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Cycloaddition Reactions: Overview

Cycloaddition Reactions: Overview

Cycloadditions are one of the most valuable and effective synthesis routes to form cyclic compounds. These are concerted pericyclic reactions between two unsaturated compounds resulting in a cyclic product with two new σ bonds formed at the expense of π bonds. The [4 + 2] cycloaddition, known as the Diels–Alder reaction, is the most common. The other example is a [2 + 2] cycloaddition.

Nitrosation of Enols

Nitrosation of Enols

The nitrosation reaction is one of the methods of preparing 1,2-diketones. The enol tautomer of the starting ketone reacts with sodium nitrite in hydrochloric acid, generating the 1,2-diketone after hydrolysis.

Cycloaddition Reactions: MO Requirements for Thermal Activation

Cycloaddition Reactions: MO Requirements for Thermal Activation

Thermal cycloadditions are reactions where the source of activation energy needed to initiate the reaction is provided in the form of heat. A typical example of a thermally-allowed cycloaddition is the Diels–Alder reaction, which is a [4 + 2] cycloaddition. In contrast, a [2 + 2] cycloaddition is thermally forbidden.

[4+2] Cycloaddition of Conjugated Dienes: Diels–Alder Reaction

[4+2] Cycloaddition of Conjugated Dienes: Diels–Alder Reaction

The Diels–Alder reaction is an example of a thermal pericyclic reaction between a conjugated diene and an alkene or alkyne, commonly referred to as a dienophile. The reaction involves a concerted movement of six π electrons, four from the diene and two from the dienophile, forming an unsaturated six-membered ring. As a result, these reactions are classified as [4+2] cycloadditions.

ortho–para-Directing Activators: –CH3, –OH, –&NoBreak;NH2, –OCH3

ortho–para-Directing Activators: –CH₃, –OH, –⁠NH₂, –OCH₃

All ortho–para directors, excluding halogens, are activating groups. These groups donate electrons to the ring, making the ring carbons electron-rich. Consequently, the reactivity of the aromatic ring towards electrophilic substitution increases. For instance, the nitration of anisole is about 10,000 times faster than the nitration of benzene. The electron-donating effect of the methoxy group in anisole activates the ortho and para positions on the ring and stabilizes the corresponding...

Cyclohexenones via Michael Addition and Aldol Condensation: The Robinson Annulation

Cyclohexenones via Michael Addition and Aldol Condensation: The Robinson Annulation

Robinson annulation is a base-catalyzed reaction for the synthesis of 2-cyclohexenone derivatives from 1,3-dicarbonyl donors (such as cyclic diketones, β-ketoesters, or β-diketones) and α,β-unsaturated carbonyl acceptors. Named after Sir Robert Robinson, who discovered it, this reaction yields a six-membered ring with three new C–C bonds (two σ bonds and one π bond).

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Updated: Nov 20, 2025

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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Published on: January 21, 2020

Bioorthogonal Reactions Utilizing Nitrones as Versatile Dipoles in Cycloaddition Reactions.

Didier A Bilodeau¹, Kaitlyn D Margison¹, Mariam Serhan¹

¹Department of Chemistry and Biomolecular Science, University of Ottawa, 10 Marie Curie, Ottawa, Ontario K1N 6N5, Canada.

Chemical Reviews

|January 19, 2021

Summary

Nitrones enable rapid bioorthogonal chemistry for labeling biological systems. Optimized nitrone reactions offer efficient tools for chemical biology research and applications.

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Published on: February 7, 2019

Area of Science:

Chemical Biology
Organic Chemistry
Biochemistry

Background:

Bioorthogonal chemistry allows for the introduction of unnatural molecules into living systems.
Nitrones are versatile reactants that can participate in highly efficient cycloaddition reactions.

Purpose of the Study:

To review the development and applications of nitrone-based bioorthogonal reactions.
To highlight the optimization of nitrone reactions for biological applications.

Main Methods:

Review of literature on nitrone-based bioorthogonal reactions.
Discussion of reaction optimization through stereoelectronic tuning.
Examples of nitrone reactions with cyclooctynes and trans-cyclooctenes (TCO).

Main Results:

Optimized nitrone reactions exhibit high efficiency, with rate constants approaching 10^2 M^-1 s^-1.
Nitrones react rapidly with cyclooctynes and TCO in bioorthogonal cycloadditions.
Copper-catalyzed nitrone-alkyne reactions are also optimized for biological use.

Conclusions:

Nitrone-based reactions are powerful tools for bioorthogonal chemistry.
These reactions facilitate the probing of biological systems with unnatural functionalities.