For nucleophilic aromatic

The generally accepted mechanism for nucleophilic aromatic substitution m nitro substituted aryl halides illustrated for the reaction of p fluoromtrobenzene with sodium methoxide is outlined m Figure 23 3 It is a two step addition-elimination mechanism, m which addition of the nucleophile to the aryl halide is followed by elimination of the halide leaving group Figure 23 4 shows the structure of the key intermediate The mech anism is consistent with the following experimental observations... 

The product of this reaction as its sodium salt is called a Meisenheimer complex after the Ger man chemist Jacob Meisenheimer who reported on their formation and reactions in 1902 A Meisenheimer complex corresponds to the product of the nucleophilic addition stage in the addition-elimination mechanism for nucleophilic aromatic substitution... 

Addition-elimination mechanism (Section 23 6) Two stage mechanism for nucleophilic aromatic substitution In the addition stage the nucleophile adds to the carbon that bears... 

The most important mechanism for nucleophilic aromatic substitution is the S Ar mechanism. The first step is usually rate determining siace this is the step ia which the aromaticity is lost. 

It is regrettable that the evidence afforded by reaction kinetics is rarely, if ever, uniquely consistent with a single mechanism or a single explanation. The results for nucleophilic aromatic substitution reactions are no exception. Legitimate questions can be raised with respect to the extent to which observations made on a particular system permit generalization to other systems. Even for the specific systems studied points of detail arise, and choices have to be made where alternatives are possible. Every such choice introduces an element of uncertainty and imposes a limitation on the extent to which the reaction mechanism is, in fact, known. 

The first widely used intermediates for nucleophilic aromatic substitution were the aryl diazonium salts. Aryl diazonium ions are usually prepared by reaction of an aniline with nitrous acid, which is generated in situ from a nitrite salt.81 Unlike aliphatic diazonium ions, which decompose very rapidly to molecular nitrogen and a carbocation (see Part A, Section 4.1.5), aryl diazonium ions are stable enough to exist in solution at room temperature and below. They can also be isolated as salts with nonnucleophilic anions, such as tetrafluoroborate or trifluoroacetate.82 Salts prepared with 0-benzenedisulfonimidate also appear to have potential for synthetic application.83... 

The addition of a nucleophile to an aromatic ring, followed by elimination of a substituent, results in nucleophilic substitution. The major energetic requirement for this mechanism is formation of the addition intermediate. The addition step is greatly facilitated by strongly electron-attracting substituents, and nitroaromatics are the best reactants for nucleophilic aromatic substitution. Other EWGs such as cyano, acetyl, and trifluoromethyl also enhance reactivity. 

A wide variety of other heterocyclic ring systems can conceivably serve as the conjugated backbone in nonlinear organic molecules. We will give examples from preliminary work on two of these, the thiazole and pyrimidine heterocycle derivatives 65-72 in Table VIII. These two heterocycles were chosen because the appropriate haloderivatives are commercially available as starting materials for nucleophilic aromatic substitution. The pyrimidine derivatives are of particular interest since their absorption edges ( 400 nm) are shifted hypsochromically an additional 30 nm relative even to the pyridines. 

We can also describe the differences between these reaction types in terms of Pearson s hard-soft description (Pearson, 1966 Pearson and Songstad, 1967). Cationic micellar head groups interact best with soft bases, e.g. relatively large anions of low charge density such as bromide or arenesulfo-nate, or anionic transition states such as those for nucleophilic aromatic substitution. They interact less readily with hard bases, e.g. high charge density anions such as OH ", or anionic transition states for deacylation. 

It is more difficult to interpret micellar effects upon reactions of azide ion. The behavior is normal , in the sense that k /kw 1, for deacylation, an Sn2 reaction, and addition to a carbocation (Table 4) (Cuenca, 1985). But the micellar reaction is much faster for nucleophilic aromatic substitution. Values of k /kw depend upon the substrate and are slightly larger when both N 3 and an inert counterion are present, but the trends are the same. We have no explanation for these results, although there seems to be a relation between the anomalous behavior of the azide ion in micellar reactions of aromatic substrates and its nucleophilicity in water and similar polar, hydroxylic solvents. Azide is a very powerful nucleophile towards carboca-tions, based on Ritchie s N+ scale, but in water it is much less reactive towards 2,4-dinitrohalobenzenes than predicted, whereas the reactivity of other nucleophiles fits the N+ scale (Ritchie and Sawada, 1977). Therefore the large values of k /kw may reflect the fact that azide ion is unusually unreactive in aromatic nucleophilic substitution in water, rather than that it is abnormally reactive in micelles. 

TABLE 6. Second-order rate constants for nucleophilic aromatic substitution reactions of 2,4-dinitrochlorobenzene and picryl chloride. Reprinted with permission from Reference 77. Copyright (1992) American Chemical Society... 

The utilization of polar polymers and novel N-alkyl-4-(N, N -dialklamino)pyridinium sedts as stable phase transfer catalysts for nucleophilic aromatic substitution are reported. Polar polymers such as poly (ethylene glycol) or polyvinylpyrrolidone are thermally stable, but provide only slow rates. The dialkylaminopyridininium salts are very active catalysts, and are up to 100 times more stable than tetrabutylammonium bromide, allowing recovery and reuse of catalyst. The utilization of b is-dialkylaminopypridinium salts for phase-transfer catalyzed nucleophilic substitution by bisphenoxides leads to enhanced rates, and the requirement of less catalyst. Experimental details are provided. 

Figure 13. Reaction scheme for nucleophilic aromatic photosubstitution (the values in parentheses refer to the photohydrolysis of 3,5-dinitroanisole in alkaline medium).

Halopyridines and other re-deficient nitrogen heterocycles are excellent reactants for nucleophilic aromatic substitution.112 Substitution reactions also occur readily for other heterocyclic systems, such as 2-haloquinolines and 1-haloisoquinolines, in which a potential leaving group is adjacent to a pyridine-type nitrogen. 4-Halopyridines and related heterocyclic compounds can also undergo substitution by nucleophilic addition-elimination but are somewhat less reactive. 

Organic molten salts such as tris-n-butyl-dodecylphosphonium halides (melting point below 40°C) have been used as reaction media for nucleophilic aromatic substitution of aryl tosylates by halide ions (Fry and Pienta, 1985). 

As expected for nucleophilic aromatic substitutions, the reactivity of the fluorine(s) can be enhanced by I and -M substituents, e.g. nitro groups. 

A variation on the aryne mechanism for nucleophilic aromatic substitution (discussed above, Scheme 2.8) is the SrnI mechanism (see also Chapter 10). Product analysis, with or without radical initiation or radical inhibition, played a crucial role in establishing a radical anion mechanism [21]. The four isomeric bromo- and chloro-trimethylbenzenes (23-X and 25-X, Scheme 2.9) reacted with potassium amide in liquid ammonia, as expected for the benzyne mechanism, giving the same product ratio of 25-NH2/23-NH2 = 1.46. As the benzyne intermediate (24) is unsymmetrical, a 1 1 product ratio is not observed. 

You may have noticed something else. The formation of trifluralin 31 showed that amines are good nucleophiles for nucleophilic aromatic substitution and the nucleophile here is an amino-alcohol 36. Direct reaction with 36 might lead to the formation of an amine instead of an ether. To avoid this, 36 is first treated with NaH to make the oxyanion and then added to 35. The alcohol is less nucleophilic but the oxyanion is more nucleophilic than the amine. We hope you now see why an understanding of reaction mechanisms is an essential preliminary to the designing of syntheses. 

A final mechanism for nucleophilic aromatic substitution occurs when aromatic halides are reacted with very strong bases, such as amide anion, or with weaker bases, such as hydroxide ion, at high temperatures. For example, an older industrial method for the... 

After a new (and unusual) mechanism, such as the benzyne mechanism for nucleophilic aromatic substitution, is proposed, experiments are usually designed to test that mechanism. A classic experiment supporting the benzyne mechanism used a radioactive carbon label. Examination of the mechanism shown in Figure 17.6 shows that the carbon bonded to the leaving chlorine and the carbon ortho to it become equivalent in the benzyne intermediate. Consider what would happen if the carbon bonded to the chlorine were a radioactive isotope of carbon (l4C) rather than the normal isotope of carbon (I2C). If we follow the position of the radioactive carbon label through the mechanism of Figure 17.6, we find that the label should be equally distributed between the carbon attached to the amino group in the product and the carbon ortho to it. 

The SN1 mechanism cannot be involved either. Strong nucleophiles are required for nucleophilic aromatic substitution, and the reaction rate is proportional to the concentration of the nucleophile. Thus, the nucleophile must be involved in the rate-limiting step. 

The addition-elimination mechanism for nucleophilic aromatic substitution requires strong electron-withdrawing substituents on the aromatic ring. Under extreme conditions, however, unactivated halobenzenes react with strong bases. For example, a commercial synthesis of phenol (the Dow process ) involves treatment of chlorobenzene with sodium hydroxide and a small amount of water in a pressurized reactor at 350 °C ... 

We have already described how nitration leads eventually to aromatic amines by reduction of the nitro group. In the next chapter you will meet the further development of these amines into diazoni-um salts as reagents for nucleophilic aromatic substitution by the S l mechanism with loss of nitrogen. In this chapter we need to address their potential for electrophilic aromatic substitution without the loss of nitrogen as this leads to the important azo dyes. Treatment of the amine with nitrous acid (H0N=0) at around 0°C gives the diazonium salt. 

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