Organic Chemistry · Reactions of Alkyl Halides: Nucleophilic Substitutions and Eliminations
Characteristics of the SN2 Reaction
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In 30 seconds
The previous topic established the SN2 mechanism, its rate law, and back-side attack. This topic examines the four variables that decide whether SN2 actually occurs — substrate, nucleophile, Leaving group The group that departs with the electron pair Full entry →, solvent — plus its stereochemical consequence. Once you can rank these four features, you can predict rates, choose conditions, and recognize SN2 in synthesis and biology. The same four features return in the SN1 topics with most rankings reversed — learn them side by side.
Why this matters
- Choosing conditions: The Williamson ether synthesis and the Finkelstein reaction R–Cl + NaI in acetone → R–I (SN2, driven by NaCl precipitation) Full entry → are SN2 processes; solvent and leaving-group choice make or break them.
- Predicting feasibility: Chemists must instantly know whether SN2 will dominate or whether elimination or SN1 interferes.
- Biological chemistry: DNA alkylation by carcinogens and enzyme methyl transfers (topic 6) obey the same nucleophile and leaving-group logic.
- Exams: Ranking nucleophiles, leaving groups, and substrates, and choosing solvents, are staple problems.
- Pharmaceutical manufacturing: SN2 alkylates amines and phenols in drug synthesis.
The college version
Core Concepts
The substrate: steric hindrance rules
SN2 reactivity falls off sharply as the carbon gets more substituted — the nucleophile must reach the back of the carbon through a crowded transition state:
CH3X > 1°> 2° ≫ 3°
Approximate relative rates (order of magnitude, ethyl = 1): methyl ≈ 30, primary ≈ 1, secondary ≈ 0.03, tertiary ≈ 10⁻⁵ — essentially zero. Allylic and benzylic halides react faster than simple alkyl halides of the same class because the transition-state charge is stabilized by the adjacent π system; neopentyl halides, (CH₃)₃CCH₂X, are famously slow despite being primary.
The nucleophile: strength and size
Nucleophilicity The ability of a species to donate a lone pair to carbon Full entry → — the ability to donate a lone pair to carbon — follows several trends:
- Charge beats neutrality: HO⁻ > H₂O; RO⁻ > ROH.
- Polarizability within a group: I⁻ > Br⁻ > Cl⁻ > F⁻; RS⁻ > RO⁻. Bigger, softer atoms give up electrons more easily.
- Basicity within a row (in aprotic solvents): HO⁻ > F⁻; more basic usually means more nucleophilic for similar-sized atoms.
- Steric bulk hurts: tert-butoxide, (CH₃)₃CO⁻, is a strong base but a poor nucleophile — it prefers elimination (E2).
Nucleophilicity and basicity are related but not identical: a species can be a strong base yet a weak nucleophile (tert-butoxide), or a strong nucleophile yet a weak base (I⁻).
The solvent: polar aprotic wins
- Polar aprotic solvents (acetone, DMF, DMSO, CH₃CN) dissolve ionic reagents but do not hydrogen-bond the nucleophile. It stays "naked," so its full electron-donating power reaches the carbon — SN2 is fast.
- Polar protic solvents (H₂O, alcohols) hydrogen-bond the nucleophile's lone pairs, wrapping it in a solvation shell that must be stripped off before attack — SN2 is slowed.
The Finkelstein reaction demonstrates this: CH₃CH₂Cl + NaI in acetone gives CH₃CH₂I, because NaCl precipitates and pulls the equilibrium forward; in ethanol the reaction is sluggish.
The leaving group: weak bases leave best
The departing group accepts the electron pair, so the best leaving groups are the weakest bases:
I- > Br- > Cl- > F- and OTs-, OMs-, H2O
This parallels conjugate-acid strength: HI (pKa ≈ −10) down to HF (≈ 3.2), with H₂O at 15.7. Hydroxide and alkoxide are terrible leaving groups — alcohols must first be converted to tosylates or protonated before substitution is possible.
Stereochemistry: complete inversion
Because the nucleophile attacks the back side, SN2 at a stereocenter proceeds with 100% inversion of configuration: a single enantiomer gives a single enantiomer of opposite configuration, never a racemic mixture (unlike SN1).
How It Works / Step-by-Step Process
Choosing SN2 conditions for a synthesis:
- Check the substrate: methyl or primary (fast), secondary (slow but possible), tertiary (impossible — plan SN1/E2 or another route).
- Pick a strong nucleophile: negatively charged and polarizable (e.g., I⁻, CN⁻, RS⁻, N₃⁻); avoid bulky bases like tert-butoxide.
- Choose a Polar aprotic solvent Solvent with a dipole but no O–H or N–H bonds (acetone, DMSO) Full entry →: DMSO, acetone, DMF, or CH₃CN — never water or alcohol if you want speed.
- Confirm the leaving group is good: I⁻, Br⁻, tosylate. If the group is OH, activate it first (tosylate or protonate).
- Predict the product: nucleophile replaces leaving group with inversion at the reacting carbon.
Common Confusions
| Do Not Confuse | With | Difference |
|---|---|---|
| SN2 substrate order (methyl > 1° > 2° ≫ 3°) | SN1 substrate order (3° > 2° > 1°) | Opposite trends: SN2 is steric, SN1 is electronic (carbocation stability) |
| Polar aprotic solvent speeds SN2 | All polar solvents speed SN2 | Protic solvents hydrogen-bond the nucleophile and slow SN2 |
| Nucleophilicity | Basicity | A strong base can be a poor nucleophile (tert-butoxide) and vice versa (I⁻) |
| Good leaving group | Strong nucleophile | The leaving group must be a weak base (stable anion); nucleophiles are often strong bases — opposite demands |
| Neopentyl is primary, so it's fast | Primary always fast | The tert-butyl shield blocks back-side attack; neopentyl halides are very slow |
| SN2 gives a racemic mixture | SN2 gives inversion | Complete inversion, never racemization — racemization is an SN1 signature |
Eli explains
The same idea, in plain words
Explain it like I’m 10
SN2 is like passing a ball through a crowd: the faster you can reach the carbon, the better. If the carbon is surrounded by big friends (bulky groups), you can't get close — the reaction is slow. In water the ball-carrier gets hugged and can't move; in a dry "naked" solvent like acetone, it is free to sprint. And whoever leaves has to be good at leaving: weak bases like iodide are happy to go, while strong bases like hydroxide would rather stay.
Worked example
Example 1: Will SN2 happen? Predicting products
Predict the major substitution product (if any) for: (a) CH₃CH₂CH₂CH₂Br + NaOCH₃ in DMSO; (b) (CH₃)₃CBr + NaOCH₃ in DMSO.
(a) Primary substrate, strong nucleophile, polar aprotic solvent — ideal SN2:
CH3CH2CH2CH2Br + CH3O- → CH3CH2CH2CH2OCH3 + Br-
Product: 1-methoxybutane.
(b) Tertiary substrate — SN2 impossible; methoxide is a strong base, so E2 elimination dominates, giving 2-methylpropene, (CH₃)₂C=CH₂.
Example 2: Relative-rate arithmetic
Using approximate relative rates (methyl ≈ 30, ethyl = 1, isopropyl ≈ 0.03), how much faster is methyl bromide than isopropyl bromide in SN2?
Ratio first:
kmethylkisopropyl = 300.03 = 1.0 × 103
Answer: methyl bromide reacts about 1000 times faster than isopropyl bromide. This ~3 order-of-magnitude gap per added methyl group is why SN2 is limited to methyl, primary, and (with strong nucleophiles) secondary substrates.
Example 3: Picking the better reagent
Which is the stronger nucleophile in acetone: (a) HO⁻ or H₂O? (b) I⁻ or F⁻? (c) CH₃O⁻ or (CH₃)₃CO⁻?
Reasoning: (a) HO⁻ — a charged species beats its neutral conjugate acid. (b) I⁻ — more polarizable, softer, and a weaker base than F⁻ (the Finkelstein reagent). (c) CH₃O⁻ — both are basic alkoxides, but tert-butoxide is too bulky to reach the carbon and prefers elimination.
Key takeaways
- Reactivity order: methyl > 1° > 2° ≫ 3° (steric); allylic and benzylic halides are faster than simple-alkyl counterparts.
- Nucleophilicity: charged > neutral; I⁻ > Br⁻ > Cl⁻ > F⁻ (polarizability); more basic within a row; bulky bases are poor nucleophiles.
- Solvent: polar aprotic (acetone, DMSO, DMF, CH₃CN) speeds SN2; polar protic (water, alcohols) slows it by solvating the nucleophile.
- Leaving groups are weak bases: I⁻ > Br⁻ > Cl⁻ > F⁻, plus tosylate, mesylate, and water.
- Stereochemistry: complete inversion — (R) substrate gives (S) product.
- Neopentyl halides are slow despite being primary (steric shield).
- Finkelstein: R–Cl + NaI in acetone → R–I; NaCl precipitates, driving the equilibrium.
Check yourself
5 review questions from the chapter. Try each one, then open the answer.
Rank these bromides by SN2 reactivity: isopropyl bromide, methyl bromide, tert-butyl bromide, ethyl bromide.
Show answer
Methyl > ethyl (1°) > isopropyl (2°) ≫ tert-butyl (3°).
Which solvent makes SN2 faster: ethanol or DMSO? Why?
Show answer
DMSO — it is polar aprotic, so the nucleophile stays unsolvated and attacks faster; ethanol would hydrogen-bond the nucleophile and slow SN2.
Which is the better leaving group: Cl⁻ or I⁻? Which is the better nucleophile in acetone: Cl⁻ or I⁻?
Show answer
I⁻ is the better leaving group (weaker base) and also the better nucleophile in acetone (more polarizable).
Why is tert-butoxide a poor nucleophile despite being a strong base?
Show answer
Its three methyl groups block back-side attack on carbon; it prefers to act as a base and cause E2 elimination.
A secondary alkyl bromide reacts with cyanide in DMSO. Which product forms and with what stereochemistry?
Show answer
SN2 product (a nitrile) with complete inversion of configuration at the reacting carbon.
Study tools & related lessonsKey vocabulary · Related
Key vocabulary
- Nucleophilicity
- The ability of a species to donate a lone pair to carbon
- Polar aprotic solvent
- Solvent with a dipole but no O–H or N–H bonds (acetone, DMSO)
- Polar protic solvent
- Solvent with O–H or N–H bonds (water, ethanol)
- Leaving group
- The group that departs with the electron pair
- Tosylate (OTs)
- A sulfonate ester made from p-toluenesulfonyl chloride
- Finkelstein reaction
- R–Cl + NaI in acetone → R–I (SN2, driven by NaCl precipitation)
- Walden inversion
- Complete configurational flip at the reacting carbon
Sources & references
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