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Related Concept Videos

Nucleophilic Aromatic Substitution of Aryldiazonium Salts: Aromatic SN101:14

Nucleophilic Aromatic Substitution of Aryldiazonium Salts: Aromatic SN1

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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,...
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Preparation of 1° Amines: Azide Synthesis01:22

Preparation of 1° Amines: Azide Synthesis

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Direct alkylation of ammonia produces polyalkylated amines, along with a quaternary ammonium salt. To exclusively prepare primary amines, the azide synthesis method can be used.
Azide ions act as good nucleophiles and react with unhindered alkyl halides to form alkyl azides. Alkyl azides do not participate in further nucleophilic substitution reactions, thereby eliminating the chances of polyalkylated products. Alkyl azides are reduced by hydride-based reducing agents, like lithium aluminum...
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Nucleophilic Aromatic Substitution: Elimination–Addition01:11

Nucleophilic Aromatic Substitution: Elimination–Addition

4.2K
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...
4.2K
Aryldiazonium Salts to Azo Dyes: Diazo Coupling01:11

Aryldiazonium Salts to Azo Dyes: Diazo Coupling

3.1K
The reaction of weakly electrophilic aryldiazonium (also called arenediazonium) salts with highly activated aromatic compounds leads to the formation of products with an —N=N— link, called an azo linkage. This reaction, presented in Figure 1, is known as diazo coupling and occurs without the loss of the nitrogen atoms of the aryldiazonium salt. Highly activated aromatic compounds such as phenols or arylamines favor the diazo coupling reaction. The coupling generally occurs at the...
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Base-Catalyzed Ring-Opening of Epoxides02:26

Base-Catalyzed Ring-Opening of Epoxides

9.0K
Due to their highly strained structures, epoxides can readily undergo ring-opening reactions through nucleophilic substitution, either in the presence of an acid or a base. The nucleophilic substitution reactions in the presence of acid are called acid-catalyzed ring-opening reactions, and nucleophilic substitution reactions in the presence of a base are called base-catalyzed ring-opening reactions. Epoxides undergo base-catalyzed ring-opening reactions in the presence of a strong nucleophile...
9.0K
Diazonium Group Substitution with Halogens and Cyanide: Sandmeyer and Schiemann Reactions01:20

Diazonium Group Substitution with Halogens and Cyanide: Sandmeyer and Schiemann Reactions

2.1K
Arenediazonium substitution reactions occur when the diazonium group is substituted by various functional groups such as halides, hydroxyl, nitrile, etc. For instance, arenediazonium salts react with copper(I) salts of chloride, bromide, or cyanide to form corresponding aryl chlorides, bromides, and nitriles. These reactions are named Sandmeyer reactions. Although the mechanism of this reaction is complicated, as illustrated in Figure 1, they are believed to progress via an aryl copper...
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Preparation of Stable Bicyclic Aziridinium Ions and Their Ring-Opening for the Synthesis of Azaheterocycles
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Intramolecular Ring-Opening Decomposition of Aryl Azetidines.

Guoyun Bai1, Thomas N O'Connell1, Michael A Brodney2

  • 1Discovery Sciences, Pfizer Worldwide Research and Development, Groton, Connecticut 06340, United States.

ACS Medicinal Chemistry Letters
|October 22, 2021
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N-substituted azetidines decompose via acid-mediated ring-opening. Understanding this mechanism helps design more stable azetidine compounds for various applications.

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Area of Science:

  • Organic Chemistry
  • Heterocyclic Chemistry

Background:

  • Azetidines, three-membered nitrogen-containing heterocycles, possess inherent ring strain.
  • This strain can compromise their stability, limiting their synthetic utility and application.

Purpose of the Study:

  • To investigate the acid-mediated decomposition pathway of N-substituted azetidines.
  • To elucidate the mechanism of intramolecular ring-opening facilitated by pendant amide groups.
  • To inform the design of novel, stabilized azetidine derivatives.

Main Methods:

  • Synthesis of a series of N-substituted azetidine compounds.
  • Acid-catalyzed reaction studies to induce ring-opening decomposition.
  • Mechanistic investigations employing spectroscopic and analytical techniques.

Main Results:

  • Demonstrated acid-mediated intramolecular ring-opening decomposition in N-substituted azetidines.
  • Identified the nucleophilic attack of a pendant amide group as the key step in the decomposition pathway.
  • Characterized the decomposition products and intermediates.

Conclusions:

  • The inherent ring strain of azetidines leads to decomposition under acidic conditions via intramolecular nucleophilic attack.
  • Elucidation of the decomposition mechanism provides a basis for designing more stable azetidine analogues.
  • This research contributes to the development of robust azetidine-based molecules.