Related Nucleophilic Aromatic Substitution Reactions

The most common types of aryl halides in nucleophilic aromatic substitutions are those that bear o- or p-nitro substituents. Among other classes of reactive aryl halides, a few merit special consideration. One class includes highly fluorinated aromatic compounds such as hexafluorobenzene, which undergoes substitution of one of its fluorines on reaction with nucleophiles such as sodium methoxide. 

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A number of syntheses of pioglitazone have been disclosed (Arita and Mizuno, 1992 Fischer et al., 2005 Les et al., 2004 Meguro and Fujita, 1986, 1987 Momose et al., 1991 Prous and Castaner, 1990 Saito et al., 1998). Two related syntheses (Fischer et al., 2005 Les et al., 2004) of pioglitazone hydrochloride are described in Scheme 8.2. The tosylate of 2-(5-ethylpyridin-2-yl)ethanol (16), formed in situ with tosyl chloride, was displaced by 4-hydroxybenzaldehyde (17) by means of benzyltributylammonium chloride and NaOH to give 4-[2-(5-ethylpyridin-2-yl)ethoxy]benzaldehyde (20). Condensation of 20 with thiazolidine-2,4-dione in basic medium afforded 5-[-4-[2-(5-ethylpyridin-2-yl)ethoxy]benzylidene]thiazolidine-2,4-dione (21). Finally, this compound was hydrogenated to provide pioglitazone (2). Alternatively, a nucleophilic aromatic substitution reaction... 

During my early years as an assistant professor at the University of Kentucky, I demonstrated the synthesis of a simple quinone methide as the product of the nucleophilic aromatic substitution reaction of water at a highly destabilized 4-methoxybenzyl carbocation. I was struck by the notion that the distinctive chemical reactivity of quinone methides is related to the striking combination of neutral nonaromatic and zwitterionic aromatic valence bond resonance structures that contribute to their hybrid resonance structures. This served as the starting point for the interpretation of the results of our studies on nucleophile addition to quinone methides. At the same time, many other talented chemists have worked to develop methods for the generation of quinone methides and applications for these compounds in organic syntheses and chemical biology. The chapter coauthored with Maria Toteva presents an overview of this work. 

Pseudobase formation by nucleophilic addition to heteroaromatic cations is closely related to the long-known Meisenheimer complex formation by nucleophilic addition to an electron-deficient neutral aromatic molecule.20-25 In both cases nucleophilic attack on an electron-deficient aromatic ring produces a c-complex—an anionic Meisenheimer complex or a neutral pseudobase molecule. Despite the intense interest over the past few years in Meisenheimer complexes as models for er-complex intermediates in nucleophilic aromatic substitution reactions, there has been little overt recognition of the relationship between Meisenheimer complexes and pseudobases derived from heteroaromatic cations. In this regard, it is interesting that the pseudobase 165, which can be regarded as the complex intermediate that would be expected for an SNAr reaction between the l-methyl-4-iodoquinolinium cation and hydroxide ion, has been spectroscopically characterized.89... 

The anionic a complexes formed between polynitroaromatic compounds and bases (1, 2), commonly known as Meisenheimer complexes, are used as models of the reaction intermediates that are considered to be formed in activated nucleophilic aromatic substitution reactions (3-6), as well as being of intrinsic interest. Thus, numerous studies describe the formation and transformation of such a complexes (7-14). As a result, a variety of structural types of these species have been characterized and subjected to detailed investigation. A number of theoretical studies relating to these species have also been reported (15). 

Nucleophilic aromatic substitution reactions have been examined in terms of a model based on the combination of a cation with an anion. The reactivities of 2,4-dinitro-halogenobenzenes with nucleophiles have been shown to be related to the basicity and polarisability of the nucleophile and the polarisability of the substrate only atoms and bonds at or near the reaction centre are involved in producing the polarisability effects. Hammett cr values have been measured for unsaturated groups —CH=NX in the 4-position for nucleophilic displacement of chlorine in 2-nitrochlorobenzene derivatives and compared with those for established activating groups. ... 

Nucleophilic aromatic substitution reactions should not be looked upon as a precise, rigidly bounded entity. These reactions might perhaps be considered as one aspect of the more general area of nucleophilic displacements on unsaturated carbon atoms. As such they are related to the many displacements occurring at carbonyl carbon atoms (the hydrolysis of esters, acid chlorides, anhydrides, and amides the aminolysis of esters, anhydrides, and acid chlorides the esterification of acids, acid chlorides, and anhydrides, etc.) and to nucleophilic displacements on double-bonded carbon in non-aromatic systems. Undoubtedly there are significant differences among these classes of reactions, but there are equally significant similarities. 

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. 

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. 

Nucleophilic vinylic substitutions are closely related to nucleophilic aromatic substitutions, as in both the leaving group leaves from an unsaturated carbon atom. However, the vinylic substitution routes are much more diverse, and disclose more of the details of the reaction. Stereochemical study of the reaction can give information on the lifetime of the intermediate and about the structure of the transition state... 

Aromatic chemistry is discussed earlier in this edition Chapter 16 covers aromaticity, and Chapter 17 presents aromatic substitution reactions. Chapters 18 and 19 discuss additions to and substitutions at the carbonyl group. To keep these chapters from being overwhelming, aldol and ester condensations are covered separately in Chapter 20, which deals with reactions of enolate and related nucleophiles. Chapter 21 presents the chemistry of radicals. 

Conjugate substitution electrophilic alkenes bearing leaving groups can promote substitution reactions at C=C related to those at C=0 Nucleophilic aromatic substitution electron-poor aromatic rings that allow substitution reactions with nucleophiles rather than the usual electrophiles... 

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