Chapter 18 — Radical Reactions: A Different Mechanism, A Different Selectivity

"Radicals don't have charges. They have unpaired electrons. The arrows are different (single-barb 'fish hooks' instead of double-barb), the selectivity is different (no charge stabilization arguments), and the kinetics are different (chain reactions). It's a parallel universe to ionic chemistry — and just as important." — paraphrase from a physical organic chemistry text

"Half of biology runs on radicals. Lipid peroxidation, vitamin E quenching, NADH single-electron transfers, photosynthesis electron transport — all radical chemistry. Master Chapter 18 to understand cellular oxidative damage."

This chapter introduces radical chemistry — a parallel mechanism to the ionic chemistry of Chapters 10-17. Radicals have unpaired electrons (rather than charges) and react via chain mechanisms (initiation → propagation → termination).

Radical chemistry is essential for: 1. Anti-Markovnikov HBr addition (Ch 15 introduced; here we explain the mechanism). 2. Allylic bromination (NBS; selective C-H bromination at allylic positions). 3. Radical polymerization (LDPE, polystyrene, polypropylene at high T/pressure). 4. Combustion (CH₄ + O₂ → CO₂ + H₂O proceeds via radicals). 5. Lipid peroxidation (oxidative damage to cell membranes). 6. Antioxidant chemistry (vitamin E quenches radicals). 7. Photoredox chemistry (modern catalytic radicals; Ch 40).

By the end of this chapter you should be able to: - Recognize radical mechanisms and use single-electron (fish-hook) arrows. - Predict radical selectivity using stability rules and BDE arguments. - Apply radical halogenation (with Br vs Cl selectivity) and explain the difference. - Use NBS for allylic bromination. - Explain the peroxide effect on HBr addition (anti-Markovnikov). - Recognize radical polymerization (LDPE) and biological radical damage (lipid peroxidation).

18.1 Homolysis vs heterolysis

A covalent bond can break in two ways:

Heterolysis (ionic; Ch 10-17)

The bond breaks asymmetrically — both electrons go to one atom: $$A-B \to A^+ + B^-$$ (or $A^- + B^+$, depending on which atom is more electronegative)

This generates ions. The arrows in mechanism are double-barb (each arrow = 2 electrons moving).

Homolysis (radical; Ch 18)

The bond breaks symmetrically — one electron to each atom: $$A-B \to A^{\bullet} + B^{\bullet}$$

This generates radicals (each with an unpaired electron). The arrows in mechanism are single-barb ("fish hooks"; each arrow = 1 electron moving).

When does each happen?

• Heterolysis is favored in polar solvents that stabilize ions; with polar bonds (C-Cl, O-H, etc.); at moderate temperatures.
• Homolysis is favored in nonpolar solvents (CCl₄, hexane); with weak bonds (peroxide O-O ~37 kcal/mol; many C-H bonds ~90-100 kcal/mol); with heat or light initiation.

The same compound (HCl, HBr, etc.) can do either, depending on conditions: - HBr in polar solvent + alkene → ionic Markovnikov addition (Ch 15). - HBr + peroxides + nonpolar solvent + alkene → radical anti-Markovnikov addition (this chapter).

18.2 Radical structure and stability

Geometry

Most carbon radicals are nearly planar (sp² hybridized) with the unpaired electron in a p orbital perpendicular to the plane. (Some are pyramidal; depends on substitution.)

Stability order

Carbon radical stability follows the same order as carbocation stability:

$$3° > 2° > 1° > methyl$$

Why? Hyperconjugation: alkyl C-H bonds donate electron density to the radical's p orbital, similar to how they stabilize cations. The energy differences between radicals are smaller than between cations (~3-4 kcal/mol per substitution vs. ~15 kcal/mol for cations).

Resonance-stabilized radicals

• Allylic radical ($CH_2=CH-CH_2^{\bullet}$): the unpaired electron can delocalize across both ends of the C=C (two resonance structures). Very stable.
• Benzylic radical ($C_6H_5-CH_2^{\bullet}$): the unpaired electron delocalizes into the aromatic ring (multiple resonance structures). Even more stable.

These are dramatically more stable than typical alkyl radicals — used in selective reactions (allylic bromination).

Bond dissociation energy (BDE)

The energy to homolyze a specific bond. For C-H bonds: - Methane C-H: 105 kcal/mol. - Ethane C-H (1°): 101 kcal/mol. - Propane C-H (2°, central): 98 kcal/mol. - Isobutane C-H (3°, central): 96 kcal/mol. - Benzyl C-H: 89 kcal/mol. - Allyl C-H: 88 kcal/mol.

Lower BDE = easier homolysis = more-stable resulting radical.

18.3 The chain reaction: initiation, propagation, termination

Radical reactions typically proceed through chain reactions with three stages:

Initiation

Generate the first radicals. Typically by homolysis of a weak bond: - Peroxide (R-O-O-R) thermally homolyzes to two RO• radicals (BDE ~37 kcal/mol). - Br-Br or Cl-Cl photochemically homolyzes (UV light gives 2 X• radicals). - AIBN (azobisisobutyronitrile): thermal initiator that gives 2 Me₂C(CN)• radicals + N₂.

Propagation

The radical reactants and products of each step are themselves radicals. The chain continues for many cycles:

For radical halogenation: 1. $X^{\bullet} + R-H \to R^{\bullet} + H-X$ (radical at start; radical at end). 2. $R^{\bullet} + X-X \to R-X + X^{\bullet}$ (radical at start; radical at end).

The two steps repeat thousands of times for each initiation event. This is what gives radical reactions their high yield from small initiator amounts.

Termination

Two radicals combine to give a non-radical product. Stops the chain: - $R^{\bullet} + R^{\bullet} \to R-R$ (radical-radical coupling). - $R^{\bullet} + X^{\bullet} \to R-X$.

Termination is rare compared to propagation (radicals are usually in low concentration), but eventually dominates as initiator runs out.

18.4 Radical halogenation

The classic radical reaction: alkane + X₂ + light or heat → alkyl halide + HX.

$$CH_4 + Cl_2 \xrightarrow{h\nu} CH_3Cl + HCl$$

Mechanism (chlorination of methane)

Initiation: $Cl_2 + h\nu \to 2 Cl^{\bullet}$

Propagation: 1. $CH_4 + Cl^{\bullet} \to CH_3^{\bullet} + HCl$ (H abstraction; rate-limiting). 2. $CH_3^{\bullet} + Cl_2 \to CH_3Cl + Cl^{\bullet}$ (halogen abstraction; fast).

Termination: any combination of two radicals.

The chain repeats; one initiating event gives many CH₃Cl molecules.

Chain length

In a typical free-radical chain, each initiation event leads to ~10⁴-10⁶ propagation cycles before termination. This is what makes radical reactions efficient with catalytic initiator.

Selectivity: H abstraction prefers stable radicals

Step 1 (H abstraction) determines selectivity. The radical preferentially abstracts H from the position that gives the most-stable radical: - 3° H > 2° H > 1° H > methyl H.

Allylic and benzylic H (giving resonance-stabilized radicals) are even more readily abstracted.

Br vs Cl: different selectivity

Bromination is more selective than chlorination:

Why is Br more selective? Because the H abstraction by Br• is endothermic (Br-H BDE 87 < C-H BDE 95-100 kcal/mol; the difference is small). Slow, endothermic step → more sensitive to substrate stability differences. Cl• abstraction is exothermic → less selective.

This is Hammond postulate in action: a late TS resembles the product (radical), so substrate stability differences propagate to the TS.

Worked example

Worked Problem 18.1: Predict the major product of: 2,3-dimethylbutane + Br₂ + heat.

Solution: 2,3-Dimethylbutane has 2 tertiary H (one on each C2 and C3) and 12 primary H (on the four methyls). Bromination is highly selective for tertiary; the major product is 2-bromo-2,3-dimethylbutane (bromine on a tertiary C). The reaction is dominated by the 3° H abstraction (Br is selective).

For chlorination of the same substrate, the product would be a mix of 1° and 3° products (Cl is less selective).

18.5 Anti-Markovnikov HBr addition (peroxide effect)

Discovered by Kharasch (1933): when HBr adds to an alkene in the presence of peroxides, the regiochemistry is anti-Markovnikov (opposite to ionic addition).

Mechanism

Initiation: peroxide → 2 RO•; RO• + HBr → ROH + Br•.

Propagation: 1. $Br^{\bullet} + RCH=CH_2 \to RCH^{\bullet}-CH_2Br$ (Br adds to less-substituted C; radical at more-substituted C, which is more stable). 2. $RCH^{\bullet}-CH_2Br + HBr \to RCH_2-CH_2Br + Br^{\bullet}$ (H abstraction from HBr; new alkyl bromide).

The radical adds to the alkene in step 1, generating a new C-Br bond at the less-substituted C (because the radical at the more-substituted C is more stable). This is anti-Markovnikov.

Why only HBr?

• HCl: H-Cl bond too strong (103 kcal/mol). Step 2 (H abstraction by alkyl radical from HCl) is thermodynamically unfavorable.
• HI: I-H bond too weak (71 kcal/mol). Step 1 (I• adding to alkene) is unfavorable.
• HBr: just right (87 kcal/mol). Both steps work.

Selectivity vs. ionic mechanism

Peroxide effect is a textbook example of radical chemistry being a competitive alternative to ionic chemistry.

18.6 NBS: Allylic bromination

N-bromosuccinimide (NBS) in CCl₄ + light (or heat with peroxides) brominates the allylic position of an alkene (the C adjacent to C=C), NOT the alkene's C=C.

$$\text{alkene-CH}_2-CR=CR' + NBS \xrightarrow{light or peroxide} \text{alkene-CHBr-CR=CR'}$$

Mechanism

NBS generates tiny amounts of Br₂ in situ (via reaction with HBr that's released as byproduct): - $NBS + HBr \to \text{succinimide} + Br_2$ - $Br_2$ is at very low concentration (~10⁻⁴ M).

At low [Br₂], the Br• radical preferentially abstracts the allylic H (giving a resonance-stabilized allylic radical):

1. $Br^{\bullet} + \text{alkene-CH}_2-... \to \text{alkene-CH}^{\bullet}-... + HBr$ (allylic H abstraction; resonance-stabilized radical).
2. $\text{alkene-CH}^{\bullet}-... + Br_2 \to \text{alkene-CHBr}-... + Br^{\bullet}$ (allylic radical + Br₂; chain continues).

At low [Br₂], step 1 (allylic H abstraction) is favored over the alternative (Br• adds to C=C of alkene, which would compete at higher [Br₂]).

Why use NBS instead of Br₂?

• Br₂ alone: high [Br₂]; Br adds to C=C (alkene addition, Section 15.6) instead of allylic position.
• NBS: low [Br₂]; allylic H abstraction is selective.

The trick: NBS slowly releases Br₂ at a rate that maintains low concentration. This makes allylic bromination selective.

Selectivity at allylic position

If the alkene has multiple allylic positions, the most-substituted (or most-stable allylic radical) wins. For example: 1-pentene + NBS → 3-bromo-1-pentene (the secondary allylic position) preferentially.

Use in synthesis

Allylic bromides are useful for: - SN2 with nucleophiles (gives allylic ethers, amines, etc.). - Forming allylic Grignard or allylmetal reagents. - Cross-coupling reactions.

NBS is the standard reagent for allylic bromination at the laboratory scale.

18.7 Radical polymerization

Many alkenes polymerize via radical chain mechanism. The classic example: low-density polyethylene (LDPE) from ethylene under high T (200 °C) and pressure (1500-3000 atm) with a peroxide initiator.

Mechanism

Initiation: peroxide → 2 RO•.

Propagation: 1. $RO^{\bullet} + CH_2=CH_2 \to RO-CH_2-CH_2^{\bullet}$ (radical adds to C=C; new alkyl radical). 2. $RO-CH_2-CH_2^{\bullet} + CH_2=CH_2 \to RO-CH_2-CH_2-CH_2-CH_2^{\bullet}$ (chain extension). 3. Repeat thousands of times.

Termination: two growing radicals combine, or an alkyl radical disproportionates.

Why low-density?

LDPE is "low-density" because the radical chain mechanism includes chain transfer (a growing radical attacks another part of itself or another chain, creating branches). Branched polyethylene packs less efficiently than linear → lower density.

In contrast, Ziegler-Natta polymerization (Ch 37) gives high-density polyethylene (HDPE) — linear, more crystalline, denser.

Other radically-polymerized monomers

• Styrene → polystyrene (foam, packaging).
• Methyl methacrylate → PMMA (Plexiglas).
• Vinyl chloride → PVC (plumbing pipes).
• Acrylonitrile → polyacrylonitrile (acrylic fibers, ABS).
• Vinyl acetate → polyvinyl acetate (Elmer's glue).

The vast majority of "radical-polymerizable" monomers are vinyl compounds (CH₂=CHR).

18.8 Combustion: a giant radical chain

The combustion of organic compounds (CH₄ + O₂ → CO₂ + H₂O) proceeds via radical chain mechanism:

Initiation: $CH_4 + O_2 \to CH_3^{\bullet} + HO_2^{\bullet}$ (slow; high T needed).

Propagation: thousands of steps involving alkyl radicals, alkoxyl radicals, peroxyl radicals, OH radicals.

Termination: radical-radical coupling.

Combustion is the most-impactful radical chemistry: gasoline engines, natural gas furnaces, fossil fuel power plants, fires, etc. The chain mechanism explains why fires propagate exponentially once started.

18.9 Lipid peroxidation: biological radical damage

Cell membranes contain polyunsaturated fatty acids (PUFAs) with allylic C-H bonds. PUFAs are vulnerable to radical damage via lipid peroxidation:

Mechanism

1. Initiation: a reactive oxygen species (ROS) — superoxide, hydroxyl radical, or peroxyl radical — abstracts a bis-allylic H from a PUFA. This gives a lipid radical.
2. Propagation: - $L^{\bullet} + O_2 \to LOO^{\bullet}$ (peroxyl radical). - $LOO^{\bullet} + LH \to LOOH + L^{\bullet}$ (chain abstraction).
3. The chain continues; many lipid molecules are oxidized per initiating event.

Damage

• Membrane lipid composition altered.
• Membrane fluidity disrupted.
• Cell signaling proteins damaged.
• Eventually, cell death (apoptosis or necrosis).

Lipid peroxidation contributes to: - Aging. - Cardiovascular disease. - Cancer. - Neurodegenerative diseases (Alzheimer's, Parkinson's). - Reperfusion injury (after ischemia).

Antioxidants quench the chain

Vitamin E (α-tocopherol) is the major lipid-soluble antioxidant. It donates an H atom to a peroxyl radical, terminating the chain:

$$LOO^{\bullet} + Vit E-OH \to LOOH + Vit E-O^{\bullet}$$

The resulting Vit E-O• radical is resonance-stabilized and unreactive. It's eventually regenerated by vitamin C (in cytoplasm) or removed.

Vitamin C (ascorbic acid) is a water-soluble antioxidant that quenches radicals in cytoplasm.

Other endogenous antioxidants: glutathione, urate, bilirubin, melatonin.

Drug development

Many drug candidates have antioxidant properties. The chemistry of vitamin E (a phenolic OH that donates H to give a stabilized phenoxyl radical) is a model for designing better antioxidants.

Biological Connection 18.1: Vitamin E and lipid peroxidation.

Vitamin E (α-tocopherol) is a phenolic compound with three methyl groups and a long isoprenoid tail. The chromanol head sits at the lipid-water interface; the tail anchors it in the lipid bilayer.

When a peroxyl radical (LOO•) is generated in the membrane, vitamin E donates its phenolic O-H. The radical is now LOOH (no longer dangerous); vitamin E becomes Vit E-O• (resonance-stabilized; unreactive on biology timescale).

Net effect: the chain is broken. Vitamin E quenches one peroxyl radical per molecule, then needs to be regenerated.

This is one of the most important antioxidant chemistries in biology.

18.10 Modern radical chemistry: photoredox

In the 21st century, photoredox catalysis has revolutionized radical chemistry. Instead of harsh thermal initiators, light + a photocatalyst (Ru(bpy)₃²⁺, Ir(ppy)₃, organic dyes) generates radicals at room temperature with high control.

Photoredox reactions: - Use single-electron transfers (similar to radical mechanisms). - Allow asymmetric radical reactions (with chiral catalysts). - Tolerate many functional groups. - Run under mild conditions.

Photoredox is used in modern drug synthesis (especially for difficult bond formations) and is an active research area.

18.11 Why this chapter matters

Radical chemistry is essential for: 1. Synthesis: NBS allylic bromination, radical halogenation, anti-Markovnikov HBr. 2. Polymers: LDPE, polystyrene, PVC, etc. 3. Combustion: powering most of human civilization. 4. Biology: lipid peroxidation, antioxidant defense. 5. Drug discovery: photoredox catalysis, oxidative stress mechanisms.

Mastering Chapter 18 gives you a parallel mechanism toolkit alongside the ionic chemistry of Chs 10-17.

18.12 Summary

1. Radicals have unpaired electrons; form by homolysis (vs. heterolysis for ions).
2. Fish-hook arrows (single-barb) show single-electron movement.
3. Stability order: 3° > 2° > 1° > methyl. Allylic and benzylic radicals are resonance-stabilized.
4. Chain reactions: initiation → propagation → termination.
5. Radical halogenation (alkane + X₂ + light): H abstraction, then X₂. Br more selective than Cl due to Hammond postulate.
6. Anti-Markovnikov HBr (peroxide effect): radical chain mechanism gives Br at less-substituted C.
7. NBS allylic bromination: low [Br₂] selects for allylic H abstraction.
8. Radical polymerization makes LDPE, polystyrene, PVC.
9. Combustion is a giant radical chain.
10. Lipid peroxidation damages cell membranes; antioxidants (vitamin E, C) quench the chain.
11. Modern photoredox catalysis generates radicals under mild conditions.

Chapter 19 turns to conjugation, dienes, and the Diels-Alder reaction.