Nitration of pyridine-N-oxide

The partial rate factor for nitration of pyridine-N-oxide in the 4 position was estimated as 4x 10"6 which is, therefore, close to that found for the 3 position of pyridine, and 2-phenylpyridine-N-oxide was evaluated as 2xl0-4 times less reactive than benzene from rate measurements in 74.7-78.6 wt. % acid at 25 °C. 

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... 

Rate coefficients have also been calculated for nitration of pyridine N-oxides as the free bases, at 25°C (Table 9.8) [67JCS(B) 1213]. 

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. 

Problem 20.28 Compare, and account for the products formed from nitration of pyridine and of pyridine N-oxide. 

Nitrations of pyridine 1-oxides in the 4-position take place on the neutral free base species. 2,6-Dimethoxypyridine 1-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. Thieno[3,2-/ Jpyridine N-oxide is nitrated by HN03-H2S04 to produce (88) with 63% yield (96CHEC-II(7)199). 

A -Oxide chemistry in these bicyclic systems largely parallels the processes described for pyridine A -oxide, with the additional possibility of benzene ring electrophilic substitution for example, mixed acid nitration of quinoline N-oxide takes place at C-5 and C-8 via the 0-protonated species, but at C-4 at lower acid strength nitration of isoquinoline A -oxide takes place at C-5. Diethyl cyanophosphonate converts quinoline and isoquinoline A -oxides into the 1- and 2-cyanoheterocycles in high yields in a process which must have 0-phosphorylation as a first step, and in which the elimination of diethylphosphate may proceed via a cyclic transition state. ... 

Noteworthy is the higher reactivity of pyridine-N-oxide toward nitration as compared to pyridine, which proceeds in HNO3/H2SO4 (via a-complex 85) to afford 4-nitropyridine-N-oxide (86) ... 

Introduction of methyl groups into the 2- and 6-positions of pyridine-N-oxide does not seem to introduce any adverse steric effect since the maximum number of ligands coordinated remains eight for the perchlorate salts (Vicentini and de Oliveira, 1975). However, only three ligands are coordinated with chloride as the anion and only four with nitrate. 

Nitration with tetranitromethane proceeds along the ion-radical ronte. Tetranitromethane is a smooth nitrating agent and mild oxidizer. It is convenient for nitration of highly activated snbstrates snch as phenols, azulene, and heterocycles in the presence of pyridine, N,iV-dialkylaniline, etc. As shown (Morkovnik 1988), these reactions inclnde one-electron transfer ... 

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. 

Dimethyl pyridine 6 was treated with hydrogen peroxide and 3,5-dimethyl pyridine-N-oxide 7 was produced. Compound 7 was nitrated with a mixture of nitric and sulfuric acids to give 3,5-dimethyl-4-nitropyr-idine-N-oxide 8. Compound 8 was converted to 3,5-dimethyl-4-methox-ypyridine-N-oxide 9 by reaction with methanol. Compound 9 was treated with a mixture of methanol and ammonium dithionite to give 3,5-dimethyl-... 

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... 

Yields in nitrations of a range of hydroxy- and alkoxypyridine A-oxides have been tabulated (70RCR627) as have the activation parameters for various substituted pyridine N-oxides [67JCS(B)1213, 67JCS(B)1235]. 

The method is excellent for the preparation of a-keto esters and a-keto acids. In the examples given (equations 26-28) the a-bromo ester or acid was treated with pyridine N-oxide and silver nitrate at 0 C. Decomposition of the isolated salt with base gave the dicarbonyl compounds in high yield. ... 

Autocatalytic nitration of phenol in a microflow system has been extensively studied Higher yields of nitrophenols were obtained when the nitration of phenol was performed in a microflow system presumably because of enhanced heat exchange and good mixing properties. Very rapid radical propagation in a confined volume also seems to be responsible. The nitration of heteroaromatic compounds, such as pyrazole and indole derivatives, as well as pyridine-N-oxide has also been conducted using a microflow system. ... 

The preferential N-nitration of pyridine would seem to indicate that direct electrophilic C-nitration is difficult to achieve expect in sterically crowded systems and when the nonbonded nitrogen electron pair is occupied such as is the case in pyridine-lV-oxides which are readily nitrated in the 4 position. Pyridinium salts have deactivated rings and are nitrated only with difficulty in the 3 position. 

The transformation shown in equation (27) is inq>ressive since DMSO had pievioasly been tried and shown to fail for this substrate. The reaction was also performed as a one-pot procedure, widi pyridine N-oxide and silver nitrate in acetonitrile followed by addition of triethylamine. This is the preferred method of these authors for these substrates. 

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