Oxidation of phenoxazines

Phenoxazines are known to be readily oxidized. According to Musso88 the first stage in the oxidation of phenoxazine with ferric... 

Besides potential pharmacological applications, a number of other uses have been described for phenoxazine derivatives. The semi-quinone radical obtained on oxidation of phenoxazine with various oxidants, which has been shown to give a characteristic absorption at about 530 mp., was used by Sawicki et al.110 in a new method for the spectrophotometric determination of nitrite the aqueous nitrite sample is treated with a 0.1% solution of phenoxazine in glacial acetic acid and the absorbance is read at 530 mp. 

Gripenberg, J., and J. Martikkala Fungus Pigments XIV. On the Oxidation of Phenoxazin-3-ones. Acta Chem. Scand. 19, 1051 (1965). 

Kinetic and spectroscopic studies have been made of the one equivalent metal ion oxidation of phenoxazine and phenothiazine, At2NH, by iron(III) in acetonitrile solutions. The data have been analyzed kinetically using the sequence... 

Oxidation of P-nicotinamide adenine dinucleotide (NADH) to NAD+ has attracted much interest from the viewpoint of its role in biosensors reactions. It has been reported that several quinone derivatives and polymerized redox dyes, such as phenoxazine and phenothiazine derivatives, possess catalytic activities for the oxidation of NADH and have been used for dehydrogenase biosensors development [1, 2]. Flavins (contain in chemical structure isoalloxazine ring) are the prosthetic groups responsible for NAD+/NADH conversion in the active sites of some dehydrogenase enzymes. Upon the electropolymerization of flavin derivatives, the effective catalysts of NAD+/NADH regeneration, which mimic the NADH-dehydrogenase activity, would be synthesized [3]. 

Such reactions are also possible in vitro, as several mild oxidizing agents are at hand nowadays. Thus, the Dess-Martin periodinane (DMP) [50] has been proven to be a versatile and powerful reagent for the mild oxidation of alcohols to the corresponding carbonyl compounds. In this way, a series of new iodine(V)-mediated reactions has been developed which go far beyond simple alcohol oxidation [51], Ni-colaou and coworkers have developed an effective DM P-mediated domino polycy-clization reaction for converting simple aryl amides, urethanes and ureas to complex phenoxazine-containing polycycles. For example, reaction of the o-hydroxy anilide 7-101 with DMP (2 equiv.) in refluxing benzene under exposure to air led to polycycle 7-103 via 7-102 in a yield of 35 % (Scheme 7.28) [52]. 

Sutherland, J.B., Freeman, J.P, Heinze, T.M. et al. (2001) Oxidation of phenothiazine and phenoxazine by Cunninghamella elegans. Xenobiotica The Fate of Foreign Compounds in Biological Systems, 31, 799-809. 

Oxidation of catechol with Ag20 in presence of /3-alanine methyl ester gave a phenoxazine-2,3-dione in low yield, and further condensation with o-phenylenediamine gave the pentacyclic compound 153 [78ZN(C)912],... 

Phenoxazin-3-ones and phenothiazin-3-ones can be prepared by the oxidation of the parent heterocycles in acidic media, but it is often more practical to employ condensation reactions between 2-amino-phenols or -thiols and quinones. Alizarin Green G (263), for example, is obtained from the aminophenol (261) and the 1,2-naphthoquinone (262). Similarly, 2-aminothiophenols (264) and 6-chloro-2-methoxy-l,4-benzoquinone (265) afford phenothiazin-3-ones (266) bearing methoxyl groups at position 1. 

Oxidation of oxalic acid with dimethyl-V,V-dichlorohydantoin and dichloroisocya-nuric acid is of first order with respect to the oxidant. The order with respect to the reductant is fractional. The reactions are catalysed by Mn(II). Suitable mechanisms are proposed.129 A mechanism involving synchronous oxidative decarboxylation has been suggested for the oxidation of a-amino acids with l,3-dichloro-5,5-dimethylhydantoin.130 Kinetic parameters have been determined and a mechanism has been proposed for the oxidation of thiadiazole and oxadiazole with trichloroiso-cyanuric acid.131 Oxidation of two phenoxazine dyes, Nile Blue and Meldola Blue, with acidic chlorite and hypochlorous acid is of first order with respect to each of the reductant and chlorite anion. The rate constants and activation parameters for the oxidation have been determined.132... 

Chemically modified electrodes (CMEs) for electrocatalytic oxidation of the reduced form of the nicotinamide adenine dinucleotide cofactor (NADH) are discussed. The work of the authors in the field is reviewed. CMEs based on adsorbed polyaromatic redox mediators (phenoxazines and phenothiazines) and the deposition of aqueous insoluble redox polymers are described. 

Some of the structures reported from this laboratory for making CMEs for electrocatalytic oxidation of NADH are summarized in Figure 5. We have found that a positively charged paraphenylene-diimine is the best basic catalytic structure (55,83,84-87,89,91,92). When it is incorporated as a part of a phenoxazine or a phenothiazine (see Figure 5) some very beneficial properties are added to the mediator. The E° values are decreased with some 300 to 400 mV compared with the free paraphenylenediimine structure (57,58,102) and they strongly adsorb on graphite electrodes to form CMEs allowing NADH to be electrocatalytically oxidized well below 0 mV (55,83,84-87,89,91,92). 

Gorton and coworkers have been particularly active in this field and produced an excellent review of the methods and approaches used for the successful chemical modification of electrodes for NADH oxidation [33]. They concentrated mainly on the adsorption onto electrode surfaces of mediators which are known to oxidise NADH in solution. The resulting systems were based on phenazines [34], phenoxazines [35, 36] and pheno-thiazines [32]. To date, this approach has produced some of the most successful electrodes for NADH oxidation. However, attempts to use similar mediators attached to poly(siloxane) films at electrode surfaces have proved less successful. Kinetic analysis of the results indicates that this is because of the slow charge transfer between the redox centres within the film so that the catalytic oxidation of NADH is restricted to a thin layer nearest the electrode surface [37, 38]. This illustrates the importance of a charge transfer between mediator groups in polymer modified electrodes. 

This type of mechanism has been proposed for a variety of different NADH oxidation systems, including phenoxazine dyes [35, 36], phenothia-zine dyes [39] and a conducting organic salt [40]. Experimental evidence for the formation of a complex during the chemical oxidation of NADH has been provided by Fukuzumi et al. [41]. These authors showed that a mixture of an NADH model compound and a quinone derivative formed a charge-transfer complex in solution as determined by UV/Vis spectros-... 

Friedel-Crafts reaction of -acetylphenoxazine in carbon disulfide with a large excess of acetyl chloride and aluminum chloride yielded 2,8-diacetylphenoxazine (28), which proved to be identical with the diacetylphenoxazine which was formed by oxidation of 2,8-diethyl-phenoxazine with potassium permanganate (see Section IV,E).61... 

A similar oxidation of 2,8-diethylphenoxazine yields 2,8-diacetyl-phenoxazine,61,82 identical with that obtained by Friedel-Crafts substitution (Section IV, B, 3). 

This method was applied to assemble integrated electrically-contacted NAD(P)-dcpcndcnt enzyme electrodes. The direct electrochemical reduction of NAD(l ) cofactors or the electrochemical oxidation of NAD(P)H cofactors are kineticaUy unfavored. Different diffusional redox mediators such as quinones, phenazine, phenoxazine, ferrocene or Os-complexes were employed as electrocatalysts for the oxidation of NAD(P)H cofactors An effective electrocatalyst for the oxidation of the NAD(P)H is pyrroloquinoline quinone, PQQ, (7), and its immobilization on electrode surfaces led to efficient electrocatalytic interfaces (particularly in the presence of Ca ions) for the oxidation of the NAD(P)H cofactors. This observation led to the organization of integrated electrically contacted enzyme-electrodes as depicted in Fig. 3-20 for the organization of a lactate dehydrogenase electrode. 

Various redox compounds that fulfil catalyst characteristics have been investigated in systems with recycling of NAD by electrocatalytic methods. Quinones, formed either by oxidation of carbon surfaces [143, 145] or adsorbed to the electrode surface [146, 147], phenazines [148, 149], phenoxazine derivatives such as Meldola Blue [182], 9-naphthoyl-Nile Blue [151, 152] and l,2-benzophenoxazine-7-one [153], and also the organic conducting salt N-methyl phenazinium tetracyanoquinodimethanide (TTF TCNQ") [154, 155], ferricinium ions [156, 157] and hexacyanoferrat(IIl) ions [158, 159] can act as catalysts for the electrochemical oxidation of NADH. It is assumed that in corresponding electron-transfer reactions a charge-transfer complex between the immobilized mediator and NADH is formed. The intermediate reduced redox mediator will be reoxidized electrochemically. Most systems mentioned, however, suffer from poor electrode stabilities. 

The actual number of protons taking part in the reduction and oxidation of the mediator depends on the structural elements of the phenoxazine. ... 

The basic understanding of phenoxazines as mediators for NADH-oxidation and as modifiers for preparation of stable CMEs are demonstrated by the work discussed above. The prospects seem therefore to be good to make optimal phenoxazine mediators with high... 

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