Non-ionic Chemical Reactions- FreeRadical

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Non-Ionic Reactions

Non-Ionic Reactions

With few exceptions, the multitude of reactions discussed in this and other introductory texts are classified as ionic

reactions. By this we mean that nucleophilic and electrophilic sites in reacting molecules bond to each other.

Furthermore, charged species such as carbocations, carbanions, conjugate acids and conjugate bases are often

intermediates on the reaction path, the overall transformation taking place in two or more discrete steps. Ionic

reactions normally occur in solution, and changes in solvents may have dramatic consequences.

Examples of ionic reactions include:

(1) Nucleophilic Substitution of Alkyl Halides.(2) Elimination Reactions of Alkyl Halides.

(3) Addition of Brønsted Acids to Alkenes.

(4) Oxidation of Alcohols.

(5) Electrophilic Aromatic Substitution.

(6) Addition of Organometallic Reagents to Aldehydes, Ketones and Carboxylic Acid Derivatives.

(7) Acylation of Nucleophilic Substrates

(8) Alkylation of Enolate Anions.

(9) Claisen and Aldol Condensations.

Here we shall consider two other classes of organic reactions: Free-Radical Reactions & Pericyclic Reactions

One type of "free-radical reaction", alkane halogenation has already been described. Reactions of this kind have

received increasing attention, thanks to their great importance in industrial chemistry. Indeed, the study of free-

radical polymerization of alkene monomers has opened the door to modern polymer chemistry.

The term "pericyclic reaction" encompasses a large and varied group of concerted thermal and photochemical

transformations. An example, previously described, is the Diels-Alder cycloaddition of dienes and dienophiles.

In contrast to ionic reactions, both free radical and pericyclic reactions may occur in the gas phase, as well as in

solution in various solvents. Also, these nonionic reactions are more tolerant of spectator functional groups than are

many ionic reactions.

Free Radicals

Organic Radicals

1. Background & Introduction

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A radical is an atomic or molecular species having an unpaired, or odd, electron. Some radicals, such as nitric oxide

(NO), are relatively stable, but most are so reactive that their isolation and long-term study is not possible under

normal laboratory conditions. The electrons in most stable organic compounds are paired in atomic or molecular

orbitals, so the total electron count is an even number. Molecular oxygen (O2) is a rare example of a stable biradical

(two unpaired electrons having the same spin), with an even number of electrons.

Early chemists used the term "radical" for nomenclature purposes, much as we now use the term "group". Many

doubted that such open-valenced species could exist, although there was circumstantial evidence for their

participation in gas phase reactions. Credit for the first isolation and characterization of a "free radical" goes to

Moses Gomberg, a young instructor at the University of Michigan. In 1900 Gomberg attempted a synthesis of

hexaphenylethane by reacting triphenylmethyl chloride with finely divided metals such as silver and zinc. When air

was excluded from the reaction, he obtained a yellow solution, the color of which darkened reversibly on heating

and cooling. This solution yielded a colorless, crystalline C38H30 hydrocarbon which Gomberg assumed to be

hexaphenylethane.

If the yellow solution was exposed to air (or oxygen) a C 38H30O2 peroxide was obtained, and identified by reductio

to the known alcohol, triphenylmethanol. In a similar fashion the yellow solution reacted with iodine to produce

triphenylmethyl iodide. These reactions will be displayed by clicking on the diagram above. Gomberg concluded that

the colored solutions contained reactive triphenylmethyl free radicals, formed by thermal dissociation of their dimer

(Keq = 2 • 10 –4 at 25º C). The exceptional stability of this carbon radical is attributed to odd electron delocalization

into the three phenyl rings. Discrete Kekule formulas demonstrate that this benzyl-like delocalization places the

electron on ortho and para carbons, but not on meta carbons. Clicking on the diagram a third time will display this

delocalization in a general way.

The resonance structures drawn here may give the impression that the triphenylmethyl radical is planar (flat).

Actually the phenyl groups are turned by about 35º, producing a shape similar to a three bladed propellor. Despite

this twist, the p-pi orbital overlap is still over 80%, so the electron delocalization is not seriously diminished. To see a

model of this unusual radical Click Here .

More than fifty years later, the reactive dimer of triphenylmethyl radical was shown to be the para-coupled

compound drawn above and not hexaphenylethane. The steric crowding of phenyl groups in the simple ethane

dimer is apparently so severe that bonding between two 3º-carbon atoms is prohibited. Since the electron

delocalization noted above places radical character at the para carbons of the phenyl groups, bonding to this

relatively unhindered location is preferred, although at the cost of one benzene ring's aromaticity. If the para-

locations are themselves hindered by large meta substituents, then an unstable hexaarylethane may actually be

formed.

Other relatively stable radicals, such as galvinoxyl have been prepared and studied. These species usually owe their

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ESR Signal Types

Triphenylmethyl ESR Spectrum

3. Methods of Generating Free Radicals

The homolytic cleavage of covalent bonds produces radicals, and since this is an endothermic process, it requires

the introduction of energy from the surroundings. Heat serves this purpose by collisional interconversion of kinetic

energy into vibrational energy, and the temperature required for bond homolysis will be proportional to the bond

dissociation energy. Absorption of light may also lead to radical species by intra- or intermolecular conversion of the

increased electronic energy into vibrational energy. As expected, weaker covalent bonds dissociate into radicals

more readily than stronger covalent bonds. The following table lists standard bond energies (D) for the C–C, C–O

and C–H bonds commonly found in organic compounds, together with bond energies for some weaker bonds that

have been found useful for generating radicals. Approximate homolysis temperatures at which half the bonds are

cleaved in one hour are also given.

Some Standard Bond Energies and Approximate Homolysis Temperatures

Bond D

kcal/mole

T ºC Bond D

kcal/mole

T ºC Bond D

kcal/mole

T ºC

C–C 85 670 O–O 34 160 O–Cl 49 280

C–H 99 850 N–N 39 230 C–I 51 350

C–O 84 680 S–S 55 440 C–Br 67 480

A. Thermal Cracking

At temperatures greater than 500º C, and in the absence of oxygen, mixtures of high molecular weight alkanes

break down into smaller alkane and alkene fragments. This cracking process is important in the refining of crudepetroleum because of the demand for lower boiling gasoline fractions. Free radicals, produced by homolysis of C–C

bonds, are known to be intermediates in these transformations. Studies of model alkanes have shown that highly

substituted C–C bonds undergo homolysis more readily than do unbranched alkanes. In practice, catalysts are used

to lower effective cracking temperatures.

B. Homolysis of Peroxides and Azo Compounds

In contrast to stronger C–C and C–H bonds, the very weak O–O bonds of peroxides are cleaved at relatively low


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temperatures ( 80 to 150 ºC ), as shown in the following equations. The resulting oxy radicals may then initiate other

reactions, or may decompose to carbon radicals, as noted in the shaded box. The most commonly used peroxide

initiators are depicted in the first two equations.

Organic azo compounds (R–N=N–R) are also heat sensitive, decomposing to alkyl radicals and nitrogen.

Azobisisobutyronitrile (AIBN) is the most widely used radical initiator of this kind, decomposing slightly faster than

benzoyl peroxide at 70 to 80 ºC. The thermodynamic stability of nitrogen provides an overall driving force for this

decomposition, but its favorable rate undoubtedly reflects weaker than normal C-N bonds.

C. Photolytic Bond Homolysis

Compounds having absorption bands in the visible or near ultraviolet spectrum may be electronically excited to such

a degree that weak covalent bonds undergo homolysis. Examples include the halogens Cl2, Br 2 & I2 (bond

dissociation energies are 58, 46 & 36 kcal/mole respectively), alkyl hypochlorites, nitrite esters and ketones.

Equations illustrating these radical producing reactions are displayed below. The covalent bonds that undergohomolysis are colored red, and the unpaired electrons in the resulting radicals are colored pink. Ketones undergo n

to π* electronic excitation near 300 nm. The resulting excited state is a diradical in which one of the odd electrons is

localized on the oxygen atom. Cleavage of an alkyl group may then take place.

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reactions of this kind are sensitive to the nature of both the attacking radical ( X•) and the R–H bond. This is

illustrated by the relative rates of hydrogen abstraction given in the following table. Each horizontal row of data is

normalized to 1º C–H (1.0), but there are also large differences between rows. Thus the rate of reaction of 1º C–H

with Cl• is a thousand times faster than with Br•. However, the less reactive bromine atom shows much greater

selectivity in discriminating between 1º, 2º and 3º C–H groups.

Certain C–H bonds are so susceptible to radical attack that they react with atmospheric oxygen (a diradical) to form

peroxides. Typical groups that exhibit this trait are 3º-alkyl, 2º & 3º-benzyl and alkoxy groups in ethers.

R–H + O2

–––> R• + •O2

H –––> R–O–O–H

The exceptional facility with which S–H and Sn–H react with alkyl radicals makes thiophenol and trialkyltin hydrides

excellent radical quenching agents, when present in excess. At equimolar or lower concentration they function well

as radical transfer agents..

Relative Reactivities (per hydrogen) of Hydrogen Atom Donors with Selected Radicals

Hydrogen Donor C2H6 RCH2R R3CH C6H5CH3 CH2=CH-CH2R RCOCH3 C6H5SH (C4H9)3SnH

Attacking Radical

CH3• 1.0 10 100 85 25 170 4•107 5•105

(CH3)3CO• 1.0 6 15 10 0.5 3.5 -- 104

Cl• 1.0 5 6 2 -- -- -- --

Br• 1.0 220 2•104 5•104 -- -- -- --

Carbon halogen bonds, especially C–Br and C–I, are weaker than C–H bonds and react with alkyl and stannyl

radicals to generate new alkyl radicals. This reaction has been put to practical use in a mild procedure for reducing

alkyl halides to alkanes. The chain reaction sequence that accomplishes this reduction is shown here. By clicking on

the diagram, three examples of this dehalogenation reaction will be displayed.

An important modification of this reduction is shown in the third example above. The use of equimolar amounts of

tributyltin hydride in reactions presents certain problems, including the toxicity presented by organostannanes,

difficulty in separating nonpolar stannanes, such as halides, bis(tributyltin) and bis(tributyltin) oxide from desired

products, and formation of tin oxides by reaction with moisture. To reduce these difficulties, a catalytic amount of the

stannanes may be used together with enough NaBH 4 (or an equivalent reagent) to convert the tributyltin halides to

the hydride. Indeed, the reduction is so facile that traces of peroxides in the reactants often initiate reaction without

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added AIBN.

4. The Configuration of Free Radicals

The configurational preferences of different reactive intermediates were noted in an earlier section. Since the

difference in energy between a planar radical and a rapidly inverting pyramidal radical is small, radicals generated a

chiral centers generally lead to racemic products. However, unlike carbocation intermediates, which prefer to beplanar, radicals tolerate being restricted to a pyramidal configuration. The following illustration shows the

decomposition of a bicyclic bridgehead acyl peroxide. Initial formation of a carboxyl radical is followed by loss of

carbon dioxide to give a pyramidal bridgehead radical. This radical abstracts a chlorine atom from the solvent,

yielding the bridgehead chloride as the major product. Although this is a 3º-alkyl halide, it does not undergo S N1

solvolysis reactions because of the strain imposed on the carbocation intermediate by its pyramidal confinement.

The concurrent formation of ester and dimeric cycloalkane products from acyl peroxides is common, and reflects acage effect in homolysis reactions. When a pair of radicals is formed by homolysis, they are briefly held in proximity

by the surrounding solvent molecules (the cage). Rapid decomposition to other radicals may occur, but until one or

both of these radicals escape the solvent cage a significant degree of coupling (recombination) may occur. A

general description of the cage effect will be displayed above by clicking on the diagram.

Cage recombination of radicals may be sufficiently rapid to preserve the configuration of the generating species. An

example will be shown above by clicking on the diagram a second time. Ester formation is clearly a cage product,

whereas 2-chloro-1-phenylpropane comes largely from radicals that have escaped the cage and lost configurationa

identity. The chiral centers in these compounds are marked by asterisks.

Reactions

Reactions of Free Radicals

For many years organic chemists considered free radical reactions to have limited applications, and to be of little

interest outside some fields of industrial chemistry. This view has changed markedly, and important examples of

substitution, addition and elimination reactions proceeding by way of radical intermediates have been developed and

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used in the synthesis of complex molecules.

Since most free radical intermediates are very reactive and have short lifetimes, all the steps in a practical chain

reaction sequence must be fast compared with possible competing reactions. This means that atom abstractions

and radical additions should be exothermic, or only mildly endothermic. Both C–H and C–X abstractions satisfy this

requirement, but the strong O–H bond does not. Also addition to C=C is energetically more favorable than addition

to C=O; and when radicals add to certain C=O functions, they bond to the oxygen, not the carbon. Another

characteristic of radical reaction sequences is fragmentation with expulsion of a small stable molecule, such as CO 2

CO & N2.

1. Substitution Reactions

The alkyl halide reduction described above is one example of a radical substitution reaction. Two other substitution

reactions are shown in the diagram below. The first two equations illustrate a useful procedure for reducing alcohols

to alkanes, known as "Barton-McCombie deoxygenation". A thionoester, such as a xanthate, is first prepared from

the alcohol, and then treated with tributyltin hydride and a radical initiator. Phenylsilane may be substituted for the

stannane as a radical carrier. In either case a radical (X• )adds to the C=S function, and the resulting •C(OR)–S–X

species fragments to R• and XSC=O. This reduction is particularly useful for 2º-alcohols, as in the second equation.

Deoxygenation of 1º-alcohols is often effected by LiAlH4 reduction of tosylate derivatives, a technique that is less

satisfactory for 2º-alcohols.

The second equation shows an interesting substitution of sulfur for bromine. Here the phenyl radical intermediate

bonds to sulfur, followed by homolysis of the tert-butyl substituent.

By clicking on the diagram, a variation of the Barton-McCombie, called "Barton decarboxylation" will be displayed

above. Here advantage is taken of e weak N–O bond to generate a carboxyl radical, which rapidly decarboxylates to

an alkyl radical. The N-hydroxy-2-thiopyridone derivative of a carboxylic acid or acid chloride is readily prepared.

Photolysis in the presence of a thiol as the hydrogen transfer agent initiates the chain reaction shown above the ligh

blue line. The alkyl radical thus prepared (in pink brackets) may then accept a hydrogen or halogen atom, depending

on other reagents chosen for the reaction. The reaction shown below the blue line illustrates the versatility of this

procedure.

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2. Intermolecular Addition Reactions

Addition reactions to carbon:carbon double bonds are among the most important free radical reactions employed by

chemists. The anti-Markovnikov addition of HBr to alkenes is one such reaction, and the peroxide initiated addition

of carbon tetrachloride to 1-hexene is another. As the following equations demonstrate, radical addition to a

substituted double bond is regiospecific (i.e. the more stable product radical is preferentially formed in the chain

addition process).

The following diagram provides other examples of radical addition to double bonds. The first two equations show

how different radicals may be generated selectively from the same compound. Although 2-propanol has three

different groups of hydrogen, simple atom abstraction by an oxy radical occurs exclusively at the 3º-carbon bonded

to oxygen. By using the xanthate derivative, the carbon-oxygen bond may be homolytically cleaved to form theisopropyl radical. Double bond conjugated with carbonyl or nitrile functions are particularly good radical acceptors,

as shown in the last two examples.

If a radical transfer reagent, such as an alkyl halide or xanthate, is not present in excess, an alkene derived radical

may exist long enough to add to other alkene molecules in a repetitive fashion, leading to a polymeric product, as

shown here. The new C–C bond(s) are colored magenta.

~~CH2CHR• + CH2=CHR –––> ~~CH2CHR –CH2CHR• + CH2=CHR –––> ~~CH2CHR –CH2CHR –CH2CHR•

Indeed, free radical polymerization of simple substituted alkenes is so facile that bulk quantities of these compounds

must be protected by small amounts of radical inhibitors during storage. These inhibitors, or radical scavengers, may

themselves be radicals (e.g. oxygen and galvinoxyl) or compounds that react rapidly with propagating radicals to

produce stable radical species that terminate the chain. Inhibitors include quinones, substituted phenols, aryl amines

and nitro compounds. For a more detailed discussion of free radical polymerization Click Here.

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4. Elimination Reactions

The use of thionoesters, such as a xanthates, as radical generating functions was described above, and these

groups may also serve as excellent radical leaving groups. This property has been put to use in the eliminative

reduction of vicinal-glycols to alkenes, as illustrated by the following example. Once again, the tolerance of radical

reactions for a variety of functional groups is demonstrated.

An industrial preparation of vinyl chloride from 1,2-dichloroethane, made by adding chlorine to ethylene, proceeds b

elimination of a chlorine atom from an intermediate carbon radical. The isomer 1,1-dichloroethane does not undergo

an equivalent radical chain elimination. Equations for this process will be shown below by clicking on the diagram.

5. Radical Recombination Reactions

Radical coupling (recombination) reactions are very fast, having activation energies near zero. Such reactions were

noted earlier in the context of the cage effect. The only reason radical coupling reactions do not dominate free

radical chemistry is that most radicals have very short lifetimes and are present in very low concentration.

Consequently, if short lived radicals are to contribute to useful synthetic procedures by way of a radical coupling, all

the events leading up to the coupling must take place in a solvent cage.

To this end, a clever reaction sequence, resulting in intramolecular functionalization of an isolated methyl group, was

designed by Derek Barton, and has been named the "Barton reaction". A general outline of this procedure is shown

below. A pair of radicals is generated by photohomolysis of the weak N–O bond of a nitrite ester. The oxy radical

abstracts a hydrogen atom from a nearby carbon, and the resulting radical couples with •NO to give a nitroso

compound. Subsequent tautomerism of the nitroso product, followed by hydrolysis, converts this function to a

carbonyl group. If oxygen is present, it bonds to the carbon radical before the •NO coupling occurs. This eventually

leads to a nitrate ester on the newly functionalized carbon.

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For the Barton reaction to work, it is necessary that the initial oxy radical be firmly oriented close to the C–H

hydrogen. This requirement is satisfied by appropriate steroid substrates, as demonstrated above by clicking on the

diagram. The nitrite ester of an axial oriented 11-hydroxyl group is prepared by reaction with nitrosyl chloride, 2.

Photolysis generates an oxy radical that is located close to the 18-methyl group. Hydrogen abstraction, followed by

coupling of the CH2• to •NO gave a nitroso compound that tautomerizes to an oxime, 3. Hydrolysis of 3 by nitrous

acid yields the corresponding aldehyde, which immediately forms the bis-hemiacetal, 4. In the presence of oxygen,

the corresponding nitrate ester, 6, is produced.

From models it appears that the axial-11-hydroxyl group is equally close to both the 18- and 19-methyl groups.

However, the two double bonds in ring A slightly change the orientation of the 19-methyl group, and hydrogen atom

abstraction from that location does not occur. If the double bond between carbons 1 & 2 is removed the orientation

of the the 19-methyl group improves, and hydrogen atom abstraction from both methyl sites takes place. This will beillustrated in the diagram by clicking on it a second time. Note that the 1º-radical at C-19 adds to the double bond

before coupling with •NO takes place. All these radical reactions must occur rapidly in a solvent cage before the •NO

escapes.

Stabilized free radicals have sufficiently long lifetimes to permit coupling outside solvent cage confinement. The

following diagram shows two such coupling reactions. The first is the photochemical reduction of benzophenone to

benzopinacol. The second is an example of the oxidative coupling of phenols, a transformation that is an important

step in the biosynthesis of alkaloids. By clicking on the diagram a stepwise description of the first reaction will be

displayed. Clicking a second time shows a mechanism for the phenol coupling.

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Pericyclic Reactions Return to Table of Contents
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Non-ionic Chemical Reactions- FreeRadical

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