Pyridine derivatives electrophilic aromatic substitution

Results on the intramolecular arylation on a 5H-indeno[l,2-b]pyridine derivative, which proceeded selectively at the pyridine ring, are also inconsistent with an electrophilic aromatic substitution mechanism for this reaction [37]. 

The reaction of quinoline (78) with bromine and sulfuric acid gives a bromi-nated quinoline derivative via reaction with Br+, but where Note that quinoline is a base, and it will react with sulfuric acid to form an ammonium salt. Remember that pyridine is much less reactive than benzene in electrophilic aromatic substitution reactions. Therefore, assume that the ring containing nitrogen is much less reactive. This leaves C5-C8 as potential sites for electrophilic substitution. Indeed, 78 reacts with bromine and srdfuric acid to give a mixture of 5-bromoquinoline and 8-bromoquinoline, with 5-bromoquinoline being the major product. ... 

There is another important factor in the low reaetivity of pyridine derivatives toward eleetrophilie substitution. The —N=CH— unit is basie beeause the electron pair on nitrogen is not part of the aromatic u system. The nitrogen is protonated or complexed with a Lewis acid under many of the conditions typical of electrophilic substitution reactions. The formal positive charge present at nitrogen in such species further reduces the reactivity toward electrophiles. 

Recently37, the importance of CT complexes in the chemistry of heteroaromatic N-oxides has been investigated in nucleophilic aromatic substitutions. Electron acceptors (tetracyanoethylene and p-benzoquinones) enhance the electrophilic ability of pyridine-N-oxide (and of quinoline-N-oxide) derivatives by forming donor-acceptor complexes which facilitate the reactions of nucleophiles on heteroaromatic substrates. 

Subsequent protic workup releases the aromatic compound. The metalative Reppe reaction can also be used to prepare iodo-substituted or homologated aromatics by treatment of the titanium aryl compound with iodine or an aldehyde, respectively. This procedure has recently been extended to include pyridine derivatives (254 and 255), where the titanacyclopentadiene intermediate can be treated with sulfonylnitriles to afford pyridines after protic workup.192 As with the alkyne cyclotrimerizations, treatment with the appropriate electrophiles affords iodo- and homologated pyridines. 

Consequently, pyridine has a reduced susceptibility to electrophilic substitution compared to benzene, while being more susceptible to nucleophilic attack. One unique aspect of pyridine is the protonation, alkylation, and acylation of its nitrogen atom. The resultant salts are still aromatic, however, and they are much more polarized. Details for reactivity of pyridine derivatives, in particular, reactions on the pyridine nitrogen and the Zincke reaction, as well as C-metallated pyridines, halogen pyridines, and their uses in the transition metal-catalyzed C-C and C-N cross-coupling reactions in drug synthesis, will be discussed in Section 10.2. 

An aryne multicomponent reaction involving isoquinoline and 5-bromo-1-methylisatin resulted in spirooxazino isoquinolines (Scheme 66).The reaction occurs with a number of iV-substituted isatins. Quinoline can replace the isoquinoline as well. Carbonyls other than the isatins can trap the anion as well. A variety of aromatic, aliphatic, and heteroaromatic aldehydes can function as the electrophile. When pyridine replaces isoquinoUne as the nucleophilic trap, the reaction forms an oxindole but not an oxazino pyridine derivative (14SL608). 

The reactivity of pyridine derives from its dual nature as both an aromatic molecule and a cyclic imine. Both electrophilic and nucleophilic substitution processes may occur, leading to a variety of substituted derivatives. 

The most widespread method of introducing nitro group in aromatic compounds, i.e., electrophilic substitution, is mainly used for the preparation of nitrodiazoles and benzazoles. The accumulation of pyridine nitrogen atoms in the cycle reduces the electrophilic substitution ability of compounds. Therefore, some indirect methods of introducing the nitro group are employed for the synthesis of triazole and tetrazole nitro derivatives. 

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. 

Dihydro compounds are often useful synthetic intermediates showing different reactivity patterns to the parent, aromatic heterocycle. For example, indolines (2,3-dihydroindoles) can be used to prepare indoles with substituents in the carbocyclic ring, via electrophilic substitution then aromatisation (20.16.1.17), and similarly, electrophilic substitutions of dihydropyridines, very difficult in simple pyridines, followed by aromatisation, can give substituted pyridines. Dehydrogenation of tetra- and hexahydro-derivatives reqnires more vigorous conditions. 

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