Heterocycles, electrophilic substitution review

In this section three main aspects will be considered. Firstly, the basic strengths of the principal heterocyclic systems under review and the effects of structural modification on this parameter will be discussed. For reference some pK values are collected in Table 3. Secondly, the position of protonation in these carbon-protonating systems will be considered. Thirdly, the reactivity aspects of protonation are mentioned. Protonation yields in most cases highly reactive electrophilic species. Under conditions in which both protonated and non-protonated base co-exist, polymerization frequently occurs. Further ipso protonation of substituted derivatives may induce rearrangement, and also the protonated heterocycles are found to be subject to ring-opening attack by nucleophilic reagents. 

For monographs, see Taylor, R. Electrophilic Aromatic Substitution Wiley NY, 1990 Katritzky, A.R. Taylor, R. Electrophilic Substitution of Heterocycles Quantitative Aspects (Vol. 47 of Adv. Heterocycl. Chem.) Academic Press NY, 1990. For a review, see Taylor, R. in Bamford Tipper Comprehensive Chemical Kinetics, vol. 13 Elsevier NY, 1972, p. 1. 

For a review of electrophilic substitution on five-membered aromatic heterocycles, see Marino, G. Adv. Heterocycl. Chem., 1971, 13, 235. 

A review covering homologation of heterocycles via lithiation-based reductive ring opening, electrophilic substitution, and cyclization includes applications to 2,7-dihydro benzothiepine derivatives <06AHC135>. 

Electrophilic substitution is much easier than in benzene. Thiophene reacts about as readily as mesitylene pyrrole and furan react as readily as phenol or even resorcinol. Electrophilic substitution of heterocycles has been reviewed (86HC(44/2)l), (90AHC(47)87), and the following conclusions were reached ... 

This review was originally intended to cover electrophilic substitution in phenyl-substituted heterocycles in general. However, it was decided to concentrate on nitration since this provides the substantial majority of studies in this area. It is the only reaction that seems to have been systematically investigated to any extent and is the only reaction for which there are data for a wide range of phenyl-substituted heterocycles. The literature has been searched to 1991. However, few references have been found in the last 5 years. 

The heterocyclic literature is enormous, and a significant fraction deals with electrophilic substitution reactions of heteroaromatics. A great many authors have provided quantitative data, but the data are scattered through the literature, rarely reviewed comprehensively, and still less interpreted. Indeed, a proper interpretation is possible only by taking the wider view. This is what this book is intended to provide. It has been found possible not only to give interpretations of all of these quantitative data—in many cases for the first time—but to consider, additionally, much of the semiquantitative and qualitative work on the electrophilic substitution of heterocycles. 

In this review we have gathered the important work on quantitative and mechanistic aspects of electrophilic aromatic reactivity of heterocycles. We have concentrated in particular on acid-catalyzed hydrogen exchange, nitration, and gas-phase elimination, these being the major efforts of our own research groups. However all other electrophilic substitution reactions are covered for completeness. 

This chapter is concerned with the electrophilic substitution of pyridaz-ine, pyrimidine, pyrazine, and their derivatives. Aspects of this topic have been reviewed previously [72AHC( 14)99 74AHC(16)1] and the general chemistry of the monocyclic azines has been surveyed in Comprehensive Organic Chemistry, Vol. 4 (1979) and Comprehensive Heterocyclic Chemistry, Vol. 3 (1984). 

Electrophilic substitution is an important type of reactions for five-membered heterocycles with one heteroatom and enables compounds with various substituents to be obtained. The present work is devoted to certain features of substrate and positional selectivities in electrophilic substitution reactions of derivatives of pyrrole, furan, thiophene and selenophene, and also the corresponding benzannulated systems, which had not been explained until recently. In a recent review (05RKZ(6)59), these problems were mainly discussed for thiophenes, while in a previous review (94H(37)2029) only monocyclic pyrrole, furan and thiophene derivatives were considered. 

In the meantime, several reviews of the chemistry of heterocyclic compounds appeared that in part cover aspects of pyridazine chemistry. They include syntheses and reactivity of pyridazinones and pyridazines, electrophilic substitutions on pyridazines, conversion of pyridazines to other compounds, photochemistry of N-oxides, hindered rotation in reduced acylpyridazines and azidotetrazolo isomerizations. ... 

Quinazolinamines with the amino groups in the heterocyclic ring are prepared by the same sort of reactions as reviewed for pyrimidines. Amination, by way of electrophilic substitution, for example, by nitration or nitrosation in the carbocyclic ring, is substituent dependent and may have to be carried out in a precursor before formation of the quinazoline ring system. 

Electrophilic substitution of thiophene has been expertly reviewed by Taylor <86HC(44/2)l>. In addition, a whole monograph has b n devoted to the compilation and analysis of quantitative data on electrophilic substitution of heterocycles <90AHC(47)87>. The highlights from the conclusions reached in the section on thiophene are presented below. 

Nevertheless, such reactions catalyzed by zeolites have been discussed in the review of 2001 (1) isomerization (double-bond shift, isomerization of tricyclic molecules, like synthesis of adamantane, isomerization of terpenes, diverse rearrangements, conversion of aldehydes into ketones), (2) electrophilic substitution in arenes (alkylation of aromatics, including the synthesis of linear alkylbenzenes, alkylation and acylation of phenols, heteroarenes and amines, aromatics nitration and halogenation), (3) cyclization, including the formation of heterocycles, Diels-Alder reaction, (4) nucleophilic substitution and addition,... 

Several reviews have been published on electrophilic homocyclic and heterocyclic aromatic substitution. Other reviews and books of relevance include polychloro-aromatic compounds, annulenes and related compounds, cyclobutadiene-metal complexes/ substitution via heteroaromatic N-oxide rearrangements/ 7T-excessiveness in heteroaromatic compounds/ and special topics in heterocyclic chemistry. The book by Jones and Bean is a mine of information on pyrrole chemistry. ... 

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