Free Radical Chemistry

Free Radical Chemistry

1. Free Radical Prepared By Dr. Krishnaswamy . G Faculty DOS & R in Organic Chemistry Tumkur University Tumakuru For II M.Sc., III Semester DOS & R in Organic Chemistry Tumkur University Tumakuru

2. An atom or group of atoms with one or more unshared electrons, which may enter into chemical-bond formation, is called a free radical. Free Radical Example Atomic hydrogen (H · ) hydroxyl (HO . ) methyl (H 3 C · ) radicals

3. Homolytic Fission

4. Free radicals can be detected by Measuring "Magnetic Susceptibility” "Electron Paramagnetic Resonance (EPR)" = "Electron Spin Resonance (ESR)“ “Electron Spin Echo (ESE)” "Chemically Induced Dynamic Nuclear Polarization (CIDNP)”

5. Typical free radical reactions are chain reactions which occur in three steps: 1 - "The initiation step" is a radical formation process. 2 - "The propagation step" is a transfer reaction of free radicals in which the site of free radical is changed.

6. There are four types of propagation reactions: "Atom transfer reactions“ Eg : Abstraction of hydrogen by a free radical: (ii) "Addition reactions“ Eg : Addition of free radical to a double bond

7. (iii) "Fragmentation reactions" (iv) "Rearrangement reactions“ Free radical change position in a molecule “ β -scission", in which an unpaired electron in a molecule splits a bond in β position and produces a free radical and a molecule containing a double bond

8. 3 - "Termination reactions" which occur in all systems where free radicals are present. There are two types of termination reactions: ( i ) "Combination" Two radicals combine

9. (ii) " Disproportionation " Transfer of hydrogen

10. Thermodynamic Stability The main factors which determine free radical stability are Conjugation , Hyperconjugation and Hybridisation.

11. Conjugation or Mesomerism

12. Hyperconjugation

13. Hybridisation p- Radical is more stable than s- Radical . As the p- character of a radical increases so does its thermodynamic stabilisation

14. This is generally due to steric factors . Kinetic Stability

15. Configuration or Geometry of Radicals

16. By Thermolysis or Photolysis . Light is a good energy source Red Light (700nm) – 167 KJmol -1 Blue Light (450nm) – 293 KJmol -1 UV- Light (200nm) – 586 KJmol -1 UV will therefore decompose many organic compounds Radical Formation or Initiation

17. Organic PEROXIDES Alkyl or Acyl derivatives of hydrogen peroxide Organic peroxides are compounds possessing one or more oxygen–oxygen bonds that are thermally and photolytically sensitive to facile homolytic cleavage.  Energy = 151 KJ/mol RADICAL INITIATORS A radical initiator is a species that acts as the reactant of the initiation step of a radical chain reaction but does not participate in any of the propagation steps.

18. Thermal decomposition of peroxides initially forms oxygen- centered free radicals from the oxygen–oxygen bond homolysis . These radicals are reactive intermediates generally having very short lifetimes, ie , half-life times less than 10 -3 s. oxygen- centered free radical

19. Diacyl derivatives of hydrogen peroxide Peresters Energy = 121 KJ/mol Benzoylperoxide (BPO)

20. PERESTERS Di- tert -butyl peroxalate

21. Anti - Markovnikovs addition of HBr

22. AZO compound (R-N=N-R') Azo group undergoes decomposition by heat and/or light, and forms carbon radical.

23. RADICAL SUBSTITUTION REACTION Step-1: "The initiation step” Heat or Uv light cause the weak halogen bond to undergo homolytic cleavage to generate two radicals and starting the chain process. Step-2: “Propagation step” Halogen radical abstracts a hydrogen to form HX and a methyl radical.   The methyl radical abstracts a bromine atom from another molecule of X 2  to form the methyl bromide product and  another  halogen radical. Step-3: “Termination step“ Various reactions between the possible pairs of radicals allow for the formation of ethane, X 2  or the product. These reactions remove radicals and terminates the cycle.

24. Selectivity of radical halogenations of alkanes Reactivity of R-H system Within the series of Sp 3  C-H bonds, the strength of the C-H bonds varies slightly depending on whether the H is 1 o , 2 o  or 3 o . Bond dissociation energy decreases due to weaker bond b/w C-H

25. Reactivity of X . The relative rates of reaction for X 2 relative to chlorine are : F =108, Cl = 1, Br = 7 x 10 -11  and I = 2 x 10 -22   i.e.  relative to chlorination, F reacts fast , Br very slow and I very, very, very slowly. Bromine radicals, Br  . , are less reactive than chlorine radicals, Cl  .  (because Br is less electronegative than Cl ). Br  .   tends to be more selective in its reactions, and prefers to react with the weaker R-H bonds.

26. Radical Halogenation of Alkanes Step-1: "The initiation step” Step-2: “Propagation step” Step-3: “Termination step“ RADICAL CHAIN MECHANISM FOR REACTION OF METHANE WITH Br 2

27. Radical Halogenation of Allylic Systems Step-1: "The initiation step” RADICAL CHAIN MECHANISM FOR ALLYLIC BROMINATION Step-2: “Propagation step” Step-3: “Termination step“

28. Radical Halogenation of Benzylic Systems Step-1: "The initiation step” Step-2: “Propagation step” Step-3: “Termination step“ RADICAL CHAIN MECHANISM FOR BENZYLIC BROMINATION

29. Benzylic and Allylic C–H bonds strengths   are quite weak  ( 89-90 kcal/mol for a primary allylic or benzylic radical) relative to tertiary C-H bonds ( 93 kcal/mol ). 1 kcal/mol = 4.184 KJ/mol 377 KJ/mol 372 KJ/mol

30. N-Bromo Succinimide (NBS) provides Low Concentration Of Br 2 Radical Allylic Bromination ( Wohl-Zigler Reaction)

31. Step-1: "The initiation step”

32. Step-2: “Propagation step” The HBr produced in last step then reacts with NBS producing Br 2  in low concentration. Br 2  is then quickly captured by the allylic radical thus keeping the concentration of HBr and Br 2  at minimum suppressing the competing electrophilic addition to the double bond.

33. Because the concentration of HBr is low (remember, HBr is needed to supply the hydrogen and convert the radical into alkyl bromide), the addition reaction reverses and proceeds by allylic bromination.

34. EXAMPLES

35. S RN 1 ( Unimolecular Radical Nucleophilic Substitution) The substitution reactions of aromatic nuclei by free radicals are still very incompletely understood. Accurate quantitative investigation of these reactions is difficult for two reasons. Free radicals are extremely reactive and attacking entity usually carries zero charge, it might be expected that the reaction would not be succeptible to directive influences due to substituents. The reactions do not proceed cleanly to give a small number of well-defined products and a large number of side reactions occur to produce a variety of products.

36. Reactivity of Aromatic Substrate C-H bond of aryl group is strong and hence phenyl radicals are less stable than alkyl radicals.

37. REACTION MECHANISM

38. Nature has evolved C—H hydroxylation reactions using heme and non- heme iron enzymes [ e.g.   cytochrome P-450 (CYP), α- ketoglutarate dependent oxygenases ] that install oxygen functionality  independently and remotely  from existing functionality.  Hydroxylation at Aliphatic and Aromatic substrate

39. In 1894, Fenton reported that the combination of hydrogen peroxide with acidic ferrous sulfate (FeSO 4 ) leads to a powerful oxidant that can oxidize aliphatic and aromatic compounds. Combination of hydrogen peroxide with ferrous sulfate (FeSO 4 ) Fenton’s Reagent

40. Fenton reaction proceeds  via  HO· radical Rate determining step Auto-oxidation

41. Formation of Hydroperoxides The slow atmospheric oxidation (slow meaning without combustion) of C-H to C-O-O-H is called autoxidation .

42. Initiation Propagation Termination

43. Initiation Propagation

44. Reaction of ene (Alkene) with enophile (singlet oxygen) Ene Reaction

45. Kolbe Electrolysis The formation of symmetrical hydrocarbons through the coupling of radicals generated from carboxylic acid at an anode via electrolysis.

46. MECHANISM Reaction at Anode Reaction at Cathode

47. EXAMPLES

48. Hunsdiecker Reaction (Bromo decarboxylation ) Treatment of the silver salt of a carboxylic acid with bromine in refluxing carbontetrachloride gives bromo compounds with elimination of carbon dioxide.

49. MECHANISM Initiation Propagation

50. EXAMPLES

51. Denitrogenative substitution reactions of arenediazonium salts

52. Gomberg -Bachmann Reaction Aryl aryl coupling reaction in presence of NaOH via radical mechanism

53. MECHANISM Diazonium derivative reacts with hydroxide ion to form diazonium oxide Diazonium oxide reacts with diazonium salt to form diazoanhydride

54. Diazo anhydride undergoes thermolysis with loss of nitrogen and forms azoxy and aryl radical. Aryl radical reacts with benzene and finally forms biaryl product

55. Meerwein Arylation Reaction Addition of aryl diazonium salt to electron deficient alkene ( α , β -unsaturated carbonyl compounds ) in presence of metal salt to give aryl-alkene coupling product Metal salt = CuCl , AgCl

56. MECHANISM Meerwein Arylation addition product Meerwein Arylation aryl-alkene coupled product

57. Oxidation of Aldehyde to Carboxylic acid