Substitution, electrophilic nitration, also

Other typical electrophilic aromatic substitution reactions—nitration (second entry) sul fonation (fourth entry) and Friedel-Crafts alkylation and acylation (fifth and sixth entnes)—take place readily and are synthetically useful Phenols also undergo elec trophilic substitution reactions that are limited to only the most active aromatic com pounds these include mtrosation (third entry) and coupling with diazomum salts (sev enth entry)... 

The addition reactions discussed in Sections 4.1.1 and 4.1.2 are initiated by the interaction of a proton with the alkene. Electron density is drawn toward the proton and this causes nucleophilic attack on the double bond. The role of the electrophile can also be played by metal cations, and the mercuric ion is the electrophile in several synthetically valuable procedures.13 The most commonly used reagent is mercuric acetate, but the trifluoroacetate, trifluoromethanesulfonate, or nitrate salts are more reactive and preferable in some applications. A general mechanism depicts a mercurinium ion as an intermediate.14 Such species can be detected by physical measurements when alkenes react with mercuric ions in nonnucleophilic solvents.15 The cation may be predominantly bridged or open, depending on the structure of the particular alkene. The addition is completed by attack of a nucleophile at the more-substituted carbon. The nucleophilic capture is usually the rate- and product-controlling step.13,16... 

Treatment of bis(dimethylaminomethylene)pyrrolizinium perchlorate (29) with cyclopentadiene-NaH in DMF gave the diatropic cyclopenta-[fc]cycl[4,2,2]azine (77), which was also obtained from the fulvene derivative (78) and 3//-pyrrolizine (25). Electrophilic substitutions (deuteration, nitration, nitrosation, acylation, bromination, Mannich reaction) occur in the 6- and 8-positions.32... 

The 1,2,5-thiadiazoles were relatively inert in electrophilic substitution reactions (see also Section 4.02.1.4). The parent ring does not react with bromine, either under irradiation or in the presence of iron(III) salts, nor does it enter the Friedel-Crafts or nitration reactions. Electrophilic deuteration has been effected in low yield under drastic conditions (250 °C in trideuterophosphoric acid). If the thiadiazole ring bears an activating group, e.g. amino or methyl, electrophilic substitution can be achieved <68AHC(9)107, 70RCR923). 

We have seen how pyridine /V-oxidcs can be used to promote electrophilic oxidation at C-2,4, and 6. They also promote ort/zo-lithiation and nucleophilic substitution making them very versatile intermediates. This is well illustrated in Queguiner s synthesis of the antibiotic caerulomy-cins. 2,2 -Bipyridyl, available as a ligand for many metals, is easily oxidised to its monoxide 146. The synthesis starts with two electrophilic substitutions. Lithiation occurs ortho to the /V-oxidc quenching with BrCN gives a good yield of the bromide 147 and a conventional electrophilic nitration occurs para to the /V-oxidc. 

The general mechanistic framework outlined in the preceding paragraphs must be further elaborated by other details to fully describe the mechanisms of the individual electrophilic substitutions. The question of the identity of the active electrophile in each reaction is important. We have discussed the case of nitration, in which, under many circumstances, the electrophile has been established to be the nitronium ion. Similar questions arise in many of the other substitution processes. Other matters that are important include the ability of the electrophile to select among alternative positions on a substituted aromatic ring. The relative reactivity of different substituted benzenes toward various electrophiles has also been important in developing a firm understanding of electrophilic aromatic substitution. The next section considers the structure-reactivity relationships that have proved most informative. 

As an example, this apply to enols or tautomeric enols such as maleic acid derivatives. While with a chemical reagent (cerium ammonium nitrate) the only process occurring is oxidative dimerization, when aromatic nitriles are used as the photochemical oxidant, selective trapping of the radicals by an electrophilic alkenes or by the nitrile itself occurs. Under these conditions, both the alkylation of alkenes and the oxidative alkylation/dimerization of dienes have been smoothly obtained (see Scheme 8) and side processes such as double alkylation or polymerization often occurring with other methods have been avoided. A three-component (Nucleophile-Olefin Combination, Aromatic Substitution) process is also possible. ... 

The fact that nitration with acetyl nitrate is sometimes accompanied by acetoxylation has been mentioned ( 5.3.3). In proposing the ion pair ACONO2H+ NOg- as the nitrating agent, Fischer, Read and Vaughan also suggested that it was responsible for the acetoxylation, which was regarded as an electrophilic substitution. 

One mode of substitution occurring when the nitrating system consists of dinitrogen pentoxide in organic solvents involves molecular dinitrogen pentoxide as the effective electrophile ( 4.2.3). Evidence that the same electrophile operates when the nitrating system consists of a solution of benzoyl nitrate in carbon tetrachloride has also been given ( 5-2)-... 

M.o. theory has had limited success in dealing with electrophilic substitution in the azoles. The performances of 7r-electron densities as indices of reactivity depends very markedly on the assumptions made in calculating them. - Localisation energies have been calculated for pyrazole and pyrazolium, and also an attempt has been made to take into account the electrostatic energy involved in bringing the electrophile up to the point of attack the model predicts correctly the orientation of nitration in pyrazolium. ... 

Ten years ago we became interested in the possibility of using nitration as a process with which to study the reactivity of hetero-aromatic compounds towards electrophilic substitution. The choice of nitration was determined by the consideration that its mechanism was probably better imderstood than that of any other electrophilic substitution. Others also were pursuing the same objective, and a considerable amount of information has now been compiled. 

The 2-nitrothiazole can be reduced to the corresponding aminothiazole by catalytic or chemical reduction (82, 85, 89). The 5-nitrothiazole can also be reduced with low yield to impure 5-aminothiazole (1, 85). All electrophilic substitution reactions are largely inhibited by the presence of the nitro substituent. Nevertheless, the nitration of 2-nitrothiazoIe to 2,4-dinitrothiazole can be accomplished (see Section IV). 

Anthraquinone dyes are derived from several key compounds called dye intermediates, and the methods for preparing these key intermediates can be divided into two types (/) introduction of substituent(s) onto the anthraquinone nucleus, and (2) synthesis of an anthraquinone nucleus having the desired substituents, starting from benzene or naphthalene derivatives (nucleus synthesis). The principal reactions ate nitration and sulfonation, which are very important ia preparing a-substituted anthraquiaones by electrophilic substitution. Nucleus synthesis is important for the production of P-substituted anthraquiaones such as 2-methylanthraquiQone and 2-chloroanthraquiaone. Friedel-Crafts acylation usiag aluminum chloride is appHed for this purpose. Synthesis of quinizatia (1,4-dihydroxyanthraquiQone) is also important. 

Like other aromatic compounds, aromatic ethers can undergo substitution in the aromatic ring with electrophilic reagents, eg, nitration, halogenation, and sulfonation. They also undergo Eriedel-Crafts (qv) alkylation and acylation. 

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