Chinese Chemical Letters  2015, Vol.26 Issue (06):681-684   PDF    
Electro-oxidation of paracetamol in the presence of malononitrile: Application for green, efficient, none-catalyst, simple and one-pot electro-synthesis of new paracetamols
Alireza Asghari , Mohsen Ameri, Ali Akbar Ziarati, Sepideh Radmannia, Ali Amoozadeh, Behruz Barfi, Leila Boutorabi    
Department of Chemistry, Semnan University, Semnan 35195-363, Iran
Abstract: Electrochemical oxidation of paracetamol has been studied in the presence of malononitrile as a nucleophile in a phosphate buffer solution (0.15 mol/L, pH 7), using cyclic voltammetric techniques. The results indicated that the N-acetyl-p-benzoquinone-imine derived from paracetamol participates in a 1,4-Michael-type addition reaction with the malononitrile to form the corresponding paracetamol derivatives (6a, 7a). The present study has led to the development of a simple, green, non-catalyst and one-pot electrochemical method with high atom economy under mild conditions.
Key words: Electro-oxidation     Cyclic voltammetry     Malononitrile     Michael addition type     Paracetamol    
1. Introduction

Paracetamol (N-acetyl-p-aminophenol or acetaminophen) is a valuable non-steroidal anti-inflammatory drug in the widespread use of pain relief and fever reduction in a variety of patients, including children,pregnant women,the elderly and those with osteoarthritis,simple headaches,and non-inflammatory musculoskeletal diseases [1, 2]. Its popularity as an analgesic and antipyretic drug gradually increased [3].

On the other hand,paracetamol is the preferred alternative to aspirin,particularly for patients who cannot tolerate aspirin [4], and its use is one of the most common causes of poisoning worldwide [5]. At the recommended dosage,there are no side effects. However,overdoses cause liver and kidney damage. It is suspected that a metabolite of paracetamol (acetaminophen) is the actual hepatotoxic agent [6].

It is well-known that paracetamol can be electrochemically oxidized to N-acetyl-p-benzoquinone-imine. The N-acetyl-p-benzoquinone- imine formed is quite reactive and can be attacked by different nucleophiles. In this direction,the electrochemical oxidation of paracetamol has been studied in the presence of a variety of nucleophiles [7, 8, 9].

Regarding the wide attractive biological activity of paracetamol, the importance of green chemistry in recent years and also electrosynthesis advantages (high selectivity,readily available starting materials,good atom economy,low-energy consumption and temperature,low cost reagents and material failure) [10],as well as the continuation of our interest in the development of green methods for carbon-carbon bond formation reactions [10, 11],we decided to electrochemical synthesis of new paracetamol derivatives. In the present work we developed a facile, reagent-less,efficient and green electrochemical method for the synthesis of new paracetamol derivatives through oxidative coupling of paracetamol and malononitrile in the aqueous medium.

2. Experimental

The reaction equipment was used as described in the Supporting information and earlier paper [10, 11]. Paracetamol, malononitrile and phosphate salts were purchased from Merck (Darmstadt,Germany). These chemicals were used without further purification.

2.1. Electrochemical synthesis of 6a and 7a

In the typical method,100 mL phosphate buffer solution (pH 7, 0.15 mol/L) containing 1 mmol of paracetamol (1a) and 1 mmol of malononitrile (3) (in the case of 7a,2 mmol paracetamol and 1 mmol malononitrile) was electrolyzed at 0.5 V vs. Ag/AgCl (KCl, 3 mol/L) via controlled-potential coulometry. The progress of the reaction was followed by thin layer chromatography (TLC). The process was interrupted during the electrolysis and the anodes (graphite) were washed in THF in order to reactivate it. At the end of electrolysis (~24 h),the product was collected by filtration. The product (6a) was purified by NaOH (0.5 mol/L) and 7a was purified by warm ethanol. After purification,the products were characterized by FT-IR,1H NMR,13C NMR,mass spectroscopy and elemental analysis (CHN).

6a: Yield: 75%. Mp: 165-167 ℃. FT-IR (KBr,cm-1): 3420 and 3370 (doublet,NH2),2192 (CN group),1652 (C=O,amide). 1HNMR (400 MHz,DMSO-d6): δ 2.35 (s,3H,CH3),6.76 (d,1H,J= 8.4 Hz,aromatic),7.60 (d,1H,J= 7.6 Hz,aromatic),8.01 (broad,2H,NH2), 8.25 (s,1H,aromatic),10.41 (broad,1H,NH). 13C NMR (100 MHz, DMSO-d6): δ 27.3,92.3,111.2,118.5,126.2,128.7,132.7,137.2, 143.7,146,168.5. MS (EI,m/z) (relative intensity): 215 (25),190 (40),172 (20),133 (38),121 (100),102 (40),93 (58),77 (100),63 (85),51 (60). Anal. Calcd. for C11H9N3O2: C,61.39; H,4.22; N, 19.53. Found: C,61.28; H,4.27; N,19.64.

7a: Yield: 72%. Mp: >260℃. FT-IR (KBr,cm-1): 3450 (broad, OH),and 3340 (singlet,NH amide),1685 (C=O,amide). 1H NMR (400 MHz,DMSO-d6): δ2.10 (s,6H,2× CH3),6.80 (d,2H,J= 8 Hz, aromatic),7.64 (d,2H,J= 8.8 Hz,aromatic),8.03 (s,2H,aromatic), 10.05 (broad,2H,OH),10.52 (broad,2H,NH). 13C NMR (100 MHz, DMSO-d6): δ18.3,27.16,108.1,118.1,125.4,126.4,132.1,137.1, 147.1,166.3. MS (EI,m/z) (relative intensity): 364 (70),340 (100), 309 (8),284 (50),247 (33),185 (15),158 (32),115 (25),57 (12). Anal. Calcd. for C19H16N4O4: C,62.63; H,4.43; N,15.38. Found: C,62.74; H,4.48; N,15.31.

3. Results and discussion

Cyclic voltammogram of 2 mmol/L paracetamol (1a) in phosphate buffer solution (0.15 mol/L,pH 7) at a glassy carbon electrode is shown in Fig. 1 (curve a). The cyclic voltammogram shows one anodic (A1) and a corresponding cathodic (C1) peak at 0.36 and 0.25 V vs. Ag/AgCl (KCl 3 mol/L) respectively,which corresponds to the transformation of paracetamol (1a) to N-acetylp- benzoquinone-imine (2a) and vice versa within a quasi-reversible two-electron process [7, 8, 9]. A peak current ratio (IpC1/IpA1) of near unity can be considered as a criterion for the stability of Nacetyl- p-benzoquinone-imine (2a) produced at the surface of the electrode under the experimental conditions. The oxidation of paracetamol in the presence of malononitrile (3) as a nucleophile was studied in details. Fig. 1 shows the cyclic voltammogram recorded for a 2 mmol/L solution of 1a in the presence of 2 mmol/L solution of 3 (curve b). The voltammogram exhibits one anodic peak at 0.38 V vs. Ag/AgCl,and the cathodic counterpart of the anodic peak (A1) at 0.14 V vs. Ag/AgCl (C1),which is seen to be decreasing in comparison to the cathodic peak of 1a in the absence of 3.

Fig. 1.Cyclic voltammograms of 2 mM of paracetamol in the absence (a),in the presence of 2 mmol/L of 3 (b),that of a 2 mmol/L of 3 in the absence of 1a (c) at the glassy carbon electrode in phosphate buffer solution (pH 7,0.15 mol/L) at a scan rate of 50 mV/s,T =25±1℃.

The multi cyclic voltammograms of 1a in the presence of 3 was recorded (data shown in Supporting information) and the voltammogram exhibits a decrease in anodic peak A1 current parallel to the shift of this peak in a positive potential. The positive shift of the A1 peak in the presence of 3 is probably due to the formation of a thin film of product at the surface of the working electrode (GC),inhibiting to a certain extent the performance of the electrode process [12, 13].

It is shown that,proportional to the augmentation of the potential scan rate (Fig. 2A) and parallel with the decrease in the rate of chemical reaction,the peak current ratio (IpC1/IpA1) increases (Fig. 2B).

Fig. 2.Typical cyclic voltammograms of 2 mmol/L 1a in the presence of 3 at the glassy carbon electrode,under optimum experimental conditions at different scan rates (10,25,50,100,150,200,300 mV/s,curves a-g) (A). Variation of peak current ratio IpC1/IpA1vs. scan rate for 2 mmol/L 1a in the presence of 2 mmol/L of 3 at scan rates of 10,25,50,100,150,200 and 300 mV/s under experimental optimum condition (B).

The controlled-potential coulometry was performed in phosphate buffer solution (pH 7,0.15 mol/L) containing 2 mmol/L of 1aand 2 mmol/L of 3 at 0.5 V vs. Ag/AgCl. The monitoring of electrosynthesis progress was carried out by cyclic voltammetry. As can be seen in Fig. 3,anodic peak (A1) decreases proportionally to the coulometry advancement. Anodic peak (A1) disappears when the charge consumption becomes about 2e- per molecule of 1a.

Fig. 3.Cyclic voltammogram of 2 mmol/L 1a in the presence of 2 mmol/L of 3,at glassy carbon electrode under experimental condition during controlled-potential coulometry at 0.5 V vs. Ag/AgCl (scan rate: 50 mV/s). Progress of coulometry is associated with decreased anodic peak (A1) current.
3.1. Effect of pH

Electrosynthesis of 6a and 7a were performed in the acidic, neutral and basic media (pH 3-9) and maximum amount of pure product was obtained at pH 7.

3.2. Investigation of mechanism reaction

Regarding to the results,it seems that the 1,4-Michael addition of 3 to N-acetyl-p-benzoquinone-imine (2a) is faster than the other side reaction and leads to the production of intermediates 4a,which is followed by an intramolecular cyclization originating from nucleophilic attacks of OH to CN groups to produce of 6a as electro-synthesis final product under the ECC electrochemical mechanism (Scheme 1). In the case of 7a,the same mechanism leads to formation of 4a as an intermediate. Then,4a can be performed 1,4-Michael-type addition to the paracetamol oxidized (2a),and the reaction stopped. Only four-electrons were consumed in this reaction (2e per molecule of 1a). Therefore,an ECC mechanism for this reaction seems to be rational (Scheme 1). The spectroscopic data confirmed the proposed mechanism for the electrochemical synthesis of 7a product.

Scheme 1.Proposed mechanism of synthesis 6a and 7a.

N-Acetyl-p-benzoquinone-imine (2a) is a bis-Michael acceptor and can be attacked by 3 from two different pathways to yield two types of intermediates (4a and 4b) (Scheme 2). Regarding to the higher stability of negative charge by C=O (carbonyl) group as an electron-withdrawing group,lesser steric hindrance on the structure of 4a in comparison with 4b and as well as due to the Nematollahi researches [14],the path a was proposed in the present work for paracetamol oxidation (1a) in the presence of 3.

Scheme 2.Investigation of mechanism.
4. Conclusion

The main target of the present work was the electrochemical synthesis of valuable new organic compounds (6a,7a) via a simple, fast,green,catalyst-free,one-pot and clean path based on electrooxidation of paracetamol in the presence of malononitrile under mild conditions. Cyclic voltammetry,controlled potential coulometry and spectroscopic data indicate that the electro-oxidation under the ECC mechanism,which is observed in Scheme 1. Safe waste,environmental synthesis,the use of electricity instead of chemical reagents (catalysts),no need of high temperature (reflux), and an one-pot conducted under mild conditions (room temperature and pressure) are features of this work.


The authors would like to thank Semnan University Research Council for financial supports of this work.

Appendix A. Supplementary data

Supplementary data associated with this article can be found,in the online version,at 036.

[1] W.T. Beaver, D. McMillian, Methodological considerations in the evaluation of analgesic combinations: acetaminophen (paracetamol) and hydrocodone in postpartum pain, Br. J. Clin. Pharmacol. 10 (Suppl. 2) (1980) 215S-223S.
[2] D.R. Mehlisch, The efficacy of combination analgesic therapy in relieving dental pain, J. Am. Dent. Assoc. 133 (2002) 861-871.
[3] R.M. Botting, Mechanism of action of acetaminophen: is there a cyclooxygenase 3 Clin. Infect. Dis. 31 (2000) S202-S210.
[4] R.V. Blanke, W.J. Decker, in: N.W. Tietz (Ed.), Textbook of Clinical Chemistry, W.B. Saunders, Philadelphia, 1986.
[5] D. Gunnell, V. Murray, K. Hawton, Use of paracetamol (acetaminophen) for suicide and nonfatal poisoning: worldwide patterns of use and misuse, Suicide Life Threat. Behav. 30 (2000) 313-326.
[6] N. Wangfuengkanagul, O. Chailapakul, Electrochemical analysis of acetaminophen using a boron-doped diamond thin film electrode applied to flow injection system, J. Pharm. Biomed. Anal. 28 (2002) 841-847.
[7] D. Nematollahi, S. Momeni, S. Khazalpour, A green electrochemical method for the synthesis of acetaminophen derivatives, J. Electrochem. Soc. 161 (2014) H75-H78.
[8] A. Amani, S. Khazalpour, D. Nematollahi, Electrochemical oxidation of acetaminophen and 4-(piperazin-1-yl) phenols in the presence of 4-hydroxy-1-methyl-2 (1H)-quinolone, J. Electrochem. Soc. 160 (2013) H33-H40.
[9] E. Tammari, M. Kazemi, A. Amani, Electrochemical oxidation of acetaminophen in the presence of barbituric acid derivatives, J. Electrochem. Soc. 161 (2014) G69-G73.
[10] M. Ameri, A. Asghari, A. Amoozadeh, M. Bakherad, D. Nematollahi, Green and highly efficient synthesis of new bis-benzofurans via electrochemical methods under ECECCC mechanism, J. Electrochem. Soc. 161 (2014) G75-G80.
[11] M. Ameri, A. Asghari, A. Amoozadeh, M. Bakherad, D. Nematollahi, Facile and onepot, electro-organic synthesis of a new bis-quinone by the ECCE mechanism in green media, Chin, Chem. Lett. 25 (2014) 1607-1610.
[12] D. Nematollahi, R.A. Rahchamani, Electrochemical synthesis of p-tolylsulfonylbenzenediols, Tetrahedron. Lett. 43 (2002) 147-150.
[13] D. Nematollahi, R.A. Rahchamani, Electro-oxidation of catechols in the presence of benzenesulfinic acid. Application to electro-organic synthesis of new sulfone derivatives, J. Electroanal. Chem. 520 (2002) 145-149.
[14] D. Nematollahi, H. Shayani-Jam, M. Alimoradi, S. Niroomand, Electrochemical oxidation of acetaminophen in aqueous solutions: kinetic evaluation of hydrolysis, hydroxylation and dimerization processes, Electrochim. Acta 54 (2009) 7407-7415.