Substitution, Elimination and Electrophilic Addition, CHEM 210/220 – Study Notes
Difficulty: Intermediate | Prerequisites: Nomenclature, structure/bonding, acids and bases, stereoisomerism.
This is the core reaction-mechanism unit of organic chemistry. You need to predict which of four competing pathways (SN1, SN2, E1, E2) a given substrate/reagent combination will follow, and you need to know the stereochemical and regiochemical outcome of each. The electrophilic addition reactions of alkenes and alkynes are the second major block: the pi bond acts as a nucleophile, and the question is always Markovnikov or anti-Markovnikov, syn or anti, and what happens at any new stereocentres. If you can master the decision frameworks here, the rest of the course becomes much more manageable.
SN2 is a one-step backside attack (inversion, needs strong nucleophile, works on primary/methyl). SN1 goes through a carbocation (racemisation, tertiary substrates, weak nucleophile). E2 is a one-step anti-periplanar elimination (strong bulky base, tertiary). E1 shares conditions with SN1 but heat favours elimination. Electrophilic additions to alkenes follow Markovnikov's rule unless the reaction is radical-initiated or involves hydroboration.
Nucleophile
An electron-rich species that attacks an electron-poor carbon. Strong nucleophiles (RS-, I-, CN-, RO-, RMgX) favour SN2. Weak nucleophiles (H2O, ROH) favour SN1.
Electrophile
An electron-poor species that accepts electrons. In electrophilic addition, the electrophile attacks the pi bond.
Leaving group
The group that departs with the bonding electrons. Better leaving groups are weaker bases: I- > Br- > Cl- >> F-. Tosylate, mesylate, and triflate are excellent leaving groups. OH is a poor leaving group unless protonated first.
Markovnikov's rule
In electrophilic addition to an alkene, the hydrogen adds to the carbon already bearing more hydrogens, forming the more stable (more substituted) carbocation intermediate.
Anti-Markovnikov addition
The opposite regiochemistry: the hydrogen (or equivalent) ends up on the more substituted carbon. Occurs in radical addition of HBr and in hydroboration.
Zaitsev's rule
In elimination reactions, the more substituted (more stable) alkene is the major product. Exception: bulky bases give the less substituted (Hofmann) product.
Anti-periplanar geometry
The spatial arrangement required for E2: the hydrogen being removed and the leaving group must be 180 degrees apart (both axial in cyclohexane). Think of it as the H and LG pointing in opposite directions on the same plane.
Mechanism: concerted, one step. The nucleophile attacks from the back side as the leaving group departs. No intermediate.
Rate law: Rate = k[substrate][nucleophile]. Second-order.
Stereochemistry: inversion of configuration (Walden inversion). Every SN2 reaction flips the stereocenter.
Favoured by: primary or methyl substrate, strong nucleophile, aprotic solvent (DMSO, DMF, acetone), good leaving group.
Steric hindrance kills SN2. Reactivity: CH3 > 1 degree > 2 degree >> 3 degree (no reaction at tertiary).
Solvent matters: aprotic solvents do not solvate the nucleophile, keeping it reactive. Protic solvents stabilise the nucleophile and slow SN2.
Mechanism: two steps. Step 1 (rate-limiting): ionisation to a carbocation. Step 2: nucleophile attacks the carbocation.
Rate law: Rate = k[substrate] only. First-order. The nucleophile does not appear in the rate law.
Stereochemistry: racemisation. The planar carbocation is attacked from both faces. Often slight inversion excess in practice.
Favoured by: tertiary (or allylic/benzylic) substrate, weak nucleophile, protic polar solvent (H2O, ROH) that stabilises ions, good leaving group.
Carbocation stability: 3 degree > 2 degree > 1 degree > CH3+. Allylic and benzylic cations get extra resonance stabilisation.
Rearrangements are possible. Hydride shifts and methyl shifts can convert a less stable carbocation to a more stable one. If a reaction gives an unexpected product, suspect a rearrangement.
Mechanism: concerted, one step. The base abstracts a beta-hydrogen at the same time as the C-X bond breaks and the pi bond forms.
Rate law: Rate = k[substrate][base]. Second-order.
Stereochemistry: requires anti-periplanar geometry (H and LG 180 degrees apart). In cyclohexane, both H and LG must be axial.
Favoured by: strong bulky base (KOtBu), high temperature, tertiary substrate.
Regioselectivity: Zaitsev's rule gives the more substituted alkene as the major product. Exception: bulky bases (t-BuO-) give the Hofmann product (less substituted alkene).
Mechanism: two steps. Step 1 (rate-limiting): ionisation to carbocation (same as SN1). Step 2: base removes a beta-hydrogen.
Rate law: Rate = k[substrate]. First-order.
No stereochemical requirement (no anti-periplanar constraint, since the carbocation is planar).
Zaitsev's rule applies.
Competes with SN1 under the same conditions. Heat favours elimination over substitution.
Two steps: (1) base removes beta-H to form a carbanion, (2) the leaving group departs. Favoured when the leaving group is poor and the beta-H is very acidic (adjacent to a carbonyl). Rate = k[substrate][base], but the carbanion is a genuine intermediate.
This is the framework for predicting which pathway dominates. Work through it in order.
Primary + strong nucleophile → SN2.
Primary + strong bulky base → E2.
Secondary + strong nucleophile in aprotic solvent → SN2.
Secondary + strong base → E2.
Secondary + weak nucleophile in protic solvent → SN1/E1 mixture.
Tertiary + any nucleophile → SN1 or E1/E2 (no SN2 at tertiary, ever).
Tertiary + strong base/heat → E2.
High temperature always favours elimination over substitution.
The two overriding principles: steric hindrance blocks SN2, and carbocation stability enables SN1/E1.
The pi bond acts as a nucleophile, attacking an electrophile. For each reaction below, know the regiochemistry (Markovnikov or anti-Markovnikov), the stereochemistry (syn or anti), and whether rearrangements can occur.
Markovnikov. Carbocation intermediate. Not stereospecific (both faces attacked). Racemic at new stereocentres.
Markovnikov. Carbocation intermediate. Prone to rearrangements. Reversible (dehydration is the reverse).
Markovnikov addition of OH. Anti addition (mercury bridge intermediate). No rearrangements. Racemic at new stereocentres.
Anti-Markovnikov addition of OH. Syn addition (B and H add to the same face). Stereospecific. No rearrangements. 9-BBN gives more selective hydroboration for bulkier substrates.
Anti addition (trans product). Bridged halonium ion intermediate, then backside attack by X-. Racemic if the alkene is symmetric. Decolourisation of Br2/CCl4 is a classic test for alkenes.
Anti addition. Markovnikov selectivity for OH (OH goes to the more substituted carbon; halogen to the less substituted). Product: trans-halohydrin.
Syn addition of H2. Both H atoms delivered from the same face of the catalyst surface. For alkynes: Lindlar's catalyst (H2/Pd-BaSO4) gives the cis (Z) alkene; Na/NH3(l) gives the trans (E) alkene.
Syn addition of oxygen across the double bond. Retention of alkene geometry: cis alkene gives cis epoxide, trans gives trans. Stereospecific.
Acid conditions: nucleophile attacks the more substituted carbon (more electrophilic C), anti addition.
Base conditions: nucleophile attacks the less substituted carbon (steric control, SN2), anti addition.
Syn addition of two OH groups. Product: cis-diol. Sharpless asymmetric dihydroxylation gives enantioselective syn diols.
Cleaves the C=C double bond. Reductive workup (Zn/H2O or Me2S) gives aldehydes and/or ketones. Oxidative workup (H2O2) gives carboxylic acids from aldehydes, ketones from internal positions.
Markovnikov. One equivalent gives a vinyl halide (anti addition). Two equivalents give a geminal dihalide (both halogens on the same carbon).
Anti addition. Product: trans-dihaloalkene.
Markovnikov. Initial enol tautomerises to a ketone. Terminal alkynes give methyl ketones. Internal alkynes give a mixture of ketones.
Anti-Markovnikov. Yields an aldehyde from a terminal alkyne (via vinyl borane, then enol, then aldehyde after oxidation).
H2/Lindlar's catalyst (Pd-BaSO4, poisoned): gives the cis (Z) alkene selectively.
Na or Li in liquid NH3 (Birch-type): gives the trans (E) alkene selectively.
H2/Pd-C (excess): full reduction to alkane.
Deprotonate terminal alkyne with NaNH2 or n-BuLi to form the acetylide anion, then react with a primary alkyl halide (SN2) to extend the carbon chain.
Students often think SN2 can occur at tertiary carbons. It cannot. Steric hindrance completely blocks backside attack at a tertiary centre.
Students often confuse Markovnikov and anti-Markovnikov conditions. Markovnikov is the default for ionic (electrophilic) addition. Anti-Markovnikov occurs only with radical HBr (peroxide-initiated) or hydroboration.
Students sometimes think Br2 addition is syn. It is anti (trans). The bridged bromonium ion forces backside attack.
Students often forget that E2 requires anti-periplanar geometry. In cyclohexane, both H and LG must be axial (anti-diaxial). If they cannot achieve this arrangement, E2 does not proceed.
Students sometimes think hydroboration gives Markovnikov alcohol. It gives anti-Markovnikov alcohol.
Students often think radical addition works with HCl and HI. Only HBr undergoes radical (peroxide-initiated) anti-Markovnikov addition.
⚠️ The SN1/SN2/E1/E2 decision framework is tested on every organic chemistry exam. Know it cold.
⚠️ For every electrophilic addition, you must state: Markovnikov or anti-Markovnikov, syn or anti, and the stereochemical outcome.
⚠️ Oxymercuration vs. hydroboration is a classic comparison question: same functional group (alcohol), opposite regiochemistry.
⚠️ Lindlar's catalyst vs. Na/NH3 for alkyne reduction: know which gives Z and which gives E.
True or false: SN2 proceeds with retention of configuration. (False. SN2 always gives inversion.)
Fill in the blank: SN1 reactions give ______ at the stereocenter. (racemisation)
True or false: E2 requires the H and leaving group to be syn-periplanar. (False. Anti-periplanar.)
Fill in the blank: Hydroboration-oxidation gives ______ (Markovnikov/anti-Markovnikov) alcohol with ______ (syn/anti) addition. (Anti-Markovnikov, syn)
True or false: Br2 addition to an alkene gives a cis product. (False. It gives a trans product via anti addition.)
Q: Predict the major product(s) when 2-bromobutane reacts with NaOCH3 in DMSO.
A: SN2 dominates (secondary substrate, strong nucleophile, aprotic solvent). The product is 2-methoxybutane with inversion of configuration at C-2. Some E2 product (but-2-ene, Zaitsev) may form as a minor product since NaOCH3 is also a base.
Q: What happens when 2-bromo-2-methylpropane (tert-butyl bromide) is heated with ethanol?
A: SN1 and E1 compete (tertiary substrate, weak nucleophile, protic solvent, heat). SN1 gives tert-butyl ethyl ether (racemic). E1 gives 2-methylpropene. Heat favours the elimination product.
Q: Give the product and stereochemistry of Br2 addition to cis-but-2-ene.
A: Anti addition through a bromonium ion gives 2,3-dibromobutane as the (2R,3R) and (2S,3S) enantiomeric pair (racemic). The product is the trans (anti) diastereomer.
Q: You want to convert 1-hexyne to hexanal. What reagent sequence would you use?
A: Hydroboration-oxidation of the terminal alkyne (BH3-THF, then H2O2/NaOH). This gives anti-Markovnikov addition, placing OH on C-1 as an enol, which tautomerises to hexanal.
Substitution and elimination reactions build directly on acid-base chemistry (the nucleophile/base distinction is essentially a question of whether it attacks carbon or hydrogen). Electrophilic addition connects to carbonyl chemistry, because both involve nucleophilic attack on an electrophilic carbon, just in different functional-group contexts.
SN1, SN2, E1, E2, E1cb, nucleophilic substitution, elimination, backside attack, Walden inversion, racemisation, carbocation, leaving group, tosylate, mesylate, triflate, aprotic solvent, protic solvent, anti-periplanar, Zaitsev's rule, Hofmann product, Markovnikov, anti-Markovnikov, electrophilic addition, HX addition, acid-catalysed hydration, oxymercuration, hydroboration, halogenation, halohydrin, bromonium ion, epoxidation, mCPBA, epoxide ring opening, OsO4 dihydroxylation, ozonolysis, Lindlar's catalyst, Birch reduction, alkyne reduction, acetylide alkylation, radical addition, NBS, free radical halogenation