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Lecture 21 Free-Radical Reactions I
9.1 Principles
Free radicals may be defined as the species that contain one or more unpaired electrons.
They are generally less stable and react in fraction of seconds with another species.
9.1.1 Formation of Free Radicals
Three general methods are used for the generation of free radicals.
9.1.1.1 Thermal Generation
Two types of compounds dissociate to give free-radicals at moderate temperature: (i)
compounds that have an intrinsically weak bond such as dialkyl peroixides (DO-O = 155
KJ mol-1), and (ii) compounds that, on fragmentation, form strongly bonded products,
such as AIBN which releases N 2.
NC N
N CN 2 CN
. + N
2
O
O
heat
heat
O
9.1.1.2 Photochemical Generation
Light can bring the fragmentation of a compound if the wavelength of the light is
correspond both to an energy greater than that of the bond to be cleaved, and to an
electronic excitation of the molecule concerned. This procedure is suitable for the
formation of alkoxy radicals from alkyl nitrite or hypochlorites.
RO
N
O
light RO.^ + NO.
RO Cl
light RO.^ + Cl.
9.1.1.3 Redox Generation
Covalent bonds may be broken by electron transfer process either by accepting an
electron from a donor or donating an electron to an acceptor.
R OEt O
Na.^ + R^ OEt O
. Na
dimerization EtO OEt R R O (^) O
R R
O
OH
In the second group, the acceptor is generally a transition-metal-ion in a high-valence
state.
Me 3 C CMe 3
OH K 3 Fe(CN) 6
O Me 3 C CMe 3
. O Me 3 C CMe 3 etc
Dimerization O O
H
H
CMe 3
CMe 3
Me 3 C
Me 3 C
O 2 -2H
O O
CMe 3
CMe 3
Me 3 C
Me 3 C
Secondly, polar effect is also operative in radical reactions. For example, the relative
reactivity of C-H bonds in butyl chloride towards chlorine atom follows:
Cl
Number refers relative electron density.
Chlorine atom is electronegative and preferentially reacts at C-H bonds of relatively high
electron density.
In contrast, alkyl radicals which are called nucleophilic radicals react preferentially at C-
H bonds with electron density low.
9.1.2.2 Addition
Free radicals undergo addition to carbon-carbon double bonds. The reaction is generally
selective. For example, addition to CH 2 =CHX takes place exclusively at the methyl
group, irrespective of the nature of X.
R.
X
. X
X
R
R
Alkynes also exhibit similar reactivity with free radicals.
9.1.2.3 Combination and Disproportionation
Two free radicals can combine by dimerization or disproportionation.
2 Br. Br 2 2CH 3.^ H 3 C^ CH 3 CH 4.^ + (^) Br.^ H 3 C Br 2Et.^ EtH + CH 2 =CH 2
These reactions are generally fast, some having negligible activation energies.
9.1.2.4 Rearrangement
Free radicals are known to rearrange in certain circumstances. For example, the addition
of free radical leads to rearrangement due to relief of strain in the cyclic system.
. CCl 3
CCl 3 .
CH 2 CCl 3
CCl 4
CH 2 CCl 3
Cl
+^. CCl 3
9.1.3 The Characteristics of Free radical Reactions
Free radical reactions may be broadly classified into two groups. In the first, the product
formation occurs from the combination of two radicals.
2CH 3.^ H 3 C-CH 3
As we can see, in chlorination, both the propagating steps are exothermic reactions. Thus,
the chain reaction competes very effectively with the termination steps and the chains are
long.
In contrast, in bromination, the first of the propagating steps is endothermic and its
activation energy is essentially at least as great as 62 kJ mol-1. Thus, the reaction is
slower than compared to chlorination. As a result, the terminating process competes with
the propagating step that leads to the chains short.
In iodination, the reaction is strongly endothermic (129 kJ mol-1) that lead to ineffective.
In the case of fluorination, both the propagating steps are exothermic that leads to violent
reaction with fragmentation of the alkyl groups. Thus, fluorination is usually carried out
by other methods.
9.2.1.2 Applications
Radical-catalyzed chlorination and bromination of alkanes take place readily, both in gas
and liquid phases. Both the thermal and photochemical generation of the halogen atoms
are used.
Initiator (^) R. SO 2 Cl 2 + (^) R.^ RCl +. SO 2 Cl
. (^) SO 2 Cl SO 2 +. Cl . (^) Cl + RH HCl +. R . R + SO 2 Cl 2 RCl + SO . 2 Cl
propagation
For example, cyclohexane reacts with sulfuryl chloride in the presence of dibenzoyl
peroxide to give cyclohexyl chloride in 89% yield.
peroxide
Cl
Similarly, the gas phase bromination of isobutane gives t-butyl bromide exclusively.
H
Br 2 Br
9.2.2 Hunsdiecker Reaction
Treatment of aqueous solution of silver oxide with carboxylic acid gives silver salt of
carboxylic acid which reacts with Br 2 to give a bromo-compound with elimination of
CO 2.
CO 2 H
Ag 2 O Br 2
Br
Mechanism
The reaction involves the formation of acyl hypobromite and its homolytic cleavage to
give acyloxy radical which loses CO 2 and the resulting radical reacts with bromine
radical or abstracts bromine from a second molecule of the hypobromite.
Ag 2 O + H 2 O AgOH + HO + Ag
O
O-H
Ag
OH O
O
Ag
Br-Br O
O Br -AgBr
-Br. O
O.^.
Br.^ Br or^
. (^) O
O Br
Br O
O.
Problems:
A. How would you employ radical reactions in the synthesis of the following compounds?
Br
Br
MeO
Br
Cl
Br
B. Complete the following reactions.
Ph Cl Ph Ph
Ag
NOCl light
Me
Br
Bu 3 SnH
light
- (^) Ph
BrCCl 3 light
- PhCHO^ + (^) CO 2 Me
Bu 3 SnH/AIBN
Text Books:
R.O.C. Norman and C. M. Coxon, Principles of Organic Synthesis , CRC Press, New
York, 2009.
J. March, Advanced Organic Chemistry , 4th^ ed, Wiley Interscience, Yew York, 1992.
Lecture 22 Free-Radical Reactions II
9.3 Formation of Carbon-Carbon Bonds
9.3.1 Addition to Carbon-Carbon Double bonds
The addition of aliphatic free radical to carbon-carbon double has wide applications. The
reaction of bromoform with 1-butene is illustrative:
Ph O O Ph
O
O
heat Ph O
O
Ph O
O
. + CHBr^3 PhCO 2 H^ +^^. CBr 3
+. CBr 3 CBr 3
CBr 3
- (^) CHBr 3 CBr^3 +^.^ CBr 3
propagation
Initiation
RX +. SnBu^ 3 R.^ + XSnBu 3
R.^ +^ X R^ Y
R
Y
. R
Y +^^. SnBu 3
R.^ +^ HSnBu (^3) RH +. SnBu 3
R
Y
+ X R
Y
Y .
Alternative method has also been developed using an aqueous mixture of copper(I)
chloride and ammonium chloride under air. Under these conditions, removal of the
proton may be facilitated by complexing between the carbon-carbon triple bond and
copper(I) ion.
R H
Cu(I)
R
Cu(I)
+ H
Since the reaction functions under air, some of the Cu(I) could be oxidized to Cu(II)
which in turn could oxidize the acetylide ion to the acetylide radical that could dimerize
to yield diynes. The following are examples of many synthetic applications. The
synthesis of phellogenic acid has been accomplished from undecylenic acid:
HO 2 C
Cu(I), O 2
HO 2 C
CO 2 H
H 2 , Pd (^) HO 2 C^ CO 2 H
Phellogenic acid
In some cases, intramolecular coupling of terminal alkynes may also occur to produce
cyclic compounds, if the resulting ring is not highly strained. For example, the synthesis
of macrocyclic lactone, exaltolide, that is partly responsible for the sweet odour of the
angelica root, could accomplished with high yield.
OH +^ Cl
O -HCl O
O
Cu(I), O 2 O
O H 2 , Pt O
O
exaltolide
Coupling of monosubstituted acetylene with 1-bromoalkyene can be performed to afford
hetero coupled product in good yield.
HO +^ Br^ Me
Cu(I) -HBr
Me
HO (^) Dehydromatricarianol
9.3.4 Acyloin Condensation
Aliphatic ester reacts with molten sodium in hot xylene to yield the disodium derivative
of acyloin which is converted into acyloin in the presence of acid. The reaction is to be
carried out under nitrogen because acyloins and their anions are prone to undergo
oxidation with air.
R OR'
O (^) Na/xylene
H
R
OH
O
R
MeO 2 C CO 2 Me
Na xylene
O
OH
N. L. Allinger, Org. Synth. 1963 , 4 , 840.
MeO 2 C CO^2 Me^ Me^3 SiO^ OSiMe 3
Na, Me 3 SiCl
E. Butkus, A. Ilinskasa, S. Stoniusa, R. Rozenbergasa, M. Urbanovab, V. Setnikac, P. Bouc, K. Volkac, Tetrahedron: Asymmetry 2002 , 13 , 633.
Me CO 2 Et
O O
CO 2 Et (^) Na/toluene
Me 3 SiCl (^) Me
O O
Me 3 SiO OSiMe 3
A. N. Blanchard, D. J. Burnell, Tetrahedron Lett. 2001 , 42 , 4779.
9.4 Formation of Carbon-Nitrogen Bonds
9.4.1 Barton Nitrite Photolysis Reaction
Photolysis of organic nitrites can be utilized to introduce functionality at unreactive
aliphatic δ-carbon.
NaOCl light H/H 2 O
OH
H OH O
R R
For example, the synthesis of aldosterone 21-acetate from corticosterone acetate has been
demonstrated.
Me
Me
OAc
O HO
O
NOCl light
Me
OAc
O HO
O
HON
HNO 2
Me
OAc
O HO
O
O
Me
OAc
O
O
O
OH
Mechanism
Photolysis of organic nitrites gives oxy-radical which abstracts hydrogen from a δ-CH
bond. The resulting alkyl radical reacts with nitric oxide liberated during the photolysis to
yield a nitroso-derivative which tautomerizes to oxime that can be hydrolyzed to carbonyl
group.
HOH
NOCl^
H (^) ONOlight
-NO.
H (^) O. (^) OH R (^) R R R (^). NO.^ OH
R N
O OH R N
OH
H R^ NOH
H OH R NOH H OH H 2 O R^ NOH
H OH H 2 O
R NOH
H OH
H-O H
-NH 2 OH
OH
R OH
-H OH
R O
Examples:
S N
O
NHBoc
O
R t-BuSH light
H
N
Boc R 78%
D. H. R. Barton, Y. Herve, P. Potier, J. Thierry, Tetrahedron 1988 , 44 , 5479.
Me
EtO 2 C
Cl O N^ S OH
Me
CO 2 Et
Barton S (^) N
E. Bacque, F. Pautrat, S. Z. Zand, Org. Lett. 2003 , 5 , 325.
9.5 Formation of Carbon-Oxygen Bonds
In a wide variety of environments, C-H bond undergoes oxidation on standing in air to
give hydroperoxides. For example, ethers proceed autoxidation to give -hydroperoxide.
O
O 2
O O^2 H
Since hydroperoxides are known to explode on heating, it is essential to remove them
(e.g. by reduction with aqueous iron(II) sulfate) from ethers before their use as solvents
for the reactions.
Isobutane can be transformed into t-butyl hydroperoxide in the presence of initiator.
Me H
Me Me O^2 Me OOH
Me Me
Alkenes are more reactive compared to alkanes due to greater stability of allyl radicals
compared to alkyl radicals.
O 2
O 2 H
9.6 Formation of Bonds to Other Elements
Elements such as sulfur, phosphorus and silicon can proceed reactions with alkenes and
alkynes via radical catalyzed process. The characteristics of these reactions are similar to
those described above. For example,
Cl 3 SiH (^) + SiCl 3
PH 3 + 3 P
3
SH +
S
