Nitration electrophilic attack

It is noteworthy that the compounds which have been shown to undergo extensive acetoxylation or side-chain nitration, viz. those discussed above and hemimellitene and pseudocumene (table 5.4), are all substances which have an alkylated ring position activated towards electrophilic attack by other substituents. 

A methyl group is an electron releasing substituent and activates all of the ring carbons of toluene toward electrophilic attack The ortho and para positions are activated more than the meta positions The relative rates of attack at the various positions m toluene compared with a single position m benzene are as follows (for nitration at 25°C)... 

Substituents can be introduced into the thia2ole ring either by using suitably substituted precursors or by direct electrophilic attack on the ring. An interesting example of the latter method is the preparation of 2-ainino-5-iiitrothia2ole [121 -66-4] from the nitrate salt of 2-aminothia2ole. 

No simple electrophilic substitution, for example nitrosation, nitration, sulfonation or halogenation of a C—H bond, has so far been recorded in the pteridine series. The strong 7T-electron deficiency of this nitrogen heterocycle opposes such electrophilic attack, which would require a high-energy transition state of low stability. 

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. 

In the section dealing with electrophilic attack at carbon some results on indazole homocyclic reactivity were presented nitration at position 5 (Section 4.04.2.1.4(ii)), sulfon-ation at position 7 (Section 4.04.2.1.4(iii)) and bromination at positions 5 and 7 (Section 4.04.2.1.4(v)). The orientation depends on the nature (cationic, neutral or anionic) of the indazole. Protonation, for instance, deactivates the heterocycle and directs the attack towards the fused benzene ring. A careful study of the nitration of indazoles at positions 2, 3, 5 or 7 has been published by Habraken (7UOC3084) who described the synthesis of several dinitroindazoles (5,7 5,6 3,5 3,6 3,4 3,7). The kinetics of the nitration of indazole to form the 5-nitro derivative have been determined (72JCS(P2)632). The rate profile at acidities below 90% sulfuric acid shows that the reaction involves the conjugate acid of indazole. 

Selective electrophilic attack has also been demonstrated, for example, during nitration,48 chlorination,37-49 bromination,32 acylation and formylation.32k... 

The mechanism of oxidation probably involves in most cases the initial formation of a glycol (15-35) or cyclic ester,and then further oxidation as in 19-7. In line with the electrophilic attack on the alkene, triple-bonds are more resistant to oxidation than double bonds. Terminal triple-bond compounds can be cleaved to carboxylic acids (RC=CHRCOOH) with thallium(III) nitrate or with [bis(trifluoroacetoxy)iodo]pentafluorobenzene, that is, C6F5l(OCOCF3)2, among other reagents. 

Nitration of the diazido dinitro derivative 81 proceeds easily to give the 4,8-diazido-2,3,9,10-tetranitro derivative 82 in 76% yield (Equation 3). The ease of the nitration of 81 stems from activation of the C-3 and C-9 positions toward electrophilic attack by the ortho-directing effect of the azido groups <1996JOC5801>. 

Generally, electrophilic attack at the 3(4)-position is negligible unless both 2(5)-positions are filled or unless it is otherwise forced, as in a cyclization.140 Probably very small amounts of 3(4)-substitution occur and are overlooked in ordinary work though they can be found, if sought carefully, even in nitrations.141 Ciranni and Clementi142 discuss this matter (the aratio) in... 

Electrophilic attack at carbon is a well-documented reaction which occurs regioselectively at the C-3 position. It was illustrated by numerous examples, including nitrations, halogenations, acylations, and Mannich reactions in CHEC(1984) and CHEC-II(1996) <1996CHEC-II(8)249>. Table 1 reports some additional recent examples. It should be noted that all these synthetic transformations were carried out in the field of medicinal chemistry. 

As mentioned earlier, oxidation of dibenzothiophene to either the sulfoxide or sulfone causes electrophilic attack to occur at the 3-position rather than at the normal 2-position. This trend is further exemplified by the behavior of 4-methyldibenzothiophene which is nitrated in the 2-position (26%), while nitration of 4-methyldibenzothiophene 5,5-dioxide occurs in the 3-position yielding 112. The structures of both of these products were deduced from their NMR spectra. 

Nitric acid-acetic anhydride mixtures give poor yields for the nitration of amides with groups that hinder the amide nitrogen against electrophilic attack. The use of higher temperatures in these reactions leads to variable amounts of the A-nitroso compound as a by-product. ... 

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... 

Acids and Lewis acids react with quinoline at the basic nitrogen atom to form quinolinium salts, and there is a question over the nature of the substrate for electrophilic attack, i.e. is it quinoline or the quinolinium cation The answer is not a simple one and appears to depend upon the reagents and reaction conditions. Thus, whereas acetyl nitrate at 20 °C gives mainly 3-nitroquinoline (Scheme 3.2), fuming nitric acid in concentrated sulfuric acid containing sulfur trioxide at 15-20 °C yields a mixture of 5-nitroquinoline (35%) and 8-nitroquinoline (43%) (Scheme 3.3). In the case of acetyl nitrate, the reaction may proceed by the 1,4-addition of the reagent to quinoline, followed by electrophilic attack upon the 1,4-dihydro derivative. 

When there is an electron-releasing substituent in the 4-position, the electrophile attacks the 1-position. This has been used as a convenient way of preparing 1-substituted dibenzofurans by removal of an amino group at the 4-position. Bromination, chlorination, and diazo coupling of 4-dibenzofuranol occur at the 1-position. Bromination and Vilsmeier-Haack formylation of 4-methoxydibenzofuran provide the 1-substituted derivatives. Nitration and bromination of 4-acetylaminodibenzofuran take a similar course. ... 

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. 

It is significant that in the two benzoquinolizinium systems examined to date, nitration, a typical electrophilic substitution reaction, occurs in the side-chain ring at the a-position which could not bear a positive charge in structures contributing to the resonance hybrid. From this it seems likely that when the benzo[a ]quinolizinium system (2) undergoes electrophilic attack, position 8 will be preferred. 

These equations show the general theoretical basis for the empirical order of rate constants given earlier for electrophilic attack on an aromatic ligand L, its metal complex ML, and its protonated form HL, one finds kt > n > hl. Conflicting reports in the literature state that coordination can both accelerate electrophilic aromatic substitution (30) and slow it down enormously (2). In the first case the rates of nitration of the diprotonated form of 0-phenanthroline and its Co(III) and Fe(III) complexes were compared. Here coordination prevents protonation in the mixed acid medium used for nitration and kML > h2l. In the second case the phenolate form of 8-hydroxyquinoline-5-sulfonic acid and its metal chelates were compared. The complexes underwent iodination much more slowly, if at all, and kL > kML ... 

Step (1) is reminiscent of electrophilic addition to an alkene. Aromatic substitution differs in that the intermediate carbocation (a benzenonium ion) loses a cation (most often to give the substitution product, rather than adding a nucleophile to give the addition product. The benzenonium ion is a specific example of an arenonium ion, formed by electrophilic attack on an arene (Section 11.4). It is also called a sigma complex, because it arises by formation of a o-bond between E and the ring. See Fig. 11-1 for a typical enthalpy-reaction curve for the nitration of an arene. 

Compounds 4 and 5 would be expected to be inert toward electrophilic substitution, and, in fact, sulfonation of the 2-phenyl derivative 201234 and nitration of the 1-phenyl derivative 202l69b lead to substitution on the phenyl rings. A series of electrophilic substitutions on the product (203) from 1 -(n-butyl)[l,2,3]triazolo[4,5-c]pyridine and dimethyl sulphate give 7-bromo-, 7-nitro-, and 7-chlorotriazolopyridin-4-ones the electrophilic attack may, in each case, be on the triazolopyridinone.169... 

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