Chapter 12 Organic Chemistry 6th Edition Radicals Reactions of Alkanes Paula Yurkanis Bruice Chapter 12 Radicals Reactions of Alkanes

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

Alkanes are very unreactive compounds because they have only strong s bonds and atoms with no partial charges However, alkanes do react with Cl2 and Br2:

Consider the relative stabilities of alkyl radicals: Alkyl groups stabilize carbocations about 5–10 times better than they stabilize radicals: Radicals: Resonance > Hyperconjugation Carbocations: Hyperconjugation > Resonance

Why does hyperconjugation stabilize carbocations more than radicals? One of the electrons is in the antibonding orbital Carbocation: Both electrons are in the bonding orbital

However, secondary hydrogens are more reactive than primary hydrogens 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

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

An example of calculating the distribution of radical chlorination products:

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

Reactivity–Selectivity Principle Monochlorination reactions: Monobromination reactions:

Radical stability important Radical stability not important Why is the bromine radical more selective than the chlorine radical? Radical stability important Radical stability not important Hammond postulate: Endothermic, a product-like (radical) transition state Exothermic, a reactant-like (alkane) transition state Therefore, the bromine atom more readily distinguishes 3º, 2º, and 1º hydrogens

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

What about fluorination and iodination? Alkanes undergo chlorination and bromination, but not iodination Fluorination is too violent a reaction to be useful:

Addition of Radicals to an Alkene Peroxide is used to generate Br radical in trace quantities

An alkyl peroxide is a radical initiator The electrophile adds to the sp2 carbon that is bonded to the greater number of hydrogens

Radicals do not rearrange as readily as carbocations:

Why is the peroxide effect observed only for the addition of HBr to alkene? Because both of the propagation steps in the HBr addition reaction are exothermic.

Stereochemistry of Radical Substitution Reactions

Stereochemistry of Radical Addition Reactions

Why are both enantiomers formed? Consider the first propagation step:

Radical Substitution of Benzylic and Allylic Hydrogens The more stable radicals form faster:

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

No Br2 addition to the alkene 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

Mechanism of NBS Bromination Azobisisobutylnitrile radical initiator

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

Designing a Multistep Synthesis Example 1 Synthesis:

Example 2 Racemic Racemic Synthesis:

Retosynthetic analysis: Example 3 Retosynthetic analysis: Synthesis:

Radical Reactions in Biological Systems Cytochrome-mediated hydroxylation of an alkane: Conversion of nicotine to a polar metabolite:

The Heme Cofactor of a Cytochrome The FeII is converted to the reactive FeV oxide

Antihistamine Metabolism: Allegra Cytochrome oxidation Site of oxidation depends on accessibility rather than radical stability

Other Reactions of Radicals Reaction of ethers to form highly explosive peroxides: Reactive Oxygen Species: Caution: Ethers may have dangerous levels of peroxides!

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

Radical Chain Terminators: Antioxidants Fat-soluble Water-soluble

Commonly Used Antioxidant Preservatives BHT is used in packaging: A radical that cannot propagate: Resonance stabilized Sterically hindered Hydroquinone is used to preserve ethers:

Naturally Occurring Antioxidants Rutin is a bioflavonoid glycoside with antioxidant and anticancer properties: Bioflavonoids afford resonance-stabilized radicals: Stars show the resonance delocation of the radical Found in citrus fruit and berries

Green Tea Antioxidants Note the abundance of phenolic hydroxyls:

Green Tea Antioxidants Formed from catechins during tea fermentation

Radicals and Stratospheric Ozone Ozone is a major constituent of smog Ozone shields Earth from harmful radiation

Chlorofluorocarbons remain very stable in the atmosphere until they reach the stratosphere: The chlorine radicals are ozone-removing agents: