1,3-dipolar cycloaddition reaction- mechanism, example, dipole, click reaction-chemarticle

Recently few chemical journals review, Using the 1,3-dipolar addition reaction-the preparation of anticancer agents-important of biochemical synthesis


Welcome to Chem Article. Today we will discuss the 1,3-dipolar cycloaddition reaction. This is the part of the cycloaddition reaction in the pericyclic reaction chapter. 
pericyclic reaction: crated by chemarticle.com 

1,3-dipolar cycloaddition reaction

The 1,3-polar addition of two components one is 1,3-diene (1,3-dipole and which is 4πe system) and another is dipolarophile (2πe system). This reaction is known as the 1,3-dipolar cycloaddition reaction.  In this reaction, dipoles have one or more canonical structures. In this 1,3-dipolar cycloaddition reaction, three atoms do not follow any HOMO/LUMO symmetry concept. It follows the dipole of the 1,3- dipole reagent. This reaction already fulfilled the concept of HOMO/LUMO symmetry.
  • During the 1,3-dipolar cycloaddition reaction the formation of five-membered heterocyclic rings
  • In case dipoles have different canonical structures, they need no process of how many large permanent structures.
  • The example of 1,3-dipole: Diazomethane (4πe system). 
  • A dipolarophile must have one triple or double bond.

The 1,3-dipolar cycloaddition examples

One of the most typical examples of a 1,3-dipolar cycloaddition reaction is the reaction between ozone (as a 1,3-dipole) and alkene; the results obtain ozonide. The final result of ozonide is formed by rearrangement of initial study materials, which are dipole and dipolarophile. 
The 1,3-dipolar cycloaddition examples
The 1,3-dipolar cycloaddition examples

The example of 1,3-dipole

Consider a dipole, which most have one or more heteroatoms. In case the combination of carbon and heteroatom (like oxygen, nitrogen, fluorine, boron, etc. all are hetero atoms) make a dipole. All dipoles must have 4π electrons in the three parallel p-orbitals.
The most common few examples of 1,3-dipole are azides, nitrile oxides, azomethine ylides, nitrones, diazo-alkanes, etc.
example of 1,3-dipole-chemarticle.com
Few examples of 1,3-dipole: azides, di-azoalkane, nitrile oxides, nitrones, azomethine ylides - chem article

Stereochemistry of 1,3-dipolar cycloaddition reaction

In these five examples of 1,3-dipole, some dipoles are relatively stable, such as diazo-alkane and azide compounds. All cycloaddition reactions occur by a concerted process. During the cycloaddition reaction (1,3-dipolar addition) the stereochemistry (Z or E) of alkene (or dipolarophile) is maintained (cis or trans configuration) the cycloadduct or stereospecificity.
In this 1,3-dipolar cycloaddition reaction regioselectivity and stereoselectivity, dependable factors are steric and electronic factors. This reaction does not predict stereoselectivity and regioselectivity using the frontier orbital theory (Molecular Orbitals Symmetry Concept). Which prediction is most difficult? Yes. 
Stereochemistry of 1,3-dipolar cycloaddition reaction-chemarticle
Stereochemistry of 1,3-dipolar cycloaddition reaction-chemarticle

The example of 1,3-dipolar cycloaddition reaction using Nitrile Oxides dipole.

  • Consider Nitrile oxide as a dipole, which reacts with alkene (where but-2-ene acts as a dipolarophile) formation of heteroatomic isoxazoline.
  • Nitrile oxides react with an alkyne, then the formation of heteroatomic isoxazole.
The formation of product heteroatomic isoxazoline shows the reductive cleavage of this compound using synthetic intermediates. The resultant of this reactive cleavage of isoxazoline is 1,3-amino-alcohols. Some examples of useful intermediates are H2, Pd/C, lithium aluminum hydride (LiAlH4).
The product isoxazoline reductive cleavage, consider the hydrolytic reduction process using synthetic intermediate example Raney nickel in aqueous acid.

Intramolecular 1,3-dipolar cycloaddition reactions

The very useful organic synthesis of 1,3-dipolar cycloaddition reaction in the same molecules, which is called intramolecular reaction. We have to check the example of organic synthesis of antitumor agents Sarcomycin (R=H) and calicheamicin. 
  • First of all, dehydration of nitro-alkene[I] and formation of isoxazoline[II] via nitrile oxide as an intermediate.
  • Then hydrolysis of isoxazoline[II] with Raney nickel in aqueous acidic acids and formation of the β-hydroxy ketone[III]
  • Finally, β-hydroxy ketone dehydrated to ethyl ester of sarcomycin. This is the mechanism of organic synthesis of antitumor agent sarcomycin[IV] when (R=Et).
Similarly, organic synthesis of calicheamicin, 
  • The organic synthesis of oxime with sodium hypochlorite and the formation of isoxazoline compound.
Intramolecular 1,3-dipolar cycloaddition reactions
Intramolecular 1,3-dipolar cycloaddition reactions: preparation of  antitumor agents Sarcomycin- chemarticle.

Sharpless click reaction

The organic synthesis of alkyne and alkyl azide gives the 1,4-isomer product. As we can be called the reduction of alkyne with reducing agent Cu(I) or copper sulfate (CuSO4), sodium ascorbate. In 2001, sir Sharpless discover the click reaction. This is the one type of example of a 1,3-dipolar cycloaddition reaction.  
  • The terminal alkyne is acted as a dipolarophile. And on the other hand, alkyl azide act as a dipole or 1,3-dipole.
  • Cu(I) or CuSO4 act as a reducing agent.
  • Follow the 1,3-dipolar cycloaddition reaction process. In the case formation of a five-member transition state, which is acts as an intermediate. In the case of intermediate is the formation of zwitterion. 
  • The formation of the final product is 1,4-isomer. In this click, the reaction does not formation of 1,5-isomer.
Click reaction-sherpless-chemarticle
Click reaction: the reaction between Alkyne and Alkyl Azide using Cu(I) or copper sulfate, Sodium ascorbate. which is give the 1,4-isomer product. 


We have to discuss the pericyclic reaction part-6. In this section, we have to talk about 1,3-dipolar cycloaddition reaction, 1,3-dipole, dipolarophile, the example of 1,3-dipole, organic synthesis of the antitumor agents sarcomycin and calicheamicin. We are seeing the preparation of dihydro pyrazole from diazomethane. The reaction 1,3-dipolar addition is very important for biochemical synthesis. Using the 1,3-dipolar addition reaction we have to synthesis the anticancer agent, which is very brief use in the medical department. This is the future of 1,3-dipolar cycloadditions. 

Recently few chemical journals review, we have seen that the 1,3 -dipolar cycloaddition reaction processes are widely used in organic synthesis (mainly this addition process is used in the preparation of anticancer agents).