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Organic Mechanisms: Radicals

Chapter 2

1) Introduction

2) Formation of Radicals (a) Homolytic Bond Cleavage

(b) Hydrogen Abstraction from Organic Molecules

(c) Organic Radicals Derived from Functional Groups

3) Radical Chain Processes

4) Radical Inhibitors

5) Determining the Thermodynamic Feasibility of Radical Reactions

6) Addition of Radicals (a) Intermolecular

(b) Intramolecular – cyclization reactions

7) Fragmentation Reactions

8) Rearrangement of Radicals

9) The SRN1 Reaction

10) Birch Reaction

11) Radical Mechanisms for Anion Rearrangements

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1) Introduction

Radicals are species that contain one or more unpaired electrons.

Radical reactions involve movements of single electrons, which means

single barb, fish hook arrows.

Radical reactions are very important industrially, and in nature/biological systems.

Single, radical electrons are usually represented by a dot, •

Radical mechanisms are written in two different ways:

(i) Each individual step is written without the use of arrows, depicting the order of events, and the single electron movement is implied.

(ii) Half headed arrows are used to illustrate the electron movement.

You need to be fluent in both types.

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Most studies show typical radicals to be pyramidal, but with very small barriers to inversion.

Radical reactions therefore tend to result in loss of stereochemistry.

Radicals are normally reactive intermediates, although we shall encounter some notable exceptions.

2) Formation of Radicals

Radicals are normally formed via homolytic cleavage of a single covalent bond.

This can be induced thermally, photochemically or chemically.

Compounds that generate radicals are called free radical initiators.

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A) Homolytic Bond Cleavage

Radicals can be generated either thermally or photochemically from chlorine and bromine.

The bromine radical is less reactive, and often brominations require heat to proceed.

Peroxides and azo compounds also generate radicals when heated.

The weak O-O bond cleaves easily and the formation of N2 is also a significant driving force (see next slide).

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AIBN is one of the most famous commercial free radical initiators.

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B) Hydrogen Abstraction from Organic Molecules

The C-H bond is quite strong, and so it is rare to observe direct C-H homolytic cleavage.

However, it is common to have other radicals react and remove a hydrogen atom from a C-H bond, thus generating a carbon radical ( = hydrogen abstraction).

E.g. •F + CH4 → HF + •CH3

The •F is very reactive, and will react (exothermically!) with almost any organic compound.

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Rates of H Abstraction

Most radicals are electron deficient (electrophilic) and therefore their stability trends resemble those of cations.

An approximate radical stability order is:

Ph• < CH2=CH• < RO• < RCH2• < R2CH• < R3C• < PhCH2•

Bear in mind that this is also reflected in the ease of hydrogen abstraction from parent compounds to generate these radicals.

i.e. PhCH3 will undergo hydrogen abstraction very rapidly.

Also it is quite difficult to abstract a hydrogen from ROH.

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C) Organic Radicals from Functional Groups

Organic radicals are commonly generated from C-Hal

C-Se

C-Hg bonds.

Halogen abstraction is a good way to generate carbon based radicals.

A typical process involves: a free radical initiator

tributyltin hydride

and an organic halide.

The sequence is: initiator generates radicals (e.g. slide 5)

radicals abstract H from Bu3Sn-H

Tin radical abstracts halogen

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A similar sequence can be used to generate radicals from organoselenium compounds.

Alkyl mercury salts can generate radicals when they are exposed to sodium borohydride.

Recall from undergraduate organic alkene reactions:

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3) Radical Chain Processes

Most useful radical reactions are chain processes.

A radical chain process is one where many moles of product are generated from every mole of radicals formed.

All radical chain processes include

i. Initiation (A process where radicals are generated from some starting reagent).

ii. Propagation (The radical enters a series of events that result in product formation AND a new radical which starts the propagation steps over again).

iii. Termination (any steps that remove radicals from the propagation steps, thus breaking the chain process).

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Initiation was discussed previously as generation of radicals.

Propagation requires many product molecules to be formed from a single radical species formed in the Initiation step.

This can only occur if the Propagation steps are exothermic.

Common termination steps include radical – radical coupling, disproportionation and abstraction.

Abstraction by a chain transfer agent removes a radical from the propagation steps, and a new radical is formed, often this leads to termination.

Remember:

Propagation steps of a chain process must add up to the overall equation for the reaction.

The overall equation cannot contain any radical species, meaning the radical generated in the last propagation step must be the same as the radical involved in the first propagation step.

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Even though it is very tempting to write product formation resulting from two radicals reacting together, this is rarely correct.

Radicals are reactive intermediates and thus are generated in only small concentrations and for very short lifetimes.

Statistically it is very unlikely that two radicals will collide and form product.

E.g. Radical Chain halogenation by tButylHypochlorite

Overall the process is:

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We can break this into the various steps:

Initiation step

The fragile O-Cl bond can be cleaved homolytically.

The tBuO• radical is the chain carrying radical, meaning this is the radical used up in the 1st propagation step, and regenerated in the last propagation step.

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Propagation steps

Here we see why one tBuO• can initiate multiple propagation cycles.

Addition of steps (1) and (2) equate to the overall reaction.

Incorrect propagation steps are:

these do not lead to product formation.

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Termination steps

i. Disproportionation

Here a radical abstracts a hydrogen atom from another radical.

It leads to a pair of saturated and unsaturated products

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Termination steps

ii. Radical Coupling

There are several radical coupling reactions that can occur.

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4) Radical Inhibitors

Radical reactions can be slowed or stopped by the presence of compounds called Radical Inhibitors.

Often this is good experimental evidence that certain reactions operate via a radical mechanism.

Common radical inhibitors include:

Basically they function as radical inhibitors since they react with radicals to form new very stable (and unreactive) radical species.

The extra stability is usually a function of resonance and / or steric protection.

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E.g.

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E.g.

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5) Determining the Thermodynamic Feasibility of Radical reactions

Bond dissociation energies (BDE) can be used to determine whether certain radical reactions are likely or not.

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Guidelines

Radical processes only give reasonable synthetic yields if every propagation step is exothermic.

The number of propagation steps per initiation is called the chain length.

Longer chains come from less stable (more reactive) radicals

e.g. tButylHypochlorite chlorination

C-H is broken +91 kcal/mol

O-H is formed -103 kcal/mol

then

O-Cl is broken +44 kcal/mol

C-Cl is formed -79 kcal/mol

So overall -12 + (-35) = -47 kcal/mol which implies a highly favorable process with a long radical chain length.

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6) Addition of Radicals

Radical additions are very common and range from simple additions to π bonds to more involved cyclization processes.

A) Intermolecular Radical Addition

E.g. Addition of trifluoromethyl iodide.

The initiation step involves homolytic cleavage of the weak C-I bond.

The •CF3 radical adds to the double bond (leading to the more stable radical intermediate).

This radical abstracts an iodide atom from CF3I to give the product and the chain-propagating radical.

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Addition of a Radical by Reduction of a C-Hg bond

Despite their toxicity, organomercury compounds are a common way to generate carbon based radicals which can undergo addition to multiple bonds.

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B) Intramolecular radical Additions (Cyclization reactions)

When a radical is generated and there is an unsaturated region in the same molecule, there is the possibility for intramolecular radical addition, which will lead to a cyclic product.

This is a very common way to prepare rings.

Synthetic strategies have to be planned using a knowledge of Baldwin’s Rules.

These cover the formation of 3 to 7 membered rings by a variety of reaction types, and include kinetic and thermodynamic considerations.

As far as radical cyclizations are concerned, exo and endo cyclizations are possible.

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For radical cyclizations, the most important guidelines are:

1) For unsubstituted –alkenyl radicals containing up to 8 carbons, the preferred mode of cyclization is EXO. ( - omega- means the alkene is at the terminus distant to the radical.

The reaction is kinetically controlled (the faster formed product = major product).

2) When the alkene is substituted the non-terminal position, reaction to form the exo product becomes sterically hindered, and the fraction of ENDO product increases.

Exo and Endo Cyclizations

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E.g. Intramolecular Cyclization of a Vinyl Radical

The overall reaction is:

The vinyl radical is formed via the initiator / Sn radical / carbon radical process described earlier.

Cyclization occurs to yield the preferred EXO adduct (as the major product).

The carbon radical abstracts a Hydrogen atom from tributyl tin to yield the product and continue the chain.

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7) Fragmentation Processes

Many radical reactions involve the loss of a small, stable molecule such as CO2, N2, CO.

Such processes are called fragmentations.

A) Loss of CO2

Diacetyl peroxide, which is a common radical initiator, homolyzes the O-O bond, to yield

carboxyl radicals, which lose CO2 to generate methyl radicals. This process occurs

around 60 to 100oC.

Generally aryl substituted carboxyl radicals will expel CO2 less readily.

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Fragmentation with loss of CO2 also occurs in the Hunsdiecker Reaction.

Here a silver salt of a carboxylic acid reacts with Bromine to generate an alkyl bromide, which is chain shortened by one carbon.

The overall reaction is:

RCO2Ag + Br2 → R-Br + CO2 + AgBr

The steps are:

RCO2Ag + Br2 → RCO2Br + AgBr

Initiation

RCO2Br → RCO2• + Br•

Propagation (I)

RCO2• → R• + CO2

Propagation (II)

R• + RCO2Br → R-Br + RCO2•

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B) Loss of a Ketone

The radical initially formed by homolytic decomposition of an alkyl peroxide can undergo further scission. tButoxy radicals are well known to decompose to acetone (small stable molecule) and a methyl radical.

C) Loss of N2

Azo compounds will often decompose with loss of N2, such as AIBN.

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D) Loss of CO

At elevated temperatures, some radicals will fragment to a new radical and carbon monoxide.

Usually the higher the temperature, the more fragmentation occurs.

E.g.

If there is a suitable hydrogen atom donor present, hydrogen abstraction can precede fragmentation.

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E) Addition followed by Fragmentation

The (normal) radical addition of Carbon tetrachloride with aliphatic double bonds involves the addition of the CCl3 radical to the double bond, followed by chlorine atom abstraction from another CCl4 to give the product.

In suitable (special) cases, the intermediate carbon radical can fragment before chlorine atom abstraction.

E.g. reaction with -pinene

The reaction starts with initiation:

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The trichloromethyl radical adds (regiospecifically) to the double bond to form a new radical.

This radical can fragment, to relieve ring strain. This new radical simply abstracts a chlorine atom to yield the product.

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8) Rearrangement of Radicals

Radical rearrangements are less common than cation rearrangements, but you should be aware of the possibility.

In radical rearrangements, the migrating groups are those that accommodate electrons in a system (vinyl, aryl, carbonyl,…), or atoms that can expand their valence shell.

Hydrogen and alkyl do not migrate to radicals. (Addition-elimination pathways can lead to such appearances though).

Fragmentation with Aryl Migration

Here there is a mixture of rearranged and non-rearranged products.

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Abstraction of the aldehyde Hydrogen gives a carbonyl radical, which in turn expels CO to give a primary alkyl radical.

This radical can either abstract a hydrogen from the starting aldehyde, or rearrange via Phenyl migration (to a tertiary radical), and then pick up a hydrogen atom.

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Halogen Migration

All halogens with the exception of F can migrate.

The radical addition of HBr to 3,3,3-trichloropropene involves the migration of a chlorine atom.

The mechanism involves regiospecific addition of the bromine radical to the double bond.

Then a chlorine atom migrates to the radical giving a more stable dichloromethyl radical, which then abstracts a hydrogen atom to give the product.

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E.g. An apparent acyl migration.

The overall reaction is:

(The color coding reveals

the rearrangement / migration).

Based on our radical knowledge, the following primary radical should be formed.

Based on the product, we presume this comes from the above radical.

It is most likely that the rearrangement is not a single step migration, but goes through a cyclopropane intermediate, which then ring opens to give the desired intermediate.

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9) The SRN1 Reaction

This reaction is a powerful synthetic reaction, which is initiated by the formation of a radical anion.

SRN1 means nucleophilic substitution proceeding through a radical intermediate and the RDS is unimolecular decay of the radical anion intermediate formed from the substrate.

SRN1 reactions occur with both aliphatic and aromatic systems.

R-X + Y- R-Y + X-

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The general mechanism is shown below:

The propagation steps are:

Note that the radical anion is consumed in the 1st propagation step, and regenerated in the 3rd step.

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SRN1 reactions are initiated by either photochemical excitation, electrochemical reduction, or electron transfer reagents.

In some cases, spontaneous thermal initiation can occur.

The leaving group, X-, is often a halide (most commonly Br- or I-).

The nucleophile is commonly RS-, PhO-, a carbanion (nitroalkane anion) or carbon anion equivalent (enolate).

Basically the nucleophile must be a good single electron transfer agent (SET agent).

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Since these reactions are free radical reactions, they are slowed down / stopped by the addition of free radical inhibitors. (e.g. di-tButyl nitroxide, 1,4-dinitrobenzene, etc.).

Addition of the propagation steps give the overall equation for an SRN1 reactions as:

R-X + Y- R-Y + X-

Notice it is the same as nucleophilic substitutions like SN1, SN2, nucleophilic aromatic substitution.

Often the only way to distinguish an SRN1 mechanistic process is to demonstrate retardation by free radical inhibitors.

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E.g. Reaction of an Enolate with an Aromatic Halide

The overall reaction is as follows:

The mechanism involves photochemical excitation of the enolate. (An Asterix, *, is used to denote an excited state).

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The enolate transfers an electron to the aromatic system.

The addition of a single electron dictates that the intermediate must have an unpaired electron, and it must also now be negatively charged. ( = radical anion).

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The radical anion loses iodide ion to generate a radical.

This radical couples with the enolate to form a new radical anion.

This new radical anion transfers an electron to the starting material to produce the product and a new molecule of starting radical anion to propagate the chain.

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10) The Birch Reduction

Typical Birch reduction conditions are sodium in liquid ammonia that contains a small amount of ethanol.

E.g. Birch Reduction of Benzoic Acid

The basic reaction conditions require the product is in the deprotonated form.

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The mechanism has sodium do an SET to the aromatic system, generating a cyclohexadienyl radical anion.

Protonation of the anion leads to a hexadienyl radical, which gets further reduced by another SET. The anion which is formed then gets protonated.

Electron withdrawing groups favour the ipso formation of anionic centers (thus they end up on saturated carbons), whereas donating groups end up on the unsaturated carbons in the reduced product.

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11) Radical Mechanism for some Anion Rearrangements

In the Wittig rearrangement (not the Wittig reaction!), an anion derived from an ether rearranges to the salt of an alcohol.

Radical scission of the anion is believed to be responsible for this reaction.

The radicals recombine to give the product.

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This type of rearrangement is also common for anions adjacent to either tri- or tetra-valent nitrogen.

E.g. Unusual Rearrangement of an anion adjacent to Nitrogen.

The paper proposed the following mechanism...

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Hydride removes the acidic proton, followed by radical scission giving a resonance stabilized anion (and radical).

The benzylic radical recombines at the carbon of the carbonyl group, and then elimination generates the product.

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