Electrophilic aromatic substitution reactions with nitration

Unlike benzene, pyridine undergoes electrophilic aromatic substitution reactions with great difficulty. Halogenation can be carried out under drastic conditions, but nitration occurs in very low yield, and Friedel-Crafts reactions are not successful. Reactions usually give the 3-substituted product. 

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)... 

All of the electrophilic aromatic substitution reactions follow this same general mechanism. The only difference is the structure of the electrophile and how it is generated. Let s look at a specific example, the nitration of benzene. This reaction is accomplished by reacting benzene with nitric acid in the presence of sulfuric acid ... 

Nitration (Section 18.4) An electrophilic aromatic substitution reaction in which benzene reacts with N02 to give nitrobenzene, C6H5NO2. 

By use of especially selected aromatic substrates—highly hindered ones—isotope effects can be detected in other kinds of electrophilic aromatic substitution, even in nitration. In certain reactions the size of the isotope can be deliberately varied by changes in experimental conditions- and in a way that shows dependence on the relative rates of (2) and the reverse of (I). There can be little doubt that all these reactions follow the same two-step mechanism, but with differences in the shape of potential energy curves. In isotope effects the chemist has an exceedingly delicate probe for the examination of organic reaction mechanisms. 

Benzene s aromaticity causes it to undergo electrophilic aromatic substitution reactions. The electrophilic addition reactions characteristic of alkenes and dienes would lead to much less stable nonaromatic addition products. The most common electrophilic aromatic substitution reactions are halogenation, nitration, sulfonation, and Friedel-Crafts acylation and alkylation. Once the electrophile is generated, all electrophilic aromatic substitution reactions take place by the same two-step mechanism (1) The aromatic compound reacts with an electrophile, forming a carbocation intermediate and (2) a base pulls off a proton from the carbon that... 

All of these effects are observed when comparing the rates of various electrophilic aromatic substitution reactions. Activating substituents increase the rate of reaction relative to benzene. The rate of reaction for the nitration of anisole, for example, was 9.7 x 10 times faster than nitration of benzene. The reaction of anisole with nitric and sulfuric acids, gave 44% of o-nitroanisole, 56% of p-nitroanisole and < 1% of m-nitro-anisole.2 9 contrasts with reactions involving deactivating substituents, where selectivity for the meta -product is usually very good. Nitration of nitrobenzene, for example, gave 1,3-dinitrobenzene in 94% yield, with only 6% of the ortho product and < 1% of the para product. ... 

The electrophilic substitution is the most characteristic reaction for these classes of compounds. Compound (21) undergoes standard electrophilic aromatic substitution reactions. Thus it forms the 6-bromo compound (58) with A7-bromosuccinimide and 6,7-dibromo compound (72) with the excess of the same reagent. It also forms the 6-nitro compound (67) with copper(II) nitrate trihydrate and 6,7-dinitro compound (68) with excess of nitronium tetrafluoroborate. The bis(trifluoro-acetoxy)thallium derivative (73) was formed from trithiadiazepine (21) and thallium(III) trifluoro-acetate in refluxing acetonitrile. Without isolation, (73) was directly converted into the pale yellow 6-iodo compound (74) with aqueous potassium iodide, into the 6-cyano compound (75) with copper(I) cyanide, and into methyl trithiadiazepine-6-carboxylate (76) with carbon monoxide and methanol in the presence of palladium chloride, lithium chloride, and magnesium oxide. Compound (21) is acetylated in the presence of trifluoromethanesulfonic acid (Scheme 7) <85CC396,87JCS(P1)217, 91JCS(P1)2945>. 

These observations support the electrophilic mechanism for substitution. If the reaction rate depends on electrophilic (that is, electron-seeking) attack on the aromatic ring, then substituents that donate electrons to the ring will increase its electron density and, hence, speed up the reaction substituents that withdraw electrons from the ring will decrease electron density in the ring and therefore slow down the reaction. This reactivity pattern is exactly what is observed, not only with nitration, but also with all electrophilic aromatic substitution reactions. 

In a nitration reaction, aromatic rings react with nitric add in the presence of sulfuric add to yield nitroarenes, which are useful synthetic intermediates because the nitro group can be reduced to an amino group by reaction with H2 and a transition metal catalyst or, alternatively, by using iron, zinc, or tin in HCl followed by base. There is no electrophilic aromatic substitution reaction that introduces the amino group directly onto the aromatic ring. 

The chemistry of aromatic compounds is dominated hy electrophilic aromatic substitution reactions, both in the laboratory and in biological pathways. Many variations of the reaction can be carried out, including halogenation, nitration, sulfonation, and hydroxylation. Friedel-Crafts alkylation and acylation, which involve reaction of an aromatic ring with carho-cation electrophiles, are particularly useful. 

Suspension polymerization was applied to prepare polynor-bomene aosslinked beads suitable for use as supports in organic synthesis. The monomers used included norbor-nene, norbom-2-ene-5-methanol, and aosslinking agents including bis(norbom-2-ene-5-methoxy)alkanes, di(norbom-2-ene-5-methyl)ether, and l,3-di(norbom-2-ene-5-methoxy) benzene. The initial resins, which were unsaturated, were subsequently modified using hydrogenation, hydrofluorination, chlorination, or bromination to yield saturated resins with varying properties. They were reported to be superior to more traditional styrene-divinylbenzene resins due to reduced interference in electrophilic aromatic substitution reactions (e.g., Friedel-Crafts acylation and nitration). 

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