Typical Reactivity of Pyridines, Quinolines and Isoquinolines

Before detailed descriptions of the chemistry of the heterocyclic systems covered in this book, and at intervals during the book, we provide six highly condensed and simplified discussions of the types of reaction, ease of such reactions, and regiochemistry of such reactions for groups of related heterocyles. In this chapter the group comprises pyridine, as the prototype electron-poor six-membered heterocycle and its benzo-fused analogues, quinoline and isoquinoline. As in each of these summary chapters, reactions are shown in brief and either as the simplest possible example, or in general terms. 

Electrophilic substitution of aromatic compounds proceeds via a two-step sequence - addition (of X ) then elimination (of H ), of which the former is usually the slower (rate-determining) step. Qualitative predictions of relative rates of substitution at different ring positions can be made by inspecting the structures of the cr-complexes 

Electrophilic substitution at carbon, in simple pyridines at least, is very difficult in contrast to the reactions of benzene - Friedel-Crafts acylations, for example, do not occur at all with pyridines. This unreactivity can be traced to two factors  

Substituents exert an influence on the ease of electrophilic attack, just as in benzene chemistry. Strongly electron-withdrawing substituents simply render the pyridine even more inert, however activating groups - amino and oxy, and even alkyl - allow substitution to take place, even though by way of the protonated heterocycle i.e. via a dicationic intermediate. The presence of halogen substituents, which have a 

Pyridine rings are resistant to oxidative destruction, as are benzene rings. In terms of reduction, however, the heterocyclic system is much more easily catalytically reduced, especially in acidic solution. Similarly, A -alkyl- and A -arylpyridinium salts can be easily reduced both with hydrogen over a catalyst, and by nucleophilic chemical reducing agents. 

The electron-deficiency of the carbons in pyridines, particularly a- and y-car-bons, makes nucleophilic addition and, especially nucleophilic displacement of halide (and other good leaving groups), a very important feature of pyridine chemistry. 

The formal replacement of a CH in benzene by N leads to far-reaching changes in typical reactivity pyridines are much less susceptible to electrophilic substitution than benzene and much more susceptible to nucleophilic attack. However, pyridine undergoes a range of simple electrophilic additions, some reversible, some forming isolable products, each involving donation of the nitrogen lone pair to an electrophile, and thence the formation of pyridinium salts which, of course, do not have a counterpart in benzene chemistry at all. The ready donation of the pyridine lone pair in this way does not destroy the aromatic 

Heterocyclic Chemistry 5th Edition John Joule and Keith Mills 2010 Blackwell Publishing Ltd 

Pyridines react with eiectrophiles by donation of the nitrogen lone pair 

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The main body of factual material is to be found in chapters entitled Reactions and synthesis of... a particular heterocyclic system. Didactic material is to be found partly in advanced general discussions of heterocyclic reactivity and synthesis (Chapters 3, 4 and 6), and partly in six short summary chapters (such as Typical Reactivity of Pyridines, Quinolines and Isoquinolines Chapter 7), which aim to capture the essence of that typical reactivity in very concise resumes. These last are therefore suitable as an introduction to the chemistry of that heterocyclic system, but they are insufficient in themselves and should lead the reader to the fuller discussions in the Reactions and Synthesis of. .. chapters. They will also serve the undergraduate student as a revision summary of the typical chemistry of that system. 

This chapter describes in general terms the types of reactivity found in the typical six-and five-membered aromatic heterocycles. In addition to discussions of classical substitution chemistry, considerable space is devoted to radical substitution, metallation and palladium-catalysed reactions, since these areas have become very important in heterocyclic manipulations. In order to gain a proper appreciation of their importance in the heterocyclic context we provide an introduction to these topics, since they are only poorly covered in general organic text-books. Emphasis on the typical chemistry of individual heterocyclic systems is to be found in the summary/revision chapters (4, 7, 10, 12, 16, and 20) 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. For the advanced student, it is recommended that this present chapter should be read in its entirety before moving on to the later chapters, and that the introductory summary/revision chapters, like Typical reactivity of pyridines, quinolines and isoquinolines should be read before the more detailed discussions. 

The reactivity of methyl groups in the 2- or 4-position of quinoline, and in the I-position of isoquinoline, is also observed in the analogous thienopyridines. 7-Methylthieno 2,3-c pyridine, for example, undergoes the typical reactions shown in Scheme 18.48... 

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