Aromatic substitution nucleophilic, 11-14, Table

AROMATIC SUBSTITUTION, NUCLEOPHILIC AND ORGANOMETALLIC TABLE 13.1. Continued)... 

In most of their reactions phenols behave as nucleophiles and the reagents that act on them are electrophiles Either the hydroxyl oxygen or the aromatic ring may be the site of nucleophilic reactivity m a phenol Reactions that take place on the ring lead to elec trophilic aromatic substitution Table 24 4 summarizes the behavior of phenols m reac tions of this type... 

The reaction of benzenesulfonic acid with sodium hydroxide (first entry in Table 24.3) proceeds by the addition-elimination mechanism of nucleophilic aromatic substitution (Section 23.6). Hydroxide replaces sulfite ion (S03 ) at the carbon atom that bear s the leaving group. Thus, p-toluenesulfonic acid is converted exclusively to p-cresol by an analogous reaction ... 

The special substituent constants for + R para-substituents are denoted by a, and those for — R para-substituents are denoted by a+ 54. They are based respectively on the reaction series discussed above. Selected values are given in Table 1. Characteristic a or a+ values are sometimes distinguished for meta-substituents also, but only for a minority of substituents which show very marked + R or — R effects do these differ significantly from ordinary a values. The range of applicability of the Hammett equation is greatly extended by means of a and cr+, notably to nucleophilic (by a ) and to electrophilic (by cr+) aromatic substitution. 

The ease of dehalogenation of C H X by Ni(ll)/ IMes HCl 1/NaO Pr decreased in the order 1 > Br > Cl F. Subsequent work showed that a 1 1 combination of Ni and NHC in the presence of NaOCHEt resulted in enhanced reactivity towards aryl fluorides [6], Again, the A-mesityl substituted ligand IMes HCl 1 imparted the highest level of catalytic activity. Table 8.2 illustrates that hydrodefluorination is sensitive to both the nature of the substituents on the aromatic ring and the specific regioisomer. Thus, 2- or 4-fluorotoluene (Table 8.2, entry 2) proceeded to only 30% conversion after 15 h, whereas quantitative conversion of 2-fluoroanisole (Table 8.2, entry 3) and high conversion of 3-fluoropyridine (Table 8.2, entry 5) was achieved in only 2-3.5 h. The reactivity of 2-fluoropyridine was compromised by more efficient nucleophilic aromatic substitution. 

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. 

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... 

Tertiary benzylic nitriles are useful synthetic intermediates, and have been used for the preparation of amidines, lactones, primary amines, pyridines, aldehydes, carboxylic acids, and esters. The general synthetic pathway to this class of compounds relies on the displacement of an activated benzylic alcohol or benzylic halide with a cyanide source followed by double alkylation under basic conditions. For instance, 2-(2-methoxyphenyl)-2-methylpropionitrile has been prepared by methylation of (2-methoxyphenyl)acetonitrile using sodium amide and iodomethane. In the course of the preparation of a drug candidate, the submitters discovered that the nucleophilic aromatic substitution of aryl fluorides with the anion of a secondary nitrile is an effective method for the preparation of these compounds. The reaction was studied using isobutyronitrile and 2-fluoroanisole. The submitters first showed that KHMDS was the superior base for the process when carried out in either THF or toluene (Table I). For example, they found that the preparation of 2-(2-methoxyphenyl)-2-methylpropionitrile could be accomplished h... 

Similarly, those reactions that are strongly assisted by withdrawal of electrons from the reaction site, such as nucleophilic aromatic substitution, give a poor fit to a Hammett plot for the substituents that are capable of withdrawing electrons by delocalization (—N02, —N2 , —C=N, and so on). An example is Reaction 16 in Table 26-7. To correlate reactivity data with structures where strong resonance effects operate, different sets of substituent constants are required.1... 

Not all radical aromatic substitutions are as immune to polar effects as is attack by phenyl. Some radicals reveal marked electrophilic or nucleophilic character. Oxygen-centered radicals, for example, are electrophilic, as would be expected if there is substantial polar contribution to the transition state. Table 9.13 lists partial rate factors for substitution by benzoyl radicals note that the orientation and activation trends found in typical electrophilic substitutions have begun to appear, but are still modest compared with the dramatic effects shown in Table 9.12 for a true heterolytic substitution.179... 

If the other reactant is an electrophile and a strong Lewis acid or proton acid is present, then the aromatic ring acts as the nucleophile and the reaction is one of the electrophilic aromatic substitution reactions listed in Table 17.2. Do not forget to consider the directive and rate effects of substituents on the aromatic ring. 

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