Pyridone nitration

Activating substitutents, i.e. groups which can release electrons either inductively or mesomerically, make the electrophilic substitution of pyridine rings to which they are attached faster, for example 4-pyridone nitrates at the 3-position via the O-protonated salt. In order to understand the activation, it is helpful to view the species attacked as a (protonated) phenol-like substrate. Electrophilic attack on neutral pyridones is best visualised as attack on an enamide. Dimethoxypyridines also undergo nitration via their cations, but the balance is often delicate, for example 2-aminopyridine brominates at C-5, in acidic solution, via the free base. ... 

It is found in practice that for a number of compounds reacting ma the predominant species an almost horizontal plot is obtained. For compounds presumed to be nitrated via the free bases, such as 2,6-lutidine i-oxide and 3- and 5-methyl-2-pyridone, slopes of approximately unity are obtained. Since this type of plot allows for the incomplete ionisation of nitric acid, it can be used at higher acidities than plots using — ( H + logio Hjo) which break down when the condition is no longer true. 

The similarity of their rate profiles, and the similarity of their rate constants for nitration at a particular temperature and acidity show that 4-pyridone, i-methyl-4-pyridone, and 4-methoxypyridine are all nitrated as their cations down to about 85 % sulphuric acid. The same is true of 2-methoxy-3-methylpyridine. In contrast, 3- and 5-methyl-2-pyridone, i,5-dimethyl-2-pyridone and 3-nitro-4-pyridone all react... 

The 2-nitration of 3-hydroxy- and 3-methoxy-pyridine in 85-96% sulphuric acid involves the conjugate acids, whilst the 3-nitration of 6-hydroxy and 6-methoxy-2-pyridone in 70-77 % sulphuric acid involves the free bases, which react at, or near to the encounter rate. ... 

By contrast, the rate-acidity profiles for nitration of 3-nitro-4-pyridone, 3-and 5-methyl-2-pyridone and l,5-dimethyl-2-pyridone resemble each other and differ from the above-indicated reaction upon the free base, and correction of the observed rates to allow for the concentration of free base actually present gave rate-acidity profiles of the expected form the corrected entropies of activation then turned out to be positive. Furthermore, if the logarithms of the corrected rate coefficients obtained in media of low acidity were plotted against +log aHlQ, then slopes of near unity were obtained (see above, p. 18), but not otherwise. A similar result was obtained from the nitration data for 4-pyridone in media of low acidity suggesting that here it reacts as the free base. A further test which was applied was to calculate the concentration of nitronium ions in the various media and to correct the observed rate coefficients for this the logarithms of these coeffi-... 

Methoxy-2-(l//)-pyridone (12 g, 96 mmol) was dissolved in 280 mL of water containing 3.84 g (96 mmol) of sodium hydroxide. A solution of silver nitrate (16.32 g, 96 mmol) in 64 mL of water was added. The mixture was vigorously stirred at room temperature for 10 min. After filtration, the solid was washed with MeOH and ether, dried in vacuo to give 21 g of silver salt in 94% yield. 

The nitration of 6-phenyl-2-pyridone (70% nitric acid or nitronium tetra-fluoroborate at RT) produces 3-nitro-6-phenyl-2-pyridone (up to 60% yield). However, nitration at 90°C with 70% nitric acid is reported to give 3-nitro-6-(4-nitrophenyl)-2-pyridone (36%), whereas at 90°C acetyl nitrate yields 50% of a mixture of 3- and 5-nitro-6-phenyl-2-pyridone (72KGS1374). 

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. 

Several pieces of evidence can be used to determine whether the nitration of a given substrate occurs through the conjugate acid (SH+) or through the small amount of neutral substrate in equilibrium with it these approaches include the determination of the rate profile and comparisons with the reactivities of model compounds (Ridd, 1971b). From such evidence, it appears that a number of nitration reactions involve the small amount of neutral substrate in equilibrium with the conjugate acid the substrates include 2,6-dichloropyridine, pyridine-1-oxide, l-methylpyrazole-2-oxide, 3-methyl-2-pyridone, acetophenone and p-nitroaniline. These reactions have been reviewed recently (Hoggett et al., 1971 see especially Chap. 8). However, for the majority of these substrates, the... 

Pyridone is one of the compounds for which the encounter rate criterion for choosing between nitration via the free base or by the conjugate acid is ambiguous ( 8.2.3). 

By the condensation of cyanoacetamide and ethoxyacetylace-tone (35-38). The resulting 3-cyano-4-ethoxymethyl-6-raethyl-2-pyridone (I) was nitrated to give nitorpyridone (II). The sequence of reactions of this route may be represented graphically (Route 1). 

Nitration of 4-pyridone 5.23 gives 5.28, and reaction with phosphorus oxychloride affords chloropyridine 5.29. This pyridone-chloropyridine conversion activates the system to nucleophilic attack by hydrazine, affording 5.30. The nitro group also facilitates nucleophilic attack by delocalisation of negative charge in the intermediate. 

Nitration of 2-pyridone, originally thought to give mainly 3-nitro-2-pyridone (47) together with some 3,5-dinitro-2-pyridone (48) and a trace of the 5-nitro derivative (49),123 was later shown to give a mixture of 47 and 48.124 Similarly, reaction of 6-methyl-2-pyridone with nitric acid in glacial acetic acid gave the product of nitration at C-3 (50).125 This preferential ortho-nitration is in marked contrast to... 

Pyridone undergoes mono- and dinitration at the /8-positions very readily.131-133 Nitration of 2,4-dihydroxypyridine (which probably exists in the 2-pyridone form, 55) occurs under very mild conditions and yields the 3-nitro product 56.134,135 If C-3 is blocked by a carb-ethoxyl group, nitration at C-5 takes place very readily.138,137 Unlike the monohydroxypyridines, which do not react with nitrous acid, 2,6-dihydroxypyridine (presumably mainly 6-hydroxypyrid-2-one) undergoes nitrosation at C-3.138... 

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). 

Nitration of 4-pyridone takes place on the free base, except at high acidity where the protonated species is involved [68JCS(B)1477]. 4-Pyri-done is less reactive than 2-pyridone toward nitration (Table 9.7), a result which contrasts with hydrogen exchange where the reactivities are identical Table 9.1). As expected, nitration of 3-nitro-4-pyridone also occurs on the free base [68JCS(B) 1477]. From this work, partial rate factors of 10 10 to 10"12 were calculated for the monocations derived from 4-pyridone and 2- and 4-methoxypyridine deactivation by NH+ in these systems was estimated as >1013 [68JCS(B)1477]. 

The similarities in rate of nitration for the uracils suggest that they are all nitrated in the dioxo forms [log /r2(fb) at 40-50°C at H0 - 10.26 uracil, 1,3 1,3-dimethyluracil, 1.7 6-methyluracil, 1.9]. 2,4-Dimethoxypyrimid-ine is slower by a factor of 104. Whereas pyrimidin-2(l//)-one and its 1-methyl derivative also react as the free bases, the rates are much lower than those of the corresponding uracils [log /c2(fb) at 115°C at H0 -9.27 for pyrimidin-2(l//)-one is 8.1 for the 1-methyl derivative the value is 8.8], and 100 times slower than 3-methyl-2-pyridone. These results reflect the deactivating effect of a second annular nitrogen and the presence of only one oxo function [71JCS(B)1]. 

---