Radical Reactions

Introduction

Radicals and carbenes are neutral, electron-deficient species that are not commonly isolable (few stable examples exist in nature).

Carbon-centred radicals are trivalent with a single non-bonding electron, whereas carbenes are divalent with two non-bonding electrons.

Their ease of formation combined with their high reactivity yet tolerance to many functional groups, and their contrasting behaviour with many ionic species has promoted much use of these intermediates in synthesis.

1) Radicals :

Radicals can be generated by homolysis of weak σ-bonds.

Homolysis is effected by photochemical, thermal or redox (electron transfer) methods.

A common method to initiate a radical reaction is to warm a peroxide such as benzoyl peroxide or azobisisobutyronitrile (AIBN).

The radical •C(CN)Me2 generated from AIBN is rather unreactive, but is capable of abstracting a hydrogen atom from weakly bonded molecules such as tributyltin hydride.

The resulting tributyltin radical reacts readily with alkyl halides, selenides and other substrates to form a carbon-centred radical.

2) Radical Abstraction Reactions :

A radical abstraction reaction, as the intermediate carbon-centred radical abstracts a hydrogen atom from the trialkyltin hydride.

3) Radical Cycle :

4) Radical Dehydroxylation :

It is most effective for secondary alcohols.

The reaction tolerates many different functional groups, as illustrated in the reduction of the thiocarbonyl compound in addition to dehydroxylation.

5) Radical Decarboxylation :

Thiohydroxamic esters , prepared from activated carboxylic acids (RCOX) and the sodium salt of N-hydroxypyridine-2-thione.

Simple thermolysis or photolysis of the esters (homolysis of the N-O bond) results in the production of alkyl radicals R•, which can attack the sulfur atom of the thiocarbonyl group to propagate the fragmentation in the presence of a hydrogen-atom source, such as tributyltin hydride.

a)

b) By using Acid Chloride.

The use of the thiohydroxamic ester has the advantage that the intermediate alkyl radical can be generated in the absence of tributyltin hydride (or other hydrogenatom source).

Therefore, in the presence of a suitable radical trap, the alkyl radical can be functionalized rather than simply reduced.

Thus, in the presence of CCl4, BrCCl3 or CHI3, the carboxylic acid RCO2H can be decarboxylated and halogenated to give the alkyl halide RCl, RBr or RI.

In the presence of oxygen gas, a hydroperoxide ROOH or alcohol product ROH can be formed.

6) Hofmann–Loffler–Freytag Reaction :

This reaction provides a method for the synthesis of pyrrolidines fromN-halogenated amines.

The reaction is effected by warming a solution of the halogenated amine in strong acid (e.g. H2SO4 or CF3CO2H), or by irradiation of the acid solution with ultra-violet light.

The initial product of the reaction is the δ-halogenated amine, but this is not generally isolated, and by basification of the reaction mixture it is converted directly to the pyrrolidine.

Example :

Intermediate :

Experiment :

7) Modification of the Hofmann–Loffler–Freytag reaction :

To avoids the harshly acidic conditions it has been developed.

The N-iodo compound is generated by reaction with iodine and iodobenzene diacetate.

8) Barton reaction :

δ- Oxidation of Alcohols :

A method for generating the alkoxy radical is by fragmentation of hypoiodites prepared in situ from the corresponding alcohol.

This can be accomplished by treatment of the alcohol with iodine and lead tetraacetate or mercury(II)oxide, or with iodine with iodobenzene diacetate.

9) Radical Addition Reactions :

In the presence of a double or triple bond, a radical species can undergo an addition reaction.

It has been known for many years that alkyl radicals add to the double bond of alkenes with the formation of a new carbon–carbon bond.

In presence of e- eithdrawing group it can form Michael addition product.

A method to access carbon radicals makes use of the one-electron reducingagent samarium diiodide, SmI2.

From a primary iodide, RI, the intermediate carbon radical R• is converted to the organometallic species RSmI2 by addition of a second electron from the SmI2.

The radical generated from 1-iodo-octane adds to carbon monoxide followed by the allyl stannane in a three-component coupling process.

Cyclization using an alkenyl radical is efficient and leads to a product containing an alkene in a defined position.

Cyclization onto an enone or enoate provides an alternative method to access a cyclic product with suitable functionality for further elaboration.

Alkyl, alkenyl, aryl and acyl radicals can all be used in cyclization reactions.

Acylradicals can be generated by addition of alkyl radicals to carbon monoxide, or more conveniently from acyl selenides, and undergo a variety of radical reactions.

One-electron oxidation of carbonyl compounds provides another entry to radical species, suitable for carbon–carbon bond formation.