Free Radicals and Halogenation

Radicals are species with an unpaired electron. They are the oddballs of organic chemistry: neither positively nor negatively charged, drawn with a single dot instead of curved arrows, and reacting via fishhook single-electron pushes. The MCAT does not test radical chemistry in great depth, but it does test the core mechanism of radical halogenation, the stability ranking of radicals, and the reasoning behind the famous bromine-chlorine selectivity difference.

A radical forms when a bond breaks homolytically - each atom walks away with one electron. Radicals are highly reactive because they are missing one electron from a normal pair, and they will seize an electron from almost any source to complete the pair.

Radical Stability Parallels Carbocation Stability

The stability trend for radicals mirrors carbocations:

3° radical > 2° radical > 1° radical > methyl radical

And with resonance stabilization:

Benzyl radical ≈ allyl radical > 3° alkyl > 2° > 1° > methyl

Why? Radicals have an unpaired electron in a p orbital. The same hyperconjugation and induction effects that stabilize a positive p-orbital vacancy also stabilize a single-electron p orbital. Adjacent alkyl groups donate a small amount of electron density into the half-filled orbital, stabilizing the radical.

Allyl and benzyl radicals get additional stabilization from resonance into adjacent pi systems, just like their cationic counterparts.

Radical Halogenation: The Core Reaction

Radical halogenation replaces a C-H bond with a C-X bond using molecular halogen (Cl₂ or Br₂) and a spark of light or heat to kick off the radical chain. The overall reaction:

R-H + X₂ → R-X + HX

The mechanism has three stages:

Stage 1: Initiation. A halogen molecule is homolytically split by light or heat:

X₂ + heat/light → 2 X• (two halogen radicals)

Each halogen now has an unpaired electron and is reactive.

Stage 2: Propagation. This is where the product actually forms, and it involves two steps that repeat many times:

Step 2a: X• + R-H → HX + R• (the halogen radical steals a hydrogen, producing HX and an alkyl radical)

Step 2b: R• + X₂ → R-X + X• (the alkyl radical attacks a new X₂ molecule, producing the product R-X and regenerating a halogen radical)

The regenerated halogen radical goes back to step 2a and the cycle continues. Thousands of product molecules can form from a single initiation event because propagation is a self-sustaining chain.

Stage 3: Termination. Two radicals find each other and combine, removing both from the system:

X• + X• → X₂
R• + R• → R-R
R• + X• → R-X

Termination ends the chain. Because radical concentrations are very low, termination steps are rare compared to propagation steps - which is why a tiny amount of initiator can produce a lot of product.

Br₂ vs. Cl₂: The Selectivity Difference

Here is where the MCAT loves to test:

Bromination (Br₂) is highly selective. On a propane molecule (which has both 1° and 2° C-H bonds), bromination gives almost exclusively 2-bromopropane, not 1-bromopropane. The 2° C-H is ~97 times more reactive than the 1° C-H.

Chlorination (Cl₂) is much less selective. On the same propane, chlorination gives a mixture roughly matching the statistical ratio of 1° to 2° hydrogens, with only a small preference for 2°. The 2° C-H is only ~4 times more reactive than the 1° C-H.

Why the difference? Two reasons interlock:

Reason 1: Bond dissociation energies. The C-H bond must break in the rate-limiting propagation step. Br• is less reactive than Cl•, so the transition state for Br-H formation looks more like a radical intermediate (late transition state). A late transition state means the stability of the resulting radical dominates the transition-state energy - and the 2° radical is much more stable than the 1° radical. So bromination strongly prefers the path that gives the more stable radical.

Reason 2: Hammond’s postulate. For a highly exothermic step (like chlorination’s H-abstraction), the transition state looks more like the starting material (early TS). The differences between 1° and 2° C-H are not amplified in the TS because the TS is not yet very radical-like. For a less exothermic step (bromination’s H-abstraction), the TS looks more like the radical product (late TS), amplifying the stability differences.

The takeaway: bromination is selective for the most substituted C-H because it has a late transition state; chlorination is unselective because it has an early transition state. This is a classic Hammond’s postulate application, and MCAT passages test it.

Benzylic and Allylic Halogenation

Radical halogenation is especially favorable at benzylic and allylic positions (C-H bonds adjacent to a benzene ring or alkene, respectively). The resulting radicals are resonance-stabilized, which makes the abstraction step faster AND more selective.

NBS (N-bromosuccinimide) is a reagent designed to selectively brominate allylic or benzylic C-H bonds at low bromine concentration (to prevent alkene addition side reactions). NBS halogenation follows the same three-stage mechanism, just with a controlled source of Br₂.

Oxygen Radicals in Biology

Radical chemistry is not just a lab curiosity. Reactive oxygen species (ROS) - superoxide (O₂•⁻), hydroxyl radical (HO•), peroxyl radicals (ROO•) - are central to oxidative stress, inflammation, and cancer biology. The same mechanism logic applies: a radical abstracts an H from a biomolecule (DNA, lipid, protein), producing a new radical that continues the chain.

Antioxidants (vitamin E, vitamin C) work as radical chain terminators. They donate an H atom to a propagating radical, forming a stabilized “antioxidant radical” that is too stable to continue the chain. This is covered in more detail in Biochemistry Ch 11.

The final section connects back to reaction outcomes: when two products are possible, which one do you get - the kinetic product (formed faster) or the thermodynamic product (lower energy)?