Michael D. Ryan

The Electrochemical Oxidation of Substituted Catechols

The oxidation of substituted catechols was studied by cyclic voltammetry, chronoamperometry, rotating ring-disk electrode, and coulometry. The results showed that the quinones that were formed from the oxidation of substituted catechols reacted with the basic forms of the starting material to yield the dimeric product. These products were generally unstable and rapidly polymerized or underwent some other irreversible reaction to form an electroinactive product. For 3,4-dihydroxyacetophenone and propriophenone, the intermediate was stable long enough to be observed in cyclic voltammetry. The rate of the coupling reaction was found to correlate well with the Hammett P-q parameters and indicated that there was substantial negative charge in the transition state. Finally, an analysis of the coulometric n-values along with the iat1/2/C values indicated that the initial coupling product was a diphenyl ether. Analysis of the coulometry products showed extensive polymerization.

Mechanism of antibacterial action: Electron transfer and oxy radicals

Most of the main categories of bactericidal agents, namely, aliphatic and heterocyclic nitro compounds, metal derivatives and chelators, quinones, azo dyes, and iminium-type ions, are proposed to exert their action by a unified mechanism. The toxic effect is believed to result generally from the catalytic production of reactive oxygen radicals that usually arise via electron transfer. Cyclic voltammetry was performed on a number of these agents. Reductions were for the most part reversible, with potentials in the favorable range of -0.20 to -0.58 V.

Cyclic voltammetry of phenazines and quinoxalines including mono- and di-N-oxides. Relation to structure and antimicrobial activity

Cyclic voltammetry data were obtained for eight phenazines and phenazine-N-oxides, and eleven quinoxalines and quinoxaline-N-oxides: 1,6-phenazine-diol-5,10-dioxide (iodinin), iodinin copper complex, 6-methoxy-1-phenazinol-5,10-dioxide 1,6-dimethoxyphenazine-5-oxide, 1,6-phenazinediol, 1,6-dimethoxyphenazine, quinoxaline-1,4-dioxide, 2-methylquinoxaline-1,4-dioxide, 2,3-diphenylquinoxaline-1,4-dioxide, 2-carboxyquinoxaline-1,4-dioxide, 5-hydroxyquinoxaline-1,4-dioxide, 5-hydroxy-8-methoxyquinoxaline-1,4-dioxide, 2-methylquinoxaline, 2,3-diphenylquinoxaline, 5-hydroxyquinoxaline, 5-hydroxy-8-methoxyquinoxaline and 2-(2-quinoxalinylmethylene)hydrazine carboxylic acid methyl ester-1,4-dioxide (Carbadox). The di-N-oxides exhibit the most positive E1/2 values within each class. Reversible first wave reductions were observed for iodinin, iodinin copper complex, 1,6-dimethoxyphenazine-5-oxide, 1,6-dimethoxyphenazine, quinoxaline-1,4-dioxide, 2-methylquinoxaline-1,4-oxide and 2,3-diphenylquinoxaline-1,4-dioxide. The results are correlated with structure. Some relationships exist between reduction potential and reported antimicrobial activity. A possible mechanism of drug action is addressed.

An integrated concept of amebicidal action: electron transfer and oxy radicals.

Cyclic voltammetry data were obtained for most of the main categories of antiamebic agents, specifically, quinones, heterocyclic nitro compounds, metal derivatives and chelators, and iminium-type ions. The reductions (our data and literature values) were for the most part reversible, with potentials usually in the favorable range of +0.10 to -0.56 V. The drug effect is believed to result generally from the catalytic production of oxidative stress usually arising from the formation of superoxide via electron transfer. In addition, relevant literature data are provided.

The electrochemical reduction of iron porphyrin nitrosyls in the presence of weak acids

Abstract The reduction of coordinated nitrosyls to ammonia in assimilatory nitrite reductases consists of a series of electron transfer/ protonation steps. Very little detail is known about these steps, either from the enzyme itself or model complexes. In this work, the mechanism for the reduction of iron nitrosyl complexes, which are nitrite reductase models, was examined in solutions with limited proton availability. In this way, the reduction mechanism can be investigated in a system which has been shown quantitatively to produce ammonia. The reduction mechanism was investigated for the reduction of Fe(P)(NO), where P is porphyrins, hydroporphyrins or oxoporphyrins, in the presence of substituted phenols using pulse polarography. In THF, the limiting current for the first wave (wave I) was unaffected by the presence of phenol, while the half-wave potential shifted to positive potentials at high concentrations of phenol. The shift in E 1 2 of the first wave, E 1 2 ,I, was consistent with a mechanism which involved the protonation of Fe(TPP)(NO)− with two protons to form Fe(TPP)(NH2O+). From the variation in the half-wave potential, the equilibrium constant for the formation of Fe(TPP)(NH2O+) from Fe(TPP)(NO)− was measured for a series of phenols. The chemical and electrochemical reversibility of the first wave in the presence of phenol was verified by the Nernstian shape of the waves, by square-wave voltammetry, and by shifts caused by the presence of phenolate ion. The reduction in the presence of 2,6-dichlorophenol was an exception in that only one proton was transferred. In addition to the changes in the first wave, a new wave was observed between the first and second waves of Fe(TPP)(NO). This new wave corresponded to a three-electron reduction of Fe(TPP)(NO)−. The kinetics of this reduction were monitored using normal pulse polarography. The behavior of the new wave in the presence of phenol was consistent with a CE mechanism which involved two phenol molecules in equilibrium with Fe(TPP)(NO) − to form Fe(TPP)(NH2O+) prior to the electron transfer. The rate constant for the reduction was measured for all the phenols for which the equilibrium constant for the formation of Fe(TPP)(NH2O+) could be measured. Changes in the macrocycle from porphyrin to isobacteriochlorin led to a significant increase in the rate of nitrosyl reduction, while the rate decreased substantially for the oxoporphyrins. Most of the changes in the rate of nitrosyl reduction were consistent with changes in the basicity of the Fe(P)(NO)− complex. It is interesting to note that Fe(P)(NH2O+), the reactive intermediate, was formed most readily for the assimilatory nitrite reductase models (iron isobacteriochlorins), and least readily for the dissimilatory nitrite reductase models (iron dioxo-isobacteriochlorin).

Cyclic voltammetry with cyclic iminium ions: Implications for charge transfer with biomolecules (metabolites of nicotine, phencyclidine, and spermine)

Abstract Recently, the theory was advanced that the iminium species plays a widespread role in living systems as a charge transfer agent. Cyclic voltammetry was applied to model compounds, 3,4-dihydro-1,5-dimethyl-2H-pyrrolium perchlorate 2 and 3,4-dihydro-1-methyl-5-phenyl-2H-pyrrolium chloride 3 , in order to provide reference data. Compounds 2 and 3 gave reductions with E p = −1.11 and −0.98 V, respectively, vs SCE (DMF). Reactions were also carried out in water and benzonitrile. Resonance and inductive effects are used to rationalize the data. Iminium ions 5, 12, and 18 are intermediary oxidative metabolites of nicotine 6 , the hallucinogenic drug phencyclidine 8 , and spermine 17a , respectively. Reduction potentials are −1.04, −0.93, and −1.10 V, respectively. It is suggested that electon transfer mediated by iminium moieties may be related to biological activity. Examples are presented of electrochemically reducible iminium compounds which exhibit physiological activity in a variety of areas.

Charge transfer mechanism for benzodiazepine (BZ) action: Correlation of reduction potential of BZ iminium with structure and drug activity

Abstract A novel mechanism for BZ action is proposed in which a BZ is protonated by GABA or protein RNH3+ to yield an iminium species that is responsible for drug activity via charge transfer (c.t.). The following evidence from our work and prior studies supports this concept: • binding sites for BZs and GABA are apparently on the same protein complex; data point to possible interaction between the two ligands; • recent theoretical studies propose reaction of basic imine of BZ with cationic RNH3+ of protein at the receptor site; • BZ is protonated by weak acids, such as acetic and GABA, to give iminium ions which exhibit appreciable and favorable increases in reduction potential in vitro; • the reduction potentials are of the same order of magnitude as for a number of other biologically active compounds; • reversible electron uptake has been shown to occur with some protonated BZ drugs; |Up - Up/2| calculations from the voltammograms of some BZs indicate the potential for reversible electrochemical processes; • correlations exist involving reduction potential of BZ iminium, structure, and drug activity; • a significant number of BZ agonists, inverse agonists, and antagonists incorporate the imine-type precursor of iminium; • the postulated c.t. pathway is in keeping with a variety of bioelectrochemical phenomena arising from active site binding.

Oxidative Ionic Metabolites of L-Methyl-4-Phenyl-L, 2, 3, 6-Tetrahydropy-Ridine (MPTP): Correlation of Electro-Reduction with Physiological Behavior

Electrochemical studies (reduction potential and reversibility) were performed on 1-methyl-4-phenylpyridinium (MPP+) and 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP+). MPP+ gave reduction potentials in the range of -1.09 to -1.11 V in organic solvents in a process which was reversible. The reduction potential of MPDP+ was -0.64 V (irreversible). Possible relationships involving the electrochemical properties, oxy radical formation, and biological activity of these and related iminium species are discussed.

Reduction potentials of anthelmintic drugs: Possible relationship to activity

Electrochemical data were acquired for several categories of anthelmintic agents, namely, iminium-type ions, metal derivatives and chelators, quinones and iminoquinones, and nitroheterocycles. Reductions usually were in the favorable range of +0.2 to -0.7 V versus normal hydrogen electrode. The drug effect is believed to result in part from either the catalytic production of oxidative stress or disruption of helminth electron transport systems. Relevant literature results are discussed.

Conjugated and cross-conjugated mesomeric betaines. correlation of electroreduction with structure and physiological activity

Electroreduction studies were performed on several cross-conjugated mesomeric betaines containing the fused pyrazolium (2) and fused imidazolium (3) ring systems. Studies at acidic pH were of principal interest. Substituent effects for 2 were in line with prior findings, and reduction potentials were comparatively negative (-0.96 to -1.34 V). Reduction potentials fit the modified Hammett equation. Compound 3 was more readily reduced (-0.88 V). The related psi-oxatriazoles (6) gave values in the range of -0.85 to -1.22 V. The electrochemical characteristics are compared with those of the mesoionic sydnones (4) and sydnoneimines (5). These mesoionic compounds were generally reduced at more positive potentials than 2 and 3. A relationship between electroreduction and physiological activity is proposed. The overall results are in keeping with the hypothesis of widespread participation of iminium-type species in biological systems.