1,3-dipolar reactions

Table of Contents

What are 1,3-dipolar reactions?

A 1,3-dipole is a system of 3 atoms with 4 π electrons delocalized on those 3 atoms. 1,3-dipolar species cannot be written as resonant Lewis structures without using charges. That is, the Lewis structure contains only paired electrons. These 1,3-dipoles contain a central heteroatom, which may have sp or sp2 hybridization, depending on whether or not it presents a double bond orthogonal to the delocalized π-system.

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This does not imply that they are polar, because the charges are not localized.

R groups can be substituents or unshared electron pairs.

The most commonly used 1,3-dipoles for cycloadditions are summarized in the following scheme.

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Although they have a central sp-hybridized heteroatom, they are easily bent to allow for cycloaddition reactions at the ends.

Compounds that can react with these 1,3-dipoles in cycloaddition reactions are known as dipolarophiles. These contain unsaturated functional groups such as C≡C, C=C, C≡N, C=N, C=O, and C=S.

1,3-dipolar cycloadditions are concerted processes, without defined reaction intermediates, which pass through asymmetric transition states. That is, one of the new σ bonds is more advanced than the other.

The polarity of the solvent has a very weak influence on the reaction rate. This shows that there is little change in polarity between the reactants and the transition state.

In practice, it is observed that the reactivity of 1,3-dipoles towards different dipolarophiles varies widely.

As for the selectivity of these reactions, a great variety of them can produce mixtures of isomers. However, others may also show a high selectivity with one of the products predominating, when it is not formed exclusively.

For example, this scheme shows the possible regioisomers obtained.

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and in this one the possible stereoisomers that can be obtained with this type of 1,3-dipolar reaction.

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For example, the cycloaddition of diazomethane with methyl acrylate gives the two possible stereoisomers A and B.

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However, the A product is formed exclusively because the interaction leading to the A product is much stronger than that of the B product.

Example 1,3-dipolar reactions (azides, NNN-)

Many azides (NNN) are isolable compounds. Therefore, it is possible to prepare them with a wide variety of substituents. Vilino, aryl and some alkyl azides decompose readily when heated. Therefore, they cannot be used in this type of cycloaddition reactions. Despite this, 1,3-dipolar azide reactions have been able to be used in the synthesis of heterocycles.

Cycloaddition with acetylenes (C≡C) or with alkenes (C=C) rich in electrons, or possessing a leaving group (such as enamines), are used for the synthesis of thiazoles.

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Also, intramolecular cycloadditions to a triple bond (C≡C) have been described.

Example of 1,3-dipolar reactions (diazocompounds, NN—C<)

Diazomethane (NNCH2) and simple diazoalkanes NNCRR’) are isolable, but thermally unstable compounds. Nevertheless, they participate in a wide variety of cycloadditions to various multiple bonds.

Once the cyclized product is obtained, a proton shift occurs.

Example 1,3-dipolar reactions (nitrile oxides, ON—C-)

There are some nitrile oxides (ONC), with bulky aryl substituents, which are isolable. However, most are generated and captured in situ.

Two routes have been described to generate them:

  • From aldoximes that chlorinate in α-position.

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  • From nitroalkanes by dehydration with phenyl isocyanate.

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Nitrile oxides with a variety of substituents (-H, -alkyl, -Br, -COOR, and -SO2Ph) also participate in 1,3-dipolar cycloaddition reactions.

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Also, the intramolecular process can be carried out.

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Example 1,3-dipolar reactions (nitrilimides, –NNC-)

Nitrilimides (NNC) are transient intermediates and can be generated by two methods:

  • From oximes. This method is analogous to that of nitrile oxides.

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  • From a heterocyclic compound that is thermally decomposed (e.g. 2H-tetrazole) or by ultraviolet light.

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Nitrilimides are also used in cycloaddition reactions, as shown in the following scheme.

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Example 1,3-dipolar reactions (nitrile sulfides, SN≡C-)

Nitrile sulfides are also generated in situ, by heating 1,3,4-oxathiazole-2-ones in solution at 110-160 ºC.

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Their cycloaddition reactions preferentially take place with various types of electron-deficient dipolarophiles such as acetylenic esters, activated nitriles and activated carbonyl compounds.

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Example 1,3-dipolar reactions (nitrones, —(O)N=C<)

Many nitrones ((O)N=C<) are isolable and stable compounds. In particular, those with C-aryl substituents. Those lacking stabilizing substituents tend to dimerize or trimerize, so they are best generated in situ.

Nitrones can be generated by two methods:

  • By oxidation of an N,N-disubstituted hydroxylamine.

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  • By condensation of N-alkyl hydroxylamines with aldehydes or ketones.

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There are many examples of addition of nitrones to double (C=C) or triple (C≡C) carbon-carbon bonds, especially to those with electron-attracting groups.

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