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Related Concept Videos

Nucleophilic Aromatic Substitution: Elimination–Addition01:11

Nucleophilic Aromatic Substitution: Elimination–Addition

Simple aryl halides do not react with nucleophiles. However, nucleophilic aromatic substitutions can be forced under certain conditions, such as high temperatures or strong bases. The mechanism of substitution under such conditions involves the highly unstable and reactive benzyne intermediate. Benzyne contains equivalent carbon centers at both ends of the triple bond, each of which is equally susceptible to nucleophilic attack. This 50–50 distribution of products is confirmed through isotopic...
Nucleophilic Aromatic Substitution: Addition–Elimination (SNAr)01:30

Nucleophilic Aromatic Substitution: Addition–Elimination (SNAr)

Nucleophilic substitution in aromatic compounds is feasible in substrates bearing strong electron-withdrawing substituents positioned ortho or para to the leaving group. The reaction proceeds via two steps: the addition of the nucleophile and the elimination of the leaving group.
The reaction begins with an attack of the nucleophile on the carbon that holds the leaving group. This results in the delocalization of the π electrons over the ring carbons. The resonance interaction between the...
Electrophilic Aromatic Substitution: Overview01:16

Electrophilic Aromatic Substitution: Overview

In an electrophilic aromatic substitution reaction, an electrophile substitutes for a hydrogen of an aromatic compound.
Nucleophilic Aromatic Substitution of Aryldiazonium Salts: Aromatic SN101:14

Nucleophilic Aromatic Substitution of Aryldiazonium Salts: Aromatic SN1

Treating arylamines with nitrous acid gives aryldiazonium salts that are effective substrates in nucleophilic aromatic substitution reactions. The diazonio group in these salts can be easily displaced by different nucleophiles, yielding a wide variety of substituted benzenes. The leaving group departs as nitrogen gas, and this easy elimination is the driving force for the substitution reaction.
In the Sandmeyer reaction, for example, the diazonio group is replaced by a chloro, bromo, or cyano...
Regioselectivity of Electrophilic Additions to Alkenes: Markovnikov's Rule02:17

Regioselectivity of Electrophilic Additions to Alkenes: Markovnikov's Rule

If a set of reactants can yield multiple constitutional isomers, but one of the isomers is obtained as the major product, the reaction is said to be regioselective. In such reactions, bond formation or breaking is favored at one reaction site over others.
The hydrohalogenation of an unsymmetrical alkene can yield two haloalkane products, depending on which vinylic carbon takes up the halogen. However, one product usually predominates, where hydrogen adds to the vinylic carbon bearing the...
Nucleophilic Substitution Reactions02:34

Nucleophilic Substitution Reactions

Historical perspective
In 1896, the German chemist Paul Walden discovered that he could interconvert pure enantiomeric (+) and (-) malic acids through a series of reactions. This conversion suggested the involvement of optical inversion during the substitution reaction. Further, in 1930, Sir Christopher Ingold described for the first time two different forms of nucleophilic substitution reactions, which are known as SN1 (nucleophilic substitution unimolecular) and SN2 (nucleophilic substitution...

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Preparation of Contiguous Bisaziridines for Regioselective Ring-Opening Reactions
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Predicting regioselectivity in nucleophilic aromatic substitution.

Magnus Liljenberg1, Tore Brinck, Björn Herschend

  • 1AstraZeneca, Sweden Operations, S-151 85 Södertälje, Sweden.

The Journal of Organic Chemistry
|March 6, 2012
PubMed
Summary

Predicting regiochemistry in nucleophilic aromatic substitution is crucial. Density Functional Theory (DFT) calculations of intermediates and transition states offer efficient, quantitative predictions for various nucleophiles and leaving groups.

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Published on: January 21, 2020

Area of Science:

  • Organic Chemistry
  • Computational Chemistry
  • Reaction Mechanisms

Background:

  • Nucleophilic aromatic substitution (SNAr) reactions are fundamental in organic synthesis.
  • Predicting the regiochemical outcome of kinetically controlled SNAr reactions is challenging.
  • Understanding reaction mechanisms aids in controlling product distribution.

Purpose of the Study:

  • To develop and evaluate computationally efficient methods for predicting regioisomer distribution in kinetically controlled SNAr reactions.
  • To assess the applicability of different theoretical approaches for various nucleophile and leaving group combinations.

Main Methods:

  • Utilizing Density Functional Theory (DFT) to calculate the relative stabilities of isomeric sigma-complex intermediates.
  • Investigating transition state structures assuming a concerted substitution step.
  • Comparing quantitative predictions with experimental outcomes for anionic and neutral nucleophiles.

Main Results:

  • The sigma-complex stability approach provided quantitative predictions for leaving groups like fluoride (F-) and hydrogen fluoride (HF).
  • This method failed for chloride (Cl/HCl) and bromide (Br/HBr) leaving groups due to difficulties in identifying relevant intermediates.
  • An alternative approach using concerted transition state structures yielded quantitatively useful results for these challenging cases.

Conclusions:

  • Computational methods, specifically DFT, can quantitatively predict regioisomer distribution in SNAr reactions.
  • The choice of theoretical approach (sigma-complex vs. concerted transition state) depends on the leaving group and nucleophile type.
  • These findings offer valuable insights for controlling reaction outcomes in SNAr chemistry.