Difficulty: Intermediate to Advanced | Prerequisites: Ch. 1–5 (bonding, stereochemistry, alcohols, leaving groups)
This is the core reaction block of the course. Chapter 6 covers the two mechanisms by which a nucleophile replaces a leaving group on a carbon (SN2 and SN1). Chapter 7 covers the two mechanisms by which a base removes a proton to form an alkene (E2 and E1), plus alkene nomenclature and stability. Chapter 8 covers the reverse process: adding reagents across an alkene double bond. If you master the four mechanisms (SN2, SN1, E2, E1) and the factors that favour each one, you have the engine that drives most of Organic I.
Nucleophile
An electron-rich species that donates an electron pair to an electrophilic carbon. In simple terms, a nucleophile is a "nucleus-lover" that seeks positive centres. Common nucleophiles: OH-, CN-, RS-, I-, Br-, NH3, H2O.
Electrophile
An electron-poor species that accepts an electron pair. The carbon bearing a leaving group in an alkyl halide is the electrophilic centre.
Leaving group
The group that departs with the bonding electron pair during substitution or elimination. Good leaving groups are weak bases: I-, Br-, Cl-, tosylate (OTs), water (when OH is protonated).
SN2 (bimolecular nucleophilic substitution)
A one-step mechanism in which the nucleophile attacks the electrophilic carbon from the back side while the leaving group departs simultaneously. Rate = k[substrate][nucleophile]. Produces inversion of configuration at the reaction centre.
SN1 (unimolecular nucleophilic substitution)
A two-step mechanism: the leaving group departs first to form a carbocation, then the nucleophile attacks. Rate = k[substrate]. Produces a racemic mixture (or near-racemic) because the planar carbocation can be attacked from either face.
E2 (bimolecular elimination)
A one-step mechanism in which a strong base removes a proton from the beta-carbon while the leaving group departs, forming a double bond. Rate = k[substrate][base]. Requires an anti-periplanar geometry between the H and the leaving group.
E1 (unimolecular elimination)
A two-step mechanism: the leaving group departs to form a carbocation, then a base removes a proton from the beta-carbon to form an alkene. Rate = k[substrate]. Follows Zaitsev's rule.
Zaitsev's rule (Saytzeff's rule)
Elimination reactions preferentially form the more substituted (more stable) alkene. In simple terms, the double bond goes to the side with more alkyl groups.
Markovnikov's rule
In the addition of HX to an alkene, the hydrogen adds to the carbon of the double bond that already has more hydrogens (the less substituted carbon), and the halide adds to the more substituted carbon. The underlying reason: the reaction goes through the more stable carbocation intermediate.
Anti-Markovnikov addition
Addition where the hydrogen ends up on the more substituted carbon and the other group on the less substituted one. Achieved with specific reagents (e.g. hydroboration-oxidation for anti-Markovnikov addition of water).
Regioselectivity
Preference for bond formation at one site over another. Markovnikov vs. anti-Markovnikov addition is a question of regioselectivity.
Stereoselectivity
Preference for one stereoisomeric product over another. Syn addition (both groups add to the same face) vs. anti addition (groups add to opposite faces).
One concerted step: the nucleophile attacks the electrophilic carbon from the side opposite the leaving group (backside attack), and the leaving group departs simultaneously.
The transition state has five groups around carbon (trigonal bipyramidal geometry), with the nucleophile and leaving group partially bonded.
Stereochemistry: always produces inversion of configuration (Walden inversion). If the starting material is R, the product is S, and vice versa.
Rate law: rate = k[substrate][nucleophile]. Both reactants appear in the rate-determining step.
Substrate effects: SN2 works best with methyl and primary substrates. Secondary substrates are slower. Tertiary substrates do not undergo SN2 because steric hindrance blocks backside attack.
Nucleophile strength matters: strong nucleophiles (OH-, CN-, RS-, I-) accelerate SN2. Weak nucleophiles (H2O, ROH) are too slow for SN2.
Solvent effects: SN2 is favoured by polar aprotic solvents (DMSO, DMF, acetone) because they do not solvate the nucleophile strongly, leaving it free to react.
Two steps: (1) the leaving group departs to form a carbocation (slow, rate-determining); (2) the nucleophile attacks the carbocation (fast).
Rate law: rate = k[substrate]. The nucleophile does not appear in the rate law because it enters after the rate-determining step.
Substrate effects: SN1 works best with tertiary substrates (most stable carbocations). Secondary substrates undergo SN1 under favourable conditions. Primary and methyl substrates essentially never go SN1.
Stereochemistry: the carbocation intermediate is planar (sp2), so the nucleophile can attack from either face. This gives a racemic mixture in principle, though in practice a slight excess of inversion product is common (ion-pair effects).
Solvent effects: SN1 is favoured by polar protic solvents (water, alcohols) because they stabilise the carbocation intermediate and the departing leaving group through solvation.
Carbocation rearrangements can occur in SN1 (but not SN2, because there is no carbocation intermediate in SN2).
Methyl, primary substrates: SN2 with a strong nucleophile.
Tertiary substrates: SN1 (or E1/E2), never SN2.
Secondary substrates: depends on the nucleophile and solvent. Strong nucleophile + polar aprotic solvent favours SN2. Weak nucleophile + polar protic solvent favours SN1.
Good leaving group is required for both mechanisms.
Temperature: higher temperature generally favours elimination over substitution.
One concerted step: a strong base removes a beta-hydrogen while the leaving group departs and a pi bond forms, all in a single transition state.
Requires anti-periplanar geometry: the H and the leaving group must be on opposite sides of the C-C bond (180 degrees apart in a Newman projection). This geometric requirement is absolute.
Regioselectivity: follows Zaitsev's rule (more substituted alkene is the major product) with most bases. Bulky bases (tert-butoxide, (CH3)3CO-) favour the less substituted alkene (Hofmann product) because the more substituted position is harder to reach sterically.
Rate law: rate = k[substrate][base].
Favoured by: strong, non-nucleophilic bases; tertiary substrates; high temperature.
Two steps: (1) the leaving group departs to form a carbocation (same as SN1 step 1); (2) a base removes a proton from the beta-carbon to form the alkene.
Rate law: rate = k[substrate]. Follows the same kinetics as SN1.
Regioselectivity: Zaitsev's rule applies (more substituted alkene is the major product).
E1 competes directly with SN1 because both share the same carbocation intermediate. Raising the temperature shifts the balance toward elimination.
Carbocation rearrangements can occur in E1.
Strong nucleophile/weak base (e.g. I-, RS-, CN-): substitution (SN2) favoured.
Strong base/weak nucleophile (e.g. tert-butoxide, LDA): elimination (E2) favoured.
Strong nucleophile AND strong base (e.g. OH-, RO-): competition. Primary substrates tend toward SN2; secondary and tertiary toward E2.
Weak nucleophile/weak base + polar protic solvent: SN1/E1 competition. Higher temperature favours E1.
Alkene naming: find the longest chain containing the double bond, number from the end nearest the double bond, change -ane to -ene, and indicate position.
E/Z nomenclature (replaces cis/trans for trisubstituted and tetrasubstituted alkenes): rank substituents on each carbon of the double bond using Cahn-Ingold-Prelog priority rules. Higher-priority groups on the same side = Z (zusammen); opposite sides = E (entgegen).
Alkene stability: more substituted alkenes are more stable. trans (E) alkenes are more stable than cis (Z) due to reduced steric strain. Stability order: tetrasubstituted > trisubstituted > disubstituted (trans > cis) > monosubstituted.
Heats of hydrogenation provide experimental evidence: more stable alkenes release less heat when hydrogenated.
Alkenes are electron-rich (the pi bond is the nucleophile). They react with electrophiles. The general pattern: the electrophile adds to one carbon of the double bond, forming a carbocation (or equivalent intermediate), and then a nucleophile adds to the other carbon.
Markovnikov addition: H adds to the less substituted carbon, X adds to the more substituted carbon.
Mechanism: the pi electrons attack H+ to form the more stable carbocation, then X- attacks the carbocation.
Carbocation rearrangements are possible if a more stable carbocation is accessible by a 1,2-shift.
Markovnikov addition of water: H adds to the less substituted carbon, OH adds to the more substituted carbon.
Requires acid catalyst (H2SO4 or H3PO4). Mechanism: protonation of the alkene forms a carbocation, water attacks, then deprotonation gives the alcohol.
Anti-Markovnikov addition of water: OH ends up on the less substituted carbon.
Two-step process: (1) hydroboration with BH3 or BH3-THF (syn addition, B goes to the less substituted carbon, H to the more substituted); (2) oxidation with H2O2/NaOH replaces B with OH, retaining configuration.
Stereochemistry: syn addition (both H and OH add to the same face of the double bond).
Br2 or Cl2 adds across the double bond to give a vicinal dihalide.
Mechanism: the electrophilic halogen attacks the pi bond to form a cyclic halonium ion (not an open carbocation), then the second halide attacks from the opposite face.
Stereochemistry: anti addition (the two halogens end up on opposite faces). This is a direct consequence of the halonium ion intermediate.
Reaction of an alkene with X2 in water gives a halohydrin (halogen on one carbon, OH on the adjacent carbon).
Markovnikov-like regiochemistry: the halogen goes to the less substituted carbon (via the halonium ion) and water attacks the more substituted carbon.
Anti stereochemistry (same mechanism as halogenation).
H2 with a metal catalyst (Pt, Pd, or Ni) adds H2 across the double bond to give an alkane.
Syn addition: both hydrogens add to the same face (they are delivered from the catalyst surface).
Not regioselective (the double bond is simply reduced).
Epoxidation with a peroxyacid (mCPBA): gives an epoxide (a three-membered ring with oxygen). Syn addition; the oxygen is delivered from the same face as the peroxyacid approaches.
Dihydroxylation with OsO4 (or OsO4 catalytic with NMO): gives a 1,2-diol (vicinal diol). Syn addition.
Ozonolysis (O3 followed by reductive workup with Zn or DMS): cleaves the double bond completely, producing two carbonyl compounds (aldehydes and/or ketones depending on substitution). Useful for determining the position of a double bond in an unknown structure.
SN2 vs. SN1 vs. E2 vs. E1 decision summary
Methyl/primary + strong nucleophile: SN2
Methyl/primary + strong bulky base: E2
Tertiary + any nucleophile/base: E2 (with strong base) or E1/SN1 (weak base, polar protic solvent)
Secondary: borderline, depends on nucleophile strength, base strength, solvent, and temperature
Markovnikov vs. anti-Markovnikov reagent summary
Markovnikov addition of HX: HBr, HCl, HI (no peroxides)
Anti-Markovnikov addition of HBr: HBr + ROOR (peroxides, radical mechanism)
Markovnikov addition of water: H3O+ (acid-catalysed hydration)
Anti-Markovnikov addition of water: (1) BH3/THF, (2) H2O2/NaOH (hydroboration-oxidation)
Stereochemistry summary for addition reactions
Syn addition: hydroboration-oxidation, catalytic hydrogenation, epoxidation, dihydroxylation (OsO4)
Anti addition: halogenation (Br2, Cl2), halohydrin formation
Nucleophilic substitution is the basis for how cells synthesise molecules. S-adenosylmethionine (SAM), the body's universal methyl donor, transfers a methyl group via an SN2-like mechanism. Drug design relies heavily on understanding which substitutions and eliminations a molecule will undergo under physiological conditions.
Alkene addition reactions underpin the petrochemical industry. The polymerisation of ethylene into polyethylene is a chain of addition reactions. Industrial production of ethanol involves the acid-catalysed hydration of ethylene.
Students often think SN1 always gives a perfectly racemic product. In practice, the leaving group partially shields one face of the carbocation (ion-pair effect), so there is often a slight excess of inversion product.
A persistent mistake is applying Markovnikov's rule as "H goes to the carbon with more hydrogens" without understanding why. The real reason is carbocation stability. If you understand the mechanism, you will never misapply the rule.
Students sometimes forget that E2 requires anti-periplanar geometry and wonder why certain substrates give unexpected products. Always draw the Newman projection and check which hydrogen is anti to the leaving group.
Confusing the conditions for hydroboration-oxidation with acid-catalysed hydration is common. Remember: BH3 then H2O2/NaOH = anti-Markovnikov; H3O+ = Markovnikov.
⚠️ The SN2/SN1/E2/E1 decision framework is the single most tested concept on Exam 3 and the final. You will be given a substrate, a reagent, and a solvent, and asked to predict the mechanism, products, and stereochemistry.
⚠️ Know the stereochemical outcome of every addition reaction: syn or anti, Markovnikov or anti-Markovnikov. A table summarising reagent, regiochemistry, and stereochemistry for each reaction is worth memorising.
⚠️ Ozonolysis is a favourite exam question: given the ozonolysis products, work backwards to determine the structure of the original alkene.
⚠️ Anti-periplanar geometry for E2 is tested by giving cyclohexane substrates where you must draw the chair, identify which hydrogen is anti to the leaving group, and predict which alkene forms.
True or false: SN2 reactions proceed with retention of configuration. (False: SN2 always gives inversion.)
Fill in the blank: The rate law for E2 is rate = k[][]. (substrate, base)
True or false: Hydroboration-oxidation gives Markovnikov addition of water. (False: it gives anti-Markovnikov addition.)
Fill in the blank: Halogenation of an alkene with Br2 proceeds by ______ addition. (Anti)
True or false: E1 and SN1 compete with each other because they share the same carbocation intermediate. (True)
Q: Predict the product(s) when (R)-2-bromobutane reacts with NaOH in DMSO. What mechanism operates, and what is the stereochemistry of the product?
A: NaOH is a strong nucleophile/base; DMSO is a polar aprotic solvent; the substrate is secondary. SN2 is favoured (strong nucleophile, polar aprotic). The product is (S)-2-butanol, formed with inversion of configuration.
Q: Predict the major product when 2-methyl-2-butene reacts with HBr.
A: Markovnikov addition. H adds to the less substituted carbon of the double bond (C3), Br adds to the more substituted carbon (C2). The major product is 2-bromo-2-methylbutane.
Q: What product(s) result from treating 1-methylcyclohexene with (1) BH3/THF, then (2) H2O2/NaOH?
A: Hydroboration-oxidation gives anti-Markovnikov, syn addition of water. The OH goes to the less substituted carbon (C2), giving trans-2-methylcyclohexanol as the major product (syn addition means both H and OH add from the same face).
Q: Ozonolysis of an unknown alkene gives acetone (CH3COCH3) and formaldehyde (HCHO). What is the structure of the alkene?
A: Rejoin the two carbonyl fragments at the C=O: the alkene is 2-methylpropene (isobutylene, (CH3)2C=CH2). Ozonolysis cleaves the double bond, and each carbon of the former double bond becomes a carbonyl carbon.
Q: When 1-bromo-1-methylcyclohexane is treated with sodium ethoxide (NaOEt) in ethanol, what is the major product and mechanism?
A: The substrate is tertiary, so SN2 is impossible. NaOEt is a strong base, favouring E2. The major product is 1-methylcyclohexene (Zaitsev product, the more substituted alkene).
SN2 and SN1 build directly on the leaving-group and carbocation concepts from Chapter 5. The stereochemical outcomes (inversion in SN2, racemisation in SN1) only make sense if you are comfortable with chirality (Chapter 4).
Elimination reactions produce alkenes, which are the starting materials for Chapter 8's addition reactions. The course is designed so that you learn to make alkenes (Ch. 7) before you learn to add to them (Ch. 8).
The addition reactions of Chapter 8 set the stage for Chapters 9-12. Alkyne chemistry (Ch. 9) follows the same electrophilic addition logic but with two pi bonds instead of one. Conjugated diene chemistry (Ch. 10-11) extends addition to systems where multiple double bonds interact.
nucleophilic substitution, SN2, SN1, backside attack, Walden inversion, racemisation, carbocation, nucleophile, electrophile, leaving group, polar aprotic solvent, polar protic solvent, DMSO, DMF, acetone, elimination, E2, E1, beta elimination, anti-periplanar, Zaitsev rule, Hofmann product, bulky base, tert-butoxide, alkene, E/Z nomenclature, cis trans, Markovnikov rule, anti-Markovnikov, hydroboration-oxidation, BH3 THF, H2O2 NaOH, hydrohalogenation, HBr HCl, acid-catalysed hydration, halogenation, bromine addition, halonium ion, bromonium ion, halohydrin, catalytic hydrogenation, Pt Pd Ni, syn addition, anti addition, epoxidation, mCPBA, dihydroxylation, OsO4, ozonolysis, reductive workup, regioselectivity, stereoselectivity, Carey organic chemistry chapter 6 7 8, CHEM 2301 UMN