Nitration of pyridines

The interest attaching to the nitration of pyridine i-oxide and its derivatives has already been mentioned ( 8.2.5). Some data for these reactions are given in tables 8.1, 8.2 and 8.4. The 4-nitration of pyridine I-oxide is shown to occur through the free base by comparison with the case of i-methoxypyridinium cation ( 8.2.2), by the nature of the rate profile ( 8.2.1), and by consideration of the encounter rate ( 8.2.3). - Some of these criteria have been used to show that the same is true for... 

The nitration of some heterocyclic compounds by nitric acid in sulphuric acid has been studied by Katritzky et al.s0 d and the results are exactly as expected in that electron-supplying substituents in the ring favour reaction on the conjugate acid whereas electron-withdrawing substituents produce reaction on the free base. Rate coefficients and the kinetic parameters for nitration of pyridine derivatives (and some benzene analogues)50 are given in Table 4a. 

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. 

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... 

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. 

The product is 2-amino-5-nitropyridine because substitution occurs preferentially at the sterically less hindered position para to NH,. The conditions are milder than those for nitration of pyridine, because NH is activating. 

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

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... 

Most nitrations of pyridines take place on the A-protonated species, and this includes the conversion of 2,6-dimethoxypyridine to the 3-nitro derivative. However, the further nitration of 2,6-dimethoxy-3-nitropyridine to the 3,5-dinitro derivative occurs on the free base. The introduction of the first nitro group reduces the basicity such that sufficient free base is now present for the reaction to take place through this minority species. 2,6-Dihalopyridines also undergo nitration as free base. 

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). 

Electrophilic substitution occurs at the 3 and 5 positions, but usually requires drastic conditions because the species actually being attacked is a pyndinium ion. For example, nitration of pyridine with KNUj and concentrated H2SO4 at 300°C gives a 15% yield of 3-nilropyridine. Electrophilic substitution in the pyridine ring is facilitated by the presence of electron-donating substituents. 

As shown in the previous section, N-alkyl nitroanilines 23 are obtained in the reaction of pyridone 1 with ketones 22 in the presence of amines. In this case, amines are introduced as the dialkylamino substituents. On the contrary, different reactivity is observed when ammonia is used instead of amines. The TCRT reaction proceeds to afford 2,3-dialkyl-5-nitropyridines 24 upon treatment of pyridone 1 with ketones 22 in the presence of ammonia (Table 2) [42,43]. The C4 - C5 - C6 unit is derived from pyridone 1, the C2 - C3 unit is derived from ketone, and the ring nitrogen (Nl) is from ammonia, namely the new ring consists of three components. As electrophilic nitration of pyridines is quite difficult, the present TCRT will be an alternative method for preparation of nitropyridine derivatives. 

Table 3 Nitration of pyridine and substituted pyridine with N2O5/SO2...

Table 4 Nitration of pyridine and substituted pyridines with nitric acid/TFAA and sodium metabisulfite...

Pyridine is virtually inert to aromatic electrophilic substitution. Consider nitration of pyridine by nitric acid. First, as pyridine is a moderate base, it will be almost completely protonated by the acid, making it much less susceptible to electrophilic attack. Second, addition of the electrophile to the small amount of unprotonated pyridine present in solution is not a facile process. 

Attack of the electrophile at the C2 or C4 position results in an intermediate cation with partial positive charge on the electronegative nitrogen atom. This is clearly not energetically favourable when compared to C3 substitution, where no partial positive charge resides on nitrogen. In fact the product of C3 substitution, nitropyridine 5.15, can be isolated from the exhaustive nitration of pyridine, but only in poor yield. 

Nitration of pyridines via rearrangement of nitramines has been studied. 4-Amino-3-bromopyridine forms, with nitric acid, the nitramine 9.67 in 85% yield 9.67 rearranges in sulfuric acid to 4-amino-3-bromo-5-nitro-pyridine (9.68) in 97% yield (62RC967). The rearrangement of 2-nitrami-no-4-nitropyridine (9.69) to 2-amino-3,4-dinitropyridine is accompanied by the formation of 4-nitro-2-pyridone (64T81), subsequently shown to arise via nitrosation (79T2895). 

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

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]. 

Propose a mechanism for nitration of pyridine at the 4-position, and show why this orientation is not observed. 

Suzuki H., Iwaya M., Mori T. C-Nitration of pyridine by the kyadai-nitration modified by the Bakke procedure. A simple route to 3-nitropyridine and meehanistic aspect of its formation. Tetrahedron Lett. 1997 38 (32) 5647-50. 

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