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Free-Radical Reactions I, Principles of Organic Synthesis, Lecture notes of Chemistry

Formation and Reactions of Free Radicals are discussed in this lesson.

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NPTEL Chemistry Principles of Organic Synthesis
Joint initiative of IITs and IISc Funded by MHRD Page 1 of 22
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 N2.
NC N N CN CN
2.+N2
OOheat
heat
O
2.
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 NO
light RO + NO
..
RO Cl light RO + Cl
..
pf3
pf4
pf5
pf8
pf9
pfa
pfd
pfe
pff
pf12
pf13
pf14
pf15
pf16
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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.

  • SO 2 Cl 2

peroxide

Cl

  • SO 2 + HCl

Similarly, the gas phase bromination of isobutane gives t-butyl bromide exclusively.

H

Br 2 Br

  • (^) HBr

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

  1. (^) Ph

BrCCl 3 light

  1. 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