Nitration and Halogenation

Nitration and Halogenation.—4-Phenylisothiazole undergoes electrophilic substitution under mild conditions, predominantly in the benzene ring. 

Nitration at 0°C yields 4-(/ -nitrophenyl)isothiazole and its o-isoner in 85 and 15% yields, respectively further action produces the 2,4-di-nitrophenyl compound. Bromination and chlorosulphonation sinilarly afford chiefly p-substituted products (65 = Br or SO2CI R = H). 

Halogenation in glacial acetic acid at 25 C yields 4-(p-bromopheiyl)-5-bromoisothiazole as a by-product (up to 20%). The substituenti thus introduced display their usual properties in aromatic systems. Firther examples of halogenations are reported below (see p. 573). 

In contrast, nitration of 4-substituted 3-phenylisothiazoles (66) a 0 °C yields exclusively 3-(m-nitrophenyl) derivatives (67). 3-Phenylisothazole itself (66 R = R = H) produces, under these conditions, 3-(/ [and /n-]nitrophenyl)isothiazole (68). The nitro-compounds show the expected behaviour, being reducible to the corresponding amines [e.g. (69)], which 

Nakagawa, and K. Takahashi, Chem. and Pharm. Bull. (Japan), 1968, 16, 160. 

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The mechanism of aromatic aulphonation may be similar to that previously described for nitration and halogenation, involving attack of the electrophilic... 

Nitration and halogenation of furfural occurs under carehiUy controlled conditions with introduction of the substituent at the open 5-position (24,25). Nitration of furfural is usually carried out in the presence of acetic anhydride, resulting in the stable compound, 5-nitrofurfuryhdene diacetate (26,27). The free aldehyde is isolated by hydrolysis and must be used immediately in a reaction because it is not very stable. 

In still other cases, the product of reaction of an electrophile with an aminoazole is from electrophilic attack at a ring carbon. This is electrophilic substitution and is the general result of nitration and halogenation (see Section 4.02.1.4). In such cases, reactions at both cyclic nitrogen and at an amino group are reversible. 

Electrophilic substitution occurs readily in Af-phenyl groups, e.g. 1-phenyI-pyrazoIes, -imidazoles and -pyrazolinones are all nitrated and halogenated at the para position. The aryl group is attacked preferentially when the reactions are carried out in strongly acidic media, where the azole ring is protonated. 

The most notable chemistry of the biscylopen-tadienyls results from the aromaticity of the cyclopentadienyl rings. This is now far too extensively documented to be described in full but an outline of some of its manifestations is in Fig. 25.14. Ferrocene resists catalytic hydrogenation and does not undergo the typical reactions of conjugated dienes, such as the Diels-Alder reaction. Nor are direct nitration and halogenation possible because of oxidation to the ferricinium ion. However, Friedel-Crafts acylation as well as alkylation and metallation reactions, are readily effected. Indeed, electrophilic substitution of ferrocene occurs with such facility compared to, say, benzene (3 x 10 faster) that some explanation is called for. It has been suggested that. 

For a discussion on the preferred site of attack for many ring systems, see de la Mare, P.B.D. Ridd, J.H. Aromatic Substitution Nitration and Halogenation Academic Press NY, 1959, p. 169. 

This reaction set may be regarded as parallel reactions with respect to consumption of species B and as a series reaction with respect to species A, V, and W. Common examples include the nitration and halogenation of benzene and other organic compounds to form polysubstituted compounds. To characterize the qualitative behavior of such systems, it is useful to consider reactions 9.3.3 and 9.3.4 as mechanistic equations and to analyze the effects of different contacting patterns on the yield of species V. We shall follow the treatment of Levenspiel (7). 

Diffusion control and pre-association in nitrosation, nitration, and halogenation, 16,1... 

Nitronate(47a) is not the only oxazete derivative. For example, sterically hindered nitroalkenes (42b-d) can be prepared by nitration and halogenation of readily available allenes (48). Compounds (42b-d) are rather smoothly isomerized into the corresponding four-membered cyclic nitronates (47b-d) by the first-order reaction equation (168). Storage of nitronate (47c) is accompanied by its slow transformation into acid chloride (47e) from which amide (47f) can be easily synthesized. 

Table 6 displays data for the isomer proportions formed in the nitration and halogenation of nitrobenzene224. As with all +/, +R substituents, the formation of the meta isomer predominates. The reactions are far slower than those of benzene itself. Partial rate factors for the reaction of nitrobenzene with HNO3-H2SO4 are as follows / , 1.08 x 10 8 fm,... 

P. De la Mare and J. H. Ridd, Aromatic Substitution Nitration and Halogenation, Butterworth, London (1959). 

The furoxan ring is notably resistant to electrophilic attack and reaction normally takes place at the substituents. Thus aryl groups attached to monocyclic furoxans and the homocyclic ring of benzofuroxans are nitrated and halogenated without disruption of the heterocycle. Reaction with acid is also slow protonation is predicted to occur at N-5 <89KGS1261> and benzofuroxans have pKj, values of ca. 8, similar to those of benzofurazans. Monosubstituted furoxans are, as expected, less stable and can be hydrolyzed to the corresponding carboxylic acid. Treatment of the parent furoxan (3) with concentrated sulfuric acid results in rearrangement to (hydroxyimino)acetonitrile oxide (HON=CHC=N —O ) and subsequent dimerization to bis(hydroxyiminomethyl)furoxan... 

Problem 11.6 Sulfonation resembles nitration and halogenation in being an electrophilic substitution, but differs in being reversible and in having a moderate primary kinetic isotope effect. Illustrate with diagrams of enthalpy H) versus reaction coordinate. ... 

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