CO-404 SYNTHETIC METHODS
Free Radicals in Organic Synthesis – 6 hours
(i)
Structure and Stability - detection, MO-theory, nature of
radicals (electrophilic, nucleophilic and charged radicals)
and thermodynamic and kinetic stability of radicals.
(ii)
Mechanisms – initiation, propagation, termination, radical
chain reactions, radical cyclizations (including tandem),
regioselectivity (‘Beckwith model or chair transition state’),
and an introduction to autoxidation.
(iii)
Alternatives to Bu3SnH – problems with Bu3SnH, silanes,
polarity reversal catalysis, reactions requiring catalytic
amounts of tin hydride.
(iv)
Single Electron Transfer Reactions (SET) in organic
synthesis. – Mechanisms of Birch reduction, pinacol
(McMurry) couplings, Sandmeyer reaction and examples of
stable radical anions and cations.
Six Lectures by Dr. Fawaz Aldabbagh + Tutorial
D. Combinatorial Chemistry – 2 hours
Automated solid phase organic synthesis. Comparing Merrifield
and Ellman approaches. Polymer supports and linkers.
Automation and robotics involved.
2 hours - Lectures by Dr. Fawaz Aldabbagh
Recommended Reading
Reactive Intermediates, C. J. Moody and G. H. Whitham,
Oxford Chemistry Primers 8.
Free Radicals in Organic Chemistry, J. Fossey, D. Lefort and J.
Sorba, John Wiley & Sons.
An Introduction to Free Radical Chemistry, A. F. Parsons,
Blackwell Science.
Organic Synthesis, M. B. Smith, Chapter 13, McGraw-Hill
International.
Organic Chemistry, J. Clayden, N. Greeves, S. Warren and P.
Wothers, Chapter 39, Oxford.
A Guide to Mechanisms in Organic Chemistry, Peter Sykes
http://www.nuigalway.ie/chem/Fawaz/fawaz.htm
ONLY POSSIBLE IN SOLUTION
water
H
+
H
Cl
0 electrons
Cl
8 electrons in outer shell
H2O
Cl
H3O
When bonds break and one atom gets both bonding electronsPairs 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.
Temperatures of over 200 oC will homolyse most bonds; on the other
hand, some bonds will undergo homolysis at temperatures little above
room temperature (to be discussed later).
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
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.
Other Peroxide Initiators
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
H
+
SnBu3
CN
Weak Tin-Hydrogen Bond
Strong Carbon-Hydrogen Bond
AA ccoom
mbbiinnaattiioonn ooff AAIIBBN
N--BBuu333SSnnH
H iiss m
moosstt ppooppuullaarr rraaddiiccaall iinniittiiaattiioonn
ppaatthhw
waayy iinn oorrggaanniicc ssyynntthheessiiss..
OrganoMetallic INITIATORS
C-M bonds have low BDE, and are easily homolysed to give radicals;
CH3
HEAT
H3C Pb CH3
Pb
+
4 CH3
CH3
aannttii--kknnoocckk aaggeennttss iinn ppeettrrooll eennggiinneess
FORMATION OF GRIGNARD REAGENTS
Ph
Mg
Ph Br
Mg Br
Ph MgBr
E
Elleeccttrroonn T
Trraannssffeerr PPrroocceesssseess
Kolbe Reaction - Electrochemical oxidation
O
R
O
1 e - oxidation
R
C
C
R
+ CO2
O
O
R
R
SET (Single Electron Transfer) reactions
SET
R
R
X
M +n
M +n+1
X
R
+
X
E.g.
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)
Fe2+
Fe3+ +
Fentons Reaction
HO
+
OH
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.
S
Sttaab
bllee aan
nd
dP
Peerrssiisstteen
ntt R
Raad
diiccaallss
LLoonngg--lliivveedd rraaddiiccaallss,, w
whhiicchh aarree uunn--rreeaaccttiivvee aanndd ssoo nnoott uusseeffuull iinn
oorrggaanniicc ssyynntthheessiiss
Gomberg - 1900
Ag
+ 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
O
N
O
TMIO
TEMPO
(orange-yellow)
(red)
Why so stable?
N
N
O
O
Stabilised via Charged Separated Structures enhanced by the
electronegativity of the N and O atoms.
N
N
O
O
No dimerization via NO-bond.
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
R
Alkoxyamine
The alkoxyamine can be separated by HPLC, and the structure
of reactive radical R determined by NMR.
EPR (Electron Paramagnetic Resonance Spectroscopy)
is used to observe radicals. Reactive radicals are
however difficult to detect, and so are converted to more
stable nitroxide radicals – Spin Trapping.
R
R
N
O
N
Ph
O
Ph
nitrosobenzene
H
R
nitroxide
O
C
H
N
R
But
Ph
O
C
N
But
Ph
nitroxide
nitrone
These Spin Traps allow us to determine the structure of R
H
C
R
C
C
N
C
N
O
O
C
C
N
O
Nitrone
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
Pyramidal
Tetrahedral
X
X
A
A
X
X
X
Pyramidal
Planar
sp3
sp2
sp3
+ p-character
+ p-character
Similarly,
AX2
X
A
X
Linear Radical
Tetrahedral
A
X
X
Non-Linear
EPR 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 , CH2F , CHF2 , CF3
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
Orbital Mixing and Substituent Effects
AX3
Planar
LUMO acceptor
SOMO
Stabilization
AX3
LUMO
Pyrimidised
SOMO
HOMO donor
Increasing the Energy of the SOMO favours pyrimidization
Acceptors (e.g. -CN) increase the energy difference between the
SOMO and LUMO, so enhance the planar character of the radical.
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 rotamer becomes the
transitional structure for rotation.
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
e-
O
CH
radical anion
Resonance Stabilised ketyl radical
3. Hyperconjugation
H
H
H
H
C
C
C
H
H
H
H
H
H
C
thermodynamic stability
CH3
H
H
C
C
H
>
H
CH3
H
C
H
C
H
H
H
>
C
C
H
>
H
H
H
CH3
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
d
C
d
c - Electron Withdrawing Group
d - Electron Donating Group
When one substituent is an attractor and the other is a donor the
stabilisation is greater than the sum of the two separate effects.
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
Conversely, in a di-acceptor or a di-donor the first interaction
pushes the SOMO away from the orbitals of the second
substituent, and thus reduces the stabilization energy.
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
Although radicals are uncharged species, they are
susceptible to polar effects, and this has a major effect
on their reactivity.
i.e. 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
Transition States
Cl H CR3
CH3 H
CR3
The B
Biigg A
Addvvaannttaaggee of using radicals in synthesis is their usually
high regioselectivity, and lack of protection required for other
function groups in a molecule, e.g. OH , as the BDE is much higher
than the activated C-H positions.
krela
O
H
R
O
H3 C
H
H
H
O
1
2700
Ph
0
3000
Bu3Sn
H
7 X 105
Weak Sn-H bond
Increasing rate of abstraction with the increased stability of the
radical.
Note, the effect of an adjacent oxygen is comparable with that of
an adjacent benzene ring; but it requires efficient overlap of the
oxygen lone pairs with the radical.
Electrophiles react faster with electron-rich alkenes (electrondonating substituents adjacent to the alkene DB).
Nucleophiles react faster with electron-poor alkenes (electronwithdrawing 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
Polar Effects are very important in free radical polymerisations,
and the formation of alternating co-polymers.
CN
R

R

Ph
Ph
Ph
CN
R
n
Ph
CN
Ph
CN
Most synthetic radical reactions are chain processes.
Reactive Radicals have very short life times, and the
probability of two radicals reacting together in solution
is often very low.
e.g. 1
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
D
Drriivviinngg FFoorrccee
W
Weeaakk ((oorr lloow
wB
BD
DE
E)) S
Snn--H
H bboonndd bbrrookkeenn –– H
Hiigghh B
BD
DE
ES
Snn--B
Brr
aanndd C
C--H
H bboonnddss ffoorrm
meedd..
Key features of chain reactions
IInniittiiaattiioonn – ‘The formation of reactive radicals.’ Rate constants
tend to be very low (10-5 s-1)
Propagation – Rate constants are very high (k = 102 M-1s-1)
Accounts for the overall reaction products.
Cyclic in nature!
RH
Bu3SnH
Bu3Sn
R
RBr
Bu3SnBr
TTeerrm
miinnaattiioonn – ‘The consumption of reactive radicals.’ Rate
constants are very high (k = 109 M-1s-1)
The overall rate of reaction is proportional to the square root of
the rate of the primary initiation step, so the overall activation
energy is dominated by the activation energy of initiation.
e.g. 2
ButBr
Bu3SnH , AIBN
slow addition
+
CN
t
Bu
CN
+
Bu3SnBr

The product forming steps;
Bu3SnH
CN
CN
But
But
But
CN
Bu3Sn
Summarised;
CN
CN
t
Bu
1
But
Bu3SnH
Bu3SnBr
ButBr
Bu3Sn
CN
t
Bu
Important Features;
Slow addition of Bu3SnH and AIBN to the refluxing reaction of
alkene (excess) allows a faster rate of radical addition (Bu t)
onto the alkene DB rather than radical reduction of Bu t by
Bu3SnH.
The alkene must be electron deficient, so making reduction of
radical 1 more favoured than addition to a further molecule of
alkene and eventual polymerisation.
Problems with Bu3SnH
1. Very Toxic
2. Often Difficult to Separate from Products
3. Slow addition of Bu3SnH is necessary to prevent
reduction of organic radicals.
At least one equivalent of Tin-hydride is required
We can overcome the use of Tin-hydride1.
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
+
H3C Si Si .
H3C
H3C Si CH
3
CH3
CH3
CH3
H3C
Si
H3C
H3C Si Si H + R .
H3C
H3C Si CH
3
CH3
Tris(trimethylsilyl)silane
R H
kH = 105 lmol-1s-1
BDE’s (kcal/mol)
Et3Si-H
95.1
[(CH3)3Si]3Si-H
84
Bu3GeH
89
Bu3Sn-H
79
Often slow addition of [(CH3)3Si]3Si-H is not required,
because the lower rate of reduction of the intermediate
carbon radical.
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 X
Et3Si● RS●
R.
R●
PhS H
RH
RX
Et3Si
.
PhSH
2.
PhS .
Et3Si H
Using Bu3SnH (0.1eq.) and NaBH4 (1 eq.)
If the tin-hydride could be re-generated, then we would
only need a catalytic amount of Bu3SnH.
Bu3Sn X
Bu3Sn .
+
R X
NaBH4
R.
Bu3Sn H
+
Bu3Sn
X
Formed by Redox Processes
Radical-Anions
RED
M
SET
M
OX
M
MA
+ A
LUMO
SOMO
1e
Energy
HOMO
HOMO
M
M
The greater the conjugation – the lower the energy of the LUMO – the
more readily M will accept an electron
N
Na
fast
e [NH3]n
Blue Solution
Na
H HH
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
Na
O
O
C
C
O
C
Drying of ether or THF stills
Birch Reduction
Li , NH3(l), EtOH, Et2O
Pinocol Coupling
In aprotic solvents, ketyl radical anions dimerise
benzene or ether
O
Mg2+
O
Mg
Mg
O
O
HO
OH
EtOH
OH
McMurry Coupling
Unlike magnesium or aluminium, titanium reacts further with
these diol products to give alkenes
O
TiCl3 , K
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
Radical-Cations
OX
M
SET
M
RED
MA
+ M
R
LUMO
LUMO
-1e
HOMO
Energy
SOMO
M
M
e.g. Very Stable – Highly coloured radical cations
R
N
N
R
R
Wurster (violenes)
N
N
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%
This regioselectivity is under enthalpy of activation control, and
is explained by conformational and electronic effects. That is in
the transition state, there is better SOMO-LUMO interactions.
The exo or endo cyclization rate depends greatly on chain
length.
And the reverse of radical cyclization is Ring-Opening.
( )
CH2
n = 1
kexo = 1.8 X 104
k-exo = 2 X 108
n
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
Alkoxy radical is strongly electrophilic, and so cyclization is
very favourable.
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
Autoxidation is the low temperature oxidation of organic
compounds, as opposed to combustion, which happens at
higher temperatures.
R
H
ROOH
Responsible for the decomposition and degrading of most
organic molecules, and it can be initiated by light, traces of
metal ions, and radical initiators.
e.g. rancidity of butter, and the perishing of rubber.
Ether and THF are particularly prone to autoxidation – Never let
ether still run dry, as you can get peroxide explosions!
ROO
H
O
O
stabilised radical
diethyl ether
O
O
oxygen exsits as a diradical
OO
very reactive - going out of control
O