Free Radicals in Organic Synthesis Convenor: Dr. Fawaz Aldabbagh Recommended Texts Chapter 10, by Aldabbagh, Bowman, Storey

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

By Thermolysis or Photolysis. 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 Radical Formation or Initiation

Peroxides When R is alkyl, loss of CO 2 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 o C, and is useful, as it selectively decomposes to benzoyl radicals below 150 o C Photochemical Reaction

Other Peroxide Initiators Azo Initiators A combination of AIBN-Bu 3 SnH is most popular radical initiation pathway in organic synthesis

OrganoMetallic INITIATORS C-M bonds have low BDE, and are easily homolyzed into radicals; FORMATION OF GRIGNARD REAGENTS Electron Transfer Processes

SET (Single Electron Transfer) reactions

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

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

– 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 Nitroxides Why so stable? Very Stable Radicals (Half-life = years)

Nitroxides are used as radical traps of carbon-centred radicals No dimerization via nitroxide, NO-bond Explain

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.

Similarly, ESR spectroscopy is usually used to determine such features

Methyl radical can be regarded as planar Unlike, carbocations, carbon-centred radicals can tolerate serious deviations from planarity e.g.  CH 3   ,  CH 2 F   ,  CHF 2   ,  CF 3   

Because of Orbital Mixing

As alkyl radicals become more substituted so they become more pyramidal. Also, when X = SR, Cl, SiR 3, GeR 3 or SnR 3 – delocalisation of the unpaired electron into the C-X bond increases. The eclipsed rotomer becomes the transitional structure for rotation Alkyl Radicals

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

1. Conjugation or Mesomerism This is the primary reason for the existence of stable radicals (see notes on nitroxides and DPPH)

2. Hybridisation  Radical is more stable than  Radical. As the p- character of a radical increases so does its thermodynamic stabilisation

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

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.

This is generally due to steric factors. b/ Kinetic Stability

The Polar Nature of Radicals Radicals can have electrophilic or nucleophilic character

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

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). e.g.

Problems with Bu 3 SnH We can overcome the use of Tin-hydride- By using Silanes as Bu 3 SnH substitutes

Prof. Chris Chatgilialoglu, Bologna BDE’s (kcal/mol) Et 3 Si-H95.1 [(CH 3 ) 3 Si] 3 Si-H84 Bu 3 GeH89 Bu 3 Sn-H79

Polarity Reversal Catalysis Et 3 Si-H can be used if a catalytic amount of alkyl thiol (RS-H) is added. Et 3 Si-H = 375 KJmol -1 RS-H = 370 KJmol -1 Et 3 Si-X = 470 KJmol -1 Prof. Brian Roberts UCL

Polarity Reversal Catalysis

Radical-Anions

Sodium Amide, (Na + NH 2 - ) is made by dissolving Na in liquid ammonia, and then waiting until the solution is no longer blue Drying Ether or THF

Birch Reduction Prof. Arthur Birch, ANU Other REDOX reactions Pinocol Coupling In aprotic solvents, ketyl radical anions dimerise

McMurry Coupling Heterogeneous Reaction occurring on the surface of the titanium metal particle generating TiO 2 and an alkene Prof. John McMurry Cornell

Sandmeyer Reaction Other Nucleophiles can also displace the diazonium ion, including Chlorides, Iodides and Cyanides Prof. Traugott Sandmeyer, Wettingen, Switzerland

Radical-Cations Wurster – isolable, highly coloured radical cation

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

Draw six-membered chair transition state for 5-exo trig cyclization Kinetic product favoured over thermodynamic product The exo or endo cyclization rate depends greatly on chain length. And the reverse of radical cyclization is Ring-Opening.

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.

Tandem or Cascade Radical Cyclizations