Aromatic rings, nucleophilic

A nitro group behaves the same way m both reactions it attracts electrons Reaction is retarded when electrons flow from the aromatic ring to the attacking species (electrophilic aromatic substitution) Reaction is facilitated when electrons flow from the attacking species to the aromatic ring (nucleophilic aromatic substitution) By being aware of the connection between reactivity and substituent effects you will sharpen your appreciation of how chemical reactions occur... 

The functionalization of electron rich aromatics rings is often accomplished by electrophilic aromatic substitution. However, electrophilic substitutions require stringent conditions or fail entirely with electron deficient aromatic rings. Nucleophilic aromatic substitutions are commonly used but must usually be conducted under aprotic conditions. In contrast, nucleophilic radicals can add to electron deficient aromatic rings under very mild conditions. 

The results of the hydrogenation of 4-substituted biphenyls suggested that hydrogen absorbed in the alloy attacks the aromatic rings nucleophilically. 

Hydroxylation of aromatic rings probably occurs by a similar mechanism i.e. the electron-rich aromatic ring nucleophilically attacks the flavin peroxide (electrophihc attack by the peroxide on the aromatic ring at activated positions) (XXXXV). 

Arylamines contain two functional groups the amine group and the aromatic ring they are difunctional compounds The reactivity of the amine group is affected by its aryl substituent and the reactivity of the ring is affected by its amine substituent The same electron delocalization that reduces the basicity and the nucleophilicity of an arylamme nitrogen increases the electron density in the aromatic ring and makes arylamines extremely reactive toward electrophilic aromatic substitution... 

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 m a phenol Reactions that take place on the ring lead to elec trophilic aromatic substitution Table 24 4 summarizes the behavior of phenols m reac tions of this type... 

The chemical production of aminophenols via the reduction of nitrobenzene occurs in two stages. Nitrobenzene [98-95-3] is first selectively reduced with hydrogen in the presence of Raney copper to phenylhydroxylamine in an organic solvent such as 2-propanol (37). With the addition of dilute sulfuric acid, nucleophilic attack by water on the aromatic ring of /V-phenylhydroxylamine [100-65-2] takes place to form 2- and 4-aminophenol. The by-product, 4,4 -diaminodiphenyl ether [13174-32-8] presumably arises in a similar manner from attack on the ring by a molecule of 4-aminophenol (38,39). Aniline [62-53-3] is produced via further reduction (40,41). 

Nucleophilic Substitutions of Benzene Derivatives. Benzene itself does not normally react with nucleophiles such as haUde ions, cyanide, hydroxide, or alkoxides (7). However, aromatic rings containing one or more electron-withdrawing groups, usually halogen, react with nucleophiles to give substitution products. An example of this type of reaction is the industrial conversion of chlorobenzene to phenol with sodium hydroxide at 400°C (8). 

Onium ions of small and large heterocyclics are usually produced by electrophilic attack on a heteroatom. In three- and four-membered rings nucleophilic attack on an adjacent carbon follows immediately, in most cases, and ring opening stabilizes the molecule. In large rings the onium ion behaves as would its acyclic analog, except where aromaticity or transannular reactions come into play (each with its electronic and steric pre-conditions). A wide diversity of reactions is observed. 

The formation of ethyl cyano(pentafluorophenyl)acetate illustrates the intermolecular nucleophilic displacement of fluoride ion from an aromatic ring by a stabilized carbanion. The reaction proceeds readily as a result of the activation imparted by the electron-withdrawing fluorine atoms. The selective hydrolysis of a cyano ester to a nitrile has been described. (Pentafluorophenyl)acetonitrile has also been prepared by cyanide displacement on (pentafluorophenyl)methyl halides. However, this direct displacement is always aecompanied by an undesirable side reaetion to yield 15-20% of 2,3-bis(pentafluoro-phenyl)propionitrile. 

The addition-elimination mechanism uses one of the vacant n orbitals for bonding interaction with the nucleophile. This permits addition of the nucleophile to the aromatic ring without displacement of any of the existing substituents. If attack occurs at a position occupied by a potential leaving group, net substitution can occur by a second step in which the leaving group is expelled. 

The replacement of reactive aromatic fluonne by nitrogen nucleophiles is a well-known process for the preparation of aromatic amines The aromatic fluonne IS activated by the presence of electron-withdrawing substituents on the aromatic ring, especially in ortho and para positions [57 38, 39] (equations 25-27)... 

Attack by the halide nucleophile at the 5/) -hybridized carbon of the alkyl group is analogous to what takes place in the cleavage of dialkyl ethers. Attack at the 5/) -hybridized carbon of the aromatic ring is much slower. Indeed, nucleophilic aromatic substitution does not occur at all under these conditions. 

Nucleophilic aromatic substitution (Chapter 23) A reaction in which a nucleophile replaces a leaving group as a substituent on an aromatic ring. Substitution may proceed by an addition-elimination mechanism or an elimination-addition mechanism. 

The benzene anion formed as shown by nucleophilic attack on an aromatic ring is called a Meisenheimer complex. 

A variety of aryl systems have been explored as substrates in the Knorr quinoline synthesis. Most notable examples are included in the work of Knorr himself who has demonstrated the high compatibility of substituted anilines as nucleophilic participants in that reaction. In the case of heteroaromatic substrates however, the ease of cyclization is dependent on the nature and relative position of the substituents on the aromatic ring." For example, 3-aminopyridines do not participate in ring closure after forming the anilide... 

Pyridinium chloride ([PyHjCl) has also been used in a number ofcyclization reactions of aryl ethers (Scheme 5.1-4) [4, 18]. Presumably the reaction initially proceeds by deallcylation of the methyl ether groups to produce the corresponding phenol. The mechanism of the cyclization is not well understood, but Pagni and Smith have suggested that it proceeds by nucleophilic attack of an Ar-OH or Ar-0 group on the second aromatic ring (in a protonated form) [4]. 

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