Electrosynthesis of Clozapine Drug Derivative via an EC Electrochemical Mechanism

Document Type: Research Paper


1 Department of Chemistry, Faculty of Sciences, Persian Gulf University, Bushehr 75169, Iran

2 Department of chemistry, Payame Noor University (PNU),19395-4697 Tehran, I.R. of Iran


The fact that oxidation, as one of the main routes of phase I metabolism of drugs, follows by conjugation reactions, and also formation of nitrenium ion as one of the clozapine oxidation products, directed us to investigate the oxidation of clozapine (CLZ) in the presence of nucleophile. The oxidation of clozapine (CLZ) has been studied on a glassy carbon electrode in the absence and presence of 2-thiobarbituric acid (TBA) as nucleophile in aqueous medium by means of cyclic voltammetry and on the graphite rods in controlled-potential coulometry. Cyclic voltammetry studies were realized for CLZ in the pHs 1.0 to 8.0. Results indicate that the electrochemical behavior of CLZ depends on the pH. Based on the obtained electrochemical results, an ECE mechanism was proposed to explain the electrochemical oxidation of CLZ. The results revealed that oxidized CLZ participates in Michael type addition reaction with TBA and via an EC mechanism converts to the corresponding new dibenzodiazepin derivatives. The product has been characterized by IR, 1H NMR, 13C NMR and MS.


[1]           A. Mohamed, M. Al-Ghannam Sheikha, IL Farmaco. 59 (2004) 907.

[2]           E. Hammam, A. Tawfik, M.M. Ghoneim, J. Pharmaceut. Biomed. Anal. 36 (2004) 149.

[3]           R. Daghrir, P. Drogui, J. Tshibangu, Electrochim. Acta 131 (2014) 79.

[4]           X. Duana, L. Tianb, W. Liua, L. Chang, Electrochim. Acta 94 (2013) 192.

[5]           E. Tammari, D. Nematollahi, Electroanalysis 23 (2011) 784.

[6]           E. Tammari, M. Kazemi, A. Amani, J. Electrochem. Soc. 161 (2014) G69.

[7]           D. Nematollahi, E. Tammari, J. Org. Chem. 70 (2005) 7769.

[8]           J.-C. Vire, J.-M. Kauffmann, G.J. Patriarche, J. Pharmaceut. Biomed. Anal. 7 (1989) 1323.

[9]           J.-M. Kauffmann, J.-C. Vireand G.J. Patriarche, Bioelectrochem. Bioenerg. 12 (1984) 413.

[10]        P. Perlmutter, Conjugate Addition Reactions in Organic Synthesis, Pergamon, Oxford, 1992.

[11]        T. Ishii, S. Fujioka, Y. Sekiguchi, H. Kotsuki, J. Am. Chem. Soc. 126 (2004) 9558.

[12]        B.A. Frontana-Uribe, R.D. Little, J.G. Ibanez, A. Palma, R. Vasquez-Medrano, Green Chem. 12 (2010) 2099.

[13]        J.B. Sperry, D.L. Wright, Chem. Soc. Rev. 35 (2006) 605.

[14]        S. Khazalpour, D. Nematollahi, Green Chem. 17 (2015) 3508.

[15]        D. Nematollahi, E. Tammari, R. Esmaili, J. Electroanal. Chem. 621 (2008) 113.

[16]        E. Tammari, A. Amani, D. Nematollahi, R. Jalili, M. Kazemi, Res. J. Chem. Environ. 17 (2013) 41.

[17]        M. Kadar, Z. Nagy, T. Karancsi, G. Farsang, Electrochim. Acta 46 (2001) 3405.

[18]        A.J. Bard, L.R. Faulker, Electrochemical Methods: Fundamentals and Applications, 2nd ed., Wiley, New   York, 2001.

[19]        J.M. Kauffmann, G.D. Christian, G.J. Patriarche, Anal. Lett. 12 (B11) (1979) 1217.

[20]        J.M. Kauffmann, G.J. Patriarche, M. Genies, Electrochim. Acta 27 (1982) 721.

[21]        D.J. Miner, J.R. Rice, R.M. Riggin, P.T. Kissinger, Anal. Chem. 53 (1981) 2258.

[22]        E. Tammari, A. Nezhadali, Sh. Lotfi, Electroanalysis 27 (2015) 1693.

[23]        H. Beiginejad, D. Nematollahi, Mo. Noroozi, Sh. Lotfi, J. Iran. Chem. Soc. 12 (2014) 325.

[24]        E. Tammari, Sh. Lotfi, J. Electroanal. Chem. 766       (2016) 162.

[25]        G.G. Hawley, The Condensed  Chemical  Dictionary, New York, YAN, 10th Ed., 1981, p. 104.

[26]        D. Nematollahi, H. Shayani-Jam, M. Alimoradi, S. Niroomand, Electrochim. Acta 54 (2009) 7407.

[27]        N. Frank, A. Bard, A. Led with, J. Electrochem. Soc. 122 (1975) 898.

[28]        A. Alvarez-Lueje, M. Perez, C. Zapata, Topics on Drug Metabolism James Paxton (Ed.), In Tech, Chap. 9, 2012, p. 221.

[29]        S.M. Van Leeuwen, B. Blankert, J.-M. Kauffmann, U. Karst, Anal. Bioanal. Chem. 382 (2005) 742.

[30]        D. Yu, B. Blankert, J.-M. Kauffmann, Biosens. Bioelectron. 22 (2007) 2707.

[31]        D.K. Gosser, Cyclic Voltammetry Simulation and Analysis of Reaction Mechanisms, VCH Publisher Inc., Hoboken, 1993.