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Fischer Projections02:18

Fischer Projections

Learning to draw Fischer projections of molecules and understanding their relevance plays a crucial role in the visual depiction of organic molecules. A Fischer projection is a two-dimensional projection on a planar surface to simplify the three-dimensional wedge–dash representation of molecules. This is especially helpful in the case of molecules with multiple chiral centers that can be difficult to draw. Here, all the bonds of interest are represented as horizontal or vertical lines. While...
Carboxylic Acids to Esters: Acid-Catalyzed (Fischer) Esterification Overview01:20

Carboxylic Acids to Esters: Acid-Catalyzed (Fischer) Esterification Overview

The Fischer esterification reaction was developed by the German chemist Emil Fischer in 1895. It is a condensation reaction between carboxylic acids and alcohols in an acidic medium to give esters and water.
Carboxylic Acids to Esters: Acid-Catalyzed (Fischer) Esterification Mechanism01:13

Carboxylic Acids to Esters: Acid-Catalyzed (Fischer) Esterification Mechanism

Carboxylic acids react with alcohols to yield esters via an acid-catalyzed condensation reaction called Fischer esterification. This is a nucleophilic acyl substitution reaction that proceeds via a tetrahedral intermediate, where a water molecule is eliminated as the leaving group.
Preparation of 1° Amines: Hofmann and Curtius Rearrangement Mechanism01:26

Preparation of 1° Amines: Hofmann and Curtius Rearrangement Mechanism

The Hofmann and Curtius rearrangement reactions can be applied to synthesize primary amines from carboxylic acid derivatives such as amides and acyl azides. In the Hofmann rearrangement, a primary amide undergoes deprotonation in the presence of a base, followed by halogenation to generate an N-haloamide. A second proton abstraction produces a stabilized anionic species, which rearranges to an isocyanate intermediate via an alkyl group migration from the carbonyl carbon to the neighboring...
Preparation of 1° Amines: Hofmann and Curtius Rearrangement Overview01:07

Preparation of 1° Amines: Hofmann and Curtius Rearrangement Overview

In the presence of an aqueous base and a halogen, primary amides can lose the carbonyl (as carbon dioxide) and undergo rearrangement to form primary amines. This reaction, called the Hofmann rearrangement, can produce primary amines (aryl and alkyl) in high yields without contamination by secondary and tertiary amines.
Amines to Alkenes: Hofmann Elimination01:16

Amines to Alkenes: Hofmann Elimination

Alkenes can be obtained from amines via an E2 elimination. The amine is first converted into a good leaving group, such as a quaternary ammonium salt. This is accomplished by treating the amine with an excess of alkyl halide, which results in a halide salt. Next, the halide salt is transformed into a hydroxide salt that functions as a base to enable elimination.
Under thermal conditions, the hydroxide can abstract a proton from the β carbon; this generates an alkene with the simultaneous...

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Related Experiment Video

Updated: Jul 2, 2026

A Direct, Regioselective and Atom-Economical Synthesis of 3-Aroyl-N-hydroxy-5-nitroindoles by Cycloaddition of 4-Nitronitrosobenzene with Alkynones
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A Direct, Regioselective and Atom-Economical Synthesis of 3-Aroyl-N-hydroxy-5-nitroindoles by Cycloaddition of 4-Nitronitrosobenzene with Alkynones

Published on: January 21, 2020

A three-component Fischer indole synthesis.

Christopher A Simoneau1, Bruce Ganem

  • 1Baker Laboratory, Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, USA.

Nature Protocols
|August 21, 2008
PubMed
Summary

This study presents a novel three-component synthesis for multiply-substituted indoles. The efficient one-pot method combines organometallic reagents, nitriles, and arylhydrazines for indole production.

Area of Science:

  • Organic Chemistry
  • Synthetic Chemistry

Background:

  • Indole derivatives are crucial scaffolds in medicinal chemistry and materials science.
  • Existing synthetic routes to multiply-substituted indoles can be lengthy and complex.

Purpose of the Study:

  • To develop an efficient, one-pot protocol for the synthesis of multiply-substituted indoles.
  • To utilize readily available starting materials: nitriles, organometallic reagents, and arylhydrazine hydrochloride salts.

Main Methods:

  • A three-component reaction involving the condensation of organometallic reagents (organolithium or Grignard) with nitriles to form metalloimines.
  • Subsequent in-situ formation of arylhydrazones under acidic conditions in the presence of arylhydrazines.
  • Integration of the Fischer indole reaction to yield the target indole products.

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Synthesis of Indoxyl-glycosides for Detection of Glycosidase Activities

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Main Results:

  • The protocol successfully generates multiply-substituted indoles through an efficient one-pot process.
  • The reaction sequence involves metalloimine formation (3 h), Fischer indole reaction (15 h), and product isolation/purification (2 h), totaling approximately 20 hours.
  • This method offers a streamlined approach compared to multi-step syntheses.

Conclusions:

  • A novel and efficient one-pot synthetic strategy for multiply-substituted indoles has been established.
  • The described protocol provides a valuable tool for accessing diverse indole structures.
  • This method simplifies indole synthesis, making it more accessible for researchers.