CS11 free radical reactions.docx
2012April11
:page 1
Free Radical Reactions
I. general comments
A. unpaired electrons, slightly pyramidal, small energy barrier to invert tetrahedral
geometry
B. normally very reactive with short lifetimes
C. If they don't react with closed shell molecules, they decay by
termination (coupling and disproportionation: examples)
D. acids, bases and polar solvent have minor affect
E. stabilized by alkyl, (tertiary > secondary > primary > methyl)
F. resonance (allyl, benzyl, heteroatom), stability is related to RH dissociation
energies
G. steric hinderance makes radicals persistent (triphenylmethyl)
H. detection by ESR – 10-8 M
1. unpaired electron - spin 1/2, two spin state, 1/2
2. transition between states = E = h = gBH
H
H
g = Lande g-factor, B = Bohr magneton, H =
magnetic field
3. splitting 2nI + 1, n = # of identical nuclei, I = spin quantum #
e.g. methyl radical gives a 1:3:3:1 quartet, no second-order effects
4. hyperfine splitting normally results from electron-proton coupling with  and 
nuclei (proton most common)
5. aH  Q (Q  22 gauss)  = spin density
for methyl radical: a = 22 G,  = 1
H 
H
CS11 free radical reactions.docx
2012April11
for benzene radical ion, a = 22/6 G = 3.8 G
:page 2
6. aH  2G  42Gcos2  :  = dihedral
angle, McConnell relation
7. cyclohexyl radical, 10 lines at RT
(18 at low T), aH = 21.5 G, aH = 35.2 G , find low T coupling???
8. steady-state generation
I. spin trapping – reactive radicals react with compounds that form stable radicals
J. CIDNP
II. generation of radicals
A. electron transfer

1. reduction: A  e  A 
O
O
+ Na
Na
Na
R C C R
R C C R
ROOH  Fe 2  RO   OH   Fe 3 , H2O2  Ti 3  HO   HO   Ti 4
O
O
O
+
+ Cu
O
O
O +
O
+ Cu+2
O

2. oxidation: D  D   e 
RCO2H  Pb4  RCO2   Pb3  H , also works with Ce+4, Mn+3 and Ag+2
B. thermal cleavage
CS11 free radical reactions.docx
2012April11
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O
O
2RO
RO OR
O
O
2
O
O
N
N
N
C
C
C
N
N
N
N
N
C
HOCl
+
N
N
2 C
N
C. photolysis: cumulated lone pairs i.e. ROOR h
 2RO , halogen, hypohalites,
also alkenes, carbonyl compounds: short lifetimes
III. propagation pathways of radicals
A. atom abstraction (ArDR) - usually monovalent (H or halogen)
1. dependent on bond energies, TS can have polar character
2. R' O  RH  R' OH  R,R  alkyl,benzyl , allyl
3. R3M  R' X  R3MX  R' ,M  Sn, Ge & Si, X  Cl,Br,I
4. rate constants
109
O +
OH +
O
OH
O
+
k for primary is 102-103
106
OH +
HO
Cl
CS11 free radical reactions.docx
+ CH3OH
CH3
CH3O
O
2012April11
CH3OH +
:page 4
CH2OH
CH2
105
+
OH +
10
+
O2
O2
105
O2H
+
10-1
O2H
+
+
10-1
O2
10-4
O2 +
O2H +
5. selectivity determined by attacking radical (bond formed), bond being broken,
and reorganization of electrons

p

p
p

CH2CH=CH2
n

CH2OR
CH2CH=O
a. PMO theory predicts orbitals closest in energy interact most strongly
b. LUMO of electron withdrawing group interacts most strongly
c. HOMO of electron donating group interacts most strongly
6. rates can be estimated for reactions where
HBr + Et
abstraction is rate determining step
broken
formed
BDE Et-H (98)
Br-H (88)
Et-H (98)
F-H (136)
10
Br + EtH
F +EtH
38
HF + Et
CS11 free radical reactions.docx
2012April11
Ea for Br = 13.2 kcal/mol, H* = 12.6 kcal/mol
:page 5
Ea for F = 0.3 kcal/mol, H* = -0.3 kcal/mol
- exothermic processes are diffusion controlled, barrier estimated from activation
energy (2-5 kcal in solution)
- endothermic barrier estimated from bond energy difference and reverse barrier
(2-5 kcal)
B. fragmentation
O
R
O
O
R + CO2
O
R N N
R + N
O
R + C O
N
R
CH3
C. addition

R'   R2C  CR2  R' R2 CR2
R  O2  RO 2 
+
R
+
R
H
O +
OEt
109
P OEt
OEt
isooctane
Et
+
+
Et
P
109
O
O
Et
Et
isooctane
Et
B
109
Et
isooctane
IV. destruction of radicals
OEt
Et
P
Et
O
Et
O
O
+
P OEt
OEt
Et
B Et
Et
P
OEt
P OEt
OEt
Et
+ Et
Et
O
B
Et
Et
+ Et
CS11 free radical reactions.docx
A. coupling and disproportionation
R  R  R  R,
2012April11
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
R  R'2 CHCH2  RH  R'2 C  CH2
B. oxidation
R   Mn  R  M(n1) , M+n = Pb+4, Ce+4, Mn+3, Ag+2
V. path combinations
A. substitution (ArDR + ARDr)
initiation
or h
X 2  
 2X 
propagation
X  CH4  XH  CH3 
CH3   X 2  CH3 X  X 
termination
step
F
Cl
Br
I
1
-31
2
17
34
2
-70
-26
-24
-21
X   X  X 2
1. several propagation (chain) steps can occur per initiation
2. barrier to termination is low but reaction is bimolecular in radical and radical
concentrations are low
3. propagation steps can compete because substrate concentration is high
4. feasibility of reaction determined by propagation steps, e. g. for methane
bromination and iodination does not occur at an appreciable rate
5. consider kinetics of Br + ethane???
or h
 2Br 
initiation Br2  
propagation
Br  CH3 CH3  BrH  CH3 CH2 ,H  10 kcal / mol
CH3 CH2   Br2  CH3 CH2Br  Br,H  23 kcal / mol
termination
rate  d[EtBr ]
Br   Br  Br2
dt
 k 2 [Br2 ][Et]  d[HBr ]
dt
 k1[Br][EtH]
first step is slow step therefore
kt
[Br]  [Et]  2[Br] 
 is termination path
CS11 free radical reactions.docx
2012April11
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at steady state [total radical] I constant therefore Rinitiation = Rtermination
Ri depends on heat and light
Ri  2k t [Br]2  [Br]  (Ri 2k t )1/ 2
1
R 2k [EtH]
rate  i 1 21 1 2
2 kt
note that rate is independent of Br2
Estimate chain length: chain length = k1[Br][EtH]
2k t [Br]
2

k1[EtH]
2k t [Br]
- must be greater than 1 for reaction to be feasible
- estimate rate of reaction: G* = H + 2-5 kcal/mol = 10 + 4 = 14 kcal/mol
log k1  13  G *
1. 4
 k1  103 M-1 s -1
if [EtH] = 1 M, then rate  10 3 (1)[Br]
for practical rate > 10-5 M/s, then [Br]  10 8 M
chain length = 102
increase [Br] to 10 -6 M, chain length is 1, rate =10-3 s-1
6. polar effects- chlorination more sensitive than bromination
CH3CH2CH2CN + Cl2
ClCH2CH2CH2CN + CH3CHClCH2CN + HCl
31%
69%
a. the chlorine radical is less selective than bromine and abstraction has early
transition state
b. therefore the stability of the radical has little influence on the TS energy
c. the -CH bonds are weakest but are also relatively electron deficient
d. the chlorine radical is electrophilic so it avoids the elecron deficient -CH
B. radical addition
1. X2 initiates as above, HX, RSH, Br3CH, BrCCl3, CCl4 initiate via peroxide
CS11 free radical reactions.docx
R'OOR'
R'O
+
R'O
Y
+ LY
+
Y
+ LY
R +
2012April11
:page 8
2R'O
R'O
R
R'O
L + Y
Y
R
Y
L + Y
LY
abstraction
HX
 RH + X
RSH
 RH + RS
X2
 RX + X
BrCCl3
 RBr + CCl3
CCl4
 RCl + CCl3
HCBr3
 RH + CBr3
2. addition to nitroso or nitrone compounds
R
R
N O + R'
R'
N O
R'
O
O
N
N
+ R'
3. two-atom 3-electron bonds
VI. inhibitors - abstraction or addition forms unreactive radicals
CS11 free radical reactions.docx
2012April11
:page 9
OH
OH
tBu
O
HO
tBu
2R
O
R + O2
RO2
R
RO2
OH
Me
O
RO4R
-tocopherol
BHT
hydroquinones
O
RSH
-
OH
+
N
-
O
R
+
N
N+
-
O
O
+
R
N
tBu
tBu
R
O-
thiol
O-
R
ascorbate
spin traps
spin adducts
VII. selected reactions
A. hydroxylation arenes
Fe2+
H2O2
H2O2
HO - + HO
+ HO - + HO
OH
OH
OH
H
H
B.
O H
O
H2SO4
O H
NH2
NH2
H2O2
NH2
O
O
N
+
O
HO
H2O2
FeSO4
NH2
O
O
+ H2O
O
H
O
NH2
NH2
NH2
O
HO H O
O
O
O H
O H
O
H
H
O H
NH2
NH2
+
N
N
NH2
O
N
O
N
C. Hunsdiecker
O
R
O
-
+
O Ag
+
Cl
R
-
O
+ Cl+
Ag
O
O
Cl
Cl
R
OCl
R
O
R + CO2
O
+ Cl
R
OCl
also works with carboxylic acids and Cu(II) , Pb(IV), Ce(IV), Mn(III), Ag(II) and halide
O
RCl +
D. autooxidation
R
O
CS11 free radical reactions.docx
2012April11
Ri
initiation (source of ROOH?)
ROOH  RO   RO 
:page 10
RO  RH  ROH  R 
R  O2  RO 2 
propagation
RO 2  RH  RO 2H  R 
propagation
2RO 2   RO 4R
termination
Inhibition:
for complete inhibition, rate of radical
scavenging by inhibition equals rate of initiation [ROOH]
since there are no chain reactions, for
injection of InH
example, in autooxidation
time
InH
InH  ROO  k

In  ROOH
Ri   d[InH ]
dt
 d[ROOH ]
t
dt
 k InH [ROO][InH ]
graphically Ri  [InH ] / t , providing a simple means of determining Ri.
E. silicon hydride (or tin hydride) reduction of alkyl halides.
ROOR  2RO 
RO   Et3 SiH  ROH  Et3 Si 
Et3 Si   RX  Et3 SiX  R 
R   Et3 SiH  RH  Et3 Si 
F. diacyl peroxide reduction, catalytic in copper,

RCO2O2CR  CuI  RCO2   RCO2  Cu2  I
ast
RCO 2   f

 R   CO2
R   Cu2  R  Cu
R  RCO 2  RCO 2R
cation may rearrange or react with added nucleophile
CS11 free radical reactions.docx
G. rearrangement
2012April11
Ph
Ph
Ph
Ph
:page 11
Ph
Ph
H. Dissolving metal reduction
1. olefins, alkynes, aromatics
H O R'
Na + R
R
C C
R
C C R
H
R
+ Na
R
R
C C R + Na
C C
H
+ Na
R
H O R'
C C
H
+ Na + O R'
R
R C C H
+ Na + O R'
H
R
note that C radicals oxidize electropositive metals
2. RX + 2Na  R2
3. esters, aldehydes and ketones (acyloin)
I. Carbenes
1. divalent carbon, six electrons, 2 non-bonding electrons
R
2. singlet
R
R
(a) paired electrons
R
(b) empty p,
sp2
lone pair
(c) concerted addition to double bond, retention of stereochemistry
3. triplet - unpaired electrons, diradical, stepwise addition to double bond, loss of
stereochemistry
4. CH2 triplet is lower in energy than singlet by 8-10 kcal/mol
CS11 free radical reactions.docx
2012April11
5.  donor (heteroatom or aromatic goups) stabilizes singlet
:page 12
6. carbene formation and reactions
a. thermal or photolytic decomposition of diazomethane,
+
H2C N
N
ketene, diazirine
(a) spin conservation yields singlet first, if reaction is
N
H2C C O
slow decays to triplet
(b) triplet sensitizers like benzophenone yields triplet directly
b. -elimination of carbanion, HCCl3 and base, CH2I2 and Zn
c. termination
d. insertion in CH bonds
e. -migration
f. addition to double bonds
J. Nitrenes are analogous to carbenes
RN
-
N
CH2 + N2
CH2
+ CO