Benzene ring, electrophile

In compounds with a fused benzene ring, electrophilic substitution on carbon usually occurs in the benzenoid ring in preference to the heterocyclic ring. Frequently the orientation of substitution in these compounds parallels that in naphthalene. Conditions are often similar to those used for benzene itself. The actual position attacked varies compare formulae (341)-(346) where the orientation is shown for nitration sulfonation is usually similar for reasons which are not well understood. 

Electrophilic substitution usually occurs preferentially in the aryl group. In compounds containing both an aryl group and a fused benzene ring, electrophiles usually attack the aryl group exclusively. 

Af-Oxide chemistry in these bicyclic systems largely parallels the processes described for pyridine 7V-oxide, with the additional possibility of benzene ring electrophilic susbstitution, for example mixed acid nitration of quinoline A -oxide takes place at C-5 and C-8 via the O-protonated species, but at C-4 at lower acid strength nitration of isoquinoline A/ -oxide takes place at C-5. ... 

Laurino examined a similar method in which methanesulfonanilides were alkylated with bromoacetaldehyde diethyl acetal and then cyclized with TiCU[4J. 1 hese methods presumably involve generation of an electrophilic intermediate from the acetal functionality, followed by an intramolecular Friedel-Crafts reaction. As a consequence, the cyclization is favoured by ER substituents and retarded by EW groups on the benzene ring. 

In conclusion, in terms of electrophilic reactivity a methyl group in the 2-position is equally reactive in the two categories of heterocycles (selenazole and thiazole). Of the two positions ortho to nitrogen, only the 2-position is activated. The 5-position is sensitive to electrophilic reagents and resembles more closely the para position of a benzene ring. 

Nitration by electrophilic aiomatic substitution is not limited to benzene alone but IS a general reaction of compounds that contain a benzene ring It would be a good idea to write out the answer to the following problem to ensure that you understand the rela tionship of starting materials to products m aromatic nitration before continuing to the next section... 

Attack of an unsubstituted benzene ring can lead to only one monosubstitution product. However, when electrophilic attack occurs at a benzene ring already containing a group, there are three possible sites of attack. 

Quantitative data are available on the effect on electrophilic substitution reactions of the fusion of a benzene ring to the b face of a furan or thiophene ring. The overall effect is to decrease reactivity this decrease is much more pronounced in the case of fusion to a furan than to a thiophene ring. As a consequence the overall reactivities of benzo[Z)]furan and benzo[Z)]thiophene are approximately equal 71AHC(13)235). 

Azoles containing a free NH group react comparatively readily with acyl halides. N-Acyl-pyrazoles, -imidazoles, etc. can be prepared by reaction sequences of either type (66) -> (67) or type (70)->(71) or (72). Such reactions have been carried out with benzoyl halides, sulfonyl halides, isocyanates, isothiocyanates and chloroformates. Reactions occur under Schotten-Baumann conditions or in inert solvents. When two isomeric products could result, only the thermodynamically stable one is usually obtained because the acylation reactions are reversible and the products interconvert readily. Thus benzotriazole forms 1-acyl derivatives (99) which preserve the Kekule resonance of the benzene ring and are therefore more stable than the isomeric 2-acyl derivatives. Acylation of pyrazoles also usually gives the more stable isomer as the sole product (66AHCi6)347). The imidazole-catalyzed hydrolysis of esters can be classified as an electrophilic attack on the multiply bonded imidazole nitrogen. 

In benz- and phenyl-azolones, electrophilic substitution often occurs in the benzene ring such reactions are considered as reactions of substituents (see Sections 4.02.3.2.1 and 4.02.3.4.1). 

Having its pyrazolic 4-position substituted, electrophilic attack on indazoles takes place in the 3-position and in the homocycle (the 5- and 7-positions). The condensation of a benzene ring results in a decrease of the aromaticity of the pyrazole moiety, as in naphthalene compared to benzene, and therefore basic ring cleavage is easier in indazoles than in pyrazoles (Section 4.04.2.1.7(v)). 

In the section dealing with electrophilic attack at carbon some results on indazole homocyclic reactivity were presented nitration at position 5 (Section 4.04.2.1.4(ii)), sulfon-ation at position 7 (Section 4.04.2.1.4(iii)) and bromination at positions 5 and 7 (Section 4.04.2.1.4(v)). The orientation depends on the nature (cationic, neutral or anionic) of the indazole. Protonation, for instance, deactivates the heterocycle and directs the attack towards the fused benzene ring. A careful study of the nitration of indazoles at positions 2, 3, 5 or 7 has been published by Habraken (7UOC3084) who described the synthesis of several dinitroindazoles (5,7 5,6 3,5 3,6 3,4 3,7). The kinetics of the nitration of indazole to form the 5-nitro derivative have been determined (72JCS(P2)632). The rate profile at acidities below 90% sulfuric acid shows that the reaction involves the conjugate acid of indazole. 

Both 1,2- and 2,1-benzisothiazoles react with electrophiles to give 5- and 7-substituted products (see Section 4.02.3.2). The isothiazole ring has little effect on the normal characteristics of the benzene ring. C-Linked substituents react almost wholly normally, the isothiazole ring having little effect except that phenyl substituents are deactivated (see Section 4.17.2.1). There are, however, considerable differences in the ease of decarboxylation of the carboxylic acids, the 4-isomer being the most stable (see Section 4.02.3.3). 

An 5-l-/w-nitrophenyl-2-benzoylethyl thioether was used to protect thiophenols -during electrophilic substitution reactions of the benzene ring. ... 

The polycyclic aromatic hydrocarbons such as naphthalene, anthracene, and phenan-threne undergo electrophilic aromatic substitution and are generally more reactive than benzene. One reason is that the activation energy for formation of the c-complex is lower than for benzene because more of the initial resonance stabilization is retained in intermediates that have a fused benzene ring. 

Section 12.1 On reaction with electrophilic reagents, compounds that contain a benzene ring undergo electrophilic aromatic substitution. Table 12.1 in Section 12.1 and Table 12.3 in this summai-y give exanples. 

Meta director (Section 12.9) A group that when present on a benzene ring directs an incoming electrophile to a position meta to itself. 

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