Free Radicals in Organic Synthesis
Convenor: Dr. Fawaz Aldabbagh
Recommended Texts
Chapter 10, by Aldabbagh, Bowman, Storey
ONLY POSSIBLE IN SOLUTION
water
H
Cl
H
+
0 electrons
Cl
8 electrons in outer shell
H2O
H3O
Cl
When bonds break and one atom gets both bonding electrons- Pairs of Ions – Driven by the Energy of solvation
Less Energy Demand
Gaseous phase
H
Cl
H
1 electron
+
Cl
7 electrons in outer shell
Monoatomic - Radicals
When bonds break and the atoms get one electron each
Radical Formation or Initiation
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
Cl
Cl
2 Cl
 G# = 243 KJmol-1
Br
Br
2 Br
 G# = 192 KJmol-1
I
2I
 G# = 151 KJmol-1
I
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
Ph
Photochemical Reaction
Ph
O
*
Ph
hv
Ph
Ph
O
Ph
OH
OH
Ph
Ph
Benzpinacol
Excited Triplet or Biradical
Ph
Ph
OH
Benzhydrol
Ph
Ph
2X
H
H-abstraction
OH
Ph
O
Ph
Peroxides
O
O
C
C
R
O
O
R
R
O
O
R
C
O
O
C
C +
O
O
R
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
O
O
O
O
O
O
DTBPO
Half-life 10 mins at 70oC
O
O
2X C
acetone
O
2X
+
+
O
CH3
Azo Initiators
Heat
N
NC
N
N
N
C
C
N
N
NC
Azobisisobutyronitrile (AIBN)
H
SnBu3
CN
Weak Tin-Hydrogen Bond
H
+
SnBu3
CN
Strong Carbon-Hydrogen Bond
A combination of AIBN-Bu3SnH is most popular radical initiation pathway in organic synthesis
OrganoMetallic INITIATORS
C-M bonds have low BDE, and are easily homolyzed into radicals;
CH3
HEAT
H3C Pb CH3
Pb
+
4 CH3
CH3
FORMATION OF GRIGNARD REAGENTS
Ph Br
Mg
Ph
Mg Br
Ph MgBr
Electron Transfer Processes
Kolbe Reaction - Electrochemical oxidation
O
R
C
O
O
1 e - oxidation
R
C
R
O
R
+ CO2
R
SET (Single Electron Transfer) reactions
SET
R
R
X
M +n+1
M +n
E.g.
+
R
X
N
CH3
N
CH3
NH 3
N
N
Br
Br
CH3
Na
CH3
radical anion
Na
N
Br
+
CH3
N
CH3
imidazoyl radical
Initiation using a metal in ammonia
ArX
+
e-NH3
(ArX)
X
Fentons Reaction
HO
+
OH
Fe3+ +
Fe2+
OH
+
OH
hydrogen peroxide
analysis
HO
OH
OH
+
OH
also,
t-BuOOH
+
Fe2+
t-BuO
+
OH +
Fe3+
All the radical initiation pathways so far discussed give very
reactive, short-lived radicals (< 10-3s), which are useful in synthesis
Gomberg - 1900
Ag
Stable and Persistent Radicals
+ AgCl
Cl
radical dimerization
triphenylmethyl radical
Original Structure - 1900
1970 Real Structure Determined by NMR
Steric Shielding is more important than Resonance Stabilisation of the radical centres- Kinetically
Stabilised Radicals (Half-life = 0.1 s)
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.
O 2N
N
N
NO 2
O 2N
diphenylpicrylhydrazyl radical, DPPH
Often – very colourful compounds
Nitroxides
N
TEMPO
(red)
Why so stable?
O
N
O
TMIO
(orange-yellow)
No dimerization via nitroxide, NO-bond
----------- Explain
Nitroxides are used as radical traps of carbon-centred radicals
Identifying reactive radicals and studying radical reactions
109 M-1s-1
N
O
+
R
N
O
Alkoxyamine
R
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.
AX3
X
X
X
A
X
Tetrahedral
sp
Pyramidal
3
X
A
A
X
X
X
Pyramidal
Planar
sp
+ p-character
X
Tetrahedral
sp3
2
+ p-character
Similarly,
AX2
X
A
X
Linear Radical
A
X
X
Non-Linear
ESR spectroscopy is usually used to determine such features
Methyl radical can be regarded as planar
H
H
Energy
C
H

CH3
CH3
10o
0o
10o
Unlike, carbocations, carbon-centred radicals can tolerate serious deviations from planarity
e.g. CH3 Fo =0, CH2F Fo =5, CHF2 Fo =12.7, CF3 Fo =17.8.
Pyramidisation
Because of Orbital Mixing
Substituent Effects
-Donors (+M) , Attractors (-)
-Acceptors (-M) , Acceptors (-)
F
(+M)
- F, - Cl , - Br , - I
- OH
- NH2
HC C
N C
AX3
Planar
LUMO acceptor
SOMO
Stabilization
AX3
LUMO
Pyrimidised
SOMO
HOMO donor
Group IV Hydrides
CH3 <
SiH 3 <
GeH3 < PbH3
Pyrimidized
Alkyl Radicals
X
X
H
H
H
H
H
Staggered
H
H
H
Eclipsed
Pyrimidized rotamer
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
a/ Thermodynamic Stability
Is quantified in terms of the enthalpy of dissociation of R-H into R and H

R
H
R
+
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)
allylic radical
benzylic radical
CH2
CH2
CH2
CH2
2. Hybridisation
Radical is more stable than Radical.
As the p- character of a radical increases so does its thermodynamic
stabilisation
Vinyl and Aryl Radicals
sp2 or radical
cannot be resonance stabilised
Very Reactive Radicals
sp3 radical - almost tetrahedral
more stable
O
O
CH
CH
-
O
CH
e
radical anion
Resonance Stabilised ketyl radical
3. Hyperconjugation
H
H
H
C
H
C
H
H
C
H
C
H
H
H
thermodynamic stability
H
H
C
H
CH3
C
H
>
H
CH3
C
H
H
H
C
>
H
C
H
CH3
H
C
H
>
H
H
C
H
9 Hyperconjugatable H s
6 Hyperconjugatable H s
3 Hyperconjugatable H s
Remember, that inductive and steric effects may also contribute to the relative stability of
the radical
4.
Captodative effect
c
c
R
H2C
RH2C
C
C
d
d
c - Electron Withdrawing Group
d - Electron Donating Group
BDE (R-H)
CH(CHO)2
CH(NO2)2
99
CH(t-Bu)2
98
CH(OCH3)2
CHCH 3(OCH3)
91
91
CH(NH2)CHO
73
CH(NH2)CO2H
76
99
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.
LUMO
SOMO
HOMO
Radical Stabilised
b/ Kinetic Stability
This is generally due to steric factors.
Half-lives increased from 10-3 to 0.1 s
triphenylmethyl radical
1,4 - Hydrogen abstraction
Radicals can be detected by normal spectroscopic methods
The Polar Nature of Radicals
Radicals can have electrophilic or nucleophilic character
Increasing Electron Affinity
Decreasing Ionization Potential
R
- e-
R
nucleophilic
+ e-
R
electrophilic
Bu3Sn
RO
Cl
R3C
F
O
R S
O
N
H
O
Cl3C
R C
O
CH3
<
CH3CH2
<
(CH3)2CH
<
(CH3)3C
Increasing Nucleophilic Character and Increasing Cation Stability
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.
X
+
H-X
H-
+

Ea
Cl
CH3
H
C(CH3)3
0.2
H
CCl3
6.5
H
C(CH3)3
8.1
H
CCl3
5.8
H-abstraction - the prefered positions of attack
CH3

Cl


OH

O
krela
O
H
R
O
H3 C
H
H
H
O
1
2700
Bu3Sn
Ph
3000
0
H
7 X 105
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.
krel
Y
Y = CHO = 34 ; Y = CO2CH3 = 6.7 ; Ph = 1.0 ;
OAc = 0.016
C
C
LUMO
SOMO
nucleophile
RO2C
SOMO
CH
RO2C
HOMO
electrophile
Reduction of Alkyl Bromides
R-Br
Initiation

AIBN
(CH3)2CCN
+
Bu3SnH
R-H
(CH3)2CCN
+ N2
(CH3)2CHCN
+
Bu3SnBr
+ R
+
Bu3Sn
Propagation
+
Bu3Sn
R-Br
+ Bu3SnH
R
R-H
Termination
2 X Bu3Sn
2XR
Bu3Sn-SnBu3
R-R
CN
2 X (CH3)2CCN
H3C C CH3
H3C C CH3
CN
R
+ Bu3Sn
Bu3Sn-R
Bu3Sn
ButBr
Bu3SnH , AIBN
slow addition
+
CN
t
Bu
+
Bu3SnBr

CN
Bu3SnH
CN
CN
But
But
But
CN
Bu3Sn
CN
CN
t
Bu
1
But
Bu3SnH
Bu3SnBr
ButBr
Bu3Sn
CN
t
Bu
Problems with Bu3SnH
We can overcome the use of Tin-hydrideBy using Silanes as Bu3SnH substitutes
Halogen-atom abstraction
R
R
R Si . +
X
R
R
R Si X +
R
.
kx = 106 lmol-1s-1
R
R
R
R Sn . +
X
R
R Sn X +
R
R.
kx = 106 lmol-1s-1
R
Hydrogen-atom abstraction
R
R
R
.
R.
+
+
R Si H
R
H
+
R Si .
R
R
R
R
R Sn H
R
R
H
+
kH = 103 lmol-1s-1
R Sn . kH = 106 lmol-1s-1
R
CH3
CH3
H3C
Si
H3C
+
H C Si Si .
CH3
CH3
H3C
Si
H3C
H3C Si Si H + R .
H3C
H3C Si CH
3
CH3
3
R
H
H3C
H3C Si CH
3
CH3
Tris(trimethylsilyl)silane
kH = 105 lmol-1s-1
BDE’s (kcal/mol)
Et3Si-H
95.1
[(CH3)3Si]3Si-H
84
Bu3GeH
89
Bu3Sn-H
79
Prof. Chris Chatgilialoglu, Bologna
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
RS-H 
Prof. Brian Roberts
UCL
Et3Si-H
Et3Si● RS●
R●
Polarity Reversal Catalysis
Et3Si X
R.
PhS H
RH
RX
Et3Si
.
PhSH
PhS .
Et3Si H
Radical-Anions
RED
M
SET
M
OX
M
MA
+ A
LUMO
SOMO
1e
Energy
HOMO
HOMO
M
M
N
Na
fast
H HH
e [NH3]n
Blue Solution
Na
slow
H
+ NH2
colourless
H2
Sodium Amide, (Na+NH2-) is made by dissolving Na in liquid ammonia, and then waiting
until the solution is no longer blue
O
Na
C
O
C
Drying Ether or THF
Na
O
O
C
C
O
C
Other REDOX reactions
Birch Reduction
Li , NH3(l), EtOH, Et2O
Prof. Arthur Birch, ANU
benzene or ether
Pinocol Coupling
In aprotic solvents, ketyl
O
Mg2+
O
Mg
Mg
O
O
HO
OH
radical anions dimerise
EtOH
OH
McMurry Coupling
O
TiCl3 , K
Prof. John McMurry
Cornell
40%
O
O
+
TiCl3 , 3 eq. Li
26%
50%
Heterogeneous Reaction occurring on the surface of the titanium metal particle
generating TiO2 and an alkene
Sandmeyer Reaction
Br
N2
NH 2
HCl , NaNO2
CuBr , Heat
HNO3
Other Nucleophiles can also displace the diazonium ion, including Chlorides,
Iodides and Cyanides
Prof. Traugott Sandmeyer, Wettingen, Switzerland
OX
M
SET
Radical-Cations
M
RED
R
MA
+ M
LUMO
LUMO
-1e
Energy
HOMO
SOMO
M
R
R
N
R
M
+
N
Wurster – isolable, highly coloured radical cation
R
3-, 5- and 6-membered radical cyclizations are usually faster than the analogous intermolecular addition.
C
C
exo
C
C
X
X
C
C
endo
C
C
X
X
6
5
1
+
2
4
3
5-hexenyl radical
5-exo
98%
6-endo
2%
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.
( )
CH2
n
n = 1
kexo = 1.8 X 104
k-exo = 2 X 108
kendo =
not observed
e.g.
'Radical Clock'
e.g.
CH2
n = 2
kexo = 1
k-exo = 4.7 X 103
kendo =
not observed
( )
CH2
n
n = 1
kexo = 1.8 X 104
k-exo = 2 X 108
kendo =
not observed
e.g.
'Radical Clock'
e.g.
CH2
n = 2
kexo = 1
k-exo = 4.7 X 103
kendo =
not observed
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.
Thorpe-Ingold Effect
kc = 1.7 X 107 s-1
ko = 1.7 X 109 s-1
ko = 3 X 108 s-1
kc = 3 X 104 s-1
Cyclization onto triple bonds is always exo, but slower than onto
DBs
Tandem or Cascade Radical Cyclizations
Two sequential 5-exo radical cyclizations
H
Br
H
Bu3SnH, AIBN
H
Capnellene
Write a full chain mechanism