Nucleophilic aromatic substitution

Summary

A nucleophilic aromatic substitution is a substitution reaction in organic chemistry in which the nucleophile displaces a good leaving group, such as a halide, on an aromatic ring. Aromatic rings are usually nucleophilic, but some aromatic compounds do undergo nucleophilic substitution. Just as normally nucleophilic alkenes can be made to undergo conjugate substitution if they carry electron-withdrawing substituents, so normally nucleophilic aromatic rings also become electrophilic if they have the right substituents.This reaction differs from a common SN2 reaction, because it happens at a trigonal carbon atom (sp2 hybridization). The mechanism of SN2 reaction does not occur due to steric hindrance of the benzene ring. In order to attack the C atom, the nucleophile must approach in line with the C-LG (leaving group) bond from the back, where the benzene ring lies. It follows the general rule for which SN2 reactions occur only at a tetrahedral carbon atom. The SN1 mechanism is possib

Official source

https://en.wikipedia.org/wiki/Nucleophilic_aromatic_substitution

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Fluorine in an heteroaromatic context

Thierry Rausis

The organometallic approach to the functionalization of arenes and heteroarenes has recently been investigated by our group introducing modifications of the standard methods. This includes, in particular, the basicity-driven heavy halogen migration, which allows the introduction of a functional group at a not directly accessible position. Then, some attentions were reported toward nucleophilic aromatic substitution and especially to a regio-controlled attack at heteroarenes. Bulky trialkylsilyl groups were used to shield a given position by steric congestion against both electrophilic and nucleophilic attack. Using different electrophiles, commercially available 2,6-difluoropyridine was selected as substrate for a large proliferation of derivatives through organolithium intermediates. To allow for more regioflexibility, one can either rely on protective groups or introduce iodine which will be subsequently submitted to a basicity gradient-driven relocation and eventually a halogen/metal exchange. A systematic investigation was undertaken to explore the scope and the limitations of this latter option. Di-, tri- and tetrahalopyridines are used to explore the substituent effect in nucleophilic substitutions with the pyridine ring. An activating substituent as chlorine directed the nucleophilic substitution at the vicinal fluorine atom. Unprecedented was the finding that bulky 3-trialkylsilyl group effectively shielded the fluorine at the adjacent 2- and 4-positions, reorienting the nucleophilic substitution to the 6-position. To exploit the regioselectivity established by the "silyl trick", some halopyridines, such as 2,4,5-trifluoropyridine or 2,4-dichloro-6-hydrazinopyridine, were prepared for the fist time. Highly substituted derivatives isolated during nucleophilic substitutions were the starting point for the development of more complex structures such 2-amino-5-bromo-4-chloro-6-fluoro-3-nitropyridine obtained by using some of the developed techniques.

EPFL2005

Diamine Synthesis via the Nitrogen-Directed Azidation of sigma- and pi-C-C Bonds

Mingming Wang, Jérôme Waser

Diamines are essential building blocks for the synthesis of agrochemicals, drugs, and organic materials, yet their synthesis remains challenging, as both nitrogens need to be differentiated and diverse substitution patterns (1,2, 1,3, or 1,4) are required. We report herein a new strategy giving access to 1,2, 1,3, and 1,4 amido azides as orthogonally protected diamines based on the nitrogen-directed diazidation of alkenes, cyclopropanes, and cyclobutanes. Commercially available copper thiophene-2-carboxylate (CuTc, 2 mol %) as catalyst promoted the diazidation of both pi and sigma C-C bonds within 10 min in the presence of readily available oxidants and trimethylsilyl azide. Selective substitution of the formed alpha-amino azide by carbon nucleophiles (electron-rich aromatic, malonate, organosilicon, organoboron, organozinc, and organomagnesium compounds) was then achieved in a one-pot fashion, leading to the formation of 1,2-, 1,3-, and 1,4-diamines with the amino groups protected orthogonally as an amide/carbamate and an azide.

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Fluorine in an heteroaromatic context

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EPFL2022