electrochemical behaviour in pHs 6–9
On the basis of the above mentioned slope, it can be concluded
that the electrode surface reaction occurring at the pH below 5.65
is a two-electron, two-proton process involving the oxidation of
“protonated” 1 (1H+) to the corresponding quinone-diimine 1a in
In neutral and basic solutions, the peak current ratio (IpC1/IpA1
of 1 is less than unity and decreases with increasing pH (Fig. 3).
)
A1
Ip c / Ip a
55
Progress of
Coulometry
18
13
0.6
0.5
0.4
a
b
45
e
c
35
25
15
5
10 6 0 110 16 0
8
d
- 1
v
/mV s
3
-2
-7
C1
-5
0.05
-0.1
0
0.1
0.2
0.3
0.15
0.25
0.35
E vs SCE/V
E vs SCE/V
Fig. 6. Cyclic voltammograms of 1 mM 4-morpholinoaniline (1) at glassy carbon
electrode, in phosphate buffer solution (pH = 7.0, c = 0.2 M). Scan rate: (a) 150 mV/s,
(b) 100 mV/s, (c) 50 mV/s and (d) 25 mV/s. t = 25 1 ◦C. (f): Variation of peak current
ratio (IpC1/IpA1) versus scan rate.
Fig. 7. Cyclic voltammograms of 0.25 mmol 4-morpholinoaniline (1) during con-
trolled potential coulometry at 0.25 V versus SCE in aqueous solution containing
phosphate buffer (pH = 7.0, c = 0.2 M). Scan rate: 100 mV/s; t = 25
1
◦C.

R. Esmaili, D. Nematollahi / Electrochimica Acta 56 (2011) 3899–3904
3903
B
C
A
O
N
NH
NH
3a
N
O
P
a
A
t
h
h
t
a
C
B
P
HI
HII
h
t
a
HI
P
NH2
O
N
NH2
H
N
O
N
O
N
NH
HII
N
O
HN HN
N
O
N
HI
HN
HII
O
N
C
N
H
O
A
NH2
N
N
O
O
B
Fig. 8. The structures of possible trimers.
Table 1
These can be related to dimerization or more reaction [21,22]. As
is shown in Fig. 5, the peak current ratio (IpC1/IpA1) is dependent to
concentration of 4-morpholinoaniline (1) and proportional to the
augmentation of it, the peak current ratio (IpC1/IpA1) decreases. The
dependence of peak current ratio (IpC1/IpA1) on the concentration
of 4-morpholinoaniline (1) is indication of dimerization reaction
after electron transfer process [21,22]. It is also seen that propor-
tional to the increase of the potential sweep rate, peak current ratio
(IpC1/IpA1) increases (Fig. 6).
Controlled-potential coulometry was performed in an aque-
ous phosphate buffer solution (c = 0.2 M, pH = 7.0), containing
0.25 mmol of 1 at 0.25 V versus SCE. The monitoring of electrolysis
progress was carried out by cyclic voltammetry (Fig. 7). It shows
that, proportional to the advancement of coulometry, the anodic
peak A1 decreased and disappears when the charge consumption
becomes about 1.5 e− per molecule of 1.
Diagnostic criteria of cyclic voltammetry, the consumption of
1.5 electron per molecule of 1, and the spectroscopic data of the
isolated product (for example, m/e = 530 in mass spectrum of final
product) indicated that the reaction mechanism of electrooxidation
of 1 is trimerization reaction (Scheme 3).
According to our results, the generation of p-quinone-diimine 1a
is followed by a Michael type addition reaction of 1 on p-quinone-
diimine 1a, producing 3. Oxidation of 3 in the next step converts it
to Michael acceptor 3a and another Michael addition reaction of 1
to 3a, producing 5 as the final product. The polymerization reaction
was circumvented during the preparative reaction because of the
insolubility of the trimer 5 in aqueous solution containing phos-
phate buffer (c = 0.2 M, pH = 7.0). The electrochemical synthesis of
trimer 5 has performed according to presented procedure in Section
2.
Experimental and calculated 1H NMR data for aromatic protons HI and HII.
Type
1H NMR data
Experimental
Trimer A
Trimer B
Two singlet peaks with ı = 5.77 and 5.91
Two doublet peaks with ı = 5.39 and 5.45
One singlet peak with ı = 4.90
Trimer C
Two singlet peaks with ı = 5.23 and 5.29
other hand, trimer A shows two doublet peaks. These results reject
synthesis of trimers A and B and confirm the structure of trimer 5.
4. Conclusions
The results of this work show that 4-morpholinoaniline (1)
is oxidized in aqueous solutions to p-quinone-diimine 1a. The
quinone-diimine 1a participates in triimerization reaction. The
reaction mechanism for anodic oxidation of 4-morpholinoaniline
(1) is presented in Scheme 3. Because of the increase in the yield and
purity of product, pH = 7.0 was selected for electrochemical synthe-
sis of 5. According to our results, it seems that the Michael reaction
of 1 to 1a and 3a (Scheme 3) leads to the formation of trimer 5 as
final product, in a good yield and purity. The presented work rep-
resents a facile, reagent-less, and environmentally friendly method
with high atom economy, for the synthesis of a unique trimer of
4-morpholinoaniline using a carbon electrode.
Acknowledgments
We acknowledge the Bu-Ali Sina University Research Council
and Center of Excellence in Development of Chemical Methods
(CEDCM) for their support of this work.
p-Quinone-diimine 3a can be attacked by 1 from sites A, B or C
to yield three types of trimers (A, B and C) (C = trimer 5) (Fig. 8).
The experimental and calculated [23] 1H NMR results of the aro-
matic protons HI and HII in trimers A, B and C and obtained product
(trimer 5) are shown in Table 1.
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