Radicals In Organic Synthesis.

Gomberg reported the 1st free radical in 1900; a century has passed since he first discovered the triphenylmethyl radical. For many years the chemistry of free radicals was very much the province of mechanistic and physical organic chemists with their application to synthesis not extending much past the occasional use of Kolbe electrolysis or oxidative coupling of phenols.

However with time these recent situations have changed. The realisation that radical methods are often very compatible with a range of functional groups, without further protection, has led to an increased interest in the use of radicals in synthesis.

Radicals or Free Radicals can be defined as a species that contains at least one unpaired electron. Radicals in general are extremely a reactive species; reacting rapidly with the majority of organic molecules. These include molecules such as alkanes, which are impervious from attack via ions. The large proportion of radicals only exist as a transient intermediate, never abundant in large concentrations. The occurrence of radical intermediates can often be inferred from the nature of the reaction products or from a study of kinetics.

The Formation of Radicals:

Most of the important radical reactions proceed by a chain mechanism, the crucial step requires the generation of a radical from an appropriate pre – cursor. The molecules bond(s) need to be broken in such a way that each fragment keeps one electron. The energy required to break the bond(s) is supplied in one of the four following ways.

(i) Photochemical cleavage- of compounds with weak bonds.

Since a quantum of light with a wavelength of 300nm corresponds to ≅ 400 kJmol-1 . It is energetically feasible to cleave weak covalent bonds by irradiation with visible or UV light

Well-known examples are halogens

e.g.: Bromine (BDE = 193kJmol-1). Is a source of bromine atoms.

(ii) Thermal cleavage- of weak bond.

Compounds that contain relatively weak bonds, that is bonds with bond dissociation energies below 160kJmol-1 can undergo homolysis at a convenient rate at a temperature below 150°C. An important group of such compounds are the diacylperoxides. Here the already weak bond of the peroxide is further weakened by the resonance stabilization of the acyloxy radical produced on homolysis. Thus the BDE of the O-O bond in diacetyl peroxide is 126kJmol-1 compared to 155kJmol-1 of MeO-OMe.

Another important group of compounds often used as precursors of radicals are the azo-compounds; these dissociate upon heating, with loss of nitrogen, to give radicals at temperatures which depend upon the nature of R group. In general the more stable the radical the more readily the dissociation occurs.

Electron Transfer Processes.

These type of formation reactions involve one electron oxidation or one electron reduction leading to the generation of radicals from spin paired precursors. Over page is an example of both kinds.

(iii) Oxidation-

If an anion loses one electron it becomes a neutral radical.

In addition, electrochemical oxidation of carboylate anions leads to acyloxy radicals, which can undergo decarboxylation to give alkyl radicals.

(iv) Reduction-

Reductions are a less familiar source of radicals. Nonetheless, the addition of an electron to a carbonium ion results in the formation of a radical

Also, the reduction of hydrogen peroxide by Fe(II) gives hydroxy radicals:

Reactivity of Radicals:

Radical reactivity can be explained by the molecular orbital theory. Singly occupied molecular orbital (SOMO), the frontier orbital of the radical, can interact with either the highest occupied molecular orbital (HOMO) or the lowest unoccupied molecular orbital (LUMO) of other molecules in order to minimise the energy difference between them:

Radicals normally do not have a charge. However, they do possess electrophilic or nucleophilic properties. Radicals that interact with electron deficient substituents will have a low-energy SOMO and show electrophilic properties. They react faster with species possessing a high-energy HOMO (e.g. electron rich alkenes) and therefore the SOMO-HOMO interaction dominates. On the other hand, radicals placed next to electron rich substituents will have a high-energy SOMO and show nucleophilic properties. They react faster with molecules having a low-energy LUMO and hence the SOMO-LUMO interaction dominates in this case.

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Stereoelectronic effects on radical’s reactions arise from geometrical preferences for optimal orbital – orbital interactions. The geometries of the relevant orbital – orbital interactions are the same as in the corresponding ionic reactions because the orbitals involved are the same. What is different is that the interacting orbitals contain an odd number of electrons. Stereoelctronic effects on reactivity are generally simpler than for ionic reactions as the reactions tend to be simpler.

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Because radicals react with low activation energies, transition states for their reactions are close in structure to the radical intermediates. Thus the major factor controlling radical reactivity is the stability of the reactant and the product. Here there is an important difference from polar intermediates; any feature, which stabilizes either a carbocation or a carboanion, will stabilize a radical. There fore a more stabilized radical will be formed faster.

Types Of Radical Reactions Observed.

This essay will describe a number of common elementary reactions involving radicals used in modern organic chemistry.

Radical combination-

This is the combination of two separate radicals to form a covalent molecule. This is an important termination step as it destroys radicals.

e.g. Dimerisation of two like radicals:

Radical combination is important in kinetic and mechanistic studies of radical reactions as a reference reaction.

Disproportionation-

This is the main other form of radical – radical reaction, in which atom transfer between two radicals occurs; leading to two spin paired molecules.

Radical Abstraction (Displacement)

This is an important and commonly seen step in many chain reactions; it often involves the attack on a hydrogen atom.

Radical reactions of this type are seen as displacement reactions, in which the radical effects back side attack on the atom undergoing displacement, with the formation of a new radical. This type of reactions will be more favorable if the bond being formed is stronger then the bond which has broken.

Atom abstraction reactions may also occur intramolecularly if a sterically favourable transition state can be obtained.

Displacement reactions in which attack occurs at a carbon atom rather than a halogen or hydrogen atom are not generally seen.

Radical Addition Reactions- To multiple bonds.

The vast majority of carbon centered radicals and a great number of hetero radicals will add to molecules containing unsaturated centres.

Alkenes, alkynes, carbonyl compounds and azo – compounds are all effective partners on this reaction. Radical addition to aromatic compounds occurs with equal facility, but the overall result of the process is usually substitution. Homolytic aromatic substitution is not particularly useful synthetically, since aromatics tend to give mixtures of isomers.

Radical Fragmentation Reactions (β elimination)-

This reaction is the microscopic reverse of radical addition.

On the whole fragmentation reactions are more favourable when the multiple bond formed has a high bond energy or where the starting radical is strained.

Rearrangement reactions-

Intramolecular versions of atom abstraction reactions, intramolecular addition reactions leading to cyclisation and intramolecular fragmentations constitute pathways for rearrangement of suitably constituted radicals.

There are also rearrangement involving 1,2 shifts, however these tend to be rare in radicals.

This is in contrast to carbonium chemistry where 1,2-alkyl (and hydride) shifts are common.

Radical Chain Reactions:

Only a small number of radical reactions used in synthesis involve radical coupling as the product forming step and the majority of synthetically useful radical reactions in solution are chain processes. Chain reactions are inherently more elegant and controllable than their non-chain counterparts in which stoichiometric radical generation is followed by recombination with concomitant destruction of the radical character.

The following example summarises the main features which characterise successful chain reactions:-

Reductive removal of a halogen atom by a tin hydride-

Initiation:

This leads to the formation of the reactive radicals.

Propagation:

This accounts for the main overall reaction

the cyclic nature of the propagation sequence is emphasised as follows-

Termination:

Radicals are consumed to give spin paired molecules

Polar Effects in Radical Reactions.

A feature of radical reactions is their susceptibility to polar effect from reactants and reagents. It’s a surprising effect as reactions are between nominally uncharged species. The polar effect can be seen in certain hydrogen abstraction reactions. For example propanoic acid is able to undergo hydrogen abstraction form either the α or β position. So in a reaction with a Cl⋅, the carboxyl group is electron withdrawing and the Cl⋅ is electronegative, thus preferentially attacks the electron rich C – H bond of the methyl even though the α radical produced may be more stable due to resonance stabilization. However an attack by an electron rich Me⋅, would occur at the electron deficient bond (α) due to the withdrawing properties of the carboxyl group.

The transition state for chlorine atom attack there is substantial electron transfer towards to electronegative chlorine leaving the carbon atom positively charged, this may be described in resonance terms as contribution from canonical to the transition state.

[ Cl- :H⋅ +CR3]

With methyl radical attack, electron transfer tends to be towards the carbon of the C – H bond being attacked, which is express as a contribution by canonical to the transition state

[ CH3+ H⋅ : -CR3]

Radical Reactions in Organic Synthesis:

Unlike ions, radicals in solution are not surrounded by a solvent shell, so that very high concentrations of ions is possible, but however high concentrations of radicals are impossible. Radicals are extremely reactive species reacting rapidly with the majority of organic molecules, including the alkanes which are normally completely resistant to the action of ions. In this section a number of examples of radical reactions in the synthetic context will be illustrated.

Intermolecular radical addition to unsaturated bonds:

Virtually all carbon-centred radicals and a great variety of heteroradical will add to molecules containing unsaturated centres. Alkenes, alkanes, carbonyl compounds and azo-compounds are all effective partners in this reaction.

An important type of radical precursor is a thiohydroxamic ester, which undergoes radical chain decarboxylative rearrangement on heating or irradiation via the propagation sequence below:-

The alkyl radical (R.) formed can be trapped by electron deficient alkenes leading to the formation of the adduct below

Addition of electron deficient radicals to electron rich alkenes is possible

e.g.

In this reaction the chain carrying species is the electrophilic radical .CH(CN)2 which adds rapidly to the nucleophilic alkene.

Other intermolecular radical addition to multiple bonds include Mcerwein arylation. In such a reaction transition metal redox processes catalyse the required electron transfer

Another important type of intermolecular radical addition to multiple bonds is found for suitable allylically substituted alkenes. The basic mode of reaction is an addition-elimination leading to overall allylic substitution.

Similarly, allene transfer via radical capture by propargyl stannane is possible:

Stereochemistry of addition:

Radical addition to 1,2-disubstituted alkene is generally non-stereospecific due to the adduct radical being planar and can be approached from either side by the transfer agent. e.g.

However, addition of HBr to alkenes is an exception. Provided that the reaction is carried out at a sufficiently low temperature and in an excess of HBr, almost completely stereospecific product formation can be achieved.

The stereospecifity of this reaction is probably due to the preference shown by the intermediate β-bromoalkyl radical for the staggered conformation in which the radical centre is non-planar.

Radical addition to cycloalkenes is very stereoselective. Thiyl radicals, silyl radicals, nitroxides and especially bromine atoms all show a marked preference for trans-addition leading to the cis-product.

e.g.

Intramoloecular radical cyclisation reactions:

Radical cyclisation reactions represent a breakthrough for synthetic radical chemistry. These reactions exhibit interesting regioselectivities and stereoselectivities and can be carried out with a variety of functional groups as radical traps.

The state of cyclisation largely depends on the substituants of the radicals and on the alkene bond. In general, electron donating groups on the radical and electron withdrawing groups (EWG) on the alkene accelerate the cyclisation.

There are two competing pathways in every radical cyclisation to an alkene:

'endo' cyclisation occurs when the radical attacks the terminal end of the multiple bonds to form a larger ring, or 'exo' cyclisation occurs when it attacks the internal end to form a smaller ring. Radical cyclisations favour 'exo' cyclisations.

e.g.

Exo – mode of cyclisation is preferred due to the maximum overlap between the singly occupied molecular orbital of the radical and the π* - orbital of the double bond being achieved for the five-membered ring transition state:

Hex-5-en-l-yl radicals generated in a variety of ways undergo rapid intramolecular addition to give cyclised products:

Hex-5-en-l-yl radicals, which are stabilised by electron withdrawing substituents attached to the radical centre, are more prone to give cyclohexane derivatives as the major product. The cyclisation of these radicals is reversible which leads to thermodynamic control of the process and therefore the thermodynamically more stable cyclohexyl radical is the main product.

The example below shows the result of intermolecular competition between 5-exocyclisation onto C=C and 6-exo addition to C=0.

It is likely that the predominance of the exo-process is the result of reversible addition to both multiple bonds but faster capture by the alkoxy radical of hydrogen from tributyltin hydride.

Intramolecular alkyl radical trapping by an electrophilic double bond is also used for the preparation of large ring lactones:

e.g.

Addition of acyclic radicals to cyclic radical acceptors may lead to the intramoloecular formation of fused systems:

Also double ('tandem') cyclisation involving multiple radical cyclisations have been used in the preparation of polycyclic compounds:

Aryl Radical Cyclisations:

The high rates of 2-(3-butenyl) phenyl and related radicals have made aryl radical cyclisation popular methods for the preparation of benzo fused five membered rings.

Aryl radical cyclisations can be directed to the endo-mode by the inclusion of a radical stabilising group at the internal alkene position.

Alternatively, inclusion of an electron-withdrawing group at the ortho position enables ring expansion of the 5-exo product:

Seven membered rings can also be synthesised (although not very favourable), by acyl radical cyclisation with a substrate that incorporates only a limited number of degrees of freedom and which carries an activated alkene:

Cyclisation also occurs on aromatic systems by intramolecular attack of alkyl or aryl radicals on an aromatic ring.

e.g.: The Pschorr Reaction:

Kolbe oxidation of carboxylic acids:

This reaction involves the anodic oxidation of carboxylates and is a useful synthetic procedure for the synthesis of long-chain compounds.

e.g.

This reaction involves the C-C coupling of two alkyl radicals:

Alcohols and esters are sometimes by-products in the Kolbe reaction. They result from further oxidation of the radical to the cation:

Fenton's reaction:

This was one of the first radical reactions discovered, and it involves the generation of hydroxyl radicals in the reaction of hydrogen peroxide with iron(II) sulphate.

The hydroxyl radicals react with an organic substrate either by hydrogen abstraction or by addition to an unsaturated system.

The organic radicals thus generated may dimerise, be further oxidised by iron (III) generated or by added copper (II) or be reduced by iron (II).

The Barton Reaction:

1,5-Hydrogen migration in radicals form the basis of an exceedingly valuable procedure for the functionalisation of angular methyl groups in steroid chemistry to give compounds that are not readily accessible by other means.

The reaction involves the generation of an alloxy radical, by the photolysis of nitrite esters or hypochlorites in an environment such that 1, 5-Hydrogen migration can occur via a mix-membered transition state.

The resultant radical recombines with the nitric oxide produced in the photolysis of nitrites to give a nitroso-compound that tautomerises to an oxime.

Hofmann-Loffler-Freytag Reaction:

The common feature of such a reaction is to introduce functionality at a position remote from functional groups already present.

This reaction is useful as a general synthesis of pyrrolidines

e.g.

The Wohl-Zeigler Reaction:

This reaction is used as a general means of brominating unsaturated compounds at an allyl or aromatic methyl position. The reaction is believed to take place by a free-radical mechanism. N-bromosuccinimide is used as a source of low-concentration bromine, which generates bromine radicals that initiate the reaction.

Auto-oxidation & antioxidants-

Auto-oxidation is a radical-chain reaction between molecular oxygen and organic compounds at moderate temperatures. This reaction always results in the formation of hydroperoxides, which then undergo further decomposition. Autoxidation is widely used in the petrochemical industry.

e.g. Autoxidation Of Aldehydes

Autoxidation Of Alkenes

The radical formed as a result reacts further by addition of oxygen or by fragmentation to give an epoxide and alkoxy radical:

Antioxidants interrupt the autoxidation radical chain, thereby retarding the autoxidation process. Compounds used as antioxidants have a readily abstractable hydrogen.

e.g.

Conclusion:

Radicals have become an important part in organic synthesis, providing a useful alternative from ions; as well as several advantages that may allow for a substitute synthesis route.

These advantages include; being neutral, salvation is less important, operation in polar and hindered environment is usually effective.

The belief that radicals are highly effective reactive intermediates have had to be re – thought. Highly effective radical chain reactions now permit for high yielding and the inter-conversion of function groups as well as the formation of carbon – carbon bonds under mild and neutral conditions

This has allowed for, a particular radical reaction can be successfully translated over a vast range of solvents and molecules of different polarity, with a much greater degree of confidence than in ionic systems. Radical chain reactions now occupy an equal place in the toolbox of the synthetic organic chemist with long standing two electron and concerted processes.