Free Radicals in Organic Synthesis - PowerPoint PPT Presentation

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Free Radicals in Organic Synthesis. Convenor: Dr. Fawaz Aldabbagh. Recommended Texts. Chapter 10, by Aldabbagh, Bowman, Storey. Heterolytic Fission. When bonds break and one atom gets both bonding electrons- Pairs of Ions – Driven by the Energy of solvation. Homolytic Fission.

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Free Radicals in Organic Synthesis

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Free Radicals in Organic Synthesis

Convenor: Dr. Fawaz Aldabbagh

Recommended Texts

Chapter 10, by Aldabbagh, Bowman, Storey

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Heterolytic Fission

When bonds break and one atom gets both bonding electrons- Pairs of Ions – Driven by the Energy of solvation

Homolytic Fission

When bonds break and the atoms get one electron each

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Radical Formation or Initiation

By ThermolysisorPhotolysis.

Light is a good energy source

Red Light – 167 KJmol-1

Blue Light – 293 KJmol-1

UV- Light (200nm) – 586 KJmol-1

UV will therefore decompose many organic compounds

Explains the instability of many iodo-compounds

Photolysis allows radical reactions to be carried out at very low temperatures (e.g. room temperature)

Useful for products that are unstable at higher temperatures

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Photochemical Reaction


When R is alkyl, loss of CO2 is very fast. Therefore, alkyl peroxides generally avoided, as they tend to be explosive. Benzoyl peroxide has a half-life of 1 hour at 90 oC, and is useful, as it selectively decomposes to benzoyl radicals below 150 oC

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Other Peroxide Initiators

Azo Initiators

A combination of AIBN-Bu3SnH is most popular radical initiation pathway in organic synthesis

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OrganoMetallic INITIATORS

C-M bonds have low BDE, and are easily homolyzed into radicals;


Electron Transfer Processes

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SET (Single Electron Transfer) reactions

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All the radical initiation pathways so far discussed give very reactive, short-lived radicals (< 10-3s), which are useful in synthesis

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Stable and Persistent Radicals

Steric Shielding is more important than Resonance Stabilisation of the radical centres- Kinetically Stabilised Radicals (Half-life = 0.1 s)

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Very Stable Radicals (Half-life = years)

– Thermodynamic Stabilisation is most important

These radicals can be stored on the bench, and handled like other ordinary chemicals, without any adverse reaction in air or light.

Often – very colourful compounds


Why so stable?

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No dimerization via nitroxide, NO-bond

----------- Explain

Nitroxides are used as radical trapsof carbon-centred radicals

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Configuration or Geometry of Radicals

Normally, configurational isomers are only obtained by breaking covalent bonds, this is not the case with radicals

With radicals, bond rotation determines the geometry and hybridisation of molecules.

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ESR spectroscopy is usually used to determine such features

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Methyl radical can be regarded as planar

Unlike, carbocations, carbon-centred radicals can tolerate serious deviations from planarity

e.g.CH3Fo = 0, CH2F Fo = 5, CHF2Fo = 12.7, CF3 Fo = 17.8.

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Because of Orbital Mixing

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Alkyl Radicals

As alkyl radicals become more substituted so they become more pyramidal.

Also, when X = SR , Cl , SiR3 , GeR3 or SnR3 – delocalisation of the unpaired electron into the C-X bond increases. The eclipsed rotomer becomes the transitional structure for rotation

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Radical Stability

a/ Thermodynamic Stability

Is quantified in terms of the enthalpy of dissociation of R-H into R and H

The main factors which determine stability are Conjugation, Hyperconjugation, Hybridisation and Captodative effects

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1. Conjugation or Mesomerism

This is the primary reason for the existence of stable radicals (see notes on nitroxides and DPPH)

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2. Hybridisation

p-Radical is more stable thans-Radical.

As the p- character of a radical increases so does its thermodynamic stabilisation

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3. Hyperconjugation

Remember, that inductive and steric effects may also contribute to the relative stability of the radical

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The phenomenon is explained by a succession of orbital interactions; the acceptor stabilizes the unpaired electron, which for this reason interacts more strongly with the donor than in the absence of the acceptor.

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b/ Kinetic Stability

This is generally due to steric factors.

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The Polar Nature of Radicals

Radicals can have electrophilic or nucleophilic character

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However, “philicity” of a radical is a kinetic property, not thermodynamic, i.e. it depends on whether the substrate is a donor or attractor.


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Electrophiles react faster with electron-rich alkenes (electron-donating substituents adjacent to the alkene DB).

Nucleophiles react faster with electron-poor alkenes (electron-withdrawing substituents adjacent to the alkene DB).


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Chain Reactions

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Chain Reactions

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Problems with Bu3SnH

We can overcome the use of Tin-hydride-

By using Silanes as Bu3SnH substitutes

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BDE’s (kcal/mol)





Prof. Chris Chatgilialoglu, Bologna

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Polarity Reversal Catalysis

Et3Si-H can be used if a catalytic amount of alkyl thiol (RS-H) is added.

Et3Si-H = 375 KJmol-1

RS-H = 370 KJmol-1

Et3Si-X = 470 KJmol-1

Prof. Brian Roberts


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Polarity Reversal Catalysis

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Sodium Amide, (Na+NH2-) is made by dissolving Na in liquid ammonia, and then waiting until the solution is no longer blue

Drying Ether or THF

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Other REDOX reactions

Birch Reduction

Prof. Arthur Birch, ANU

Pinocol Coupling

In aprotic solvents, ketyl radical anions dimerise

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McMurry Coupling

Prof. John McMurry


Heterogeneous Reaction occurring on the surface of the titanium metal particle generating TiO2 and an alkene

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Sandmeyer Reaction

Other Nucleophiles can also displace the diazonium ion, including Chlorides, Iodides and Cyanides

Prof. Traugott Sandmeyer, Wettingen, Switzerland

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Wurster – isolable, highly coloured radical cation

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Radical Cyclisations

3-, 5- and 6-membered radical cyclizations are usually faster than the analogous intermolecular addition.

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Kinetic product favoured over thermodynamic product

Draw six-membered chair transition state for 5-exo trig cyclization

The exo or endo cyclization rate depends greatly on chain length.

And the reverse of radical cyclization is Ring-Opening.

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The ‘Radical Clock’ is a standard fast reaction of known rate constant, which the rates of other competing radical or product radical reactions can be measured.

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Tandem or Cascade Radical Cyclizations

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