Reminder: Alkane Halogenation via Free-Radical Chain Reaction

2 ++

+

3 ++

overall + +

Selectivity in Radical Halogenation

Cl2 + h

Expected from statistical 25% 75% distribution: (2/8 H’s) (6/8 H’s)

Observed: 60% 40%

Radical halogenation is selective for the most substituted C-H. More Substituted Radicals Are More Stable (by Hyperconjugation)

For So, ,

C H p more stable than

C-H  ( • orbital is actually in between p & sp3)

Two electrons decrease in energy, Stability trend for R CC:•: one electron increases in energy. 3 3° > 2° > 1° > CH3 Net effect is stabilization.

Bond Dissociation Enthalpies

BDE: Enthalpy required to break a bond into component radicals (A( —B → A• + •B)

Bond BDE (()kcal/mol) Bond BDE (()kcal/mol)

Cl—Cl 58 CH3—Cl 84 H—Cl 103 CH3CH2—Cl 81 (CH3)2CH—Cl 80 CH3—H 104 (CH3)3C—Cl 79 CH3CH2—H 98 (CH3)2CH—H 95 CH3—Br 70 (CH3)3C—H 91 CH3CH2—Br 68 C6H5CH2—H 88 (CH3)2CH—Br 68 CH2=CH-CH2—H 86 (CH3)3C—Br 65 Selectivity in Radical Halogenation

1° radical— less stable

Ea(2°) < Ea(1°)

2° radical— more stable

Radical halogenation goes through the most stable radical. E

reaction coordinate

Selectivity in Radical Halogenation

• Bromination is even more selective than chlorination.

Cl2 + h

60% 40%

Br2 CH3 CH CH3 CH3 CH2 CH2 h Br Br

97% 3% Selectivity in Radical Halogenation

• Halogenation at allylic, benzylic sites is particularly preferred.

Cl2 h

resonance (and not stabilized here)

Br2 h

Resonance is usually more stabilizing than substitution. This explains low BDEs of allylic, benzylic C-H bonds.

Bond Dissociation Enthalpies

BDE: Enthalpy required to break a bond into component radicals (A( —B → A• + •B)

Bond BDE (()kcal/mol) Bond BDE (()kcal/mol)

Cl—Cl 58 CH3—Cl 84 H—Cl 103 CH3CH2—Cl 81 (CH3)2CH—Cl 80 CH3—H 104 (CH3)3C—Cl 79 CH3CH2—H 98 (CH3)2CH—H 95 CH3—Br 70 (CH3)3C—H 91 CH3CH2—Br 68 C6H5CH2—H 88 (CH3)2CH—Br 68 CH2=CH-CH2—H 86 (CH3)3C—Br 65 Allylic and Benzylic Bromination with NBS

Problem:Br2 also reacts with double bonds.

Generated by Br2 Br2 addition to double bond. + (We’ll learn this later.) h

Solution: Use a different reagent (w/ the same mechanism).

• NBS also halogenates N-bromosuccinimide benzylic positions. (NBS) • Will not halogenate unactivated C-H’s. • Requires either light (h) or a chemical radical (+ trace R•) source (e.g., AIBN) to exclusively. provide R•.

Multiple Halogenations

Problem: Once one C-H has been converted to a C-X, another one can be. This can lead to a mixture of products.

At the beginning of the reaction, Cl• will always find starting material.

But as the halogenation proceeds, Cl• will encounter and react with molecules that are already chlorinated.

Solution: Monohalogenated product can be made by incomplete reaction, followed by purification of product from starting material. Multiple Halogenations

Solution: Multiply halogenated products can also be made, as long as the pattern of selectivity allows it.

…is possible (because Br2 of selectivity for benzylic h position), but…

…is not possible (would Cl2 not happen selectively). h