Nitration of pyridine A-oxides

This improves reactivity towards electrophiles. Consideration of resonance structures shows positions 2, 4, and 6 are now electron rich. Nitration of pyridine A-oxide occurs at C-4 very little 2-nitration... 

Calculated Free-Base Rate Coefficients for Nitration of Pyridine A -Oxides"... 

Nitrations of pyridine A-oxides at the 4-position take place on the neutral free base species. 2,6-Dimethoxypyridine A-oxide is nitrated as the conjugate acid to yield the 3-nitro derivative a second nitration to give the 3,5-dinitro analogue takes place on the free base. 

The preferred position for electrophilic substitution in the pyridine ring is the 3 position. Because of the sluggishness of the reactions of pyridine, these are often carried out at elevated temperatures, where a free radical mechanism may be operative. If these reactions are eliminated from consideration, substitution at the 3 position is found to be general for electrophilic reactions of coordinated pyridine, except for the nitration of pyridine-N-oxide (30, 51). The mercuration of pyridine with mercuric acetate proceeds via the coordination complex and gives the anticipated product with substitution in the 3 position (72). The bromina-tion of pyridine-N-oxide in fuming sulfuric acid goes via a complex with sulfur trioxide and gives 3-bromopyridine-N-oxide as the chief product (80). In this case the coordination presumably deactivates the pyridine nucleus in the 2 and... 

Electrophilic nitration and bromination of pyridine A -oxides can be controlled to give 4-substituted products " by way of attack on the free Af-oxide. Under conditions where the A -oxide is O-protonated, substitution follows the typical pyridine/pyridinium reactivity pattern thus, in fuming sulfuric acid, bromination shows / -regioselectivity, mercuration, however, takes place at the a-position. ... 

Af-Oxide chemistry in these bicyclic systems largely parallels the processes described for pyridine 7V-oxide, with the additional possibility of benzene ring electrophilic susbstitution, for example mixed acid nitration of quinoline A -oxide takes place at C-5 and C-8 via the O-protonated species, but at C-4 at lower acid strength nitration of isoquinoline A/ -oxide takes place at C-5. ... 

The explanation once again can be found in resonance theory. This is illustrated in Scheme 6.23 with the nitration of pyridine N-oxide. Resonance form 6.11 has tetravalent N bearing a positive charge, which is a stable form of N. 

An example of the application of this test to a compound that nitrates as its free base is provided by pyridine 1-oxide. Under an identical set of conditions, nitration of this N-oxide had a half life of 20 min, whilst 1-methoxypyridinium gave no nitro compound in 144 h. Two further criteria have been used to provide confirmatory evidence, namely comparison of the rate of nitration for the reactive species with the encounter controlled rate, and by determination of the Arrhenius parameters. 

Nitration of pyridines in other than nitric or sulfuric acids is of little interest here because either no reaction or N-nitration takes place (see Section 2.05.2.10). However, pyridine 1-oxide is considerably more reactive and treatment with benzoyl nitrate ultimately leads to the 3-nitro derivative (Scheme 25) (60CPB28). Annelation of a benzene ring bestows greater reactivity on the 3-position in quinoline, compared with pyridine, and reaction with nitric acid in acetic anhydride furnishes the 3-nitro derivative (ca. 6%) (Scheme 26). This isomer has also been obtained, again at low yield (6-10%), by treatment of quinoline with tetranitratotitanium(IV) in carbon tetrachloride (74JCS(P1)1751>. Nitration of benzo analogues of pyridine occurs much more readily in the benzene ring, and Chapter 2.06 should be consulted for these reactions. 

As has already been mentioned in Section II, pyridine A-oxide is much more susceptible to electrophilic attack than is pyridine. Nitration with fuming nitric acid in sulfuric acid at 90° or with potassium nitrate or nitric acid in fuming sulfuric acid at 100-130° gives up to 90% yields of 4-nitropyridine A-oxide together with a small amount of the 2-isomer (formation of 2-isomer reported by... 

The pyrazine mono-iV-oxides show close similarity in their reactions to the pyridine AT-oxides.402-404 In the latter compounds the electronreleasing ability of the iV-oxide function is demonstrated by the activation of the a- and y-ring carbon atoms to electrophilic attack. Pyrazine mono-AT-oxides are predictably less activated to electrophilic substitution, and thus there have been no reports of the successful nitration of pyrazine /V-oxides. The pyrazine ring is, however, activated by the A-oxide function to nucleophilic attack, especially if the positive charge of the N atom is enhanced by formation of an intermediate with an electron acceptor. Thus, phosphoryl chloride treatment of pyrazine 1-oxide yields chloropyrazine391 and similar... 

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