Related Nucleophilic Aromatic Substitutions

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. 

Here it is the combined electron-attracting effects of the six fluorine substituents that stabilize the cyclohexadienyl anion intermediate and permit the reaction to proceed so readily. 

Write equations describing the addition-elimination mechanism for the reaction of hexafluorobenzene with sodium methoxide, clearly showing the structure of the ratedetermining intermediate. 

Halides derived from certain heterocyclic aromatic compounds are often quite reactive toward nucleophiles. 2-Chloropyridine, for example, reacts with sodium methoxide some 230 million times faster than chlorobenzene at 50°C. 

Offer an explanation for the observation that 4-chloropyridine is more reactive toward nucleophiles than 3-chloropyridine. 

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Nucleophilic Aromatic Substitution 490 The Addition-Elimination Mechanism of Nucleophilic Aromatic Substitution 492 Related Nucleophilic Aromatic Substitutions 494 12.22 Summary 496 Problems 500... 

Nucleophilic aromatic substitution can also occur by an elimination-addition mechanism This pathway is followed when the nucleophile is an exceptionally strong base such as amide ion m the form of sodium amide (NaNH2) or potassium amide (KNH2) Benzyne and related arynes are intermediates m nucleophilic aromatic substitutions that pro ceed by the elimination-addition mechanism... 

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. 

It might be expected that the activating effect of p-NO2 on nucleophilic aromatic substitution would be related to the a value of the substituent. From various studies of nucleophilic aromatic substitution, Miller and Parker213 obtained a <7 value for /2-NO2 of 1.27, very close to the values based on the ionization of substituted phenols or anilinium ions (Section ELD). 

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. 

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... 

Relation to Nucleophilic Aromatic Substitution by the SNAr Mechanism... 

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. 

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... 

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... 

Pyridines and related nitrogen heterocyclic (azabenzenoid) compounds Polyfluoroaromatic nitrogen heterocyclic systems are all activated, relative to the corresponding benzenoid compounds, towards nucleophilic aromatic substitution. The magnitude of this activation is illustrated by the effects of a ring nitrogen, relative to C—F at the same position, for attack by ammonia [91] (Figure 9.32). 

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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