Difficulty: Intermediate to Advanced | Prerequisites: Alkene addition reactions, stereochemistry, functional groups, acid-base concepts
When an alkyl halide meets a nucleophile or base, four reactions compete: SN1, SN2, E1, and E2. Which one wins depends on three things: the degree of the substrate (primary, secondary, or tertiary), whether the reagent is a strong base or a good nucleophile (or both), and the solvent. This unit also covers how to convert alcohols into substrates with good leaving groups, the key strategies for forming C-C and C-X bonds, and the Diels-Alder reaction for building six-membered rings.
SN2 (bimolecular nucleophilic substitution)
A one-step mechanism in which the nucleophile attacks the electrophilic carbon at the same time as the leaving group departs. The rate depends on the concentration of both the nucleophile and the substrate. Inversion of stereochemistry at the carbon (backside attack).
Think of it as opening a door by pushing one person out the back while you walk in the front.
SN1 (unimolecular nucleophilic substitution)
A two-step mechanism. First, the leaving group departs on its own to form a carbocation. Then the nucleophile attacks. The rate depends only on the substrate concentration (the slow step is leaving-group departure). Produces a racemic mixture at a chiral centre because the carbocation is planar.
In simple terms, the leaving group leaves first, then anything nearby can attack the flat carbocation from either face.
E2 (bimolecular elimination)
A one-step mechanism in which a strong base removes a beta-hydrogen at the same time as the leaving group departs, forming a double bond. Rate depends on both base and substrate. Requires anti-periplanar geometry (the H and the leaving group must be 180° apart).
Think of it as the base and the leaving group cooperating in a single, concerted step to create the alkene.
E1 (unimolecular elimination)
A two-step mechanism. First the leaving group departs to form a carbocation (same first step as SN1). Then a base removes a neighbouring H to form the alkene. Rate depends only on the substrate. Competes with SN1 under the same conditions.
In simple terms, the leaving group goes first, and then a proton is lost to make the double bond.
Leaving group
The atom or group that departs with the bonding electrons. Good leaving groups are weak, stable bases (I-, Br-, RSO3-, H2O). Bad leaving groups are strong bases (OH-, RO-, F-).
Think of it as: the better the leaving group is at being stable on its own, the more easily it leaves.
Zaitsev product (Zaitsev's rule)
In elimination reactions, the more substituted alkene is the major product (unless a bulky base is used). This is because the more substituted double bond is more stable.
In simple terms, the alkene with more R groups on the double bond wins.
Diels-Alder reaction
A [4+2] cycloaddition between a conjugated diene (4 pi electrons) and a dienophile (2 pi electrons) to form a six-membered ring. Concerted, stereospecific, and does not require a catalyst.
Think of it as two molecules clicking together like puzzle pieces to make a new ring.
Endo rule (Alder endo rule)
In a Diels-Alder reaction, when the dienophile carries a substituent with multiple bonds (C=O, C≡N), that substituent preferentially ends up in the endo position (pointing "down," toward the diene). The endo product is kinetically favoured.
In simple terms, the bulky group on the dienophile tucks underneath rather than sticking out.
Both the nucleophile/base and the electrophile (substrate) must be considered together.
Primary (1°) substrate:
Without beta-branching: SN2 dominates
Exception: t-BuO- (very bulky, sterically congested) gives mainly E2
With beta-branching: SN2 and E2 compete
Good nucleophiles that are weak bases (halides, P and S nucleophiles): SN2 predominates
Strong bases (OH-, RO-, NH2-): E2 predominates
Secondary (2°) substrate:
Generally SN2 vs E2 (SN1/E1 are disfavoured because 2° carbocations need high temperature)
Good nucleophiles that are weak bases: maximises SN2
Strong bases: maximises E2
Tertiary (3°) substrate:
Without strong base: SN1 and E1 via carbocations (these always compete with each other)
With strong base: E2
The rate of E2 is proportional to the concentration of base
Strong base promotes E2 especially with highly branched substrates (3°, or 2° with beta-branching)
Strong bases: OH-, RO-, NH2-
Bulky species may not be strong bases but will act as bases because they cannot fit in to do substitution
Good nucleophiles and strong bases: OH-, RO-, NH2-
Good nucleophiles and weak bases: Cl-, Br-, I-, N3-, S and P nucleophiles
Weak nucleophiles and weak bases: ROO- (carboxylate ions), H2O, ROH
Good leaving groups: RSO3-, I- (halogens are generally good LGs because they are weak, stable bases, except F- due to high electronegativity), H2O
Bad leaving groups: F-, RCO2-, CN-, OH-, MeO-, EtO-, RO-
The last five are the worst; you must convert them to better leaving groups for substitution
Protic solvents: ROH, formic acid, acetic acid (stabilise carbocations, favour SN1/E1)
Aprotic solvents: DMSO, DMF, acetone, acetonitrile, HMPA (favour SN2)
TsCl / pyridine (cold): replaces -OH with -OTs
Retention of stereochemistry (the C-O bond is not broken in this step)
The -OTs is now an excellent leaving group for later substitution
SOCl2 / ether: replaces -OH with -Cl
SN2 mechanism with inversion of stereochemistry
Cannot use on tertiary substrates (SN2 does not work at 3° carbon)
PBr3 / ether: replaces -OH with -Br
SN2 mechanism with inversion of stereochemistry
Same limitation: cannot use for tertiary substrates
Gilman reagent (R2CuLi) + R'-X → R-R'
Alkyne alkylation: deprotonate a terminal alkyne with NaNH2 in liq. NH3, then react the acetylide anion with a primary halide via SN2
HX addition to an alkene (Markovnikov)
HX addition to an alkyne (Markovnikov)
NBS / CCl4 / hv for allylic bromination
X2 / hv for radical halogenation at the most substituted position (Br is more selective than Cl)
General: a conjugated diene + a dienophile → a cyclohexene
[4+2] cycloaddition: 4 pi electrons from the diene, 2 from the dienophile
Concerted (one step), no intermediates
Endo rule: when the dienophile has a substituent with multiple bonds (C=O, C≡N), that substituent goes endo ("down," toward the diene pi system)
Stereochemistry is retained:
If substituents on the dienophile are trans on the double bond, they remain trans on the ring
If substituents on the dienophile are cis on the double bond, they remain cis on the ring
This follows from the concerted, suprafacial mechanism
The SN2 reaction is the basis for the Williamson ether synthesis, one of the most common methods for making ethers in the lab. Diels-Alder reactions are used extensively in total synthesis of natural products and pharmaceuticals because they build complex ring systems in a single step with precise stereocontrol.
Students assume that a strong nucleophile always gives substitution and a strong base always gives elimination. In reality, many species (OH-, RO-, NH2-) are both strong nucleophiles and strong bases. The substrate is what tips the balance: a 1° substrate steers toward SN2, a 3° substrate steers toward E2.
A frequent mistake is thinking SN1 can happen at a primary carbon. It cannot under normal conditions: 1° carbocations are far too unstable. Primary substrates go through SN2 or E2.
Students often forget that TsCl/pyridine does not break the C-O bond, so stereochemistry is retained. The inversion happens later, when a nucleophile displaces the -OTs in a subsequent SN2 step.
In Diels-Alder, students sometimes think the endo rule applies to all substituents. It applies specifically to substituents on the dienophile that have multiple bonds (C=O, C≡N). Simple alkyl groups do not follow the endo rule in the same way.
⚠️ The SN1/SN2/E1/E2 decision tree is the single most tested concept in this unit. Expect at least one problem giving you a substrate and a reagent and asking you to predict the mechanism and product.
⚠️ Converting -OH to a leaving group is a common synthesis step. Know all three reagents (TsCl, SOCl2, PBr3) and their stereochemical outcomes.
⚠️ Diels-Alder problems will test the endo rule and stereochemistry retention. If substituents are cis on the dienophile, they stay cis on the ring.
⚠️ Synthesis problems often require you to chain together reactions from all three sets of notes: form a C-C bond (Gilman or acetylide), install a functional group (addition reaction), then convert or substitute (SN2, E2). Practise multi-step synthesis.
Fill in the blank: A 3° substrate with a strong base undergoes ______ (SN1/SN2/E1/E2).
Answer: E2
True or False: SOCl2 converts -OH to -Cl with retention of stereochemistry.
Answer: False. SOCl2 gives inversion (SN2 mechanism).
Fill in the blank: In a Diels-Alder reaction, substituents that are cis on the dienophile will be ______ on the product ring.
Answer: cis (stereochemistry is retained)
True or False: SN1 is a viable mechanism for a primary alkyl halide.
Answer: False. Primary carbocations are too unstable for SN1.
Fill in the blank: The best leaving groups are weak, stable ______.
Answer: bases
Q: You treat 2-bromobutane with NaOH in DMSO. What mechanism predominates, and what is the major product?
A: 2° substrate + strong base/good nucleophile + aprotic solvent favours SN2. The major product is 2-butanol with inversion of configuration at C-2.
Q: You treat 2-bromo-2-methylpropane (tert-butyl bromide) with NaOEt in ethanol. What mechanism and product?
A: 3° substrate + strong base = E2. The product is 2-methylpropene (isobutylene). SN2 is impossible at a 3° carbon.
Q: How would you convert (R)-2-butanol into (S)-2-bromobutane?
A: Treat with PBr3 in ether. PBr3 replaces -OH with -Br via an SN2 mechanism, giving inversion of stereochemistry: (R)-alcohol becomes (S)-bromide.
Q: You run a Diels-Alder reaction between 1,3-butadiene and trans-1,2-dibromoethylene. What is the stereochemical relationship of the two Br atoms in the product?
A: The two Br atoms are trans on the cyclohexene ring. Diels-Alder retains the stereochemistry of the dienophile: trans in, trans out.
Q: You need to convert 1-butyne into 1-hexyne by adding a two-carbon fragment. Propose reagents.
A: 1. NaNH2 in liquid NH3 to deprotonate the terminal alkyne. 2. React the acetylide anion with bromoethane (a primary halide) via SN2. This extends the chain by two carbons.
SN1, SN2, E1, E2, nucleophilic substitution, elimination reaction, substitution vs elimination, substrate degree, primary secondary tertiary, nucleophile, electrophile, leaving group, good leaving group, bad leaving group, tosylate, OTs, TsCl pyridine, SOCl2, thionyl chloride, PBr3, phosphorus tribromide, stereochemistry inversion, retention, Walden inversion, backside attack, carbocation, racemic mixture, strong base, weak base, bulky base, t-BuO, protic solvent, aprotic solvent, DMSO, DMF, Zaitsev rule, Hofmann product, Diels-Alder, cycloaddition, 4+2, diene, dienophile, endo rule, Alder endo, concerted mechanism, stereochemistry retention, C-C bond formation, Gilman reagent, acetylide alkylation, organic chemistry synthesis, orgo 2, ochem exam review
The SN2 mechanism connects to every reaction in this course where a nucleophile attacks an electrophilic carbon, including epoxide ring-opening and the Williamson ether synthesis. E2 is the reverse of addition reactions from the first set of notes: addition puts groups across a double bond, elimination removes them to regenerate one. The Diels-Alder reaction bridges into aromatic chemistry and more advanced pericyclic reactions, which appear in later coursework. Synthesis strategy ties everything together: a strong final-exam problem will ask you to combine C-C bond formation, functional group installation, and substitution or elimination in a multi-step route.