Electrophilic aromatic substitution reactions approach

The monomers described so far have all been prepared by starting with 4-bromobenzocyclobutene, 2. A different approach to the preparation of monomers begins with the parent hydrocarbon benzocyclobutene 1 by carrying out electrophilic aromatic substitution reactions [36]. Benzocyclobutene readily undergoes a Friedel-Crafts benzoylation reaction with a variety of substituted acid chlorides (Fig. 7). 

Scheme 2.3.3). The approach has been used to make imidazoles (11) with dimethylamino groups in the 4- and/or 2-positions. Such compounds are not well known (they are inclined to be sensitive to the elfects of air and moisture, and their behaviour in electrophilic aromatic substitution reactions parallels that of i (A(-dimethylaniline [8]), and the method is of value for that reason alone. Its wider application to imidazole synthesis seems unlikely. 

The product formed when the nitrogen of a tertiary amine shares its lone pair with a nitrosonium ion caimot be stabilized by loss of a proton. A tertiary aryl amine, therefore, can undergo an electrophilic aromatic substitution reaction with a nitrosonium ion. The product of the reaction is primarily the para isomer because the bulky dialkyl-amino group blocks approach of the nitrosonium ion to the ortho position. 

This method of preparation of ylides from the corresponding triazolinedi-ones is limited in its synthetic utility. Oxidation of suitable urazolyl compounds seems to be a much more versatile entry to this class of highly reactive dipolar compounds. Starting substituted urazoles are often readily available by simple nucleophilic substitution reactions of urazoles with suitable alkyl halides. As is evident from the preceding sections, many other substituted urazoles can be prepared by the ene-type reaction of TADs, by the reaction of TADs with ketones, or by their electrophilic aromatic substitution reactions. Oxidation of these urazoles, e.g., 501, 428, 504, and 506, can be effected with tert-butyl hypochlorite, or, in some cases, excess PTAD can be used. Various approaches and utilization of this synthetic strategy are best seen in the following examples. 

Heteracalixarenes are important molecular architectures in supramo-lecular chemistry. In the year 2014, an efficient approach for the synthesis of functionalized selenoethers and selenacalix[4]thiophenes, [2,5-(ji-Se) (3,4-dialkoxythiophene) (14TL5232). The selenoethers were prepared by the reaction of various phenols with SeCl2 (shown below) and the latter were synthesized by conventional electrophilic aromatic substitution reactions of dialkoxythiophene and SeCl2. 

We will examine two very different approaches to perhydrohistrionicotoxin. The first one revolves around the chemistry of 27-acyliminium ions, a field largely developed by the Speckamp group in the Netherlands. In Chapter 8 we saw that iminium ions (the nitrogen analogs of oxocarbenium ions) are excellent electrophiles (Mannich reaction). N-Acyliminium ions are even more electrophilic than iminium ions. They react with both heteroatom and carbon nucleophiles as expected. An early use of an N-acyliminium ion in synthesis is the cyclization of enamide 16 to 18 in an electrophilic aromatic substitution reaction. This reaction was an early step in Stork s approach to lycopodine. The reaction presumably proceeds through N-acyliminium ion 17, generated by protonation of the enamide. 

We will address this issue further in Chapter 10, where the polar effects of the substituents on both the c and n electrons will be considered. For the case of electrophilic aromatic substitution, where the energetics of interaction of an approaching electrophile with the 7t system determines both the rate of reaction and position of substitution, simple resonance arguments are extremely useful. 

The general approaches for the synthesis of poly(arylene ether)s include electrophilic aromatic substitution, nucleophilic aromatic substitution, and metal-catalyzed coupling reactions. Poly(arylene ether sulfone)s and poly(arylene ether ketone)s have quite similar structures and properties, and the synthesis approaches are quite similar in many respects. However, most of the poly(arylene ether sul-fone)s are amorphous while some of the poly(arylene ether)s are semicrystalline, which requires different reaction conditions and approaches to the synthesis of these two polymer families in many cases. In the following sections, the methods for the synthesis of these two families will be reviewed. 

Four years later, we reported an improved iron-mediated total synthesis of furostifoline (224) (689). This approach features a reverse order of the two cyclization reactions by first forming the carbazole nucleus, then annulation of the furan ring. As a consequence, in this synthesis the intermediate protection of the amino function is not necessary (cf. Schemes 5.178 and 5.179). The electrophilic aromatic substitution at the arylamine 1106 by reaction with the iron complex salt 602 afforded the iron... 

Aromatic substitution reactions are often complicated and multistep processes. A correlation, however, in many cases can be found between the charged attacking species and the electron density distribution in the molecule attacked during electrophilic and nucleoph c substitution. No such correlation is expected in radical substitution where the attacking particles are neutral, rather a correlation between the reactivities of separate bonds and a free valency index of the bond order. This allows the prediction of the most reactive bonds. Such an approach has been used by researchers who applied quantum calculations to estimate the reactivities of the isomeric thienothiophenes and to compare them with thiophene or naphthalene. " Until recently quantum methods for studying reactivities of aromatics and heteroaromatics were developed mainly in the r-electron approximation (see, for example, Streitwieser and Zahradnik ). The M orbitals of a sulfur atom were shown not to contribute substantially to calculations of dipole moments, polarographic reduction potentials, spin-density distribution, ... 

Coumarins are readily accessed via the Pechmann condensation of phenols and 1,3-dicarbonyl compounds, which proceeds via electrophilic aromatic substitution of the phenol followed by dehydration and lactonization <1984CHEC, 1996CHEC-II>. In this manner, the amino acid bearing coumarins 676 are formed by a Pechmann condensation of phenols and 2-amino-6-ethoxy-4,6-dioxohexanoic acid 677 (Scheme 161) <2004AGE3432>. The popularity of this approach results from the wide range of readily available substrates (phenols and 1,3-dicarbonyl compounds). However, a major drawback is that electron withdrawing groups on the phenolic component dramatically reduces the yield of a Pechmann reaction. 

Particularly high-yield preparations of both alkyl- and aryldichlorophosphines are obtained through the use of aluminum chloride. The aluminum chloride mediated reaction of phosphorus trichloride with haloalkanes generates an intermediate that can be reduced to the corresponding alkyldichlorophosphine (equation 4). For the preparation of aryldichlorophosphines, aluminum chloride serves a Friedel-Crafts catalyst for electrophilic aromatic substitution by phosphorus on the aromatic ring (equation 5). These synthetic approaches to dihalophosphines have been reviewed. ... 

In al this we have estimated the stability of a carbonium ion on the same basis the dispersal or concentration of the charge due to electron release or electron withdrawal by the substituent groups. As wc shall see, the approach that has worked so well for elimination, for addition, and for electrophilic aromatic substitution works for still another important class of organic reactions in which a positive charge develops nucleophilic aliphatic substitution by the S l mechanism (Sec. 14.14). It works equally well for nucleophilic aromatic substitution (Sec. 25.9), in which a negative charge develops. Finally, we shall find that this approach will help us to understand acidity or basicity of such compounds as carboxylic acids, sulfonic acids, amines, and phenols. 

In our study of electrophilic aromatic substitution (Sec. 11.19 and Sec. 30.9), we found that we could account for orientation on the following basis the controlling step is the attachment of the electrophilic reagent to the aromatic ring, which takes place in .uch a way as to yield the most stable intermediate carbonium ion. Let us apply this approach to the reactions of pyrrole. 

A point of interest in lithiation mediated aromatic substitution reaction is, how to effect substitution at a less active position (in lithiation reactions) in presence of the more active. In one approach, after effecting lithiation at the more active position, the metallation mixture is treated with ClSiMe, which introduces — SiMcj at that point. Further lithiation now occurs at the second position. After reacting with a suitable electrophile, the SiMcj group is replaced by H by acid cleavage of the C—Si bond. The following example illustrates the approach... 

Although the use of aluminum and tin reagents have provided fruitful approaches to the preparation of C-arylglycosides, the majority of this chemistry centers around reactions utilizing Lewis acid catalysis. Of particular importance are reactions proceeding via electrophilic aromatic substitution. This type of chemistry has been widely applied to a sugars bearing a variety of... 

The previous sections leave no doubts that aromatic compounds, react with positively charged electrophiles to form a-complexes-arenium ions. But are they the primary intermediates It is not by accident that the problem of preliminary formation of radical cations has arisen. Its statement is an attempts to explain the orientational peculiarities of electrophilic aromatic substitution of hydrogen. The widespread view that the orientation in the reactions of aromatic compounds with electrophiles is dictated by the relative stabilities of the cr-complexes explains but a part of the accumulated material. In the first place this refers to the meta- and para-orienting effects of electron-releasing substituents in benzene in terms of the QCT -approach and to that of the relative reactivity of various aromatic substrates... 

This polarization, in turn, causes the ring carbons to bind the it electrons more tightly, decreases their availability to an approaching electrophile, raises the activation energy for electrophilic aromatic substitution, and decreases the reaction rate. Figure 12.6 illustrates this effect by comparing the electrostatic potential maps of fluorobenzene and benzene. 

Electrophilic aromatic substitution is the most important reaction of aromatic compounds because it has broad applications for a wide variety of aromatic compounds. In contrast, nucleophilic aromatic substitution has restricted applications. In nucleophilic aromatic substitution, a strong nucleophile replaces a leaving group, such as a halide. What is the mechanism of nucleophilic aromatic substitution It cannot be the S]m2 mechanism because aryl halides cannot achieve the correct geometry fw back-side displacement The aromatic ring blocks approach of the nucleophile to the back of the carbon bearing the halogen. 

There are several lines of evidence for formation of cr complexes as intermediates in electrophilic aromatic substitution. One particularly informative approach involves measurement of isotope effects on the rate of substitution. If removal of the proton at the site of substitution were concerted with introduction of the electrophile, a primary isotope effect would be observed in reactions in which electrophilic attack on the ring is rate-determining. This is not the case for nitration nor for several other types of aromatic substitution reactions. Nitration of aromatic substrates partially labeled by tritium shows no selectivity between protium- and tritium-substituted sites. Similarly, the rate of nitration of nitrobenzene is identical to that... 

Tiithioorthoester Activation. Electron-rich aromatic rings undergo electrophilic aromatic substitution with tris(phenylthio) methane in the presence of DMTSF. Subsequent hydrolysis results in an aldehyde and a net electrophilic formylation . Intramolecular reaction between a tris(phenylthio)methane unit and an alcohol represents an approach to lactone formation which utilizes the chemoselectivity of DMTSF ... 

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