Electrochemical oxidation of acetaminophen in the presence of Barbituric acid derivatives

Article abstract of DOI:10.1149/2.1111409jes

Electrochemical oxidation of acetaminophen (1) in the presence of barbituric acid (2a), 1, 3-dimethyl barbituric acid (2b), 2- thiobarbituric acid (2c) and 1, 3-diethyl-2-thiobarbituric acid (2d) as nucleophiles in aqueous solution has been studied using cyclic voltammetry and controlled-potential coulometry. The results indicate that the p-quinone imine derived from electrooxidation of acetaminophen (1) participates in a Michael addition reaction with 2a-d to form the corresponding barbituric acid derivatives (7a-d). In addition, the homogeneous rate constants were estimated by comparing the experimental cyclic voltammetric responses with the digital simulated results. The electrochemical synthesis of 7a-d has been successfully performed in an undivided cell in good yields and purity at biological pH.

Full text of DOI:10.1149/2.1111409jes

Journal of The Electrochemical Society, 161 (9) G69-G73 (2014)
G69
0013-4651/2014/161(9)/G69/5/$31.00 © The Electrochemical Society
Electrochemical Oxidation of Acetaminophen in the Presence
of Barbituric Acid Derivatives
Esmail Tammari,a,z Maryam Kazemi,b and Ameneh Amanic
aDepartment of Chemistry, Faculty of Sciences, Persian Gulf University, Bushehr 75169, Iran
bDepartment of Chemistry, Payame Noor University, Tehran, Iran
cDepartment of Medicinal Plants Production, Nahavand University, Nahavand, Iran
Electrochemical oxidation of acetaminophen (1) in the presence of barbituric acid (2a), 1,3-dimethyl barbituric acid (2b), 2-
thiobarbituric acid (2c) and 1,3-diethyl-2-thiobarbituric acid (2d) as nucleophiles in aqueous solution has been studied using cyclic
voltammetry and controlled-potential coulometry. The results indicate that the p-quinone imine derived from electrooxidation of
acetaminophen (1) participates in a Michael addition reaction with 2a-d to form the corresponding barbituric acid derivatives (7a-d).
In addition, the homogeneous rate constants were estimated by comparing the experimental cyclic voltammetric responses with the
digital simulated results. The electrochemical synthesis of 7a-d has been successfully performed in an undivided cell in good yields
and purity at biological pH.
© 2014 The Electrochemical Society. [DOI: 10.1149/2.1111409jes] All rights reserved.
Manuscript submitted May 5, 2014; revised manuscript received June 9, 2014. Published June 26, 2014.
Electrochemistry provides a versatile means for the selective re-
duction and oxidation of organic compounds. The importance of
an electrochemical synthesis lies not only in the selectivity of the
reaction, but also in the formation of electrons at the electrode
surface.1,2 Since the electrons are reagent free, pollution of the en-
vironment by spent reagents can be avoided. In addition, electrosyn-
thesis can lead to efficient and sometimes unexpected synthesis of
compounds, which cannot be easily prepared by conventional organic
synthesis.1,2 As an electroactive substance, acetaminophen (paraceta-
mol) has also attracted much interest. Acetaminophen (paracetamol)
(N-acetyl-p-aminophenol) is a popular, antipyretic and non-steroidal
anti-inflammatory drug.3 It is the preferred alternative to aspirin, par-
ticularly for patients who cannot tolerate aspirin4 It has been shown
that N-acetyl-p-benzoquinone-imine (NAPQI) is the main in vivo and
in vitro oxidation product of acetaminophen.5
On the other hand barbituric acid and its derivatives are widely
used in the preparation of barbiturates, dyes, and polymerization
catalysts.6 Also barbituric acid derivatives are well known to pos-
sess antibacterial,7 sedatives,8 herbicides,9 fungicides10 and antiviral
agents.11 Our previous studies show that the electrochemically gen-
erated NAPQI is a reactive intermediate and as a Michael acceptor,
participates in different types of reactions12–16 However, until now, no
report has been published about the electrooxidation of acetaminophen
in the presence of barbituric acid derivatives. In this work electrochem-
ical oxidation of acetaminophen (1) has been studied in the presence of
barbituric acid (2a) 1,3-dimethylbarbituric acid (2b), 2-thiobarbituric
acid (2c) and 1,3-diethyl-2-thiobarbituric acid (2d) as nucleophiles
(Fig. 1).
inum gauze constitute the counter electrode. The working electrode
potentials were measured versus SCE (all electrodes from AZAR elec-
trode). The homogeneous rate constants were estimated by analyzing
the cyclic voltammetric responses using the cyclic voltammetry digi-
tal simulation DIGIELCH software.18 All chemicals (acetaminophen,
barbituric acid, 1,3-dimethylbarbituric acid, 2-tiobarbituric acid and
1,3 diethyl 2-tiobarbituric acid) were reagent-grade materials from
Aldrich and phosphate salts and other inorganic salts were of pro-
analysis grade from E. Merck. These chemicals were used without
further purification.
Synthesis of compounds 7a-d.— A solution (ca. 80 mL) of phos-
phate buffer (0.2 M, pH = 7.2) containing 2 mmol of acetaminophen
(1) and 2 mmol of 2-thiobarbituric acid (2c) was electrolyzed in an un-
divided cell equipped with a glassy carbon anode and a large stainless
steel gauze as cathode, at 25◦C at 0.50 V versus SCE. The electrolysis
was terminated when the decay of the current became more than 95%.
The process was interrupted several times during the electrolysis (due
to the formation of a film of product at the surface of the electrode)
and the graphite anode was washed in acetone in order to reactivate it.
At the end of electrolysis, a few drops of phosphoric acid were added
to the solution and the cell was placed in a refrigerator overnight. The
precipitated solid was collected by filtration and was washed several
times with water. After recrystallization, products were characterized
by IR, 1H NMR and MS.
X
R
R
X = O R= H
X = O R = CH3
7a
7b
7c
7d
N
N
Some electrochemical techniques such as: cyclic voltammetry us-
ing diagnostic criteria derived by Nicholson and Shain for various
electrode mechanisms and controlled-potential coulometry were used.
These methods provide a powerful independent route for quantitative
characterization of complex electrode processes.17 The present work
has led to the development of a facile electrochemical method for the
synthesis of new and unique barbituric derivatives in good yield and
purity.
O
O
O
N
OH
X = S
X = S
R = H
R = C2H5
HN
O
O
Experimental
Characterization of product 7a (C20H18N4O7).— Mp > 273◦C
(Dec.). 1H NMR (300 MHz DMSO-d6) δ (ppm): 1.99 (s, 6H, methyl),
6.82–7.46 (m, 6H, aromatic), 9.27–9.86 (broad, NH, OH), 11.48 (s,
NH: barbituric acid). IR (KBr): 3219, 3061, 2926, 1616, 1712, 1502,
Apparatus and reagents.— Cyclic voltammetry and controlled-
potential coulometry were performed using an Autolab model PG-
STAT 20 potentiostat/golvanostat. The working electrode used in the
voltammetry experiments was a glassy carbon disk (1.8 mm diame-
ter), and platinum wire was used as counter electrode. The working
electrode used in controlled-potential coulometry was an assembly of
four carbon rods (6 mm diameter and 4 cm length) and a large plat-
1408, 1234, 1233 cm−1
.
Characterization of product 7b (C22H22N4O7).— M.p > 270◦C
(Dec.). 1H NMR (300 MHz DMSO-d6) δ (ppm): 2.01 (s, 6H
methyl), 3.22 (s, 6H methyl), 6.88–7.46 (m, 6H, aromatic), 9.87–9.96
(broad, NH, OH). IR(KBr): 3361,3300, 3280, 1640, 1600, 1417, 1273,
zE-mail: esmail.tammari@gmail.com
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Journal of The Electrochemical Society, 161 (9) G69-G73 (2014)
Figure 1. Chemical structure of acetaminophen (1), barbituric acid (2a), 1,3-dimethyl barbituric acid (2b), 2-thiobarbituric acid (2c) and 1,3-diethyl-2-
thiobarbituric acid (2d).
1260,1257, 1240 cm−1. MS; m/z (relative intensity) = 454(M++2H.,
The oxidation of acetaminophen (1) in the presence of 2-
thiobarbituric acid (2c) as a nucleophile was studied in some details.
Figure 2 (curve b) shows the cyclic voltammogram obtained for a
1 mM solution of 1 in the presence of 3 mM 2-thiobarbituric acid in
aqueous solution containing 0.2 M phosphate buffer (pH 7.2). In these
conditions, the cathodic counterpart of the anodic peak A1 decreases.
Furthermore, it is seen that proportional to the augmentation of poten-
tial sweep rate, the height of C1 peak of 1 increases (Figure 3, curves
a-e). A similar situation is observed when the 2-thiobarbituric acid
to acetaminophen (1) concentration ratio is decreased. A plot of the
peak current ratio (IpA1/IpC1) versus v for a mixture of acetaminophen
(1) and 2-thiobarbituric acid (2c) confirms the reactivity of 1a toward
2-thiobarbituric acid, appearing as an increase in the height of the
cathodic peak C1 at higher scan rates (Fig. 3, inset). On the other hand
the current function for A1 peak, (IPA1/v1/2), changes only slightly
with increasing the scan rate.17
2.5), 430 (36), 257 (13), 229 (88), 196 (33), 165 (34), 111 (66), 160
(95), 169 (100).
Characterization of product 7c (C20H18N4O6S).— M.p > 243◦C
(Dec.). 1H NMR (300 MHz DMSO-d6) δ (ppm): 1.98 (s, 6H methyl),
6.81–7.42 (m, 6H aromatic), 9.75 (s, 2OH), 9.83 (s, 2NH), 11.0
(broad, NH). IR(KBr): 3412, 2954, 2910, 2900, 1658, 1612, 1503,1463,
1376,1203 cm−1. MS; m/z (relative intensity) = 442 (M++2H., 3.5),
256 (2), 111 (6), 71 (14), 57 (26), 43 (34), 19 (100).
Characterization of product 7d (C22H22N4O6S).— M.p > 250◦C
(Dec.). 1H NMR (300 MHz DMSO-d6) δ (ppm): 1.13 (s, 6 H methyl),
1.96 (s, 6H, methyl), 4.36 (s, 4H, ethyl protons) 6.80–7.41 (m, 6H
aromatic), 9.74 (s, 2OH), 9.82 (s, 2NH). IR(KBr): 3269, 2978, 2870,
1662, 1595, 1504, 1371,1342, 1261 cm−1
.
Controlled potential coulometry was performed in aqueous solu-
tion (0.2 M phosphate buffer, pH 7.2) containing 0.2 mmol of 1 and
0.2mmol of 2-tiobarbituric acid (2c) at 0.45 V versus SCE. The mon-
itoring of electrolysis progress was carried out by cyclic voltammetry
(Fig. 4). It is shown that anodic peak A1 decreases proportionally to
the advancement of coulometry. All anodic and cathodic peaks disap-
pear when the charge consumption becomes about 3e− per molecule
of 1. These observations allow us to propose the pathway in Scheme 1
for the electrooxidation of 1 in the presence of 2-tiobarbituric acid
(2c).19–21
According to our results, it seems that the 1,4 (Michael) ad-
dition reaction of enolate anion 3c to N-acetyl-p-benzoquinone-
imine (NAPQI) (1a) is faster than other secondary reactions, leading
presumably to the intermediate (5c). The oxidation of this compound
Results and Discussion
Voltammetric study.— Figure 2 curve a, shows cyclic voltammo-
gram recorded for 1 mM acetaminophen (1) in aqueous solution con-
taining 0.2 M phosphate buffer (pH 7.2). The voltammogram shows an
anodic peak (A1) in the positive-going scan and a cathodic counterpart
peak (C1) in the negative-going scan which corresponds to the trans-
formation of acetaminophen (1) to N-acetyl-p-benzoquinone-imine
(NAPQI) (1a) and vice-versa within a quasi-reversible two-electron
process.15,16 In these conditions, peak current ratio (IpC1/IpA1) nearly
unity, particularly during the repetitive recycling of potential, can be
considered as a criterion for the stability of p-quinone imine produced
(1a) at the surface of electrode under the experimental conditions.
Figure 2. (a) Cyclic voltammogram of 1 mM acetaminophen (1) (b) Cyclic
voltammogram of 1 mM acetaminophen in present of 3 mM 2-tiobarbituric
acid (2c), (c) Cyclic voltammogram of 1mM 2-tiobarbituric acid in phosphate
buffer solution (c = 0.2 M, pH = 7.2). Scan rate: 50 mV s−1. T = 25 1◦C.
Figure 3. Typical voltammograms of 1 mM acetaminophen in the presence
of 3 mM 2-tiobarbituric acid in phosphate buffer solution (c = 0.2 M,
pH = 7.2) in various scan rates. Scan rate are: 10, 25, 75 and 100 mVs−1
.
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Journal of The Electrochemical Society, 161 (9) G69-G73 (2014)
G71
Figure 5. (a): Cyclic voltammograms of 1 mM acetaminophen (b) Cyclic
voltammogram of 1 mM acetaminophen in the present of 3 mM 1,3- dimethyl-
barbituric acid (2b), (c) Cyclic voltammogram of 1mM 1,3-dimethylbarbituric
acid in phosphate buffer solution (c = 0.2 M, pH = 7.2). Scan rate: 50 mV
Figure 4. Cyclic voltammograms of 0.2 mmol acetaminophen in the presence
of 0.2mmol 2-tiobarbituric acid in 0.2 M phosphate buffer, pH = 7.2 during
controlled potential coulometry at 0.30 V vs. SCE, after consumption of: (a)
0.0, (b) 10, (c) 20, (d) 30 and (e) 40 C. Scan rate: 100 mVs−1. Inset: variation
of peak current vs charge consumed. T = 25 1◦C.
s
−1. T = 25 1◦C.
(5c) is easier than the oxidation of parent starting molecule (1) by
virtue of the presence of an electron-donating group. It can be seen
from the mechanism written above that, as the chemical reaction
[eqn. (2)] occurs, 1 is regenerated through homogeneous oxidation
and hence, can be reoxidized at the electrode surface. Thus, as the
chemical reaction takes place, the apparent number of electrons trans-
ferred increases from the limits of n = 2 to 3 electrons per molecule.
The reaction product (7c) can also be oxidized at a lower potential than
O
N
O-
OH
R
N
R
O
O
-H+
- 4e- - 4H+
N
N
X
X
2
2
N
R
R
O
HN
2a-d
3a-d
1a
1
O
O
R
N
R
N
R
N
X
R
O
X
O
O
X
O
R
O-
O
N
OH
OH
- 2e- - 2H+
N
+H+
-H+
N
N
N
X
R
+
R
N
O
O
O
O
R
N
HN
HN
1a
3a-d
6a-d
O
5a-d
4a-d
O
O
X
O
R
R
O
R
O
N
N
X
R
O
N
O
O
N
O
O
O
OH
X = O R= H
X = O R = CH3
2a, 3a, 4a, 5a, 6a, 7a
2b, 3b, 4b, 5b, 6b, 7b
2c, 3c, 4c, 5c, 6c, 7c
2d, 3d, 4d, 5d, 6d, 7d
Isolated Yield =%57
Isolated Yield =%63
Isolated Yield = %75
Isolated Yield = %78
+H+
X = S
X = S
R = H
R = C2H5
1a
7a-d
6a-d
N
HN
O
O
O
Overall reaction:
X
R
R
O
N
N
OH
R
R
O
O
O
OH
- 6e- - 6H+
N
N
2
+
X
HN
O
N
HN
O
1
2a-d
7a-d
O
O
Scheme 1. Proposed ECEC mechanism for the electrochemical oxidation of acetaminophen (1) in the presence of 2a-c.
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Journal of The Electrochemical Society, 161 (9) G69-G73 (2014)
Table I. Observed homogeneous rate costants, kobs (M−1
s
−1), for
the studied acetaminophen in the presence of barbituric acid (2a),
1,3-dimethyl barbituric acid (2b), 2-thiobarbituric acid (2c) and
1,3-diethyl-2-thiobarbituric acid (2d).
ka of 1a
ka of 1a
ka of 1a
ka of 1a
obs
obs
obs
obs
with 3a
with 3b
with 3c
with 3d
0.12 0.01
0.19 0.01
0.15 0.01
0.21 0.01
aEach second-order rate constant is the average of three determinations
and is reported together with the standard deviation.
were obtained experimentally as the midpoint potential between the
anodic and cathodic peaks (Emid). The heterogeneous rate constants
(0.002 cm s−1) for the oxidation of acetaminophen (1) were estimated
using experimental working curves.25,26 All these parameters were
kept constant throughout the digital simulation process. The parame-
ter kobs were allowed to change. There was good agreement between
the simulated voltammograms with those obtained experimentally
(Fig. 6). The calculated values of the second-order rate constants for
the reaction of acetaminophen (1) with barbituric acid derivatives
(2a-d) are shown in Table I.
As can be seen, the correlation is quite satisfactory. The ob-
served homogeneous rate constants (kobs) of electrooxidation of ac-
etaminophen with barbituric acid derivatives (2a-d) is closely related
to the electron-donating strength of the substituted groups (X, R1)
on 2a-d. The calculated observed homogeneous rate constants (kobs
)
were found to vary in the order of kobs(3d) > kobs(3b) > kobs(3c)
> kobs(3a). As can be expected the presence of electron-donating
groups such as ethyl (3d) or methyl (3b) on nucleophile ring causes
an increase in kobs. Also according to the magnitude of kobs, 3c is much
better nucleophile as compared with 3a because of the presence of S
atom in 3c, instead of O atom in the structure of 3a.
Conclusions
The present results complete the previous reports on the anodic
oxidation of acetaminophen in aqueous solutions.14 The results of
this work show that acetaminophen is oxidized in water to its p-
quinone imine (1a). The p-quinone imine generated is then attacked
by the enolate anion of 3a-d to form barbituric acid derivatives. The
overall reaction mechanism for anodic oxidation of acetaminophen
in the presence of barbituric acid and some of its derivatives as the
nucleophile is presented in Scheme 1. The Michael addition reaction
of these nucleophiles to the p-quinon imine (1a) formed leads to the
formation of new and unique barbituric derivativesas final products,
in good yield and purity.
Figure 6. Cyclic voltammogrms of 1 mM acetaminophen (1) in the presence
of (I) 3 mM barbituric acid (2a), (II) 1,3-dimethyl barbituric acid (2b), (III)
2-thiobarbituric acid (2c) and (IV) 1,3-diethyl-2-thiobarbituric acid (2d) at pH
= 7.2, (a) experimental (b) simulated. Scan rate 100 mVs−1
.
the starting 1 compound. However, overoxidation of 7c was circum-
vented during the preparative reaction because of the insolubility of
the product in this medium. The mechanism was established by using
IR, 1H NMR, and MS techniques. In the mass spectrum of compound
7c, molecular ion [M + 2H] was recorded. This mass is related to
protonation of the NH groups22–24 and is another proof for production
of 7c in electrooxidation of 1 in the presence of 2c. The sum total
voltammetry, coulometry and spectroscopy results imply on an ECEC
electrochemical mechanism.17 The proposed ECEC electrochemical
mechanism is presented in Scheme 1.
The same results was obtained in electrooxidation of ac-
etaminophen (1) in the presence of barbituric acid (2a), 1,3- dimethyl-
barbituric acid (2b) and 1,3- diethyl 2-tio-barbituric acid (2d)
(Fig. 5).
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