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 + Cl
0 electrons 8 electrons in outer shell
H 2O
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 + Cl
1 electron 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 I 2I G# = 151 KJmol-1
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 OH
Photochemical Reaction
Ph Ph * Ph
hv Ph
O O OH
Ph
Ph Ph Benzpinacol
Excited Triplet or Biradical
Ph OH Ph
Benzhydrol
2X OH
Ph Ph H H-abstraction Ph
O
Ph
Peroxides
O
O C
R O
C O R
R O C
O
O R
O C C + R
O O
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
acetone
2X C + 2X O
+
O
CH3
Azo Initiators
Heat
NC N
N N C C
N
N N
NC
Azobisisobutyronitrile (AIBN)
H SnBu3 H + SnBu3
CN CN
Weak Tin-Hydrogen Bond 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 1 e - oxidation O
R C R C R + CO2
O O
R R
SET (Single Electron Transfer) reactions
SET
R X R X R + X
M +n M +n+1
E.g. N CH3 N
NH3 CH3
N N
Br Br
CH3 Na CH3
Na radical anion
N
CH3
Br +
N
CH3
imidazoyl radical
Initiation using a metal in ammonia
ArX + e-NH3 (ArX)
Fentons Reaction
+ Fe2+ Fe3+ + OH + OH
HO 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 ( H C C > H C C > H C
H CH3 H CH3 H H 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 C RH2C C
d d
c - Electron Withdrawing Group
d - Electron Donating Group
BDE (R-H)
CH(CHO)2 99
CH(NO2)2 99
CH(t-Bu)2 98
CH(OCH3)2 91
CHCH3(OCH3) 91
CH(NH2)CHO 73
CH(NH2)CO2H 76
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
Decreasing Ionization Potential Increasing Electron Affinity
- e- + e-
R R R
nucleophilic electrophilic
Bu3Sn RO
Cl F
R3C O
R S N H
O
Cl3C O
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- H-X +
Ea
H C(CH3)3 0.2
Cl
H CCl3 6.5
H C(CH3)3 8.1
CH3
H CCl3 5.8
H-abstraction - the prefered positions of attack
OH
CH3
Cl
O
krela
O H R
O H3 C
H
H H Bu3Sn H
O Ph
7 X 105
1 3000
0
2700
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 electrophile
HOMO
Reduction of Alkyl Bromides
R-Br R-H
Initiation
AIBN (CH3)2CCN + N2
(CH3)2CCN + Bu3SnH (CH3)2CHCN + Bu3Sn
Propagation
Bu3Sn + R-Br Bu3SnBr + R
R + Bu3SnH R-H + Bu3Sn
Termination
2 X Bu3Sn Bu3Sn-SnBu3
2XR R-R
CN
H3C C CH3
2 X (CH3)2CCN
H3C C CH3
CN
R + Bu3Sn Bu3Sn-R
Bu3SnH , AIBN
slow addition CN Bu3SnBr
ButBr + Bu
t +
CN
Bu3SnH
CN
CN
But But
But
CN
Bu3Sn
CN
CN
t
Bu
1
But
Bu3SnBr Bu3SnH
Bu3Sn
ButBr
CN
t
Bu
Problems with Bu3SnH
We can overcome the use of Tin-hydride-
By using Silanes as Bu3SnH substitutes
Halogen-atom abstraction
R R
.
R Si . + X R R Si X + R kx = 106 lmol-1s-1
R R
R R
R Sn . + X R R Sn X + R. kx = 106 lmol-1s-1
R R
Hydrogen-atom abstraction
R R
. + +
R R Si H R H R Si . kH = 103 lmol-1s-1
R R
R R
R. + R Sn H R H + R Sn . kH = 106 lmol-1s-1
R R
CH3 CH3
H3C CH3 H3C CH3
Si H3C Si
H3C
H3C Si Si H + R . H C Si Si .
3
+ R H
H3C H3C
H3C Si CH H3C Si CH
3 3
CH3 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 Et3Si-H Et3Si● RS● R●
Prof. Brian Roberts
UCL
Polarity Reversal Catalysis
Et3Si X PhS H
R. RH
RX
.
Et3Si
PhS .
PhSH Et3Si H
Radical-Anions RED
SET M M
OX
M + A MA
LUMO SOMO
1e
HOMO HOMO
Energy
M M
N
fast H HH
Na Na e [NH3]n H + NH2
Blue Solution slow 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 O
C
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
Mg
Pinocol Coupling
O Mg O Mg2+ O O
In aprotic solvents, ketyl
radical anions dimerise
EtOH
HO OH
OH
McMurry Coupling
O
TiCl3 , K
Prof. John McMurry
40% Cornell
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
NH2 N2 Br
HCl , NaNO 2 CuBr , Heat
HNO3
Other Nucleophiles can also displace the diazonium ion, including Chlorides,
Iodides and Cyanides
Prof. Traugott Sandmeyer, Wettingen, Switzerland
OX
SET M M
Radical-Cations
RED
R + M MA
LUMO LUMO
-1e
HOMO SOMO
Energy
M M
R R
+
N N
Wurster – isolable, highly coloured radical cation
R 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
+
4 2
3 5-exo 6-endo
5-hexenyl radical 98% 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.
n = 1 kexo = 1.8 X 104
CH2
( )
n
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
n = 1 kexo = 1.8 X 104
CH2
( )
n
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 H
Bu3SnH, AIBN
Br
H
Capnellene
Write a full chain mechanism