Pyridine radical substitution

Qualitatively, the results shown in Tables IV and V indicate that the methyl radical, just as the phenyl radical, substitutes pyridine preferentially in the 2- and 4-positions. The absence of the 3-isomer in these reactions is probably a result of the method of analysis... 

Thus the activity of the methyl groups in this reaction decreases in the series C-4 > C-5 > C-3. This may be considered as evidence of the inhibiting effect of the nitrogen hetero atom on the radical substitution in methyl groups at C-3 and, to a lesser extent, at C-5 (compare the effect of the heterocyclic nitrogen in the pyridine and azole series ) and of a similar effect of the electron-accepting substituents in the 4-position on the methyl group at C-5. 

Free radical substitution of pyridines usually occurs principally at position 2 (Table 25), which is in agreement with theoretical calculations (69CCC1110). 2-Substitution is more favored in methylation than in phenylation of pyridine. This suggests that the methyl has more nucleophilic character than the phenyl radical. Furthermore, methylation of pyridine in acidic solution gives 13-fold excess of 2- over 4-substitution, although the overall yield is low. Alkyl and aryl radicals have been generated from diverse sources (Table 25). 

Homolytic (free-radical) substitution may occur in any of the 2 to 6 positions of pyridine. Thus, the reaction of pyridine with benzene-diazonium salts gives a mixture of 2-, 3-, and 4-phenylpyridine. 

Hydrogen-bonding motifs have also been observed with verdazyl radical-substituted pyridines, which co-crystallize with hydroquinone <2001JA7154>, and with iV-oxide derivatives of pyridine, such as found in co-crystals of 4,4 -bipyridine-iV-oxide and cyclohexanetricarboxylic acid <2005CE0551, 2005CGD1683>, bipyridine-iV-oxides with amino and nitrobenzoic acids <2005CGD727>, and bipyridine-iV-oxides and diphenols <2005CGD1041>. 

Pyridines undergo radical substitution reactions preferentially at the 2-position. Yields and regioselectivity are generally higher if the reaction is carried out in an acid medium. The presence of a strongly electron-donating substituent (OH, OR, NR2) on the pyridine ring can alter the reactivity pattern of electrophilic and radical substitution. 

The free radical substitution reactions, other than phenylation, of pyridine and its derivatives have received but scant attention. Alkylation of pyridine itself has been studied briefly, the alkyl radicals being generated either by the thermolysis of diacyl peroxides or of lead tetraacetate in acetic acid, or by electrolysis of the carboxylic acid precursor (for summary, see Norman and Radda369). Most of the available results are summarized in Table XIV. These figures on isomer ratios are not very reliable since the analyses were carried out by... 

In the photostimulated reaction of SCH2C02Et ions with 2-bromo-3-cyano or 3-bromo-4-cyano pyridines, the substitution product formed is deprotonated, and the anion formed reacts with the cyano group to give ultimately the ring closure substitution products 304 (90%) and 305 (98%), respectively. The yields are high, because in these cases fragmentation of the radical-anion intermediates does not take place288. 

The charge distribution in pyridine leads to deactivation for electrophilic substitution, the least for the position 3 (formation of 3-bromopyridine) at higher temperatures mainly 2-bromo-pyridine is produced by radical substitution. With sodium amide 2-aminopyridine is produced as a nucleophilic substitution reaction. 

Free-Radical Substitutions of Heteroaromatic Compounds R. 0. C. Norman and G. K. Radda The Action of Metal Catalysts on Pyridines G. M. Badger and W. H. F. Sasse... 

The reactions of DPAt and radical cations of other aromatic hydrocarbons with pyridine and substituted pyridines are among the most intensively studied electrode reactions of positive ions. The first definitive study of the mechanism of the reaction employed the rotating disk electrode (Manning et al 1969). Data were found to fit ECE working curves (Fig. 21) for the reactions of DPA7 with 4-cyanopyridine, 4-acetoxypyridine, pyridine and 4-methylpyridine. Pseudo first order rate constants of about 3, 10, 30, 300... 

Regioselective nucleophilic, electrophilic, and radical substitution in pyridines, di-, tri-, and tetrazines 88AHC(44)199. 

Free-radical substitution of pyridines 79ZVK134 89H(28)489 90-JHC79. 

It has also been shown in radical substitution at the 2-position of a series of 4-substituted (CN, MeO, Me) protonated pyridines, that the cyclopropyl radical is the least nucleophilic of the cycloalkyl radicals This low nucleophilicity is consistent with the observed difficulty in oxidizing the cyclopropyl radical by Cu ". The lack of reactivity of the 2-phenylcyclopropyl radical, generated by the thermal decomposition of the 2-phenyl-cyclopropanepercarboxylic acid, towards the 0-0 peracid bond to yield 2-phenylcyclo-propanol is also in line with the radical s weak nucleophilicity However from a study of relative rates of hydrogen abstraction to olefin addition of the cyclopropyl radical to a variety of olefins (Table 7) Stefani and coworkers concluded that the cyclopropyl radical was decidedly nucleophilic. 

Bromination at 450° C hardly occurs, but when the pumice is impregnated with ferrous or cuprous bromide a much better yield of 2,4,6-tribromopyridine is obtained. When pyridine is brominated at 180°C in the presence or absence of impregnated pumice only 2-bromo- and 2,6-dibromopyridine are formed. These facts are not consistent with an electrophilic substitution, which should take place at the 3-position. On the other hand, the high temperature coefficient of the reaction (cf. Table XV) and the fact that ultraviolet light has no effect on the reaction argue against a simple free-radical substitution.140... 

This chapter describes in general terms the types of reactivity found in the typical six- and five-membered aromatic heterocycles. We discuss electrophilic addition (to nitrogen) and electrophilic, nucleophilic and radical substitution chemistry. This chapter also has discussion of orf/to-quinodimethanes, in the heterocyclic context. Organometallic derivatives of heterocycles, and transition metal (especially palladium)-catalysed chemistry of heterocycles, are so important that we deal with these aspects separately, in Chapter 4. Emphasis on the typical chemistry of individual heterocyclic systems is to be found in the summary chapters (7, 10, 13, 15, 19 and 23), and a more detailed examination of typical heterocyclic reactivity and many more examples for particular heterocyclic systems are to be found in the chapters - Pyridines Reactions and Synthesis , etc. 

Radical substitution of pyridines, in acid solution, is a preparatively useful process. For efficient reaction, the radicals must be nucleophilic , like CHaOH, alkyl", and acyl". A hydroxymethylation provides the... 

At temperatures where bromine (500 °C) and chlorine (270 °C) are appreciably dissociated into atoms, 2- and 2,6-dihalo-pyridines are obtained via radical substitution. ... 

Irradiation of iodopyridines generates pyridinyl radicals, which will effect radical substitution of aromatic componnds. Pyridinyl radicals can be generated from halo-pyridines, using tin hydrides, and participate in typical radical cyclisation reactions. Each of the three bromo-pyridines is converted, by tris(trimethylsilyl)silane and azobis(isobutyronitrile), into a radical which substitutes benzene. ... 

Using their CNDO results Helland and Skancke calculated indices of reactivity (frontier electron density, FED, for electrophilic substitution frontier orbital density, FOD, for nucleophilic substitution frontier radical density, FRD, for radical substitution) for the thienopyridines. It was indicated that the FED index has its highest value for C-3 in the [2,3-]- and 3,2- -fused systems and for C-2 in the [3,4-1-fused isomers. As far as the former group is concerned, the predictions are in agreement with experimental observations (see Section IV,A.). Little experimental evidence is available for the [3,4-]-fused systems, but it seems highly probable that they would have a considerable tendency to undergo addition reactions at the 1,3-positions, since the product would contain a normal rather than a quinoid pyridine ring [Eq. (23)]. 

No evidence is available to confirm the predictions that free-radical substitution of [2,3-1- and [3,2]-fused systems will occur at C-3, of the 3,4-6 -isomer at C-l, and of thieno[3,4-c]pyridine at C-3. 

Oxopentylation of heteroaromatics. The oxidation of 1-methylcyclobutanol (ring cleavage) in the presence of pyridine and related substances leads to useful yields of the products. The reaction involves radical substitution on protonated heteroaromatics. Manganese(III) acetate is a comparable reagent. 

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