Nucleophilic aromatic substitution (SNAr) is a type of reaction in organic chemistry where a nucleophile replaces a leaving group on an aromatic ring. It is also known as aromatic nucleophilic substitution or S_NAr reaction.
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In typical nucleophilic substitution reactions, such as SN1 or SN2, the nucleophile attacks an electrophilic carbon atom. However, in nucleophilic aromatic substitution, the aromatic ring is relatively unreactive and does not readily undergo nucleophilic attack. Therefore, the reaction proceeds through a mechanism involving the formation of an intermediate called a Meisenheimer complex.
The general mechanism for nucleophilic aromatic substitution involves the following steps:
- Nucleophile attack: The nucleophile attacks the aromatic ring, typically targeting an electron-deficient carbon atom. This can occur at different positions on the ring, such as ortho (2), meta (3), or para (4) positions, depending on the substituents present.
- Formation of Meisenheimer complex: The initial attack forms a Meisenheimer complex, which is an intermediate with a negatively charged aromatic ring. This complex is stabilized by resonance and involves a charge transfer between the nucleophile and the aromatic ring.
- Rearrangement and leaving group expulsion: The Meisenheimer complex rearranges to stabilize the negative charge and allow for the expulsion of the leaving group. This rearrangement often involves the migration of substituents or electron density within the ring.
- Regeneration of aromaticity: After the leaving group is expelled, the aromaticity of the ring is restored through a process that involves the transfer of electrons.
Nucleophilic aromatic substitution reactions can proceed under different reaction conditions, depending on the nature of the nucleophile and the substituents on the aromatic ring. Some common nucleophiles used in SNAr reactions include alkoxides, amines, thiols, and cyanide ions.
Nucleophilic aromatic substitution reactions are widely utilized in organic synthesis for the functionalization of aromatic compounds. They can introduce various functional groups onto aromatic rings, allowing for the synthesis of a diverse range of compounds, including pharmaceuticals, dyes, and agrochemicals.
It’s important to note that nucleophilic aromatic substitution reactions are highly dependent on the electronic and steric effects of the substituents on the aromatic ring. The presence of electron-withdrawing or electron-donating groups and the position of these groups relative to the nucleophilic attack can significantly influence the reactivity and regioselectivity of the reaction.
ACTUAL NOTES:
PATH: PHARMD/PHARMD NOTES/ PHARMD FIRST YEAR NOTES/ ORGANIC CHEMISTRY/ PHARMACEUTICAL ORGANIC CHEMISTRY/NUCLEOPHILIC AROMATIC SUBSTITUTION.
