Facile and clean electrochemical synthesis of new acetaminophen derivatives through electrochemical oxidation of acetaminophen in the presence of thiouracil derivatives

Article abstract of DOI:10.1080/17415993.2016.1262372

The electrochemical oxidation of acetaminophen (1a) is carried out in the presence of thiouracil derivatives (3a–c), as nucleophiles, in an acetate buffer solution (0.15 M, pH 5) mixed with Dimethylformamide (DMF) using cyclic voltammetry and coulometry under a constant potential. The results obtained indicate that N-acetyl-p-benzoquinone-imine derived from acetaminophen participates in a 1,4-Michael-type addition reaction with thiouracils to form the corresponding acetaminophen derivatives (4a–c) in good yields and with high purities using a facile, catalyst-free, and one-pot electrochemical method using three carbon electrodes in an undivided cell under mild conditions. The products obtained were characterized after purification by IR, ¹H NMR, and ¹³C NMR spectroscopies, and by the elemental analysis method.

Full text of DOI:10.1080/17415993.2016.1262372

Journal of Sulfur Chemistry
ISSN: 1741-5993 (Print) 1741-6000 (Online) Journal homepage: http://www.tandfonline.com/loi/gsrp20
Facile and clean electrochemical synthesis
of new acetaminophen derivatives through
electrochemical oxidation of acetaminophen in
the presence of thiouracil derivatives
Alireza Asghari, Mohsen Ameri, Samira Taghipour & Omid Ghaderi
To cite this article: Alireza Asghari, Mohsen Ameri, Samira Taghipour & Omid Ghaderi (2016):
Facile and clean electrochemical synthesis of new acetaminophen derivatives through
electrochemical oxidation of acetaminophen in the presence of thiouracil derivatives, Journal
of Sulfur Chemistry, DOI: 10.1080/17415993.2016.1262372
To link to this article: http://dx.doi.org/10.1080/17415993.2016.1262372
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Date: 08 December 2016, At: 06:14

JOURNAL OF SULFUR CHEMISTRY, 2016
http://dx.doi.org/10.1080/17415993.2016.1262372
Facile and clean electrochemical synthesis of new
acetaminophen derivatives through electrochemical
oxidation of acetaminophen in the presence of thiouracil
derivatives
Alireza Asghari, Mohsen Ameri, Samira Taghipour and Omid Ghaderi
Department of Chemistry, Semnan University, Semnan, Iran
ABSTRACT
ARTICLE HISTORY
The electrochemical oxidation of acetaminophen (1a) is carried out
in the presence of thiouracil derivatives (3a–c), as nucleophiles, in
an acetate buffer solution (0.15 M, pH 5) mixed with Dimethylfor-
mamide (DMF) using cyclic voltammetry and coulometry under a
constant potential. The results obtained indicate that N-acetyl-p-
benzoquinone-imine derived from acetaminophen participates in a
Received 13 July 2016
Accepted 12 November 2016
KEYWORDS
Electrochemical oxidation;
acetaminophen; thiouracil
derivatives; cyclic
voltammetry; Michael
addition
1
,4-Michael-type addition reaction with thiouracils to form the cor-
responding acetaminophen derivatives (4a–c) in good yields and
with high purities using a facile, catalyst-free, and one-pot electro-
chemical method using three carbon electrodes in an undivided cell
under mild conditions. The products obtained were characterized
1
13
after purification by IR, H NMR, and C NMR spectroscopies, and
by the elemental analysis method.
1. Introduction
Electrochemical synthesis is known as one of the most efficient methods that can pro-
vide significant advantages in the synthesis of organic compounds [1]. High selectivity,
readily available starting materials, high yield, low-energy consumption and reaction tem-
perature, and low-cost reagents are some advantages of such electro-synthetic reactions
[
2]. Acetaminophen (paracetamol, N-acetyl-p-aminophenol) is a valuable drug, which
CONTACT Alireza Asghari
aasghari@semnan.ac.ir
Department of Chemistry, Semnan University,
Semnan35195-363, Iran
©
2016 Informa UK Limited, trading as Taylor & Francis Group

2
A. ASGHARI ET AL.
has extensive applications in the pharmaceutical industry with widespread use in pain
relief and fever reduction in a variety of patients, including children, pregnant women,
the elderly, and those with osteoarthritis, simple headache, and non-inflammatory muscu-
loskeletal diseases [3,4]. It is an anti-pyretic, non-steroidal anti-inflammatory drug [5], and
a preferred alternative to aspirin, particularly for the patients who cannot tolerate aspirin
[
6]. Its use is one of the most common causes of poisoning worldwide [7], and it is an
analgesic compound that has a high therapeutic value. It is also used as a precursor of peni-
cillin, and as a stabilizer for hydrogen peroxide and photographic chemicals. It is a suitable
alternative when the patients are sensitive to aspirin [8]. On the other hand, thiouracil
derivatives are potential therapeutics acting as anti-viral, anti-oxidant, anti-cancer, and
anti-microbial agents [9–12]. It is well known that acetaminophen can be electrochemically
oxidized to N-acetyl-p-benzoquinone-imine, which is quite reactive and can be attacked
by different nucleophiles. With this in mind, the electrochemical oxidation of paracetamol
has been studied in the presence of a variety of nucleophiles [13–15].
Regarding the attractive pharmaceutical properties of the acetaminophen and thiouracil
derivatives, we anticipated that the synthesis of new acetaminophen derivatives with the
thiouracil moiety could be useful from the viewpoint of medicinal chemistry and drug
design. Therefore, we investigated the electrochemical oxidation of acetaminophen in the
presence of thiouracil derivatives, as nucleophiles, and presented a facile, reagentless, effi-
cient, and one-pot electrochemical method for the synthesis of some new acetaminophen
derivatives.
2. Results and discussion
2.1. Voltammetric studies
The electrochemical oxidation of acetaminophen (1a) was performed in both the absence
and presence of nucleophiles (the thiouracil derivatives). Figure 1 (curve a) shows the cyclic
voltammogram of 2 mM of acetaminophen in a mixed solution of acetate buffer (0.15 M,
pH 5) and DMF (80:20, v:v). One anodic peak (A1) and its corresponding cathodic peak
(
C1) can be observed in this figure. These peaks (A1 and C1) correspond to the transforma-
tion of 1a to N-acetyl-p-benzoquinone-imine (2a) and vice versa within a quasi-reversible
two-electron process [16]. The peak current ratio (IpC1/IpA1) was approximately equal to
one, particularly during the potential recycling because at the optimum pH value (pH 5),
the side-reactions such as hydrolysis or dimerization and/or polymerization were too slow
to be observed on the time scale of cyclic voltammetry [16]. This can be considered as a cri-
terion for the stability of 2a produced at the surface of the electrode under the experimental
conditions. However, in the presence of thiouracil (3a), the cathodic peak (C1) decreased
(Figure 1, curve b). This means that N-acetyl-p-benzoquinone-imine (2a), formed at the
surface of the electrode, was consumed by a chemical reaction with 3a, and as a conse-
quence, the current for the C1 peak decreased during the reverse scan. In Figure 1, curve c
is related to 2 mM solution of 3a in the absence of 1a. The same electrochemical behaviour
was observed for 1a in the absence and presence of 3b and 3c in a 0.15 M acetate buffer
solution (pH 5) mixed with DMF (80:20 v:v) (data not shown).
−
1
The effect of scan rate on the cyclic voltammograms of 2 mM (2 mmol L ) of
acetaminophen in the presence of 2 mM of thiouracil is shown in Figure 2. As can be

JOURNAL OF SULFUR CHEMISTRY
3
Figure 1. Cyclic voltammograms of 2 mM of acetaminophen (1a) in the absence (a) and presence (b) of
2
mM of thiouracil and 2 mM of 3a in the absence of 1a (c) at glassy carbon electrode in a 0.15 M acetate
−
1
buffer solution (pH 5) mixed with DMF (80:20 v:v) at a scan rate of 50 mV s
.
seen in this figure, upon an increase in the potential scan rate, the current for the C1 peak
increased. In other words, the peak current ratio (IpC1/IpA1) increased with an increase in
the scan rate. On the other hand, the current function for peak A1 (IpA1/v1/2) decreased
slightly with increase in the scan rate (Figure 3). These data indicate that the electro-
oxidation of 1a in the presence of 3a followed an EC (E: electrochemical, C: chemical)
mechanism [17].
The multi-cyclic voltammograms of 1a (2 mM) in the presence of 2 mM of thiouracil
indicate that in the second and third cycles, the currents for the A1 and C1 peaks decreased
and their potentials shifted to more positive and negative potentials, respectively (Figure
4
). This current decrement and potential shift is due to the formation of a thin film of
product on the electrode surface, which inhibits, to a certain extent, the performance of
the electrode processes [18].
Coulometry was performed under a constant potential (0.55 V) for 0.4 mmol of
acetaminophen in the presence of 0.4 mmol of thiouracil in a 100 mL mixed solution

4
A. ASGHARI ET AL.
Figure 2. Typical voltammograms of 2 mM of acetaminophen (1a) in the presence of 3a (2 mM) at
aglassy carbon electrode in optimized conditions at scan rates of 10, 25, 50, 80, 100, 150, 200, 300, and
−
1
500 mV s
.
Figure 3. Variation in peak current ratios IpC1/IpA1 and IpA1/ν1/2 versus scan rate for 2 mM of
acetaminophen (1a) in the presence of 2 mM of 3a (curves a and b) at scan rates of 10, 25, 50, 80, 100,
−1
1
50, 200, 300, and 500 mV s under optimum experimental conditions.
of acetate buffer (0.15 M, pH 5) and DMF (80:20, v:v). Figure 5 shows the cyclic
voltammograms recorded for monitoring the electrolysis progress. It is clear that propor-
tionally to the advancement of coulometry anodic peak (A1) decreases, indicating the
acetaminophen consumption and the occurrence of the desired reaction. The A1 peak
−
disappeared when charge consumption was about 2e per molecule of 1a.

JOURNAL OF SULFUR CHEMISTRY
5
Figure 4. Multi-cyclic voltammograms of 2 mM of acetaminophen (1a) in the presence of 2 mM of 3a
at a glassy carbon electrode in a 0.15 M acetate buffer solution (pH 5) mixed with DMF (80:20 v:v); scan
−
1
rate: 50 mV s
.
Regarding the coulometric, cyclic voltammetric, and spectroscopic results, it seems that
the 1,4-Michael addition of 3a (or 3b and/or 3c) to N-acetyl-p-benzoquinone-imine (2a)
is faster than the other side-reactions, and leads to the final product (4a) via an EC (E:
electrochemical and C: chemical) mechanism (Scheme 1).
2
.2. Effect of pH
Previous studies carried out on the electrochemical oxidation of acetaminophen in various
media (acidic, neutral, and basic) show that acetaminophen is subjected to the side-
reactions in strongly acidic and basic conditions. In a strongly basic solution, the rate of
hydroxylation, and in a strongly acidic solution, the rate of hydrolysis is fast. In mild acidic
and basic conditions (pH 5 and pH 9), the peak current ratio for the electrochemical oxi-
dation of acetaminophen is near one [16]. Thus, these pH values could lead to the best
results for the electro-synthesis of acetaminophen derivatives. Thus, the electrochemical
synthesis of 4a–c was performed in acidic, neutral, and basic media (pH 3–10.5) in order
to investigate the effect of pH on the electro-synthesis process. The results obtained were in
agreement with our prediction, and the maximum amounts of pure products were obtained
at pH 5. The results obtained were tabulated in Table 1.
3. Conclusion
In the present work, the electrochemical synthesis of some new acetaminophen deriva-
tives (4a–c) was performed via a simple, fast, green, catalyst-free, one-pot, and clean
path based on the electro-oxidation of acetaminophen (1a) in the presence of thiouracils
3
a–c in mild conditions. The results obtained showed that the electro-generated N-acetyl-
p-benzoquinone-imine (2a) reacted chemically with thiouracils 3a–c to give the final
valuable products (4a–c), via an EC mechanism, after consumption of 2e per molecule
−

6
A. ASGHARI ET AL.
Figure 5. (a) Cyclic voltammogram of 0.4 mmol of acetaminophen (1a) in the presence of 0.4 mmol of
a at a glassy carbon electrode in a 0.15 M acetate buffer solution (pH 5) mixed with DMF (80:20 v:v)
3
−
1
during controlled-potential coulometry at 0.55 V vs. Ag/AgCl (scan rate: 100 mV s ). After consumption
of 0°C, 5°C, 10°C, 20°C, 30°C, and 50°C. Progress of coulometry is associated with decreased anodic peak
(A1) current. Curve b shows variation in peak current versus charge consumption.
of 1a. An environmentally friendly synthesis, the use of electricity instead of chemical
reagents (catalysts), no need for high reaction temperature (reflux), and a one-pot pro-
cess conducted under mild conditions (room temperature and pressure) are the attractive
features of this work.
4. Experimental
4
.1. Apparatus and reagents
All the chemicals used in this work were reagent-grade materials. Phosphate salts, solvents,
and reagents were of pro-analysis from E-Merck. The required chemicals were used with-
out further purification. The apparatus used was the same as that used in our previous
works [2,19,20].

JOURNAL OF SULFUR CHEMISTRY
7
Scheme 1. Proposed mechanism.
Table 1. Investigation of product yields (4a–c) at various pH values.
pH value
3
4
5
6
7
8
9.2
10.5
Yield (%) 4a
Yield (%) 4b
Yield (%) 4c
22
9
13
53
46
58
76
78
79
63
65
61
52
49
50
23
31
36
11
17
14
0
0
0

8
A. ASGHARI ET AL.
4.2. Procedure for electrochemical synthesis of acetaminophen derivatives (4a–c)
An estimated 0.4 mmol of thiouracil (3a) (or thiouracil derivatives) was dissolved in 16 mL
of DMF in an undivided cell, and then 64 mL of an acetate buffer solution (0.15 M, pH 5)
and 0.4 mmol of acetaminophen were added to the cell to give a final solution of 80 mL.
Finally, an electrolysis process was performed under a constant potential (0.55 V). The pro-
cess was terminated when the current decay became greater than 95%. It was interrupted
for several times to wash the carbon anode in acetone in order to reactivate it. The process
was monitored by cyclic voltammetry (CV). At the end of electrolysis, the cell was kept at
ambient temperature for 24 h to evaporate the solvent in order to reduce the volume of the
solution to half of its initial amount. Then each one of the precipitated solids were collected
by centrifugation and subsequently washed with water. After purification, the products
1
13
obtained were characterized using the FT-IR, H NMR, and C NMR spectroscopies, and
the elemental analysis technique.
4
.3. Characterization of products
4
.3.1. N-(4-hydroxy-3-((6-oxo-1,6-dihydropyrimidin-2-yl)thio)phenyl)acetamide (4a)
−
1
Yield: 76%. Mp: >260°C (decomposed). FT-IR (KBr, cm ): 3450 (broad, OH), 2975
1
(
broad, NH), 1660 (C=O, amide). H NMR (400 MHz, Dimethyl sulfoxide (DMSO)-d ):
6
δ (ppm) 2.04 (s, 3H, CH ), 5.96 (d, 1H, J = 6.8 Hz, aromatic), 6.77 (d, 1H, J = 9.2 Hz, aro-
3
matic), 7.46 (d, 1H, J = 6.4, aromatic), 7.66 (d, 1H, J = 8.4 Hz), 8.22 (s, 1H), 9.92 (broad,
1
3
1H, OH), 10.28 (broad, 1H, NH), 12.29 (broad, 1H, NH). C NMR (100 MHz, DMSO-
d6): δ 22.3, 76.7, 102.01, 111.4, 114.5, 126.5, 128.8, 132.9, 151.2, 158.0, 159.3, 168.8, 170.2.
Anal. Calcd. for C H N O S: C, 51.98; H, 4.00; N, 15.15. Found: C, 51.82.; H, 4.08; N,
1
2
11
3
3
1
5.06.
4.3.2. N-(4-hydroxy-3-((4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)thio)
phenyl)acetamide (4b)
−
1
Yield: 78%. Mp: >260°C (decomposed). FT-IR (KBr, cm ): 3300 (broad, OH), 3000
1
(
broad, NH), 1666 (C=O, amide). H NMR (400 MHz, DMSO-d ): δ (ppm) 1.98 (s, 3H,
6
CH ), 2.08 (s, 3H, CH ), 5.92 (s, 1H, aromatic), 6.57 (d, 1H, J = 6.8 Hz, aromatic), 7.53
3
3
(
d, 1H, J = 8.0, aromatic), 8.21 (s, 1H), 9.88 (broad, 1H, OH), 10.32 (broad, 1H, NH).
1
3
C NMR (100 MHz, DMSO-d ): δ 18.4, 28.9, 76.7, 101.4, 112.2, 115.3, 126.8, 128.6, 133.2,
6
1
50.2, 159.6, 160.2, 168.2, 178.7. Anal. Calcd. for C H N O S: C, 53.60; H, 4.50; N, 14.42.
13 13 3 3
Found: C, 53.72; H, 4.38; N, 14.36.
4.3.3. N-(4-hydroxy-3-((6-oxo-4-propyl-1,6-dihydropyrimidin-2-yl)
thio)phenyl)acetamide (4c)
−
1
Yield: 79%. Mp: >260°C (decomposed). FT-IR (KBr, cm ): 3200 (broad, OH), 2962
1
(
broad, NH), 1661 (C=O, amide). H NMR (400 MHz, DMSO-d ): δ (ppm) 0.85 (t, 3H,
6
CH ), 1.35 (m, 2H, CH ), 1.69 (t, 2H, CH ), 2.03 (s, 1H, CH ), 5.92 (s, 1H, aromatic), 6.61
3
2
2
3
(
d, 1H, J = 8.4 Hz, aromatic), 7.59 (d, 1H, J = 8.4, aromatic), 8.18 (s, 1H), 9.88 (broad, 1H,
13
OH), 10.20 (broad, 1H, NH), 12.23 (broad, 1H, NH). C NMR (100 MHz, DMSO-d ): δ
6
1
2.7, 24.4, 26.7, 38.6, 76.7, 101.0, 112.5, 113.6, 127.9, 129.4, 134.1, 150.6, 150.6, 161.2, 169.5,

JOURNAL OF SULFUR CHEMISTRY
9
1
70.7. Anal. Calcd. for C H N O S: C, 56.41; H, 5.37; N, 13.16. Found: C, 56.32; H, 5.28;
15 17 3 3
N, 13.03.
Acknowledgement
The authors thank the Semnan University Research Council for the financial support of this work.
Disclosure statement
No potential conflict of interest was reported by the authors.
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