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Chapter 12

• Radicals• Reactions of Alkanes

Organic Chemistry 6th Edition

Paula Yurkanis Bruice

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Petroleum is a complex mixture of alkanes and cycloalkanes that can be separated by distillation:

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Alkanes are very unreactive compounds because they have only strong bonds and atoms with no partial charges

However, alkanes do react with Cl2 and Br2:

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Consider the relative stabilities of alkyl radicals:

Alkyl groups stabilize carbocations about 5–10 times better than they stabilize radicals:

Radicals: Resonance > HyperconjugationCarbocations: Hyperconjugation > Resonance

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Why does hyperconjugation stabilize carbocations more than radicals?

Carbocation:Both electrons

are in the bondingorbital

Radical:One of theelectrons is

in the antibondingorbital

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The Distribution of Products Depends on Probability and Reactivity

Probability is based on relative number of primary and secondary protons, 6:4

However, secondary hydrogens are more reactive than primary hydrogens

Therefore, probability and reactivity both contribute to product distribution

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To determine the the product distribution, consider both probability and reactivity:

• Probability: the number of hydrogens that can be abstracted that will lead to the formation of the particular product

• Reactivity: the relative rate at which a particular hydrogen is abstracted

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An example of calculating the distribution of radical chlorination products:

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The Reactivity–Selectivity PrincipleRadical bromination is more selective than radical chlorination:

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Reactivity–Selectivity PrincipleMonochlorination reactions:

Monobromination reactions:

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Why is the bromine radical more selective than the chlorine radical?

Hammond postulate: • Endothermic, a product-like (radical) transition state• Exothermic, a reactant-like (alkane) transition state

Radical stability important

Radical stability not important

Therefore, the bromine atom more readily distinguishes 3º, 2º, and 1º hydrogens

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The more reactive a species is, the less selective it will be:

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What about fluorination and iodination?

Alkanes undergo chlorination and bromination, but not iodination

Fluorination is too violent a reaction to be useful:

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Addition of Radicals to an Alkene

Peroxide is used to generate Br radical in trace quantities

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An alkyl peroxide is a radical initiator

The electrophile adds to the sp2 carbon that is bonded tothe greater number of hydrogens

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Radicals do not rearrange as readily as carbocations:

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Why is the peroxide effect observed only for the additionof HBr to alkene?

Because both of the propagation steps in the HBr addition reaction are exothermic.

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Stereochemistry of Radical Substitution Reactions

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Stereochemistry of Radical Addition Reactions

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Why are both enantiomers formed?

Consider the first propagation step:

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The more stable radicals form faster:

Radical Substitution of Benzylic and Allylic Hydrogens

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The percentage of substitution at the benzylic or allyliccarbon is greater for bromination. Note the reactivity–selectivity principle:

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Because of the presence of an alkene functional group, N-bromosuccinimide is used as a brominating agent for allylic compounds:

No Br2 addition to the alkene

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Mechanism of NBS Bromination

Azobisisobutylnitrileradical initiator

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Advantage: The low concentrations of Br2 and HBr present during NBS bromations result in no alkene addition reactions:

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Designing a Multistep Synthesis

Example 1

Synthesis:

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Example 2

Racemic

Racemic

Synthesis:

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Example 3

Retosynthetic analysis:

Synthesis:

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Radical Reactions in Biological SystemsCytochrome-mediated hydroxylation of an alkane:

Conversion of nicotine to a polar metabolite:

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The Heme Cofactor of a Cytochrome

The FeII is converted to the reactive FeV oxide

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Antihistamine Metabolism: Allegra Cytochrome

oxidation

Site of oxidation depends on

accessibility rather than radical stability

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Other Reactions of Radicals

Reaction of ethers to form highly explosive peroxides:

Caution: Ethers may have dangerous levels of peroxides!

Reactive Oxygen Species:

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Reactive Oxygen Species (ROS) Are Common in Biological Systems

Oxidation of an unsaturated fat:

Terminating the radical chain reaction with a phenolic compound:

Radical is resonance stabilized and not propagated

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Radical Chain Terminators: Antioxidants

Water-soluble

Fat-soluble

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Commonly Used Antioxidant PreservativesBHT is used in packaging:

Hydroquinone is used to preserve ethers:

A radical that cannot propagate:• Resonance stabilized

• Sterically hindered

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Naturally Occurring AntioxidantsRutin is a bioflavonoid

glycoside with antioxidant and anticancer properties:

Found in citrus fruit and berries

Bioflavonoids afford resonance-stabilized

radicals:

Stars show the resonance delocation

of the radical

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Green Tea AntioxidantsNote the abundance of phenolic hydroxyls:

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Green Tea Antioxidants

Formed from catechinsduring tea fermentation

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Radicals and Stratospheric Ozone

• Ozone is a major constituent of smog

• Ozone shields Earth from harmful radiation

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Chlorofluorocarbons remain very stable in the atmosphere until they reach the stratosphere:

The chlorine radicals are ozone-removing agents: