Electrochemical Oxidation of 4‐Methyl‐1,4‐dihydropyridines in Protic and Aprotic Media. Spin Trapping Studies

Abstract

This work reports the electrochemical oxidation of a new series of 4‐methyl‐1,4‐dihydropyridine derivatives with platelet activation factor antagonistic activity. Differential pulse and cyclic voltammetry studies on a glassy carbon electrode showed an irreversible single peak due to the oxidation of the dihydropyridine ring via two electrons. Rotating disk electrode studies show a linear dependence between the current and the rotating rate, indicating that the oxidation process is diffusion‐controlled. Calculated diffusion coefficients did not exhibit significant differences between the derivatives. Voltammetric apparent normalpKnormala values for the protonation‐deprotonation equilibrium of the N‐heterocyclic nitrogen are compared with 4‐phenyl substituted 4‐aryl‐1,4‐dihydropyridine (1,4-DHP) derivatives. Based on voltammetric experiments on glassy carbon electrodes, it is seen that the potential peak values are directly related to the electron density on the dihydropyridine ring, wherein C-5 substituent with electron‐withdrawing character produces the most oxidizable 1,4-DHP derivative. The oxidation mechanism follows the general pathway: electron, H+ , electron, H+ , with formation of an unstable cation radical in the first step. A one‐electron oxidation intermediate was confirmed with controlled potential electrolysis and electron spin resonance experiments. On applying N‐benzilydene‐t‐butylamine‐N‐oxide as the spin trap, the unstable radical intermediates from the oxidation of 4‐methyl‐1,4‐dihydropyridine derivatives were intercepted. Comparison of the electron spin resonance spectra of the nitroxide spin adducts revealed no significant differences in the splitting constants of the radicals. © 1999 The Electrochemical Society. All rights reserved.

Electrolytic Oxidation of C4-Nitrofuryl 1,4-Dihydropyridines in Nonaqueous Medium

“…On the other hand, the aromatization of the 1,4-dihydropyridine ring to the corresponding pyridine derivative constitutes the most important in vivo reaction to terminate the pharmacological effect in the current clinically used drugs. 37 Finally, on the basis of findings presented here and other previous studies 27,29,31,33,34 Scheme 2 concerning the oxidation mechanism in an aprotic medium can be postulated. This mechanism is supported by two experimental facts: ͑i͒ the generation of the neutral dihydropyridyl radical intermediates C-centered was demonstrated by the trapping of these species with PBN and their characteristic spin adducts were determined by the ESR technique for the three compounds and ͑ii͒ the pyridine derivatives were identified by GC-MS as the final oxidation products in the aprotic medium.…”

“…3c͒ is in good agreement with the experimental one. In previous work 27,33 on the electro-oxidation of 1,4-DHP derivatives, the formation of different types of radical intermediates was discussed. Primarily, a radical cation PyH +• is formed and, after its deprotonation, a neutral radical Py • ͑dihydropyridyl radical͒ is formed.…”

“…21,22 Investigations dealing with the electrochemical oxidation of some 1,4-DHPs have previously been performed in both nonaqueous [23][24][25][26] and aqueous media. [27][28][29] We recently reported 30 the synthesis and electrochemical oxidation of some new 3,5-͑substituted͒-4-͑5Ј-nitro-2Ј-furyl͒-1,4-DHP derivatives in a protic medium. In that paper, a detailed study in aqueous medium on the electro-oxidation of these compounds is reported.…”

Reactivity of 1,4-Dihydropyridines toward Alkyl, Alkylperoxyl Radicals, and ABTS Radical Cation

“…Oxidation of DHPs and Its Reactivity with Free Radicals. The electrooxidation process of DHPs is an ECEC type of mechanism, i.e., the sequence: e, H+, e, H+ ( − ). The electrochemical oxidation of the DHP compounds generates as the final product the pyridine derivative ().…”

Substituent Effects on the Electrochemistry and Photostability of Model Compounds of Calcium Channel Antagonist Drugs

“…These molecules contain two different redox centers, a nitro group capable of electroreduction, and a dihydropyridine moiety capable of electro-oxidation. Investigations dealing with the electrochemical oxidation of some DHPs have previously been performed in both nonaqueous and aqueous [4][5][6][7][8][9] media but the investigations are mostly related with the electroreduction of the nitroaromatic group. [10][11][12][13][14][15][16] The presence of the nitro group in their structures is not essential for pharmacological activity but it confers to them relevant electronic and toxicological characteristics.…”