Nucleophilic aromatic substitution

Source: Wikipedia, the free encyclopedia.

A nucleophilic aromatic substitution (SNAr) is a

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 possible but very unfavourable unless the leaving group is an exceptionally good one. It would involve the unaided loss of the leaving group and the formation of an aryl cation. In the SN1 reactions all the cations employed as intermediates were planar with an empty p orbital. This cation is planar but the p orbital is full (it is part of the aromatic ring) and the empty orbital is an sp2 orbital outside the ring.[1]

Nucleophilic aromatic substitution mechanisms

Aromatic rings undergo nucleophilic substitution by several pathways.

  1. SNAr (addition-elimination) mechanism
  2. aromatic
    diazonium salts
  3. benzyne mechanism (E1cB-AdN)
  4. SRN1 mechanism
  5. ANRORC mechanism
  6. Vicarious nucleophilic substitution

The SNAr mechanism is the most important of these. Electron withdrawing groups activate the ring towards nucleophilic attack. For example if there are

para to the halide
leaving group, the SNAr mechanism is favored.

SNAr reaction mechanism

The following is the reaction mechanism of a nucleophilic aromatic substitution of 2,4-dinitrochlorobenzene (1) in a basic solution in water.

Nucleophilic aromatic substitution
Nucleophilic aromatic substitution

Since the

hydroxyl group
. This Meisenheimer complex is extra stabilized by the additional electron-withdrawing nitro group (2b).

In order to return to a lower energy state, either the hydroxyl group leaves, or the chloride leaves. In solution, both processes happen. A small percentage of the intermediate loses the chloride to become the product (2,4-dinitrophenol, 3), while the rest return to the reactant (1). Since 2,4-dinitrophenol is in a lower energy state, it will not return to form the reactant, so after some time has passed, the reaction reaches chemical equilibrium that favors the 2,4-dinitrophenol, which is then deprotonated by the basic solution (4).

The formation of the

resonance-stabilized Meisenheimer complex is slow because the loss of aromaticity due to nucleophilic attack results in a higher-energy state. By the same coin, the loss of the chloride or hydroxide is fast, because the ring regains aromaticity. Recent work indicates that, sometimes, the Meisenheimer complex is not always a true intermediate but may be the transition state of a 'frontside SN2' process, particularly if stabilization by electron-withdrawing groups is not very strong.[2] A 2019 review argues that such 'concerted SNAr' reactions are more prevalent than previously assumed.[3]

carbanions.[5]

Nucleophilic aromatic substitution reactions

Some typical substitution reactions on arenes are listed below.

Nucleophilic aromatic substitution is not limited to arenes, however; the reaction takes place even more readily with

aromatic para position because then the negative charge is effectively delocalized at the nitrogen position. One classic reaction is the Chichibabin reaction (Aleksei Chichibabin, 1914) in which pyridine is reacted with an alkali-metal amide such as sodium amide to form 2-aminopyridine.[6]

In the compound methyl 3-nitropyridine-4-carboxylate, the meta nitro group is actually displaced by

cesium fluoride in DMSO at 120 °C.[7]

Nucleophilic aromatic substitution at pyridine
Nucleophilic aromatic substitution at pyridine

Asymmetric nucleophilic aromatic substitution

With carbon nucleophiles such as 1,3-dicarbonyl compounds the reaction has been demonstrated as a method for the

benzylated
at N and O).

Asymmetric nucleophilic aromatic substitution

See also

References

  1. ISBN 978-0-19-927029-3
    .
  2. PMID 27281221
    .
  3. PMID 30990931
    .
  4. ^ a b Clayden J. Organic Chemistry. Oxford University Press.
  5. ^
    doi:10.1021/acs.jchemed.6b00680
    .
  6. ISBN 0-471-85472-7
    .
  7. PMID 17962783
    .
  8. PMID 15771481
    .
Wikimedia Commons has media related to Nucleophilic aromatic substitution reactions.
Retrieved from "https://en.wikipedia.org/w/index.php?title=Nucleophilic_aromatic_substitution&oldid=1219375090"