For electrophilic aromatic substitution reactions

If the Lewis base ( Y ) had acted as a nucleophile and bonded to carbon the prod uct would have been a nonaromatic cyclohexadiene derivative Addition and substitution products arise by alternative reaction paths of a cyclohexadienyl cation Substitution occurs preferentially because there is a substantial driving force favoring rearomatization Figure 12 1 is a potential energy diagram describing the general mechanism of electrophilic aromatic substitution For electrophilic aromatic substitution reactions to... 

Figure 12.1 is a potential energy diagram describing the general mechanism of electrophilic aromatic substitution. For electrophilic aromatic substitution reactions to... 

Resole syntheses entail substitution of formaldehyde (or formaldehyde derivatives) on phenolic ortho and para positions followed by methylol condensation reactions which form dimers and oligomers. Under basic conditions, pheno-late rings are the reactive species for electrophilic aromatic substitution reactions. A simplified mechanism is generally used to depict the formaldehyde substitution on the phenol rings (Fig. 7.21). It should be noted that this mechanism does not account for pH effects, the type of catalyst, or the formation of hemiformals. Mixtures of mono-, di-, and trihydroxymethyl-substituted phenols are produced. 

SbCls has been used as a Lewis acid catalyst for electrophilic aromatic substitution reactions. Treatment of benzene with CI2 and NOCl, then molten SbCls (135-145 °C) gives chlorobenzene [5]. 

Section 15.9 General Mechanism for Electrophilic Aromatic Substitution Reactions... 

In looking at vancomycin and teicoplanin, the hydroxyls are but one choice for functionalization reactions. Each natural product also possesses electron-rich arenes, which may be platforms for electrophilic aromatic substitution reactions. In parallel studies of enantioselective and atropisomer-selective bromination reactions [161-164], we were gaining experience with catalyst-controlled bromina-tions, and we wondered whether these might be extended to site-selective reactions. We speculated that an appropriately positioned Lewis base, such as a dimethyl amide unit, could assist in the delivery of electrophilic bromine... 

Heterocycles are aromatic compounds, and they undergo aromatic substitution reactions similar to reactions of aromatic hydrocarbons (see Chapter 21, Section 21.3). In some cases, electrophilic aromatic substitution reactions are faster than benzene due to the presence of the heteroatom, but in other cases the reaction is slower. In other words, the nature of the heteroatom and the size of the ring have a profound influence on the rate of reaction as well as the site of reaction. The basic principles of reactivity and regioselectivity in these cases are governed by the same fundamental principles discussed for benzene derivatives in Chapter 21. For electrophilic aromatic substitution reactions of heterocycles, a cationic intermediate is formed however, the presence of the electron-rich heteroatom must be taken into account. The major site of substitution in this reaction is the one that gives the more stable intermediate. 

The problem is somehow to relate the differences in e (inferred from relative rate data) to a number based on quantum chemical calculations. To do this in a sensible way requires that we have some idea of the detailed way in which the reaction proceeds-we have to know what the reaction coordinate is. In some cases, this is fairly well known. For electrophilic aromatic substitution reactions, evidence suggests that a... 

THE GENERAL MECHANISM FOR ELECTROPHILIC AROMATIC SUBSTITUTION REACTIONS... 

For the sake of clarity, only one of the three resonance contributors of the carbocation intermediate is shown in this and subsequent mechanisms for electrophilic aromatic substitution reactions. Bear in mind, however, toat each carbocation intermediate actually has the three resonance contributors shown in Section 19.3. 

Although it has been reported in a Molecular Modelling study that the formation of a formyl dication (HCOH ) by the action of HF/SbFs on CO is associated with extremely high activation energy, this species has been proposed by several authors as the active electrophile in formylation reactions utilising CO and HF/SbFs. The formation of a formyl dication could, therefore, also be invoked as plausible explanation for electrophilic aromatic substitution reactions in case of full protonation of both CO and the aromatic substrate by the HF/BF3 super acid (Eq 2.24). 

Now that we ve outlined the general mechanism for electrophilic aromatic substitution we need only identify the specific electrophile m the nitration of benzene to have a fairly clear idea of how the reaction occurs... 

Because the carbon atom attached to the ring is positively polarized a carbonyl group behaves m much the same way as a trifluoromethyl group and destabilizes all the cyclo hexadienyl cation intermediates m electrophilic aromatic substitution reactions Attack at any nng position m benzaldehyde is slower than attack m benzene The intermediates for ortho and para substitution are particularly unstable because each has a resonance structure m which there is a positive charge on the carbon that bears the electron withdrawing substituent The intermediate for meta substitution avoids this unfavorable juxtaposition of positive charges is not as unstable and gives rise to most of the product... 

The orbital and resonance models for bonding in arylamines are simply alternative ways of describing the same phenomenon Delocalization of the nitrogen lone pair decreases the electron density at nitrogen while increasing it m the rr system of the aro matic ring We ve already seen one chemical consequence of this m the high level of reactivity of aniline m electrophilic aromatic substitution reactions (Section 12 12) Other ways m which electron delocalization affects the properties of arylamines are described m later sections of this chapter... 

Rate data are also available for the solvolysis of l-(2-heteroaryl)ethyl acetates in aqueous ethanol. Side-chain reactions such as this, in which a delocalizable positive charge is developed in the transition state, are frequently regarded as analogous to electrophilic aromatic substitution reactions. In solvolysis the relative order of reactivity is tellurienyl> furyl > selenienyl > thienyl whereas in electrophilic substitutions the reactivity sequence is furan > tellurophene > selenophene > thiophene. This discrepancy has been explained in terms of different charge distributions in the transition states of these two classes of reaction (77AHC(21)119>. 

Electrophilic aromatic substitution reactions are important for synthetic purposes and also are one of the most thoroughly studied classes of organic reactions from a mechanistic point of view. The synthetic aspects of these reactions are discussed in Chapter 11 of Part B. The discussion here will emphasize the mechanisms of several of the most completely studied reactions. These mechanistic ideas are the foundation for the structure-reactivity relationships in aromatic electrophilic substitution which will be discussed in Section 10.2... 

At this point, attention can be given to specific electrophilic substitution reactions. The kinds of data that have been especially useful for determining mechanistic details include linear ffee-energy relationships, kinetic studies, isotope effects, and selectivity patterns. In general, the basic questions that need to be asked about each mechanism are (1) What is the active electrophile (2) Which step in the general mechanism for electrophilic aromatic substitution is rate-determining (3) What are the orientation and selectivity patterns ... 

Table 12.2 summarizes orientation and rate effects in electrophilic aromatic substitution reactions for a variety of frequently encountered substituents. It is arianged in order of decreasing activating power the most strongly activating substituents are at the top, the most strongly deactivating substituents are at the bottom. The main features of the table can be summarized as follows ... 

The synthesis of an alkylated aromatic compound 3 by reaction of an aromatic substrate 1 with an alkyl halide 2, catalyzed by a Lewis acid, is called the Friedel-Crafts alkylation This method is closely related to the Friedel-Crafts acylation. Instead of the alkyl halide, an alcohol or alkene can be used as reactant for the aromatic substrate under Friedel-Crafts conditions. The general principle is the intermediate formation of a carbenium ion species, which is capable of reacting as the electrophile in an electrophilic aromatic substitution reaction. 

With a substituted aromatic ring compound 2, mixtures of isomeric coupling products may be formed the ort/zo-product usually predominates. The rules for regiochemical preferences as known from electrophilic aromatic substitution reactions (see for example Friedel-Crafts acylation), do not apply here. 

The hydroxyl group is a strongly activating, ortho- and para-directing substituent in electrophilic aromatic substitution reactions (Section 16.4). As a result, phenols are highly reactive substrates for electrophilic halogenation, nitration, sulfonation, and lTiedel-Crafts reactions. 

No electrophilic aromatic substitution reactions of toluene, ethylbenzene, and cumene occur with BBrj in the dark the electrophile is too weak for these reactions. The photochemical reactions followed by hydrolysis give the p-isomers of the corresponding boronic acids as the major products (delocalization band in Scheme 9) [44]. 

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