Oxidation of pyridines

Riboflavin was first isolated from whey in 1879 by Blyth, and the structure was determined by Kuhn and coworkers in 1933. For the structure determination, this group isolated 30 mg of pure riboflavin from the whites of about 10,000 eggs. The discovery of the actions of riboflavin in biological systems arose from the work of Otto Warburg in Germany and Hugo Theorell in Sweden, both of whom identified yellow substances bound to a yeast enzyme involved in the oxidation of pyridine nucleotides. Theorell showed that riboflavin 5 -phosphate was the source of the yellow color in this old yellow enzyme. By 1938, Warburg had identified FAD, the second common form of riboflavin, as the coenzyme in D-amino acid oxidase, another yellow protein. Riboflavin deficiencies are not at all common. Humans require only about 2 mg per day, and the vitamin is prevalent in many foods. This vitamin... 

Pyridine-N-oxide has been prepared by oxidation of pyridine with perbenzoic acid,4 with monoperphthalic acid,6 with peracetic acid (hydrogen peroxide and acetic acid),6-7 and with hydrogen peroxide and other carboxylic acids.7... 

Figure 6.5 Substitution on the ring of an O-methyl-N-oxide of pyridine.

SCHEME 154. Oxidation of pyridine derivatives using MTO/H2O2... 

Oxidation of pyridines with BTSP in the presence of catalytic amounts of inorganic rhenium derivatives gives high yields of their analytically pure N-oxides by simple workups, typically a filtration or a Kugelrohr distillation (equations 59-61). ... 

Only very powerful nucleophilic reagents such as HO-, NHJ, RLi, LAH, etc., react effectively at the ring carbon atoms of simple pyridines (c/. equation 22), and even then forcing conditions may be required. Oxidation of pyridine to 2-pyridone with potassium hydroxide, for example, requires a temperature of ca. 300 °C. Nevertheless, some of these reactions can be of very considerable synthetic importance, especially the classical Chichibabin reaction for the preparation of 2-amino, alkylamino and hydrazino heterocycles (equation 28). The sequence of substitution is C-2, then C-6 and finally C-4. The Chichibabin reaction also requires rather vigorous conditions and often proceeds in only moderate yield the simplicity of the approach, however, is such that it often represents the method of choice for the preparation of the requisite substituted heterocycle. 

Antimony pentachloride complexes of A-oxides of pyridine, quinoline and isoquinoline rearrange on heating to give the corresponding pyrid-2-one, carbostyril or isocarbostyril, e.g. Scheme 118 (81T1871). 

Proposed Mechanisms for Reduction Reactions. Any mechanism proposed for the reduction of niobium(V) halides with pyridine must incorporate the necessary two-electron oxidation-reduction step required for the oxidation of pyridine to l-(4-pyridyl) pyridinium ion. In view of the known acid properties of the niobium(V) halides and the rapid reaction of the tantalum (V) halides to give 1 to 1 pyridine adducts, the mechanism must also include the initial coordination of pyridine to the niobium(V) halide. The reduction might then proceed through the steps shown opposite. 

The existence of a substituted pyridine molecule such as III was considered as a probable intermediate for the oxidation of pyridine to l-(4-pyridyl) pyridinium ion by thionyl chloride (10). The authors believe the mechanism of the reaction with thionyl chloride to be similar to that proposed here, but further discussion of... 

In a number of earlier studies the oxidation of NADH or NADPH was assayed under conditions (acid pH, Mn ) in which there was a large component of what appears to be a chain reaction propagated by free radicals Under these conditions it is difficult to be certain how much of the formation of O and of the oxidation of pyridine nucleotides was due to turnover of the enzyme and how much was due to the chain reaction. 

Deoxygenation of N-oxides,4 TiCl4 -NaBH4 (1 2) in DME reduces the N-oxide of pyridine and mcthylpyridines (picolines) to the corresponding heterocycles in high yield. However the N-oxide of quinolines and isoquinolines is reduced further to dihydro derivatives of the hetcrocyclcs. Pyridine, quinoline, and isoquinoline themselves are not reduced by this low-valent titanium species. Reduction of heterocyclic N-oxides with TiCI, has been reported (6, 588). 

Oxidative reactions of pyridines are commercially more interesting than reductive ones because catalytic hydrogenation of pyridines is a generally useful method, whereas catalytic oxidation is not. In contrast, anodic oxidation of pyridines is widely applicable and can replace methods that use expensive oxidants such as permanganate salts or chromic oxide. Consider, as an example, oxidation of a methylpyridine to produce 1 kg of the pyr-idinecarboxylic acid this process would consume about 3 worth of potassium permanganate at 100% efficiency and would produce 0.7 kg of byproduct Mn02 for disposal or recycle. The same anodic reaction would consume only 0.30 of electrical power (for oxidation) and would not produce a significant amount of material for disposal. 

Very little work has been done on selectivity in anodic reactions of pyridines. Selective methoxylation and acetoxylation are known for al-kylbenzenes, but such reactions have not been reported for alkylpyridines. Also, reports on the oxidation of pyridines having aldehyde, ketone, halogen, hydroxyalkyl, or aminoalkyl functionalities are sparse. 

The reaction depicted also proceeds between pyridine oxide in its neutral form and the double amount of benzophenone metal-ketyl. Pyridine bases (not N-oxides) do not react with the ketyls. The N-oxides of pyridine and y-picoline give both the N-oxide of the pyridyl carbinol and the pyridyl carbinol without the N-oxide oxygen. Yields can be 70 and 80%, respectively (depending on the metal nature in the metal-ketyl). Having pronounced physiological activity, these compounds are the key materials in syntheses of atropine-like drugs. 

Aki, S. and Abraham, M., Catalytic supercritical water oxidation of pyridine comparison of catalysts, Indust. Eng. Chem. Res., 38(2), 358-367, 1999. 

Oxidation of Pyridines Fe203-catalyzed direct oxidation of pyridine by combined use of molecular oxygen (latm) and isovaleraldehyde in 1,2-dichloroethane gives pyridine N-oxide in 89% isolated yield [145]. Isovaleraldehyde was converted into the corresponding acid under the reaction conditions (Scheme 3.44). 

Scheme 3.44 Fe203-catalyzed oxidation of pyridine to its N-oxide.

Figure 9-11. The oxidation of pyridine-2(l//)-thione with an excess of copper(n) gives the corresponding disulfide.

As shown in the literature [96, 97], at low-temperatures liquid hydrogen peroxide participates in N-oxidation of pyridine bases, and the process is catalyzed by organic acids and their anhydrides. 

A hydrogen peroxide and acetic acid mixture is also used in the following reactions carbon-carbon bond break [50], aromatic hydrocarbon and phenol oxidation to n-quinones [51], 2,6-dihaloanilines oxidation to nitroso-compounds and synthesis of N-oxides of pyridine... 

Coulombe, R.A.J., D.R Briskin, R.J. Keller, W.R. Thomley, and R.P. Sharma. 1987. Vanadate-dependent oxidation of pyridine nucleotides in rat liver microsomal membranes. Biochim. Biophys. Acta 255 267-273. 

One-electron oxidation of pyridine (V-oxides with lead tetraacetate gives (V-oxide radical cations (Equation 39) <2002RJC729>. 

Jin L, Abraham MA. Low temperature catalytic oxidation of 1,4-dichloro-benzene. Ind Eng Chem Res 1991 30 89-95 Aki S, Abraham MA. Catalytic supercritical water oxidation of Pyridine comparison of catalysts. Ind Eng Chem Res 1999 38 358-367. 

The reaction of a Grignard reagent with quaternary salts obtained from. V-oxides of pyridine, quinoline, and their homologs has been utilized401,402 for the preparation of 2-alkylated compounds. 

Yamaguchi, K., Mizugaki,T., Ebitani, K. and Kaneda, K. (1999). Heterogeneous N-oxidation of pyridines using a combined oxidant of hydrogen peroxide and nitriles catalysed by basic hydrotalcites. New J. Chem. 23, 799. 

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