Nucleophilic aromatic regioselectivity

For any of the nucleophilic aromatic reactions covered in this chapter, regioselectivity, when more than one activated position is available, depends in most cases on the selectivity of attack by the nucleophile. However, when the conversion of the cr-adduct to product is the rate-limiting step, as in the VNS reaction, the final product distribution may differ from that expected, based on the relative electrophilic reactivity of the possible reaction sites.15 Important roles are played by deactivating steric effects and by stabilizing specific interactions such as those, for example, between an ion-paired nucleophile and a nitro activating group, which favor attack at the ortho position. 

In a separate report, the regioselectivity and reactivity problems in the substitution of pyrimidines were avoided using 4,6-dichloro-5-nitropyrimi-dine as starting material,17 a very electron-poor heterocycle, which is highly reactive in nucleophilic aromatic substitutions. It reacts readily with the free amino group of the (trialkoxybenzhydrylamine) Rink linker on solid phase. This heterocycle could serve as a scaffold by itself and could also be used as a building block (precursor) to make other heterocycles such as purines. 

The regioselective functionalization of nitrobenzene and benzonitrile derivatives has been performed via nucleophilic aromatic substitution of hydrogen by phosphorus-stabilized carbanions.41 Lithium phosphazenes have been found to be the most suitable nucleophiles for the substitution of hydrogen in nitrobenzene. This method represents a convenient alternative to the vicarious nucleophilic substitution for the synthesis of benzylic phosphorus derivatives using phosphorus-stabilized anions that do not bear a leaving group at the carbanionic centre. 

Parker, K. A. Coburn, C. A. Regioselectivity in intramolecular nucleophilic aromatic substitution. Synthesis of the potent anti HIV-18-halo TIBO analogues. J. Org. Chem. 1992, 57, 97— 100. 

More involved studies of the oxidation of plant phenols [27], as well as the introduction of thallium and hypervalent iodine complexes and the use of electrochemical methods, have emphasized the importance of another intermediate involved in oxidative coupling reactions, namely the phenoxonium ion 8 [28-30]. Due to its ionic nature, reaction through an oxo-nium ion can improve the regioselectivity of bond formation and lead to fewer unwanted products (for example, no coupling via the oxygen atom). The coupling reaction can then be viewed as an electrophilic aromatic substitution between 17 and a nucleophilic aromatic unit 15 (Scheme 5). 

Heating the diazonium salt below in the presence of methyl acrylate gives a reasonable yield of a chloroacid. Why is this unlikely to be nucleophilic aromatic substitution by the S l mechanism (Chapter 23) Suggest an alternative mechanism that explains the regioselectivity. 

Scheme 11.13 Regioselective and enantioselective nucleophilic aromatic substitution reactions.

Jorgensen developed a catalytic regioselective and enantioselective nucleophilic aromatic substitution reaction of activated aromatic compounds with 1,3-dicarbonyl compounds under phase-transfer conditions. This was crucial for obtaining the C-arylated product 61 predominantly with high enantioselectivity by replacing a benzyl with a benzoate group in the cinchona alkaloids-derived phase-transfer catalyst (Scheme 11.13) [49]. 

Scheme 2.42 The regioselectivity of a second nucleophilic aromatic substitution in perfluoroaromatic systems. The negatively charged primary addition product is stabilized best by fluorine in the ortho position (o), second best in the meta (m), and least in the para position (p). Only for attack of the nucleophile in the para position (right) is the complex stabilized by two ortho and two meta fluorines (Nu = nucleophile X = first substituent, e.g. OMe, NMe2) [95].

This chapter is also about functionalisation. But it deals with the addition of a difficult electrophile ( RO+ ) to familiar nucleophiles aromatic compounds, including the pyridines of chapter 32, and enols and enolates. As well as the difficulties of creating suitable reagents that control chemo- and regioselectivity, stereoselectivity and asymmetric induction are important. 

Using electrophilic and nucleophilic aromatic substitution in five- and six-membered heterocycles. Chemo- and regioselectivity The synthesis of pyridazines... 

Buncel E, Dust JM, and Terrier F, Rationalizing the regioselectivity in polynitroarene anionic sigma-adduct formation. Relevance to nucleophilic aromatic substitution, Chem. Rev., 95, 2261, 1995. 

Klan et al. recently studied temperature-sensitive, regioselective photochemical nucleophilic aromatic substitution of 4-nitroanisole by the hydroxide anion in... 

Extensive discussions regarding the factors that affect the regioselectivity of such nucleophilic aromatic substitution processes have been published in the course of developing the chemistry of pentafluoropyridine and related heteroaromatic systems. 

Checking your understanding of nucleophilic aromatic substitution involving decisions on chemoselectivity and regioselectivity. 

The formation of substituted anilides from the reaction of amides with nitrobenzene is the first example of the direct formation of aromatic amide bonds via nucleophilic aromatic substitution for hydrogen. This reaction proceeds in high yield and regioselectivity, and does not require the use of halogenated materials or auxiliary leaving groups. Furthermore, these studies have demonstrated that the use of O2 as the terminal oxidant in NASH reactions can result in a highly selective and environmentally favorable route for the production of PNA and PPD. 

Functionalization of metallabenzenes through nucleophilic aromatic substitution of hydrogen is a new motif of the chemistry of aromatic compounds. Cationic osma-and iridabenzenes have recently been shown to undergo regioselective nucleophilic aromatic substitution of hydrogen at the position 4 relative to the metal in a two-step addition-oxidation process (Scheme 27) [113]. 

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