Electrophilic aromatic substitution oxygen

Oxygen stabilized carbocations of this type are far more stable than tertiary carbocations They are best represented by structures m which the positive charge is on oxygen because all the atoms have octets of electrons m such a structure Their stability permits them to be formed rapidly resulting m rates of electrophilic aromatic substitution that are much faster than that of benzene... 

Pyrrole, furan, and thiophene, on the other hand, have electron-rich aromatic rings and are extremely reactive toward electrophilic aromatic substitution— rnore like phenol and aniline than benzene. Like benzene they have six tt electrons, but these tt electrons are delocalized over five atoms, not six, and ar e not held as strongly as those of benzene. Even when the ring atom is as electronegative as oxygen, substitution takes place readily. 

In most of their- reactions phenols behave as nucleophiles, and the reagents that act on them are electrophiles. Either the hydroxyl oxygen or the aromatic ring may be the site of nucleophilic reactivity in a phenol. Reactions that take place on the ring lead to electrophilic aromatic substitution Table 24.4 summarizes the behavior of phenols in reactions of this type. 

Despite the synthetic utility of this transformation, nearly eighty years elapsed between the discovery of the Bischler-Napieralski reaction and the first detailed studies of its mechanism. " Early mechanistic proposals regarding the Bischler-Napieralski reaction involved protonation of the amide oxygen by traces of acid present in P2O5 or POCI3 followed by electrophilic aromatic substitution to provide intermediate 5, which upon dehydration would afford the observed product 2. However, this proposed mechanism fails to account for the formation of several side products that are observed under these conditions vide infra), and is no longer favored. 

The mechanism for that step is closely related to that of the Friedel-Crafts acylation. Upon subsequent hydrolysis the o-substituted Lewis acid-coordinated phenolate 7 is converted to the free o-acylphenol 2. By an analogous route, involving an electrophilic aromatic substitution para to the phenolate oxygen, the corresponding para-acylphenol is formed. 

Chapter 11 focuses on aromatic substitution, including electrophilic aromatic substitution, reactions of diazonium ions, and palladium-catalyzed nucleophilic aromatic substitution. Chapter 12 discusses oxidation reactions and is organized on the basis of functional group transformations. Oxidants are subdivided as transition metals, oxygen and peroxides, and other oxidants. 

Despite many applications of the iron-mediated carbazole synthesis, the access to 2-oxygenated tricyclic carbazole alkaloids using this method is limited due to the moderate yields for the oxidative cyclization [88,90]. In this respect, the molybdenum-mediated oxidative coupling of an arylamine and cyclohexene 2a represents a complementary method. The construction of the carbazole framework is achieved by consecutive molybdenum-mediated C-C and C-N bond formation. The cationic molybdenum complex, required for the electrophilic aromatic substitution, is easily prepared (Scheme 23). 

An oxygen substituent directly attached to the ring strongly activates it toward electrophilic aromatic substitution. Phenyl acetate is much more reactive than benzene or methyl benzoate. 

This cation cannot yield the product of electrophilic aromatic substitution by loss of a proton from the ring but can lose a proton from oxygen to give a cyclohexadienone derivative. 

More involved studies of the oxidation of plant phenols [27], as well as the introduction of thallium and hypervalent iodine complexes and the use of electrochemical methods, have emphasized the importance of another intermediate involved in oxidative coupling reactions, namely the phenoxonium ion 8 [28-30]. Due to its ionic nature, reaction through an oxo-nium ion can improve the regioselectivity of bond formation and lead to fewer unwanted products (for example, no coupling via the oxygen atom). The coupling reaction can then be viewed as an electrophilic aromatic substitution between 17 and a nucleophilic aromatic unit 15 (Scheme 5). 

The other simple five-membered heterocycles are furan, with an oxygen atom instead of nitro- pyrrole gen, and thiophene with a sulfur atom. They also undergo electrophilic aromatic substitution very Ft ft readily, though not so readily as pyrrole. Nitrogen is the most powerful electron donor of the three, 1 J> oxygen the next, and sulfur the least. Thiophene is very similar to benzene in reactivity. N... 

The aromatic ring is deactivated toward electrophilic aromatic substitution by the combined electron-withdrawing inductive effect of electronegative nitrogen and oxygen. The lone pair of electrons of nitrogen can, however, stabilize by resonance the ortho and para substituted intermediates but not the meta intermediate. 

The acylium ion would have a longer lifetime in concentrated sulfuric acid than in aqueous hydrochloric acid because the concentration of water in the former acid is extremely low. In aqueous hydrochloric acid, the starting ketones are more likely to be in equilibrium with their hydrates, and the intermediate acylium ion might never form. If it does form, it will react so rapidly with the nucleophilic oxygen of water that the electrophilic aromatic substitution cannot occur. 

The effects of—NH2 and —OH on electrophilic aromatic substitution can be accounted for by assuming that nitrogen and oxygen can share more than a pair of electrons with the ring and can accommodate a positive charge. 

The first step in the Combes reaction is the acid-catalyzed condensation of the diketone with the aromatic amine to form a Schiff base (imine), which then isomerizes to the corresponding enamine. In the second step, the carbonyl oxygen atom of the enamine is protonated to give a carbocation that undergoes an electrophilic aromatic substitution. Subsequent proton transfer, elimination of water and deprotonation of the ring nitrogen atom gives rise to the neutral substituted quinoline system. 

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