Free Radical Chemistry

1. +R RRR
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.
Example
Atomic hydrogen (H·)
hydroxyl (HO.)
methyl (H3C·) radicals

3. H Cl H Cl+
1 electron 7 electrons in outer shell
Less Energy Demand
Gaseous phase
Monoatomic - Radicals

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.
A +A A A

6. There are four types of propagation reactions:
(i) "Atom transfer reactions“
Eg: Abstraction of hydrogen by a free radical:
(ii) "Addition reactions“
Eg: Addition of free radical to a double bond
A + RH AH R+
A + C C C CA

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
A + C CC CA

C
H2
CR
R
R C CH2R
R
R

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

9. (ii) "Disproportionation"
+R HRR
H2
C
H
C R + R C
H
C
H
R
Transfer of hydrogen

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

11. Conjugation or Mesomerism
CH2
CH2 CH2
CH2
allylic radical
benzylic radical

12. CC
H
H
H
CH3
CH3
CC
H
H
H
H
CH3
CC
H
H
H
H
H
CH
H
H
>> >
9 Hyperconjugatable H s
6 Hyperconjugatable H s
3 Hyperconjugatable H s
CC
H
H
H
H
H
CCH
H
H
H
H
thermodynamic stability
Hyperconjugation

13. sp2
or radical
cannot be resonance stabilised
Vinyl and Aryl Radicals
Very Reactive Radicals
Hybridisation
pRadical is more stable than Radical.
As the p- character of a radical increases so does its thermodynamic
stabilisation

14. This is generally due to steric factors.
Kinetic Stability
triphenylmethyl radical
1,4 - Hydrogen abstraction
Half-lives increased from 10-3
to 0.1 s
Radicals can be detected by normal spectroscopic methods

15. A
X
X X
A
X
X
X
A
X
X
X
AX3
sp2
+ p-character+ p-character
sp3 sp3
PlanarPyramidal PyramidalTetrahedral Tetrahedral
X A X A
X X
AX2
Linear Radical Non-Linear
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
Cl Cl 2 Cl
Br Br 2 Br
I I 2 I
 G#
= 243 KJmol-1
 G#
= 192 KJmol-1
 G#
= 151 KJmol-1

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. O
C
R O
O
C
R
O
O
C
R O
O
C
R
O
C
O
O
R+
Diacyl derivatives of hydrogen peroxide Peresters
Energy = 121 KJ/mol
Benzoylperoxide (BPO)

20. O
O
O
O
O
O
C
O
O
2 X O2 X+
DTBPO
Half-life 10 mins at 70o
C
O
acetone
CH3
+
PERESTERS
Di-tert-butyl peroxalate

21. Anti - Markovnikovs
addition of HBr

22. NC N
N
NC
N N
CN C
N
Azobisisobutyronitrile (AIBN)
Heat
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.
X X X X

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
X2 to form the methyl bromide
product and another halogen
radical.
X XHH CH3 CH3
CH3 X X CH3 XX
Step-3: “Termination step“
Various reactions between the possible
pairs of radicals allow for the formation
of ethane, X2 or the product. These
reactions remove radicals and
terminates the cycle.
X
CH3
CH3 CH3X X
XX X
CH3 CH3H3C

24. Selectivity of radical halogenations of alkanes
Reactivity of R-H system
Within the series of Sp3 C-H bonds, the strength of the C-H bonds varies
slightly depending on whether the H is 1o, 2o or 3o.
H3C H
H3CH2C H
HC H
H3C
H3C
C H
CH3
CH3
H3C
R HType
1o
2o
3o
Bond Energy
435 KJ / mol
410 KJ / mol
397 KJ / mol
380 KJ / mol
Bond
dissociation
energy
decreases
due to
weaker bond
b/w C-H

25. Reactivity of X.
The relative rates of reaction for X2 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 Br2

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 Br2
Radical Allylic Bromination (Wohl-Zigler Reaction)

31. Step-1: "The initiation step”
O
O
O
O
O
O
Heat
light
N
O
O
Br
N
O
O
Br

32. Step-2: “Propagation step”
The HBr produced in last step then reacts with NBS producing Br2 in
low concentration.
Br2 is then quickly captured by the allylic radical thus keeping the
concentration of HBr and Br2 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. SRN1 (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
H C H
Sp2
Sp3
BDE = 464 KJ/mol BDE = 397 KJ/mol
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 (FeSO4) leads to a powerful oxidant that can
oxidize aliphatic and aromatic compounds.
Combination of hydrogen peroxide with ferrous sulfate (FeSO4)
Fenton’s Reagent
Fe2+
+ H2O2 Fe3+
+ HO-
OH+
R CH3
R
H2
C OH
OH

40. Fe2+
+ H2O2 Fe3+
+ HO-
OH+
OH + R H R H OH+
+ O OR RO
+ R H H OR+RO R
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.
+R H O O
1
R OOH

42. +
O O
R H
Sens
O O
3 1
h
R
R OO
+
+
+
O O
1
R OO R H R OOH R
R
+
+R OO
R
R OO
R
R + R OO
Non radical product
Initiation
Propagation
Termination

43. +
H2SO4 O O
1
OOH
Cumene Cumene hydroperoxide
+ O O
1
O OH+
+ +
OOH
+ O O
1
O O
O O
Initiation
Propagation

44. +
O
O
1
OOH
H
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.
R ONa
O
R R CO2 NaOH H2
Electrolysis
2 2 2

46. MECHANISM
Reaction at Anode
Reaction at Cathode
R O
O
R O
O
R CO2
R R R R
2 2 2 2
R ONa
O
R O
O
Na2 2 2
Na e Na H2O NaOH H2
2 2 2

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.
R OAg
O
R Br CO2 AgBr
R ONa
O
AgNO3
Br2

49. MECHANISM
R OAg
O
Br2
R O
O
Br
Acyl hypobromite
AgBr
R O
O
Br
Acyl hypobromite
R O
O
Br
Acyloxy radical

R CO2
R R Br
R O
O
R O
O
Br
R O
O
Initiation
Propagation

50. EXAMPLES

51. N2
Goberg-Bachmann Reaction Meerwein Reaction
Baltz Schiemann Reaction
Sandmeyer Reaction
X
F
R
EWG(1924) (1939)
(1927)
(1884)
X = Cl, Br, I
Denitrogenative substitution reactions of
arenediazonium salts

52. Gomberg-Bachmann Reaction
Aryl aryl coupling reaction in presence of NaOH via radical
mechanism
N2
X NaOH
N2
NH2
NaNO2 HX
R
R
R
R1

53. MECHANISM
N
R
N
OH N
R
N
OH N
R
N
OOH
H2O
Diazonium oxide
N
R
N
ON
R
N
N
R
N
O
N
N
R
Diazonium derivative reacts with hydroxide ion to form diazonium oxide
Diazonium oxide reacts with diazonium salt to form diazoanhydride

54. N2
N
R
N
O
N
N
R
N
R
N
O
R

Diazo anhydride undergoes thermolysis with loss of nitrogen and forms
azoxy and aryl radical.
R
R1
R
R
H
R
R1
Aryl radical reacts with benzene and finally forms biaryl product

55. N
R
N
X
R EWG
R
Metal Salt R
R
EWG
R
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. N2
R
N
R
N
R
R EWG
R
+ e
R
R
EWG
R
R
R
EWG
R
- e
+ X
R
R
EWG
R X R
R
EWG
R
- HX
MECHANISM
Meerwein Arylation
addition product
Meerwein Arylation
aryl-alkene coupled
product

57. Oxidation of Aldehyde to Carboxylic acid