Nitration and Sulfonation

Nitration and suifonation of benzene introduce two different functional groups on an aromatic ring. Nitration is an especially useful reaction because a nitro group can then be reduced to an NH2 group, a common benzene substituent, in a reaction discussed in Section 18.14. 

Generation of the electrophile in both nitration and sulfonation requires strong acid. In nitration, the electrophile is N02 (the nitronium ion), formed by protonalion of HNO3 followed by loss of water (Mechanism 18.3). 

In sulfonation, protonation of sulfur trioxide, SO3, forms a positively charged sulfur species ( SOsH) that acts as an electrophile (Mechanism 18.4). 

These steps illustrate how to generate the electrophile E for nitration and sulfonation, the process that begins any mechanism for electrophilic aromatic substitution. To complete either of these mechanisms, you must replace the electrophile by either or S03H in the general mechanism (Mechanism 18.1). Thus, the two-step sequence that replaces H by E is the same r ardless of E. This is shown in Sample Problem 18.1 u.sing the reaction of benzene with the nitronium ion. 

Sample Problem 18.1 Draw a stepwise mechanism for the nitration of a benzene ring. 

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Complexation of bromine with iron(III) bromide makes bromine more elec trophilic and it attacks benzene to give a cyclohexadienyl intermediate as shown m step 1 of the mechanism (Figure 12 6) In step 2 as m nitration and sulfonation loss of a proton from the cyclohexadienyl cation is rapid and gives the product of electrophilic aromatic substitution... 

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. 

The mode of attack of electrophilic reagents (E ) at ring carbon atoms is jS to the heteroatoms as shown, for example, in (11) and (12) the intermediates usually revert to type by proton loss. Halogenation takes place more readily than it does in benzene (Section 4.02.1.4.5). Nitration and sulfonation also occur however, in the strongly acidic environment required the compounds are present mainly as less reactive hydroxyazolium ions, e.g. (13). 

In azole chemistry the total effect of the several heteroatoms in one ring approximates the superposition of their separate effects. It is found that pyrazole, imidazole and isoxazole undergo nitration and sulfonation about as readily as nitrobenzene thiazole and isothiazole react less readily ica. equal to m-dinitrobenzene), and oxadiazoles, thiadiazoles, triazoles, etc. with great difficulty. In each case, halogenation is easier than the corresponding nitration or sulfonation. Strong electron-donor substituents help the reaction. 

Nitration and sulfonation of aromatic compounds probably occur via the formation of the nitryl and sulfonyl cations ... 

The halogenation of selenazoles goes less smoothly than the nitration and sulfonation. For example the bromination of 2,4-dimethyl-selenazoie with cold bromine first gives an unstable monobromo derivative (mp 168°C). This is transformed easily into a compound of mp 205°C (decomp.) which Haginiwa assumes is the hydrogen bromide salt of 2,4-dimethyl-5-bromoselenazole. 

The presently known electrophilic substitution reactions all occur at the 4-position of the isoxazole nucleus, corresponding to the j3-position in pyridine. Thus the influence of the nitrogen atom is predominant. The introduction of alkyl and, particularly, aryl substituents into the isoxazole nucleus markedly increases its reactivity (on the other hand, during nitration and sulfonation the isoxazole nucleus also activates the phenyl nucleus). 

Mercuration and chloromethylation reactions as well as halogena-tion seem to proceed with preliminary coordination followed by substitution in the coordination compound. Such reactions as nitration and sulfonation in concentrated acids appear to proceed differently as evidenced by the substitution of the phenyl nucleus on nitration and by the sulfonation of phenylisoxazolcs. 

Many variations of the reaction can be carried out, including halogenation, nitration, and sulfonation. Friedel-Crafts alkylation and acylation reactions, which involve reaction of an aromatic ling with carbocation electrophiles, are particularly useful. They are limited, however, by the fact that the aromatic ring must be at least as reactive as a halobenzene. In addition, polyalkylation and carbocation rearrangements often occur in Friedel-Crafts alkylation. 

Liquid-liquid reactors. Examples of liquid-liquid reactions are the nitration and sulfonation of organic liquids. Much of the discussion for gas-liquid reactions also applies to liquid-liquid reactions. In liquid-liquid reactions, mass needs to be transferred between two immiscible liquids for the reaction to take place. However, rather than gas-and liquid-film resistance as shown in Figure 7.2, there are two liquid-film resistances. The reaction may occur in one phase or both phases simultaneously. Generally, the solubility relationships are such that the extent of the reactions in one of the phases is so small that it can be neglected. 

Pyridinones and quinolinones undergo electrophilic attack at the (3 -position (12,13) fairly easily and disubstitution is well known in the pyridine series. Pyridinones are more easily halogenated than benzene, but the highly acidic conditions used for nitration and sulfonation makes these less easy reactions. Electrophiles also attack at the oxygen (14), but this is considered as a substituent reaction and therefore will be dealt with in Chapter 2.06. 

The reactions of the higher hydrocarbons with electrophilic reagents are more complex than of naphthalene. For example, phenanthrene can be nitrated and sulfonated, and the products are mixtures of 1-, 2-, 3-, 4-, and 9-substituted phenanthrenes ... 

Halogenation, nitration, and sulfonation of hydroxyanthraquinones present no special difficulties. Modification of the hydroxyl group (boric esters, ethers) alters the mode of substitution. Derivatives of the hydroxyl groups frequently enable a different or more selective substitution than the free hydroxy compounds... 

Bromination of 3-hydroxypyridine takes place readily in aqueous solution at 20°C giving a 50% yield of the 2,4,6-tribromo derivative (50RTC1281) this is indicative of the greater ease of halogenation compared to nitration and sulfonation. 

Batch nitrations and sulfonations, e.g., reactions of toluene or chlorobenzene with a mixture of sulfuric and nitric acids... 

Because of the presence of nitrogen in the aromatic ring, electrons in pyridine are distributed in such a way that their density is higher in positions 3 and 5 (the P-positions). In these positions, electrophilic substitutions such as halogenation, nitration, and sulfonation take place. On the contrary, positions 2, 4, and 6 (a- and y-positions, respectively) have lower electron density and are therefore centers for nucleophilic displacements such as hydrolysis or Chichibabin reaction. In the case of 3,5-dichlorotrifluoropyridine, hydroxide anion of potassium hydroxide attacks the a- and y-positions because, in addition to the effect of the pyridine nitrogen, fluorine atoms in these position facilitate nucleophilic reaction by decreasing the electron density at the carbon atoms to which they are bonded. In a rate-determining step, hydroxyl becomes attached to the carbon atoms linked to fluorine and converts the aromatic compound into a nonaromatic Meisenheimer complex (see Surprise 67). To restore the aromaticity, fluoride ion is ejected in a fast step, and hydroxy pyridines I and J are obtained as the products [58],... 

In practical terms, it is usually possible to get high yields of para products from these reactions. Both nitration and sulfonation of bromobenzene give enough material to make the synthesis worthwhile. Though mixtures of products are always bad in a synthesis, electrophilic aromatic substitution is usually simple to carry out on a large enough scale to make separation of the major product a workable method. 

Pyridines without strong activation, diazines with a single strongly activating substituent and diazinones, undergo nitration and sulfonation under classical conditions with difficulty (reactivity approximately that of z-dinitrobenzene) and halogenation somewhat more readily. 

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