Heterocyclic compounds electrophilic aromatic substitution

In addition to benzene and naphthalene derivatives, heteroaromatic compounds such as ferrocene[232, furan, thiophene, seienophene[233,234], and cyclobutadiene iron carbonyl complex[235] react with alkenes to give vinyl heterocycles. The ease of the reaction of styrene with substituted benzenes to give stilbene derivatives 260 increases in the order benzene < naphthalene < ferrocene < furan. The effect of substituents in this reaction is similar to that in the electrophilic aromatic substitution reactions[236]. 

The great variety of available structural types causes heterocyclic aromatic compounds to range from exceedingly reactive to practically inert toward electrophilic aromatic substitution. 

Kawase, M., et al.. Electrophilic Aromatic Substitution with N-Methoxy-N-acylnitrenium Ions Generated from N-Chloro-N-methoxyamides Syntheses of Nitrogen Heterocyclic Compounds Bearing a N-Methoxy-amide Group, J. Org. Chem., 54 3394-3403 (1989). 

Electrophilic aromatic substitution reactions of compounds 10 occur in a fashion characteristic for heterocyclic analogues of azulene, and are specific at positions 5 and 7 <1994CB1479>. Thus, 10a (R = H, R = Ph) was successfully brominated, formylated, and acylated, as shown in Scheme 7. 

The Friedel-Crafts reaction involves an electrophilic aromatic substitution that facilitates the alkylation or acylation of arenes (135) and heterocyclic compounds catalyzed by acidic catalysts. Zinc oxide has been found to be an effective catalyst for the Friedel-Crafts acylation of activated and nonactivated aromatic compounds (135) (Hosseini-Sarvari and Sharghi 2004) under solvent-free and room temperature conditions (Scheme 9.44). The catalyst provides a large surface area for the reaction. This Friedel-Crafts reaction is a safe and environmentally benign method which requires simple workup, mild reaction conditions and a short reaction time. 

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. 

Rate and Regioselectivity in the Nitration of (Trifluoromethyl)benzene 474 Substituent Effects in Electrophilic Aromatic Substitution Activating Substituents 476 Substituent Effects in Electrophilic Aromatic Substitution Strongly Deactivating Substituents 480 Substituent Effects in Electrophilic Aromatic Substitution Halogens 482 Multiple Substituent Effects 484 Retrosynthetic Analysis and the Synthesis of Substituted Benzenes 486 Substitution in Naphthalene 488 Substitution in Heterocyclic Aromatic Compounds 489... 

Electrophilic aromatic substitution is a general reaction of all aromatic compounds, including polycyclic aromatic hydrocarbons, heterocycles, and substituted benzene derivatives. A substituent affects two aspects of electfophilic aromatic substitution ... 

Pyrrole, fiiran, and thiophene are heterocyclic aromatic compounds that undergo electrophilic aromatic substitution reactions preferentially at C-2. They are more reactive than benzene toward electrophilic aromatic substitution. 

Replacing one of benzene s carbons with a nitrogen forms pyridine, a heterocyclic aromatic compound that undergoes electrophilic aromatic substitution reactions at... 

The direct ruthenium catalysed allylation with allylic alcohol derivatives of various aromatic compounds and heterocycles such as furans and thiophenes was performed by Nishibayashi with cationic thiolate-bridged diruthenium(III, II) catalysts. The reaction is consistent with an electrophilic aromatic substitution by the electrophilically activated allyl moiety [68]. Allylation also takes place with the alkene metathesis Grubbs catalyst [69]. More importantly using (phosphine-sulfonate)ruthenium(II) catalyst Bmneau et al. have recently shown that allyl alcohols are activated generating an allyl-ruthenium(IV) intermediate leading to C3-allylation of indole with high regioselectivity in favour of the branched allyl derivative [(Eq. 84)] [167]. 

Udenfriend et al. observed that aromatic compounds are hydroxyl-ated by a system consisting of ferrous ion, EDTA, ascorbic acid, and oxygend Aromatic and heteroaroinatic compounds are hydroxylated at the positions which are normally most reactive in electrophilic substitutions. For example, acetanilide gives rise exclusively to the o-and p-hydroxy isomers whereas quinoline gives the 3-hydroxy prod-uct. - The products of the reaction of this system w ith heterocyclic compounds are shown in Table XIII. 

Heterocyclic amines are compounds that contain one or more nitrogen atoms as part of a ring. Saturated heterocyclic amines usually have the same chemistry as their open-chain analogs, but unsaturated heterocycles such as pyrrole, imidazole, pyridine, and pyrimidine are aromatic. All four are unusually stable, and all undergo aromatic substitution on reaction with electrophiles. Pyrrole is nonbasic because its nitrogen lone-pair electrons are part of the aromatic it system. Fused-ring heterocycles such as quinoline, isoquinoline, indole, and purine are also commonly found in biological molecules. 

This awareness in a short time led to new homolytic aromatic substitutions, characterized by high selectivity and versatility. Further developments along these lines can be expected, especially as regards reactions of nucleophilic radicals with protonated heteroaromatic bases, owing to the intrinsic interest of these reactions and to the fact that classical direct ionic substitution (electrophilic and nucleophilic) has several limitations in this class of compound and does not always offer alternative synthetic solutions. Homolytic substitution in heterocyclic compounds can no longer be considered the Cinderella of substitution reactions. 

A-Amine oxides can be reduced (deoxygenated) to tertiary amines. Such a reaction is very desirable, especially in aromatic nitrogen-containing heterocycles where conversion to amine oxides makes possible electrophilic substitution of the aromatic rings in different positions than it occurs in the parent heterocyclic compounds. The reduction is very easy and is accomplished by catalytic hydrogenation over palladium [736, 737], by borane [738], by iron in... 

Aromatic compounds and their reactions are a big part of any Organic 11 course. We introduce you to the aromatic family, including the heterocyclic branch, in Chapter 6. (You may want to brush up on the concept of resonance beforehand.) Then in Chapters 7 and 8, you find out more than you ever wanted to know about aromatic substitution reactions, starring electrophiles and nucleophiles. 

M n Part II we spend a lot of time and pages on aromatic systems, starting with benzene. You examine benzene s structure, its resonance stabilization, and its stability. Next you study benzene derivatives and heterocyclic aromatic compounds, and then we address the spectroscopy of these aromatic compounds. And in Chapters 7 and 8 we introduce you to aromatic substitution by both electrophiles and nucleophiles, and you get to see a lot of reactions and a lot of examples. In this part you also start working with many more named reactions. 

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