Nitro deactivation

It will be noticed that this account makes no allowance for the electrostatic interaction of the positive pole with the electrophile, the nitro-nium ion. This should generally work for deactivation, and its influence at nuclear positions should be in the order ortho > meta > para. This point is resumed below. 

The nitration of nitro- and dinitro-biphenyls has been examined by several workers. i - As would be expected, nitration of the nitro-biphenyls occurs in the phenyl ring. Like a phenyl group, a nitrophenyl group is 0 -directing, but like certain substituents of the type CH CHA ( 9.1.6) it is, except in the case of w-nitrophenyl, deactivating. Partial rate factors for the nitration at o °C of biphenyl and the nitro-biphenyls with solutions prepared from nitric acid and acetic anhydride are given below. The high o p-v2X o found for nitration of biphenyl... 

These acylating agents are the most commonly used (246). Acid chlorides react with 5-nitro-2-aminothiazoIe (88) despite the deactivating effect of the nitro group (Scheme 61) (247), but more vigorous conditions are required (248). 

Even when deactivated by nitro substitution on C-5, the 2-aminothiazoles still undergo diazotization (35, 338-340). As with carbonyl derivatives (Section III.2.B), competition may occur between N nucleophilic reactivity and nitrosation of the 5-position when it is unsubstituted (341-344). 

Very strongly deactivating 0 II —CCI —C=N —SO3H -CF3 —NO2 (acyl chloride) (cyano) (sulfonic acid) (trifluoromethyl) (nitro) Meta directing... 

This makes the nitro group a powerful electron withdrawing deactivating substituent and a meta director... 

Neither Friedel-Crafts acylation nor alkylation reactions can be earned out on mtroben zene The presence of a strongly deactivating substituent such as a nitro group on an aromatic ring so depresses its reactivity that Friedel-Crafts reactions do not take place Nitrobenzene is so unreactive that it is sometimes used as a solvent m Friedel-Crafts reactions The practical limit for Friedel-Crafts alkylation and acylation reactions is effectively a monohalobenzene An aromatic ring more deactivated than a mono halobenzene cannot be alkylated or acylated under Friedel-Crafts conditions... 

Electron-attracting substituents in the coupling components such as halogen, nitro, sulfo, carboxyl, and carbonyl, are deactivating and tend to retard coupling. 

The effect of substituents on the reactivity of heterocyclic nuclei is broadly similar to that on benzene. Thus mem-directing groups such as methoxycarbonyl and nitro are deactivating. The effects of strongly activating groups such as amino and hydroxy are difficult to assess since simple amino compounds are unstable and hydroxy compounds exist in an alternative tautomeric form. Comparison of the rates of formylation and trifiuoroacetylation of the parent heterocycle and its 2-methyl derivative indicate the following order of sensitivity to substituent effects furan > tellurophene > selenophene = thiophene... 

Mercury(II) acetate tends to mercurate all the free nuclear positions in pyrrole, furan and thiophene to give derivatives of type (74). The acetoxymercuration of thiophene has been estimated to proceed ca. 10 times faster than that of benzene. Mercuration of rings with deactivating substituents such as ethoxycarbonyl and nitro is still possible with this reagent, as shown by the formation of compounds (75) and (76). Mercury(II) chloride is a milder mercurating agent, as illustrated by the chloromercuration of thiophene to give either the 2- or 2,5-disubstituted product (Scheme 25). 

Dimethylpyrazole 1.4- Dimethyl-3-nitropyrazole The attack at the 3- and 5-positions occurs on the free base. Standard rates 1,4-dimethylpyrazole (attack at the 3-position), log /co = 3.55, l,4-dimethyl-3-nitropyrazole (attack at the 5-position), log /c = -4.73 (deactivating effect of the nitro group) 75JCS(P2)1632... 

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. 

The cyano, nitro, and quaternary ammonium groups are strongly deactivating and weto-directing. Electrophilic substitutions of compounds with these substituents require especially vigorous conditions and fail completely with all but the most reactive electrophiles. 

From resonance structure (12) it is obvious that a —I—M-substit-uent strongly deactivates the 2-position toward electrophilic substitution, and one would thus expect that monosubstitution occurs exclusively in the 5-position. This has also been found to be the case in the chlorination, bromination, and nitration of 3-thiophenecarboxylic acid. Upon chlorination and bromination a second halogen could be introduced in the 2-position, although further nitration of 5-nitro-3-thiopheneearboxylic acid could not be achieved. Similarly, 3-thiophene aldehyde has been nitrated to 5-nitro-3-thiophene aldehyde, and it is further claimed that 5-bromo-3-thiopheneboronic acid is obtained upon bromination of 3-thiopheneboronic acid. ... 

Steric hindrance to activation by carboaromatic nitro groups is well-known, but there seems to be no analogy in the chemistry of azines. The lone-pair of azine-nitrogen has a steric effect comparable " to, somewhat greater than, or somewhat less " than a hydrogen atom. It is not certain whether bulky groups such as i-butyl produce a steric distortion of the lone-pair orbital and whether activation or deactivation results. 

The ortho indirect deactivating effect of the two methyl groups in 2,6-dimethyl-4-nitropyridine 1-oxide (163) necessitates a much higher temperature (about 195°, 24 hr) for nucleophilic displacement of the nitro group by chloride (12iV HCl) or bromide ions N HBr) than is required for the same reaction with 4-nitropyridine 1-oxide (110°). With 5-, 6-, or 8-methyl-4-chloroquinolines, Badey observed 2-7-fold decreases in the rate of piperidino-dechlorination relative to that of the des-methyl parent (cf. Tables VII and XI, pp. 276 and 338, respectively). 

Greater para than ortho deactivation is seen in the hydrolysis (HCl in AcOH, 100°, 1 hr) of the nitro group in 5,6-diphenyl-2-nitro-3-pyrazinone (218) but not in 6-phenyl- or 3,6-diphenyl-2-nitro-5-pyrazinone (219). Similarly, acid hydrolysis of a 2-bfomo substituent in 3-pyrazinone, but not in 5-pyrazinone, is readily accomplished. All flve of these pyrazinones are stable in strong alkali or alkoxide as a result of complete anionization. Decreased reactivity of... 

The relation of the activation by a nitro group to that by an azine-nitrogen in various bicyclic positions provides information in support of that available from studies of azines and forms the basis for certain predictions of azine reactivity. The data tabulated in Section IV, A, 2 also provide a few comparisons of leaving groups, nucleophiles, and deactivating and activating substituents (cf. Sections II, E and III, A, 2). 

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