Free Radicals in Organic Synthesis
Convenor: Dr. Fawaz Aldabbagh
Recommended Texts
Chapter 10, by Aldabbagh, Bowman, Storey
H Cl H Cl+
0 electrons 8 electrons in outer shell
water
H2O
H3O Cl
ONLY POSSIBLE IN SOLUTION
H Cl H Cl+
1 electron 7 electrons in outer shell
Less Energy Demand
Gaseous phase
Monoatomic - Radicals
When bonds break and one atom gets both bonding electrons- Pairs of Ions – Driven by the Energy of solvation
When bonds break and the atoms get one electron each
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
Br Br 2 Br
I I 2 I
G# = 243 KJmol-1
G# = 192 KJmol-1
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
Radical Formation or Initiation
Ph
O
Ph
hvPh
O
Ph
*
Ph
OH
PhPh
O
Ph
H-abstraction
Ph
Ph
OH
H2 X
Ph
Ph
OH
Ph
PhOH
Benzpinacol
Benzhydrol
Excited Triplet or Biradical
O
CR O
OC
R
O
O
CR O
OC
R
O
C
O
O
R+
Peroxides
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
Photochemical Reaction
OO
O
O
OO
C
O
O
2 X O2 X+
DTBPO
Half-life 10 mins at 70oCO
acetone
CH3
+
NC N
N
NCN N
CN C
N
Azobisisobutyronitrile (AIBN)
Heat
CN
H SnBu3
CN
H SnBu3+
Weak Tin-Hydrogen Bond Strong Carbon-Hydrogen Bond
Other Peroxide Initiators
Azo InitiatorsAzo Initiators
A combination of AIBN-Bu3SnH is most popular radical initiation pathway in organic synthesis
HEATPb CH34
CH3
PbH3C CH3
CH3
+
Ph Br Mg Ph Mg Br Ph MgBr
OC
OR
OC
OR R + CO2
1 e - oxidation
Kolbe Reaction - Electrochemical oxidation
R R
OrganoMetallic INITIATORSC-M bonds have low BDE, and are easily homolyzed into radicals;
FORMATION OF GRIGNARD REAGENTS
Electron Transfer Processes
SET (Single Electron Transfer) reactionsSET (Single Electron Transfer) reactions
R X R X R + XSET
M +n M +n+1
N
N
CH3
Br
NaNa
N
N
CH3
Br
N
N
CH3
NH3
Br +
imidazoyl radical
CH3
radical anion
ArX + e-NH3 (ArX)
Initiation using a metal in ammonia
E.g.
CH3
CH3
Fentons Reaction
HO OH Fe2+ Fe3+ OH OH+ + +
hydrogen peroxide
HO OH OH OH+
analysis
also,
Fe2+ Fe3+OHt-BuO+ + +t-BuOOH
All the radical initiation pathways so far discussed give very
reactive, short-lived radicals (< 10-3s), which are useful in synthesis
Stable and Persistent Radicals
ClAg
Gomberg - 1900
triphenylmethyl radical
Original Structure - 1900
radical dimerization
1970 Real Structure Determined by NMR
AgCl+
Steric Shielding is more important than Resonance Stabilisation of the radical centres- Kinetically Stabilised Radicals (Half-life = 0.1 s)
N N
O2N
O2N
NO2
diphenylpicrylhydrazyl radical, DPPH
N O
TEMPO
N O
TMIO
(red) (orange-yellow)
– Thermodynamic Stabilisation is most importantThese radicals can be stored on the bench, and handled like other ordinary chemicals, without
any adverse reaction in air or light.
Often – very colourful compoundsNitroxides
Why so stable?
Very Stable Radicals (Half-life = years)
Nitroxides are used as radical traps of carbon-centred radicals
N O R+ N O R109 M-1s-1
Alkoxyamine
Identifying reactive radicals and studying radical reactions
No dimerization via nitroxide, NO-bond
----------- Explain
Configuration or Geometry of RadicalsNormally, 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.
A
X
X X
A
XX
XA
XX
X
AX3
sp2
+ p-character+ p-charactersp3 sp3
PlanarPyramidal PyramidalTetrahedral Tetrahedral
Similarly,
X A X AX X
AX2
Linear Radical Non-Linear
ESR spectroscopy is usually used to determine such features
CHH
H
CH3CH3
0o 10o10o
Energy
Pyramidisation
Methyl radical can be regarded as planar
Unlike, carbocations, carbon-centred radicals can tolerate serious deviations from planarity e.g. CH3 , CH2F , CHF2 , CF3
Because of Orbital Mixing
-Donors (+M) , Attractors (-)- F, - Cl , - Br , - I
- OH- NH2
FSubstituent Effects
-Acceptors (-M) , Acceptors (-)HC C
N C
(+M)
LUMO
SOMO
Stabilization
AX3
SOMO
Planar
acceptor
HOMO donor
AX3
Pyrimidised
LUMO
Group IV Hydrides
CH3 < SiH3 < GeH3 PbH3<
Pyrimidized
HH
X
H H
X
H H
H
H
Staggered EclipsedPyrimidized 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
Alkyl Radicals
a/ Thermodynamic StabilityIs 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 MesomerismThis is the primary reason for the existence of stable radicals (see notes on nitroxides and DPPH)
CH2CH2 CH2
CH2
allylic radical
benzylic radical
sp2 or radical
cannot be resonance stabilised
Vinyl and Aryl Radicals
Very Reactive Radicals
2. HybridisationRadical is more stable than Radical.
As the p- character of a radical increases so does its thermodynamic
stabilisation
CH
O
CH
O
sp3 radical - almost tetrahedral
more stable
radical anion
CH
O
e-
Resonance Stabilised ketyl radical
3. Hyperconjugation
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
Remember, that inductive and steric effects may also contribute to the relative stability of the radical
H2C C
d
c
R RH2C C
d
c
c - Electron Withdrawing Group
d - Electron Donating Group
4. Captodative effect
CH(CHO)2
CH(NO2)2
CH(t-Bu)2
CH(OCH3)2
CHCH3(OCH3)
CH(NH2)CHO
CH(NH2)CO2H
BDE (R-H)
99
99
98
9191
73
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.
SOMO
HOMO
LUMO
Radical Stabilised
This is generally due to steric factors.
triphenylmethyl radical
1,4 - Hydrogen abstraction
Half-lives increased from 10-3 to 0.1 s
Radicals can be detected by normal spectroscopic methods
b/ Kinetic Stability
The Polar Nature of Radicals
Radicals can have electrophilic or nucleophilic character
RR Relectrophilicnucleophilic
+ e-- e-Increasing Electron AffinityDecreasing Ionization Potential
ROCl
R S
O
O
F
N H
R CO
O
Cl3C
Bu3Sn
CH3 < CH3CH2 < (CH3)2CH < (CH3)3C
R3C
Increasing Nucleophilic Character and Increasing Cation Stability
X + H- H-X +
ClH C(CH3)3
H CCl3
H C(CH3)3
H CCl3CH3
Ea
0.2
6.5
8.1
5.8
O
OH
Cl
CH3
H-abstraction - the prefered positions of attack
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.
HO
H
O H3CH
Ph
Bu3Sn H
12700
0 30007 X 105
O H Rkrela
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.
Y
Y = CHO = 34 ; Y = CO2CH3 = 6.7 ; Ph = 1.0 ; OAc = 0.016
krel
LUMO
SOMO
C C
nucleophile
SOMO
HOMO
RO2C
CH
RO2C electrophile
AIBN (CH3)2CCN
(CH3)2CCN Bu3SnH+ (CH3)2CHCN Bu3Sn+
Initiation
Reduction of Alkyl Bromides
Propagation
R-Br R-H
Bu3Sn R-Br+ Bu3SnBr R+
R + Bu3SnH R-H Bu3Sn+
Termination
Bu3Sn Bu3Sn-SnBu3
R R-R
(CH3)2CCN
+ N2
R +
2 X
2 X
2 X
Bu3Sn Bu3Sn-R
C
C
CH3H3C
CN
CH3H3C
CN
CN
ButBr + ButCN
Bu3SnH , AIBN
+ Bu3SnBrslow addition
CN
But
ButCN
Bu3SnH
Bu3Sn
ButCN
CN
But
ButCN
Bu3SnH
Bu3Sn
ButCN
Bu3SnBr
ButBr
1
Problems with Bu3SnH
We can overcome the use of Tin-hydride-
By using Silanes as Bu3SnH substitutes
X R Si
R
R
R
X R
Sn
R
R
R
X RX RSn
R
R
R
R
R
Si
R
R
R
H
Sn
R
R
R
H
R H Si
R
R
R
Si
R
R
R
R H Sn
R
R
R
+ .+
.++.
Halogen-atom abstraction
Hydrogen-atom abstraction
.
.
+
+
+ .
.
+ .
kx = 106 lmol-1s-1
kx = 106 lmol-1s-1
kH = 103 lmol-1s-1
kH = 106 lmol-1s-1
Si
Si
Si
SiCH3
CH3
CH3CH3
CH3
CH3
CH3CH3
CH3
.Si
Si
Si
SiCH3
CH3
CH3CH3
CH3
CH3
CH3CH3
CH3
H R H.+ +
kH = 105 lmol-1s-1Tris(trimethylsilyl)silane
R
Prof. Chris Chatgilialoglu, Bologna
BDE’s (kcal/mol)
Et3Si-H 95.1
[(CH3)3Si]3Si-H 84
Bu3GeH 89
Bu3Sn-H 79
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
Prof. Brian RobertsUCL
RS -H Et3Si-H Et3Si● RS● R●
R X
Et3Si XR H
Et3Si H
PhS H
Et3Si .PhS.
R .
PhSH
Polarity Reversal Catalysis
Radical-Anions
M M
M + A MA
SET
OX
RED
LUMO
HOMOEnergy
1 eSOMO
HOMO
M M
Na Nafast
e [NH3]nslow
NH H
HNH2
Blue Solution+H
H2
colourless
Sodium Amide, (Na+NH2-) is made by dissolving Na in liquid ammonia, and then waiting
until the solution is no longer blue
C
O
C
O
C
O
C
O
Na
Na
C
O
Drying Ether or THF
Birch Reduction
Li , NH3(l), EtOH, Et2O
Prof. Arthur Birch, ANU
OMg
O Mg2+O OMg
benzene or ether
HO OH
EtOH
OH
Other REDOX reactions
Pinocol CouplingIn aprotic solvents, ketyl
radical anions dimerise
OTiCl3 , K
OO
+
40%
50%26%
TiCl3 , 3 eq. Li
McMurry Coupling
Heterogeneous Reaction occurring on the surface of the titanium metal particle
generating TiO2 and an alkene
Prof. John McMurryCornell
Sandmeyer Reaction
NH2HCl , NaNO2
N2
HNO3
CuBr , Heat
Br
Other Nucleophiles can also displace the diazonium ion, including Chlorides,
Iodides and Cyanides
Prof. Traugott Sandmeyer, Wettingen, Switzerland
M M
R + M MA
SET
OX
RED
LUMO
HOMOEnergy
- 1 eLUMO
SOMO
M M
Radical-Cations
N N
R
R R
R+
Wurster – isolable, highly coloured radical cation
C C
X
C C
X
exo
C C
X
endoC C
X
+1
2
34
5
6
5-exo 6-endo
98% 2%5-hexenyl radical
3-, 5- and 6-membered radical cyclizations are usually faster than the analogous intermolecular addition.
Draw six-membered chair transition state for 5-exo trig cyclization
Kinetic product favoured over thermodynamic product
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
'Radical Clock'
n = 2 kexo = 1
k-exo = 4.7 X 103
kendo = not observed
e.g.
e.g.CH2
CH2( )
n
n = 1 kexo = 1.8 X 104
k-exo = 2 X 108
kendo = not observed
'Radical Clock'
n = 2 kexo = 1
k-exo = 4.7 X 103
kendo = not observed
e.g.
e.g.CH2
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.
ko = 1.7 X 109 s-1
ko = 3 X 108 s-1
kc = 1.7 X 107 s-1
kc = 3 X 104 s-1
Thorpe-Ingold Effect
Cyclization onto triple bonds is always exo, but slower than onto DBs
Tandem or Cascade Radical Cyclizations
BrBu3SnH, AIBN
H H
H
Capnellene
Two sequential 5-exo radical cyclizations
Write a full chain mechanism