Alkyl pyridines electrophilic substitution

Pyridine lies near one extreme in being far less reactive than benzene toward substitution by electrophilic reagents. In this respect it resembles strongly deactivated aromatic compounds such as nitrobenzene. It is incapable of being acylated or alkylated under Friedel-Crafts conditions, but can be sulfonated at high temperature. Electrophilic substitution in pyridine, when it does occur, takes place at C-3. 

The presently known electrophilic substitution reactions all occur at the 4-position of the isoxazole nucleus, corresponding to the j3-position in pyridine. Thus the influence of the nitrogen atom is predominant. The introduction of alkyl and, particularly, aryl substituents into the isoxazole nucleus markedly increases its reactivity (on the other hand, during nitration and sulfonation the isoxazole nucleus also activates the phenyl nucleus). 

The range of preparatively useful electrophilic substitution reactions is often limited by the acid sensitivity of the substrates. Whereas thiophene can be successfully sulfonated in 95% sulfuric acid at room temperature, such strongly acidic conditions cannot be used for the sulfonation of furan or pyrrole. Attempts to nitrate thiophene, furan or pyrrole under conditions used to nitrate benzene and its derivatives invariably result in failure. In the case of sulfonation and nitration milder reagents can be employed, i.e. the pyridine-sulfur trioxide complex and acetyl nitrate, respectively. Attempts to carry out the Friedel-Crafts alkylation of furan are often unsuccessful because the catalysts required cause polymerization. 

Only a few investigations of electrophilic substitution reactions of pseudo-azulenes containing a pyrrole-type nitrogen have been reported. There are many examples of alkylations (see Table VI). An alkylation always takes place at the nitrogen of the five-membered ring. For 7H-pyrrolo[2,3-b]-pyridine 68 azocoupling and reaction with dithiolium salts have been reported.166... 

Within the limits imposed there exists a number of available procedures for introducing alkyl substituents onto the pyridine ring. All of these involve either nucleophilic or homolytic substitution since alkylation via electrophilic substitution, e.g. Friedel Crafts alkylation, is not possible with the TT-deficient pyridine nucleus. 

Pyridinium salts show the properties that have been discussed above, but in extreme, thus they are highly resistant to electrophilic substitution but, conversely, nucleophiles add very easily. Especially useful are the adducts formed from iV" -C02R salts with alkyl- or aryllithiums (see above). The hydrogens of pyridinum a- and y-alkyl side-chains are further acidified compared with an uncharged alkyl pyridine. 

Comparatively little is known about other electrophilic substitution reactions of pyridine. Exceptions are activated systems, e.g. 3-hydroxypyridine 23 which undergoes azo-coupling, carboxylation and hydroxymethylation. Its 0-ethyl ether 24 can be ring-alkylated by a Friedel-Crafts method [49] ... 

Reactions of dibenzopyridines show analogies with pyridine, quinoline and isoquinoline. Acridine and phenanthridine are A-protonated by strong protic acids, iV-alkylated by alkyl halides and A-oxidized by peroxy acids. Electrophilic substitutions of acridine often result in disubstitution at the 2- and 7-positions (e.g. nitration giving 3), whereas those of phenanthridine occur at different positions (e.g. nitration mainly at the 1- and 10-position yielding 4 and 5) ... 

Reactions of pyridazine also show analogies to pyridine [136]. Electrophiles attack the ring N-atoms, for instance in protonation, alkylation or A -oxidation. S Ar reactions at the ring C-atoms are difficult to carry out, even in the presence of activating substituents due to the deactivation by the additional N-atom. However, iV-oxidation facilitates the substitution in some cases. 

The alkylation of pyridine [110-86-1] takes place through nucleophilic or homolytic substitution because the 7C-electron-deficient pyridine nucleus does not allow electrophilic substitution, eg, Friedel-Crafts alkylation. Nucleophilic substitution, which occurs with alkali or alkaline metal compounds, and free-radical processes are not attractive for commercial applications. Commercially, catalytic alkylation processes via homolytic substitution of pyridine rings are important. The catalysts effective for this reaction include boron phosphate, alumina, silica—alumina, and Raney nickel (122). 

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